Effects of exercise on blood flow in the hypertrophied heart

Effects of Exercise on Blood Flow in the Hypertrophied Heart

ROBERT J. BACHE, MD, FACC THOMAS I?. VROBEL, MD

Minneapolis,

Minnesota

From the Department of Medicine (Division of Cardiology), University of Minnesota School of Medicine, Minneapolis, Minnesota. This study was supported by U. S. Public Health Service Grants HL-20598 and HL-2 1872 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Dr. Bathe is the recipient of Research Career Development Award l-K04-HL00367 from the U. S. Public Health Service. Manuscript received June 8, 1979. accepted June 15, 1979. Address for reprints: Robert J. Bathe, MD, University of Minnesota Hospitals, Department of Medicine, Box 338-Mayo Memorial Bldg, Minneapolis, Minnesota 55455.

This study was carried out to examine the response of regional myocardial blood flow to exercise in normal dogs and in dogs with left ventricular hypertrophy. Left ventricular hypertrophy, with an approximately 50 percent increase in left ventricular mass, was produced by means of perinephritic hypertension. The animals were studied approximately 5 months after the induction of hypertension. Myocardial blood flow to four transmural layers of the left ventricular wall was measured using left atrial injections of 15 p radioactive microspheres at rest and during two levels of treadmill exercise to increase heart rates to 200 and 260 beats/min, respectively. Mean left ventricular blood flow during resting control conditions was similar in the two groups of dogs. In addition, blood flow increased similarly during exercise so that heart rate or the product of heart rate and systolic blood pressure predicted myocardial blood flow equally well in normal dogs and in those with left ventricular hypertrophy. During resting conditions, subendocardial btood flow significantly exceeded subepicardial blood flow in normal dogs, but exertion abolished this perfusion gradient, resulting in uniform transmural myocardial blood flow during exercise. In contrast, in dogs with left ventricular hypertrophy, blood flow to the subendocardium of the left ventricle significantly exceeded subepicardial blood flow both at rest and during exercise. Nevertheless, this study failed to demonstrate any exercise-induced perfusion deficit within the hypertrophied left ventricle.

Previous clinical and experimental data have demonstrated that the pressure-overloaded hypertrophied heart may exhibit abnormal contractile function, which may eventually lead to cardiac failure.1-3 Linzbach4 suggested that the basis for this abnormality may reside in the inability of the coronary vasculature to increase proportionately with the degree of myocardial hypertrophy. In support of this, patients with left ventricular hypertrophy may have angina pectoris and changes in electrocardiographic repolarization consistent with subendocardial ischemia in the absence of demonstrable coronary artery disease.2 Despite these findings suggesting inadequate coronary perfusion, myocardial blood flow is generally within normal limits in the hypertrophied heart during resting conditions. 5,6 However, any potential perfusion abnormality would be most likely to occur during periods of increased cardiac activity when the ability of the coronary vascular system to deliver blood is maximally taxed. In support of this hypothesis, several recent studies suggest that myocardial blood flow in the hypertrophied heart may not increase normally during coronary vasodilation produced by pharmacologic vasodilators or during reactive hyperemia.7-g However, these stimuli for vasodilation may not behave identically with coronary vasodilation, which occurs in response to increased myocardial oxygen consumption. Because no previous measurements of blood flow in the hypertrophied heart during exercise are available, this study was designed to assess the ability of myocardial blood flow in the hypertrophied heart to respond

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to the physiologic stress of exercise. Studies were carried out in chronically instrumented awake dogs in which left ventricular hypertrophy had been produced by perinephritic hypertension as well as in normal control dogs.

pressures, as well as left ventricular pressure at both normal and high gain for measurement of end-diastolic pressure, were recorded continuously on an eight channel direct-writing oscillograph. Measurements of regional myocardial blood flow were made using serial injections of microspheres 15 p in diameter labeled with gamma-emitting radionuclides cerium141, strontium-85, and niobium-95 (3M Company), diluted in 10 percent low molecular weight dextran. Before injection the microspheres were mixed for at least 15 minutes in an ultrasonic bath. During each intervention, approximately 3 X lo6 microspheres were injected through the left atria1 catheter over a 15 second interval. Beginning 5 seconds before injection, a reference sample of arterial blood was withdrawn from the aortic catheter at a constant rate of 15.0 ml/min for 90 seconds. Measurements of myocardial blood flow were made during quiet resting conditions and during two levels of exercise that increased heart rates to approximately 200 beats/min (light exercise) and 260 beats/min (heavy exercise). The mean speed and grade were: light exercise 3.0 miles/hour and 5 percent grade; heavy exercise 4.0 miles/hour and 10 percent grade. Microspheres were injected 3 minutes after the dog had achieved the desired speed and grade, and the exercise was continued for 2 minutes after completion of the injection. Hemodynamic variables were monitored continuously to ensure that a steady state existed before and after the injection of microspheres.

Methods Production

Studies were carried out in

of hypertension:

11 adult mongrel dogs weighing 21 to 29 kg. Six dogs served as controls, whereas in five animals left ventricular hypertrophy was produced by means of perinephritic hypertension. The dogs to be made hypertensive were anesthetized with intravenous sodium pentobarbital (25 mg/kg body weight), a left flank incision was made under sterile conditions and the left kidney was dissected free and loosely wrapped in silk. The wrapped kidney was returned to its normal position, the incision closed and the animal allowed to recover. Four to 6 weeks after the initial operation, the dog was reanesthetized and a right nephrectomy was performed with use of a right flank incision. Postoperatively, blood pressure measurements were taken at weekly intervals using a Doppler ultrasound transducer (Arterio-Sonde model 1020); all dogs included in the study sustained at least a 50 mm Hg increase in systolic blood pressure after operation. The reliability of cuff blood pressure measurements was established by comparison with intraarterial pressure obtained by direct puncture of the femoral artery in each dog. After recovery from operation, the animals were trained to run on a motor-driven treadmill. Experimental preparation: Four to 7 months after the initial operation (mean 5.7 f 0.7 months), the dogs were anesthetized with sodium pentobarbital(25 mg/kg), ventilated with a respirator and subjected to left thoracotomy at the fourth intercostal space. A polyvinyl catheter, with a 3.5 mm outside diameter, was inserted into the ascending aorta by way of the left internal thoracic artery. Similar catheters were inserted into the left atrium and left ventricle and secured in place with purse-string sutures. The catheters were filled with heparin-saline solution and tunneled into a subcutaneous pouch at the base of the neck. This same surgical procedure was carried out in the six normal control dogs. Retraining on the treadmill was begun 5 to 7 days after operation, and the studies were performed 14 to 21 days after thoracotomy. Pressure and myocardial blood flow measurements: On the day of study the three catheters were attached to miniature pressure transducers (Ailtech Model MSlO) that were fastened at the mid chest level to a nylon vest that the dog had been trained to wear. In addition, the arterial catheter was attached to a constant rate withdrawal pump to facilitate blood sampling. Phasic and mean aortic and mean left atria1

TABLE

Anatomic myocardial specimens: After completion of the

study, the dog was killed with a lethal dose of sodium pentobarbital. The heart was removed and fixed in 10 percent buffered formalin. After fixation, the atria and great vessels, right ventricle and epicardial vessels were dissected from the left ventricle. The left ventricle was then weighed and divided into six circumferential regions representing the intraventricular septum, posterior free wall, posterior papillary muscle region, lateral wall, anterior papillary muscle region and anterior free wal1.l” The myocardium from each region was divided into four transmural layers of equal thickness from epicardium to endocardium, weighed and placed in vials for counting. For the remainder of this report, these layers will be referred to as layers 1 through 4, layer 1 being the most epicardial and layer 4 the most endocardial layer. Myocardial and blood reference samples were counted in Packard model3912 gamma counting system at window settings corresponding to the peak energies of each radionuclide. The counts per minute recorded in each energy window were corrected for background activity and for overlapping counts contributed by the accompanying isotopes with a digital computer. Blood flow to each myocardial specimen (Q,) was computed using the formula Qm = Q&,,/C,, where Qr = reference blood flow (mUmin), C, = counts/min of myocardial

I

Hemodynamic Data at Rest and During Two Levels Left Ventricular Hypertrophy (LVH) Heart Rate (beatsjmin) N Rest Exercise Light Heavy

of Exercise

in Six Normal

Dogs (N) and Five Dogs With Hypertension

MAP LVH

93 f 6

99 f 4

192 f 7 250 f 8

200 f 4 259 f 8

LVSP

N

LVH

N

and

LVEDP LVH

N

92 f 9

139 f

15’

124f

11

169 f

16’

4fl

112f8 130 f 10

174 f 198 f

18” 19”

147 f 172 f

11 16

222 f 22’ 258 f 21‘

5f2 5f2

LVH 6f2 12 f 4’ 13 f 2’

P (probability) <0.05 in comparison with normal dogs. Values are mean f standard error of the mean. LVEDP = left ventricular end-diastolic pressure (mm Hg); LVSP = left ventricular systolic pressure (mm Hg); MAP = mean arterial pressure (mm Hg). l

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specimen and C, = counts/min of reference blood specimen. The blood flow from each myocardial specimen (ml/min) was divided by sample weight and expressed as milliliters per minute per gram of myocardium. Data from individual myocardial specimens were examined using a threeway analysis of variance test for significant effects of the experimental in-

/ 0 Normal

Y”)

? Left Ventricular Hypertrophy

tervention, the circumferential position and the transmural layer on blood flow. When significant effects were found, pair-wise comparisons were performed to determine where significant differences existed. Because the circumferential position of the myocardial specimen was not found to exert a statistically significant effect on blood flow, data from all six circumferential regions were pooled. Thus, during each intervention all myocardial blood flow data were reduced to the mean values representing the four transmural layers. Mean left ventricular blood flow for each intervention was determined by averaging flow to all left ventricular samples for each dog. Endocardial/epicardial blood flow ratios were obtained by dividing flow to layer 1 by flow to layer 4.

/ /

Results

y=o.O/64x-0404 r=09/

/’

Blood pressures and left ventricular weight (Table I): Mean left ventricular weight for the six normal dogs was 103 f 5 g whereas the average body weight was 23.6 f 1.0 kg, with a left ventricular/body weight ratio of 4.3 f 0.2 g/kg. The body weight of the hypertensive dogs was similar at 24.1 f 1.2 kg whereas the mean left ventricular weight was increased to 153 f 16 g (P
TABLE

AND VROBEL

Heart

Rate (beats/min)

FlGtjRE 1. Mean left ventricular myocardial blood flow is plotted against heart rate for each dog studied at rest and during light and heavy exercise. The regression equation with 95 percent confidence limits is shown for the six normal animals. There was no significant difference in the relationship of myocardial blood flow to heart rate between the normal dogs and dogs with left ventricular hypertrophy.

of animals at rest and showed similar progressive increaser; with exercise. Examination of the relation between mean myocardial blood flow and heart rate showed a close linear correlation between these variables that was virtually identical in the normal dogs and in the dQgs with left ventricular hypertrophy (Fig. 1). Similarly, plotting the product of heart rate and systolic blood pressure against myocardial blood flow demonstrated a linear relation that was similar in the normal dogs and in the dogs with left ventricular hypertrophy (Fig. 2). Although myocardial blopd flow per unit mass

II

Hemodynamic Data at Rest and During Two Levels of Exercise in Six Normal Dogs (N) and Five Dogs With Hypertension and Left Ventricular Hypertrophy (LVH) Light Exercise

Rest Data MBFIg (ml/min.g) MBFltotal LV (ml/min) Endo/Epi CVR/g of myocardium (mm Hg/ml-mineg) CVWtotal LV (mm Hg/ml-min)

Heavy Exercise LVH N

N

LVH

N

LVH

1.15 f 0.11

1.50 f 0.08

2.69 f 0.28

2.84 f 0.29

3.74 f 0.37

4.43 f 0.21

125 f 17 1.28 f 0.12+

239 f 82’ 1.32 f 0.08+

301 f 37 1.13 f 0.11

473 f 109’ 1.21 f 0.06+

388 f 45 1.05 f 0.08

708 f 114’ 1.09 f 0.05

77.1 f 6.5

92.7 f 9.9’

44.6 f 6.3

62.4 f 5.5’

36.7 f 6.0

44.9 f 3.9

0.72 f 0.06

0.64 f 0.09

0.42 f 0.05

0.43 f 0.05

0.35 zt 0.05

0.30 f 0.02

l P < 0.05 in comparison with normal dogs. + P <0.05 in comparison with endo/epi of 1.0. Values are mean f standard error of the mean. CVR = coronary vascular resistance; Endo/Epi = flow to layer l/flow to layer 4; LV = left ventricle; LVH = left ventricular hypertrophy; MBF = myocardial blood flow.

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/ /’ y=OO702x+ -0570 r=O83

20

00

Heart

Rate

I

I

I

40

60

00

x Systolic

Blood Pressure

x.16’

FIGURE 2. Mean left ventricular myocardial blood flow is plotted against the heart rate X systolic blood pressure product for each dog studied at rest and during light and heavy exercise. The regression equation with 95 percent confidence limits is shown for the six normal animals. There was no significant difference in the relationship of myocardial blood flow to the heart rate X systolic blood pressure product between normal dogs and dogs with left ventricular hypertrophy.

was similar in the two groups of dogs, the larger left ventricular mass resulted in a greater total left ventricular blood flow in the hypertensive animals both at rest and during exercise (P <0.05) (Table II). Coronary vascular resistance per unit of myocardial mass was significantly greater in the dogs with left ventricular hypertrophy at rest and during light exercise (P <0.05) but was not significantly different from that in the control dogs during heavy exercise (Table II). However, because of the increased left ventricular mass in the hypertensive dogs, there was no significant difference in total left ventricular coronary vascular resistance between the normal and hypertensive dogs (Table II). Examination of the transmural distribution of perfusion demonstrated that subendocardial blood flow exceeded subepicardial blood flow in both groups of dogs at rest (Table II). In the normal dogs, exercise resulted in 2 significant decrease in the endocardiallepicardial flow ratio to values that were not significantly different from unity. In the animals with left ventricular hypertrophy the endocardial/epicardial flow ratio remained significantly greater than 1.0 during light exercise, but decreased to a value not significantly different from unity during heavy exercise.

Discussion In response to perinephritic hypertension, the dogs in our study sustained an approximately 50 mm Hg increase in resting mean arterial pressure that was associated with an approximately 50 percent increase in

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relative left ventricular mass. This degree of hypertrophy is similar to that reported from other laboratories7J1 in which renovascular or perinephritic hypertension was produced in dogs. Renal function, as assessed from serum creatinine and blood urea nitrogen levels, was not compromised throughout the course of this study, and the animals remained vigorous with a normal hematocrit level and stable body weight. In addition, they were able to exercise as well as the normal dogs, so that there was no difference between the two groups of animals in the amount of external work required to attain a given increment in heart rate. Left ventricular end-diastolic pressures were normal at rest in the dogs with left ventricular hypertrophy but increased significantly during exercise. However, because no independent measurement of myocardial mechanical function was available, it is not clear whether this increase in left ventricular end-diastolic pressure during exercise was the result of decreased left ventricular compliance associated with the increased myocardial mass or whether it represented some degree of ventricular dysfunction that became manifest during the stress of exercise.12 Myocardial blood flow in normal versus hypertensive dogs: There was no significant difference in blood flow per gram of myocardium at rest or during exercise between the normal dogs and those with left ventricular hypertrophy. This similarity in blood flow between normal and hypertrophied hearts is in agreement with the concept that as the hypertrophic response results in thickening of the left ventricular wall, systolic stress (and thus the myocardial oxygen requirement) decreases in proportion to the increased wall thickness to return to normal or near normal levels.13 The regression equation relating mean myocardial blood flow (MBF) to heart rate (HR) in both the normal and hypertensive dogs in this study (MBF = 0.0164 HR 0.404) compares very well with the relation observed in normal human subjects during upright exercise (MBF = 0.0187 HR - 0.650).14 Thus, the absolute values for myocardial blood flow and the response of myocardial blood flow to exercise appear to be remarkably similar in the normal human heart and in the normal and the hypertrophied dog heart. Transmural distribution of blood flow in hypertrophied versus normal heart: Few previous data are available on the transmural distribution of myocardial blood flow in the hypertensive heart with left ventricular hypertrophy. Mueller et a1.7 found no difference in the pattern of transmural perfusion between normal and hypertrophied hearts during resting conditions, and flow to the subendocardium exceeded subepicardial flow in both groups. Similarly, in our study subendocardial blood flow exceeded subepicardial flow in both normal and hypertrophied hearts at rest. Because coronary autoregulation appears to regulate blood flow in response to myocardial metabolic needs, the higher subendocardial flow observed in normal hearts may reflect higher oxygen consumption in the subendocardium, a concept that is in agreement with theoretic and experimental data indicating that the

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greatest systolic wall stress exists in the subendocardium of the normal heartI In the normal dogs, exercise abolished the transmural heterogeneity of perfusion so that blood flow became essentially uniform. In the hypertrophied heart the transmural perfusion gradient favoring the subendocardium also persisted during light exercise, although it was abolished during heavy exercise. Thus, in this experimental model of left ventricular hypertrophy, exercise did not reveal any tendency toward underperfusion of the subendocardium. Coronary vasodilation reserve capacity: In dogs with left ventricular hypertrophy secondary to renovascular hypertension, Mueller et a1.7 observed that the maximal cross-sectional area of the total left ventricular coronary bed during coronary vasodilation produced by infusion of adenosine did not appear to increase as hypertrophy of the myocardium occurred. However, because aortic pressure was increased approximately in proportion to the increase in left ventricular mass, the ability to perfuse maximally the left ventricle was not impaired because of the increased coronary perfusion pressure. The animals in our study showed a normal ability to increase myocardial blood flow during exercise, and there was no evidence of impaired coronary perfusion. However, the minimal coronary vascular resistance attained during heavy exercise in this study

AND VROBEL

was still approximately twice the minimal coronary resistance observed by Mueller et al7 during adenosine infusion. Thus, even during the relatively heavy level of exercise used in our study, considerable vasodilator reserve capacity would be present within the left ventricular vasculature. Clinical implications: The data from this study indicate that the heart rate and the product of heart rate and systolic blood pressure may be used to predict myocardial blood flow during exercise in the dog with left ventricular hypertrophy just as they are used in the normal dog heart. The finding that the regression equation describing the relation between myocardial blood flow and heart rate in these dogs was essentially similar to that previously observed in normal human subjects suggests that this relation would also be similar in human subjects with hypertension and left ventricular hypertrophy.14 Although our study failed to demonstrate any perfusion abnormality at rest or during treadmill exercise in these dogs with left ventricular hypertrophy and a normal coronary arterial anatomy, the occurrence of occlusive coronary artery disease in clinical hypertension and left ventricular hypertrophy would be expected to result in perfusion abnormalities based on the extent of the coronary vascular disease present.

References 1 Mason DT: Regulation of cardiac performance in clinical heart disease: interaction between contractile state, mechanical abnormalities and ventricular compensatory mechanisms. Am J Cardiol 32:437-448, 1973 2. Goodwin JF: Hypertrophic diseases of the myocardium. Prog Cardiovasc Dis 16: 199-238, 1973 3. Cooper G IV, Sataba RM,Harrison CE, Coleman HM III: Mechanisms for abnormal energetics in pressure-induced hypertrophy in cat myocardium. Circ Res 33:213-223, 1973 4. Linzbach AJ: Heart failure from the point of view of quantitative anatomy. Am J Cardiol 5370-382, 1960 5. Rowe GG, Castillo CA, Maxwell GM, Crumpton CW: A hemodynamic study of hypertension including observations on coronary blood flow. Ann Intern Med 54:405-412, 1961 6. Malik AB, Abe T, O’Kane H, Geha AS: Cardiac function, coronary flow and oxygen consumption in stable left ventricular hypetlrophy. Am J Physiol225:186-191, 1973 7. Mueller TM, Marcus ML, Kerber RE, Young JA, Barnes RW, Abboud FM: Effect of renal hypertension and left ventricular hypertrophy on the coronary circulation in dogs. Oirc Res 42:543-549, 1978 8. O’Keefe DD, Hoffman JIE, Cheitlln R, O’Neill MJ, Allard JR, Schapkin E: Coronary blood flow in experimental canine left

ventricular hypertrophy. Circ Res 43:43-51, 1978 9. Rembert JC, Kleinman LH, Fedor JM, Wechsler AS, Greenfield JC Jr: Myocardial blood flow distribution in concentric left ventricular hypertrophy. J Clin Invest 62:379-386, 1978 10. Ball RM, Bathe RJ, Cobb FR, Greenfield JC Jr: Regional myocardial blood flow during graded treadmill exercise in the dog. J Clin Invest 5543-49, 1975 11. West JW, Mercker H, Wendel H, Foltz EL: Effect of renal hypertension on coronary blood flow, cardiac oxygen consumption and related circulatory dynamics in the dog. Circ Res 7:476-485, 1959 12 Kennedy JW, Twiss RD, Blackman JR, Dodge HT: Quantitative angiocardiography. Relationships of left ventricular pressure, volume and mass in aortic valve disease. Circulation 38:838-845, 1960 13. Meerson FZ: The myocardium in hyperfunction, hypertrophy and heart failure. Circ Res 25:ll-82-11-99, 1969 14. Kitamura K, Jorgensen CR, Gobel FR, Taylor HL, Wang Y: Hemodynamic correlates of myocardial oxygen consumption during upright exercise. J Appl Physiol 32:516-522, 1972 15. Wong AVK, Rautaharju PM: Stress distribution within the left ventricular wall approximated as a thick ellipsoidal shell. Am Heart J 75:649-662, 1968

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