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Am J Physiol Heart Circ Physiol 275: H1274-H1282, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 4, H1274-H1282, October 1998

Effect of treadmill exercise on transmural distribution of blood flow in hypertrophied left ventricle

Dirk J. Duncker1,2, Yutaka Ishibashi1, and Robert J. Bache1

1 Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455; and 2 Laboratory for Experimental Cardiology, Thoraxcenter, Erasmus University, 3000 DR Rotterdam, The Netherlands

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

Pressure-overload left ventricular (LV) hypertrophy (LVH) is associated with increased vulnerability to subendocardial hypoperfusion during exercise. Abnormal perfusion could be the result of failure of the coronary vessels to grow in proportion to the degree of myocyte hypertrophy or could be due to increased extravascular forces acting on the intramural coronary vasculature. This study assessed the contribution of extravascular forces by examining the effect of exercise on the distribution of myocardial blood flow when coronary vasomotor tone was abolished with a maximal vasodilating dose of intracoronary adenosine. One year after ascending aortic banding in six dogs, the LV-to-body weight ratio was 7.80 ± 0.38 g/kg compared with 4.57 ± 0.20 g/kg in nine normal dogs (P < 0.01). Under awake resting conditions blood flow in LVH hearts increased from 1.17 ± 0.27 ml · min-1 · g-1 during basal conditions to 5.78 ± 1.06 ml · min-1 · g-1 during adenosine (at a coronary pressure of 100 ± 6 mmHg), whereas in normal dogs blood flow increased from 1.22 ± 0.17 to 5.26 ± 0.71 ml · min-1 · g-1 (at a coronary pressure of 62 ± 4 mmHg). At rest the transmural distribution of blood flow during adenosine was not different between hypertrophied and normal hearts, with subendocardial-to-subepicardial (Endo-to-Epi) blood flow ratios of 1.01 ± 0.09 and 1.14 ± 0.13, respectively (P = not significant). During adenosine infusion, treadmill exercise to produce heart rates of 200-220 beats/min caused redistribution of blood flow away from the subendocardium that was much more marked in LVH (Endo-to-Epi blood flow ratio = 0.35 ± 0.04) than in normal hearts (Endo-to-Epi blood flow ratio = 0.76 ± 0.09, P < 0.05 vs. LVH). In comparison with normal, the exaggerated decrease in subendocardial blood flow produced by exercise in LVH hearts resulted from abnormally increased extravascular compressive forces, including a greater decrease in diastolic duration and an increase in LV end-diastolic pressure.

coronary artery; extravascular compressive forces; adenosine; diastole; subendocardium

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

LEFT VENTRICULAR (LV) hypertrophy (LVH) secondary to chronic pressure overload is associated with increased susceptibility to subendocardial hypoperfusion and ischemia during exercise (2, 7, 25). Abnormal perfusion in the hypertrophied heart has been ascribed to 1) decreased vascular density, which occurs as the coronary vessels fail to grow in proportion to the degree of myocardial hypertrophy (36), 2) hypertensive vascular changes due to exposure of the coronary vessels to high perfusion pressure (23), or 3) increased extravascular forces acting on the intramural coronary vessels (17). Data obtained from coronary pressure-flow curves in isolated hearts (38) as well as in open-chest (17) and awake resting dogs (19) indicate that both minimum coronary vascular resistance and extravascular compressive forces are abnormally increased in the hypertrophied LV. Furthermore, we observed that exercise caused an exaggerated increase in zero-flow pressure in hypertrophied hearts (19), suggesting that an abnormally great increase in extravascular compressive forces contributes to limitation of coronary blood flow (20).

Although these previous studies documented abnormalities of the mean coronary pressure-flow characteristics in the hypertrophied heart, they did not assess the influence of exercise-induced changes in extravascular forces on the transmural distribution of myocardial blood flow. This is of importance because both clinical observations and experimental findings have demonstrated that the subendocardium of the hypertrophied LV is especially vulnerable to ischemia during exercise (2). Consequently, the present study was carried out to investigate the effects of exercise on the transmural distribution of myocardial blood flow in chronically instrumented awake dogs with pressure-overload LVH. Maximum coronary vasodilation was produced with adenosine to eliminate the influence of active vasomotion and directly reveal the effects of extravascular forces on the distribution of myocardial blood flow. Adenosine was administered by the intracoronary route to avoid potentially confounding systemic hemodynamic effects.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Studies were performed in 15 mongrel dogs, 6 animals with LVH, and 9 normal controls. All experiments were performed in accordance with the "Guiding Principles in the Care and Use of Laboratory Animals" as approved by the Council of the American Physiological Society and with prior approval of the Animal Care Committee of the University of Minnesota.

Production of Supravalvular Aortic Stenosis

At 6-9 wk of age, six dogs were sedated with acepromazine (0.4 mg/kg im) and anesthetized with thiamylal sodium (25-30 mg/kg iv), intubated, and ventilated with oxygen-enriched room air. A thoracotomy was performed through the third right intercostal space. The ascending aorta was dissected from the surrounding tissue ~1.5 cm above the aortic valve and encircled with a polyethylene band 2.5 mm in width. While LV and distal aortic pressures were measured simultaneously, the band was tightened until a 20- to 25-mmHg peak systolic pressure gradient was achieved across the aortic constriction. The chest was then closed, air was evacuated from the thorax, and the animals were allowed to recover. Thereafter, animals were maintained in enclosed runs on a standard laboratory diet until 10-14 mo of age, at which time they were returned to the laboratory for study.

Surgical Instrumentation

After sedation with acepromazine (0.5 mg/kg im), dogs were anesthetized with pentobarbital sodium (30-35 mg/kg iv), intubated, and ventilated with a mixture of oxygen (30%) and room air (70%). Respiratory rate and tidal volume were set to keep arterial blood gases within physiological limits. A left thoracotomy was performed through the fifth intercostal space, and the heart was suspended in a pericardial cradle. A polyvinyl chloride catheter of 3.0 mm OD and filled with heparinized saline was inserted into the left internal thoracic artery and advanced into the ascending aorta. Similar catheters were introduced into the right and left atria through the atrial appendages and the LV at the apical dimple. A solid-state micromanometer (model P5, Konigsberg Instrument Company, Pasadena, CA) was also introduced into the LV at the apex. Approximately 1.5 cm of the proximal left anterior descending coronary artery (LAD) was dissected free, and a Doppler flow velocity probe (Hartley, Houston, TX) was positioned around the artery. Immediately distal to the flow probe a hydraulic occluder (3.0 mm OD) was placed around the vessel. A silicone catheter (0.3 mm ID) bonded to a larger silicone catheter (1.6 mm ID) was introduced into the coronary artery immediately distal to the hydraulic occluder. The pericardium was then loosely closed, and the catheters and electrical leads were tunneled subcutaneously to exit at the base of the neck. The chest was closed in layers, and the pneumothorax was evacuated. Catheters were flushed daily with heparinized saline.

Hemodynamic Measurements

Studies were performed with the animals in the awake state 2-3 wk after surgery. Recordings of phasic and mean aortic pressure and coronary perfusion pressure were measured with Gould P23XL pressure transducers positioned at midchest level. LV pressure was measured with the micromanometer that was calibrated from the fluid-filled LV catheter. The first derivative of LV pressure (LV dP/dt) was obtained via electronic differentiation of the LV pressure signal. Mean coronary pressure was measured with the silicone catheter in the LAD. Phasic and mean coronary blood flow were measured with a Doppler flowmeter system (Hartley). Data were recorded on an eight-channel direct-writing oscillograph (Coulbourne Instruments, Lehigh Valley, PA).

Myocardial Blood Flow

To measure the transmural distribution of coronary blood flow, we injected ~3 × 106 microspheres, 15 µm in diameter and labeled with 141Ce, 51Cr, 85Sr, 95Nb, or 46Sc (NEN, Boston, MA), into the left atrium. Before injection, microspheres were agitated for 15 min in an ultrasonic bath. An arterial blood reference sample was withdrawn at a constant rate of 15 ml/min, starting 10 s before injection of microspheres and continuing for 90 s.

At the end of the experiment, the area perfused by the LAD was identified by injection of 5 ml of Evans blue dye into the coronary artery catheter. Immediately thereafter, the dogs were killed with an overdose of intravenous pentobarbital in accordance with the "Guiding Principles in the Care and Use of Animals" of the American Physiological Society. The hearts were excised, weighed, and fixed in 10% buffered Formalin. The atria, aorta, right ventricular free wall, and large epicardial blood vessels were dissected from the LV and discarded. Duplicate samples were obtained from the center of the blue-stained region of the LV perfused by the LAD and were divided into four layers of equal thickness from epicardium to endocardium and placed in vials for counting. Each myocardial sample weighed at least 0.5 g so that the minimum number of microspheres was >400 per sample. Myocardial and blood reference samples were counted in a gamma spectrometer (model 5912, Packard Instrument, Downers Grove, IL). The counts per minute (cpm) of radioactivity and the corresponding sample weights were entered into a digital computer programmed to correct for background activity and to calculate the corrected cpm per gram of myocardial tissue. Blood flow to the myocardial specimen (Qm, ml · min-1 · g myocardium-1) was computed as Qm = Qr × Cm/Cr, where Qr is the rate of withdrawal of reference blood sample (ml/min), Cm is the radioactivity of the myocardial specimen (cpm/g myocardium), and Cr is the radioactivity of the reference blood sample (cpm).

Experimental Protocol

Dogs were studied in the awake state in random order under control conditions or during maximum vasodilation produced by infusion of adenosine (50 µg · kg-1 · min-1) into the coronary artery catheter. This dose of adenosine usually produced maximal coronary vasodilation, as evidenced by absence of reactive hyperemia after a 15-s coronary artery occlusion and no further increase in coronary blood flow when the dose was increased to 100 µg · kg-1 · min-1. These criteria were not met in two of the nine control animals and in one of the six LVH animals, in which the dose was increased to 100 µg · kg-1 · min-1. This dose caused maximal vasodilation in all animals. Adenosine was dissolved in warm saline so that the desired dose was infused at a rate of 0.3-0.6 ml/min.

After the dogs had been standing quietly on the treadmill for 10 min, baseline measurements were made of LV, aortic, and coronary pressures, maximal rate of rise of LV pressure (LV dP/dtmax), and coronary blood flow velocity, and radioactive microspheres were injected to determine the transmural distribution of myocardial blood flow. Subsequently, animals received either no treatment or an intracoronary infusion of adenosine. Dogs were then exercised at 6.4 km/h at 15% grade. After 3 min of exercise, when systemic and coronary hemodynamics had reached a stable level, hemodynamic measurements were repeated, and radioactive microspheres were injected.

Data Analysis

Heart rate, LV peak systolic and end-diastolic pressures (measured at the onset of positive LV dP/dt), LV dP/dtmax, mean aortic and mean coronary pressures, mean coronary Doppler shift, and duration of diastole (taken as time interval between onset of positive LV dP/dt and 20 ms before peak negative LV dP/dt) were measured from the strip-chart recordings. Coronary blood flow was computed using the equation Q = 2.5Delta f · d2, where Q is the coronary blood flow (in ml/min), Delta f is the Doppler shift (in kHz), and d is the internal diameter of the coronary artery (in mm) within the flow probe (31). The factor 2.5 is a constant derived from the speed of sound in tissue (c = 1.5 × 105 cm/s), the ultrasonic frequency of the sound beam emitted (f0 = 10 MHz), the cosine of the angle at which the sound beam is emitted (45°), and unit conversion factors: [c · (pi /4) · 3]/(2f0 · cos 45°) (31). Because in the chronically instrumented animals the flow probe adheres to the coronary artery, the internal diameter of the flow probe is equal to the external diameter of the artery. To obtain the inner diameter of the coronary artery, we subtracted the arterial wall thickness, which in our experience is 20% of the external diameter of the coronary artery. In this way, any error in the computation of the coronary internal diameter would affect control and intervention conditions equally.

Intragroup comparisons of data were performed using one-way ANOVA with replications. When a significant effect was observed, individual comparisons were made using the Wilcoxon signed-rank test and a modified Bonferroni correction (29). To compare measurements obtained in dogs with LVH with those obtained in normal animals, we used two-way ANOVA. When a significant effect was observed, individual comparisons were made with the Mann-Whitney U test and a modified Bonferroni correction (29). Multivariate stepwise regression analysis was performed using all individual data points from each animal to determine the contributions of exercise-induced changes in duration of diastole and in LV end-diastolic pressure to the responses of subendocardial-to-subepicardial (Endo-to-Epi) blood flow ratio in normal and LVH dogs during maximal coronary vasodilation. Statistical significance was accepted at P <=  0.05 (2-tailed). All data are presented as means ± SE.

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Anatomic data. LV weight of the animals with supravalvular aortic stenosis was 182 ± 14 g compared with the 108 ± 6 g for the normal dogs (P < 0.05). Body weights were similar in normal (23.6 ± 0.8 kg) and LVH animals (23.3 ± 1.3 kg). The LV-to-body weight ratio was 7.80 ± 0.38 g/kg in the six dogs with aortic banding vs. 4.57 ± 0.20 g/kg in the normal animals (P < 0.05), representing a 71% increase in relative LV mass.

Systemic Hemodynamics

Basal conditions. Under resting conditions heart rate and mean arterial pressure in the normal animals were 128 ± 8 beats/min and 91 ± 5 mmHg, respectively (Table 1). These values were not different from those in the dogs with LVH (107 ± 4 beats/min and 82 ± 3 mmHg, respectively). LV systolic (198 ± 8 mmHg) and end-diastolic (14.9 ± 2.0 mmHg) pressures were higher in the LVH dogs than in the normal animals (113 ± 3 and 3.9 ± 1.4 mmHg, respectively; both P < 0.01). LV dP/dtmax and maximal rate of fall of LV pressure (LV dP/dtmin) were not different in the LVH and normal animals.

                              
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  		Table 1.   Effects of exercise on systemic hemodynamics under basal conditions and during intracoronary infusion of adenosine in normal dogs and dogs with LVH

Treadmill exercise in the normal animals increased heart rate to 210 ± 8 beats/min (P < 0.01), mean aortic pressure to 114 ± 3 mmHg (P < 0.01), LV systolic pressure to 146 ± 3 mmHg (P < 0.01), LV dP/dtmax to 4,950 ± 340 mmHg/s (P < 0.01), and LV dP/dtmin to -4,540 ± 480 mmHg/s (P < 0.01) but had no significant effect on LV end-diastolic pressure (Table 1). Exercise caused similar increases in heart rate, LV dP/dtmax, and LV dP/dtmin in LVH animals, but the increases in LV systolic pressure (to 272 ± 14 mmHg) and LV end-diastolic pressure (to 32.9 ± 4.9 mmHg) were significantly greater than in the normal animals. Unlike the normal animals, in LVH animals mean aortic pressure failed to increase in response to exercise.

Maximal coronary vasodilation with adenosine. Under resting conditions, intracoronary infusion of adenosine had no effect on any of the systemic hemodynamic variables in either the normal or LVH dogs (Table 1). In addition, adenosine had no effect on the systemic hemodynamic responses to exercise in either experimental group.

Coronary Hemodynamics

Basal conditions. Under resting conditions mean coronary artery pressure was higher in the LVH dogs (112 ± 3 mmHg) than in the normal animals (87 ± 6 mmHg, P < 0.01) (Table 1). LAD blood flow (ml/min) was 70% higher in LVH than in the normal dogs (P < 0.05), which paralleled the 69% greater absolute LV mass. Treadmill exercise produced an increase in coronary artery pressure that was significantly greater in the LVH animals (to 151 ± 6 mmHg) than in the normal animals (to 104 ± 4 mmHg, P < 0.05). Exercise produced 66 ± 8 and 69 ± 6% increases in coronary blood flow in normal and LVH animals, respectively.

Maximal coronary vasodilation with adenosine. During resting conditions adenosine produced a nearly fourfold increase in coronary artery blood flow in both groups (Table 1). The increments in coronary flow were accompanied by decreases in distal coronary artery pressure that reached levels of statistical significance in the normal animals. During adenosine infusion coronary pressure increased from 62 ± 4 mmHg at rest to 79 ± 4 mmHg during exercise (P < 0.01) in the normal animals, whereas coronary blood flow did not change. During adenosine infusion in the LVH animals, exercise increased mean coronary pressure from 100 ± 6 at rest to 142 ± 6 mmHg (P < 0.01). Despite the greater increase in coronary pressure in the LVH animals (P < 0.05 vs. normal animals), exercise did not alter coronary artery blood flow during adenosine infusion in these animals (Table 1).

Regional Myocardial Blood Flow

Basal conditions. Under basal resting conditions, mean transmural blood flow normalized per gram of myocardium was similar in the normal and hypertrophied LV (Table 2). The transmural distribution of blood flow favored the subendocardium in the normal animals, whereas blood flow was more evenly distributed across the LV wall in the LVH group (Fig. 1), reflected by the Endo-to-Epi blood flow ratios in the normal animals (1.49 ± 0.09) and LVH dogs (1.12 ± 0.11) (Table 2). During exercise, myocardial blood flow increased uniformly across the LV wall in normal dogs. In contrast, in the LVH animals the increase in blood flow produced by exercise was significantly greater in the subepicardium than in the subendocardium (Fig. 1). As a result, the Endo-to-Epi blood flow ratio during exercise was lower in the LVH animals (0.82 ± 0.10) than in the normal dogs (1.26 ± 0.07; P < 0.05).

                              
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  		Table 2.   Effects of exercise on blood flow in the myocardium perfused by the LAD under basal conditions and during infusion of adenosine into the LAD in normal dogs and dogs with LVH


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  		Fig. 1.   Myocardial blood flow in 4 layers across the left ventricular (LV) anterior wall of 9 normal dogs (A) and 6 dogs with LV hypertrophy (LVH; B) from outer [subepicardial (Epi)] to inner [subendocardial (Endo)] layer. Myocardial blood flow data are shown at rest (open symbols) and during exercise (filled symbols), both in absence (circles) and presence (squares) of intracoronary adenosine (50-100 µg · kg-1 · min-1). OM, outer midmyocardium; IM, inner midmyocardium. * P < 0.05, exercise vs. rest; dagger  P < 0.05, LVH vs. normal.

Maximal coronary vasodilation with adenosine. Under resting conditions, adenosine produced a four- to fivefold increase in myocardial blood flow measured with microspheres in both normal and LVH animals so that mean flow was not different between the normal and hypertrophied LV (Table 2, Fig. 1). Furthermore, Endo-to-Epi blood flow ratios during adenosine infusion were also not significantly different between the normal and hypertrophied ventricles, indicating that at rest the flow reserve in the hypertrophied LV was transmurally homogeneous. Exercise did not significantly alter mean myocardial blood flow during adenosine infusion in either the normal or hypertrophied hearts. However, exercise caused a transmural redistribution of blood flow away from the subendocardium in both groups. This redistribution of flow was most marked in the hypertrophied LV, in which the Endo-to-Epi blood flow ratio fell from 1.01 ± 0.09 at rest to 0.35 ± 0.04 during exercise, compared with the normal animals in which the Endo-to-Epi blood flow ratio decreased from 1.14 ± 0.13 at rest to 0.76 ± 0.09 during exercise. In the normal animals the transmural redistribution of blood flow produced by exercise resulted from a decrease in flow to the subendocardium, as well as an increase in subepicardial flow. In the hypertrophied hearts exercise caused a more prominent decrease in subendocardial blood flow that was significant for the inner two myocardial layers, as well as an increase of subepicardial flow that was greater than in the normal animals.

Figure 2 shows the effect of exercise on the duration of diastole, expressed as seconds per minute spent in diastole, in normal and LVH dogs. There was no difference in diastolic duration between normal and LVH dogs under resting conditions, but during exercise the duration of diastole shortened significantly more in the LVH compared with the normal animals. Figure 3 presents the Endo-to-Epi blood flow ratios during adenosine infusion in normal and hypertrophied hearts at rest and during exercise as a function of the diastolic duration (Fig. 3A) or LV end-diastolic pressure (Fig. 3B). Stepwise multivariate regression analysis (using all individual data points from each animal) indicated that diastolic duration and LV end-diastolic pressure together could explain 73% of the variability (r2) of the Endo-to-Epi blood flow ratio in normal and hypertrophied hearts. With the regression coefficients obtained from multivariate stepwise regression analysis and with the use of the Endo-to-Epi blood flow ratio of the normal dogs under resting conditions as a starting point (offset point), the dashed lines show the predicted changes in Endo-to-Epi blood flow ratios based on a change in either the diastolic duration or the LV end-diastolic pressure. The data show that in the normal dogs the exercise-induced decrease in Endo-to-Epi blood flow ratio could be explained entirely by the decrease in diastolic perfusion time. In contrast, in the LVH dogs the exercise-induced decrease in Endo-to-Epi blood flow ratio resulted from both the decrease in diastolic perfusion time and an increase in LV end-diastolic pressure.


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  		Fig. 2.   Diastolic duration in 9 normal dogs (open symbols) and 6 dogs with LVH (filled symbols) at rest and during exercise in presence of intracoronary adenosine. * P < 0.05, exercise vs. rest; dagger  P < 0.05, LVH vs. normal.


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  		Fig. 3.   Subendocardial-to-subepicardial (Endo-to-Epi) blood flow ratios in hypertrophied (squares) and normal (circles) dogs at rest (open symbols) and during treadmill exercise (filled symbols) in presence of maximum coronary vasodilation produced by intracoronary infusion of adenosine. Endo-to-Epi blood flow ratios have been plotted as a function of diastolic perfusion time (A) and LV end-diastolic pressure (LVEDP; B). Dashed lines represent predicted relation based on stepwise multivariate regression analysis, i.e., using the regression coefficients obtained from multivariate stepwise regression analysis and the Endo-to-Epi blood flow ratio of normal dogs under resting conditions as a starting point (offset point).

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

This is the first report examining the effect of LVH on the transmural distribution of myocardial blood flow during exercise in the maximally vasodilated coronary circulation in which adenosine was administered by the intracoronary route to avoid potentially confounding systemic hemodynamic effects. During resting conditions adenosine caused marked increases of myocardial blood flow that were not different between normal and hypertrophied LV, likely because coronary perfusion pressure was higher in the hypertrophied than in the normal hearts. At rest the transmural distribution of blood flow was essentially uniform across the LV wall in both normal and hypertrophied hearts. During adenosine infusion exercise caused a decrease of subendocardial blood flow that was markedly greater in hypertrophied than in normal hearts. The findings indicate that exercise causes abnormally great increases of extravascular forces in the hypertrophied heart that preferentially limit blood flow to the subendocardium.

Maximum Myocardial Blood Flow During Resting Conditions

Several laboratories have reported that LVH is associated with increased myocardial intercapillary distances, which are most marked in the subendocardium (10, 16, 43). However, studies of renovascular hypertensive rats (37) and dogs (43), as well as dogs (8) and swine (11) subjected to ascending aortic banding, failed to demonstrate a significant decrease in arteriolar densities in either the subendocardial or subepicardial layer. Vascular abnormalities might also result from chronic exposure of the coronary vessels to high perfusion pressures, independently of the degree of myocardial hypertrophy. Vascular medial hypertrophy has been described in coronary arterioles of hypertensive rats (23, 37, 44), but normal vessel wall-to-lumen ratios were observed in aortic banded swine (11) and renovascular hypertensive dogs (42, 43). Bishop et al. (8) banded the ascending aorta of dogs at 8 wk of age to result in a 68% increase in LV mass 10-14 mo later. Small arteries (OD >100 µm) showed a significant increase in wall-to-lumen ratio, but arterioles (OD <100 µm) had nearly normal wall-to-lumen ratios. Furthermore, no differences were observed between the subendocardial and subepicardial layers. Alyono et al. (1) reported that maximum myocardial blood flow rates were decreased in dogs with LVH secondary to valvular aortic stenosis in which coronary pressures were not increased, indicating that hypertensive vascular changes are not required to account for the impaired minimum coronary vascular resistance in the hypertrophied LV. The increased length of the coronary vessels required to subtend the hypertrophied ventricle could contribute to the increased resistance to blood flow. Furthermore, there is evidence for a greater than normal pressure loss across the intramural penetrating arteries that supply the subendocardium in the hypertrophied LV (24).

Several previous studies in awake resting dogs with pressure-overload LVH have examined the distribution of blood flow across the LV wall during maximal coronary vasodilation produced by intravenous infusion of adenosine. In canine models of renovascular hypertension the transmural distribution of myocardial blood flow during maximal coronary vasodilation is not different from normal, although in these models the degree of hypertrophy is usually modest (LV wt-to-body weight ratios of 5.0-6.5 g/kg) (35, 36, 42, 43). Studies in canine models of supravalvular aortic stenosis, which produces a greater degree of hypertrophy (LV wt-to-body wt ratios of 7.0-9.0 g/kg), have generally reported significantly lower Endo-to-Epi blood flow ratios compared with normal dogs (3, 8, 26). Hemodynamic alterations produced by intravenous adenosine could have contributed to the lower Endo-to-Epi blood flow ratios in these previous studies. Intravenous adenosine in doses sufficient to produce maximal coronary vasodilation (generally 1 mg · kg-1 · min-1) can decrease mean arterial pressure by as much as 30 mmHg (3, 8, 26). The resultant reflex tachycardia would be expected to cause transmural redistribution of blood flow away from the subendocardium (6). Only one previous study failed to find an Endo-to-Epi blood flow ratio less than normal in LVH animals during intravenous adenosine (6). In that study heart rates were maintained constant by atrial pacing at 100 beats/min, which may account for the similar distribution of blood flow in the normal and hypertrophied hearts. Hittinger et al. (26) reported that intravenous adenosine decreased diastolic and systolic wall stresses in normal animals but, paradoxically, diastolic and systolic stresses remained elevated in the hypertrophied hearts. When LV wall stresses were reduced by hemorrhage, the Endo-to-Epi blood flow ratio during adenosine infusion was no longer lower in hypertrophied than in normal hearts. The present study demonstrates that when systemic hemodynamic changes are minimized by administering adenosine by the intracoronary route, the increase in myocardial blood flow during maximal coronary vasodilation is essentially uniformly distributed across the hypertrophied LV wall in the resting awake animals.

Myocardial Blood Flow During Exercise With Intact Coronary Vasomotor Tone

In the presence of normal coronary vasomotor tone, exercise caused a modest decrease of the Endo-to-Epi blood flow ratio in the normal hearts, although even during exercise subendocardial blood flow was significantly greater than subepicardial flow. In normal dogs myocardial lactate consumption continued and vasodilator reserve was not exhausted during heavy treadmill exercise in dogs, suggesting that the decreased Endo-to-Epi blood flow ratio did not result in ischemia (4, 33, 45). In the hypertrophied hearts exercise resulted in relative subendocardial underperfusion with an Endo-to-Epi blood flow ratio significantly less than 1.0. This was not the result of exhaustion of vasodilator reserve in this region, suggesting that the smaller increase of subendocardial blood flow during exercise does not imply subendocardial ischemia, although vasodilator reserve can persist in ischemic myocardium (34). Hittinger et al. (27) reported that, unlike normal dogs in which exercise resulted in increased systolic wall thickening in both the subendocardium and subepicardium, in animals with pressure-overload hypertrophy exercise resulted in increased subepicardial wall thickening but decreased subendocardial thickening. Subendocardial wall thickening decreased within the first 3 s after the onset of exercise, at a time when LV pressure and wall stresses had not increased (28). This suggests that the decreased Endo-to-Epi blood flow ratio in the hypertrophied hearts during exercise may have been the result of relatively lower metabolic demands in this region rather than insufficient perfusion. It is possible that heavier levels of exercise that result in greater oxygen demands could cause exhaustion of vasodilator reserve in the subendocardium. This is supported by data of Hittinger et al. (27), who reported that after a period of heavy exercise (heart rates of ~250 beats/min) subendocardial wall thickening remained below preexercise levels for up to 1 h, suggesting postischemic subendocardial stunning.

Effect of Exercise on Maximum Myocardial Blood Flow

During adenosine infusion, exercise caused an exaggerated redistribution of blood flow away from the subendocardium in the hypertrophied LV. This implies that in the hypertrophied heart exercise produced an exaggerated increase in extravascular compressive forces that selectively impeded blood flow to the inner half of the LV wall. Increased compressive forces during systole could have resulted from increased LV systolic elastance or the higher LV systolic pressure during exercise (15, 39, 40), whereas compressive forces during diastole were increased by the shorter duration of diastole and increased diastolic intracavitary pressure. Without measurements of LV volume and wall thickness it is not possible to estimate LV elastance. Furthermore, it is difficult to differentiate between the contributions of LV systolic pressure and diastolic pressure because both of these variables increased during exercise. In previous studies we found that LV end-diastolic pressure is the better predictor of the greater impediment of coronary blood flow in hypertrophied compared with normal hearts (17, 19). Also, LV end-diastolic pressure was shown to be the better predictor of blood flow impediment caused by treadmill exercise in both normal hearts and hypertrophied hearts (19). On the basis of these findings we entered diastolic duration and end-diastolic pressure into the multivariate stepwise regression program; the resultant analysis indicated that the greater decrease in the duration of diastole together with the increase in LV end-diastolic pressure contributed to the greater decrease in Endo-to-Epi blood flow ratio in the hypertrophied LV.

An interesting finding was that, during maximal coronary vasodilation, exercise caused an increase in subepicardial blood flow. This increase in subepicardial blood flow occurred in the normal hearts but was especially marked in the hypertrophied hearts. The increase in subepicardial blood flow was likely facilitated by the increase in coronary artery pressure that occurred during exercise. It has been demonstrated previously that when coronary inflow was limited to systole, blood flow to the outer half of the LV was essentially normal, whereas blood flow to the inner half of the wall was decreased in proportion to the depth of the muscle layer (12). This implies that during systole intramyocardial pressure in the outer half of the LV wall is less than coronary artery pressure so that blood flow can continue relatively unimpeded. Thus the increase in subepicardial flow during exercise may be due in part to the increase in systolic pressure proximal to the constricting band in animals with hypertrophy. However, atrial pacing also tended to increase subepicardial blood flow during maximum coronary vasodilation with adenosine even though pacing caused a slight decrease in coronary pressure in LVH dogs (6), indicating that other factors contributed to the increase in subepicardial flow. In the maximally vasodilated coronary circulation, subendocardial blood flow is lower in the beating heart than in the nonbeating heart (at identical coronary pressures), whereas subepicardial blood flow is higher in beating compared with nonbeating hearts (22, 30). This transmural redistribution of flow occurs because the compressing effect of cardiac contraction pumps blood from the subendocardial vessels in a retrograde direction, while antegrade flow continues in the subepicardial vessels during systole (12). It is likely that this mechanism, which has been termed the "intramyocardial pump" (41), contributed to the increase in subepicardial blood flow during exercise in the present study. Spaan et al. (41) demonstrated that the systolic intramyocardial pumping action of the contracting myocardium is facilitated by a coronary stenosis, which increases the oscillatory component of pressure while decreasing the diastolic-systolic variations in main stem flow. In the supravalvular aortic stenosis model, coronary pressure is high during systole, thus opposing retrograde flow out of the main stem, and antegrade systolic flow is high. These conditions would act to augment the redistribution of blood from subendocardium to subepicardium during systole. It is less likely that such an increase in subepicardial blood flow would occur when pressure-overload hypertrophy results from aortic valve stenosis in which coronary pressure during systole is not increased.

It is possible that adrenergic coronary vasoconstriction during exercise could have contributed to the decrease of the Endo-to-Epi blood flow ratio in the hypertrophied hearts. Adenosine causes vasodilation principally of coronary arterioles <150 µm in diameter (14, 32), whereas alpha 1-adrenergic receptors are present in coronary microvessels of all sizes (13). During maximal vasodilation of the arterioles, up to 45% of coronary resistance is located in vessels with a diameter >150 µm (14); adrenergic constriction of these segments might increase minimum coronary resistance and impede coronary flow. The intramural penetrating arteries that supply blood to the innermost layers of the ventricle represent a special case. These small arteries have diameters of 200-500 µm (9, 21), a size range that would be expected to respond to adrenergic vasoconstriction. Constriction of these vessels during exercise could act to selectively restrict blood flow to the subendocardium. Previously we reported that in dogs with LVH produced by ascending aortic banding, alpha 1-adrenergic tone restrained the exercise-induced increase in coronary flow (5, 18) so that, after alpha 1-adrenergic blockade with prazosin, coronary flow during exercise was ~25% greater than during control exercise. However, the adrenergic limitation of blood flow in the hypertrophied LV was transmurally uniform across the wall from epicardium to endocardium (18). Those findings suggest that the exercise-induced redistribution of blood flow in the hypertrophied LV during maximum vasodilation in the present study was not the result of exaggerated alpha -adrenergic vasoconstriction of the intramural penetrating arteries.

In conclusion, under resting conditions the distribution of maximum myocardial flow (and hence flow reserve) across the LV wall was not different between normal and hypertrophied ventricles. The finding of a normal transmural distribution of maximum myocardial blood flow under resting conditions implies that the abnormal redistribution of maximum blood flow away from the subendocardium in the hypertrophied hearts during exercise was not caused by structural vascular abnormalities but is the result of abnormally increased extravascular compressive forces.

    ACKNOWLEDGEMENTS

The authors acknowledge the expert technical assistance provided by Melanie Crampton, Bryan Jones, and Paul Lindstrom.

    FOOTNOTES

This study was supported by National Heart, Lung, and Blood Institute Grants HL-21872 and HL-20598. D. J. Duncker's research was made possible in part by a Research Fellowship awarded by the Royal Netherlands Academy of Arts and Sciences.

Address for reprint requests: R. J. Bache, Cardiovascular Div., Dept. of Medicine, Univ. of Minnesota Medical School, Box 508 UMHC, 420 Delaware St. SE, Minneapolis, MN 55455.

Received 2 September 1997; accepted in final form 21 May 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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Am J Physiol Heart Circ Physiol 275(4):H1274-H1282
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