Hemodynamic Mechanisms Responsible for Reduced Subendocardial Coronary Reserve in Dogs With Severe Left Ventricular Hypertrophy
Background Reduced subendocardial coronary reserve is a hallmark of left ventricular hypertrophy (LVH). The goal of this study was to determine whether hemodynamic, as opposed to structural, mechanisms were responsible for the reduced subendocardial coronary reserve.
Methods and Results The effects of near-maximal vasodilation with adenosine were examined in 10 conscious dogs with LVH (79% increase in ratio of LV weight to body weight) induced by aortic banding in puppies with and without preload reduction. At baseline, LV end-diastolic pressure, LV end-diastolic circumferential and compressive radial wall stresses, and LV myocardial blood flow were similar in dogs with LVH and sham-operated controls, while LV end-systolic circumferential wall stress tended to be greater in the LVH group compared with the control group. In control dogs, adenosine reduced LV circumferential end-systolic and end-diastolic wall stresses and compressive radial subendocardial wall stress; LV subendocardial blood flow increased (from 1.41±0.16 to 3.58±0.27 mL · min−1 · g−1) and the ratio of subendocardial to subepicardial blood flow decreased from 1.30±0.07 to 0.69±0.05. In dogs with LVH, during adenosine infusion, LV circumferential end-systolic and end-diastolic wall stresses and LV radial subendocardial wall stresses remained elevated, the increase in LV subendocardial blood flow was significantly smaller (from 1.11±0.11 to 2.27±0.24 mL · min−1 · g−1, P<.05), and the subendocardial/epicardial ratio fell to a lower level (from 1.22±0.17 to 0.35±0.03, P<.05). When LV wall stresses during adenosine were reduced in a subgroup of 5 dogs with LVH, the endocardium/epicardium ratio during adenosine infusion was no longer different from that in control dogs (0.63±0.11), nor was the level of subendocardial blood flow different (3.42±0.60 mL · min−1 · g−1).
Conclusions These data suggest that hemodynamic factors, eg, compressive forces, are an important component of the reduced subendocardial coronary reserve as opposed to structural alterations, even in the presence of severe LVH.
Reduced subendocardial coronary reserve in response to physiological stress such as pacing,1 2 3 4 5 exercise,6 7 8 9 10 11 or the coronary vasodilator adenosine1 2 12 is a hallmark of left ventricular hypertrophy (LVH). Increased vulnerability to abnormal perfusion in the hypertrophied heart has been ascribed to structural alterations, eg, vascular rarefaction or vascular hypertrophy,13 14 although a role for hemodynamic factors, eg, increased extravascular forces, has also been implicated.15 16 17 In dogs with severe LVH and heart failure, exhaustion of subendocardial blood flow reserve is associated with myocyte necrosis and fibrosis, suggesting that structural alterations play an important role in the development of heart failure.12 Furthermore, a recent study from our laboratory demonstrated in dogs with severe but compensated LVH that there were no transmural differences in vascular morphology and no reduction in volume percentage capillary space, suggesting that at this phase of the process of hypertrophy, structural alterations may not be the primary mechanism responsible for the reduced subendocardial coronary reserve.18 In support of this concept, it is well recognized that compressive forces across the myocardial wall affect the coronary circulation.15 16 17 18 19 20
Therefore, the goal of the present investigation was to examine the effects of near-maximal coronary vasodilation with adenosine infusion on regional myocardial blood flow in control dogs and in dogs with severe but compensated LVH under normal conditions and in dogs with LVH when preload was altered. In one set of experiments, preload was normalized in the dogs with LVH to match responses in sham-operated control dogs. In another set of experiments, preload was elevated further in dogs with LVH. It was considered important to calculate global circumferential and regional radial wall stresses because our hypothesis was that the compressive subendocardial radial stress, rather than structural changes, dictated the abnormal subendocardial blood flow response during near-maximal coronary vasodilation in dogs with LVH.
The rationale for evaluating this additional wall stress component stems from the fact that radial wall stress is the only compressive stress; the other two components, namely circumferential and meridional, are tensile.
Mongrel puppies of either sex 8 to 10 weeks of age were anesthetized with sodium thiamylal 12.5 mg/kg, maintained with halothane (1 vol%), and ventilated with a respirator (Harvard Apparatus). A right thoracotomy was performed through the fourth intercostal space with sterile surgical technique. The ascending aorta above the coronary arteries was isolated and dissected of surrounding tissue. A 1-cm-wide Teflon cuff was placed around the aorta and tightened until a thrill could be palpated over the aortic arch, and the chest was closed. In the littermates designated as controls, a right thoracotomy was performed, the aortic root dissected, and the chest closed without implantation of a band. The Teflon band created a fixed supravalvular aortic lesion, which became relatively more stenotic as the puppies grew.
Implantation of Instrumentation
At approximately 1 year of age, 10 adult aortic-banded (LVH) dogs, 6 additional nonbanded but sham-operated littermates, and 3 mongrel dogs were instrumented. After induction with sodium thiamylal (12.5 mg/kg) and maintenance with halothane anesthesia (1 to 2 vol%), an incision was made in the fifth left intercostal space by use of sterile surgical technique. Tygon catheters (Norton Elastics and Synthetic Division) were implanted in the descending thoracic aortas and left atria of all the dogs and in the LV chambers of the banded dogs. In all dogs, piezoelectric ultrasonic dimension crystals were implanted on opposing anterior and posterior endocardial surfaces of the left ventricle to measure LV ID. Full-wall thickness was also measured in all dogs by implantation of piezoelectric ultrasonic dimension crystals on opposing endocardial and epicardial surfaces in the same equatorial plane as the ID crystals. Endocardial crystals were placed through a stab wound in the epicardium and advanced obliquely to, but not through, the endocardium. In addition, a piezoelectric ultrasonic dimension crystal was advanced obliquely to the midwall of the myocardium between the endocardial and the epicardial crystals for assessment of LV regional wall motion. Placement of these crystals was aided by intraoperative measurements of wall thickness. A solid-state miniature pressure transducer (model P5, Konigsberg Instruments) was implanted in the LV chamber to measure LV pressure in all dogs. Pacing electrodes were implanted on the left atrium. The thoracotomy incision was closed in layers, and the animals were allowed to recover for 2 weeks before study. The animals used in this study were maintained according to the guidelines in “Care and Use of Laboratory Animals” from the Institute of Laboratory Animal Resources, National Council (Department of Health and Human Services publication [NIH] No. 85-23, revised 1985).
Statham strain-gauge manometers (model P23ID, Statham Instruments) connected to the chronically implanted catheters were calibrated with a mercury manometer and used to measure aortic, left atrial, and LV pressures. LV pressure was also measured with a solid-state miniature pressure gauge calibrated in vitro with a mercury manometer and in vivo with the LV catheter and Statham strain-gauge manometer. The calibration for diastolic LV pressures, including zero pressure, was obtained from the simultaneous left atrial pressure measurement. In 1 dog, the LV pressure gauge did not operate properly. LV ID, LV full-wall thickness, and subendocardial and subepicardial wall thicknesses were measured with an ultrasonic transit-time dimension gauge, which was calibrated before, during, and after the experiment. The positions of all catheters and crystals were confirmed at autopsy. Full-wall thickness and subendocardial wall thickening were measured directly from piezoelectric crystals in all dogs, whereas subepicardial wall thickening could be measured in 7 of the LVH dogs and 7 control dogs.
Blood Flow Measurements
Regional myocardial blood flow was measured with isotopically labeled microspheres (15±2 μm in diameter, New England Nuclear) in 9 control dogs and in 10 dogs with LVH. The radioactive label of the microspheres (141Ce, 113Sn, 114In, 51Cr, 103Ru, 95Nb, 85Sr, or 46Sc) was chosen randomly. The microspheres were suspended in 0.01% Tween 80 solution (10% dextran) agitated by direct application of an ultrasonic probe to ensure dispersion of the microspheres and placed in an ultrasonic bath for at least 30 minutes before injection. Before the injection of microspheres, 0.8 mL Tween 80 dextran solution (without microspheres) was injected to determine whether the diluent for the microsphere suspension would have an adverse effect on measurement of cardiac or systemic hemodynamics. Approximately 1 to 2 million microspheres were injected through the catheter implanted in the left atrium for determination of blood flow. A reference sample of arterial blood was withdrawn (7.75 mL/min) from the catheter in the descending thoracic aorta. Reference sample withdrawal was initiated 15 seconds before microsphere injection and continued for approximately 90 seconds after the injection was completed. At the end of the experiments, the dogs were killed with a lethal dose of sodium pentobarbital (50 mg/kg IV). The atria and the right ventricular free walls were removed and weighed. The LV free wall plus septum was also weighed. Samples of myocardial tissue from the right ventricular (RV) free wall were separated into subendocardial and subepicardial layers. Tissue samples from the LV free wall, septum, and anterior and posterior papillary muscles were subdivided into four equal transmural layers from epicardium to endocardium, weighed, and placed in a gamma counter (Canberra Industries) with appropriately selected energy windows. The raw counts were corrected for background and crossover and compared with the reference blood sample to obtain flow expressed in milliliters per minute per gram of tissue. The blood flow data from the four LV areas were averaged to yield one number for LV blood flow. Endocardial/epicardial (Endo/Epi) blood flow ratios per gram were obtained by dividing blood flow per gram in the subendocardial layer by that in the subepicardial layer.
Experiments were performed in a quiet laboratory with the unsedated, conscious dogs resting comfortably in the right lateral position. Near-maximal coronary vasodilation was assessed in 9 control dogs and 10 dogs with severe but compensated LVH by use of intravenous administration of adenosine (4.7 μm · kg−1 · min−1). Radioactive microspheres were injected for measurement of regional myocardial blood flow at baseline and during adenosine infusion. Because adenosine altered LV end-diastolic pressure and wall stresses in dogs with LVH, the adenosine infusion was repeated in 5 dogs with LVH after preload was reduced with mild hemorrhage (14±2 mL/kg), and heart rate was held constant with implanted left atrial electrodes. Radioactive microspheres were again injected during near-maximal vasodilation. Finally, to examine the relation between radial end-diastolic subendocardial wall stress and myocardial blood flow, end-diastolic pressure was further increased in 5 dogs with LVH by acute volume overload (42±8 mL/kg), with heart rate held constant at approximately 150 beats per minute. Radioactive microspheres were again injected during near-maximal vasodilation induced by adenosine.
The data were recorded on a multichannel tape recorder (model 101, Honeywell) and played back on a direct-writing oscillograph (Mark 200, Gould-Brush). A cardiotachometer (model 9857B, Beckman Instruments) triggered by the LV pressure pulse provided instantaneous records of heart rate, and LV dP/dt was derived from the LV pressure signals by use of operational amplifiers connected as differentiators with a frequency response of 700 Hz. A triangular wave signal was substituted for the pressure signals to calibrate directly the differentiator. LV end-diastolic dimensions were measured at the onset of LV contraction, indicated by the initial increase in LV dP/dt. LV end systole was defined as the point of maximum negative dP/dt. LV circumferential end-diastolic and end-systolic stresses were calculated with a cylindrical model: stress=1.36(PD/2h), where P is LV pressure, D is short-axis ID, and h is wall thickness.21 The average radial end-diastolic subendocardial (ςendo/ed) and subepicardial (ςepi/ed) wall stresses were calculated with the following formulas:
where aed is end-diastolic radius (end-diastolic short axis diameter×0.5), hen and hep are the subendocardial and subepicardial wall thicknesses, respectively, at end diastole, and bed=aed+hen+hep (see the Appendix).
Statistical analysis was performed by use of super anova (Abacus Concepts) on a Macintosh computer. The data are reported as mean±SEM. The data were analyzed by ANOVA, with a repeated-measures factor used for the administration of adenosine and a grouping factor used to differentiate the normal group of animals from the animals with LVH. Fisher’s least-significant difference was used as a post hoc test. When stresses were normalized, an ANOVA with two repeated measures was used because the same animals were examined both before and after normalization of stress and before and with administration of adenosine. Significance was recorded for values of P≤.05.
Chronic pressure overload induced by aortic banding caused a 79% increase (P<.01) in the LV weight/body weight ratio in dogs with LVH compared with controls (Table 1⇓). There were no major differences in either the body weights or the RV weight/body weight ratio between groups (Table 1⇓).
Baseline Hemodynamics and LV Function
Table 2⇓ shows baseline systemic hemodynamics. At baseline, mean arterial pressure and heart rate were similar in both groups, whereas diastolic arterial pressure was greater (P<.05) in dogs with LVH compared with normal dogs.
Table 3⇓ lists baseline LV hemodynamics and dimensions. At baseline, LV systolic pressure was significantly greater (P<.01) in dogs with LVH compared with control dogs. LV dP/dt, LV end-diastolic and end-systolic diameters, and LV end-diastolic pressure were not significantly different in the two groups. LV end-diastolic wall thickness was greater (P<.05) in dogs with LVH compared with control dogs. Table 4⇓ shows the LV wall stresses in both groups of animals. Baseline LV circumferential end-systolic wall stress tended to be greater in dogs with LVH compared with control dogs (107±14 versus 78±4 g/cm2), but the difference was not statistically significant (P=.07). LV end-diastolic circumferential stress and LV radial end-diastolic subendocardial and subepicardial wall stresses were not different in the two groups, but baseline values for radial subepicardial wall stress were lower (P<.05) and relatively insignificant compared with radial subendocardial wall stress (−6.4±0.7 versus −7.8±0.7, control versus LVH subendocardial wall stress, and −1.5±0.2 versus −1.6±0.2, control versus LVH subepicardial wall stress).
Effects of Adenosine on Systemic LV Hemodynamics and LV Wall Stresses
Table 2⇑ shows the effects of near-maximal vasodilation induced by adenosine infusion on systemic hemodynamics. Both groups showed significant decreases in mean and diastolic arterial pressures and increases in heart rate. After adenosine infusion, systemic hemodynamics were similar in the two groups. Table 3⇑ gives the responses of LV hemodynamics to adenosine infusion. In both groups, LV systolic pressure and LV end-diastolic and end-systolic diameters decreased (P<.05), although the decrease in LV end-systolic diameter was less (P<.05) in dogs with LVH compared with control dogs. Similar nonsignificant changes in LV dP/dt were observed in both groups. However, in control dogs, LV end-diastolic pressure decreased significantly (P<.05) during adenosine infusion, but in dogs with LVH, LV end-diastolic pressure remained elevated during adenosine infusion, with the resultant responses being different (P<.01). Table 4⇑ shows the effects of adenosine on LV wall stresses. During adenosine infusion, the changes in LV circumferential end-systolic wall stress were not different; however, LV circumferential end-systolic stress was greater (P<.01) during adenosine infusion in dogs with LVH compared with control dogs. During adenosine infusion, LV circumferential end-diastolic wall stress and LV compressive radial end-diastolic subendocardial stress decreased significantly in control dogs but remained elevated in dogs with LVH, with the resultant responses being significantly different (P<.01). This was most apparent for the compressive radial subendocardial wall stress (−3.9±0.6 versus −9.1±0.9 g/cm2, respectively, Fig 1⇓). Radial end-diastolic subepicardial stress demonstrated a qualitatively similar pattern, but the changes with adenosine infusion were minor because of the relatively low baseline values.
Effects of Adenosine Infusion on Regional Myocardial Blood Flow
Table 5⇓ describes the transmural myocardial blood flows in the left ventricle at baseline and during near-maximal vasodilation induced by adenosine infusion. At baseline, values were not different in the two groups. In response to adenosine infusion, the increase in blood flow in the subendocardium was less (P<.01) and the increase in the subepicardium was greater (P<.05) in dogs with LVH compared with control dogs. The LV Endo/Epi ratio fell to a greater extent (P<.01) in dogs with LVH (0.35±0.03) compared with control dogs (0.69±0.05).
Effects of Alterations in Preload
To determine whether compressive forces could play a role in the impairment of subendocardial myocardial blood flow during near-maximal vasodilation induced by adenosine, additional experiments were performed in a subgroup of 5 dogs with LVH. In the first set of experiments, heart rate was kept constant, and LV end-diastolic pressure was decreased by mild hemorrhage (14±2 mL/kg) to simulate the hemodynamics observed both at baseline and during adenosine infusion in control dogs (Table 6⇓). At baseline, mild hemorrhage did not affect mean arterial pressure, LV subendocardial and subepicardial blood flows, and the Endo/Epi ratio. LV systolic pressure, LV end-diastolic pressure (5.8±1.5 versus 9.1±2.0 mm Hg), and LV radial subendocardial wall stress (−4.4±1.1 versus −7.0±1.5) were less (P<.05) at baseline during preload reduction than before preload reduction. After preload reduction during near-maximal vasodilation with adenosine, LV circumferential end-systolic and end-diastolic wall stresses and LV radial subendocardial wall stress decreased in dogs with LVH (Fig 2⇓). LV subendocardial blood flow increased to the level observed in control dogs (3.42±0.60 mL · min−1 · g−1 versus 3.58±0.27 mL · min−1 · g−1, Fig 3⇓, right), and the LV Endo/Epi ratio (0.63±0.11) was no longer different from that observed in control dogs (0.69±0.05, Fig 4⇓).
In another set of experiments, preload was increased by use of volume load. Fig 5⇓ displays the relation between radial end-diastolic subendocardial wall stress and subendocardial blood flow (top) and Endo/Epi ratio (bottom) during adenosine infusion under all three conditions studied. A good correlation was observed between LV radial end-diastolic stress and subendocardial blood flow (r=.69) and Endo/Epi ratio (r=.71).
With the development of LVH, baseline myocardial function is generally preserved without major changes in baseline levels of myocardial perfusion across the LV wall.1 2 9 12 22 However, reduced subendocardial coronary reserve in response to near-maximal vasodilation has been a hallmark of LVH.1 2 3 4 5 6 7 8 9 10 11 12 Our current results confirm this with adenosine, as near-maximal vasodilation induced selective impairment in subendocardial blood flow in dogs with LVH. Our hypothesis was that the abnormal levels of LV end-diastolic wall stresses in dogs with LVH during near-maximal vasodilation are particularly responsible for the impairment in subendocardial blood flow. Indeed, when the elevated LV wall stresses during adenosine infusion were normalized by preload reduction in dogs with LVH, subendocardial blood flow and the Endo/Epi ratio were actually no longer different from values observed in sham-operated control dogs.
These data suggest that the reduced subendocardial reserve in this model of LVH cannot be explained by structural alterations. This is consistent with morphologic data obtained recently from our laboratory in dogs with LVH.18 In that study, no transmural differences in capillary or arteriolar density were observed in the hypertrophied hearts; in fact, the volume percentage of capillary space was not reduced in this model of LVH.18 We also showed previously that in dogs with compensated LVH, subendocardial fibrosis is only modestly elevated,12 making it improbable that this structural alteration is responsible for the reduced coronary reserve. Finally, when preload was elevated during adenosine infusion in dogs with LVH in the present study, there was further compromise of subendocardial coronary reserve (Fig 5⇑), supporting the concept of the critical role of subendocardial compressive forces in dictating coronary blood flow distribution in LVH. Because perfusion of the subendocardial layer is related to the diastolic coronary pressure minus the back pressure, which is reflected by the subendocardial compressive forces, it follows that perfusion of the subendocardial layers would be enhanced when the increased compressive forces characteristic of LVH were alleviated. This is indeed what we observed in the dogs with LVH when preload was reduced.
These data also argue against the possibility that there is impaired smooth muscle vasoactivity, potentially caused by perivascular fibrosis or other factors, in this model of severe hypertrophy. It is also well recognized that preload plays a primary role in the transmural distribution of myocardial blood flow; eg, in healthy dogs, an increase in preload selectively reduces myocardial blood flow in the subendocardial layers. For example, Ellis and Klocke23 showed that an increase in preload from 6 to 20 mm Hg reduced subendocardial blood flow from 1.40 to 1.10 mL · min−1 · g−1. Recently, Duncker et al17 examined the role of extravascular compressive forces during near-maximal coronary vasodilation with adenosine using the coronary pressure-flow relation in anesthetized dogs with LVH induced by aortic banding. Their results demonstrated an increase in minimum coronary resistance and an increase in extravascular compressive forces during near-maximal vasodilation,17 consistent with the findings in the present study. In that study, however, the effects of the extravascular compressive forces on regional myocardial blood flow were not assessed. Interestingly, in a study by Jeremy et al,24 when intracoronary adenosine was delivered to dogs with renovascular hypertension–induced LVH, the reduction in coronary reserve was more prominent at higher pressures in the hypertrophied heart.
The impaired subendocardial coronary reserve in dogs with LVH was observed in the presence of increased LV circumferential end-diastolic and end-systolic wall stresses and subendocardial radial stress. During adenosine infusion in dogs with LVH, subendocardial wall stress actually increased; in sham-operated control dogs, it decreased. These data paralleled those for LV diastolic pressure, which can be discerned from inspection of the model used for radial subendocardial wall stress, which is influenced most heavily by the LV pressure measurement. The observed alteration in subendocardial blood flow in association with increases in LV end-diastolic radial wall stress in the present study extends to the hypertrophied heart the findings from previous studies in normal preparations that demonstrated the influence of the distribution of myocardial stress on coronary blood flow19 23 and the effects of vascular compression on the diameters of subendocardial and subepicardial microvessels.25
In contrast to the present study where the emphasis is on diastolic stresses, other investigators examined the effects of strain on the regulation of blood flow. However, this interest has been concentrated on systole. Downey et al26 concluded from their studies that although myocardial fiber shortening strain contributed to extravascular compression, this effect was evenly distributed. However, they did not study diastolic flow patterns as a function of diastolic pressure. On the other hand, Williams et al27 compared flow distributions with perfusion limited to systole and with coronary perfusion during the whole cardiac cycle in unloaded, beating hearts. Using adenosine to maximally dilate the arteries and obviate autoregulation, they found a gradient of extravascular compression across the LV wall attributable to strain changes. This result is qualitatively similar to what one might expect for the radial stress distribution, which decreases from the endocardium to the epicardium. Unfortunately, the data available in the present study were insufficient to evaluate radial strains accurately. On the other hand, it must be noted that strain results from the application of a stress that is not only a function of strain but also the elasticity of the material, which varies with load; therefore, stress might be a more sensitive parameter than strain.
In summary, the present study demonstrates that hemodynamic, rather than structural, factors are critical in mediating the reduced subendocardial blood flow reserve observed in dogs with chronic pressure-overload LV hypertrophy. The elevated LV end-diastolic pressure and wall stresses, particularly in the subendocardial region, play a primary role in mediating the abnormal subendocardial coronary reserve because when LV end-diastolic pressure and circumferential and radial subendocardial wall stresses were normalized, subendocardial blood flow responses to near-maximal vasodilation in dogs with LVH were normal. These conclusions may not be extrapolated to all models of hypertrophy, particularly models associated with significantly reduced subendocardial capillary density. Importantly, however, similar findings were observed in experimental cardiomyopathy, which is characterized by a dilated heart, increased wall stress, and no hypertrophy.28 In that model, reducing the increased load to control levels also normalized the deficit in subendocardial coronary reserve.28
LVH is a major risk factor for cardiovascular morbidity and mortality29 ; LV wall stress is increased at rest at the stage of heart failure and increased further during the stress of catecholamine infusion30 or exercise.9 10 11 Chronic treatment with vasodilators, eg, angiotensin-converting enzyme inhibitors, can improve the morbidity and mortality of heart failure.31 32 Reduction in loading conditions is part of the rationale for the use of vasodilators in the therapeutic regimen in heart failure.33 Their beneficial effects are usually explained by the blockade of the renin-angiotensin and the sympathetic systems. However, as demonstrated in the present study, elevated compressive forces during episodes of vasodilation reduce subendocardial perfusion, whereas reduction of compressive forces improves perfusion. This mechanism could also play a role in the pathogenesis of heart failure34 35 and in the salutary action of vasodilator and converting enzyme inhibitor therapy.
Evaluation of Subendocardial and Subepicardial Radial Wall Stresses
Assuming a cylindrical annulus at the site where geometric measurements are made, the radial wall stress (ςr) at any radius r is given by
where P is the LV cavity pressure and a and b are the inner and outer radii respectively.21 In particular, the average subendocardial (ςren) and superepicardial (ςrep) radial wall stresses take the form
where hen and hep are the subendocardial and subepicardial wall thicknesses, respectively, and b=a+hen+ hep.
If the full LV wall thickness is given by h=hen+ hep and ID by D, the above expressions for radial wall stresses may be written in the form
This work was supported in part by US Public Health Service grants HL-38070, HL-33107-11, and HL-33065-08, as well as RR-00168 and INSERM. We wish to thank Amy Kerdok for her technical assistance.
- Received January 3, 1995.
- Revision received March 8, 1995.
- Accepted March 9, 1995.
- Copyright © 1995 by American Heart Association
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