Hypertension & Left Ventricular Hypertrophy · Expert Answers to Three Key Questions Do coronary circulation abnormalities play an important role in the pathogenesis of hypertensive

1

Dialogues in Cardiovascular Medicine - Vol 10 . No. 1 . 2005

Lead Article Pathophysiology and treatment of hypertensive left ventricular hypertrophyE. Agabiti-Rosei, M. L. Muiesan 3

Expert Answers to Three Key Questions Do coronary circulation abnormalities play an important role in the pathogenesis of hypertensive left ventricular hypertrophy? - A. Ganau, G. Talanas 21

How important is it to assess and attempt to control cardiac fibrosis in hypertension? - J. Díez 28

Hypertension and left ventricular hypertrophy: how much attention should we pay to the renin-angiotensin-aldosterone system? - B. M. W. Schmidt, R. E. Schmieder 33

Fascinoma Cardiologica Heart and Literature: Another kind of heart - F. Scheffler 41

Summaries of Ten Seminal Papers - A. Ferro 45

Hypertension &Left Ventricular Hypertrophy

Electrocardiographic left ventricular hypertrophy and risk ofcoronary heart disease. The Framingham study – W. B. Kannel

and others

Echocardiographic determination of left ventricular mass inman. Anatomic validation of the method – R. B. Devereux and

N. Reichek

Prognostic implications of echocardiographically determinedleft ventricular mass in the Framingham Heart Study – D. Levy

and others

Ambulatory blood pressure is superior to clinic blood pressurein predicting treatment-induced regression of left ventricularhypertrophy. SAMPLE Study Group – G. Mancia and others

Signaling pathways for cardiac hypertrophy and failureJ. J. Hunter and K. R. Chien

Association of change in left ventricular mass with prognosisduring long-term antihypertensive treatment – M. L. Muiesan

and others

Cardiovascular morbidity and mortality in the LIFE study: a randomised trial against atenolol – B. Dahlöf and others.

Left ventricular midwall mechanics in systemic arterial hyper-tension. Myocardial function is depressed in pressure-overloadhypertrophy – G. Shimizu and others

Reduction of cardiovascular risk by regression of electrocardio-graphic markers of left ventricular hypertrophy by the angio-tensin-converting enzyme inhibitor ramipril – J. Mathew and others

A meta-analysis of the effects of treatment on left ventricularmass in essential hypertension – A. U. Klingbeil and others

Bibliography of One Hundred Key Papers 57

At some point in the natural history of hyper-tension, the compensatory increase in leftventricular (LV) mass ceases to be beneficial.It becomes a preclinical disease and an inde-

pendent risk factor for congestive heart failure, ischemicheart disease, arrhythmia, sudden death, and stroke.1

LV hypertrophy (LVH) is adequately and most com-monly diagnosed using electrocardiography (ECG)and, more particularly, M-mode and two-dimensional(2D) echocardiography, which provide comprehensivewall, chamber, and LV mass measures, together withsystolic and diastolic performance indices, while re-maining cheap, widely available, and wholly noninva-sive (Table I). Sophisticated and more accurate tech-niques, such as magnetic resonance imaging (MRI) orcine computerized tomography, are inevitably moreexpensive and time-consuming, and of limited avail-ability.

DETERMINANTS OF HYPERTENSIVE LVH

The high prevalence of LVH in hypertension reflectsthe increased afterload imposed on the LV. However,other important determinants include demographiccharacteristics, the nature of the hemodynamic load,neurohumoral and growth factors, and underlying ge-netic factors.


3

Pathophysiology and treatment of hypertensive left ventricular hypertrophyEnrico Agabiti-Rosei,* MD, FESC; Maria Lorenza Muiesan,† MD *Full Professor of Internal Medicine - University of Brescia - Brescia - ITALY † Associate Professor of Internal Medicine - University of Brescia - Brescia - ITALY

At some point in the natural history of hypertension,the compensatory increase in left ventricular (LV) massceases to be beneficial. LV hypertrophy (LVH) becomesa preclinical disease and an independent risk factorfor congestive heart failure, ischemic heart disease,arrhythmia, sudden death, and stroke. The multiplemechanisms involved, in addition to elevated bloodpressure, include body size (obesity), demographics(age, gender, and race), and contributions by fibro-genic cytokines and neurohumoral factors, notablyangiotensin II, which favor interstitial collagen depo-sition and perivascular fibrosis. These tissue changes,in conjunction with geometric abnormalities, primarilyconcentric hypertrophy, are responsible for the insidi-ous dysfunction associated with LVH, beginning withdecreased coronary reserve and altered diastolic ven-tricular filling and relaxation. The cardinal investiga-tion is echocardiography: [Doppler transmitral flowvelocities expressed as the early (E) to atrial (A) waveratio reveal LVH as a state of potential or actual my-ocardial ischemia]. All antihypertensive drugs regressLVH, notably the angiotensin-converting enzyme in-hibitors, which may also target the detrimental tissuechanges. Regression enhances systolic midwall per-formance, normalizes autonomic function, and restorescoronary reserve. The resulting improvement in prog-nosis has enshrined the detection, prevention, and reversal of LVH in the current guidelines of hyperten-sion management

Keywords: left ventricular hypertrophy; regression; antihypertensive treat-ment; cardiovascular risk; clinical trialAddress for correspondence: Prof Enrico Agabiti-Rosei, InternalMedicine, Medical and Surgical Sciences, University of Brescia, c/o 2a Medicina Spedali Civili di Brescia, Piazza Spedali Civili 1, 25100 Brescia, Italy (e-mail: [email protected])

Dialogues Cardiovasc Med. 2005;10:3-18

Table I. Left ventricular hypertrophy (LVH) parameters measured byechocardiography.

• Left ventricular geometry, left atrium, aortic root

• Left ventricular systolic dysfunction

• Diastolic filling abnormalities

• Stroke work

• Total artery compliance

• Myocardial ischemia (stress echocardiography)

Blood pressure

Hypertension is the fundamental trigger to the se-quence of biological events leading to the developmentof LVH. However, the relationship between LV massand clinic blood pressure is rather weak. LV mass ismore closely related to mean 24-hour blood pressure.2

Several studies investigating the relative importanceof day and night blood pressure have focused on theabsence of a nocturnal dip in blood pressure.3,4 How-ever, the dipper/nondipper classification is arbitraryand poorly reproducible. There is also the possibilitythat increased blood pressure is the consequence,rather than the cause, of LVH and associated vascularstructural changes. Volume load, inotropy, and arterialcompliance are also important determinants of thedevelopment and degree of LVH.

Demographics

Age, gender, race, and body size can all influence LVmass, possibly mediated via cardiac load. Thus, LVHprevalence increases with age, in both hypertensivesand normotensives, perhaps due to the combination ofage-related blood pressure elevation and declining aor-tic compliance. Aging also accounts for specific tissuechanges, notably interstitial fibrosis and myocyte loss.Similarly, there is a gender difference in LV mass, whichbecomes evident in adolescence and remains constantduring adult life; although the age-related increase inLV mass is greater in postmenopausal women than inmen, gender is not a significant determinant of cardio-vascular complications or of the prognostic impact ofLVH. Hypertensive LVH is more evident in blacks thanin whites at similar increases in blood pressure; cer-tain cardiovascular complications, such as heart failureand sudden death, are also more common in blacks.

Body size, notably obesity, which compounds hemo-dynamic load independently of a clear-cut increase inblood pressure, is a major determinant of LV mass.With dietary sodium, it is associated with increasedplasma volume and cardiac output, and may be respon-sible for hypertensive LVH.5

It has been suggested that by considering these mea-surable factors and hemodynamic load, echocardio-graphic LV mass could be assessed in the individualpatient by deviation from the value appropriate for agiven cardiac workload, corrected for gender and bodysize. Patients with an LV mass inappropriate to thestroke work for their gender and body size tend to clus-ter with metabolic risk factors. LV mass that overcom-pensates for hemodynamic load is associated withhigh cardiovascular risk. However, it is not yet knownwhether the morphological alteration conferring thehigher risk is the presence of inappropriate LV mass orthe development of LVH per se.6,7 The definition andclinical evaluation of “inappropriate” LV mass requirefurther study.


Pathophysiology and treatment of hypertensive left ventricular hypertrophy - Agabiti-Rosei and Muiesan

4

SELECTED ABBREVIATIONS AND ACRONYMS

CATCH Candesartan Assessment in the Treatmentof Cardiac Hypertrophy

ELSA European Lacidipine Study on Athero- sclerosis

ELVERA Effects of amlodipine and lisinopril on LeftVEntriculaR mAss and diastolic function

HOPE Heart Outcomes Prevention Evaluation

IGF-I insulin-like growth factor–I

LIFE Losartan Intervention For Endpoint reduction in hypertension

LIVE LVH regression: Indapamide Versus Enalapril

LVH left ventricular hypertrophy

MAPK mitogen-activated protein kinase

PIUMA Progetto Ipertensione Umbria Monitorag-gio Ambulatoriale

PRESERVE Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement

QTL quantitative trait loci

RAAS renin-angiotensin-aldosterone system

RACE RAmipril Cardioprotective Evaluation

REASON PREterax in regression of Arterial Stiffnessin a contrOlled double-bliNd study

REGAAL LVH REGression with the Angiotensin Antagonist Losartan

SAMPLE Study on Ambulatory Monitoring of bloodPressure and Lisinopril Evaluation

SILVHIA Swedish Irbesartan Left Ventricular hyper-trophy Investigation Versus Atenolol

SNP single nucleotide polymorphism

TGF-β1 transforming growth factor β1

TIMP-1 tissue inhibitor or metalloproteinase–1

TOMHS Treatment Of Mild Hypertension Study

VA Veterans Administration (cooperative study)

Neurohumoral factors

Early experiments showed that the sympathetic nervoussystem induced LVH in a number of situations: evensubhypotensive doses of norepinephrine increased LVmass. In humans, the effect is less clear-cut: if in pheo-chromocytoma LVH prevalence is relatively low andLV mass appears to increase proportionately to bloodpressure, in essential hypertension LVH is associatedwith altered autonomic activity and a blunted responseto β-adrenoceptor stimulation.8-10

Experimental studies also revealed the role of the renin-angiotensin-aldosterone system (RAAS) in mediatingLVH. By stimulating the angiotensin receptor, angio-tensin II induces hypertrophy and hyperplasia in myo-cytes and smooth muscle cells, and may regulate my-ofibroblast collagen synthesis. Excess angiotensin IIproduction may regulate the expression of fibrogeniccytokine transforming growth factor-β1 (TGF-β1). Au-tocrine induction by TGF-β1 of the genes coding forextracellular matrix proteins determines perivascularand interstitial fibrosis. Angiotensin II may also de-press collagenase activity, hence favoring interstitialcollagen deposition.

Aldosterone may also stimulate extracellular collagendeposition and myocardial fibrosis.11,12 A key determi-nant of collagen degradation is the activation of met-alloproteinases (a family of zinc-containing proteinsthat also includes stromalysins, collagenases, andgelatinases) and a multifunctional protein, tissue in-hibitor of metalloproteinase–1 (TIMP-1), produced byconnective tissue cells and macrophages, and proba-bly regulated by angiotensin II.13

The pathogenic role of the RAAS in the developmentof hypertensive LVH requires confirmation, althoughLV mass is significantly increased in renovascular hy-pertension and primary aldosteronism compared withessential hypertension.14,15 There is also a correlationbetween LV mass and plasma aldosterone, which isindependent of blood pressure.12

Insulin

Hypertensive LVH is often associated with insulin re-sistance and high insulin levels. Significant correlationbetween LV mass and insulin and insulin-like growthfactor–I (IGF-I) was observed in a cohort of 101 essen-tial hypertensives with normal glucose tolerance fromthe Progetto Ipertensione Umbria Monitoraggio Am-bulatoriale (PIUMA); in addition, IGF-I was a main de-

terminant of LV mass and geometry, independent ofblood pressure.16 Very high LVH prevalence (>70%) hasbeen repeatedly observed in diabetics, associated withchanges in systolic and diastolic function dispropor-tionate to the increase in blood pressure. The involve-ment of IGF-I may clarify the link between obesity, bloodpressure elevation, LVH, and the metabolic syndrome.

Leptin is another possible neuroendocrine determi-nant. LVH in an animal model of leptin deficiency(the ob/ob mouse) reversed rapidly in response to ex-ogenous leptin, suggesting that myocardial leptin receptors could be involved in cardiac remodeling.17

Other major metabolic cardiovascular risk factors, no-tably hypercholesterolemia and diabetes, also deter-mine LV mass and the prevalence of LVH. Thus, lowplasma high-density lipoprotein (HDL) cholesterollevels have been associated with increased LV mass,independently of blood pressure.

Genetics

Analysis of LV mass heritability in 2624 subjects in theFramingham Heart Study showed a closer correlationbetween LV mass in first-degree relatives than in sec-ond-degree relatives or couples, suggesting that about30% of LV mass variance is genetic.18 Studies of genet-ic influence on LV mass have focused on candidategenes, ie, gene polymorphisms that may be involvedin the hypertrophic cell process, using the genomewidescan technique to screen for a large number of genet-ic polymorphisms associated with the phenotype.

Polymorphisms associated with the RAAS were theinitial target. In 1994, Schunkert et al described an as-sociation between insertion/deletion polymorphismof the angiotensin-converting enzyme (ACE I/D ) andECG LVH.19 Attempts at confirmation brought mixedresults: a 1997 meta-analysis of five case-control stud-ies in 3285 subjects found no association between theD allele and an increased risk of echocardiographicLVH.20 The ACE I/D genotype may only have a signifi-cant effect on LV mass in particular circumstances, eg,vigorous exercise, hypertension, renal failure, or car-diac ischemia.

There is unconfirmed evidence of an association be-tween LVH and aldosterone synthase genetic poly-morphism.21 Studies are ongoing on the role of othercandidate genes, including those related to α- and β-adrenoceptors and components of the signal trans-duction mechanisms involved in cardiac hypertrophy,ie, G proteins, and mitogen-activated protein kinase



5

(MAPK) regulated by calcium-dependent phosphatase.Genomewide scans are becoming easier to performthanks to DNA microarray technology and the increas-ing number of single nucleotide polymorphisms (SNP)that have been identified. Putative chromosomal quan-titative trait loci (QTL) influencing the variability ofcardiac mass have been described in animals, but notas yet any specific genes related to increased LV mass—nor have any similar results been obtained in humans.

METHODS OF ASSESSING LVH

LVH has become integral to the diagnostic workup andtreatment strategy in hypertension, as recommendedby the European Society of Hypertension (ESH) andEuropean Society of Cardiology (ESC).22

The most common diagnostic tools are the ECG andechocardiogram. ECG remains the conventional meth-od, despite low sensitivity compounded by increasingage and body weight. New ECG criteria in addition torepolarization abnormalities and increased voltagehave been proposed in recent years, the Cornell methodbeing the most sensitive.23 The ECG can also be usedto detect patterns of ventricular overload (“strain”) orischemia, indicating higher risk.

Since ECG and echocardiographic LVH predict mortalityindependently of one another and other cardiovascu-lar risk factors, they convey, at least in part, differentprognostic information,24 in particular when the ECGshows a strain pattern.25

Echocardiography is now widely available in the in-dustrialized world for determining LV mass. It is time-and cost-effective, specific, ideal for serial mass andfunction follow-up, and more sensitive than ECG.

LV mass is calculated from the LV interventricular sep-tum and posterior wall thicknesses and internal diam-eter using the Penn or American Society of Echocar-diography (ASE) formulas, each of which has beenvalidated by autopsy.26,27 All studies evaluating theprognostic significance of changes in LV mass have ap-plied one or both formulas to M-mode measures madeunder 2D control. Values obtained using different for-mulas have given superimposable results.28 However,despite its advantages, echocardiography is not infal-lible, and technical error is always possible, due to themethod itself, the quality of the examination, or inter-preter inexperience. An Italian Society of Hypertensionstudy of the reliability of repeat echocardiographyrecordings and interpretations in 260 normotensive

and hypertensive subjects in 16 centers attributed bi-ological significance to changes in LV mass exceeding10% to 15%.29 Similarly, the Prospective RandomizedEnalapril Study Evaluating Regression of VentricularEnlargement (PRESERVE) found an intraclass correla-tion coefficient of 0.93 between two measures (screen-ing and randomization) of echocardiographic LV massin 183 hypertensive patients with LVH.30 Changes ±35 gand ±17 g represented probabilities of biological sig-nificance of 95% and 80%, respectively.

Under normal cardiac loading conditions, body size,and in particular lean body mass, is the most impor-tant determinant of heart size. For this reason, LV massis usually normalized to body size. Normalization tobody weight or other size measures (eg, body surfacearea) are inaccurate when body composition is altered,as in obesity. A surrogate of lean mass, body height,with LV mass indexed to height to the allometric pow-er of 2.7, is particularly useful when evaluating the im-pact of abnormal body composition on LV anatomy,as in obesity or anorexia nervosa, but it is no betterthan other indices for prognostic purposes. Two maindefinitions of echocardiographic LVH based on prog-nostic data are in current use: (i) LV mass indexed toheight (m2.7) ≥51 g in both genders31; and (ii) LV massindexed to body surface area (m2) >125 in both gen-ders (Table II).

Echocardiography is also useful in assessing the dif-ferent types of LV geometric adaptation to increasedcardiac load (Figure 1).32 The characteristics of con-centric hypertrophy are increases in both mass andrelative wall thickness, whereas those of eccentric hy-pertrophy are increased mass and a relative wall thick-ness < 0.45. Remodeling is said to be concentric whenthickness increases with respect to radius, but withoutan increase in LV mass. Concentric hypertrophy ap-



6

LV mass/h (g/m2.7) >51 (M & F)

LV mass/BSA (g/m2) >125 (M & F)

LV mass/BSA (g/m2) ≥117 (M); ≥104 (F)

LV mass/BSA (g/m2) ≥125 (M); ≥110 (F)

LV mass/BSA (g/m2) ≥131 (M); ≥100 (F)

LV mass/h (g/m) ≥143 (M); ≥102 (F)

LV mass/h (g/m) ≥149 (M); ≥114 (F)

LV mass/h (g/m2.7) >50 (M); >47 (F)

Table II. Left ventricular hypertrophy (LVH) diagnostic values.

Abbreviations: BSA: body surface area; F: females; h, height; M: males.

pears to carry the highest risk and eccentric hypertrophyan intermediate risk, while concentric remodeling isprobably associated with a smaller, albeit noteworthyrisk. Geometries also differ in their hemodynamics, withelevated total peripheral resistance and low cardiac out-put in concentric hypertrophy, and normal total periph-eral resistance and high cardiac output in eccentrichypertrophy. Whether the geometries represent struc-tural alterations of myocardial tissue is unknown.

Geometric patterns of LV adaptation have mechanicalconsequences. LV systolic performance can be mea-sured both at the endocardium by fractional shortening,reflecting chamber function, and at the midwall, wherecircumferential fiber contraction makes a greater con-tribution to stroke volume.33 Midwall fractional short-ening has important prognostic significance.34,35 In ad-dition, Doppler transmitral flow and LV outflow tractstudies can be used to measure several indices of dias-tolic function, reflecting both passive filling and activerelaxation.

Newer imaging methods such as MRI offer more accu-rate measures of LV mass, even in ventricles with asym-metrically increased thickness or abnormal contractility.MRI has provided important pathophysiologic infor-mation (midwall mechanics), but the duration, com-plexity, and cost of the examination hinder wider use.3D reconstruction of 2D echocardiographic images hasincreased the reproducibility of LV mass measurements

and improved the display of changesin the segmental contractility of theLV wall. However, given the difficultyof obtaining accurate orientation ofthe 2D planar images, their time-con-suming planimetric reconstructionin 3D and identification of the exter-nal border of LV walls, technologi-cal advance is required before therecan be a dramatic increase in use.Methods have been developed toquantify tissue composition. Studiesin animals and humans have shown

that LV acoustic properties under physiological andpathological conditions are influenced by several tis-sue components, in particular myocardium, contrac-tile and elastic tissue, collagen and inelastic tissue, aswell as by structures such as arteries, veins, myocytes,and sarcomeres. Results with videodensitometry andintegrated backscatter to characterize tissue in severaldiseases associated with abnormal myocardial tissue,hypertensive LVH, and diabetes indicate that this tech-nique can complement clinical evaluation by reveal-ing preclinical end-organ damage.36,37 Further repro-ducibility and feasibility studies are required to assessthe clinical applications of these techniques in patientswith hypertension and other risk factors.

PROGNOSTIC SIGNIFICANCE OF LVH

Whether assessed by ECG or echocardiography, LVHis a well-documented harbinger of morbidity and mor-tality. In several studies the adjusted risk of cardiovas-cular morbidity associated with baseline LVH rangesfrom 1.5 to 3.5 with a weighted risk ratio of 2.3 for allstudies combined (Table III, page 8)38-40; the adjustedrisk of all-cause mortality associated with baselineLVH ranges from 1.5 to 8, with a weighted mean riskratio of 2.5 for all studies combined.41

The structural remodeling of cardiomyocytes, non-my-ocytes, and fibroblasts that occurs in cardiac hypertro-phy contributes to perivascular fibrosis, initially around



7

1st tertile(LVMI <91 g/m2)

2nd tertile(LVMI 91-117 g/m2)

3rd tertile(LVMI >117 g/m2)

75±11 g/m2

79±9 g/m2

104±7 g/m2

104±8 g/m2

141±21 g/m2

149±32 g/m2

**§

§

**§

RWT <0.44

RWT ≥0.44

P<0.001 **: vs patients with eccentric geometry §: vs 1st tertile with eccentric geometry

30

40

CV

eve

nts

(%

)

20

10

0

Figure 1. Cardiovascular events associated withconcentric versus eccentric geometry.

Abbreviations: LVMI: left ventricular mass index;RWT: relative wall thickness.

Reproduced from reference 82: Muiesan ML,Solvetti M, Monteduro C, et al. Left ventricularconcentric geometry during treatment adverselyaffects cardiovascular prognosis in hypertensivepatients. Hypertension. 2004;43:1-8. Copyright © 2004, American Heart Association, Inc.

intramural coronary arteries and thereafter in the in-terstitial space.42 Increases in fibrillar collagen types Iand III lead to progressive abnormalities of diastolicventricular filling and relaxation, systolic dysfunction,arrhythmias, and conduction disturbances, thus greatlycompounding the risk associated with LVH.1 Excessventricular collagen may be due to increased collagensynthesis, but also to insufficient collagen degradationby interstitial collagenase.

The resulting pathophysiological and clinical changesaccounting for increased risk in hypertensive LVH in-clude both diastolic and systolic dysfunction, the latterbeing initially detected only during exercise. LV systolicfunction depends closely on myocardial afterload, asshown by the linear relationship between LV endocar-dial fractional shortening and end-systolic stress. Inmost cases of mild-to-moderate hypertension, LV sys-tolic function is well preserved. Indeed, “supranormal”LV ejection fraction and fractional shortening have beenfound in hypertensive subgroups with mild LVH, pos-sibly reflecting enhanced myocardial contractility. How-ever, this contrasts not only with experimental datashowing progressive impairment of contractility duringgradual hypertension onset, but also with the Fram-ingham evidence that hypertension remains, directlyor indirectly, the most important predictor of conges-tive heart failure in the general population.

The paradox has been resolved by showing that LV frac-tional shortening or ejection fraction, measured atthe endocardium, reflects chamber dynamics, but doesnot necessarily provide a direct measure of myocardialfiber shortening43: the circumferential fibers respon-sible for LV short-axis shortening are located in themidportion of the LV walls, between two longitudinalshells responsible for long-axis shortening and twist-ing. Switching to a more physiologic midwall mechan-ics index related to circumferential end-systolic stress

reveals that myocardial chamber function is often over-estimated in hypertension, particularly if LV wall thick-ness is increased.35 Several studies have shown thatLV midwall function is commonly reduced by 15% to20% in hypertensive patients. The subgroup with de-pressed LV midwall function displays other featuresassociated with an elevated cardiovascular risk profile,eg, concentric geometry, elevated peripheral resistanceand heart rate, overweight, or obesity. Higher midwallfractional shortening is associated with female gender,in both hypertensive patients and the general popula-tion. Low midwall fractional shortening has proved anindependent predictor of cardiovascular morbidity andmortality in hypertensive patients, as well as in healthyelderly subjects and American Indians in two generalpopulation–based surveys.35,36,44,45

Diastolic dysfunction may be observed early in the nat-ural history of hypertension and also in the normoten-sive children of hypertensive parents.46 It becomesmore frequent in the presence of hypertensive LVH,and is influenced by advancing age, high heart rateand obesity. There is also a gender difference: in hy-pertensive LVH, impaired diastolic relaxation affectsexercise capacity more severely in women, particularlyif elderly, than in men.

LV diastolic dysfunction has been increasingly diag-nosed in asymptomatic hypertension thanks to echo-cardiography, initially from measurements made onM-mode tracings and subsequently from Doppler trans-mitral flow velocities,50 corrected for a number of well-characterized determinants such as age, gender, heartrate, and blood pressure. The velocities—A wave (atri-al contraction and emptying) and E wave (early LV fill-ing)—occur in three patterns representing worseningdiastolic LV filling: (i) slowed relaxation, with an invert-ed E/A ratio, slowed deceleration time, and increasedisovolumic relaxation time; (ii) pseudonormalization,

8



Table III. Studies of the association between baseline left ventricular hypertrophy (LVH) and cardiovascular events.

Abbreviations: CVD: cardiovascular disease; DM: diabetes mellitus; HTN: hypertension; LVH: left ventricular hypertrophy; LVMI: left ventricular massindex; RR: relative risk.

Age Left ventricular LVH prevalence Follow-upStudy Patients n (y) mass index (%) (years) RR

Levy et al, 199038 Framingham 3220 56≥143 g/m (M) 16 4 1.53≥102 g/m (F) 21 1.55

Koren et al, 199139 HTN/CVD/DM 280 47 ≥125 g/m2 27 10 2.2

Muiesan et al, 199540 Hypertension 151 45≥134 g/m2 (M)

44 10 3.6≥110 g/m2 (F)

with a preserved E/A ratio, but shortened decelerationtime due to abnormalities of both relaxation and com-pliance; and (iii) restrictive pattern, with an increasedE/A ratio (>1.5–2) associated with a very abrupt decel-eration time, suggestive of elevated atrial pressure,and an abnormal pressure rise in a stiff LV. Pseudonor-malization is best diagnosed by analyzing pulmonaryvenous filling patterns and/or the Valsalva maneuver.

The PIUMA study showed an association between E/Aratio changes and significant increases in cardiovas-cular events in a cohort of 1839 middle-aged hyperten-sives.48 Even more recent data come from a communitysurvey in 2042 subjects aged 45 years or older thatfound diastolic dysfunction, evaluated by comprehen-sive transmitral, outflow tract and pulmonary flow Dop-pler examination, in 47% of hypertensives and 25.5%of subjects with a normal ejection fraction (>50%). Thefrequency of congestive heart failure increased dra-matically with the severity of diastolic dysfunction.49

Diastolic dysfunction is thought to precede systolic dys-function, although evidence to this effect from longi-tudinal studies is lacking. Several studies using varioustechniques have shown that diastolic LV performancesignificantly influences exercise capacity in hyperten-sive LVH. Diastolic dysfunction (combined with incip-ient systolic dysfunction) is more prevalent in LVH,suggesting that it represents an accelerated transitionphase from compensatory LVH to heart failure. Indeed,heart failure is diastolic in one third of cases or more.Although it may be associated with a lower mortalityrate than other forms of heart failure, morbidity is high.Early recognition and appropriate therapy could helpto prevent progression to diastolic heart failure anddeath. Although several studies have evaluated the ef-fect of antihypertensive treatment on diastolic function,the clinical implications remain to be established.46

LVH and failure are frequently associated with coronaryartery disease, and hypertension is a major risk factorfor coronary atherosclerosis. In ECG LVH, use of a “def-inite LVH” pattern comprising ST-segment and T-waveabnormalities was strongly associated with an increasedincidence of acute infarction and sudden death.3-6 Theassociation was weaker when LVH was defined by volt-age criteria, suggesting that altered repolarization re-flects reduced coronary perfusion.

LVH is associated with structural and functional changesin arteries, both large50,51 and small.15,52,53 Structuralchanges are particularly evident in concentric LVH.The association between LVH and extracranial carotidatherosclerosis might also explain the increased risk of

cerebrovascular events (stroke and transient ischemicattacks) in ECG or echocardiographic LVH. LVH is thusa risk factor for vascular events.

The vascular changes consistently observed in LVH arelargely responsible for the reduced coronary reserve.Concomitant atherosclerosis in epicardial coronaryvessels53 and structural alterations and rarefaction ofsmall coronary vessels54 limit blood supply when oxy-gen demand is increased by the greater tissue mass.Compensatory angiogenesis is inadequate during thedevelopment of adult LVH. Decreased subendocardialcoronary perfusion leads to myocyte necrosis and repar-ative fibrosis, encouraging the progression to heartfailure. Other extravascular mechanisms compoundingthe impairment of coronary reserve include changesin wall tension, heart rate, and contractility, at a timewhen the oxygen requirement, measured by the tripleproduct (heart rate � LV mass � end-systolic stress), isprogressively increased compared with patients withnormal LV mass and geometry.

The ability to regulate coronary flow is weakest duringexercise when oxygen demand increases. Under rest-ing conditions, the reduction in coronary flow reservemay not have important consequences, but during theexercise-induced increase in oxygen requirement itbecomes symptomatic and a factor in progressive LVdysfunction. Functional changes further weaken thevasodilator response of the coronary microcirculation.Endothelial dysfunction precedes morphologicalchanges in the vascular wall and triggers remodeling. In summary, LVH is a state of potential or actual myo-cardial ischemia.

There is a predisposition to ventricular arrhythmias inhypertensive LVH, explaining the risk of sudden death.Proposed causes include repolarization abnormalities(QT dispersion) due to the concomitant increase in fi-brous tissue, changes in coronary structure and func-tion, diuretic-induced hypokalemia, and autonomicdysfunction (adrenergic hyperactivity and reduced car-diac responsiveness to β-adrenergic stimulation). Im-paired ventricular filling, left atrial enlargement, andslowing of atrial conduction velocity all encourage atri-al fibrillation, increasing the risk of cerebrovascularthromboembolism.

Since hypertensive LVH is an independent risk factorfor cardiovascular morbidity and mortality, the possi-bility of reversal or even prevention by lowering bloodpressure and modifying other pathogenetic factors isa major goal in antihypertensive therapy.



9

LVH REGRESSION ON ANTIHYPERTENSIVE TREATMENT

LV mass can be decreased by nonpharmacological in-tervention, notably weight loss, which is effective inobese hypertensives independently of blood pressure.The multicenter Treatment Of Mild Hypertension Study(TOMHS) monitored echocardiographic LV mass in819 mild hypertensives annually for 4 years and foundthat lifestyle intervention reduced blood pressure sig-nificantly and decreased LV mass substantially in 30%of patients.55 However, there is still no hard evidenceof an independent effect by dynamic exercise, dietarysodium, or alcohol restriction.

Multiple studies have shown that blood pressure reduc-tion reverses LVH. The important determinants aretreatment duration and the degree of blood pressurereduction. The Study on Ambulatory Monitoring ofblood Pressure and Lisinopril Evaluation (SAMPLE)showed that changes in LV mass on ACE inhibitor ther-apy were significantly related not to changes in officeblood pressure, but to the degree of mean 24-hourblood pressure control.56 Subsequent evidence hasalso shown the importance of homogeneity, or mini-mal daily fluctuation, in blood pressure control, asexpressed in the “smoothness index.”57

However, since blood pressure is not the sole determi-nant of LVH and fibrosis, the differing response of LVmass to different classes of antihypertensive drugs wasascribed to interference in nonhemodynamic factorssuch as the RAAS and sympathetic nervous system. Sev-eral meta-analyses were therefore conducted of stud-

ies demonstrating reversal of echocardiographic LVHusing different antihypertensive drugs. Dahlöf et al58

calculated that for the same decrease in blood pressurethe decrease in LV mass was greatest with ACE inhib-itors, a conclusion confirmed by Cruickshank et al.59

Three years later, however, in a comparative review ofdiuretics, β-blockers, calcium channel blockers, andACE inhibitors, Fagard showed that each reduced LVmass to a degree similar to that of the other threeclasses combined, and that direct comparison couldnot separate ACE inhibitors from calcium channelblockers.60 Two more recent meta-analyses, by Jenningsand Wong61 and Klingbeil et al,62 confined to random-ized, double-blind parallel group comparisons, haveconfirmed that the main determinants of LVH regres-sion are the degree of blood pressure reduction andbaseline LV mass. However, both studies also observedthat ACE inhibitors, angiotensin II receptor blockers,and calcium channel blockers were more effective thanβ-blockers and diuretics given the same decrease inblood pressure.

Large randomized blinded studies (Table IV) compar-ing two or more different antihypertensive drugs haveprovided other data. The TOMHS results were the leastinstructive, due to the low prevalence of LVH and theefficacy of lifestyle intervention.58 The RAmipril Cardio-protective Evaluation (RACE) study showed significantLVH regression on the ACE inhibitor versus none onatenolol, at comparable levels of blood pressure reduc-tion.63 Unfortunately, high dropout rendered largelyinconclusive the comparison by the Department ofVeterans Affairs Cooperative Study Group of 1 year’smonotherapy with six different antihypertensive agents



10

Patients Treatment DrugStudy (n) duration (y) comparison

CATCH 182 1 Candesartan = enalapril

ELSA 174 4 Lacidipine = atenolol

ELVERA 166 2 Amlodipine = lisinopril

LIFE 960 4.5 Losartan > atenolol

LIVE 269 1 Indapamide > enalapril

PRESERVE 235 1 Nifedipine = enalapril

RACE 111 0.5 Ramipril > atenolol

REASON 124 1 Perindopril/indapamide > atenolol

REGAAL 183 1 Losartan > atenolol

SILVHIA 112 1 Irbesartan > atenolol

VA Cooperative Study 230 1 HCTZ, captopril > clonidine, diltiazem, prazosin, atenolol

Table IV. Studies com-paring left ventricular hypertrophy (LVH) regression on differentantihypertensive drugs.

Study acronyms:see box on page 4.

in 587 male hypertensives.64 Two other randomizeddouble-blind parallel studies employing centralizedechocardiographic LVH criteria compared the effect onLV mass of an ACE inhibitor and a calcium antagonist(PRESERVE [Prospective Randomized Enalapril StudyEvaluating Regression of Ventricular Enlargement]:enalapril vs nifedipine65; ELVERA [Effects of amlodipineand lisinopril on Left VEntriculaR mAss and diastolicfunction (E/A ratio)]: lisinopril versus amlodipine).66

Both found similar benefits with both drugs, as did theEuropean Lacidipine Study on Atherosclerosis (ELSA)study with the calcium antagonist lacidipine and theβ-blocker atenolol after treatment for 1 and 4 years.67

The results of the comparative LVH regression: Inda-pamide Versus Enalapril (LIVE) study showed a reduc-tion in LV mass on indapamide, suggesting that diu-retics can also regress LVH.68 As for angiotensin IIantagonists, they have been found more effective thanthe β-blocker atenolol,69-71 and similar to enalapril.72

The Losartan Intervention For Endpoint reduction inhypertension (LIFE) trial versus atenolol in hypertensiveECG LVH confirmed the superiority of angiotensin IIantagonists over β-blockers.73 Finally, a very recentlypublished study (REASON, PREterax in regression ofArterial Stiffness in a contrOlled double-bliNd study)found that the low-dose combination strategy, nowproposed in several cases by the ESH/ESC guidelines,demonstrated superior LVH regression using perindo-pril/indapamide versus atenolol.74

However, it should be kept in mind that interdrug dif-ferences tend to fade with time, since treatment dura-tion is associated with progressive blood pressurecontrol and decrease in LV mass, although β-blockersseem to be less effective in reversing LVH than otherclasses of drugs. In addition, blood pressure may beresistant if there is target-organ damage requiring theuse of combination antihypertensive therapy. Severalmajor intervention trials comparing the effects of sin-gle antihypertensive drugson LV mass have in factlargely been comparisonsof combination therapiesin that most patients weretaking more than one drug.Thus, over 50% of SAMPLEpatients received lisinoprilplus a diuretic,56 whileabout 90% of LIFE patientsreceived a diuretic in addi-tion to their β-blocker orangiotensin II blocker.73

The RACE patients were also stratified by the additionor nonaddition of a diuretic to their basal therapy: LVmass was similarly reduced in each subgroup, withramipril proving superior to atenolol both alone andin combination.63

There is increasing interest in the effect of antihyper-tensive treatment on myocardial tissue composition,with particular respect to perivascular and interstitial fi-brous tissue. Thus, for similar decreases in blood pres-sure after treatment for 6 months, Brilla et al showedthat lisinopril decreased myocardial collagen and hy-droxyproline content, and improved some diastolicfunction parameters, whereas hydrochlorothiazide hadnone of these effects, and only reduced myocyte diam-eter.75 Recent experimental and human evidence sug-gests that angiotensin II antagonists may also regressmyocardial fibrosis.76

Long-term studies thus indicate that all classes of antihypertensive drugs can lower blood pressure andregress LVH, with any initial interclass differences tend-ing to fade with time. Differences in the reduction ofLV mass for similar decreases in blood pressure aregenerally marginal, although there remains the possi-bility that drug classes differ markedly in their effecton cardiac structure and composition.

CLINICAL AND PROGNOSTIC SIGNIFICANCE OF LVH REGRESSION

Since LVH is such an important independent risk fac-tor in hypertension, there is no lack of consensus as tothe desirability of regression and prevention. Regres-sion is associated with numerous benefits such asenhanced systolic midwall performance, normalizedautonomic function, enhanced coronary reserve, and,possibly, enhanced diastolic filling and decreased ven-tricular arrhythmia. All contribute to the improved prog-nosis (Table V) demonstrated in several studies over



11

Presence of LVH Reversal of LVH

Systolic dysfunction (midwall depression) Unchanged (or improved at midwall)

Diastolic filling abnormalities Unchanged or improved

Autonomic dysfunction Autonomic near-normalization

Predisposition to ventricular arrhythmias Fewer arrhythmias

Reduced coronary reserve Improved coronary reserve

Associated vascular structural changes Improved

Table V. Pathophysiological and clinical consequences of left ventricular hypertrophy (LVH) regression.

➤

➤

➤

➤

➤

➤

the years using ECG measures. Normalization of ECGLVH in 524 Framingham subjects over a mean 5-yearfollow-up was associated with reduction in cardiovas-cular risk. Regression of Sokolow LVH criteria in theHeart Outcomes Prevention Evaluation (HOPE) studywas similarly associated with a reduction in cardiovas-cular events; no change—or worsening—of this sim-ple ECG index implied a less favorable outcome. Thelarge long-term LIFE study showed that the greaterregression of LVH with losartan was associated withfewer cardiovascular events (Table VI).73,77,78

In addition, further observations in a smaller numberof patients using the more sensitive echocardiographictechnique have shown that patients who fail to achieveLVH regression or who develop LVH during follow-upare much more likely to suffer morbid events (Table VII).

We ourselves demonstrated this for the first time in 151uncomplicated hypertensives followed for 10 years:Cox survival analysis adjusted for conventional cardio-vascular risk factors showed the persistence of LVH atthe end of follow-up as the most important independ-ent predictor of cardiovascular events.40

Moreover, regression of LVH was associated with asignificantly lower cardiovascular risk not statisticallydifferent from that observed in patients who neverdeveloped LVH during follow-up. Verdecchia et al ob-tained similar results in a larger group of 430 patientsover a shorter period (3.2 years).79 In 172 hypertensivepatients followed for 11.3 years, Koren et al observedcardiovascular events in 29% with LVH at follow-upversus in 9% of those without.80

In the echocardiographic substudy of the LIFE trialthat included 941 patients followed for over 4 years,the better prognosis associated with the significantdecrease in LV mass from baseline to end of study wasdue mainly to a decrease in the incidence of stroke.81

These cumulative findings highlight the prognosticvalue of the LV mass response to treatment. Bloodpressure was not significantly associated with cardio-vascular events in these studies, although it cannotbe excluded that the changes observed in the LV massindex at least partially reflected blood pressure control.

Baseline LV geometry confers differing cardiovascularrisk in hypertension, concentric hypertrophy being theleast favorable. We recently evaluated the relationshipbetween prognosis and the response of LV geometryto antihypertensive treatment in 436 uncomplicated



12

Events (%) by LVH status

Reference Patients (n) Events (n) Persistence Regression None

Muiesan et al,40 1995 151 23 38 12.5 5

Verdecchia et al,79 1998 430 31 21 6.2 5.4

Koren et al,80 2002 172 34 19.8 8.8 9.6

Total 753 88 26.3 9.2 6.7

Table VI. Prognostic implications of baseline electrocardiographic featuresand their serial changes in subjects with left ventricular hypertrophy (LVH).

Table VII. Prognosticimplications of baseline

electrocardiographicfeatures and their

serial changes in subjectswith left ventricularhypertrophy (LVH).

Levy et al,77 1994

• 524 patients; 52% males; mean follow-up: 5.1 years; ECG voltage and repolarization criteria for LVH; 269 cardiovascular (CV) events

• Greater 2-year age-adjusted incidence of CV events in patients with increased voltage and/or repolar-ization criteria

Mathew et al,78 2001

• 8281 patients at high risk (HOPE, Heart Outcomes Prevention Evaluation) mean follow-up 5 years Sokolow criteria for LVH

• 925 events (12.3%) in 7539 patients with LVH regres-sion or prevention vs 117 (15.8%) in 742 patientswith LVH development/persistence

Devereux et al,81 2002

• 9193 hypertensives (LIFE, Losartan Intervention For Endpoint reduction in hypertension), mean followup 4.5 years, Sokolow and Cornell criteria for LVH

• 13% CV events risk reduction in patients treated withlosartan (15.3 % mean decrease of ECG LVH) in respect to patients treated with atenolol (9 % de-crease in ECG LVH)

hypertensives (M: n=249; F: n=187; age 18-71 years)over 6.4 years.82 Persistence of LVH from baseline tofollow-up was confirmed as an independent predictorof cardiovascular events. Cardiovascular morbidity andmortality were significantly greater with concentric thaneccentric geometry, whether in the presence (P=0.04)or absence of LVH (P=0.02) at follow-up. Cardiovascu-lar events were significantly more frequent with per-sistent concentric geometry (P<0.0001) for similar LVmass at follow-up (Figure 1).82

Thus, an increase in echocardiographic LV mass in response to antihypertensive therapy, or a failure to decrease, confers a worse prognosis, while completeregression significantly reduces— indeed virtually nor-malizes—cardiovascular risk. In addition, the responseof LV geometry to treatment may also have prognosticsignificance with and without LVH.

FUTURE GOALS

Focuses of future concern will include the biochemistryof the adaptive changes in energy metabolism andcontractile proteins, notably the role of transmittersand transductional factors, as well as the timing ofthese responses to blood pressure changes, neurohu-moral activation, and the development of structuralalterations in other organs.

Techniques such as tissue characterization and non-invasive quantitative analysis of coronary flow will de-scribe the respective contributions of perivascular andintraventricular fibrosis and myocardial ischemia tothe mechanisms of LVH risk, and hopefully reveal waysin which these advances can be translated into indi-vidual patient benefit. However, we already know morethan enough to realize that a major goal in the man-agement of hypertension is the detection, prevention,and reversal of LVH.



13

THREE KEY QUESTIONS

The story of left ventricular hypertrophy (LVH) in hy-pertension is that of a good thing gone bad: hyper-tension initially triggers a potentially beneficialcompensatory increase in left ventricular mass, butthis ultimately evolves to a problem, becoming adisease in its own right, as well as a risk factor, en-dangering the heart and the patient’s life. The turn-ing point in the pathophysiology of LVH is fibrosis,which, added to concentric hypertrophy, heraldsleft ventricular dysfunction. Antonello Ganau andGiuseppe Talanas take a close look at the patho-genesis of LVH, and ask: “Do coronary circulationabnormalities play an important role in the patho-genesis of hypertensive LVH?” and establish a firmlink, even though the chicken-and-egg conundrumremains entire: is LVH the cause or the consequenceof a defect in myocardial perfusion in hypertension?In view of the pivotal role of tissue alterations in thedisease process, Javier Díez addresses the question:“How important is it to assess and attempt tocontrol cardiac fibrosis in hypertension?” In do-ing so he opens up exciting preventive and ther-apeutic prospects. Bernhard M. W. Schmidt andRoland E. Schmieder examine another importantquestion: “Hypertension and left ventricular hy-pertrophy: how much attention should we pay tothe renin-angiotensin-aldosterone system?” Thisquestion is of particular relevance in view of evi-dence that drugs modulating the RAAS have bene-ficial effects that are additive to, and independentof, their blood-pressure–lowering effect. To con-clude, by whichever means, LVH regression hasbenefits and as such detection, prevention, and re-versal of LVH are now major targets in the manage-ment of hypertension.

REFERENCES

1. Frohlich ED.

Risk mechanisms in hypertensive heart disease.

Hypertension. 1999;34:782-789.

2. Parati G, Pomidossi G, Albini E, Malaspina D, Mancia G.

Relationship of 24-hour blood pressure mean and variability toseverity of target-organ damage in hypertension.

J Hypertens. 1987;5:93-98.

3. Verdecchia P, Schillaci G, Guerrieri M, et al.

Circadian blood pressure change and left ventricular hypertrophyin essential hypertension.

Circulation. 1990;81:528-536.

4. Rizzoni D, Muiesan ML, Montani G, Zulli R, Calebich S,Agabiti-Rosei E.

Relationship between initial cardiovascular structural changes anddaytime and nighttime blood pressure monitoring.

Am J Hypertens. 1992;5:180-186.

5. de Simone G, Devereux RB, Roman MJ, Alderman MH,Laragh JH.

Relation of obesity and gender to left ventricular hypertrophy innormotensive and hypertensive adults.


6. de Simone G, Palmieri V, Koren M, Mensah G, RomanMJ, Devereux RB.

Prognostic implications of the compensatory nature of left ventricularmass in arterial hypertension.

J Hypertens. 2001;19:119-125.

7. Palmieri V, Watchell K, Gerdts E, et al.

Left ventricular function and hemodynamic features of inappropriateleft ventricular hypertrophy in patients with systemic hypertension:the LIFE study.

Am Heart J. 2001;141:784-791.

8. Grassi G, Gianattasio C, Cleroux J, Cuspidi C,Sampieri L, Mancia G.

Cardiopulmonary reflex before and after regression of left ventricu-lar hypertrophy in essential hypertension.


9. Rizzoni D, Agabiti-Rosei E, Castellano M, et al.

The effect of loading and unloading cardiopulmonary receptors onatrial natriuretic peptide in hypertensive patients with and withoutleft ventricular hypertrophy.

Clin Exp Hypertens. 1992;14:717-732.

10. Trimarco B, De Luca N, Ricciardelli B, et al.

Cardiac function in systemic hypertension before and after reversalof left ventricular hypertrophy.

Am J Cardiol. 1988;62:745-750.

11. Duprez D, Bauwens F, De Buyzere M, et al.

Influence of arterial blood pressure and aldosterone on left ventric-ular hypertrophy in moderate essential hypertension.

Am J Cardiol. 1993;71:17A-20A.

12. Schlaich MP, Schobel HP, Hilgers K, Schmieder RE.

Impact of aldosterone on left ventricular structure and function inyoung normotensive and mildly hypertensive subjects.

Am J Cardiol. 2000; 85:1199-1206.

13. Woessner JF.

Matrix metalloproteinases and their inhibitors in connective tissueremodeling.

FASEB J. 1991;5:2145-2154.

14. Rizzoni D, Muiesan ML, Porteri E, et al.

Relations between cardiac and vascular structure in patients withprimary and secondary hypertension.

J Am Coll Cardiol. 1998;32:985-992.

15. Rossi GP, Sacchetto A, Pavan E, et al.

Remodeling of the left ventricle in primary aldosteronism due toConn’s adenoma.

Circulation. 1997;95:1471-1478.

16. Verdecchia P, Reboldi G, Schillaci G, et al.

Circulating insulin and insulin growth factor-1 are independentdeterminants of left ventricular mass and geometry in essential hypertension.

Circulation. 1999;100:1802-1807.

17. Barouch LA, Berkowitz DE, Harrison RW, et al.

Disruption of leptin signaling contributes to cardiac hypertrophyindependently of body weight in mice.

Circulation. 2003;108:754-759.

18. Post W, Larson M, Myers RH, Galderisi M, Levy D.

Heritability of left ventricular mass.

Hypertension. 1997;30:1025-1028.

19. Schunkert H, Hense HW, Holmer SR, et al.

Association between a deletion polymorphism of the angiotensinconverting enzyme gene and left ventricular hypertrophy.

N Engl J Med. 1994;330:1634-1638.

20. Staessen J, Wang JG, Ginocchio G, et al.

The deletion/insertion polymorphism of the angiotensin-convertingenzyme and cardiovascular-renal risk.

J Hypertens. 1997;15:1579-1592.

21. Castellano M, Rossi F, Rivadossi F, et al.

Aldosterone synthase gene polymorphism and cardiovascular phe-notypes in a general population.

J Hypertens. 2000;18(suppl 4):174. Abstract.



14

22. Guidelines Committee.

2003 European Society of Hypertension–European Society ofCardiology guidelines for the management of arterial hypertension.

J Hypertens. 2003;21:1011-1053.

23. Devereux RB, Roman MJ.

Evaluation of cardiac and vascular structure and function by echo-cardiography and other non-invasive techniques. In: Laragh JH,Brenner BM, eds.

Hypertension: Pathophysiology, Diagnosis and Management.2nd ed. New York, NY: Raven Press; 1995:1969-1985.

24. Sundstrom J, Lind L, Arnlow J, et al.

Echocardiographic and electrocardiographic diagnoses of left ven-tricular hypertrophy predict mortality independently of each otherin a population of elderly men.

Circulation. 2001;103:2346-2351.

25. Okin P, Roman MJ, Lee ET, Galloway JM, Howard B,Devereux RB.

Combined echocardiographic left ventricular hypertrophy and elec-trocardiographic ST depression improve prediction of mortality inAmerican Indians. The Strong Heart Study.


26. Sahn DJ, DeMaria A, Kisslo J, Weyman A.

The Committee on M-mode Standardization of the American Societyof Echocardiography: recommendations regarding quantitation inM-mode echocardiography. Results of a survey of echocardio-graphic measurements.

Circulation. 1978;58:1072-1083.

27. Devereux RB, Alonso DR, Lutas EM, et al.

Echocardiographic assessment on left ventricular hypertrophy:Comparison to necropsy findings.

Am J Cardiol. 1986;57:450-458.

28. Muiesan ML, Salvetti M, Monteduro C, Donato F,Rizzoni D, Agabiti-Rosei A.

Various ways of calculating echocardiographic left ventricularmass and their relative prognostic values.

J Hypertens. 1998;16;1201-1206.

29. de Simone G, Muiesan ML, Ganau A, et al.

Reliability and limitations of measurement of echocardiographicmeasurement of left ventricular mass for risk stratification and fol-low-up in single patients: the RES trial. Working Group on Heartand Hypertension of the Italian Society of Hypertension. Reliabilityof M-mode Echocardiographic Studies.

J Hypertens. 1999;17:1960-1964.

30. Palmieri V, Dahlof B, DeQuattro V,

Reliability of echocardiographic assessment of left ventricularstructure and function. The PRESERVE study.

J Am Coll Cardiol. 1999;34:1625-1632.

31. de Simone G, Devereux RB, Daniels SR, Koren MJ,Alderman MH, Laragh JH.

Effect of growth on variability of left ventricular mass: assessmentof allometric signals in adults and children and of their capacityto predict cardiovascular risk.

J Am Coll Cardiol. 1995;25:1056-1062.

32. Ganau A, Devereux RB, Roman MJ, et al.

Patterns of left ventricular hypertrophy and geometric remodelingin arterial hypertension.

J Am Coll Cardiol. 1992;19:1550-1558.

33. Shimuzu G, Zile MR, Blaustein AS, Gaasch WH.

Left ventricular chamber filling and midwall fiber lengthening inpatients with left ventricular hypertrophy: overestimation of fibervelocities by conventional midwall measurements.

Circulation. 1985;71:266-272.

34. de Simone G, Devereux RB, Koren MJ, Mensah GA,Casale PN, Laragh JH.

Midwall left ventricular mechanics. An independent predictor ofcardiovascular risk in arterial hypertension.

Circulation. 1996;93:259-265.

35. Muiesan ML, Salvetti M, Rizzoni D, Castellano M,Monteduro C, Agabiti-Rosei E.

Persistence of left ventricular hypertrophy is a stronger indicator ofcardiovascular events than baseline LV mass or systolic performance.A ten years follow-up.

J Hypertens. 1996;14(suppl 5):S43-S51.

36. Di Bello V, Pedrinelli R, Giorgi D, et al.

Ultrasonic videodensitometric analysis of two different models ofleft ventricular hypertrophy: athlete's heart and hypertension.


37. Ciulla M, Paliotti R, Hess B, et al.

Echocardiographic patterns of myocardial fibrosis in hypertensivepatients: endomyocardial biopsy versus ultrasonic tissue character-ization.

J Am Soc Echocardiogr. 1997;10:657-664.

38. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP.

Prognostic implications of echocardiographically determined leftventricular mass in the Framingham Heart Study.

N Engl J Med. 1990;322:1561-1566.

39. Koren MJ, Devereux RB, Casale PN, Savage DD,Laragh JH.

Relation of left ventricular mass and geometry to morbidity andmortality in uncomplicated essential hypertension.

Ann Intern Med. 1991;114:345-352.

40. Muiesan ML, Salvetti M, Rizzoni D, Castellano M,Donato F, Agabiti-Rosei E.

Association of change in left ventricular mass with prognosis duringlong-term antihypertensive treatment.

J Hypertens. 1995;13:1091-1097.



15



16

41. Vakili B, Okin P, Devereux RB.

Prognostic implications of left ventricular hypertrophy.

Am Heart J. 2001:141;334-341.

42. Weber KT.

Collagen matrix synthesis and degradation in the developmentand regression of left ventricular hypertrophy.

Cardiovasc Rev Rep. 1991;12:61-69.

43. Aurigemma GP, Silver KH, Priest MA, Gaasch WH.

Geometric changes allow normal ejection fraction despite depressedmyocardial shortening in hypertensive left ventricular hypertrophy.


44. Verdecchia P, Schillaci G, Reboldi G, Ambrosio G,Pede S, Porcellati C.

Prognostic value of midwall shortening fraction and its relationwith left ventricular mass in systemic hypertension.

Am J Cardiol. 2001;87:479-482.

45. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J,Kitzman D.

Predictive value of systolic and diastolic function for incident con-gestive heart failure.

J Am Coll Cardiol. 2001;37:1042–1048.

46. Agabiti-Rosei E, Muiesan ML.

Hypertension and diastolic function.

Drugs. 1993;46(suppl 2):61-67.

47. Quinones MA, Otto C, Stoddard M, Waggoner A,Zoghbi W.

Recommendations for quantifications of Doppler echocardiography:a report from the Doppler quantification Task Force of the Nomen-clature and Standards Committee of the American Society of Echo-cardiography.


48. Schillaci G, Pasqualini L, Verdecchia P, et al.

Prognostic significance of left ventricular diastolic dysfunction inessential hypertension.

J Am Coll Cardiol. 2002;39:2005-2011.

49. Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW,Bailey KR, Rodeheffer RJ.

Burden of systolic and diastolic ventricular dysfunction in thecommunity: appreciating the scope of the heart failure epidemic.

JAMA. 2003;289:194-202.

50. Roman MJ, Pickering TG, Schwartz JE, Pini R,Devereux RB.

Association of carotid atherosclerotic and left ventricular hypertrophy.


51. Muiesan ML, Pasini GF, Salvetti M, et al.

Cardiac and vascular structural changes. Prevalence and relationto ambulatory blood pressure in a middle-aged general populationin Northern Italy. The Vobarno Study.

Hypertension. 1996;27:1046-1052.

52. Lucarini A, Spessot M, Picano E, et al.

Lack of correlation between cardiac mass and arteriolar structuralchanges in mild-to-moderate hypertension.

J Hypertens. 1991;9:1187-1191.

53. Niteberg A, Anthony I.

Epicardial coronary arteries are not adequately sized in hyperten-sive patients.


54. Rizzoni D, Palombo C, Porteri E, et al.

Relationship between coronary vasodilator capacity and small artery remodeling in hypertensive patients.

J Hypertens. 2003;21:615-621.

55. Neaton JD, Grimm RH, Prineas RJ, et al, on behalf ofTreatment of Mild Hypertension Study Research Group.

Treatment of Mild Hypertension Study. Final results.

JAMA. 1993;270:713-724.

56. Mancia G, Zanchetti A, Agabiti-Rosei E, Benemio G,et al, for the Sample Study Group.

Ambulatory blood pressure is superior to clinic blood pressure in pre-dicting treatment-induced regression of left ventricular hypertrophy.

Circulation. 1997;95:1464-1470.

57. Parati G, Omboni S, Rizzoni D, Agabiti-Rosei E,Mancia G.

The smoothness index: a new reproducible and clinically relevantmeasure of the homogeneity of the blood pressure reduction withtreatment for hypertension.

J Hypertens. 1998;16:1685-1693.

58. Dahlöf B, Pennert K, Hansson L.

Reversal of left ventricular hypertrophy in hypertensive patients. A meta-analysis of 109 treatment studies.

Am J Hypertens. 1992;5:95-110.

59. Cruickshank JM, Lewis J, Moore V, Dodd A.

Reversibility of left ventricular hypertrophy by differing types ofantihypertensive therapy.

J Human Hypertens. 1992;6:85-90.

60. Fagard RH.

Reversibility of left ventricular hypertrophy by antihypertensive drugs.

Neth J Med. 1995;47:173-179.

61. Jennings G, Wong J.

Reversibility of left ventricular hypertrophy and malfunction byantihypertensive treatment. In: Hansonn L, Birkenhager WH, eds.

Handbook of Hypertension (vol 18): Assessment of Hyper-tensive Organ Damage. Elsevier Science BV; 1997:185-223.

62. Klingbeil A, Schneider M, Martus P, Messerli F,Schmieder R.

A meta-analysis of the effects of treatment on left ventricular massin essential hypertension.

Am J Med. 203;115:41-46.

63. Agabiti-Rosei E, Ambrosioni E, Dal Palu C, MuiesanML, Zanchetti A, on behalf of the RACE Study Group.

ACE-inhibitor ramipril is more effective than the beta-blockeratenolol in reducing left ventricular hypertrophy in hypertension.Results of the RACE (Ramipril Cardioprotective Evaluation) study.

J Hypertens. 1995;13:1325-1334.

64. Gottdiener J, Reda D, Massie BM, Materson BJ,Williams DW, Anderson RJ.

Effect of single-drug therapy on reduction of left ventricular massin mild to moderate hypertension comparison of six antihyperten-sive agents: the Department of Veterans Affairs Cooperative StudyGroup on Antihypertensive agents.

Circulation. 1997;95:2007-2014.

65. Devereux RB, Palmieri V, Sharpe N, et al.

Effects of once daily angiotensin-converting enzyme inhibition andcalcium channel blockade-based antihypertensive treatment regi-mens on left ventricular hypertrophy and diastolic filling in hyper-tension. The Prospective Randomised Enalapril Study EvaluatingRegression of Ventricular Enlargement (PRESERVE) trial.

Circulation. 2001;104:1248-1254.

66. Terpstra WF, May JF, Smit AJ, et al.

Long-term effects of amlodipine and lisinopril on left ventricularmass and diastolic function in elderly, previously untreated hyper-tensive patients: the ELVERA trial.

J Hypertens. 2001;19:303-309.

67. Agabiti-Rosei E, Muiesan ML, Trimarco B, Reid J,Hennig M, Zanchetti A.

Changes of LV mass and ABPM during long-term antihypertensivetreatment in ELSA.

J Hypertens. 2002;20(suppl 4):S4. Abstract.

68. Gosse P, Sheridan DJ, Dubourg O, et al.

Regression of left ventricular hypertrophy in hypertensive patientstreated with indapamide SR 1.5 mg versus enalapril 20 mg: TheL.I.V.E. Study.

J Hypertens. 2000;18:1465-1475.

69. Thurmann P, Kenedi P, Schmidt A, Harder S,Rietbrock N.

Influence of the angiotensin II antagonist valsartan on left ventric-ular hypertrophy in patients with essential hypertension.

Circulation. 1998;98:2037-2042.

70. Malmqvist K, Kahan T, Edner M, et al.

Regression of left ventricular hypertrophy in human hypertensionwith irbesartan.

J Hypertens. 2001;19:1167-1176.

71. Dahlof B, Zanchetti A, Diez J, et al, for the REGAALStudy Investigators.

Effects of losartan and atenolol on left ventricular mass and neu-rohormonal profile in patients with essential hypertension and leftventricular hypertrophy.

J Hypertens. 2002;20:1855-1864.

72. Cuspidi C, Muiesan ML, Valagussa L, Salvetti M, DiBiagio C, Zanchetti, on behalf of the CATCH investigators.

Comparative effects of candesartan and enalapril on left ventric-ular hypertrophy in patients with essential hypertension: theCandesartan Assessment in the Treatment of Cardiac Hypertrophy(CATCH) study.

J Hypertens. 2002;20:2293-2300.

73. Okin PM, Devereux RB, Jern S, et al, for the LosartanIntervention For Endpoint reduction in hypertension (LIFE)Study Investigators.

Regression of electrocardiographic left ventricular hypertrophy bylosartan versus atenolol. The Losartan Intervention For Endpointreduction in hypertension. (LIFE) Study.

Circulation. 2003;108:684-690.

74. de Luca N, Mallion JM, O’Rourke MF, et al.

Regression of left ventricular mass in hypertensive patients treatedwith perindopril/indapamide as a first-line combination: the REA-SON echocardiographic study.

Am J Hypertens. 2004;17:660-667.

75. Brilla CG, Funck RC, Rupp H.

Lisinopril-mediated regression of myocardial fibrosis in patientswith hypertensive heart disease.

Circulation. 2000;102:1388-1393.

76. Lopez B, Querejeta R, Varo N, et al.

Usefulness of serum carboxy-terminal propeptide of procollagentype I in assessment of the cardioreparative ability of antihyperten-sive treatment in hypertensive patients.

Circulation. 2001;104:286-291.

77. Levy D, Salomon M, D'Agostino RB, Belanger AJ,Kannel WB.

Prognostic implications of baseline electrocardiographic featuresand their serial changes in subjects with left ventricular hypertrophy.

Circulation. 1994;90:1786-1793.

78. Mathew J, Sleight P, Lonn E, et al, for the HeartOutcomes Prevention Evaluation (HOPE) Investigators.

Reduction of cardiovascular risk by regression of electrocardio-graphic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril.

Circulation. 2001;104:1615-1621.

79. Verdecchia P, Schillaci G, Borgioni I, et al.

Prognostic significance of serial changes in left ventricular massin essential hypertension.

Circulation. 1998;97:48-54.

80. Koren MJ, Ulin RJ, Koren AT, Laragh JH, Devereux RB.

Left ventricular mass changes during treatment and outcome inpatients with essential hypertension.

Am J Hypertens. 2002;15:1021-1028.



17

81. Devereux RB, Watchell K, Gerdts E, et al.

Prognostic significance of left ventricular mass change duringtreatment of hypertension.

JAMA. 2004;292:2350-2356.

82. Muiesan ML, Solvetti M, Monteduro C, et al.

Left ventricular concentric geometry during treatment adversely affects cardiovascular prognosis in hypertensive patients.




18

eft ventricular hypertrophy(LVH) is the most importantpreclinical manifestation ofhypertensive organ damage1

and a strong predictor of cardiovas-cular events in subjects with arterialhypertension2 or coronary arterydisease,3 as well as in the generalpopulation.4

Cardiac hypertrophy is an adaptiveresponse to a sustained elevation inworkload (eg, arterial hypertensionor valve disease) and has the effectof decreasing ventricular wall stresscompensating for the increasedworkload. If mechanical overload isnot relieved, progressive ventriculardilatation occurs with a consequentincrease in wall stress, afterloadmismatch, and deterioration of leftventricular (LV) pump function.5

MYOCARDIAL HYPERTROPHY AND

CORONARY BLOOD FLOW

There is overwhelming evidence thatthe compensated hypertrophiedheart is characterized by increasedsusceptibility to subendocardial is-chemia. Patients with LVH and an-giographically normal epicardialcoronary arteries may exhibit elec-trocardiographic signs of subendo-cardial ischemia6 or develop effortangina pectoris.7 In the normal rest-ing awake animal, the subendocar-

dial blood flow is greater than thesubepicardial flow, reflecting highersystolic wall stress and oxygen re-quirements in the deepest myocar-dial layers, and this flow gradientis preserved during exercise.8 In con-trast, in hypertrophied hearts, thesubendocardial blood flow increasesinadequately during exercise, andthe ratio of subendocardial-to-sub-epicardial blood flow is reduced.9,10

These data explain the increasedvulnerability of the hypertrophiedheart to subendocardial hypoper-fusion.

Perfusion abnormalities in the hy-pertrophied heart could be causedby an increase in the minimumcoronary vascular resistance result-ing from a decrease in the minimumcross-sectional area of the vascularbed per gram of myocardium. Thelatter can result from structural coro-nary alterations such as vascularrarefaction, as the number of capil-laries fails to match the growth ofcardiomyocytes per unit area, orfrom a decrease in vascular lumendue to lumenal encroachment re-sulting from vascular medial hyper-trophy.11 A recent study has shownthat a single administration of vas-cular endothelial growth factor(VEGF), given intrapericardially dur-ing the compensated phase of hy-pertrophy, increases myocardialperfusion by promoting microvas-

Do coronary circulation abnormalities play an important role in the pathogenesis of hypertensive left ventricular hypertrophy? Antonello Ganau, MD; Giuseppe Talanas, MD

Chair of Cardiology - University of Sassari - Sassari - ITALY

L

Keywords: hypertension; myocardial hypertrophy;coronary artery disease; myocardial perfusion;endothelial dysfunction; microvascular diseaseAddress for correspondence:Prof Antonello Ganau, Università di Sassari, Cattedra di Cardiologia, Istituto di Clinica Medica,Viale San Pietro 8, 07100 Sassari, Italy(e-mail: [email protected])



21

Hypertensive left ventricular hyper-trophy (LVH) is a powerful predictorof coronary events. It is character-ized by coronary circulation abnor-malities such as impaired coronaryblood flow autoregulation, decreas-ed coronary reserve, increased min-imal coronary vascular resistance,subendocardial underperfusionduring exercise, and increased riskof myocardial infarction and deathin the presence of coronary occlu-sion. These abnormalities appearto play a significant role in thepathogenesis of cardiac complica-tions in arterial hypertension. Al-though the imbalance between coro-nary supply and myocardial needshas often been incriminated in thepathogenesis of hypertensive LVH,no convincing evidence has beenprovided to date that LVH is theconsequence, rather than the cause,of a primary defect of myocardialperfusion in hypertensive patients.

cular growth,12 thus supportingthe vascular rarefaction hypothesis.Abnormal myocardial perfusion mayalso be due to the increase in ex-travascular intramyocardial forces,eg, the perivascular fibrosis13 thatcompresses the vasculature andhence impedes blood flow. The hy-pertrophic growth of cardiomyocytesand remodeling of extracellular ma-trix, not associated with a parallelincrease in the microvascular bed,result in a decrease in capillary den-sity and impaired coronary flow re-serve, while the increased distanceof diffusion reduces the supply ofnutrients to the hypertrophied my-ocytes.

The myocyte-to-capillary mismatchis aggravated during states of highworkload or ischemia, when an in-creased demand for substrates andoxygen occurs, and may contributeto the decline in contractile functiontaking place in the late phase of hy-pertrophy.

Alterations in coronary vasomotortone originating from either endo-thelial14 or vascular smooth muscledysfunction may also play a role inimpairing myocardial perfusion. Arecent study showed an increase inmyocardial perfusion reserve andmaximal coronary flow in asymp-tomatic patients with hypertension-induced LVH after long-term treat-ment with lisinopril, but not with anangiotensin II receptor antagonist.15

Furthermore, post-treatment hyper-emic flow was not different in thegroup treated with lisinopril com-pared with the control group. Sincethe angiotensin II receptor antago-nist did not improve maximal myo-cardial perfusion, the possible expla-nation for the augmented blood flowin the lisinopril arm might be theincreased availability of bradykininand, consequently, vasodilatorprostaglandins and nitric oxide. Inthis experiment15 myocardial perfu-

sion reserve improved in the absenceof significant reduction in LV mass,suggesting that the improvementin coronary vasodilator capacitywas not due to reduction in extra-vascular compressive forces on thecoronary microvasculature (Table I).

CORONARY FLOW IN PHYSIOLOGICAL AND

HYPERTENSIVE LVH

A recent study compared restingcoronary flow velocity, determinantsof myocardial oxygen demand, coro-nary vasodilator capacity, and epi-

cardial vessel remodeling in subjectswith exercise-induced physiologicalLVH and in hypertensive patientswith LVH.16 The relationship betweenresting coronary flow velocity anddeterminants of myocardial oxygenwas impaired in hypertensive LVHand preserved in physiological LVH.Maximal coronary vasodilation atthe microcirculatory level was pre-served in athletes with physiologi-cal LVH, while it was impaired inhypertensive LVH. In addition, phys-

iological LVH was associated with afavorable remodeling and enhancedvasodilator capacity of the epicar-dial vessels. In fact, the vasodilatorresponse of the left main coronaryartery to dipyridamole was 5 timeshigher in athletes compared with hy-pertensive patients.16 These resultssuggest that the pathologic natureof the hypertensive hypertrophy,rather than the increase of myocar-dial mass per se, modifies the rela-tionship between resting flow ve-locity and determinants of restingmyocardial oxygen demand. Themechanisms underlying the age-de-

pendent decrease in coronary flowreserve are also different in olderathletes and hypertensive subjects:in older athletes the reduction incoronary flow reserve is almost en-tirely due to an increase in basalblood pressure, cardiac work, andflow velocity rather than to reducedvasodilator capacity. In older hyper-tensive subjects, the further reduc-tion in coronary flow reserve is theresult of decreased hyperemic flowvelocity and increased minimum


May coronary perfusion abnormalities cause hypertensive LVH? - Ganau and Talanas

22

Table I. Potential causes of abnormal coronary perfusion in hypertension.

Primary mechanism Functional consequences

Increased myocardial mass Increased basal O2 consumptionReduced coronary reserve

Myocardial and periarteriolar Increased extravascular force andfibrosis reduced vascular lumen

Increased coronary resistance

Decrease in capillary density per Increased coronary resistancecardiomyocyte unit area (rare- Reduced coronary reserve faction of the vascular bed) Increased diffusion distance

Reduced supply of nutrients tomyocytes

Vascular medial hypertrophy Decreased vascular lumenwith lumen encroachment Increased coronary resistance

Reduced coronary reserve

Endothelial or vascular smooth Increased coronary vasomotor muscle dysfunction tone and resistance

Reduced coronary autoregulationand coronary reserve

coronary vascular resistance, sug-gesting a role of aging in impairingcoronary vasodilator capacity in ar-terial hypertension.16 Morphometricstudies in various animal modelssuggest that the growth of the coro-nary microvascular bed does not ad-equately match the magnitude ofmyocardial growth, and a relativedecrease in microvascular densityoccurs in hypertensive LVH.17,18 Fur-thermore, hypertension-inducedLVH is characterized not only by my-ocyte hypertrophy, but also by col-lagen deposition within the ventric-ular wall and around the coronaryvessels.19,20 The myocardial fibrosisincreases the stiffness of the LVchamber, impairs LV relaxation, andmay interfere with coronary vaso-dilator capacity, which is likely toinitiate and maintain a process ofmyocardial underperfusion and mal-nutrition leading to depression ofmyocardial performance and furtherincrease in interstitial fibrosis.21,22

It has been reported that hyperten-sive LVH is associated with a sig-nificant increase in the expressionof brain natriuretic peptide (BNP)mRNA, angiotensin-converting en-zyme (ACE) mRNA, and endothe-lin-1 (ET-1) mRNA compared withexercise-induced LV physiologicalhypertrophy.23 Pathological cardiachypertrophy is partly induced byendothelin24 and angiotensin II,25

the latter being able to enhance col-lagen deposition and reduce colla-gen degradation by inhibiting tissuemetalloproteinase-1.26

CORONARY FLOW ANDLEFT VENTRICULAR

GEOMETRY

LV geometric adaptation to hyper-tension is heterogeneous,27 reflect-ing the interactions of pressure andvolume load, inotropic state, andaging.28-30 Hypertensive subjectscan be classified into four patterns

based on LV mass and relative wallthickness.27 Patients with concentrichypertrophy are characterized byvery elevated peripheral resistance27

and the highest risk of cardiovas-cular morbidity and mortality.2,31

Sekiya and coworkers have assessedthe responses of coronary vasomo-tion to vasoactive agents in the leftanterior descending artery of hyper-tensive patients with angiographi-cally normal coronary arteries.32 Thisstudy has shown that endothelium-dependent vasodilation induced byacetylcholine is progressively im-paired as LVH progresses. The en-dothelium-independent vasodilationinduced by adenosine, which reflectsthe vasodilator capacity of the mi-crovessels or, in other words, coro-nary flow reserve, was impaired onlyin patients with concentric hyper-trophy. Thus, both severe coronaryendothelial dysfunction and abnor-mality of coronary microvasculardilatation coexist in hypertensivepatients with concentric hypertro-phy, and may contribute to the in-creased cardiovascular morbidityand mortality associated with LVconcentric hypertrophy.

DEVELOPMENT OF HYPERTENSIVE LVH: DOES

IMPAIRMENT OF CORO-NARY BLOOD FLOW PLAY A

PATHOGENETIC ROLE?

While there is strong evidence thatLVH may induce abnormalities ofmyocardial perfusion, the hypothe-sis has also been raised that an in-adequate coronary blood flow mayin turn be a stimulus for myocardialhypertrophy. Few studies have in-vestigated the pathogenetic role ofcoronary blood flow abnormalitiesin inducing LVH. Although the asso-ciation of LVH with coronary athero-sclerosis and myocardial infarctionhas been demonstrated by necropsystudies more than half century ago,only the advent of coronary angiog-

raphy and ventriculography permit-ted to study in vivo both the coro-nary vessels and LV mass. In 1973,Pech and coworkers33 investigatedthe association between coronaryabnormalities and LVH in patientswith chronic ischemic heart disease.The authors selected patients withangina pectoris who were free ofhypertension, cardiomyopathies, orvalvular disease and underwent di-agnostic cardiac catheterization andangiocardiography. Patients weresubdivided into four groups ac-cording to the severity of coronaryatherosclerosis. LV mass was signif-icantly increased in patients withcoronary artery disease comparedwith those with normal coronary an-giography. Among patients with doc-umented coronary lesions, the twogroups with occlusion or with criti-cal stenosis of a major coronaryvessel had higher LV mass than thegroup with small plaques or lesssevere coronary stenosis. In the ab-sence of apparent causes of LVH,the authors speculated that the in-crease in LV weight could be attrib-uted to proliferation of connectivetissue for repairing the hypoxicnecroses and/or to vicarious hyper-trophy of the remaining myocardi-um.33 While this paper providedclear evidence that LVH and coro-nary artery disease can be associat-ed, no direct action of ischemia onmyocardial hypertrophy could bedemonstrated.

Gould and coworkers34 studied 54patients with angiographically prov-en coronary artery disease and ob-served that hypertrophy developsafter myocardial infarction in pro-portion to LV dilatation and may re-sult in a syndrome of massive LVH,hypokinesia, and heart failure quan-titatively identical to that found inprimary cardiomyopathies. Patientswith mild-to-moderate degrees ofischemic injury had intermediatedegrees of hypertrophy, suggesting



23

that coronary atherosclerosis withmyocardial infarction was causalrather than merely coexistent. Theauthors proposed the following se-quence of events leading to cardiachypertrophy: regional injury and celldeath→increased end systolic vol-ume →higher wall stress →hyper-trophy of the remote viable myocar-dium.34 Thus, the authors identifiedthe excess of left ventricular loaddue to loss of contractile tissue,rather than the reduced myocardialperfusion, as the primary stimulusfor myocardial hypertrophy.

A more direct link between myocar-dial ischemia and myocardial hy-pertrophy was demonstrated byAnversa and coworkers.35 They in-vestigated the growth response ofmyocytes after acute myocardial in-farction in rats. The animals werekilled 3 days after ligation of the leftcoronary artery. Elevated LV end-di-astolic pressure and decreased firstderivative of LV pressure and sys-tolic arterial pressure indicated sig-nificant impairment of ventricularfunction. Absolute infarct size wasdetermined morphometrically bymeasurement of the fraction of my-ocyte nuclei lost and averaged 57%.

Hypertrophy of the surviving LVmyocytes was 28%. These resultsshowed, on a cellular basis, that my-ocardial hypertrophy occurred aftersevere ischemia. Since LVH resultedfrom changes in the cellular shapecharacteristic of a combination ofpressure and volume overload hy-pertrophy, the authors suggestedthat the loss of cardiac cells and theconsequent dilation of LV chamberresulted in a greater regional wallstress on the remaining myocytes,responsible for compensatory ec-centric hypertrophy of the viableventricular myocardium.35 This com-bination of necrotic tissue, chamberdilation, and remote hypertrophyis now well known as postinfarction

ventricular remodeling. The authorsfound that the myocyte volume pernucleus increased by 21% also inthe nonischemic right ventricle. Theyspeculated that the right hypertro-

phy could reflect pulmonary hyper-tension or an increase in right ven-tricular pressure to maintain thepressure gradient across the pul-monary vascular bed.35 Once again,



24

Peak values DevelopmentControl in cross- of collateral Regression

sectional area flow

Days 14±5 20±7 30±8

No. of occlusions 123±52 180±66

Length (mm) 10 10.50±0.34* 10.55±0.34 10.37±0.50

Wall thickness (mm) 10 10.45±0.22 10.10±0.18 10.07±0.38

Cross-sectional area100 109.7±4.3* 106.5±4.2* 104.3±4.6

(mm2)

Days

Number of coronary occlusions

Functionalrecovery

Incr

ease

(%

)

70 14 21

180

28

10

7.5

5

2.5

0

Increase in cross-sectional area of ischemic myocardial segment (%)Increase in myocardial segment length (%)Increase in myocardial segment thickness (%)

1

Figure 1. Effects of repeated transitory ischemia on thickness, length, and cross-sectional area of themyocardial segment exposed to brief repeated coronary occlusions in 5 dogs. The left circumflex coro-nary artery was occluded for 2 minutes and occlusion was repeated at time intervals of 30 minutes per8 hours a day and for 5 days a week. The functional recovery due to collateral flow development in-duced partial regression of hypertrophy, despite the repetition of coronary occlusions. The ischemicsegment recovered almost entirely both baseline thickness and length a few days after cessation of theocclusions.

Adapted from reference 36: Fujita M, Mikuniya A, McKown DP, McKown MD, Franklin D. Re-gional myocardial volume alterations induced by brief repeated coronary occlusions in consciousdogs. J Am Coll Cardiol. 1988;12:1048-1053. Copyright © 1988, American College of CardiologyFoundation. Published by Elsevier Inc.

Table II. End-diastolic length, thickness, and cross-sectional area of a myocardial segment beforeand after repeated episodes of transitory ischemia due to brief coronary occlusions in 5 dogs.*P<0.05 vs control.

Adapted from reference 36: Fujita M, Mikuniya A, McKown DP, McKown MD, Franklin D. Regional myocardial volume alterations induced by brief repeated coronary occlusions in consciousdogs. J Am Coll Cardiol. 1988;12:1048-1053. Copyright © 1988, American College of CardiologyFoundation. Published by Elsevier Inc.

there was no direct evidence of acause-effect relationship betweenmyocardial ischemia and LVH.

In 1988, Fujita and coworkers inves-tigated whether brief repeated coro-nary occlusions induced changesin regional myocardial geometry indogs.36 In this study, 5 consciousdogs were instrumented with ultra-sound crystals for measurementsof subendocardial segment lengthand transmural wall thickness inthe ischemic area, subendocardialsegment length in the normally per-fused area, coronary flow, and LVpressure. After recovery from sur-gery, 2-minute occlusions of thecircumflex coronary artery were re-peated at 30-minute intervals for 8hours, 5 days a week, over an aver-age period of 20±7 days. The end-diastolic segment length did notchange significantly in the normalarea throughout the experiment. Bycontrast, in the ischemic area, theend-diastolic regional cross-section-al area (product of segment lengthand wall thickness), measured dailyin the preocclusion state, was in-creased by 9.7% (P<0.05) after 14days of repeated coronary occlu-sions. After 10 days of functional re-covery, the myocardial thickness inthe ischemic zone was not differentfrom the baseline value, whereasmyocardial segment length and vol-ume remained increased, revealingthe persistence of regional hyper-trophy after removal of the ischem-ic stimulus (Table II; Figure 1).36

These data indicate that regionalmyocardial hypertrophy may occurin response to repeated episodesof ischemia. However, the lack ofhistology did not allow to assesswhether the regional increase in my-ocardial volume was attributable tomyocyte hypertrophy or rather tointerstitial edema or fibrosis. In thisexperimental model, the stimulusfor regional myocardial hypertrophy

might be either the repeated hypox-ia or the increase in regional wallstress secondary to the ischemia-in-duced systolic wall thinning.

CONCLUSIONS

In summary, up to now there is noconclusive evidence that the mis-match between coronary blood flowsupply and myocardial metabolicneeds is important in the pathogen-esis of LVH in hypertension. Otherstimuli appear to be more relevant,such as hemodynamic pressure orvolume load and neurohumoral fac-tors. The development of LVH is as-sociated with myocyte-capillarymismatch, which increases the vul-nerability of the hypertrophied my-ocardium to ischemia and predis-poses the cardiac muscle to a higherrisk of infarction and to more ex-tensive hypoxic necroses comparedwith patients without LVH. Theseabnormalities of myocardial perfu-sion and metabolism may play animportant role in the transition fromthe compensated phase of hyper-trophy to progressive left ventriculardilation and heart failure, elicitingthe vicious circle of ischemia →chamber dilation →increase in wallstress →LVH → further ischemia.Normalization of the coronary re-serve with antihypertensive drugsmight slow down or interrupt theprogression of the hypertensiveheart disease.

REFERENCES

1. Mensah GA, Pappas TW, Koren MJ,Ulin RJ, Laragh JH, Devereux RB.

Comparison of classification of hypertensionseverity by blood pressure level and WorldHealth Organization criteria for predictionof concurrent cardiac abnormalities andsubsequent complications in essential hypertension.

J Hypertens. 1993;11:1429-1440.

2. Koren MJ, Devereux RB, Casale PN,Savage DD, Laragh JH.

Relation of left ventricular mass and geome-try to morbidity and mortality in hypertension.

Ann Intern Med. 1991;114:342-352.

3. Ghali JK, Liao Y, Simmons B, Castaner A, Cao G, Cooper RS.

The prognostic role of left ventricular hyper-trophy in patients with or without coronaryartery disease.

Ann Intern Med. 1992;117:831-836.

4. Bikkina M, Levy D, Evans JC, et al.

Left ventricular mass and the risk of stroke inan elderly cohort: the Framingham Study.

JAMA. 1994;272:33-36.

5. Ross J Jr, Franklin D, Sasayama S.

Preload, afterload and the role of afterloadmismatch in the descending limb of cardiacfunction.

Eur J Cardiol. 1976;4 (suppl):77-86.

6. Harris CN, Aronow WS, Parker DP,Kaplan MA.

Treadmill stress test in left ventricular hypertrophy.

Chest. 1973;63:353-357.

7. Goodwin JR.

Hypertrophic diseases of the myocardium.

Prog Cardiovasc Dis. 1973;16:199-238.

8. Laughlin MH, Korthuis RJ, DunckerDJ, Bache RJ.

Regulation of blood flow to cardiac andskeletal muscle during exercise. In: RowellLB, Shepherd JT, eds. Exercise: regulationand integration of multiple systems.

New York, NY: Oxford University Press1996:705-769.



25



9. Bache RJ, Dai XZ, Alyono D, Vrobel TR, Homans DC.

Myocardial blood flow during exercise indogs with left ventricular hypertrophy pro-duced by aortic banding and perinephritichypertension.

Circulation. 1987;76:835-842.

10. Bache RJ, Dai XZ.

Myocardial oxygen consumption during exercise in the presence of left ventricularhypertrophy secondary to supravalvularaortic stenosis.

J Am Coll Cardiol. 1990;15:1157-1164.

11. Intengan HD, Schiffrin EL.

Structure and mechanical properties of re-sistance arteries in hypertension: role of ad-hesion molecules and extracellular matrixdeterminants.


12. Friehs I, Moran AM, Stamm C, et al.

Promoting angiogenesis protects severelyhypertrophied hearts from ischemic injury.

Ann Thor Surg. 2004;77:2004-2011.

13. Schwartzkopff B, Brehm M,Mundhenke M, Strauer BE.

Repair of coronary arterioles after treatmentwith perindopril in hypertensive heart disease.


14. Brush JE Jr, Faxon DP, Salmon S,Jacob AK, Ryan TJ.

Abnormal endothelial-dependent coronaryvasomotion in hypertensive patients.


15. Akinboboye OO, Chou RL,Bergmann SR.

Augmentation of myocardial blood flow inhypertensive heart disease by angiotensinantagonists.


16. Kozakova M, Galetta F, GregoriniL, et al.

Coronary vasodilator capacity and epicardialvessel remodeling in physiological and hyper-tensive hypertrophy.


17. Tomanek RJ, Palmer PJ, Peiffer JL,Schreiber KL, Eastham CL, Marcus ML.

Morphometry of canine coronary arteries,arterioles, and capillaries during hyperten-sion and left ventricular hypertrophy.

Circ Res. 1986;58:38-46.

18. Tomanek RJ, Aydellote MR, Butters CA.

Late-onset renal hypertension in old ratsalters myocardial microvessels.

Am J Physiol. 1990;259:H1681-H1687.

19. Brilla CG, Janicki JS, Weber KT.

Impaired diastolic function and coronaryreserve in genetic hypertension: role of in-terstitial fibrosis and medial thickening ofintramyocardial coronary arteries.

Circ Res. 1991;69:107-115.

20. Sun Y, Weber KT.

Cardiac remodeling by fibrous tissue: roleof local factors and circulating hormones.

Ann Med. 1998;30(suppl 1):3-8.

21. Vatner SF, Hittinger L.

Coronary vascular mechanism involved indecompensation from hypertrophy to heartfailure.

J Am Coll Cardiol. 1993;22(suppl A):34A-40A.

22. Vogt M, Strauer BE.

Systolic ventricular dysfunction and heartfailure due to coronary microangiopathy inhypertensive heart disease.

Am J Cardiol. 1995;76:48D-53D.

23. Iemitsu M, Miyauchi T, Maeda S,et al.

I. Physiological and pathological cardiachypertrophy induce different molecular phe-notypes in the rat.

Am J Physiol Reg Integr Comp Physiol.2001;281:R2029-R2036.

24. Shubeita HE, McDonough PM,Harris AN, et al.

Endothelin induction of inositol phospholipidhydrolysis, sarcomere assembly, and cardiacgene expression in ventricular myocytes: aparacrine mechanism for myocardial genehypertrophy.

J Biol Chem. 1990;265:20555-20562.

25. Yamazaki T, Komuro I, Kudoh S,et al.

Angiotensin II partly mediates mechanicalstress-induced cardiac hypertrophy.

Circ Res. 1995;77:258-265.

26. Funck RC, Wilke A, Rupp H, Brilla CG.

Regulation and role of myocardial collagenmatrix remodeling in hypertensive heartdisease.

Adv Exp Med Biol. 1997;432:35-44.

27. Ganau A, Devereux RB, RomanMJ, et al.

Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension.

J Am Coll Cardiol. 1992;19:1550-1558.

28. Ganau A, Devereux RB, PickeringTG, et al.

Relation of left ventricular hemodynamicload and contractile performance to leftventricular mass in hypertension.


29. Ganau A, Arru A, Saba PS, et al.

Stroke volume and left heart anatomy inrelation to plasma volume in essential hypertension.


30. Ganau A, Saba PS, de Simone G,Roman MJ, Realdi G, Devereux RB.

Aging induces left ventricular concentric remodeling in normotensive subjects.

J Hypertens. 1995;13:1818-1822.

31. Krumholz HM, Larson M, Levy D.

Prognosis of left ventricular geometric pat-terns in the Framingham Heart Study.


32. Sekiya M, Funada J, Suzuki J,Watanabe K, Miyagawa M, Akutsu H.

The influence of left ventricular geometryon coronary vasomotion in patients with essential hypertension.

Am J Hypertens. 2000;13:789-795.

33. Pech HJ, Witte J, Romaniuk R,Parsi RA, Portstmann W.

Left ventricular mass in coronary arterydisease without hypertension: haemody-namic and angiocardiographic study.

Br Heart J. 1973;36:362-367.

26



27

34. Gould KL, Lipscomb K, HamiltonGW, Kennedy JW.

Left ventricular hypertrophy in coronary artery disease. A cardiomyopathy syndromefollowing myocardial infarction.

Am J Med. 1973;55:595-601.

35. Anversa P, Loud AV, Levicky V,Guideri G.

Left ventricular failure induced by myocar-dial infarction. I. Myocyte hypertrophy.

Am J Physiol. 1985;248:H876-H882.

36. Fujita M, Mikuniya A, McKownDP, McKown MD, Franklin D.

Regional myocardial volume alterations in-duced by brief repeated coronary occlusionsin conscious dogs.

J Am Coll Cardiol. 1988;12:1048-1053.

28


esearch over the past sev-eral decades has identifiedthe dynamic nature of col-lagen turnover in normal

and diseased tissues and an ever-expanding array of matrix functionsthat include the initiation and mod-ulation of tissue growth and repair.1

In kidneys, lungs, and liver, fibrosisis considered a final common path-way to organ failure. This holds truefor the heart as well.2 Given the im-portant role of fibrous tissue in lead-ing to cardiac failure, noninvasivemethods are being developed to ad-dress fibrous tissue formation anddegradation in patients with chroniccardiovascular diseases. In addition,the concept is emerging that man-agement of these patients musttarget the adverse structural cardiacremodeling associated with thesediseases.

MYOCARDIAL FIBROSIS ISPRESENT IN THE HUMAN

HYPERTENSIVE HEART

A number of studies performed inpostmortem human hearts3-5 andendomyocardial human biopsies6-8

have shown that myocardial colla-gen volume fraction, a morphomet-ric measure of the amount of tissuecollagen, is consistently increasedin hypertensive patients with leftventricular hypertrophy comparedwith normotensive controls. Further-more, immunohistochemical analy-sis shows exaggerated accumulation

of fibrillar collagen types I and IIIwithin the myocardial interstitiumand surrounding intramural coronaryarteries and arterioles (Figure 1).9Hypertensive myocardial fibrosis is the result of increased collagentype I and III synthesis by fibroblastsand unchanged or decreased extra-cellular collagen degradation bymatrix metalloproteinases.10 Hemo-dynamic and nonhemodynamic fac-tors are involved in this disequilib-rium in collagen metabolism thatoccurs in hypertension.10 In this re-gard, various lines of evidence sug-gest that, besides hypertension, an-giotensin II also plays a major rolein the development of hypertensivemyocardial fibrosis.11

MYOCARDIAL FIBROSISHAS A DETRIMENTALCLINICAL IMPACT IN

HYPERTENSION

Although several other risk factorsfor congestive heart failure havebeen identified, arterial hyperten-sion is the most common risk factorin the general population.12 Sever-al arguments support the conceptthat myocardial fibrosis has a par-ticularly important influence in thetransition from compensated leftventricular hypertrophy to heart fail-ure in patients with hypertensiveheart disease.13 Firstly, interstitialfibrosis compromises the rate of re-laxation, diastolic suction, and pas-sive stiffness, contributing to im-

How important is it to assess and attempt to control cardiac fibrosis in hypertension? Javier Díez, MD, PhD

Professor of Vascular Medicine and Director - Division of Cardiovascular Pathophysiology - Center for Applied Medical Research and University Clinic - School of Medicine - University of Navarra - Pamplona - SPAIN

Keywords: arterial hypertension; collagen;echoreflectivity; fibrosis; hypertensive heart disease; left ventricular hypertrophy; peptide Address for correspondence:Javier Díez, Professor of Vascular Medicine andDirector, Division of Cardiovascular Pathophysiol-ogy, Center for Applied Medical Research andUniversity Clinic, School of Medicine, Universityof Navarra, C/Pío XII, 55, 31008, Pamplona, Spain.(e-mail: [email protected])


RFibrous tissue accumulation is an integral feature of the adversestructural remodeling of myocardialtissue following a cardiac insult.Given the importance of fibroustissue in leading to myocardialdysfunction and failure, noninva-sive assessment of fibrosis couldprove a clinically useful tool, par-ticularly given the potential forcardioprotective and cardiorepara-tive pharmacological strategies.This approach represents an excit-ing and innovative strategy, andavailable data set the stage forlarge-scale and long-term trials,where this noninvasive assessmentof myocardial fibrosis in patientswith hypertensive heart diseaseand other cardiac diseases couldprove useful.

paired diastolic function. Secondly,since neither the collagen networknor the fibroblasts contribute to sys-tolic contraction, increased collagendeposition and fibroblast volumemeans that systolic work is beingperformed by a smaller proportionof the cardiac mass, thereby con-tributing to systolic dysfunction.

Myocardial fibrosis also predisposesto diminished coronary reserve andventricular arrhythmias, which inturn, confer increased risk of adversecardiovascular events to patientswith hypertensive heart disease.13

The overall amount of perivascularfibrosis is a limiting factor for vas-cular distensibility. On the otherhand, interstitial fibrosis would facil-itate arrhythmias both by anatomicuncoupling due to myocardial het-erogeneity and by a reentry mecha-nism generated by the zigzag propa-gation of the transverse waveform.

MYOCARDIAL FIBROSISMUST BE DETECTED IN

HYPERTENSIVE PATIENTS

Assessment of the extent of collagenaccumulation in myocardial tissuemay be relevant in both improvingthe diagnosis of hypertensive heartdisease and optimizing the preven-tion of heart failure and adverse car-diovascular events in patients withthis condition.

Although microscopic examinationof cardiac biopsies is the most reli-able method for documenting andmeasuring myocardial fibrosis, it isan invasive methodology unadaptedto large-scale application, and thatmay be subject to sampling error.Thus, the development of noninva-sive methods to document the

presence of myocardial fibrosis inhypertensive patients would havebroader application.

Tissue characterization by ultraso-nography refers to the detailed eval-uation of the entire reflected ultra-sound signal in an effort to extractinformation regarding actual tissuecharacter. A correlation between al-terations in echoreflectivity, namely,diminution in the cyclic variation(CV) in returning ultrasound signalor backscatter signal, and histolog-ically assessed collagen volumefraction was recently shown in theheart of hypertensive patients,6,14

suggesting that in these patientscollagen content is the major deter-minant of regional echo intensity.Furthermore, as shown by the re-ceiver operating characteristics curve(ROC) analysis, CV in the apex is ahighly sensitive and specific param-eter in the identification of severemyocardial fibrosis in patients withhypertensive heart disease (Figure 2and Table I, page 30).

On the other hand, emerging exper-imental and clinical experience sug-gests promising prospects for theuse of radioimmunoassay of variousserum peptides arising from themetabolism of collagen types I andIII in arterial hypertension.15 Morespecifically, the measurement ofserum concentrations of carboxy-

terminal propeptide of procollagentype I or PICP (a peptide that iscleaved from procollagen type I dur-ing the synthesis of fibril-formingcollagen type I) has been shown tocorrelate directly with collagen vol-ume fraction in patients with hyper-tensive heart disease.16 Interesting-ly, as shown by ROC-curve analysis,serum PICP possess high sensitivityand specificity for predicting severemyocardial fibrosis in hypertensivepatients (Figure 2 and Table I). Inaddition, changes in serum PICPinduced by antihypertensive treat-ment have been shown to correlatedirectly with changes in collagenvolume fraction in patients with hy-pertensive heart disease.17 Thus,measurement of PICP may provideindirect diagnostic information onboth the extent of myocardial fibro-sis and the ability of antihyperten-sive treatment to diminish collagentype I synthesis and reduce myocar-dial fibrosis in hypertensive patients.Interestingly, in a recent study, wedemonstrated that the CV of back-

29


How important is it to control cardiac fibrosis in hypertension? - Díez

Figure 1. Histological section of myocardial biopsy specimen from a patient with essential hypertension, showing perivascular (left panel, col-lagen volume fraction = 8.65%) and interstitial (right panel, collagen volume fraction = 8.05%) severe fibrosis. (Picrosirius red staining � 20).

30

scatter signal is abnormally dimin-ished in those patients with hyper-tensive heart disease and abnor-mally high serum concentrations ofPICP.18 Furthermore, the associationof these two parameters predictedwith great accuracy the presence ofsevere myocardial fibrosis in hyper-tensive patients (Table I). Thus, thecombination of these two method-ologies may be useful for the non-invasive assessment of cardiac fibro-sis in hypertensive heart disease.

MYOCARDIAL FIBROSIS CAN BE REDUCED IN

HYPERTENSIVE PATIENTS

Recent biopsy-based clinical stud-ies provide evidence that other goalsbeyond reduction in blood pressure

should be set in hypertensive pa-tients, such as repair of cardiac fi-brosis.17,19-21 Schwartzkopff et al19

reported that treatment with perin-dopril induced a significant decreasein periarteriolar fibrosis. Brilla et al20

showed that treatment with lisino-pril, but not with hydrochloroth-iazide, reduced myocardial fibrosis,independently from blood pressurecontrol and left ventricular hyper-trophy regression, and that this wasassociated with improved left ven-tricular diastolic function. We haveshown that treatment with losartanfor 1 year was associated with inhi-bition of collagen type I synthesisand regression of myocardial fibro-sis in patients with essential hyper-tension (Figure 3).17 In contrast,hypertensive patients treated with

amlodipine did not show any sig-nificant changes in collagen type Imetabolism or myocardial fibrosis.Interestingly, the effect of the twocompounds on blood pressure wassimilar during the entire treatmentperiod. More recently, we reportedthat the ability of losartan to in-duce regression of severe myocar-dial fibrosis was independent of itscapacity to reduce blood pressureor left ventricular mass, but wasassociated with a decrease in my-ocardial stiffness in hypertensivepatients.21 These data confirm ex-perimental studies in rats with genetic hypertension where phar-macological interference with theproduction and actions of angio-tensin II has proved to be effectivein reversing cardiac fibrosis, overand above the antihypertensive ef-ficacy.22,23

CONCLUSIONS

In hypertensive heart disease, it isnot the quantity of myocardium, butrather its quality that accounts forthe increased risk of adverse car-diovascular events. Thus, strategiesdirected toward the identificationof the changes in myocardial struc-ture (eg, fibrosis) involved in thetransition from compensated leftventricular hypertrophy to heart fail-ure are likely to offer the greatestpromise of reducing the incidenceof congestive heart failure and itsassociated mortality among hyper-tensive patients.

On the other hand, current manage-ment of hypertension should notsimply focus on reduction in blood



Specificity

Sensi

tivi

ty

0.3 0.40 0.1 0.2 0.5 0.6 0.7 0.8 0.9 1.0

1.0

0.9

0.8

0.7

0.6

0.5

0.3

0.4

0.1

0.2

0

CV

PICP

Figure 2. Receiver operating characteristics(ROC) curve for carboxy-terminal propeptide ofprocollagen type I (PICP) (area under the curve =0.76±0.10, mean±SEM) and cyclic variation (CV)of backscatter in the apex (area under the curve =0.76±0.08), plotted for various cutoff values, todetermine severe myocardial fibrosis. (Adaptedfrom references 16 and 18).

Cutoff Sensitivity Specificity Relative riskParameters value (%) (%) (95% CI)

PICP 127 µg/L 75 78 4.80 (1.19-19.30)

CV 2.90 dB 75 63 2.50 (0.72-34.70)

PICP+CV 126 µg/L + 2.65 dB 95 81 6.50 (2.31-31.05)

Table I. Overall performance of different parameters for predicting hypertensives with severe fibrosisaccording to receiver operating characteristics (ROC) curves.

Abbreviations: CI, confidence interval; CV, cyclic variation of the backscatter signal in the apex;PICP, carboxy-terminal propeptide of procollagen type I.

pressure and left ventricular mass,it must also target the adverse struc-tural myocardial remodeling that ispresent in hypertensive heart dis-ease.24 Thus, as stated recently bythe European Society of Hyperten-sion (ESH) and the European Soci-ety of Cardiology (ESC) in theirguidelines for the management ofarterial hypertension, “future stud-ies should investigate treatment-induced effects on indices of colla-gen content or fibrosis of the leftventricular wall, rather than on itsmass only.”25

In this conceptual framework, thedata reviewed here set the stage forlarge-scale and long-term clinicaltrials aimed at determining whetherchanges in the CV of ultrasonic back-scatter signal and/or serum concen-tration of PICP are linked to changesin cardiac function and prognosis inpatients with hypertension.

REFERENCES

1. Mutsaers SE, Bishop JE, McGrouther G, Laurent GJ.

Mechanisms of tissue repair: from woundhealing to fibrosis.

Int J Biochem Cell Biol. 1997;29:5-17.

2. Weber KT, Brilla CG, Janicki JS.

Myocardial fibrosis: functional significanceand regulatory mechanisms.

Cardiovasc Res. 1993;27:341-348.

3. Tanaka M, Fujiwara H, Onodera T,Wu DJ, Hamashima Y, Kawai C.

Quantitative analysis of myocardial fibrosisin normals, hypertensive hearts, and hyper-trophic cardiomyopathy.

Br Heart J. 1986;55:575-581.

4. Olivetti G, Melissari M, Balbi T, et al.

Myocyte cellular hypertrophy is responsiblefor ventricular remodeling in the hypertro-phied heart of middle aged individuals inthe absence of cardiac failure.

Cardiovasc Res. 1994;28:1199-1208.

5. Rossi MA.

Pathologic fibrosis and connective tissuematrix in left ventricular hypertrophy dueto chronic arterial hypertension in humans.

J Hypertens. 1998;16:1031-1041.

6. Ciulla M. Paliotti R, Hess DB, et al.

Echocardiographic patterns of myocardialfibrosis in hypertensive patients: endomyocar-dial biopsy versus ultrasonic tissue charac-terization.


7. Schwartzkopff B, Brehm M,Mundehenke M, Strauer BE.



8. Brilla CG, Funck RC, Rupp RH.

Lisinopril-mediated regression of myocardialfibrosis in patients with hypertensive heartdisease.

Circulation. 2000;102:1388-1393.

9. Pardo Mindán FJ, Panizo A.

Alterations in the extracellular matrix ofthe myocardium in essential hypertension.

Eur Heart J. 1993;14(suppl J):12-14.

10. Weber KT.

Fibrosis and hypertensive heart disease.

Curr Opin Cardiol. 2000;15:264-272.

11. González A, López B, Querejeta R,Díez J.

Regulation of myocardial fibrillar collagenby angiotensin II. A role in hypertensiveheart disease?

J Mol Cell Cardiol. 2002;34:1585-1593.

12. Levy D, Larson MG, Vasan RS,Kannel WB, Ho KKL.

The progression from hypertension to con-gestive heart failure.

JAMA. 1996;275:1557-1562.

13. Díez J, López B, González A,Querejeta R.

Clinical aspects of hypertensive myocardialfibrosis.

Curr Opin Cardiol. 2001;16:328-335.

3131



Figure 3. Histological section of myocardial biopsy specimen from a patient with essential hypertension and myocardial fibrosis before (leftpanel, collagen volume fraction = 5.96%) and after (right panel, collagen volume fraction = 3.12%) treatment with losartan. (Picrosirius redstaining � 20).



32

14. Picano E, Pelosi G, Marzilli M, et al.

In vivo quantitative ultrasonic evaluation ofmyocardial fibrosis in humans.


15. López B, González A, Varo N,Laviades C, Querejeta R, Díez J.

Biochemical assessment of myocardial fibrosis in hypertensive heart disease.

Hypertension. 2001;38:1222-1226.

16. Querejeta R, Varo N, López B, et al.

Serum carboxy-terminal propeptide of pro-collagen type I is a marker of myocardialfibrosis in hypertensive heart disease.

Circulation. 2000;101:1729-1735.

17. López B, Querejeta R, Varo N, et al.

Usefulness of serum carboxy-terminalpropeptide of procollagen type I to assess thecardioreparative ability of antihypertensivetreatment in hypertensive patients.

Circulation. 2001;109:286-291.

18. Maceira A, Barba J, Varo N, Beloqui O, Díez J.

Ultrasonic backscatter and serum marker ofcardiac fibrosis in hypertensives.


19. Schwartzkopff B, Brehm M,Mundhenke M, et al.



20. Brilla CG, Funck RC, Rupp H.

Lisinopril-mediated regression of myocar-dial fibrosis in patients with hypertensiveheart disease.

Circulation. 2000;102:1388-1393.

21. Díez J, Querejeta R, López B,González A, Larman M, MartínezUbago JL.

Losartan-dependent regression of myocar-dial fibrosis is associated with reduction ofleft ventricular chamber stiffness in hyper-tensive patients.

Circulation. 2002;105:2512-2517.

22. Brilla CG, Janicki JS, Weber KT.

Cardioreparative effects of lisinopril in ratswith genetic hypertension and left ventricu-lar hypertrophy.

Circulation. 1991;83:1771-1779.

23. Varo N, Etayo JC, Zalba G, et al.

Losartan inhibits the post-transcriptionalsynthesis of collagen type I and reverses leftventricular fibrosis in spontaneously hyper-tensive rats.

J Hypertens. 1999:17-107-114.

24. Weber KT.

Cardioreparation in hypertensive heart disease.

Hypertension. 2001;38(pt 2):588-591.

25. Guidelines Subcommittee.

2003 European Society of Hypertension–European Society of Cardiology guidelinesfor the management of arterial hypertension.

J Hypertens. 2003;21:1011-1053.

33


eft ventricular hypertrophy(LVH) has been shown to bean important independentrisk factor for cardiovascular

morbidity and mortality.1 It also hasbeen proposed that correction ofLVH reduces the associated elevat-ed cardiovascular risk.2,3 Therefore,reduction of LVH is one importantgoal of antihypertensive treatment.This raises the question of whetherall antihypertensive medicationsare similarly effective or whethersome are superior with regard to re-duction in LVH. The aim of this re-view is to define how important arole the renin-angiotensin-aldo-sterone system (RAAS) plays in thedevelopment of LVH and to whichextent drugs blocking the RAAS canachieve regression of LVH.

PHYSIOLOGY AND PHARMACOLOGY OF

THE RAAS

Figure 1 (page 34) shows the well-known cascade of the RAAS. Thephysiological function of the RAASis to regulate blood pressure andto maintain salt and water homeo-stasis. The principal effectors of thesystem are angiotensin II and aldo-sterone. Angiotensin II is a potentvasoconstrictor and has profibrotic,hypertrophy-inducing, and growth-promoting effects on the heart aswell as other organs. It exerts itseffects through (at least) two recep-tors: the angiotensin II type 1 recep-tor (AT1) and type 2 receptor (AT2).The main effects of angiotensin IIare mediated by the AT1 receptor.

Hypertension and left ventricular hypertrophy: how much attention should we pay to the renin-angiotensin-aldosterone system?Bernhard M. W. Schmidt, MD; Roland E. Schmieder, MD

Department of Medicine IV - University of Erlangen-Nürnberg - GERMANY

Left ventricular hypertrophy (LVH)is an important independent car-diovascular risk factor. Angioten-sin II and aldosterone, the effectorsof the renin-angiotensin-aldosteronesystem (RAAS), have been foundto increase LVH in a blood-pressure–independent fashion in several an-imal models of RAAS activationand in observational studies in hu-mans. Pharmacological interven-tions interacting with the RAAS,namely, angiotensin-convertingenzyme inhibition, blockade of theangiotensin II type 1 receptor, andantagonism at the mineralocorti-coid receptor, have been shown toreduce LVH. These beneficial effectsare in addition to, and independentfrom, their blood pressure–loweringproperties and improve cardiovas-cular prognosis. The main questionto be answered in the future is whichcombination of drugs interferingwith the RAAS will prove to be mostbeneficial.

Keywords: hypertension; left ventricular hypertrophy; risk factor; RAAS; angiotensin II;ACE inhibition; prognosisAddress for correspondence:Prof Dr Roland E. Schmieder, Universität Erlan-gen-Nürnberg, Medizinische Klinik IV, Kranken-hausstraße 12, 91054 Erlangen, Germany(e-mail: [email protected])


L

SELECTED ABBREVIATIONS AND ACRONYMS

4E-LVH Eplerenone, Enalapril and Eplerenone/Enalapril–Left Ventricular Hypertrophy (study)

ARB angiotensin receptor blocker

AT1, AT2 angiotensin II type 1 (2) (receptor)

LIFE Losartan Intervention For Endpoint reduction in hypertension

LVH left ventricular hypertrophy

LVMI left ventricular mass index

MR mineralocorticoid receptor

PICχEL Preterax In a double-blind Controlled study Versus Enalapril in Left ventricular hypertrophy

RAAS renin-angiotensin-aldosterone system

VALUE Valsartan Antihypertensive Long-term Use Evaluation

34


Hypertension and LVH: how much attention should we pay to the RAAS? - Schmidt and Schmieder

Activation of the AT2 receptor hasbeen shown to be at least in part,and in some tissues completely, an-tagonistic to activation of the AT1

receptor. Aldosterone regulates re-nal sodium handling and also ex-erts profibrotic effects on the heart,kidney, and blood vessels. It actsmainly via the mineralocorticoid re-ceptor (MR), although nongenomiceffects of aldosterone are also welldescribed.4

Drugs blocking the RAAS includethe angiotensin-converting enzyme(ACE) inhibitors, selective antago-nists at the AT1 receptor (ARBs, an-giotensin receptor blockers), andantagonists at the MR (MR antago-nists). The role of renin inhibitors isnot further discussed, since at themoment orally active compoundsare not available (though aliskirenmay be, in the near future). The ef-fects of these drug classes are sim-ilar, but clearly not identical. ACEinhibitors cause a decrease in an-giotensin II levels and thereby de-creased activity at the AT1 and AT2

receptors, but they increase brady-kinin levels. ARBs cause an increasein angiotensin II levels via a nega-tive feedback loop, and therefore in-crease the activity at the AT2 recep-tor. Higher bradykinin levels andactivation of the AT2 receptor arespecific effects of ACE inhibitorsand ARBs, respectively, which mightcontribute to the effect of eitherclass in addition to RAAS blockade.This also means that ACE inhibitorsand ARBs do not have identicalpharmacological profiles.

Blockade of the MR only affects theactions of aldosterone, and leavesangiotensin II concentrations un-changed or even increased, whereasplasma aldosterone levels are in-creased. This, in turn, could promotenonclassic effects of aldosterone.

The pharmacological differences be-tween these drug classes are onereason why combination of differentdrug classes might be more effectivethan monotherapy. Another reasonfor combining various RAAS block-

ing drugs is that, over time, ACE-in-hibitor blockade of the RAAS mightbecome incomplete, leading to aloss of suppression of aldosteroneplasma levels. This phenomenon iscalled aldosterone escape and oc-curs in about one third of patientstreated with ACE inhibitors, andthus limits their effectiveness.

In the following sections, we discussthe evidence from experimentalstudies, observational human data,and clinical trials confirming therole of the RAAS in inducing LVH.

RAAS AND LVH: EXPERIMENTAL EVIDENCE

There is strong evidence from cellculture and animal experiments thatangiotensin II exerts profibrotic,hypertrophy-inducing, and growth-inducing effects, which cause hy-pertrophy of the left and right ven-tricles. The mechanisms by whichangiotensin II causes these effectsare complex and still the subject ofintensive research. These effects ap-pear to mainly result from, amongothers, an increase in transforminggrowth factor β (TGFβ) production,5

the activation of myocardial calci-neurin,6 and an increase in intracel-lular calcium.7 Although these ef-fects seem to be mediated by theAT1 receptor,8 conflicting findingshave also been reported.9

With regard to aldosterone, chronicelevation of aldosterone levels com-bined with sodium intake inducesmyocardial fibrosis in rat left andright ventricles. The observation thatfibrosis takes place even in the rightventricle argues for the concept thatthe fibrotic processes are bloodpressure–independent.10,11 Further-more, it has been proposed that aldosterone causes fibrosis and hy-pertrophy by interaction with an-giotensin II. It has been shown inaldosterone-salt–treated rats that

Angiotensinogen

MR antagonists

Angiotensin IBradykinin

Inactivefragments

Angiotensin II

Aldosterone

ACE

ACEI ARBAT1R

Renin

CathepsinCAGE, tonin

Cathepsint-PA, tonin

AT1R

MR

AT2R

Figure 1. Schematic view of the renin-angiotensin-aldosterone system (RAAS) and possible phar-maceutical interventions.

Abbreviations: ACE, angiotensin-converting enzyme; ACEI, angiotensin-converting enzyme inhibitor;ARB, angiotensin receptor blocker; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 1receptor; CAGE, chymostatin-sensitive angiotensin II–generating enzyme; MR, mineralocorticoid re-ceptor; t-PA, tissue plasminogen activator.

35

aldosterone increases AT1 receptormRNA and the ventricular densityof the AT1 receptor. Robert et alshowed that myocardial fibrosis wasalmost blunted to the same extentby ARBs as by spironolactone.12

RAAS AND LVH: OBSERVATIONAL

HUMAN DATA

Renal artery stenosis

Renal artery stenosis causes exces-sive renin release from the maculadensa, which causes activation ofthe RAAS, leading to an increase incirculating angiotensin II and aldo-sterone. Accordingly, patients withrenovascular hypertension havepronounced hypertensive end-organdamage when compared with pa-tients with essential hypertension.In one study, 32.6% of patients withrenovascular hypertension exhibitedLVH, in contrast to only 10.8% of pa-tients with essential hypertension.13

Primary hyperaldosteronism

Primary hyperaldosteronism is char-acterized by elevated aldosteronelevels accompanied by suppressedrenin and angiotensin II, thus ex-cluding significant concurrent effectsof angiotensin II. In a cross-section-al study, LVH was shown to be morepronounced and to precede otherorgan damage, eg, of eyes or kidneys,in patients with primary hyperal-dosteronism, compared with pa-tients with essential hypertension.14

Patients with Conn’s adenoma ex-hibited a greater left ventricularmass and relative wall thicknessthan patients with essential hyper-tension matched for other confound-ing determinants of left ventricularmass.15 In parallel with the exagger-ated concentric left ventricular re-modeling and mass, these patientswere characterized by an impaired

diastolic filling of the left ventricle.These studies therefore suggest ablood pressure–independent effectof aldosterone on left ventricularstructure and function.

Essential hypertension

In essential hypertension, a connec-tion between angiotensin II as wellas aldosterone and LVH has beenrepeatedly documented. In 68 other-wise healthy untreated young mild-ly hypertensive men, we showed thatpatients with angiotensin II levelshigh with respect to the correspon-ding urinary salt excretion hadgreater left ventricular mass thanpatients with relatively low angio-tensin II levels (Figure 2).16 Sincehigh sodium intake suppresses theactivity of the RAAS, our results sug-

gest that a different reactivity of theRAAS in concert with an increasedsalt intake is responsible for the de-velopment of LVH in essential hy-pertension. It has been reported thatin patients with essential hyperten-sion serum aldosterone levels areclosely related to left ventricular

mass after correction for the effectsof blood pressure.17 In a cohort ofhypertensive patients of young ageand with only mild hypertension, aclose relationship between urinaryaldosterone excretion during highsalt intake and left ventricular masswas consistently demonstrated.18

Genetic polymorphisms of the RAAS

Several linkage studies have beenperformed trying to link polymor-phisms of genes of the RAAS to hy-pertension and hypertensive end-organ damage, especially LVH. In astudy in 120 normotensive and mild-ly hypertensive young men, it wasshown that hypertensive subjectswith the –344 CC genotype of the al-dosterone synthase promoter had a

greater left ventricular end-diastolicdiameter and smaller relative wallthickness than those with the TTgenotype. The latter showed a great-er increase in urinary sodium excre-tion after oral sodium loading. Ac-cordingly, suppression of aldosteronelevels was found in hypertensive



P<0.05

600

500

400

100

200

300

Relatively low Relatively medium Relatively high

Le

ft v

en

tric

ula

r m

ass

Angiotensin II level

Figure 2. Left ventricular mass in mildly essential hypertensive patients with relative-ly high angiotensin II levels for their salt intake was significantly higher than in pa-tients with relatively low angiotensin II levels for their salt intake.

Modified from reference 16: Schmieder RE, Langenfeld MR, Friedrich A, SchobelHP, Gatzka CD, Weihprecht H. Angiotensin II related to sodium excretion modulatesleft ventricular structure in human essential hypertension. Circulation. 1996;94:1304-1309. Copyright © 1996, American Heart Association, Inc.

36

subjects with the –344 TT and –TCgenotype, but not in patients withthe CC genotype. This suggests thatdecreased ability to suppress aldo-sterone levels on salt loading islinked with early eccentric left ven-tricular remodeling in hypertensiveswith the –344 CC genotype of thealdosterone synthase promoter.19

In a similar study, it could be shownthat the +1675 G/A-polymorphism ofthe AT2 receptor is linked to LVH inyoung mildly hypertensive males.20

Blood pressure levels as potentialconfounding factors were ruled outby including 24-hour ambulatoryblood pressure into the analysis. TheWHO-MONICA (World Health Or-ganization–MONItoring trends anddeterminants in CArdiovascular dis-eases) study, a large epidemiologi-cal study in Augsburg, confirmedthe link between AT2-receptor poly-morphism and the degree of LVH.Interestingly, this AT2-receptor poly-morphism has also been found tobe a powerful prognostic marker forcoronary heart disease.21

These and other studies suggest thatpolymorphisms modulating the ac-tivity of the RAAS influence leftventricular structure. Thus, thesedata support the view that activityof the RAAS is linked to LVH.

RAAS AND LVH: THERAPEUTIC

CLINICAL TRIALS

Meta-analyses

Several meta-analyses have beenperformed, all of which consistentlyshowed that drugs blocking theRAAS are superior to conventionalantihypertensives with regard toreduction of LVH. The most recentmeta-analysis, by Klingbeil et al,22

included for the first time a largeramount of data from ARB trials. Inthis meta-analysis, 3767 patients

from 146 active treatment arms and346 patients from 17 placebo armswere included. All studies were ran-domized, double-blinded, controlled,parallel group studies, using echo-cardiography for the diagnosis. Re-sults were adjusted for blood pres-sure and treatment duration. Leftventricular mass index (LVMI) de-creased by 13% with ARBs, by 11%with calcium antagonists, by 10%with ACEIs, by 8% with diuretics, andby 6% with β-blockers (Figure 3).22

The difference in reduction of left

ventricular mass among the fiveantihypertensive drug classes wasstatistically significant (P=0.004). Inpairwise comparison between drugclasses, ARBs, calcium antagonists,and ACE inhibitors all reduced LVMIsignificantly more than β-blockers.

The LIFE study

Losartan Intervention For Endpointreduction in hypertension (LIFE)was a large-scale study in which9193 patients were randomized toan either losartan- or atenolol-basedantihypertensive regimen. The popu-lation was at high risk for cardiovas-cular events, since LVH was, besides

hypertension, the main inclusioncriterion. During a mean follow-upof 4.8 years, 11% of losartan-treatedand 13% of atenolol-treated hyper-tensive patients reached the com-posite primary end point (death,myocardial infarction, stroke), whichreflects a 13% reduction in relativerisk with losartan treatment.23 Fur-ther analyses revealed that aboutone third of the benefit of losartan,compared with atenolol, was attrib-utable to the greater reduction inLVH.

LVH was assessed by using ECG cri-teria. Losartan reduced the Cornellproduct by 10% and the Sokolow-Lyon index by 16%. The reductionswere only 4% and 8%, respectively,in the atenolol-treated group. Thiseffect became significant already 6months after the start of treatment(Figure 4a).24 Of note, this discrepanteffect between losartan and atenol-ol was evident throughout the en-tire follow-up period of 4.8 years. Inother words, the superiority of ARBsin reducing LVH does not diminishover time. Importantly, in this study,blood pressure was nearly identicalin both treatment groups. Further-more, analysis of regression lines



*

*

†

20

15

10

0

5

Diuretics β-Blockers Calciumantagonists

ACEinhibitors

Angiotensin IIreceptor

antagonists

Re

du

ctio

n in

le

ft v

en

tric

ula

r m

ass

(%

)

Figure 3. Meta-analysis of the efficacy of different antihypertensive drug classes indecreasing left ventricular mass. *P<0.05 vs �-blockers; †P<0.01 vs �-blockers.

Modified from reference 22: Klingbeil AU, Schneider M, Martus P, Messerli FH,Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass inessential hypertension. Am J Med. 2003;115:41-46. Copyright © 2003, Elsevier, Inc.

37



comparing changes in LVH clearlyshow the pressure independence ofthese effects (Figure 4b).24 There-fore, the results of this study reflecta blood pressure–independent ef-fect of RAAS blockade on LVH com-pared with β-blockade.

The 4E-LVH Study

In this small study (4E-LVH, Eplere-none, Enalapril and Eplerenone/Enalapril–Left Ventricular Hyper-trophy study), monotherapy withenalapril 40 mg (n=54) or the new

MR antagonist eplerenone 200 mg(n=50) was compared with the com-bination of both (enalapril 10 mg,eplerenone 200 mg). Left ventricu-lar mass was assessed by magneticresonance imaging (MRI), which isable to assess changes in LVH withvery high sensitivity. Eplerenoneand enalapril reduced left ventricu-lar mass similarly, by 14.5±3.4 g and19.7±3.2 g, respectively. The combi-nation therapy reduced left ventric-ular mass by 27.2±3.4 g. This de-crease was significantly greater thanwith eplerenone alone (P=0.007),whereas this difference was not sig-nificant (P=0.107) compared withenalapril. These data suggest thatcombination therapy to block theRAAS might be more effective thanjust blocking single steps of the cas-cade (Figure 5, page 38).25

The PICχEL study

Low-dose combination therapy is anew therapeutic option for the first-line therapy of hypertension. ThePreterax In a double-blind Controlledstudy Versus Enalapril in Left ven-tricular hypertrophy (PICχEL) studycompared the effect on LVH regres-sion of a low-dose combination ofperindopril 2 mg and indapamide0.625 mg with enalapril 10 mg mono-therapy in a parallel group, dou-ble-blinded, randomized trial with556 patients with LVH at baseline.To achieve blood pressure control,doses could be increased up toperindopril 8 mg and indapamide2.5 mg or enalapril 40 mg. After anobservation period of 52 weeks,perindopril/indapamide therapyhad lowered LVMI by 13.6%, where-as enalapril alone had loweredLVMI by 3.9% only (P<0.001). Thisgreater LVMI reduction remainedsignificant, even after adjustmentfor the greater blood pressure re-duction obtained with the perindo-pril/indapamide combination ver-sus enalapril.26,27

Figure 4. (A) Prevalence of left ventricular hypertrophy (LVH) during the Losartan InterventionFor Endpoint reduction in hypertension (LIFE) study as assessed by the Cornell product. (B) Bloodpressure–independent effect of losartan versus atenolol of LVH in the LIFE trial shown by the down-ward shift of the ∆ Cornell product / ∆ blood pressure regression line.

Modified from reference 24: Okin PM, Devereux RB, Jern S, et al. Losartan Intervention for End-point reduction in hypertension Study Investigations. Regression of electrocardiographic left ventricu-lar hypertrophy by losartan versus atenolol: the Losartan Intervention for Endpoint reduction in Hy-pertension (LIFE) Study. Circulation. 2003;108:684-690. Copyright © 2003, American HeartAssociation, Inc.

P=0.879P<0.001

P<0.001P<0.001 P<0.001 P<0.001 P<0.001 P<0.001

Baseline 6 Months 1 Year 2 Years 3 Years 4 Years 5 Years Last

100

80

60

0

20

Pre

vale

nce

of

LVH

(%

)

Cornell Product LVH

40

Losartan

Atenolol

A

∆ Systolic blood pressure (mm Hg)

∆ C

orn

ell P

rod

uct

(m

m•m

s)

–60–120 –100 –80 –20 20 60

500

400

300

200

100

0

–100

–200

–300

–400

–500

–600

–700

–800

LosartanAtenolol

–40 0 40

B

38



The VALUE trial

Valsartan Antihypertensive Long-term Use Evaluation (VALUE) wasa large-scale trial comparing theeffects of valsartan and amlodipineon cardiovascular outcome in 15 245hypertensive patients at high car-diovascular risk. This study failed toshow a superiority of the ARB withregard to the combined cardiac endpoint and confirmed the beneficialeffects on development of conges-tive heart failure, although the val-sartan-treated group had a worseblood pressure control.28 To date,no data about the effects of thesetwo drugs on LVH are yet available.Furthermore, inadequate bloodpressure control has been identi-fied as a determinant of LVH in theVALUE trial.29

CONCLUSION

There is now strong evidence forspecific blood pressure–independ-ent effects of angiotensin II and aldosterone on the myocardium.Thus, in patients with LVH, weshould pay much attention toachieving adequate blockade of the RAAS.

The main question to be answeredin the future is which combinationof drugs interfering with the RAASwill achieve the most beneficial effects. Finally, the VALUE trial re-minds us that, alongside the favor-able effects of RAAS blockade, whichexceed the effect of blood pressurelowering alone, strict blood pres-sure control is the most importantissue of antihypertensive therapy.

REFERENCES

1. Schillaci G, Verdecchia P, Porcellati C, Cuccurullo O, Cosco C,Perticone F.

Continuous relation between left ventricularmass and cardiovascular risk in essentialhypertension.


2. Muiesan ML, Salvetti M, Rizzoni D,Castellano M, Donato F, Agabiti-Rosei E.

Association of change in left ventricularmass with prognosis during long-term anti-hypertensive treatment.

J Hypertens. 1995;13:1091-1095.

3. Verdecchia P, Angeli F, Borgioni C,et al.

Changes in cardiovascular risk by reductionof left ventricular mass in hypertension: a meta-analysis.

Am J Hypertens. 2003;16(11 pt 1):895-899.

4. Schmidt BMW, Oehmer S, Delles C,et al.

Rapid nongenomic effects of aldosterone onhuman forearm vasculature.


5. Schultz Jel J, Witt SA, Glascock BJ,et al.

TGF-�1 mediates the hypertrophic cardio-myocyte growth induced by angiotensin II.

J Clin Invest. 2002;109:787-796.

6. Nagata K, Somura F, Obata K, et al.

AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats.


7. Ostrom RS, Naugle JE, Hase M, et al.

Angiotensin II enhances adenylyl cyclasesignaling via Ca2+/calmodulin. Gq-Gs cross-talk regulates collagen production in cardiacfibroblasts.

J Biol Chem. 2003;278:24461-24468.

8. Unger T.

The role of the renin-angiotensin system inthe development of cardiovascular disease.

Am J Cardiol. 2002;89(2A):3A-9A.

0

EPL

Change in left

ve

ntr

icula

r m

ass

(g)

(n=50)ENAL(n=54)

EPL/ENAL(n=49)

–10

–20

–30

–40

‡

*†

–14.5

–19.7

–27.2

Figure 5. Change in left ventricular mass in the Eplerenone, Enalapriland Eplerenone/Enalapril– Left Ventricular Hypertrophy (4E-LVH) study.EPL = eplerenone, ENAL = enalapril; *P<0.007 vs eplerenone; †P=0.107vs enalapril; ‡P=0.258 vs enalapril.

Modified from reference 25: Pitt B, Reichek N, Willenbrock R, et al.Effects of eplerenone, enalapril, and eplerenone/enalapril in patients withessential hypertension and left ventricular hypertrophy: the 4E-left ven-tricular hypertrophy study. Circulation. 2003;108:1831-1838. Copyright© 2003, American Heart Association, Inc.

9. Ichihara S, Senbonmatsu T, PriceE Jr, Ichiki T, Gaffney FA, Inagami T.

Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-inducedhypertension.

Circulation. 2001;104:346-351.

10. Brilla CG, Weber KT.

Reactive and reparative myocardial fibrosisin arterial hypertension in the rat.


11. Brilla CG, Weber KT.

Mineralocorticoid excess, dietary sodium,and myocardial fibrosis.

J Lab Clin Med. 1992;120:893-901.

12. Robert V, Heymes C, Silvestre JS,Sabri A, Swynghedauw B, Delcayre C.

Angiotensin AT1 receptor subtype as a car-diac target of aldosterone—Role in aldos-terone-salt induced fibrosis.


13. Losito A, Fagugli RM, Zampi I, et al.

Comparison of target organ damage in renovascular and essential hypertension.

Am J Hypertens. 1996;9:1062-1067.

14. Shigematsu Y, Hamada M,Okayama H, et al.

Left ventricular hypertrophy precedes other tar-get-organ damage in primary aldosteronism.


15. Rossi GP, Sacchetto A, Pavan E,et al.

Remodeling of the left ventricle in primaryaldosteronism due to Conn’s adenoma.

Circulation. 1997;95:1471-1478.

16. Schmieder RE, Langenfeld MR,Friedrich A, Schobel HP, Gatzka CD,Weihprecht H.

Angiotensin II related to sodium excretionmodulates left ventricular structure in human essential hypertension.

Circulation. 1996;94:1304-1309.

17. Duprez DA, Bauwens FR,Buyzere ML, et al.

Influence of arterial blood pressure and al-dosterone on left ventricular hypertrophy inmoderate to essential hypertension.

Am J Cardiol. 1993;71:17A-20A.

18. Schlaich MP, Schobel HP, HilgersK, Schmieder RE.

Impact of aldosterone on left ventricularstructure and function in young normoten-sive and mildly hypertensive subjects.

Am J Cardiol. 2000;85:1199-1206.

19. Delles C, Erdmann J, Jacobi J, et al.

Aldosterone synthase (CYP11B2) –344 C/Tpolymorphism is associated with left ventricu-lar structure in human arterial hypertension.


20. Schmieder RE, Erdmann J, DellesC, et al.

Effect of the angiotensin II type 2-receptorgene (+1675 G/A) on left ventricular struc-ture in humans.


21. Jones A, Dhamarit SS, Payne JR,et al.

Genetic variants of angiotensin II receptorsand cardiovascular risk in hypertension.


22. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE.

A meta-analysis of the effects of treatmenton left ventricular mass in essential hyper-tension.

Am J Med. 2003;115:41-46.

23. Dahlof B, Devereux RB, KjeldsenSE, et al; LIFE Study Group.

Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.

Lancet. 2002;359:995-1003.

24. Okin PM, Devereux RB, Jern S,et al; Losartan Intervention for End-point reduction in hypertension StudyInvestigations.

Regression of electrocardiographic left ventric-ular hypertrophy by losartan versus atenolol:the Losartan Intervention for Endpoint re-duction in Hypertension (LIFE) Study.

Circulation. 2003;108:684-690.

25. Pitt B, Reichek N, Willenbrock R,et al.

Effects of eplerenone, enalapril, and eplere-none/enalapril in patients with essential hy-pertension and left ventricular hypertrophy:the 4E-left ventricular hypertrophy study.

Circulation. 2003;108:1831-1838.

26. Gosse P, Dubourg O, Gueret P, et al.

Efficacy of very low dose perindopril 2 mg/indapamide 0.625 mg combination on leftventricular hypertrophy in hypertensive patients: the P.I.C.X.E.L. study rationaleand design.

J Hum Hypertens. 2002;16:653-659.

27. Dahlöf B, Gosse P, Guéret P, et al,on behalf of the PICXEL InternationalCoordinators and Investigators Group.

The P.I.C.X.E.L study: benefits of Preteraxon LVH reduction.


28. Julius S, Kjeldsen SE, Weber M,et al; VALUE trial group.

Outcomes in hypertensive patients at highcardiovascular risk treated with regimensbased on valsartan or amlodipine: the VALUErandomised trial.

Lancet. 2004;363:2022-2031.

29. Schmieder RE, Kjeldsen SE,Julius S, Ekman S, Hua T.

Determinants of the new development of leftventricular hypertrophy on treated hyper-tensives: the VALUE-trial.




39


41

s day after day flies by, inthese increasingly hectictimes, we are busily occupiedin the office, in the ward, or

in the lab, treating patients or carryingout research, wielding stethoscopes,pills, test tubes, electrocardiographs,and the other paraphernalia of ourtrade, reassuring an anxious parent, orbreathlessly dashing off to apply thepaddles to resuscitate a patient who’sturned blue—in short, up to our earsin cardiological pursuits. So, we maywell ask, what room or time is left forthe ordinary, everyday, romantic visionof the heart—ultimately, the only onethat really counts—the antithesis ofthe charts in Gray’s anatomy, of theabstract shapes revealed by x rays orscans, or of the garish mass pulsatingduring open-chest surgery: I am talkingabout the classic, card-deck, valentine,Cupid’s arrow heart—in short: ♥ ! Ofcourse such considerations hold truenot only for the cardiologist, but like-wise for the gynecologist, the pediatri-cian, the psychiatrist: through the veilof disease, are we still able to marvelabout the beauty of love, of a woman,of a child, or of the mind?

PHRASES, IDIOMS,SAYINGS, PROVERBS

Let us, then, stray a bit from our narrowfield of interest, and look at the heartfrom a linguistic perspective: no organ

has inspired so many phrases, idioms,sayings, and proverbs, a sure sign of itsimportance in our collective wisdom.Take your pick from the following.

“To love with all one’s heart”; “She isso kind at heart”; I have your best in-terests at heart”; “You broke my heart”;“Sick at heart”; “She knew him by heart”;“Why did he have a change of heart?”;“He wears his heart on hissleeve”; He is so close tomy heart”; “Take heart!”; “Idrank to my heart’s content”;“Cross my heart and hopeto die”; I love you from thevery bottom of my heart”;“I♥NY”; I♥Huckabee’s”;“This gives me much heart”;

“I didn’t have the heart totell her”; “His heart is inthis project” “Take care youdon’t lose heart”; “Shepoured out her heart to hermother”; “His heart was inhis mouth as he pushedthe door open”; “My heartsinks”; “This person surelyhas his heart in the rightplace”; “He had his heartset on doing things right”;“Father took heart fromthe good news”; “You re-ally shouldn’t take this somuch to heart”; “This storytugs at my heartstrings”;

“What a heartthrob he is!” “How veryheart-warming!” “Let’s have a heart-to-heart discussion”. “Absence makesthe heart grow fonder”; “Cold hands,warm heart”; “The way to a man’sheart is through his stomach”; “Faintheart never won fair lady; “A heart ofgold”; “In one’s heart of hearts”; “Thiswarms the cockles of my heart”; “Whatthe eye doesn’t see, the heart doesn’t

Address for correspondence:Frederick Scheffler, MD, Ramsey County Lane,St Paul, Minnesota, USA


A

Heart and LiteratureAnother kind of heart

Frederick Scheffler, MDRamsey County Lane - St Paul - Minnesota - USA

The anatomical heart:Anatomia Reformata, by Thomas Bartholin, published at The Hague, Netherlands by Adrien Vlacq, in 1660. © BIUM, Paris.

“He wears his heart on his sleeve.” “My heart sinks.”

© M

arc

M.,

2005

.

grieve over”; “To win somebody’sheart”; “To harden one’s heart”; “aheavy/light heart”; “My heart bleedsfor you”; “His heart missed a beat”;“Her head should rule her heart”;

You can surely think of plenty more…

POETRY

Poetry is the true haven of the heart;the following quotations are merelyintended to whet your appetite andstart you off on your own “ausculta-tion” of the bards of the heart.

And what shoulder, and what art,Could twist the sinews of thy heart?And when thy heart began to beat,What dread hand? and what dread

feet?William Blake (1757-1827)

Songs of Experience: The Tiger

Be near me when my light is low,When the blood creeps, and the

nerves prickAnd tingle; and the heart is sick,And all the wheels of Being slow.

Alfred Tennyson (1809-1892)In Memoriam A. H. H. Canto 50

I pray thee leave, love me no more,Call home the heart you gave me,I but in vain the saint adore,That can, but will not, save me.

Michael Drayton (1563-1631)To His Coy Love

The heart has its reasons which rea-son knows nothing of. (Le cœur a sesraisons que la raison ne connaît pas).

Blaise Pascal (1623-1662)Pensées, sect. 4, No. 211

The desires of the heart are as crooked as corkscrews

Not to be born is the best for manThe second best is a formal orderThe dance’s pattern, dance while

you can.Dance, dance, for the figure is easyThe tune is catching and will not stop

Dance till the stars come down with the rafters

Dance, dance, dance till you drop.W. H. Auden (1907-1973)

Death’s Echo

In the deserts of the heartLet the healing fountain start,In the prison of his daysTeach the free man how to praise.

W. H. Auden (1907-1973)In Memory of W. B. Yeats

To wake the soul by tender strokes of art

To raise the genius, and to mend the heart;

To make mankind, in conscious virtue bold,

Live o’er each scene, and be what they behold:

For this the Tragic Muse first trod the stage.

Alexander Pope (1688-1744)Prologue to Addison’s Cato

The thing on the blind side of the heart,

On the wrong side of the door,The green plant growth, menacingAlmighty lovers in the Spring;There is always a forgotten thing,And love is not secure.

G. K. Chesterton (1874-1936)The Ballad of the White Horse

WILLIAM SHAKESPEARE(1564-1616)

The greatest bard of all is, of course,the one with the capital B, the Bard,aka, Shakespeare. He makes amplereference to our favorite organ in hisworks. To name a few, and for thoseamong us who thrive on statistics,the word “heart” comes up 40 timesin the Romeo and Juliet; 28 times inA Midsummer Night’s Dream; 39times in Othello; 36 times in Hamlet;16 times in The Tempest; and 59 timesin King Lear, the all-time winner.Excerpts:

The Sonnets

Mine eye and heart are at a mortal war,How to divide the conquest of thy sight;Mine eye my heart thy picture’s sight

would bar,My heart mine eye the freedom of

that right.My heart doth plead that thou in him

dost lie,—A closet never pierc’d with crystal

eyes—But the defendant doth that play deny,And says in him thy fair appearance

lies.To side this title is impanelledA quest of thoughts, all tenants to

the heart;And by their verdict is determinedThe clear eye’s moiety, and the dear

heart’s part:—As thus; mine eye’s due is thy

outward part,—And my heart’s right, thy inward

love of heart.Sonnet 46

Much Ado About Nothing

He hath a heart as sound as a bell, andhis tongue is the clapper: for what hisheart thinks his tongue speaks.

Act III, scene 2BeatriceYou have stayed me in a happy hour. Iwas about to protest that I loved you.BenedickAnd do it with all thy heart.


Another kind of heart - Scheffler

42

Poet and writer W. H. Auden(1907-1973). © Bettmann/CORBIS.

43

BeatriceI love you with so much of my heartthat none is left to protest.

Act IV, scene 1

Othello

Were I the Moor, I would not be Iago:In following him, I follow but myself;Heaven is my judge, not I for love

or duty,But seeming so, for my peculiar end:For when my outward action doth

demonstrateThe native act and figure of my heartIn compliment extern, ‘tis not long

afterBut will I wear my heart upon my

sleeveFor daws to peck at: I am not what I am.

Act I, scene I

Julius Caesar

By heaven, I had rather coin my heart,And drop my blood for drachmas,

than to wringFrom the hard hands of peasants

their vile trashBy any indirection.

Act IV, scene 3

King Lear

A servingman, proud in heart andmind; that curled my hair, wore glovesin my cap; serv’d the lust of my mis-tress’ heart and did the act of darknesswith her; swore as many oaths as Ispake words, and broke them in thesweet face of heaven; one that sleptin the contriving of lust, and wak’d todo it. Wine lov’d I deeply, dice dearly;and in woman out-paramour’d theTurk. False of heart, light of ear, bloodyof hand; hog in sloth, fox in stealth,wolf in greediness, dog in madness,lion in prey. Let not the creaking ofshoes nor the rustling of silks betraythy poor heart to woman. Keep thyfoot out of brothel, thy hand out ofplacket, thy pen from the lender’s book,and defy the foul fiend. Still throughthe hawthorn blows the cold wind; sayssuum, mun, hey, no, nonny. Dolphinmy boy, my boy, sessa! let him trot by.

Act III, scene 4

Macbeth

I would not have such a heart in mybosom for the dignity of the wholebody.

Act V, scene 1

Romeo and Juliet

RomeoO, she doth teach the torches to burn

bright!It seems she hangs upon the cheek

of nightLike a rich jewel in an Ethiope’s ear;Beauty too rich for use, for earth

too dear!So shows a snowy dove trooping

with crows,As yonder lady o’ver her fellow shows.The measure done, I’ll watch her

place of stand,And touching hers, make blessed

my rude hand.Did my heart love till now? forswear

it, sight!For I ne’er saw true beauty till this night.

Act II, scene 1

Can I go forward when my heart is here?

Turn back, dull earth, and find thycentre out.

Act II, scene 1



WilliamShakespeare(1564-1616):engraving afterMartin Droeshout’soriginal, whichappeared in theFirst Folio editionof Shakespeare’splays in 1623. © ChrisHellier/CORBIS.

Olivia Hussey and Leonard Whiting starringin the 1968 production of Shakespeare’s

Romeo and Juliet directed byFranco Zeffirelli. © Bettmann/CORBIS.

RomeoIf my heart’s dear love…JulietWell, do not swear: although I joy

in thee,I have no joy of this contract to-night:It is too rash, too unadvised, too

sudden;Too like the lightning, which doth

cease to beEre one can say “It lightens.” Sweet,

good night!This bud of love, by summer’s ripening

breath,May prove a beauteous flower when

next we meet.Good night, good night! as sweet

repose and restCome to thy heart as that within my

breast!Act II, scene 2

Hamlet

Queen: O Hamlet! thou hast cleft my heart in twain.

Hamlet: O! Throw away the worser part of it,

And live the purer with the other half.

Act III, scene 4

Love’s Labour Lost

Had she been light like you,Of such a merry, nimble, stirring spirit,She might ha’ been a grandma ere

she died;And so may you; for a light heart

lives long.Act V, scene 2

And this last quote from Love’s LabourLost brings us back to our usual con-

cerns: counseling patients on how tochange their lifestyle to avoid stress,a risk factor for heart disease… Well, I guess it’s high time to get back towork:

Heart: A hollow muscular organ thatreceives the blood from the veins andpropels it to the arteries. In mammalsit is divided by a musculomembra-nous septum into two halves…

Stedman’s Medical Dictionary27th Edition

♥♥♥

44



46


Summaries of Ten Seminal Papers - Ferro

Electrocardiographic left ventricular hypertrophy and risk ofcoronary heart disease. The Framingham study

W. B. Kannel, T. Gordon, W. P. Castelli, J. R. Margolis

Ann Intern Med. 1970;72:813-822

erhaps the most remarkable and certainly oneof the best known epidemiological studies in thehistory of medicine is the Framingham HeartStudy. For 50 years, the residents of Framing-ham, Massachusetts, USA, have been synony-

mous with the remarkable advances made in the preventionof heart disease. Data collected from these residents haveresulted in over 1000 scientific papers, identified major riskfactors associated with cardiovascular diseases, creatednew opportunities and avenues for interventional clinicaltrials based on the study’s findings, and produced a revo-lution in preventative medicine.

One such example of a revolution in thinking generated bythe Framingham Study is represented by this paper. Formany years before, it was recognized that certain electro-cardiographic criteria, characterized by large voltage QRScomplexes, which may or may not be accompanied by ST-segment and T-wave abnormalities (so-called “strainpattern”), were associated with left ventricular hypertrophy(LVH), as confirmed on autopsy and other evidence. How-ever, the prognostic implications, if any, of finding suchchanges on the electrocardiogram (ECG) were entirely un-clear. This paper demonstrated clearly for the first timethat the presence of LVH on the ECG was associated witha significant and important increase in the development ofclinically apparent coronary heart disease, over the 14 yearsfollow-up of the study. Subjects with “definite” LVH (de-fined by a combination of several of the following ECG find-ings: increased R-wave amplitude in the left precordialleads associated with ST-segment depression and T-waveflattening or inversion; deep S waves over the right pre-cordial leads; left axis deviation; and slight prolongationof the ventricular activation time) had a threefold increasein coronary heart disease risk, even after adjustment forcoexisting hypertension. Those with “possible” LVH (ECGcharacteristics similar to, but less striking than, those insubjects with “definite” LVH—predominantly consistingof tall R waves with no ST-segment or T-wave changes) hada twofold increase in risk, which was virtually abolishedafter adjustment for hypertension.

These findings have been corroborated in numerous largestudies since. The precise meaning and significance ofstrain pattern in the presence of LVH by QRS voltage cri-teria may not always be entirely clear. In some cases, thesechanges may merely reflect the altered electrical propertiesof a hypertrophied myocardium. But in many cases, theymay truly signify the presence of underlying, perhaps clini-cally silent, ischemic heart disease, or even myocardial ischemia with a relatively normal coronary arterial system.The most common cause of LVH is hypertension. We nowknow that hypertension is itself associated with the devel-opment of atherosclerotic disease, including coronary heartdisease. Independently of this, as LVH (whatever the etiol-ogy) progresses, portions of the myocardium may not re-ceive adequate blood flow even if the arterial supply isrelatively undiseased.

The findings of this study emphasize the need to take thepresence of ECG evidence of LVH seriously, particularly inthe presence of repolarization changes; and in such cases,it is reasonable to investigate in more detail for the possi-ble presence of underlying coronary disease, even in theabsence of clinical symptoms or signs.

P

Muammar al-Qaddafi is proclaimed Premier of Lybia; Japan becomes the fourth country to launch a satellite into orbit; and

John Lennon pays £1344 in fines for 69 people who had protested against the South African

rugby team playing in Scotland

1970

or many years, electrocardiography was used asthe standard noninvasive method for detectingthe presence of left ventricular hypertrophy (LVH);LVH detection assumed widespread importancewith the realization that it provided an accurate

and independent predictor of coronary heart disease andcardiac death. To this day, electrocardiography is used bymany as an initial screening test for the presence of LVH inthose at risk of developing it, especially patients with hy-pertension. However, the major drawback of ECG for LVHdetection is its lack of sensitivity; although ECG criteria forthe diagnosis of LVH have undergone a series of refine-ments over the years, it is estimated that ECG can detectthe presence of LVH in only 10% to 15% of cases. Further-more, the voltage criteria for LVH lack specificity, so thatlarge-voltage QRS complexes can be seen in the presenceof a structurally normal heart, especially in young patientswith a thin chest wall. A clear need was perceived, there-fore, for a more accurate, sensitive, and specific noninvasivemeasure of left ventricular mass (LVM).

With the increasingly widespread use of echocardiographyin the 1970s, it was apparent that this technique had thepotential to provide much more accurate estimates of LVM.Although the presence of LVH, especially if moderate tosevere, was often obvious by eye, there was a need to de-velop a method allowing for the numerical determinationof LVM, especially for the less obvious cases of LVH. Thispaper was the first to describe a method for doing so inan accurate, reproducible, and widely applicable manner;although some earlier papers, notably by Rackley over 10years previously, had provided echocardiographic formulaefor LVM calculation, they were extremely complex to applyand therefore of limited usefulness.

Devereux and Reichek examined the left ventricular echo-cardiograms of 34 subjects who had died and undergoneautopsy within 4 months of echocardiography. All subjectsstudied had no evidence of significant myocardial infarc-tion, ventricular aneurysm, severe right ventricular overload,or hypertrophic cardiomyopathy. They found that an accu-rate estimate of LVM, which corresponded closely to autop-

sy LVM, could be obtained by the application of a simplecube formula, across the range of LVMs studied (101-505 g):

LVM= 1.04 ([LVIDp+PWTp+IVSTp]3 – [LVIDp]3) – 13.6 g

where LVIDp is left ventricular internal diameter, PWTp isposterior wall thickness, and IVST is interventricular sep-tal thickness (all measured using the Penn Convention).This equation is still used in modified form for the echo-cardiographic calculation of LVM. Later analyses againstautopsy specimens found that the original formula over-estimated autopsy-determined LVM, and a mathematicalmodification is now in widespread use:

LVM= 0.832 ([LVIDp+PWTp+IVSTp]3 – [LVIDp]3) + 0.6 g

In clinical practice, echocardiography remains the standardand most widely applicable method for the determinationof LVM. In recent years, magnetic resonance imaging (MRI)has provided an even more accurate and reproduciblemethod to determine LVM, and is being used ever morewidely in research studies involving the measurement ofcardiac chamber volumes and structure. In time, it may wellalso supplant echocardiography for this purpose in clini-cal practice, but at the time of writing this is true in onlya handful of centers.



47

Echocardiographic determination of left ventricular mass in man.Anatomic validation of the method

R. B. Devereux, N. Reichek

Circulation. 1977;55:613-618

F

President Jimmy Carter pardons Vietnam War draft evaders;

Sarah Lowndes Dylan files for divorce from her husband of 11 years, Bob Dylan; and

scientists report using bacteria in the laboratory to make insulin

1977



48

his paper follows on very naturally from the twodiscussed above. To recap, the first by Kannelet al (the same group as that who conductedthe present study) demonstrated that left ven-tricular hypertrophy (LVH) on the electrocar-

diogram predicted future risk of coronary heart disease. Thesecond by Devereux and Reichek showed that left ventricu-lar mass (LVM) could be accurately assessed by echocar-diography. In the present study, Levy et al show that LVMas determined by echocardiography is predictive of clinicalevents, including death, attributable to cardiovasculardisease.

Once again, in this study, the residents of Framingham wereused. Over 3000 Framingham subjects aged 40 or older,who had no clinical evidence of cardiovascular disease,underwent echocardiography, with determination of LVMaccording to the Devereux and Reichek formula; LVM wasdivided by height for each subject, in order to correct for dif-ferences in heart size in subjects of different body size, andLVH was defined by an LVM >143 g/m in men and 102 g/min women.

Subjects were followed up for 4 years, and it was foundthat LVM was directly related to clinical events, even aftercorrection for all other known cardiovascular risk factors(including electrocardiographic evidence of LVH). For everyincrease of 50 g/m in height-corrected LVM, there was (afteradjustment for other risk factors) approximately a 50% increase in relative risk of cardiovascular disease in bothsexes. For the same increase in height-corrected LVM, theincidence of cardiovascular death was increased by almost75% in men and by over 100% in women; and all-causemortality was increased by approximately 50% in men and100% in women.

These results once again underline the role of LVM as animportant, and independent, predictor of cardiovascularmorbidity and mortality. The question arises as to the mech-anisms by which increased LVM may increase cardiovas-cular risk. Several possibilities suggest themselves. In thefirst place, LVH increases myocardial oxygen demand while

decreasing coronary flow reserve, creating a supply-demandmismatch, which will predispose to cardiac ischemia andsudden death. Secondly, many factors that predispose toLVH (especially hypertension, but also aortic stenosis andobesity) are also associated with atherosclerotic disease,including coronary heart disease. Finally, LVH is known topredispose to ventricular dysrhythmias, and hence suddendeath, even in the absence of overt coronary disease.

An alternative explanation is that increasing LVM is notcausative, but rather is associated with factors predispos-ing to cardiac events. Thus, for example, in a group of hy-pertensive patients with similar blood pressure readingsat a given time point, LVM may be related to the durationof the hypertension; a longer history of hypertension wouldbe expected to be associated (independently) with both agreater LVM and a higher risk of cardiovascular disease.

The question of whether LVM is an independent cause ofcardiovascular events, or is simply an epiphenomenon,remains unclear. Further large-scale trials are needed toshow whether regression of LVH is independently associ-ated with a reduction in cardiovascular risk. For the present,it seems prudent to consider LVH an important prognosticdeterminant, especially in patients with other cardiovas-cular risk factors or with established coronary disease.

T

Former leader of Panama Manuel Noriega surrenders to American troops;

The Leaning Tower of Pisa is closed to the public due to safety concerns;

The first McDonald’s opens in Moscow, Russia

1990

Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study

D. Levy, R. J. Garrison, D. D. Savage, W. B. Kannel, W. P. Castelli

N Engl J Med. 1990;322:1561-1566



49

etermination of office blood pressure (OBP)has, for many decades, been the standardmethod for detecting hypertension and itsresponse to treatment. Indeed, to this day,physicians generally use office-based read-

ings for this purpose, as well as for determining the needfor antihypertensive therapy. It has been well recognizedfor many years, however, that OBP readings can be mislead-ing. The well-known syndrome of “white-coat” hypertensionwill result in artificially high OBP; and many patients ex-hibit wide variability in their blood pressure throughout theday. The use of 24-hour ambulatory blood pressure (ABP)monitoring has greatly facilitated the detection of white-coat syndrome, and has allowed much more accurate as-sessment of what has been termed blood pressure “load”over the 24-hour period, which in turn is believed to cor-relate much more closely with the presence and severity oftarget-organ damage (such as left ventricular hypertrophy,LVH) and other hypertensive complications than officereadings. What was not clear until recently was whether re-gression of LVH in response to antihypertensive treatmentwas predicted better by OBP or ABP, and this was the sub-ject of this paper.

Mancia et al treated 206 essential hypertensive patients withLVH (as determined by echocardiography) with the angio-tensin-converting enzyme inhibitor lisinopril, with or with-out addition of the thiazide diuretic hydrochlorothiazide,aiming for a target diastolic pressure below 90 mm Hg. Aspredicted, therapy decreased both systolic and diastolicblood pressure readings very effectively, as measured bothby OBP and ABP; additionally, it reduced left ventricularmass index (LVMI). They found that the pretreatment LVMIcorrelated very well with both systolic and with diastolicaverage ABP, but did not correlate with OBP. They also foundthat, in response to antihypertensive treatment, LVMI re-duction correlated well with the reduction in average ABPs,and the correlation was just as strong if they studied LVMIreduction in relation to average daytime or nighttime

ABPs; by contrast, there was no relationship between LVMIreduction and OBP decrease.

These findings were confirmatory of previous studies, whichcollectively suggest that target-organ damage in hyperten-sion relates better to ABP than to OBP. The findings alsodemonstrated, for the first time, that LVH regression is muchbetter predicted by reduction in ABP than in OBP. This pa-per added to the accumulating evidence that ABP is moremeaningful, and more predictive of future disease (or itsprevention by antihypertensive therapy), than is OBP.

The fact remains, however, that ABP measurement in theclinical situation is much more laborious, technically diffi-cult, and logistically complex to organize than determina-tion of OBP. It is also more expensive, and therefore largelyas a result of this less widely available. For these reasons,most large trials of antihypertensive therapy have contin-ued to use OBP rather than ABP, and practicing physicianshave continued to use OBP, despite its relative drawbacks.Wider availability of ABP monitoring, and the establishmentof firm evidence-based guidelines for blood pressure tar-gets as determined by ABP rather than OBP, must be desir-able objectives for improving treatment of hypertensionand prevention of its complications.

D

Bill Clinton starts his second term as President of the United States;

Madeleine Albright becomes the first female US Secretary of State; and it is revealed that French Museums have nearly 2000 pieces

of art that were stolen by the Nazis

1997

Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricularhypertrophy. SAMPLE Study Group.*

G. Mancia, A. Zanchetti, E. Agabiti-Rosei, G. Benemio, R. De Cesaris, R. Fogari, A. Pessina, C. Porcellati, A. Rappelli, A. Salvetti, et al

Circulation. 1997;95:1464-1470

*Study on Ambulatory Monitoring of Blood Pressure andLisinopril Evaluation



50

unter and Chien, in this paper, provide a verygood overview of the cellular and molecularchanges associated with cardiac hypertrophyand failure. Both may be primarily geneticin origin (for example, hypertrophic cardio-

myopathy or idiopathic dilated cardiomyopathy), or mayresult from various mechanical, hemodynamic, hormonal,and pathological stimuli. Either way, characteristic changesare found in a variety of mediator molecules and signalingpathways in the heart, and these may explain many of thestructural and functional changes seen.

The paper starts by defining the different morphologicaltypes of cardiac hypertrophy, as seen at the cellular level:physiological hypertrophy (as occurs in athletes, where thecardiac myocytes exhibit proportional increases in lengthand width), eccentric hypertrophy (as occurs in dilated car-diomyopathy, with a relatively greater increase in myocytelength than width), and concentric hypertrophy (found inpressure overload, where myocyte width is increased to agreater degree than length). It also describes the morphol-ogy of hypertrophic cardiomyopathy, where myofibrillardisarray is seen, with secondary myocyte hypertrophy.

The review then describes the different biological systemsthat have been used to study the genetic and molecularmechanisms of cardiac hypertrophy and failure, principallycultured cardiac myocytes and genetically altered animals(mainly knockout and transgenic mice). The data from suchstudies have allowed a much greater mechanistic insightinto the processes of cardiac hypertrophy and failure atthe cellular level.

Cardiac hypertrophy is associated with increased expres-sion of embryonic genes, including those for natriureticpeptides and fetal contractile proteins. Pressure overloadcauses the local release of a variety of growth factors, in-cluding endothelin-1, angiotensin II, and insulin-like growthfactor–I (IGF-I); and also certain interleukin-6-related cy-tokines, such as cardiotrophin-1. The former appear to actpredominantly via Gp proteins and ras (retrovirus-associ-ated DNA sequence), while the latter work through gp130.

p38 mitogen-activated protein kinases are also activatedthrough the action of growth factors. Interestingly, ras,Gp, and the b isoform of p38 simulate the hypertrophicresponse, whereas Gp and the a isoform of p38 stimulateapoptosis. Thus, many of the same signals that trigger hy-pertrophy also mediate apoptosis, the latter favoring thedevelopment of chamber dilatation and heart failure, cre-ating a type of “ying-yang” effect. On the other hand, gp130pathway activation, while stimulating hypertrophy, blocksapoptosis. The resultant effect of pressure overload, there-fore, depends on the balance between the prohypertrophicand proapoptotic pathways.

In the context of dilated cardiomyopathy, genetic defectsin the structural components of the linkage between cy-toskeleton and extracellular matrix result in chamber di-latation and heart failure, and mutations in one of severalsuch proteins may give rise to the same clinical picture. Inthe case of myocyte loss in the context of myocardial infarc-tion, biomechanical stress induces the growth factor andcytokine responses described above, but here apoptosispredominates, leading to progressive ventricular dilatationand failure.

Much research is currently ongoing in this area. The hopeis that, if we can better understand the molecular patho-genesis of cardiac remodeling, this will in the future allowbetter therapeutic strategies to treat or even to preventthe development of heart failure.

H

Signaling pathways for cardiac hypertrophy and failure

J. J. Hunter, K. R. Chien

N Engl J Med. 1999;341:1276-1283

The People’s Republic of China launches the first Shenzhou spacecraft;

Hungary, Poland, and the Czech Republic join NATO; and thirty-one people die in the

British Ladbroke Grove rail disaster

1999



51

Association of change in left ventricular mass with prognosis during long-term antihypertensive treatment

M. L. Muiesan, M. Salvetti, D. Rizzoni, M. Castellano, F. Donato, E. Agabiti-Rosei

J Hypertens. 1995;13:1091-1095

uiesan et al, in this study, return to thetheme of whether left ventricular hyper-trophy (LVH) is an important and inde-pendent predictor of cardiovascularevents. Some years before the publication

of the Heart Outcomes Prevention Evaluation (HOPE)study, these investigators examined the prognostic valueof changes in left ventricular mass index (LVMI) with time,in hypertensive patients.

A group of just over 200 hypertensive patients who had un-dergone echocardiography 7 to 13 years previously, con-sidered to be of acceptable technical quality, were identi-fied. Of these patients, 151 were available and underwentrepeat echocardiography, which was considered technicallyoptimal. LVMI was calculated on both the initial and follow-up echocardiogram, and changes in LVMI over follow-upwere related to the occurrence of nonfatal cardiovascularevents. Antihypertensive treatment was not standardized,so that diuretics, β-blockers, calcium antagonists, and an-giotensin-converting enzyme inhibitors were used, eitheralone or in various combinations, in these patients; how-ever, there was no difference in the class(es) of drugs usedin patients with and without LVH, and none of the patientshad received antihypertensive therapy at baseline. LVH wasdefined by an LVM>134 g/m2 in men and >110 g/m2 inwomen. By these criteria, approximately 50% of patients hadnormal LVMI at both examinations; around 20% showedregression of LVH, 25% showed LVH at both visits, and onlya small minority (7 out of 151) developed LVH between thefirst and second visits.

The investigators found that, after adjustment for traditionalcardiovascular risk factors, the incidence of nonfatal car-diovascular events was higher in those patients who hadLVH at both examinations than in those who either hadnormal LVMI at both visits or those who exhibited regres-sion of LVH; the relative risk was approximately 3.5 in theformer group. There was no significant difference in eventsin the latter two groups. So far as the group who showeddevelopment of LVH over the follow-up period was con-cerned, because of the very small numbers in this group,

it was not possible to assign an accurate relative risk tothem; however, since 2 out of these 7 patients suffered anonfatal cardiovascular event (a proportion comparable tothe group with LVH at both time points), it seems highlyprobable that their relative risk was also elevated.

When the relative importance of various prognostic factorsat baseline or follow-up, or both, was evaluated, only ageand LVH status associated significantly with the occurrenceof events; male sex was of borderline significance, and clin-ic blood pressure (systolic or diastolic) was not significant.No significant interaction was seen between age, sex, andLVH status. Indeed, the presence of LVH at the end of fol-low-up was the most important factor related to the occur-rence of nonfatal cardiovascular events.

These data indicated that LVH persistence or increase is as-sociated with a higher risk for cardiovascular events, where-as risk is significantly reduced, and probably normalized,by complete regression of LVH. This paper added to thegrowing body of evidence that LVH is an independent andimportant predictor of future cardiovascular events, andthat adequate regression of LVH will largely (or even per-haps completely) abrogate the increase in risk. Today, thisis largely taken for granted, and one of the important goalsof hypertension treatment, aside from lowering blood pres-sure, is to ensure that LVH, when present, is adequatelytreated.

M

Austria, Finland, and Sweden enter the European Union; a magnitude 7.2 earthquake

kills over 5000 in Kobe, Japan; andBill Clinton authorizes a $20 billion loan

to Mexico to stabilize its economy

1995



52

eporting on the Losartan Intervention For End-point reduction in hypertension (LIFE) study,the authors address the age-old question ofwhether any particular type of antihyperten-sive drug offers advantages over others. The

groundbreaking nature of this study was that, for the firsttime, a clear advantage was found for one drug over an-other, in terms of reducing clinical cardiovascular events,for the same degree of blood pressure lowering.

Angiotensin II is a potent growth factor for cardiac myocytes.It has been widely assumed, therefore, that blockade eitherof the production or of the action of angiotensin II shouldbe especially effective in preventing or in regressing left ven-tricular hypertrophy (LVH). In this study, over 9000 hyperten-sive patients with established LVH (as determined by elec-trocardiography) were randomized to receive treatment witheither losartan (an angiotensin receptor blocker) or atenolol(a β-blocker); add-on antihypertensive therapy using otherdrug classes was then permitted if necessary, with the goalof reducing sitting blood pressure to <140/90 mm Hg.

The investigators found that both arms (losartan- andatenolol-based therapy) had very similar baseline bloodpressures, and achieved near-enough identical blood pres-sure reductions throughout a minimum of 4 years’ follow-up. However, LVH regression, as judged electrocardiograph-ically, was indeed superior in the losartan-treated group.The question was, did this correspond with a lower rate ofcardiovascular events in this group?

The answer was unequivocally yes. The primary compositeend point—death, myocardial infarction, or stroke—wassignificantly reduced, by 13%, in the losartan group as com-pared with the atenolol group. In secondary analyses, al-though no difference was seen in myocardial infarctionbetween the groups, stroke was decreased by 25% in losar-tan-treated as compared with atenolol-treated patients,and this finding was highly significant.

Another interesting finding was that losartan therapy wasassociated with less new-onset diabetes than atenolol ther-

apy. Indeed, a large number of trials using angiotensin re-ceptor blockers (including the recently published ValsartanAntihypertensive Long-term Use Evaluation [VALUE] study)now suggest that these drugs do indeed decrease the like-lihood of development of diabetes (and the same may betrue of the angiotensin-converting enzyme inhibitors), butthe mechanism for this effect remains entirely unclear. Itappears, therefore, that angiotensin receptor blockade withlosartan confers clinical benefits over β-blockade withatenolol, in hypertensive patients with LVH.

It is interesting to speculate whether the same result wouldhave been found for a different (non–β-blocker) comparatordrug. As discussed for the Klingbeil et al paper (see lastsummary), β-blockers may reduce central aortic pressureless than other antihypertensive drug classes, for the samedegree of lowering of peripheral arterial pressure, and insome cases may actually increase central pressure. Themore recent VALUE study showed that valsartan reducedblood pressure less than did amlodipine, a calcium channelblocker. However, the primary end point of cardiac morbid-ity and mortality was similar in the two groups. This againmight suggest a benefit of angiotensin blockade indepen-dent of blood pressure lowering, although the interpretationof this study is complicated by the fact that blood pressurelowering was inferior in the valsartan group. Further trialsare needed to determine whether the angiotensin receptorblockers do indeed offer benefits over other antihyperten-sive drug classes, beyond blood pressure reduction.

R

Cardiovascular morbidity and mortality in the LosartanIntervention For Endpoint reduction in hypertension study (LIFE):a randomised trial against atenolol

B. Dahlöf, R. B. Devereux, S. E. Kjeldsen, S. Julius, G. Beevers, U. de Faire, F. Fyhrquist, H. Ibsen, K. Kristiansson, O. Lederballe-Pedersen, et al; LIFE Study Group

Lancet. 2002;359:995-1003

Launch of Operation Anaconda, the US invasion of Afghanistan; death of

Niki de Saint Phalle, the French sculptor (knownfor her “Nanas”), painter, and film maker;

and a new order of insects, resembling praying mantises, the Mantophasmatodea, common name

“Gladiators,” is discovered in Namibia

2002



53

or many years, it was unclear whether myocardi-um that had undergone pressure-overload hyper-trophy, for example, in response to hypertension,exhibited normal contractility during systole.Most in vitro studies on myocardium obtained

from animal models of cardiac hypertrophy had suggestedthat such heart muscle was hypocontractile; by contrast,studies in humans with left ventricular hypertrophy (LVH)had suggested that contractility of hypertrophic myocardi-um was normal, or even perhaps increased. It had beensuggested that this difference might be due to the fact that,in human studies, chamber volume changes had been stud-ied rather than myocardial mechanics; and a direct extrap-olation from chamber dynamics to myocardial function isonly justified if it is assumed that the myocardium thickensto the same degree across the whole left ventricular wallduring systole.

However, theoretical considerations, as well as a variety ofexperimental data in both animals and humans, had sug-gested that the inner part of the left ventricular wall thick-ens more than the outer part, during systole. Thus, for ex-ample, a circumferential mid-wall fiber would exhibit relativemigration towards the epicardium during systole and, asa consequence of such differential movements, chambervolume changes would overestimate overall myocardialcontractile function.

To study this, Shimizu et al developed an ellipsoidal modelof the left ventricle, in which the left ventricular wall wasdivided into two shells (inner and outer) of equal thicknessat end-diastole. It was assumed that the volume of eachshell did not change during systole and diastole. Usingthis model, wall thickness and midwall fiber position werecalculated during the cardiac cycle, in the left ventricularcineangiograms of 14 subjects with normal blood pressureand 15 subjects with hypertension. Using this model, theseworkers found that midwall fractional shortening was sig-nificantly lower in hypertensives with an increased leftventricular mass index than in hypertensives with normalleft ventricular mass index or in normotensives. This wasso despite no difference being seen in ejection fraction be-

tween these groups, as determined from chamber volumechanges during the cardiac cycle using standard methods.

This paper demonstrates convincingly that simple analysisof chamber dynamics in the left ventricle does not easilytranslate to give accurate information on myocardial func-tion, and that in the presence of left ventricular hypertrophyit overestimates myocardial contractility, due to a greaterdegree of thickening of the inner as compared with theouter left ventricular wall in this situation. Both chambervolume changes and midwall fractional shortening haveimportant clinical correlates. Ejection fraction will be amore direct determinant of cardiac output (which also de-pends on left ventricular chamber volume and heart rate),and hence tissue perfusion and arterial systolic pressure.On the other hand, depressed myocardial function, evenin the presence of an apparently normal ejection fraction,can presage the future development of cardiac failure, andbe an indication of reduced preload, increased afterload,or myocardial ischemia. Furthermore, the demonstrationthat LVH is associated with myocardial contractile dysfunc-tion is, in itself, another strong indicator that regressionof the hypertrophy with appropriate therapies must be animportant goal in such patients.

F

Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy

G. Shimizu, Y. Hirota, Y. Kita, K. Kawamura, T. Saito, W. H. Gaasch

Circulation. 1991;83:1676-1684

A Michigan court bars Dr Jack Kevorkian from assisting in suicides;

Iraq fires 8 Scud missiles into Israel; and Lithuanians vote for independence

1991

54



his paper addresses the question of whetherregression of left ventricular hypertrophy (LVH)gives rise to an improvement in cardiovascularmorbidity and mortality, irrespective of effectson blood pressure. For the reasons described

in the following summary, angiotensin-converting enzyme(ACE) inhibition was used to cause LVH regression.

Approximately 9000 patients were enrolled into the HeartOutcomes Prevention Evaluation (HOPE) study. These pa-tients were judged to be at high risk of vascular disease,or had diabetes with at least one additional cardiovascularrisk factor (hypertension, dyslipidemia, smoking, or micro-albuminuria). The participants were randomized to receiveeither 10 mg ramipril daily or placebo; for treatment of hy-pertension, investigators were encouraged to use antihy-pertensive agents other than ACE inhibitors. The patientswere followed up for 4 to 6 years. At baseline, it was foundthat 676 of the patients had LVH as determined electrocar-diographically, and they were equally distributed in theramipril and placebo arms. By the end of the study, fewerpatients in the ramipril arm showed development or per-sistence of LVH as compared with the control arm; andmore ramipril-treated patients exhibited regression or pre-vention of LVH than control patients. In terms of clinicalevents, the primary outcome measure (cardiovascular death,myocardial infarction, or stroke) was reduced by approxi-mately 20% in those patients who showed LVH regression/prevention as compared with those who showed LVH development/persistence; of the constituents of this endpoint, cardiovascular death and myocardial infarction wereeach reduced in the LVH regression/prevention group, andthere was a trend to a reduction in stroke although thisdid not reach significance. Highly significant reductionswere also seen in heart failure, revascularizations, totalmortality, and sudden death/cardiac arrest, in the LVH re-gression/prevention patients.

In this paper, it was claimed that the benefits of ramipril interms of LVH were independent of blood pressure reduc-tion, since the effect on LVH status remained significantafter adjusting for drop in systolic blood pressure. Indeed,

the effect of ramipril on blood pressure in this study wassmall (mean 3/2 mm Hg), and was judged by the investiga-tors to be too small to account for the LVH regression andreduction in clinical events seen. However, because accord-ing to the HOPE protocol ramipril was given once daily atbedtime, and blood pressure was measured in the officeduring the day, the 24-hour reduction of blood pressure mayhave been underestimated. In a subsequently publishedsubstudy of HOPE, 38 of the patients underwent 24-hourambulatory blood pressure (ABP) measurement beforerandomization and after 1 year. At 1 year, ramipril did notsignificantly reduce office blood pressure or daytime ABPin these subjects; however, 24-hour ABP was significantlyreduced (10/4 mm Hg), mainly because of a more pro-nounced and significant blood pressure–lowering effect dur-ing the night (17/8 mm Hg). On the basis of this, it seemslikely that the effects on cardiovascular morbidity and mor-tality seen with ramipril in the HOPE study may, to a largerextent than ascribed in the present paper, relate to effectson blood pressure patterns over the 24-hour period.

Regardless of the dependence or independence of the find-ings on blood pressure effects, HOPE was a landmark study,showing that ACE inhibition confers marked benefits inpatients at high risk of cardiovascular disease; and, largelyas a result of HOPE, as well as more recent studies, ACEinhibitors are now routinely used in clinical practice insuch patients.

T

Reduction of cardiovascular risk by regression of electro-cardiographic markers of left ventricular hypertrophy by theangiotensin-converting enzyme inhibitor ramipril

J. Mathew, P. Sleight, E. Lonn, D. Johnstone, J. Pogue, Q. Yi, J. Bosch, B. Sussex, J. Probstfield, S. Yusuf; Heart Outcomes Prevention Evaluation (HOPE) Investigators

Circulation. 2001;104:1615-1621

Tom Cruise and Nicole Kidman announce that they have separated; the foot and mouth

disease crisis begins in the UK; andErik Weihenmayer (Boulder, Colorado) becomes

the first blind person to reach the summit of Mount Everest

2001

s mentioned in the preceding summary, oneof the major questions that has plaguedphysicians involved in the treatment of hyper-tension over the last 40 years, with the devel-opment of various classes of antihypertensive

drug with different mechanisms of action, is whether anydrug class is superior to any other in terms of preventingcardiovascular morbidity and mortality. This remains to alarge extent unanswered in terms of clinical events, butmany workers have examined the differential effects of dif-ferent drug classes on cardiovascular surrogate end points.

This study by Klingbeil et al was a meta-analysis of eightytrials of blood pressure reduction (146 active treatmentarms with 3767 patients, 17 placebo arms with 346 pa-tients). The constituent trials studied the effects of diuretics,β-blockers, calcium channel antagonists, angiotensin-con-verting enzyme (ACE) inhibitors, and angiotensin receptorblockers, on left ventricular mass index (LVMI) as deter-mined by echocardiography. These workers found that, afteradjustment for treatment duration and change in diastolicblood pressure, there were indeed differences between thedifferent drug classes in terms of effects on LVMI. Angio-tensin receptor blockers, ACE inhibitors, and calcium antag-onists reduced LVMI by 10% to 13%, whereas diuretics andβ-blockers reduced LVMI by 6% to 8% only. When pairwisecomparisons were performed to compare individual drugclasses directly, β-blockers were significantly less effectivethan angiotensin receptor blockers, ACE inhibitors, or cal-cium antagonists in decreasing LVMI.

The reason for this lesser effect of β-blockers is not clear.However, there has long been a suspicion that β-blockersmay not be as good as diuretics in preventing clinicalevents; for example, the Medical Research Council trial ofmild hypertension treatment in the 1980s showed thatbendrofluazide decreased stroke more than propranololtreatment, and this difference was highly significant. More-over, the recently published Losartan Intervention For End-point reduction in hypertension (LIFE) study (see previoussummary) showed that, in patients with hypertension andLVH, losartan reduced the primary end point and LVMI

significantly more than did atenolol. Other work suggeststhat, although β-blockers reduce peripheral arterial pres-sure well, they may have a much lesser effect on centralaortic pressure (and indeed in some cases may actuallycause central pressure to rise) than other antihyperten-sive drug classes.

Angiotensin II is known to be a potent growth factor forcardiac myocytes, and it is logical that blockade of its pro-duction or action should prevent, or even regress, cardiachypertrophy especially well. Intracellular calcium accumu-lation also stimulates cell growth, so again one might pre-dict an antihypertrophic effect for calcium channel blockers.Whether these mechanisms underlie the differences seenin this study remains uncertain, however.

Nor is it entirely clear whether such differences in effectson LVMI are clinically meaningful. However, on the basis ofthis paper as well as other more recent evidence, for exam-ple, from the LIFE study, it seems logical to use drugs oth-er than β-blockers in patients with hypertension and LVH.The most effective drugs for regressing left ventricular hy-pertrophy would appear to be ACE inhibitors, angiotensinreceptor blockers, and calcium antagonists, and theseshould probably be the antihypertensive drugs of choicein such patients.

A

55



A meta-analysis of the effects of treatment on left ventricularmass in essential hypertension

A. U. Klingbeil, M. Schneider, P. Martus, F. H. Messerli, R. E. Schmieder

Am J Med. 2003;115:41-46

The US Supreme Court upholds California’s “Three strikes and you’re out” law,

on the basis of which any person convicted of more than two felonies gets a life sentence,

with no parole before 25 years; WHO issues a global alert on SARS; and

Sweden rejects adopting the euro in a referendum

2003


Agabiti-Rosei E, Ambrosioni E, Dal Palu C, Muiesan ML, ACE-inhibitor ramipril is more effective than the beta-blocker atenololZanchetti A, on behalf of the RACE Study Group. in reducing left ventricular hypertrophy in hypertension: results of

the RACE (ramipril cardioprotective evaluation ) study.

J Hypertens. 1995;13:1325-1334.

Agabiti Rosei E, Muiesan ML. Hypertension and diastolic function.

Drugs. 1993;46(suppl 2):61-67.

Agabiti-Rosei E, Muiesan ML, Trimarco B, Reid J, Changes of LV mass and ABPM during long-term antihypertensive Hennig M, Zanchetti A. treatment in ELSA.

J Am Coll Cardiol. 2000;35:1760-1768.

Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function: new insights from a combined hemodynamic andDoppler echocardiographic study.


Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Predictive value of systolic and diastolic function for incident Kitzman D. congestive heart failure.

J Am Coll Cardiol. 2001;37:1042-1048.

Aurigemma GP, Silver HK, Priest MA, Gaasch WH. Geometric changes allow normal ejection fraction despite depressedmyocardial shortening in hypertensive left ventricular hypertrophy.

J Am Coll Cardiol. 1995;26;195-202.

Badenhorst D, Veliotes D, Maseko M, et al. Adrenergic activation initiates chamber dilatation in concentric hypertrophy.


Bella JN, Palmieri V, Liu JE, et al. Relationship between left ventricular diastolic relaxation and systolic function in hypertension. The Hypertension Genetic Epidemiology Network (HyperGEN) Study.


Bella J, Palmieri V, Roman MJ, et al. Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults. The Strong Heart Study.

Circulation. 2002;105:1928-1933.

Bibliography of One Hundred Key Papersselected by Enrico Agabiti-Rosei, MD, FESC; Maria Lorenza Muiesan, MDInternal Medicine - Medical and Surgical Sciences - University of Brescia - Brescia - ITALY

57

Hypertension &Left Ventricular Hypertrophy

58


Bibliography of One Hundred Key Papers

Bella J, Watchell K, Palmieri V, et al. Relation of left ventricular geometry and function to systemic hemo-dynamics in hypertension: the LIFE Study.

J Hypertens. 2002;19:127-134.

Bikkina M, Levy D, Evans JC, et al. Left ventricular mass and risk of stroke in an elderly cohort. The Framingham Heart Study.

JAMA. 1994;272:33-36.

Blake J, Devereux RB, Herrold EM, et al. Relation of concentric left ventricular hypertrophy and extracardiactarget organ damage to supranormal left ventricular performance in established essential hypertension.

Am J Cardiol. 1988;62:246-252.

Boeder WA, Noble NA. Transforming growth factor � in tissue fibrosis.

N Engl J Med. 1994;331:1286-1292.

Boluyt MO, O’Neill L, Meredith AL, et al. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure: marked upregulation of genes encoding extracellular matrix components.

Circ Res. 1994;75:23-32.

Bonow RO, Udelson JE. Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management.

Ann Intern Med. 1992;117:502-510.

Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients withhypertensive heart disease.

Circulation. 2000;102:1388-1393.

Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone.


Brogan WCD, Hillis LD, Flores ED, Lange RA. The natural history of isolated left ventricular diastolic dysfunction.

Am J Med. 1992;92:627-630.

Capasso JM, Strobeck JF, Sonnenblick EH. Myocardial mechanical alterations during gradual onset long-termhypertension in rats.

Am J Physiol. 1981;241:H435-H441.

Casale PN, Devereux RB, Milner M, et al. Value of echocardiographic left ventricular mass in predicting cardio-vascular morbid events in hypertensive men.

Ann Int Med. 1986;105:173-178.

Cruickshank JM, Lewis J, Moore V, Dodd A. Reversibility of left ventricular hypertrophy by differing types of anti-hypertensive therapy.

J Hum Hypertens. 1992;6:85-90.

Cuocolo A, Sax FL, Brush JE, Maron BJ, Bacharach SL, Left ventricular hypertrophy and impaired diastolic filling in Bonow RO. essential hypertension.

Circulation. 1990;81:978-986.

Cuspidi C, Lonati L, Sampieri L, et al. Left ventricular concentric remodelling and carotid structural changes in essential hypertension.

J Hypertens. 1996;14:1441-1446.

59



Cuspidi C, Marabini M, Lonati L, et al. Cardiac and carotid structure in patients with established hyper-tension and white-coat hypertension.

J Hypertens. 1995;13:1707-1711.

Cuspidi C, Muiesan ML, Valagussa L, Salvetti M, Comparative effects of candesartan and enalapril on left ventricularDi Biagio C, Zanchetti. A on behalf of the CATCH hypertrophy in patients with essential hypertension: the candesartaninvestigators. assessment in the treatment of cardiac hypertrophy (CATCH) study.

J Hypertens. 2002;20:2293-2300.

Dahlöf B, Pennert K, Hansson L. Reversal of Left Ventricular Hypertrophy in Hypertensive Patients. A Meta-analysis of 109 Treatment Studies.

Am J Hypertens. 1992;5:95-110.

Dahlöf B, Zanchetti A, Diez J, et al, for the REGAAL Effects of losartan and atenolol on left ventricular mass and neuro-Study Investigators. hormonal profile in patients with essential hypertension and left

ventricular hypertrophy.

J Hypertens. 2002;20:1855-1864.

de Simone G, Devereux R, Celentano A, Roman MJ. Left ventricular chamber and wall mechanics in the presence of concentric geometry.

J Hypertens. 1999;17:1001-1006.

de Simone G, Devereux RB, Koren MJ, Mensah GA, Midwall left ventricular mechanics. An independent predictor of Casale PN, Laragh JH. cardiovascular risk in arterial hypertension.

Lancet. 2004;363:1881-1891.

de Simone G, Palmieri V, Koren M, Mensah G, Prognostic implications of the compensatory nature of left ventricularRoman MJ, Devereux RB. mass in arterial hypertension.

J Hypertens. 2001;19:119-125.

Devereux RB. Hypertensive cardiac hypertrophy, pathophysiology and clinical characteristics. In: Laragh JH, Brenner BM, eds.

Hypertension, Pathophysiology, Diagnosis and Management. 2nd edition. New York, NY: Raven Press; 1995.

Devereux RB, Agabiti-Rosei E, Dahlöf B, et al. Regression of left ventricular hypertrophy is a surrogate end-point for morbid events in hypertension treatment trials.

J Hypertens. 1996;14(suppl 2):s95-s102.

Devereux RB, Bella JN, Palmieri V, et al. Left ventricular systolic dysfunction in a biracial sample of hyper-tensive adults. The HyperGEN study.


Devereux RB, de Simone G, Pickering TG, Relation of left ventricular midwall function to cardiovascular risk Schwartz JE, Roman MJ. factors and arterial structure and function.

Hypertension. 1998;31:929:936.

Devereux RB, Palmieri V, Sharpe N, et al. Effects of once daily angiotensin-converting enzyme inhibition and calcium channel blockade-based antihypertensive treatment regimenson left ventricular hypertrophy and diastolic filling in hypertension.The prospective randomised enalapril study evaluating regression of ventricular enlargement (PRESERVE) trial.

Circulation. 2001;104:1248-1254.

Devereux RB, Roman MJ, Palmieri V, et al. Left ventricular wall stresses and wall stress-mass-heart-rate productsin hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study.

J Hypertens. 2000;18:1129-1138.

60



Devereux RB, Watchell K, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy: treatment effects and prognostic implications in the LIFE trial.

J Hypertens. 2002;20(suppl 4):S5.

Diamond JA, Krakoff LR, Goldman A, et al. Comparison of two calcium channel blockers on hemodynamics, leftventricular mass, and coronary vasodilatory response in advanced hypertension.

Am J Hypertens. 2001;14:231-240.

Edwards DR, Murphy G, Reynolds JJ, et al. TGF � modulates the expression of collagenase and metalloproteinaseinhibitor.

EMBO J. 1987;6:1899-1904.

Everett AD, Tufro-McReddie A, Fisher A, Gomez RA. Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-beta 1 expression.


Fagard RH. Reversibility of left ventricular hypertrophy by antihypertensive drugs.

Neth J Med. 1995;47:173-179.

Fagard R, Pardaens K. Left ventricular diastolic function predicts outcome in uncomplicatedhypertension.

Am J Hypertens. 2001;14:504-508.

Frohlich E. Risk mechanisms in hypertensive heart disease.

Hypertension. 1999;34(pt 2):782-789.

Gardin JM, Drayer J, Weber M, et al. Doppler echocardiographic assessment of left ventricular systolic anddiastolic function in mild hypertension.

Hypertension. 1987;9:II90-II96.

Gerdts E, Bjornstad H, Toft S, Devereux RB, Omvik P. Impact of diastolic Doppler indices on exercise capacity in hyper-tensive patients with electrocardiographic left ventricular hypertrophy(a LIFE substudy).

J Hypertens. 2002;20:1223-1229.

Gosse P, Sheridan DJ, Dubourg O, et al. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the L.I.V.E. Study.

J Hypertens. 2000;18:1465-1475.

Gottdiener J, Reda D, Massie BM, Materson BJ, Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Groupon Antihypertensive agents.

Circulation. 1997;95:2007-2014.

Hanrath P, Mathey DG, Siegert R, Bleifeld W. Left ventricular relaxation and filling patterns in different forms of left ventricular hypertrophy: an echocardiographic study.

Am J Cardiol. 1980;45:15-23.

Hinderliter AL, Light KC, Willis PW IV. Patients with borderline elevated blood pressure have enhanced leftventricular contractility.

Am J Hypertens. 1995:8:1040-1045.

61

Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of ChronicHeart Failure in the adult: executive summary; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guide-lines for the Evaluation and management Of Heart Failure).

J Am Coll Cardiol. 2001;38:2101-2113.

Inamura T, McDermott PJ, Kent RL, Nagatsu M, Acute changes in myosin heavy chain synthesis rate in pressure Cooper G, Carabello BA. versus volume overload.

Circ Res. 1994;75:418-425.

Ishikawa Y, Homcy CJ. The adenylyl cyclases as integrators of transmembrane signal transduction.

Circ Res. 1997;80:297-304.

Jennings G, Wong J. Reversibility of left ventricular hypertrophy and malfunction by antihypertensive treatment. In: Hansonn L, Birkenhager WH, eds.

Handbook of Hypertension. Vol 18. Assessment of hypertensive organ damage. Amsterdam, Netherlands: Elsevier Science BV; 1997:185-223.

Kannel WB. Prevalence and natural history of electrocardiographic left ventric-ular hypertrophy.

Am J Med. 1983;75(suppl A):4-11.

Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram: prevalence, incidence and mortality in the Framingham Study.

Ann Intern Med. 1969;71:89-105.

Koren MJ, Ulin RJ, Koren AT, Laragh JH, Devereux RB. Left ventricular mass changes during treatment and outcome in patients with essential hypertension.

Am J Hypertens. 2002;15:1021-1028.

Kozakowa M, Palombo C, Pratali L, Pittella G, Galetta F, Mechanisms of coronary flow reserve impairment in human hyper-L'Abbate A. tension. An integrated approach by transthoracic and transesophageal

echocardiography.


Levy D, Kenchaiah S, Larson MG, et al. Long term trends in the incidence of and survival with heart failure.

N Engl J Med. 2002;347:1397-1400.

Levy D, Larson MG, Vasan RS, Kannel WB, Ho KKL. The progression from hypertension to congestive heart failure.

JAMA. 1996;275:1557-1562.

Levy D, Salomon M, D'Agostino R, Belanger A, Kannel WB. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy.

Circulation. 1994;90:1786-1793.

Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of five antihypertensive monotherapies and placebo forchange in left ventricular mass in patients receiving nutritional-hy-gienic therapy in the Treatment of Mild Hypertension Study (TOMHS).

Circulation. 1995;91:698-706.

Little WC, Downes TR, Applegate RJ. Invasive evaluation of left ventricular diastolic performance.

Herz. 1990; 15:362-376.



62



Loaldi A, Pepi M, Agostoni PG, Guazzi M. Cardiac rhythm in hypertension assessed through 24-hour ambula-tory electrocardiographic monitoring. Effect of load manipulation with atenolol, verapamil and nifedipine.

Br Heart J. 1983;50:118-126.

Lopez B, Querejeta R, Varo N, et al. Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihyperten-sive treatment in hypertensive patients.

Circulation. 2001;104:286-291.

Lorell BH, Carabello BA. Left ventricular hypertrophy pathogenesis, detection and prognosis.

Circulation. 2000;102:470-479.

Lucarini A, Picano E, Lattanzi F, et al. Dipyridamole echocardiography stress testing in hypertensive patients.Targets and tools.

Circulation. 1991;83(suppl III):III68-III72.

Lucarini A, Spessot M, Picano E, et al. Lack of correlation between cardiac mass and arteriolar structural changes in mild-to-moderate hypertension.

J Hypertens. 1991;9:1187-1191.

Magrini F, Reggiani P, Roberts N, Meazza R, Ciulla M, Effects of angiotensin blockade on coronary circulation and coronaryreserve.

Am J Med. 1988;84:55-60.

Malmqvist K, Kahan T, Edner M, et al. Regression of left ventricular hypertrophy in human hypertension with irbesartan.

J Hypertens. 2001;19:1167-1176.

Mandinov L, Eberli FR, Seiler C, Hass OM. Diastolic heart failure.


Mercadier JJ, de la Bastie D, Menasche P, et al. Alpha-myosin heavy chain isoform and atrial size in patients with various types of mitral valve dysfunction: a quantitative study.

J Am Coll Cardiol. 1987;9:1024-1030.

Molkentin JD. Calcineurin and beyond: cardiac hypertrophic signaling.

Circ Res. 2000;87:731-738.

Morgan HE, Baker KM. Cardiac hypertrophy.


Moser M, Hebert PR. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials.

J Am Coll Cardiol. 1996;27;1214-1218.

Motz W, Vogt M, Rabenau O, Scheler S, Luckoff A, Evidence of endothelial dysfunction in coronary resistance vessels inpatients with angina pectoris and normal coronary angiograms.

Am J Cardiol. 1991;68:996-1003.

Muiesan ML, Pasini GF, Salvetti M. Cardiac and vascular structural changes. Prevalence and relation to ambulatory blood pressure in a middle-aged general population in Northern Italy. The Vobarno Study.

Hypertension. 1996;27:1046-1052.

63

Muiesan ML, Rizzoni D, Zulli R, et al. Effect of changes in blood pressure and left ventricular mass induced by antihypertensive treatment on ventricular arrhythmias in essential hypertension.

J Hypertens. 1993;11(suppl 5):s300-s301.

Muiesan ML, Rizzoni D, Salvetti A, et al. Structural changes in small resistance arteries and left ventricular geometry in patients with primary and secondary hypertension.

J Hypertens. 2002;20:1439-1446.

Muiesan ML, Rizzoni D, Zulli R, Calebich S, Left ventricular systolic function during stress as related to impairedAgabiti-Rosei E. diastolic filling in essential hypertension.

High Blood Press. 1992;1:287-295.

Muiesan ML, Rizzoni D, Zulli R, et al. Cardiovascular characteristics in normotensive subjects with or without family history of hypertension.

Clin Exp Hypertens. 1996;18:901-920.

Muiesan ML, Salvetti M, Monteduro C, et al. Changes in midwall systolic performance and cardiac hypertrophy reduction in hypertensive patients.

J Hypertens. 2000;18:1651-1656.

Muiesan ML, Salvetti M, Rizzoni D, Monteduro C, Persistence of left ventricular hypertrophy is a stronger indicator of Castellano M, Agabiti-Rosei E. cardiovascular events than baseline left ventricular mass or systolic

performance: 10 years of follow-up.


Nakajima H, Nakajima O, Salcher O, et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta 1 transgene in the heart.

Circ Res. 2000;86:571-579.

Niteberg A, Anthony I. Epicardial coronary arteries are not adequately sized in hyperten-sive patients.


Palatini P, Visentin P, Mormino P, et al, on behalf of Left ventricular performance in the early stages of systemic hyper-the HARVEST Study group. tension.

Am J Cardiol. 1998;81:418-423.

Palmieri V, Watchell K, Gerdts E, et al. Left ventricular function and hemodynamic features of inappropriateleft ventricular hypertrophy in patients with systemic hypertension: the LIFE study.

Am Heart J. 2001;141:784-791.

Parati G, Omboni S, Rizzoni D, Agabiti-Rosei E, Mancia G. The smoothness index: a new reproducible and clinically relevant measure of the homogeneity of the blood pressure reduction with treatment for hypertension.

J Hypertens. 1998;16:1685-1693.

Pepi M, Alimento M, Maltalgliati A, Guazzi M. Cardiac hypertrophy in hypertension: repolarization abnormalities elicited by rapid lowering of pressure.


Perlini S, Muiesan ML, Cuspidi C, et al. Midwall mechanics are improved after regression of hypertensiveleft ventricular hypertrophy and normalization of chamber geometry.

Circulation. 2001;103:678-683.



Pfeffer MA, Pfeffer JM. Cardiac hypertrophy in the spontaneously hypertensive rat: adaptation or primary myopathy? In: Tarazi RC, Dunbar JB, eds.

Perspectives in Cardiovascular Research. New York, NY: Raven Press; 1983;8:193.

Pierdomenico SD, Lapenna D, Guglielmi MD, et al. Vascular changes in hypertensive patients with different left ventric-ular geometry.

J Hypertens. 1995;13:1701-1706.

Pinto Y, Pinto-Sietsma SJ, Philipp T, et al. Reduction in left ventricular messenger RNA for transforming growth factor �1 attenuates left ventricular fibrosis and improves survival without lowering blood pressure in hypertensive TGR(mRen2)27 rats.

Circulation. 2000;36:747-754.

Polese A, De Cesare N, Montorsi P, et al. Upward shift of the lower range of coronary autoregulation in hypertensive patients with hypertrophy of the left ventricle.

Circulation. 1991;83:845-853.

Quinones MA, Otto C, Stoddard M, Waggoner A, Recommendations for quantifications of Doppler echocardiography:Zoghbi W. a report from the Doppler quantification Task Force of the

Nomenclature and Standards Committee of the American Society of Echocardiography.


Radice M, Alli C, Avanzino F, Di Tullio M, Mariotti G, Left ventricular structure and function in normotensive adolescents Taioli E. with a genetic predisposition to hypertension.

Am Heart J. 1986111:115-120.

Rakusan K, Flanagan MF, Geva T, Southern J, Morphometry of human coronary capillaries during normal growth Van Praagh R. and the effect of age on left ventricular pressure-overload hypertrophy.


Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Burden of systolic and diastolic ventricular dysfunction in the Bailey KR, Roedeheffer RJ. community.

JAMA. 2003;289:194-202.

Rizzoni D, Muiesan ML, Porteri E, et al. Relations between cardiac and vascular structure in patients with primary and secondary hypertension.


Rizzoni D, Palombo C, Porteri E, et al. Relationship between coronary vasodilator capacity and small arteryremodelling in hypertensive patients.

J Hypertens. 2003;21:615-621.

Roman MJ, Pickering TG, Schwartz JE, Pini R, Association of carotid atherosclerotic and left ventricular hypertrophy.Devereux RB. J Am Coll Cardiol. 1995;25:83-90.

Rudic RD, Shesely EG, Meeda N, Smithies O, Segal SS, Direct evidence for the importance of endothelium-derived nitric Sessa WC. oxide in vascular remodelling.

J Clin Invest. 1998;101:731-736.

Sabbah NH. The cellular and physiological effects of beta-blockers in heart failure.

Clin Cardiol. 1999;22:16-20.

64



Sadler DB, Aurigemma G, Williams D, Reda D, Systolic function in hypertensive men with concentric remodeling. Materson B, Gottdiener J. Hypertension. 1997;30:777-781.

Savage DD, Abbott RD, Anderson SJ, Padgett S. Determinants of left ventricular mass and reference values based on a large population-based sample of apparently healthy subjects: the Framingham Study.

Circulation. 1983;68(suppl III):111-136.

Savage DD, Drayer Jim, Henry WM, et al. Echocardiographic assessment of cardiac anatomy and function in hypertensive subjects.

Circulation. 1979;59:623-632.

Schillaci G, Pasqualini L, Verdecchia P, et al. Prognostic significance of left ventricular diastolic dysfunction in essential hypertension.

J Am Coll Cardiol. 2002;39:2005-2011.

Schillaci G, Vaudo G, Reboldi G, et al. High-density lipoprotein cholesterol and left ventricular hypertrophyin essential hypertension.

J Hypertens. 2001;19:2265-2270.

Schillaci G, Verdecchia P, Borgioni C, Ciucci A, Porcellati C. Early cardiac changes after menopause.


Shimuzu G, Zile MR, Blaustein AS, Gaasch WH. Left ventricular chamber filling and midwall fiber lengthening in patients with left ventricular hypertrophy: overestimation of fiber velocities by conventional midwall measurements.

Circulation. 1985;71:266-272.

Sihm I, Schroeder AP, Aalkjær C, et al. The relation between peripheral vascular structure, left ventricular hypertrophy and ambulatory blood pressure in essential hypertension.

Am J Hypertens. 1995;8:987-996.

Spann JF, Buccino RA, Sonnenblick EH, Braunwald E. Contractile state of cardiac muscle obtained from cats with experi-mentally produced ventricular hypertrophy and heart failure.

Circ Res. 1967;21:341-354.

St John Sutton M. Mitral flow derived Doppler indices of left ventricular diastolic function.

Eur Heart J. 2000;21:1298-1300.

Sun Y, Zhang JQ, Zhang J, Ramires FJ. Angiotensin II, transforming growth factor beta1 and repair in the infarcted heart.


Tarazi RC, Frohlich ED. Is reversal of cardiac hypertrophy a desirable goal of antihyperten-sive therapy?

Circulation. 1987;75(suppl I):I113-I117.

Tarazi RC. Regression of left ventricular hypertrophy: partial answers for persistent questions.

J Am Coll Cardiol. 1984;3:1349-1351.

Terpstra WF, May JF, Smit AJ, et al. Long-term effects of amlodipine and lisinopril on left ventricularmass and diastolic function in elderly, previously untreated hyper-

tensive patients: the ELVERA trial.

J Hypertens. 2001;19:303-309.

65



Thurmann P, Kenedi P, Schimdt A, Harder S, Rietbrock N. Influence of the angiotensin II antagonist valsartan on left ventric-ular hypertrophy in patients with essential hypertension.

Circulation. 1998;98:2037-2042.

Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure,an epidemiological perspective.

J Am Coll Cardiol. 1995:1565-1574.

Vasan RS, Levy D. The role of hypertension in the pathogenesis of heart failure: a clinical mechanistic overview.

Arch Intern Med. 1996;156:1789-1796.

Vatner SF, Hittinger L. Coronary vascular mechanisms involved in decompensation from hypertrophy to heart failure.

J Am Coll Cardiol. 1993;22(suppl A):34A-40A.

Vatner SF, Vatner DE, Homcy CJ. Beta-adrenergic receptor signaling: an acute compensatory adjust-ment-inappropriate for the chronic stress of heart failure. Insights from Gsa overexpression and other genetically engineered animal models.

Circ Res. 2000;86:502-506.

Verdecchia P, Schillaci G, Borgioni I, et al. Prognostic significance of serial changes in left ventricular mass in essential hypertension.


Verdecchia P, Schillaci G, Reboldi G, Ambrosio G, Pede S, Prognostic value of midwall shortening fraction and its relation Porcellati C. with left ventricular mass in systemic hypertension.

Am J Cardiol. 2001;87:479-482.

Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system.

Circulation. 1991;83:1849-1853.

Weber KT, Eghbali M. Collagen matrix synthesis and degradation in the development and regression of left ventricular hypertrophy.

Cardiovasc Rev Rep. 1991;12:61-69.

66



67

GENERAL INSTRUCTIONS

• Manuscripts should be provided onword-processor disks (3.5-in, for IBM,IBM-compatible, or Apple computers)with three hard copies (text and fig-ures) printed on one side of standard-sized white bond paper, double-spaced, with 2.5-cm margins. Pagesmust be numbered. Standard typedpage = 25 lines of 75 characters (including spaces) double-spaced, 2.5-cm margins = a total of 275words per page.

• All texts should be submitted inEnglish. In the case of translations, the text in the original language shouldbe included.

• On the title page, provide title ofmanuscript (title should be concise,not exceeding 120 characters, includingspaces), short running title, keywords,and acknowledgments, as well as fullnames (first name, middle name(s),and last name) with highest academicdegrees (in country-of-origin language),affiliations/address, telephone No., fax No., and E-mail address.

• Illustrations (photographs, tables, graphs,figures–high-quality printouts, glossyprints, and/or high-quality scans asjpg files) should be of good quality orprofessionally prepared, numbered according to their order, with properorientation indicated (eg, “top,” or“left”), and SHORT legends provided,not repetitive of text. As figures and graphs may need to bereduced or enlarged, all absolute valuesand statistics should be provided. All illustrations should be cited in thetext, with distinct numbering for fig-ures and tables. Illustrations will bereproduced in full color only whenclearly necessary, eg, images from nu-clear medicine or histology.

• Include HEADINGS using a consistentstyle for the various levels of headings,to highlight key points and facilitatecomprehension of the text. The Publisher reserves the right to addor delete headings when necessary.

• Abbreviations should be used sparinglyand expanded at first mention.

• Use Système International (SI) units.

• Use generic names of drugs.

• All references should be cited in thetext and numbered consecutively us-ing superscript arabic numerals. Theauthor-date system of citation is NOTacceptable. “In press” references are tobe avoided. In the bibliography, titlesof journals should be abbreviated ac-cording to the Index Medicus. All au-thors should be listed up to six; if thereare more, only the first three shouldbe listed, followed by “et al” (Uniformrequirements for manuscripts submitted tobiomedical journals: see www.icmje.org ).Where necessary, references will bestyled to Dialogues in CardiovascularMedicine copyediting requirements.Authors bear total responsibility forthe accuracy and completeness of allreferences and for correct text citation.Example of style for references:

1. Ouriel K, Geary K, Green RM, Geary JE,DeWeese JA. Factors determining survival afterruptured abdominal aneurysm. J Vasc Surg.1990;11:493-496.

2. Darling RC, Brewster DC, Ottinger LW. Autopsy study of unoperated abdominal aorticaneurysms: the case for early resection.Circulation. 1977;56(suppl II):II161-II164.

3. Schulman JL. Immunology of influenza. In:Kilbourne ED, Alfade RT, eds. The InfluenzaViruses and Influenza. Orlando, Fla: AcademicPress Inc; 1975:373-393.

• Copyediting: all contributions toDialogues in Cardiovascular Medicine willbe styled by the Publisher’s editorialdepartment according to the specifica-tions of the current edition of theAmerican Medical Association Manual ofStyle, Williams & Wilkins. Page proofswill be sent to authors for approval andshould be returned within 5 days. If thistime is exceeded, changes made by theeditorial department will be assumedto be accepted by the author. Authorsare responsible for all statements madein their work, including changes madeby the editorial department and au-thorized by the author. The Publisherwill edit Editorials, Abstracts, andSeminal Paper Summaries to requiredsize if their length does not complywith specific requirements.

• Copyright of articles will be transferredto the Publisher of Dialogues inCardiovascular Medicine. For reproduction

of existing work, it is the author’s re-sponsibility to obtain copyright fromthe author(s) (including self) and thepublisher(s) and provide copies of theseauthorizations with the manuscript.

LEAD ARTICLE

The lead article should not exceed 25 standard typed pages (maximum8000 words), including an abstract of no more than 200 words, no more than50 references, and a minimum of 5 -maximum of 10 illustrations (figures and/or tables). A maximum of 5-10 keywordsshould be included. The 3 questions forthe respondents should be introducedin or after the conclusion. A separate listof “10 references of seminal papers”as well as a separate list of “100 KeyReferences” should be provided.

RESPONDENT ARTICLES

Respondent articles should not exceed25 standard typed pages (maximum2500 words), including an abstract of no more than 125 words, no more than10 references, and a mimimun of 3 -maximum of 5 illustrations (figures andtables). A maximum of 5-10 keywordsshould be included.

SEMINAL PAPER SUMMARIES

Seminal paper summaries take up onepage of Dialogues in Cardiovascular Medicine:the length of each summary should IM-PERATIVELY be comprised between500 and 600 words, ie, not exceed3000 characters. Summaries that aretoo short or too long will be returned tothe author or edited by the Publisher.No figures, tables or references shouldbe included in seminal paper summaries.

FASCINOMA CARDIOLOGICAARTICLES

Fascinoma Cardiologica articles (A Lexiconof the Heart; Icons of Cardiology; Plants andthe Heart; Trails of Discovery, etc) should notexceed 2000 words (8 standard typedpages), should include 3 to 5 illustra-tions (figures and tables), and cite nomore than 15 references. A maximum of5-10 keywords should be included. No abstract.

Instructions for authors

Documents

Hypertension & Left Ventricular Hypertrophy · Expert Answers to Three Key Questions Do coronary circulation abnormalities play an important role in the pathogenesis of hypertensive