Myocardial Blood Flowin Congestive and Hypertrophic Cardiomyopathy

Relationship to Peak Wall Stressand Mean Velocity of Circumferential Fiber Shortening

MELVIN B. WEISS, M.D., KENT ELLIS, M.D.,ROBERT R. SCIACCA, M.S., LYNN L. JOHNSON, M.D.,

DONALD H. SCHMIDT, M.D., AND PAUL J. CANNON, M.D.

SUMMARY Myocardial blood flow/unit mass (MBF) and thedeterminants of myocardial oxygen consumption were measured inseven control subjects (group I) and 15 patients (pts) with cardio-myopathy (CM), group II (group Ila-congestive CM: 10 pts; groupIlb-hypertrophic CM: 5 pts). In group I left ventricular (LV) MBFwas 64±8 (SD) ml/lOg - min; it was significantly lower in Ila(45 ± 15 ml/lOOg. min, P < 0.01) and IIb (39±7 ml/100g min,P < 0.01). However, calculated total LV flow (LV mass X MBF)was increased in the two CM groups. In nine CM pts, LV MBF in-creased in response to atrial pacing from 41±7 to 63±13ml/lOOg * min.

PATIENTS WITH CARDIOMYOPATHY frequentlycomplain of chest pain suggestive of ischemic heart diseasedespite the presence of widely patent coronary arteries.' Inaddition, these patients often manifest varying degrees ofmyocardial hypertrophy and impaired ventricular perfor-mance. The relationship between these abnormalities andmyocardial perfusion is largely unknown. There have beenonly a few studies, each involving small numbers of patients,of the myocardial circulation in cardiomyopathies and thesestudies have yielded conflicting results.4The first purpose of this study was to measure average left

ventricular as well as regional myocardial perfusion at restin patients with cardiomyopathy and to compare the valuesobtained with those in a control group of patients with nor-

mal coronary arteriograms and normal ventricular perfor-mance. For the study, patients with cardiomyopathy were

divided into two functional categories, congestive cardio-myopathy and hypertrophic cardiomyopathy, by criteriadeveloped by Goodwin.8 In nine of the cardiomyopathypatients, myocardial blood flow was also measured duringright atrial pacing in order to evaluate the circulatoryresponse to an increase in myocardial oxygen consumption.The second purpose of this study was to investigate in man

the relationship between myocardial blood flow and three ofthe major determinants of myocardial oxygen consump-

tion: heart rate, myocardial contractility, and wall stress.'-12For this purpose, heart rate, mean velocity of circum-ferential fiber shortening (MVcf), and peak left ventricular(LV) systolic wall stress were measured in the control sub-

From the Departments of Medicine and Radiology, College of Physiciansand Surgeons, Columbia University, 630 West 168th Street, New York, NewYork.

Supported by NIH grants HL 14148 and HL 14236.Address for reprints: Dr. Melvin B. Weiss, Department of Medicine,

College of Physicians and Surgeons, 630 West 168th Street, New York, NewYork 10032.

Received July 28, 1975; revision accepted April 6, 1976.

484

In group Ila, calculated peak wall stress was normal (4.39±0.77dynes/cm' X 106) but mean velocity of circumferential fiber shorten-ing (MVcf) was significantly reduced (0.53±0.18 vs 1.26±0.12 cir-cum/sec, P < 0.01). In llb, MVcf was normal but peak stress wassignificantly reduced (2.80±0.75 vs 4.51±1.10 dynes/cm' X 106,P < 0.05). Multiple regression analysis based on all pts yielded,MBF = 16.9 MVcf + 9.30 Stress + 0.26 Heart Rate - 26.4,(r = 0.79). The data indicate that MBF is reduced in CM patientsand the regression analysis suggests that MBF in these 22 pts withnormal coronary arteriograms was determined largely by heart rate,peak stress, and ventricular performance.

jects and in the patients with congestive and hypertrophiccardiomyopathy. The aim of this part of the study was todetermine if the measured myocardial blood flow at restcould be related to these factors in patients with widely vary-ing levels of ventricular performance.

Methods

Patient Selection

All patients who were scheduled for cardiac catheteriza-tion and coronary airteriography at Columbia PresbyterianMedical Center for clinical indications were considered aspotential candidates for this study. Informed consent wasobtained from each patient for measurements of regionalmyocardial blood flow according to protocols approved bythe Human Investigation Committee and the Joint Radio-isotope Committees of this institution. The clinical indi-cations for catheterization included chest pain suggestive ofcoronary artery disease, cardiomegaly of unknown etiology,or symptoms of congestive heart failure. Patients were ex-cluded from the study if they had a history of hypertension,findings indicative of valvular heart disease, pulmonary dis-ease, pericardial disease, diabetes mellitus, or the presenceof a stenosis of greater than 50% by arteriography. Eightpatients were excluded from the study because the ven-triculograms were technically inadequate for accurate quan-titative analysis.Group I (control subjects) consisted of seven patients. At

the time of study all seven were considered normal onphysical examination and had normal chest X-rays and elec-trocardiograms. All had normal intracardiac pressures, cor-onary arteriograms, and left ventriculograms.Group II consisted of 15 patients with the clinical diag-

nosis of cardiomyopathy. All of this group had hemo-dynamic and/or ventriculographic evidence of abnormal leftventricular function, i.e., the left ventricular end-diastolicpressure was increased above normal at rest or in response

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TABLE 1. Clinical, Hemodynamic and Angiographic Data (mean - SD)Group I Group Ila Group Ilb

Age 51 -6 44 13 49 - 11Sex 6F/1M 4F/6M 2F/3MHR (beats/min) 82 6 95 16 72 ='= 10LVP (mm Hg) 116 18/8 3 110 15/16 - 10* 138 32/12 - 11LVEDV (ml/m2) 75 10 173 49** 70 10EF (%) 65='5 29 9** 68 - 17h (mm) 8.0 1.2 9.9 1.3** 15.4 - 3.8**LV Mass (g/m2) 81 - 17 166 45** 185 - 75**LVEDV/h (ml/cm) 160 34 302 j63** 88 26***P < 0.05.**P < 0.01.Statistical comparisons are against group I.Abbreviations: Group I = control; Group Ila = congestive cardiomyopathy; Group IIb = hypertrophic cardiomyopathy; HR =

heart rate; LV = left ventricular; P = pressure; LVEDV = left ventricular end-diastolic volume; EF = ejection fraction; h = LVwall thickness.

to exercise or there was angiographic evidence of anincreased left ventricular end-diastolic volume or left ven-tricular mass. The patients were subsequently divided intocongestive and hypertrophic cardiomyopathy subgroups ac-cording to criteria developed by Goodwin,8 which dependupon the ventricular functional characteristics apparent onthe left ventriculograms. Clinical, hemodynamic, and angio-cardiographic data of all groups are summarized in table 1and figure 1.Group Ila (congestive cardiomyopathy) consisted of ten

patients. All of the patients presented with symptoms andsigns of left ventricular failure. In this group left ventricularhypertrophy was associated with left ventricular dilatation.The patients fit the classification of congestive cardiomyop-athy8 because left ventricular systolic and diastolic volumeswere increased, left ventricular mass was increased, the ejec-tion fraction was reduced below the normal (i.e., < 55%)and the ratio of left ventricular end-diastolic volume to wall

thickness was increased above normal (LVEDV/h). Theetiology of the cardiomyopathy varied: ethanol, 3; peripar-tum, 2; viral, 1; idiopathic, 4.Group Ilb (hypertrophic cardiomyopathy, obstructive

and nonobstructive) was composed of five patients. All fivepatients had unexplained cardiomegaly and four of the fivecomplained of chest pain. The patients fit the classificationof hypertrophic cardiomyopathy8 because their ventriculo-grams revealed marked hypertrophy of the left ventricularfree wall, septal and papillary regions, with a left ventric-ular mass that was increased above normal but end-dia-stolic and systolic volumes and ejection fractions that werewithin the range of normal found in this and other labora-tories. The LVEDV/h ratio in this group was lower thannormal. In group Ilb, three of the five patients had restinggradients across the aortic outflow tract and one patientdeveloped a significant gradient (160 mm Hg) after twominutes of isoproterenol infusion (4 /tg/min).

(ml/mr2LVEDV

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I JIa lbFIGURE 1. Summary ofangiographic determinations in the three study groups. (group I: control, group IIa: congestivecardiomyopathy, group IIb: hypertrophic cardiomyopathy). Left ventricular end-diastolic volume (L VEDV) normalizedto body surface area was elevated in group IIa. Ejection fraction (EF) was depressed in group IIa. Left ventricular wallthickness was increased in both group IIa and group IIb and LVEDV/wall thickness was increased in group lIa anddepressed in group IIb.

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Cardiac Catheterization Technique

Left ventricular catheterization and coronary arteriog-raphy were performed with the patients in the postabsorp-tive state premedicated with secobarbital 100 mg, prometh-azine hydrochloride 25 mg, and atropine sulfate 0.5 mg. Nopatient had received propranolol within 48 hours of study.Intracardiac pressures were recorded on a switched beam os-

cillographic recorder* using Statham P23db pressuretransducers.

Initially the coronary arteriography was performed. Thenthe patient was positioned for myocardial blood flow studies.A small amount of Renografin (1-2 cc) was used to locatethe coronary arteries. A period of approximately 10 min was

allowed to elapse before the measurement of myocardialblood flow was performed. The left ventriculograms were

then performed after another lapse of approximately 20 min.Coronary arteriography was performed using the Judkins

technique.'3 All coronary arteriograms were filmed in multi-ple views on both 35 mm cine film exposed at 50 frames persecond and on serial cut films after a hand injection of from3-9 ml of contrast material. All films were reviewed by atleast three independent observers.The left ventriculograms were performed at least 20 min

following the last injection of contrast material into the cor-onary arteries. In mid-inspiration, approximately 40 ml ofsodium and meglumine diatrizoates (Hypaque-76) was

power injected over 2-3 sec into the cavity of the left ventri-cle. The ventriculograms were recorded in a shallow rightanterior oblique position, using 6 or 9 inch image intensifierson 35 mm cine film at a filming rate of 50 frames per second.The earliest well-visualized beat in each study was analyzed.Cardiac cycles following an extrasystole were not used.Analysis was limited to the first five beats after the injectionof contrast material and only to those ventriculograms inwhich all chamber margins were well visualized.'4 Allpatients were in normal sinus rhythm except E.L. (groupIla) who was in atrial fibrillation; a beat representing an

average cycle length was analyzed in this instance.

Myocardial Blood Flow Determination

Myocardial perfusion was measured at rest using radio-active '33xenon and a multiple-crystal scintillation camera as

is described and illustrated in detail elsewhere.'5 In brief, a

left anterior oblique coronary angiogram was obtained withradioactive-radiopaque markers on the chest wall in order tolocalize the heart borders. Without changing the patient'sposition the cine camera was removed and replaced by themultiple-crystal scintillation camera.t The multiple-crystalscintillation camera used for these studies contains a rec-

tangular grid of 294 separate, collimated, thallium acti-vated Nal crystals arranged in 21 columns of 14 crystals.After the locations of the radioactive markers were recordedby the camera, approximately 20-25 mCi of 133xenon was in-jected as a bolus into the left coronary artery.: The washoutof radioactivity from the heart was recorded by the scintilla-

tion camera and rate constants of tracer clearance werecomputed by a monoexponential analysis of the initial por-tions of the washout curves. Myocardial blood flow (MBF)rates were calculated using the Schmidt-Kety formula: F =

K X X/p where F is myocardial capillary flow inml/lOOg min, K is the experimentally determined rate con-

stant, X is the blood: myocardium partition coefficient (0.72)for xenon obtained by Conn in the normal dog heart16 and pis the specific gravity of myocardium (1.05). Using theradioactive-radiopaque markers, the crystals overlying theleft ventricle were then averaged and are presented as meanleft ventricular myocardial blood flow (ml/lOOg min) alongwith the standard deviation. Total left ventricular flow(ml/min) was estimated by multiplying the mean left ven-tricular flow expressed in ml/lOOg min by left ventricularmass calculated from the left ventriculogram.

Pacing Studies

In nine of the cardiomyopathy patients right atrial pacingwas instituted using a temporary demand pacing box.§Heart rate was increased in graded increments until a max-imum heart rate of 150 beats/min was attained. The tachy-cardia was then sustained for five minutes under electro-cardiographic monitoring before another myocardial bloodflow determination was performed. No patient developedchest pain or ECG changes in response to atrial pacing.

In five of the nine patients with cardiomyopathy who un-

derwent pacing, simultaneous myocardial metabolic studieswere successfully performed. A Goodale-Lubin catheter wasplaced at least two centimeters into the coronary sinus andits position was verified by an injection of a small amount ofcontrast material. The catheter was then secured in placeand was used to obtain blood samples for pH, Pco2, oxygen,and lactate analysis. Blood samples were obtainedsimultaneously at the time of the myocardial blood flowdetermination from both the coronary sinus and the prox-

imal ascending aorta at the resting heart rate and after fiveminutes of atrial pacing. Blood pH, Pco2 and Po2 were

measured using a pH meter and a blood gas analyzer.¶jArterial and coronary sinus lactate concentrations weremeasured in duplicate by an enzymatic technique.**Hemoglobin concentration was measured from a venous

blood sample.tt Oxygen saturation was determined from a

nomogram relating blood pH and P.2 to oxygen satura-tion.'7 Oxygen content was subsequently calculated from theformula: 02 content = hemoglobin concentration X oxygen

saturation X 1.34.'" The oxygen and lactate extraction ratioswere calculated as the difference between the arterial andcoronary sinus blood concentrations divided by the arterialconcentration.

Calculations

From the cineangiogram, silhouettes of the left ventric-ular cavity were drawn at end-diastole and end-systole. Thedrawings were always made to the outside margins of thepapillary muscles. The long axis of the left ventricle was

§Medtronic, Inc., Model 5880 A, Minneapolis, Minn."Radiometer, Copenhagen, Denmark.**Biochemica Test Combination, Boehringer, Mannheim GBH.ttlnstrumentation Laboratory, Inc., Co-Oximeter Model 182, Lexington,

Mass.

*Electronics for Medicine DR-12, White Plains, New York.tAutofluoroscope Model 5600, Baird Atomic, Bedford, Mass.TComparison of blood pressure and heart rate prior to the measurement of

myocardial blood flow and after the injection of "'xenon showed no signifi-cant changes in blood pressure (115.8/74.7 to 113.5/74.8 mm Hg) and asmall, but significant change in heart rate (85.6 to 88.7, P < 0.01).

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taken as the longest measured line from the apex to themargin of the aortic valve. Ventricular volumes were calcu-lated using the single plane area-length method:"9

2

V = 4/3 -7r(L)f f(1/ (2 )( 2)(1

where V = volume, Lf = length of the major axis in thefrontal projection and Df = diameter of the minor axis inthe frontal projection (calculated by the area-lengthmethod). However, the irregular shape of the ventricularchamber at end-systole in hypertrophic cardiomyopathymay limit somewhat the accuracy of this technique. Correc-tion factors for magnification were obtained from a gridfilmed in the plane occupied by the left ventricle. Regressionequation corrections were not used for reasons previouslyreported.20* A representative left ventricular wall thicknesswas measured from the RAO projection of the ventriculo-gram in end-diastole for the four centimeter segment justbelow the equator and left ventricular mass was thencalculated.2' Ejection fraction was calculated from the for-mula:

EF EDV ESVx 100 (2)EDV

where EF = ejection fraction; EDV = left ventricular end-diastolic volume; and ESV = left ventricular end-systolicvolume.Mean velocity of circumferential fiber shortening (MVcf)

was calculated from the formula:22

Mvf= EDD ESD 3MVcf =EDD LVET (3)

where EDD = left ventricular minor diameter at end-diastole; ESD = left ventricular minor diameter at end-systole (both derived by the area-length method in order toeliminate the effect of irregularities in the LV wall20); andLVET = left ventricular ejection time (sec), measured fromthe central aortic pressure tracing immediately prior to theventriculogram. There were no appreciable changes in heartrate during the filming of the angiograms. Qualitativeevaluation of all the ventriculograms did not detect any ap-parent wall motion abnormality.

Left ventricular tension and stress were calculated for theminor equatorial circumference assuming a thin-walledellipsoid as a model of the left ventricle,22 where:

Stress = h [1I- a2(2b + h)] (4)

P = pressure in dynes/cm2, b = minor semiaxis, a = majorsemiaxis, and h = wall thickness in centimeters. Values ob-tained by this formula overestimate values obtained assum-

ing a thick walled ellipsoid, but only slightly and to an extentwhich is similar when groups of patients are compared.24 25

LV tension was calculated by the following:

Tension = Stress X h (5)

Peak tension and stress were calculated by substitutinginto equation (4) the dimensions of the left ventricle at end-diastole and peak systolic pressure. Pressure was measuredfrom the left ventricular pressure curves immediately beforethe ventriculogram.The double product was calculated as the product of the

aortic peak systolic pressure and the heart rate recorded im-mediately after the intracoronary injection of "3'xenon forthe determination of myocardial blood flow. Stroke workwas calculated by multiplying the average developed leftventricular pressure by the stroke volume determinedangiographically.

Results

The mean left ventricular myocardial blood flow per unitmass of tissue averaged 64 ± 8 ml/lOOg * min at rest ingroup I (table 2, fig. 2). In both cardiomyopathy groups themean left ventricular myocardial blood flow was

significantly reduced (group Ia : 45 ± 15 ml/lOOg. min,P < 0.01, and group Ilb: 39 ± 7 ml/lOOg * min, P < 0.01).Figure 3 demonstrates the regional perfusion pattern over

the left ventricle in patient M.J. (male) with hypertrophiccardiomyopathy. Local myocardial perfusion rates were

diffusely depressed throughout the left ventricle in thispatient as in all of the other subjects with either type of car-

diomyopathy. Although blood flow/unit mass was depressedin the cardiomyopathy patients, estimated total LV myocar-

dial blood flow (the product of flow per unit mass andcalculated LV mass) was significantly increased in thepatients with either form of cardiomyopathy (group I:

86 ± 14 ml/min; group hIa: 128 ± 42 ml/min, P < 0.05;group lIb: 134 ± 48 ml/min, P < 0.05) (fig. 2).

Mean LV MBF(ml/lOOg/ min)

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I Ha I bFIGURE 2. Summary of myocardial blood flow (MBF)measurements in the three groups. Mean L VMBF (ml/lOOg - min)was reduced in group hIa and group Ilb. However, estimated totalflow (LV MBF) (LV mass X mean LV MBF), in ml/min, was

significantly elevated in the two cardiomyopathy groups.

*Paired analysis of stroke volumes determined from green dye cardiac out-put determinations (SVG) and stroke volumes determined angiographically(SVA) in 14 patients studied in this laboratory revealed no significantdifference. Furthermore, regression analysis demonstrated no significantdifferences from the line of identity. (SVA = 0.991 SVG + 2.5, r = 0.975, SE =5.87.)

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CONTROL

MEAN LV FLOW (44ml/lOOg.min)

PACING

MEAN LV FLOW (58ml1OOg.min)

LAD CIRC LAD CIRC(42 ml/lOOg min) (47m1l/OOg min) (56ml/IOOg. min) (60 mi/lOOg min)FIGURE 3. Example of the regional myocardial perfusion patterns at rest and during atrial pacing to a heart rate of 150beats/min in a patient with hypertrophic cardiomyopathy. Myocardial bloodflow (ml/lOOg * min)for the entire left ven-tricle as well as in the LAD and circumflex subregions was reduced at rest and increased uniformly in response to atrialpacing.

Regional myocardial blood flow was also measured dur-ing right atrial pacing in nine patients (seven in group Ila;two in group Ilb) (figs. 3, 4). During atrial pacing, the dou-ble product rose and mean LV myocardial blood flow in-creased significantly in all of the patients (41 ± 7ml/100g* min to 63 ± 13 ml/100g. min). Table 3 showsresults of metabolic studies in five of these patients. Myo-cardial oxygen and lactate extraction ratios were normal atrest. During atrial pacing, none of the patients demonstrateda significant increase in myocardial oxygen extraction andmyocardial lactate extraction did not change significantly.Only one patient (S. A.) manifested a slight amount of lac-tate production during pacing which was unassociated withchest pain or altered ECG.

Data obtained at rest for LV peak wall stress and meanvelocity of circumferential fiber shortening appear in table 2and figure 5. In group I, calculated peak stress averaged4.51 ± 1.10 dynes/cm2 X 105 and the mean velocity of thecircumferential fiber shortening averaged 1.26 ± 0.12 cir-cum/sec. In patients of group Ila, the average calculatedpeak stress (4.39 ± 0.77 dynes/cm2 X 105) was notstatistically different from the control patients. The averageMVcf in the patients of group Ila was significantly belowcontrol values (0.53 ± 0.18 circum/sec, P < 0.01). In thepatients of group Ilb, calculated peak stress wassignificantly reduced below the control patients (2.80 ± 0.75dynes/cm2 X 105, P < 0.05). However, MVcf was notsignificantly different (1.39 ± 0.35 circum/sec). Thus, ingroup Ila, congestive cardiomyopathy, MVcf was depressed

(ml/l10g min)100

90

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HR* BPSFIGURE 4. The mean L V perfusion rates (ml/lOg min) at restand during atrial pacing in nine patients with cardiomyopathy(group IIa, 7, group JIb, 2). Myocardial bloodflow rates are plottedagainst the double product (systolic blood pressure X heart rate).

* Control* Pacing

I I

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TABLE 2. Myocardial Perfusion and Determinants of Myocardial Oxygen ConsumptionPeak stress Peak tension Stroke Double

LV MBF LV MBF/beat MBFt MVCF (dynes/ (dynes/ work productPt/Sex (ml/100 g * min) (ml/100 g * beat) (ml/min) (circum/sec) cm2 - 105) cm * 105) (g * m) (HR -BP.)

Group IMF / F 61 11 0.76 79 1.21 5.24 3.85 76 10900PH / F 61 9 0.71 87 1.43 3.75 3.09 90 9350MO /F 59 10 0.68 105 1.40 3.20 3.13 90 9400Cs / M 63 9 0.73 101 1.20 4.45 3.37 100 8600MS / F 77 20 1.08 63 1.17 6.54 3.19 92 10700SK / F 74 8 0.94 81 1.11 4.04 3.03 54 9100PR / F 55 10 0.63 83 1.32 4.36 3.71 93 11410Mean 64 0.79 86 1.26 4.51 3.34 85 9923SD 8 -0.16 * 14 -0.12 *1.10 0.32 15 *1064

Group IIaNC / F 45 A 8 0.45 140 0.65 4.49 4.53 73 10500GO /M 40 11 0.60 123 0.30 4.01 3.67 42 5700MJ / F 43 9 0.43 123 0.45 3.72 3.67 67 13300EL /M 45 13 0.50 185 0.58 4.45 5.22 133 11500EC / M 83 * 14 0.65 145 0.78 6.25 4.84 95 16800AM / M 50 10 0.49 165 0.56 4.48 4.48 80 11000MD / M 36 7 0.36 72 0.25 3.93 3.20 26 10700JG / M 43 7 0.50 175 0.40 4.24 4.45 87 8600FL / F 24 5 0.26 74 0.61 3.51 3.49 81 8800SA / F 44 13 0.53 77 0.75 4.86 4.01 79 9800Mean 45 0.48 128 0.53 4.39 4.16 76 10670SD *15 *0.11 * 42 -0.18 0.77 0.65 29 *2954* P < 0.01 P < 0.01 P < 0.05 P < 0.01 NS P < 0.01 NS NS

Group IIbMJ / M 44 7 0.51 155 0.82 2.49 3.59 67 12000BJ / F 48 * 10 0.72 167 1.63 3.57 5.59 131 15600HJ / M 33 * 7 0.50 181 1.29 1.68 3.55 59 7900BJ / M 32 * 6 0.52 85 1.68 3.32 3.92 113 9100KW / F 40 * 6 0.50 80 1.54 2.94 2.94 77 10000Mean 39 0.55 134 1.39 2.80 3.92 89 10920SD * 7 *0.10 48 *0.35 *0.75 *1.00 31 *3014* P < 0.01 P < 0.05 P < 0.05 NS P < 0.05 NS NS NS

*Statistical comparisons are against group I.tMBF is total myocardial blood flow calculated using ventriculographic assessment of LV mass.Abbreviations: Group I = control: Group Ila = congestive cardiomyopathy; Group IIb = hypertrophic cardiomyopathy; LVMBF = left ventricular

myocardial blood flow; MVcf = mean velocity of circumferential fiber shortening; HR = heart rate; BP = systolic blood pressure; SD = standard deviation;NS = not significantly different.

and calculated peak wall stress was not different from con-trol; whereas in group Ilb, hypertrophic cardiomyopathy,peak wall stress was depressed and MVcf was not differentfrom control. There were no significant differences amongthe three groups of patients in the double product or strokework.

Multiple regression analysis was performed in order to ex-plore whether the observed variation in measured LV myo-cardial blood flow rates (range: 24 to 83 ml/lOOg * min) wasrelated to the major determinants of myocardial oxygenconsumption. The heart rate, MVcf, peak wall stress andmyocardial perfusion rates in the 22 patients were fit* toyield the following relationship:

MBF = 16.9 MVcf + 9.30 Stress + 0.26 HR - 26.4(r = 0.79)where MBF = myocardial blood flow (ml/lOOg - min), Stress= calculated peak systolic stress (dynes/cm2 X l0), MVcf =mean velocity of circumferential fiber shortening (cir-cum/sec) and HR = heart rate (beats/min). The analysis in-dicated that 63% of the total variation in LV myocardial

*Biomedical Computer Programs, Health Sciences Computing Facility,University of California, Los Angeles.

blood flow was explained by these three variables.26 In addi-tion, further testing by stepwise addition of each variable tothe multiple regression equation showed that each variable,

PEAK STRESS MVcf

(dynes/cm2.105 ) ( circumf. /sec)

1.6

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GROUP: I lIa Ib I Ia ECbFIGURE 5. Summary ofpeak wall stress and mean velocity ofcir-cumferential fiber shortening (MV0f) findings in the three groups.Peak wall stress was depressed in group IIb but normal in groupIIa. In contrast, mean velocity of circumferential fiber shorteningwas lower in group IIa but normal in group fIb.

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TABLE 3. Myocardial Metabolic Data

Control Pacing (HR = 150)Oxygen Lactate Oxygen Lactate

Content A-CS) Content (A CS) Content (A-CS) Content (A,SCPt Sex Sample (ml/100 ml) VAI 02 (mg/100 ml) A! L (ml/100 m) A 02 (mg/100 ml ) L

Group Ila M A 18.0 0.45 8.0 0.16 18.0 0.49 9.5 0.32CS 9.9 6.7 9.2 6.5

Group Ila M A 19.4 0.59 7.2 0.14 19.3 0.52 8.1 0.27CS 7.9 6.2 9.2 5.9

Group IIa F A 17.3 0.68 11.8 0.14 17.1 0.69 11.5 0.10CS 5.5 10.2 5.3 10.4

Group IIa F A 16.2 0.48 10.2 0.16 16.4 0.45 9.3 -0.04CS 8.5 8.6 9.1 9.7

Group IIb M A 21.9 0.48 7.5 0.25 21.8 0.56 6.6 0.20CS 11.3 5.6 9.7 5.3

Mean 0.54 0.17 0.54 0.17

Abbreviations: Group Ia = congestive cardiomyopathy; Group lIb = hypertrophic cardiomyopathy; A = arterial; CS = coronary sinus; A-CS)myocardial extraction ratio; HR = heart rate; L = lactate. A

individually, was signiflcantly related to myocardial bloodflow.* The standard deviation of the estimated myocardialblood flow after these three variables are included was 9.9ml/lOOg * min as compared to the average observed stan-dard deviation of the LV flow measurements, 9.6ml/lOOg * min (table 2). This analysis indicated that MVcf,peak wall stress, and heart rate were significantly related tomyocardial blood flow in these patients.

Discussion

Left Ventricular Myocardial Perfusion in Cardiomyopathy:Reduced Flow/Mass; Increased Total Flow

The present study of myocardial blood flow and ventric-ular performance in patients with cardiomyopathy wasprompted by two considerations. First, there are few studiesof cardiomyopathy in which myocardial blood flow has beensystematically measured. Second there is a paucity of infor-mation concerning the relationship between ventricular per-formance and myocardial blood flow in man.

Regional left ventricular myocardial blood flow and thethree major determinants of myocardial oxygen consump-tion [heart rate, ventricular performance (MVcf) and peakwall stress] were measured at rest in three groups of patientswith normal coronary arteriograms. The control subjectshad normal physical examinations, ECGs, and chest films,and their hemodynamic and ventriculographic measure-ments were within normal limits. The study population con-sisted of 15 patients with the clinical diagnosis of cardio-myopathy. These patients were divided into two functionalsubgroups, congestive cardiomyopathy and hypertrophiccardiomyopathy, based upon the ventriculographic findingsaccording to criteria of Goodwin.8The results indicated that mean left ventricular myo-

cardial blood flow rates were reduced in the patients withcardiomyopathy. Significant reductions in blood flow/unitmass of tissue from control values were found in both thecongestive cardiomyopathy and hypertrophic cardio-myopathy subgroups (fig. 2). As illustrated in figure 3, theflow reductions occurred diffusely throughout the ventricle;the coefficient of variation of the regional LV flow rates in

'See Appendix.

the cardiomyopathy patients was not significantly greaterthan in the controls. However, estimated total LV myo-cardial blood flow (mean LVMBF X LV Mass) in thepatients with cardiomyopathy was not reduced but was infact significantly higher than in the control group (fig. 2).This finding is consistent with large coronary arteries andrapid transit of contrast material observed frequently on thecoronary arteriograms of cardiomyopathy patients.'

Past studies of myocardial blood flow in patients with car-diomyopathies are quite contradictory. Wendt et al.,' usingthe nitrous oxide washout technique, found diminished myo-cardial blood flow per unit mass of tissue in five patients withidiopathic cardiomyopathy. Henry et al.,6 using the moresensitive helium washout technique, obtained similar results.However, Gorlin et al.5 reported that both myocardial bloodflow and myocardial oxygen consumption were normal in agroup of patients with hypertrophic cardiomyopathy.Horwitz et al.,7 using '33xenon and a single crystal detector,also reported normal average left ventricular myocardialblood flow per unit mass of tissue in a small group ofpatients with primary myocardial disease. Some of the dis-crepancies may be related to the differences in techniquesemployed to measure myocardial blood flow.27 An alter-native explanation for the wide range of reported LV perfu-sion values is that ventricular performance characteristicsvaried between the different patient groups chosen for study(see below).

Technical Considerations

Regional left ventricular myocardial blood flow rates inthe present studies were measured with "3"xenon and amultiple-crystal scintillation camera.'15 28 'The mean LVmyocardial perfusion rate in each patient was calculated byaveraging the flow rates from all of the detectors locatedover the left ventricle. It must be recalled, however, that theprimary data obtained in these studies were the rate con-stants of '33xenon clearance from the myocardium calculatedby monoexponential analysis of the initial portions of themultiple precordial washout curves. The expression of theprimary data in terms of myocardial capillary blood flow(ml/ lOOg * min) must be interpreted with caution to the ex-tent that it involves use of an assumed partition coefficient

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and assumptions inherent in monoexponential analysis oftge data. As discussed elsewhere,'5 the principle reasons forselecting this form of analysis were 1) the close correlationsbetween myocardial flow/g measured in this manner withradioxenon and flow/g measured with a coronary arteryflowmeter in normal dogs29-32 and 2) data which indicatedthat possible errors due to "'xenon in retrocardiac lung or incardiac fat would most probably be minimized by this formof analysis.28' 30 32

Possible Explanations for Reduced Flow/Mass in Cardiomyopathy

First, it is possible that the low average LV myocardialblood flow/unit mass of tissue found in the patients with car-diomyopathy was not real but apparent because a largeamount of myocardium had been replaced by fibrous tissue.This seems unlikely for three reasons: 1) The blood flow ratein fibrous tissue33 or myocardial scar34 is very low (<20ml/lOOg - min). A monoexponential analysis of the initialslope of the local '33xenon myocardial washout curves wasmade in the present study. If a significant amount of lowflow tissue were present, it would constitute a second flowcompartment in parallel with the normal myocardial tissue.The amount of tracer initially distributed to each flow com-partment following a bolus injection is proportional to therelative total flow to each compartment, i.e., flow rate perunit mass times the mass of each compartment. However,the blood flow rate per unit mass of fibrous tissue is less than25% of normal healthy myocardium. Thus, relatively littletracer would enter or leave fibrotic tissue relative to normalmyocardium during the first 40 seconds of the washout curveand therefore analysis of the initial slope of the radioxenonwashout curve would be least affected by the content offibrosis and/or fat.'5 2) The increment in LV myocardialblood flow induced by atrial pacing in the patients with car-diomyopathy was similar to that produced by atrial pacingin a control group of patients with normal coronary arterio-grams studied by Conti et al.3' If the 30% reduction inresting LV perfusion in the cardiomyopathy group were dueexclusively to replacement fibrosis, the increment in flowproduced by pacing would be expected to be proportionatelyless, not equal to that of a group of normal subjects. 3)Histological studies of hearts of autopsied patients with con-gestive3' 36 or hypertrophic37 cardiomyopathy have revealedvariable but not large amounts of intramyocardial fibroustissue.A second possible explanation for reduced resting LV per-

fusion in cardiomyopathy patients is the presence of "smallvessel" coronary disease involving vessels below the resolu-tion of current diagnostic coronary arteriography (200,t).Some pathological studies have shown scattered small vesselocclusive disease in patients with congestive and hyper-trophic types of cardiomyopathy.3810 However, no physio-logical evidence to support the hypothesis of coronary smallvessel disease was obtained in the present study. Left ven-tricular myocardial blood flow rates increased during atrialpacing (fig. 4) and there was no associated chest pain, ECGabnormalities or increase in myocardial oxygen extractionor evidence for myocardial lactate production (table 3).The fact that mean LV myocardial blood flow increased

significantly in the cardiomyopathy patients during atrialpacing does not prove that patients with cardiomyopathy do

not experience myocardial ischemia. The method formeasuring regional myocardial perfusion in the presentstudies cannot distinguish subendocardial from subepi-cardial blood flow." In the presence of a heterogeneoustransmural distribution of blood flow, we believe that theregional measurements using the present form ofmathematical analysis provide a weighted average of all flowcompartments present in the cross-section of myocardialtissue viewed by each of the scintillation crystals."5 Buckberget al.,4' using radioactive microspheres, have shown thatsubendocardial myocardial ischemia can be induced in dogswith normal coronary arteries by procedures which lowercoronary driving pressure and shorten diastolic coronary fill-ing time. It is conceivable that during exercise or otherstresses which increase myocardial oxygen consumption to agreater degree than atrial pacing, regions of subendocardialischemia might develop, particularly in the markedly hyper-trophied myocardial walls of group Ilb patients with LVoutflow gradients. Alternatively, the intercapillary distancefor diffusion of oxygen within the myocardium may increaseas cardiac muscle cells hypertrophy.42 A reduction of tissueoxygen tension might occur during an abrupt increase inmetabolic demand in this situation even if the myocardialcapillary blood flow increased by an amount appropriate fornonhypertrophied muscle.A third possible explanation for the reduced left ventric-

ular myocardial blood flow in the cardiomyopathy patientsis that myocardial metabolic demand is reduced as a conse-quence of altered functional characteristics of the hyper-trophied ventricles. Therefore, lower myocardial perfusionrates would be appropriate for reduced levels of myocardialperformance. The data of this study suggest that this may bethe most likely explanation. In group Ila, congestive car-diomyopathy, the reduction in ventricular performance asestimated by MVcf was associated with a decrease in LVmyocardial perfusion; whereas in group lIb, hypertrophiccardiomyopathy, lowered peak wall stress was associatedwith diminished myocardial perfusion.

MVcf and Peak Wall Stress in Cardiomyopathy

There is no general consensus concerning the optimalclinical index which reflects the inotropic state of the heart inpatients with heart disease. Mean velocity of circumferentialfiber shortening (MVcf) was selected as the parameter ofcardiac performance to be measured in this regard in thepresent study because it has been more sensitive in iden-tifying differences in cardiac performance among groups ofcardiac patients than indices based upon pressuremeasurements during the isovolumic phase of ventricularcontraction.43' 4 MVcf was significantly and markedlydepressed in the patients with congestive cardiomyopathy,group IIa, confirming previous observations in this dis-order6, 22 and was normal in most of the patients with hyper-trophic cardiomyopathy. MVcf has not been measured inany large group of patients with hypertrophic car-diomyopathy and the concept that ventricular performancein hypertrophic cardiomyopathy may be normal is con-troversial. However, Hugenholtz et al." using Vmax as an in-dex of ventricular performance found that nine of 11 youngpatients with left ventricular hypertrophy due to aorticstenosis and one of two patients with hypertrophic car-

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diomyopathy had a normal Vmax. Cardiac performance inhypertrophied cardiac muscle may depend on the length oftime that hypertrophy has been present, as well as otherneural and hormonal influences.46

In the present study, wall stress was calculated assuming athin wall ellipsoid model for the left ventricle. Values ob-tained by this formula are higher than values obtainedassuming a thick wall ellipsoid.25 However, the degree ofoverestimation is slight and does not differ greatly betweenpatient groups.24 Heterogeneity across the wall, bendingmovement, and shear stresses are not accounted for in suchanalysis.47 The calculated wall stress is therefore consideredonly a rough index of mean wall stress.

Peak stress was calculated using the peak systolic pressureand the dimensions of the left ventricle at end-diastole. Thisapproximation overestimates peak stress as evidenced by thehigher values for peak stress found in the controls (group I)when compared with values obtained in control patients byother investigators.24' 48 Nevertheless, in normal ventriclespeak stress occurs shortly after aortic valve opening, i.e.,before any substantial decrease in ventricular dimen-sions"48. and before the production of peak systolicpressure. Therefore peak stress measured in the mannerutilized in these studies is probably not very different fromthe true peak stress. In addition, the calculation of peakstress was performed in the same manner in all three studygroups. In congestive cardiomyopathy (group Ila) peakstress has been shown to occur slightly later and to be main-tained longer than in normal ventricles.48 The ventricles ofthese patients, however, are dilated and have low ejectionfractions8' 48, 50, 51 So that relatively little change in ventric-ular dimensions occurs before developed peak pressure ismaximal. Thus, equatorial wall stress calculated from end-diastolic dimensions and peak pressure cannot differ sub-stantially from the peak stress calculated on the basis ofsimultaneously measured pressures and dimensionsthroughout ventricular systole.

In the hypertrophic cardiomyopathy subjects (group Ilb),calculated peak left ventricular stress was significantlyreduced.48 In this group ventricular emptying has beenshown to be rapid in early systole.52 Peak stress is morelikely to occur very early in systole48 while chamber dimen-sions are still relatively unchanged from those at end-diastole. The quick rise in systolic pressure enhances thisprobability. Therefore, the use of end-diastolic dimensionsseems reasonable. If anything, calculated peak stress doneby this method would overestimate true peak stress. Despitethis negative bias, the hypertrophic cardiomyopathy groupstill had significantly lower peak stress, thus adding furthersignificance to this finding.

Determinants of Myocardial Perfusion in CardiomyopathyNumerous studies in animals and a few in humans have

established that there is a direct relationship between therate of myocardial blood flow per unit mass and the rate ofmyocardial oxygen consumption.35' 53-56 Another body of ex-perimental evidence has indicated that the major deter-minants of myocardial oxygen consumption are heart rate,myocardial contractility and peak ventricular wall stress.9-12Variations of these three factors in animal preparations wereassociated with directionally similar and proportional

changes in the oxygen consumption of the heart. Althoughthe implication of these experiments is that at rest the rate ofmyocardial blood flow per unit mass is determined by theperformance characteristics of the ventricle, there has beenonly one attempt to document this relationship in man.Henry et al.8 found that mean LV myocardial blood flow perunit mass of tissue was related directly to ventricular func-tion as estimated by MVcf in a small series of patients withventricular failure of diverse etiologies. No relationship ofblood flow to wall stress was found in that study in whichstress did not differ significantly between the control groupand the group with impaired cardiac performance.

In order to test whether the reduced mean LV myo-cardial blood flow rates in the patients with cardiomyopathymight be related to altered ventricular performance, a multi-ple regression analysis was performed. In the three groups ofpatients with normal coronary arteries but differing patternsof ventricular function, heart rate, MVcf and peak wallstress were tested as factors relating to myocardial perfu-sion. The analysis indicated that 63% of the total variation inthe mean LV myocardial blood flow rates measured at restin the 22 patients was explained by these three variables.Further testing by stepwise addition of each variable to themultiple regression equation indicated that each variable in-dividually (including peak wall stress) was related to the rateof myocardial blood flow. It must be noted, however, thatthe regression equation is merely descriptive of therelationship in these patients. It is presented only to showthe order of magnitude of the regression coefficients and isnot intended to be used in a predictive fashion. The standarddeviation of the estimated LV myocardial blood flow was 9.9ml/lOOg * min. This represents the variation that was notaccounted for by the three variables and closely approachesthe measurement variance as assessed by the average inter-crystal variation observed in each study. Thus, the analysisindicated that heart rate, MVcf, and peak wall stress weremajor determinants of the differing rates of myocardialblood flow in the three groups of patients with normal cor-onary arteries. The assumptions inherent in the techniquesutilized in this study limit our ability to quantify the in-terrelationships between the determinants of myocardialoxygen consumption and myocardial blood flow. Moredefinitive studies await the advent of more accurate quan-titative imaging techniques.The results of this study imply, therefore, that the reduc-

tions in myocardial blood flow per unit mass of tissue foundin the cardiomyopathy patients resulted from reductions inmyocardial performance: depressed ventricular performancein congestive cardiomyopathy, depressed peak wall stress inthe hypertrophic cardiomyopathy. However, the relation-ship between heart rate, MVcf, and peak wall stress andmyocardial blood flow found in the control and cardio-myopathy groups needs to be confirmed and extended bystudy of patients with other forms of heart disease. In anycase, the demonstration that mechanical characteristics ofventricular performance at rest significantly influence thebasal rates of LV myocardial blood flow in patients withnormal coronary arteriograms has implications for the studyof myocardial perfusion in patients with coronary artery dis-ease. It implies that the physiological effects of a coronarylesion which affects regional myocardial blood flow must beinterpreted against the relationship between myocardial per-

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fusion and ventricular performance which exists in that in-dividual patient.

Appendix

The computer program employed for the stepwise regression was

BMD02R, Health Sciences Computing Facility, UCLA. The computationproceeded in the following manner:

Step I

The program selected the independent variable with the highest correlationwith blood flow, peak stress, which had a correlation coefficient of 0.66. Thisvariable was entered into the regression to yield the following equation:

Flow = 9.18 Stress + 12.7The F value at this stage was 15.75 (P < 0.01) and the standard error was

11.6.

Step 2

The program then selected the remaining independent variable with thehighest partial correlation with blood flow. This variable was MVcf which hada partial correlation of 0.51. The regression equation at this stage was:

Flow = 10.32 Stress + 13.07 MVcf - 4.6The F value at this step was 13.41 (P < 0.01) and the standard error was 10.3.

Step 3

The remaining variable, heart rate, with a partial correlation of 0.33, wasthen included in the regression equation. This yielded:

Flow = 9.30 Stress + 16.9 MVcf + 0.26 H.R. -26.4The final F value was 10.22 (P < 0.01) with a standard error of 9.9.

AcknowledgmentThe authors wish to gratefully acknowledge the assistance on this project of

Drs. William Casarella, David Blood, George Mallis and John Burris andalso the technical assistance of Deborah L. Fowler, B.S., Katalin Boros,M.S., Richard Schrieber, B.S. and of Ms. Carole Michel in typing themanuscript.

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24. Hood WP, Thomson WJ, Rackley CE, Rolett EL: Comparison ofcalculations of left ventricular wall stress in man from thin walled andthick walled ellipsoidal models. Circ Res 24: 575, 1969

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50. Hamby RI, Catangay P, Apiado 0, Khan AH: Primary myocardial dis-ease. Clinical, hemodynamic and angiocardiographic correlates in fiftypatients. Am J Cardiol 25: 625, 1970

51. Gould KL, Lipscomb K, Hamilton GW, Kennedy JW: Relation of leftventricular shape, function and wall stress in man. Am J Cardiol 34: 627,1974

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Retrograde Coronary Artery Flowin Aortic Valve Disease

ROBYN J. CARROLL AND HERMAN L. FALSETTI, M.D.

SUMMARY Retrograde coronary artery flow was observed angi-ographically in 43 patients with aortic stenosis and/or regurgitation.

In the 24 patients with pure or predominant aortic stenosis,retrograde flow was seen in all 24 during end-systole. In the eightpatients with pure aortic regurgitation, retrograde flow was seenmainly during end-diastole (6/8). Among the 11 patients with stenosisand regurgitation, retrograde flow was both end-systolic and end-diastolic. Dominant left coronary arteries were seen in 13 patients;13 showed retrograde flow in the dominant arteries. Dominant rightcoronary arteries were seen in 25 patients: all 25 showed retrogradeflow equally in the right and left coronary. Five of the 43 patientscould not be evaluated for dominance because of coronary artery

THE MECHANISM OF ANGINA PECTORIS is a sub-ject of great interest, especially in patients with aortic valvedisease and normal coronary arteries. It is suspected thatthese patients have inadequate coronary flow in spite of nor-mal coronary arteries. Several experimental studies ofphasic coronary flow have shown reverse systolic flow indogs with congenital subaortic stenosis' and reverse diastolicflow in dogs with mechanically induced aortic regurgita-tion.2 Although phasic coronary flow has not been in-vestigated in patients with aortic valve disease, it has beenshown that patients with aortic stenosis have impaired cor-onary vascular reserve3 and subendocardial underper-fusion.4 Abnormalities of phasic coronary flow can be seenon the coronary arteriograms of patienrts with aortic stenosisand/or aortic regurgitation, but have not yet been describedin detail. The purpose of this study is to describe angio-graphic retrograde coronary flow in a series of patients withaortic valve disease and to correlate it with clinical informa-tion and hemodynamic parameters.

From the Cardiovascular Center, Department of Internal Medicine,University of Iowa and Veterans Administration Hospitals, Iowa City, Iowa.Supported in part by grants from the Iowa Heart Association, University

of Iowa College of Medicine, Veterans Administration and NationalInstitutes of Health Grant HL 014388.Address for reprints: Robyn J. Carroll, Division of Cardiology, Mount

Sinai School of Medicine, 5th Avenue and 100th Street, New York, NewYork 10029.

Received June 9, 1975; revision accepted March 29, 1976.

occlusions. The severity of retrograde flow did not correlate withusual clinical, hemodynamic or tension-stress parameters: angina,electrocardiographic abnormality, end-diastolic pressure or volume,end-systolic pressure or volume, ejection fraction, severity of aorticregurgitation, peak or mean valve gradient, aortic valve area, myo-cardial tension and stress calculations, or DPTI:SPTI.

In summary, retrograde coronary artery flow was seen in all 43patients with severe aortic valve disease. The time in the cardiac cyclewhen retrograde flow occurred was related to the type of valve dis-ease. Retrograde flow was seen mainly in the coronary arteriessupplying the left ventricle and may result from increased regionalmyocardial stresses.

Methods

Proximal coronary artery retrograde flow was evaluatedin 43 consecutive patients (33 male, 10 female, ages 33 to 67)with aortic stenosis and/or aortic regurgitation. All patientsincluded in the study had undergone diagnostic cardiaccatheterization because of syncope, chest pain, and/or con-gestive heart failure. Informed consent was obtained fromall patients. Catheterization was carried out with patientsunder mild sedation (sodium pentobarbital, meperidine, orpromethazine hydrochloride), local anesthesia, and in thefasting state. Pressures were recorded with fluid-filledcatheters connected to P23Db Statham transducers. The leftventricle was injected with 25 to 40 ml of meglumine diatri-zoate and sodium diatrizoate (Renografin 76) from acatheter passed retrograde across the aortic valve ortranseptally. Cineangiograms were made at 60 frames persecond with the patients in the right anterior obliqueposition during deep inspiration. Selective coronary arteri-ography was performed by either the Sones or Judkinstechnique after administration of nitroglycerin. Coronaryarteriograms were recorded on all patients using a 6* imageintensifier on 35 mm film. Some patients had additionalangiograms recorded on 70 mm spot film (1-4 frames/sec).Aortic angiograms were performed by injecting 25 to 50 mlof meglumine diatrizoate (Renografin 76) from a catheterplaced 2 to 3 cm above the aortic valve in either the rightanterior or left anterior oblique position. Cardiac output

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M B Weiss, K Ellis, R R Sciacca, L L Johnson, D H Schmidt and P J Cannonpeak wall stress and mean velocity of circumferential fiber shortening.

Myocardial blood flow in congestive and hypertrophic cardiomyopathy: relationship to

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