Heart (Supplement 3) 1996;76:92-97

Hypertension, hypertrophy, heart failure

M Gary Nicholls

Heart failure presents a number of difficulties.Its very definition has proved taxing, and theclinical diagnosis is frequently incorrect.Patients with objective abnormalities of leftventricular function are not infrequentlyasymptomatic, hence treatment is oftendelayed. Even when a firm diagnosis issecured, only a minority of patients receiveoptimal medical treatment. Of concern is theincreasing incidence and prevalence of heartfailure in Western countries, with attendanthigh morbidity and mortality rates and escalat-ing costs of management. The close associa-tion, as cause and effect, between hyper-tension and heart failure-well recognised inearlier years-appears to be dismissed orignored by some observers, especially in thedevelopment of guidelines for the manage-ment of hypertension or heart failure.Some of these matters will be discussed to

emphasise the importance of long standinghypertension as a preventable risk factor forleft ventricular hypertrophy and heart failurein Western countries.

Department ofMedicine, TheChristchurch School ofMedicine,Christchurch Hospital,Christchurch, NewZealandM G NichollsCorrespondence to:Professor M G Nicholls.

Heart failure: a public health problemHeart failure affects around one to three percent of the population in Western countries,and the incidence and prevalence are increas-ing.1 2 In fact, the one to three per cent preva-lence quoted is likely to be an underestimatewhen one considers the difficulties in making aclinical diagnosis of heart failure3-5 and thehigh incidence of asymptomatic cardiac dys-function,6 especially after acute myocardialinfarction.7The economic cost of managing established

heart failure is approximately one to two percent of total health care expenditure.8-'0 Thisenormous burden to patients and the taxpayer,accounted for largely by costs associated withhospital admission, is likely also to be anunderestimate and to be increasing.

Hypertension as a risk factor for heartfailureBefore the widespread availability of antihy-pertensive drugs, the commonest cause ofheart failure in Western countries was hyper-tension. For example, 55% of patients whodied from heart failure between 1910 and1938 in a Minnesota study had, at necropsy,underlying hypertensive heart disease."l Thefigure was 38% in the necropsy series ofWartman and Hellerstein carried out inCleveland, Ohio, between 1935 and 1940.12

There are few long term observational stud-ies of sizeable hypertensive populations receiv-ing no, or limited, treatment. What studiesexist'3 indicate that congestive heart failurewas the cause of death in more than 50% ofhypertensive patients (table). Bechgaard deter-mined that a lesser fraction (24%) of totaldeaths in 1038 hypertensive (blood pressure160/100 mm Hg), middle aged (53 years old)Danish patients, followed for 40 years from1932, was due to heart failure, but thisexceeded deaths from stroke (17%) ormyocardial infarction (16%).'' In the studythat Perera reported in 1955, 50% of 500essential hypertensive patients in New Yorkfollowed until death in the absence of antihy-pertensive treatment developed heart failure.'5Here, as in the study of Bechgaard,'4 heart fail-ure was considered to have contributed todeath in a much greater number of patients(38%) than did stroke (9%), myocardialinfarction, and renal insufficiency (6%).The association between hypertension and

heart failure was shown by Smirk in 1957 tobe "dose-related",'6 that is, the higher the arte-rial pressure, the greater was the risk of devel-oping heart failure (fig 1). Workers inFramingham noted the same phenomenon 15years later.'7 Such a "dose" relation would beanticipated if the link between hypertensionand heart failure was one of cause and effect.The Framingham study, initiated in 1948,

was pivotal in confirming an associationbetween hypertension and the subsequentdevelopment of heart failure in Western soci-ety. Of 5192 subjects in the general populationof Framingham followed for 16 years, 142developed heart failure, of whom 75% hadprior hypertension on routine biennial exami-nations.'7 The original Framingham study wasextended in 1971 to include children of theoriginal participants and spouses of these chil-dren, in the Framingham Offspring Study.'8Among the total of 9405 participants followedfrom 1948 to 1988, heart failure developed in652, ofwhom 70% ofmen and 78% ofwomen

Glossary of trialsEWPHE-European Working Party on High Blood Pressure in theElderly trialSHEP-Systolic Hypertension in the Elderly ProgramSOLVD-Studies of Left Ventricular DysfunctionSTOP-Hypertension-Swedish Trial of Old Patients withHypertensionTOMHS-Treatment of Mild Hypertension Study

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Caulse of death of patients with hypertensive disease as rcported by various investigatos *

Murphy Bell anid Goldrin1Xget al W7lite Clawsonl Clawzvsonl PFlaxmitan anid Cliasis Total

Caiuse oldath ) ° ) 11 %

Congestive heart failure 171 56.4 53 53-0 78 56-0 187 44 5 122 645 56 49.6 667 52 8Coronary thrombosis andsudden death _ 31 31 0 37 26 5 67 15 9 15 7-9 22 19 5 172 13 6Cerebral vascular accident 45 14 9 6 6 0 16 11 5 81 19 5 13 6-9 17 15-0 178 14 0Uraemia 23 7-6 5 5-0 8 5 5 36 8 5 31 16 4 4 3-5 107 8 5Other causes 64 21 1 5 5 0 - -- 49 11 6 8 4 3 14 12 4 140 11 1rrotal 303 100 139 420 189 113 1264

*From Goldring W, Chasis H. Hypertension and hypotensive disease. NY Commonwealth Fund, 1945.Reproduced with permission from Doyle.

had an antecedent diagnosis of hypertension.Forty per cent of patients had both coronaryheart disease and hypertension before develop-ing heart failure (fig 2). Of importance is theobservation that there was no change in thefrequency of hypertension as the attributablecause of heart failure during the four decadesof observation."' Additional data fromFramingham reveal that even borderline iso-lated systolic hypertension was associated withan increased risk of developing heart failure.'The primacy of hypertension as the main

risk factor for heart failure was confirmed inthe Swedish study of men born in 1913, even

Figurc 1 Relationi ofm7leanl "basal" bloodpressure (basal diastolicanid basal systolic) - 2 tothe percenitagc inlcidcice ofcongestive heart failure orleft ventricular failure in aseties of hypertensivepatients. Reprodiuced withpermission fronm Smirk. "

0

.0

a) I

C)

._2-

as

aEc;

Males100

90

8070 - Females

60

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40-*

30 r ---

20 *I

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80-99 100-119 120-139 140-159 160-179 180-199

Basal blood pressure

WOMEN

30% 37%

--.1-5 -.

..7.... .

n = 331 n = 321

___No HTN or CHD Hypertension alone_~ CHD + HTN Coronary heart disease alone

Figirc 2 Prevalencc of coronary heart disease (CHD) and hypertension (H7TX) alonie,and in cowubinationl, among Framingham Heart Study! paticnits zvith conigestive heartfailure. Reproduced zwith pennission fronti Ho et al.""

though hypertensives were defined narrowly asthose receiving antihypertensive drug treat-ment or who had blood pressure readings of175/115 mm Hg or higher.'More recently, hypertension was found in

the USA to be the strongest predictor of hospi-tal admission for congestive heart failure inboth blacks and whites over a median periodof 9 5 years (starting from 1978-1984) afteran insurance examination." This study sug-gested that differences in the prevalence ofhypertension, and diabetes and obesity to alesser extent, accounted for the contrastinghospital admission rates for heart failurebetween blacks and whites.22 Even in the1970s and 1980s, therefore, hypertensionappears to be the dominant risk factor forheart failure.

Underestimation of hypertension as arisk factor for heart failureIt is probable that the impact of hypertensionas a cause of heart failure has been underesti-mated by available data. Why is this likely tobe so?

First, patients with hypertension andimpaired left ventricular function, whethersystolic," diastolic,' or mixed, are not infre-quently asymptomatic and would not havebeen defined as having heart failure, particu-larly in the early studies noted above.

Second, heart failure generally takes a con-siderable period of time to develop in hyper-tensives-except in the elderly. Thenumerous antihypertensive drug trials lastingtwo to five years in young and middle agedpatients carried out over the last threedecades"' are too brief to reveal either the asso-ciation of hypertension and heart failure inpatients taking placebo, or the protectiveeffects of antihypertensive drug treatment.Although the incidence of heart failure, com-pared to coronary heart disease and stroke, inplacebo treated elderly hypertensives is diffi-cult to define from published data, the protec-tive effect of antihypertensive treatment inregard to heart failure is clear.-

Third, while exceptions can occur, arterialpressure generally falls with the developmentof heart failure. Previously hypertensivepatients presenting to medical attention for thefirst time because of heart failure will often,therefore, be normotensive or hypotensive.Predisposing hypertension remains unsus-pected in a percentage of these patients, espe-cially since the earlier hypertrophied left

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ventricle can, through impaired coronary flowreserve with chronic myocardial ischaemia,transform into a dilated, failing ventricle.27

Fourth, blood pressure declines after acutemyocardial infarction.28 Here again, priorhypertension can remain unsuspected sincethe first clinical presentation is acute myocar-dial infarction in a patient with now normal orlow blood pressure. The true impact of hyper-tension as a predisposing factor for acutemyocardial infarction and subsequent heartfailure can only be appreciated from long termobservational studies in unselected popula-tions-as in the Framingham study. Hospitalbased studies will, predictably and inevitably,provide a different picture.29

Fifth, mortality after acute myocardialinfarction in previously hypertensive men isalmost three times that in men who had beennormotensive.30 Those dying of heart failuresoon after infarction are often hypotensive,and prior hypertension may again remainunsuspected.

Sixth, hypertensives have a disproportion-ately high rate of clinically unrecognisedmyocardial infarction.3' These patients arelikely to seek medical attention when symp-toms of cardiac failure develop-at whichstage they may be normotensive, and theunderlying disorder labelled as coronary heartdisease. Yet again, only a long termFramingham-like study can reveal the likelycontribution of longstanding hypertension toheart failure in this population of patients.

Finally, there is, experimentally, an associa-tion between left ventricular overload andarrhythmias,32 and, clinically, between hyper-tension, left ventricular hypertrophy, fre-quency of arrhythmias (including atrialfibrillation), and sudden death.33-35 The firstclinical presentation in a patient's evolutionfrom hypertension to heart failure may be witha symptomatic arrhythmia, at which time thearterial pressure can be near normal.Established heart failure may supervene, withno awareness that hypertension was the pri-mary predisposing disorder and arrhythmiasimply a precipitating factor.

At the risk of excessive repetition, the truerelation between longstanding hypertensionand the development of left ventricular hyper-trophy36 and heart failure can only be gaugedwith accuracy from long term studies of unse-lected populations "undistorted by the selec-tive bias of hospital admission practices".17Recent and frequent claims that hypertensionis now a lesser risk factor for heart failure thanin earlier years seem unlikely and are notproven by the data presented.

Does antihypertensive treatment preventheart failure?In that epidemiological associations may notnecessarily indicate cause and effect, it is perti-nent in the present discussion to inquirewhether antihypertensive treatment has animpact on the development of heart failure.The Veteran's Administration Cooperative

study reported in 1970 that antihypertensive

drug treatment of males with diastolic pres-sures in hospital of 90-114 mm Hg preventedthe subsequent development of heart failure(no cases in treated patients, 11 cases in thoserandomised to placebo).3738A review of recent antihypertensive drug

trials in the elderly shows a lesser frequency ofclinical heart failure in patients receiving activeantihypertensive therapy compared to thoserandomised to placebo. For example, therewas a 63% reduction in severe congestiveheart failure in the EWPHE24; 39 patientsdeveloped heart failure in the placebo arm ofSTOP compared to 19 in the actively treatedgroup25; and in SHEP, 109 placebo treatedpatients developed left ventricular failure com-pared to 56 in the active group.26

Whereas this protective action of antihyper-tensive drug treatment is clear in the elderlyand in severe grades of hypertension, it is lessobvious from many recent studies. But cardiacfailure, like mortality,3940 is an end point ofdubious usefulness for short term (two to fiveyears) interventional studies in mild to moder-ate hypertension in the early and middledecades of life. Life expectancy-in large partthrough the development of heart failure-isshortened considerably in untreated young,mild essential hypertensives,4' 42 but prematuredeath may be decades away and, at least forheart failure, is unlikely to be detectable inbrief interventional studies-except in theelderly.

If antihypertensive treatment is truly protec-tive, how does one explain the paradox ofincreasing use of antihypertensive drug ther-apy-along with (in the USA) a decline in thepopulation average for blood pressure43 yetan increasing prevalence of, hospital admis-sions for, and mortality from heart failure?43 44The answer is, most likely, that antihyperten-sive treatment postpones the development ofclinical heart failure by some years or decades,but does not prevent it for ever.45 In addition,populations in Western countries are livinglonger and are therefore able to develop heartfailure either directly from the myocardialeffects of hypertension, or following myocar-dial infarction.

Differing perspectives on preventingheart failureIn view of the discussion so far, it is.of interestto consider the recommendations of variousindividuals and the numerous "guidelines"published in recent years regarding treatmentof hypertension and prevention of heartfailure.Framingham workers stated in 1972, "It is

clear that a prophylactic approach (to prevent-ing heart failure) is indicated and that the key tothis is the early, vigorous and sustained controlof hypertension".''7 They went on to state, "Toawait the onset of symptoms or evidence oftarget-organ involvement before treatinghypertension seems imprudent".'7 They havereinforced this message repeatedly since,8 46and others concur.47By contrast, recent guidelines for the man-

agement of hypertension, while acknowledging

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treatment benefits are probably being underes-timated, focus firmly on coronary heart diseaseand stroke as the potentially preventable com-

plications,48-50 basing this perspective largelyon short term antihypertensive drug studies inmiddle aged patients.23 The extreme end of thespectrum is enunciated by the New Zealandguidelines, which suggest that antihypertensivedrug treatment for hypertension (150-170mm Hg systolic and/or 90-100 mm Hg dias-tolic) should, in general, be given only if therisk of a major cardiovascular disease event infive years is more than about 10%.1' The focusis on a five year time interval for stroke andmyocardial infarction; heart failure receives nosubstantial mention.5' These recommenda-tions would leave the vast majority of youngand middle aged hypertensives without drugtreatment for years, even decades.

Assessments of the cost-effectiveness oftreating hypertension also tend to ignore longterm implications and heart failure in particu-lar, concentrating again on prevention ofstroke and coronary heart disease from shortterm antihypertensive drug trials.52-54 TheWorld Hypertension League, at least, is awarethat "the full economic burden (of hyperten-sion) is incompletely documented since theattributable risk of hypertension to diseasesother than stroke and coronary heart disease isuncertain".55 Some commentators, whilelamenting the high economic costs of treatingestablished heart failure, fail to mention thepossibility that the early diagnosis and treat-ment of hypertension might be cost-effective.56The longer term view, discussed recently byZanchetti, should be considered.40

Clearly, the perspective of individual com-

mentators and committees is dependent uponwhether they focus dominantly on brief anti-hypertensive drug trials of middle agedpatients, or on data noted earlier in this paper,especially those from Framingham. Only thelatter emphasise the link over the long termbetween hypertension and its complications,including heart failure. The link betweenhypertension and end stage renal failure,another disorder of interest to both cliniciansand economists, likewise needs to be consid-ered in the development of managementguidelines for hypertension, if the long termview is felt to be important.57

The future: selecting hypertensivepatients for early treatmentThere is unlikely ever to be a placebo con-

trolled trial of antihypertensive treatment inmiddle aged patients lasting decades that iscapable of defining clearly the protective effectagainst heart failure (and other complicationsof hypertension); uncertainties will remainregarding which patients with mild or moder-ate essential hypertension, particularly in theearly and middle decades of life, shouldreceive drug treatment.The presence of left ventricular hypertrophy

in hypertension has powerful prognostic impli-cations for the development of heart failure, as

well as arrhythmias, sudden death, and

myocardial ischaemia.58-60 Furthermore,regression of left ventricular hypertrophy byantihypertensive therapy is associated with areduced risk of cardiovascular events, com-pared to a lack of regression.61 A case might bemade, therefore, for estimation of left ventricu-lar mass by echocardiography as a guide todrug treatment in all hypertensive individualswhere advisability of treatment is otherwiseuncertain.62 Such a policy has major implica-tions since 12-20% of mild essential hyperten-sives and 50% of mild to moderatehypertensives have left ventricular hypertro-phy.58 63 A bonus of widespread use of echocar-diography is the detection of abnormal leftventricular function, either systolic or dias-tolic, as a further guide to implementation ofantihypertensive drug treatment.

Hypertensive patients with increased circu-lating concentrations of natriuretic peptides(or more likely their propeptides, which haveslower plasma clearance rates and prolongedhalf lives in the circulation) may be entering anearly stage of atrial distension or ventriculardecompensation.64 Use of these markers hasbeen proposed for the diagnosis of heart fail-ure,65 and as a guide to angiotensin convertingenzyme (ACE) inhibitor treatment after acutemyocardial infarction.66 Their use, perhapsalong with echocardiography, in decidingwhen to introduce antihypertensive treatment,might repay scrutiny.

Other circulating factors could providesome guide for antihypertensive treatment,although available data are preliminary.Procollagen peptides, for example, mightreflect increased myocardial synthesis of type Iand type III collagen in the hypertensivestate.67 Attenuation of heightened collagensynthesis within the left ventricle by early anti-hypertensive treatment68 seems a laudablegoal; however, more information is needed.

Antihypertensive drugs, left ventricularhypertrophy, and heart failureIf early and vigorous antihypertensive treat-ment seems desirable with a view to prevent-ing long term complications, especially heartfailure, is one group of antihypertensive agentspreferable to others? No answer based on satis-factory study data exists.

In theory, antihypertensive drugs whichblock growth promoting and sodium retainingactivities could provide more protectionagainst heart failure than drugs with equalantihypertensive effects but which stimulategrowth promoting and sodium retaining activi-ties. There is widespread speculation thatACE inhibitors (and angiotensin II receptorblockers) might more successfully prevent andreverse the cardiac consequences,6970 and per-haps the vascular effects of hypertension7'rather than alternative drug groups-especiallythose which activate the renin-angiotensin andsympathetic nervous systems. Hope for suchspeculation comes from evidence, still short ofbeing definitive, that some agents, especiallyACE inhibitors, induce more rapid and possi-bly more complete reversal of left ventricular

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hypertrophy than other drug groups.74-76Seemingly contradictory results fromTOMHS77 are understandable since it was astudy ill equipped to address this particularissue.78

Additional support for the concept comesfrom SOLVD, in which a retrospective analy-sis suggested that ACE inhibition reducedmorbidity and mortality, and also hospitaladmissions for heart failure, when comparedto placebo in hypertensive patients withimpaired left ventricular systolic function.79Although a percentage of placebo patientsreceived diuretic therapy, this was not a formaldiuretic versus ACE inhibitor trial, so there isno definite comparative information.

OverviewHeart failure in Western countries is a com-mon, debilitating disorder with a high shortterm mortality. It accounts for one to two percent of total health care budgets. The mainrisk factor identified in the first half of this cen-tury, and from subsequent long term popula-tion studies, is hypertension. Antihypertensivetreatment delays, by years and perhapsdecades, the onset of heart failure. Recentpublished recommendations and cost-benefitanalyses for antihypertensive drug treatmentlargely ignore the potential benefits in the longterm from delaying the onset or preventingheart failure (and other disorders such aschronic renal failure).

Consideration should be directed to theearly identification of hypertensive patientswith evidence of cardiac abnormalities, per-haps using a combination of echocardiographyand plasma markers of myocardial dysfunc-tion. Comparative effectiveness of the differentantihypertensive drug groups in preventingand reversing the cardiovascular complicationsof hypertension needs to be clarified. In thecase of heart failure and chronic renal failure,such comparative antihypertensive drug stud-ies will need to be long term, or in elderlyhypertensives, to give useful information.

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