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
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
1029
BLOOD FLOW IN HYPERTROPHIED HEART-BACHE
AND VROBEL
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)
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
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
1029
BLOOD FLOW IN HYPERTROPHIED HEART-BACHE
AND VROBEL
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)
