Normalization of impaired coronary circulation in hypertrophied rat hearts

We tested the hypothesis that impaired coronary autoregulation, decreased flow reserve, and diminished reactive hyperemic response in hypertrophied hearts with coronary arterial hypertension may be reversible after relief of pressure overload. In 4-week ascending aortic banded rats, in vivo peak systolic left ventricular pressure increased to 178 +/- 8 mm Hg (103 +/- 6 mm Hg in sham-operated control group). This increased pressure produced myocardial hypertrophy, and the left ventricular weight/body weight ratio was 46% above that of the control group. After the rats were killed, the coronary perfusion pressure-flow relations were obtained during resting conditions and maximal vasodilation after a 40-second period of ischemia in beating but nonworking isolated hearts perfused with Tyrode's solution with bovine red blood cells and albumin. In hearts from control rats, coronary autoregulation (i.e., a slight decrease in flow with reduction of pressure) was observed in the range of 50-100 mm Hg of perfusion pressure. A pronounced reactive hyperemic response was observed: a peak flow/resting flow ratio of 2.9 +/- 0.1 and a repayment ratio of 1.7 +/- 0.2 at 100 mm Hg of perfusion pressure. In hearts of banded rats the resting pressure-flow relation was rectilinear in the range of 25-175 mm Hg of perfusion pressure. Flow reserve and the time of reactive hyperemia to one half peak flow decreased at 50, 100, and 150 mm Hg of perfusion pressure compared with values in control rat hearts. Four weeks after debanding, peak systolic left ventricular pressure and cardiac hypertrophy had normalized. The impaired autoregulation, decreased flow reserve, and diminished reactive hyperemic response had completely reversed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary reserve is depressed in postmyocardial infarction reactive cardiac hypertrophy

After a myocardial infarction (MI), the remaining myocardium undergoes a compensatory reactive hypertrophy. Although coronary perfusion to the surviving myocardium can be an important determinant of cardiac function in this setting, there are no available data regarding myocardial blood flow in reactive hypertrophy. Accordingly, we measured coronary blood flow and reserve using radioactive microspheres in rats 4 weeks after induction of an MI by ligation of the left coronary artery. Maximal coronary dilation was induced by Carbochrome, a potent coronary vasodilator, infused at a rate of 0.45 mg/kg/min up to a total dose of 12 mg/kg. Sham-operated rats served as controls. All animals in the infarct group had a large MI affecting 30-51% (average, 41%) of the left ventricle. Left ventricular end-diastolic pressure was significantly elevated (30 +/- 6.5 vs. 8.0 +/- 2.5 mm Hg in sham-operated rats, p less than 0.01) and baseline hemodynamic indexes of cardiac performance were significantly (p less than 0.01) reduced in this group. Myocyte cross-sectional area measurements were used as an index to quantify the degree of reactive hypertrophy and indicated that the infarcted animals had, on average, a 30% hypertrophic response of the surviving left ventricular myocardium. In the infarcted animals, both coronary flow and vasodilator reserve in the surviving myocardium were depressed. Maximal coronary blood flow in the remaining myocardium was significantly lower than that measured in the sham-operated animals (839 and 1,479 ml/min/100 g, respectively; p less than 0.001). Similarly, minimal coronary resistance was significantly higher in the MI group as compared with the sham group (0.12 vs. 0.07 mm Hg/ml/min/100 g, respectively; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of pressure-induced right ventricular hypertrophy on left ventricular diastolic properties and dynamic geometry in the conscious dog

To determine whether chronic pressure overload and hypertrophy of the right ventricle alter the diastolic properties of the left ventricle, six adult dogs underwent banding of the pulmonary artery and were instrumented for studies 8 months later. Fourteen control dogs were also studied. Pressure and dimension data were collected from the dogs while they were awake and unsedated. The anterior-posterior, septal-free wall, and base-apex axis diameters of the left ventricle were measured with ultrasonic dimension transducers. Right and left ventricular pressures were measured with micromanometers. Pulmonary arterial banding resulted in increased right ventricular/body mass ratios (2.70 +/- 0.36 g/kg vs 1.52 +/- 0.15 g/kg control; p less than or equal to .05) and increased left ventricular/body mass ratios (4.84 +/- 0.64 g/kg vs 4.21 +/- 0.49 g/kg control; p less than or equal to .05). Right ventricular peak systolic and end-diastolic pressures were higher among the banded dogs (50 +/- 20/7 +/- 5 mm Hg vs 31 +/- 6/3 +/- 2 mm Hg control; p less than or equal to .05). A rearrangement in the three-dimensional geometry of diastolic filling occurred in the banded dogs. Extension from unstressed diastolic dimension (strain) in the base-apex axis was significantly larger in the banded dogs at left ventricular transmural pressures of 12, 8, and 4 mm Hg; strains in the septal-free wall axis were significantly smaller at transmural pressures of 12 and 8 mm Hg. Normalized diastolic left ventricular pressure-volume data and midwall circumferential stress-strain data were fit to the Kelvin viscoelastic equation. The normalized pressure-volume relationships of the banded dogs lay significantly to the left of those of the controls, indicating a loss of left ventricular chamber compliance. The midwall circumferential stress-strain relationships of the banded dogs were also shifted to the left, indicating a loss of intrinsic myocardial compliance. Thus, during the course of right ventricular hypertrophy caused by right ventricular pressure overload, alterations in the mass, geometry, and material properties of the left ventricle occur. At 8 months the chamber compliance of the left ventricle is compromised by these changes.     

Coronary pressure-flow relations in hypertensive left ventricular hypertrophy. Comparison of intact autoregulation with physiological and pharmacological vasodilation in the dog

Coronary pressure-flow relations during autoregulated and vasodilated flow states were compared between eight dogs with renovascular hypertension and left ventricular hypertrophy and 12 normal dogs. Each relation was constructed from serial steady-state measurements of end-diastolic coronary pressure and flow during perfusion of the circumflex artery by an extracorporeal circuit at controlled diastolic pressures of 20-200 mm Hg. Autoregulated pressure-flow relations were compared at three levels of myocardial oxygen demand: resting, high (dobutamine 10 micrograms/kg/min), and low (propranolol 2.5 micrograms/kg/min). Autoregulatory capacity was assessed by calculation of closed-loop flow gain. At each level of myocardial oxygen demand, the lower limit of autoregulation occurred at higher perfusion pressures in the hypertrophy group (rest 65 +/- 3, high 92 +/- 4, low 66 +/- 4 mm Hg) than in the normal group (rest 53 +/- 2, p less than 0.05; high 75 +/- 5, p less than 0.05; low 51 +/- 3 mm Hg) (p less than 0.05). Maximum autoregulatory gain was similar in the normal and hypertrophy groups during resting and low myocardial oxygen demand but was reduced in the hypertrophy group during dobutamine studies. When coronary flow decreased below the lower limit of autoregulation, systolic shortening was reduced in both normal and hypertrophy groups. However, as the autoregulatory limits were at higher pressures in the hypertrophy group, shortening in this group deteriorated at perfusion pressures that did not affect the normal heart. Coronary pressure-flow relations during physiological (peak hyperemia after 15-second flow occlusion) and pharmacologica (intracoronary adenosine 400 micrograms/min) vasodilation was curvilinear and fitted by quadratic regression. During hyperemic vasodilation, maximal conductance per unit mass of myocardium was less in the hypertrophy group over a wide range of perfusion pressures. At a diastolic perfusion pressure of 80 mm Hg, maximum conductance was 4.6 +/- 0.5 ml/min/100 g/mm Hg in the normal group and 3.4 +/- 0.4 ml/min/100 g/mm Hg (p less than 0.05) in the hypertrophy group. Intracoronary adenosine elicited further vasodilation in both groups, but maximum conductance remained less in the hypertrophy group (8.5 +/- 1.7 ml/min/100 g/mm Hg at a perfusion pressure of 80 mm Hg) than in the normal group (13.5 +/- 2.0 ml/min/100 g/mm Hg) (p less than 0.05). Maximal coronary flow reserve is reduced in left ventricular hypertrophy, with a consequent shift of the lower limit of autoregulation to higher perfusion pressures. Thus, as coronary perfusion pressure is decreased, coronary flow and myocardial shortening become impaired at higher     

Collagen deposition and the reversal of coronary reserve in cardiac hypertrophy.

The aim of this study was to clarify how collagen deposition or medial hypertrophy of the vascular wall affects the coronary dilator reserve in pressure-overloaded hearts and whether inhibition of collagen deposition reverses the abnormalities after relief of pressure overload. We used ascending aortic banding and debanding methods and superimposed beta-aminopropionitrile in some of the banded rats (50 mg/kg i.p., twice a day). Ten weeks of banding increased in vivo peak systolic left ventricular pressure and produced medial hypertrophy, an increase in collagen deposition in the myocardial and perivascular tissues, and myocardial hypertrophy in the banded group without beta-aminopropionitrile treatment. Superimposition of beta-aminopropionitrile treatment on banding inhibited the increase in collagen deposition. In the groups debanded after the 10-week banding period, both with and without beta-amino-propionitrile treatment, medial and myocardial hypertrophy regressed 4 weeks after debanding. We estimated coronary dilator reserve in Langendorff preparations perfused with modified Tyrode's solution containing oxygenated bovine red blood cells and serum albumin. The ratio of reactive peak flow after brief ischemia-to-resting flow decreased in both of the banded groups. After debanding, the ratio remained lower in the banded group without beta-aminopropionitrile treatment than in the control group. However, debanding in the group with beta-aminopropionitrile treatment increased the ratio to a level similar to that of the control group. Thus, in pressure-overloaded cardiac hypertrophy with coronary hypertension, coronary reserve seems to be determined by medial hypertrophy independently of collagen deposition, but collagen deposition plays an important role in the reversal of vasodilator reserve after relief of the overload.     

Effect of coronary stenosis on myocardial blood flow during exercise in the chronically pressure-overloaded hypertrophied left ventricle

This study was performed to determine if a coronary artery stenosis would result in more-severe perfusion abnormalities in hypertrophied compared with normal canine hearts during exercise. Studies were performed in eight normal control dogs and in seven adult dogs in which a 67% increase in left ventricular mass wa produced by banding the ascending aorta at 9 weeks of age. Myocardial blood flow was measured by the microsphere method during treadmill exercise in the presence of a coronary artery stenosis that decreased distal coronary perfusion pressure to 55 or 42 mm Hg. At a coronary pressure of 55 mm Hg, mean myocardial blood flow was decreased by 23 +/- 5% in normal control dogs but was decreased by 53 +/- 10% in dogs with left ventricular hypertrophy (LVH) (p less than 0.05, comparing normal vs. LVH dogs). Similarly, at a coronary pressure of 42 mm Hg, mean blood flow was decreased by 53 +/- 6% below control in normal dogs but was decreased by 76 +/- 5% below control values in dogs with LVH (p less than 0.01, comparing normal vs. LVH dogs). In both groups of dogs, the stenosis caused a gradient of hypoperfusion, worsening from epicardium to endocardium. However, for each level of stenosis, subendocardial blood flow and the ratio of subendocardial to subepicardial blood flow was less in LVH than in normal canine hearts. These findings demonstrate that the presence of LVH secondary to long-term pressure overload is associated with an increased vulnerability to myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis.     

Effects of inhibition of nitric oxide formation on regional blood flow in experimental myocardial infarction.

BACKGROUND. Large myocardial infarction is associated with reactive hypertrophy and dilation of the left ventricle, depressed coronary flow reserve, and the development of heart failure including systemic vasoconstriction. We hypothetized that changes in endothelial function, e.g., in the synthesis or action of nitric oxide in the coronary and peripheral vasculatures, might be involved in the depressed coronary flow reserve and increased systemic vascular resistance observed in postinfarction myocardial hypertrophy and failure. METHODS AND RESULTS. The regional blood flow changes that occur as a result of inhibiting the basal release of nitric oxide with NG-monomethyl-L-arginine (L-NMMA) and how this regional pattern may be altered in large MI (infarct size, 30-51% of left ventricle) were examined. Measurements were made 24 hours and 8 weeks after myocardial infarction or sham operation in conscious rats. The left ventricular end-diastolic pressure and effects of L-NMMA on left ventricular end-diastolic pressure was similar 24 hours and 8 weeks after myocardial infarction. The effects of L-NMMA (30 mg/kg i.v.) on heart rate and blood pressure were similar in infarcted and sham animals. L-NMMA exerted a marked vasoconstriction in the renal, splanchnic, cutaneous, and cerebral circulations of similar magnitude in sham-operated rats and animals with myocardial infarction. The coronary vasoconstrictor effect of L-NMMA was attenuated significantly in the hypertrophied right and noninfarcted left ventricle of 8-week-old infarcted rats (p less than 0.01 versus sham-operated animals) but not 24 hours after induction of myocardial infarction when cardiac hypertrophy has not yet developed. The increase in left ventricular coronary resistance in 8-week-old infarcted animals was inversely related to infarct size (r = -0.787, p = 0.012, n = 9). Nitroglycerin exerted similar increases in coronary blood flow in rats with chronic myocardial infarction and sham-operated animals, arguing against a reduced vascular responsiveness to nitric oxide. Transmission electron microscopy of coronary resistance vessels in 8-week-old infarcted animals did not reveal endothelial abnormalities. CONCLUSIONS. These data suggest that the basal release of nitric oxide in the renal, intestinal, and cutaneous circulations is not affected adversely in this model of myocardial infarction and failure. However, the blunted coronary vasoconstrictor effect of L-NMMA late after large myocardial infarction supports the view that the basal release of nitric oxide is impaired in postinfarction reactive cardiac hypertrophy.     

Myocardial dysfunction with increased ventricular compliance in volume overload hypertrophy

The aim this study was to evaluate systolic and diastolic function in volume overload induced myocardial hypertrophy in rats. Volume overload myocardial hypertrophy was induced in thirteen male Wistar rats by creating infrarenal arteriovenous fistula (AVF). The results were compared with a SHAM operated group (n=11). Eight weeks after surgery, tail-cuff blood pressure was recorded, then rats were sacrificed for isolated heart studies using Langendorff's preparation. AVF rats presented increased left and right ventricular weights, compared to controls. The increased normalized ventricular volume (V0/LVW, 0.141+/-0.035 mL/g vs. 0.267+/-0.071 mL/g, P<0.001) in the AVF group indicated chamber dilation. Myocardial hydroxyproline concentration remained unchanged. There was a significant decrease in +dP/dt (3318+/-352 mm Hg s(-1) vs. 2769+/-399 mm Hg s(-1); P=0,002), end-systolic pressure-volume relation (246+/-56 mm Hg mL(-1) vs. 114+/-63 mm Hg mL(-1); P<0,001), and -dP/dt (1746+/-240 mm Hg s(-1) vs. 1361+/-217 mm Hg s(-1), P<0.001) in the AVF group, which presented increased ventricular compliance (DeltaV(25): SHAM=0.172+/-0.05 mL vs. AVF=0.321+/-0.072 mL, P<0.001) with preserved myocardial passive stiffness (Strain(25): SHAM=13.5+/-3.0% vs. AVF=12.3+/-1.9%, P>0.05). We conclude that volume-overload induced hypertrophy causes myocardial systolic and diastolic dysfunction with increased ventricular compliance. These haemodynamic features help to explain the long-term compensatory phase of chronic volume overload before transition to overt congestive heart failure.     

Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure

Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg. kg-1. d-1], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39+/-0. 16 mg/g) than in the cyclosporine-treated banded group (3.95+/-0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02+/-0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6+/-6.1 mm Hg) and nontreatment groups (48.7+/-4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774+/-656 mm Hg/s) than in the nontreatment banded group (6604+/-516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66+/-3.0%) than in the nontreatment banded group (79+/-1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure.     

Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy

Fifty patients with hypertrophic cardiomyopathy underwent invasive study of coronary and myocardial hemodynamics in the basal state and during the stress of pacing. The 23 patients with basal obstruction (average left ventricular outflow gradient, 77 +/- 33 mm Hg; left ventricular systolic pressure, 196 +/- 33 mm Hg, mean +/- 1 SD) had significantly lower coronary resistance (0.85 +/- 0.18 versus 1.32 +/- 0.44 mm Hg X min/ml, p less than 0.001) and higher basal coronary flow (106 +/- 20 versus 80 +/- 25 ml/min, p less than 0.001) in the anterior left ventricle, associated with higher regional myocardial oxygen consumption (12.4 +/- 3.6 versus 8.9 +/- 3.3 ml oxygen/min, p less than 0.001) compared with the 27 patients without obstruction (mean left ventricular systolic pressure 134 +/- 18 mm Hg, p less than 0.001). Myocardial oxygen consumption and coronary blood flow were also significantly higher at paced heart rates of 100 and 130 beats/min (the anginal threshold for 41 of the 50 patients) in patients with obstruction compared with those without. In patients with obstruction, transmural coronary flow reserve was exhausted at a heart rate of 130 beats/min; higher heart rates resulted in more severe metabolic evidence of ischemia with all patients experiencing chest pain, associated with an actual increase in coronary resistance. Patients without obstruction also demonstrated evidence of ischemia at heart rates of 130 and 150 beats/min, with 25 of 27 patients experiencing chest pain. In this group, myocardial ischemia occurred at significantly lower coronary flow, higher coronary resistance and lower myocardial oxygen consumption, suggesting more severely impaired flow delivery in this group compared with those with obstruction. Abnormalities in myocardial oxygen extraction and marked elevation in filling pressures during stress were noted in both groups. Thus, obstruction to left ventricular outflow is associated with high left ventricular systolic pressure and oxygen consumption and therefore has important pathogenetic importance to the precipitation of ischemia in patients with hypertrophic cardiomyopathy. Patients without obstruction may have greater impairment in coronary flow delivery during stress.     

Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.     

Nonuniform loss of regional flow reserve during myocardial ischemia in dogs

To determine whether coronary vasodilator reserve that persists during myocardial ischemia is present in all left ventricular regions, we measured regional blood flow in 192 left ventricular pieces (mean weight, 201 mg) in each of eight dogs by using radioactive microspheres while perfusing the left main coronary artery at 70, 50, 40, and 30 mm Hg. Flows were measured before and during adenosine infusion to determine flow reserve. Perfusion at 40 and 30 mm Hg produced ischemia in all dogs. At 70 mm Hg, 100% of left ventricular regions had significant flow reserve, compared with 92%, 55%, and 8% during perfusion at 50, 40, and 30 mm Hg, respectively. A greater amount of flow reserve and a greater number of regions responded to adenosine in the subepicardium than in the subendocardium at 50, 40, and 30 mm Hg. We conclude that coronary flow reserve persists in only a subset of left ventricular regions during ischemia and that the number of regions with persistent flow reserve decreases with perfusion pressure. These findings may best be explained by a model in which regional ischemia is a maximal coronary vasodilator and persistent pharmacological vasodilator reserve seen when global markers indicate ischemia simply reflects persistent endogenous flow reserve in myocardial regions not yet ischemic.     

Influence of hypertension with minimal hypertrophy on diastolic function during demand ischemia

Hearts with advanced pressure-overload hypertrophy from systemic hypertension have been shown to have an increased susceptibility to the development of diastolic dysfunction in response to tissue hypoxia and ischemia. It is not known if this propensity to develop diastolic dysfunction in response to ischemia is dependent on the presence of a substantial increase in left ventricular mass, or alternatively, is characteristic of hearts subjected to mild chronic hypertension early in the development of cardiac hypertrophy. We tested the hypothesis that systemic hypertension associated with mild left ventricular hypertrophy increases the susceptibility to the development of diastolic dysfunction in response to demand ischemia. The effects of demand ischemia (6 minutes) were studied in hearts from New Zealand white rabbits with chronic systemic hypertension produced by the one-kidney, one-wrap method (n = 15) and compared with age-matched, sham-operated control rabbits (n = 11) with similar left ventricular mass (5.4 +/- 0.2 vs. 5.4 +/- 0.3 g, respectively). The hearts were studied using an isolated, isovolumic (balloon in left ventricle) preparation with absent pericardium that was perfused with fresh whole blood. At baseline, coronary perfusion pressure was 100 mm Hg with comparable coronary flow per gram left ventricular weight; the hearts were paced at a physiological rate of 3 Hz, and the left ventricular balloon volume was adjusted to achieve a left ventricular end-diastolic pressure of 15 mm Hg in both groups. Left ventricular balloon volume was similar in both groups and volume was thereafter held constant. At baseline, left ventricular systolic pressure (114 +/- 4 vs. 95 +/- 3 mm Hg, p less than 0.001) and developed pressure (18.9 +/- 1.2 vs. 15.1 +/- 0.9 mm Hg/g, p less than 0.05) were higher in the hearts from the hypertensive group in comparison with the control group. During the first minute of global ischemia produced by reducing coronary perfusion pressure from 100 to 20 mm Hg, there was an immediate fall in left ventricular systolic pressure in both groups without an increase in diastolic pressure. In response to the superimposition of pacing tachycardia (heart rate, 6 Hz) during the remaining 5 minutes of the period of ischemia, left ventricular developed pressure was comparable. However, isovolumic left ventricular end-diastolic pressure (measured during long diastoles obtained with transient cessation of pacing) rose to a significantly higher level in the hearts from hypertensive rabbits than in those from the control rabbits (29 +/- 3 vs. 18 +/- 2 mm Hg, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)     

Left ventricular hypertrophy in a canine model of reversible pressure overload.

OBJECTIVE: The goal of therapy for left ventricular pressure overload should include regression of the associated left ventricular hypertrophy, but this process is incompletely understood. The aim of the study was to characterise the extent and time course of the progression and regression of pressure overload left ventricular hypertrophy in a canine hypertrophy model. METHODS: Six puppies were studied longitudinally with haemodynamic and echocardiographic measurements for 10 months. The study animals underwent ascending aortic banding at nine weeks of age which produced an initial gradient of 30 mm Hg. Subsequent growth led to an increase in gradient and the development of left ventricular hypertrophy. Then thoracotomy was again performed to remove the band. One month later, balloon aortoplasty was performed to remove the residual gradient. The animals were then observed for six months. RESULTS: Growth increased the gradient to 105(SEM 10) mm Hg three months after banding. The left ventricular weight to body weight ratio (g.kg-1), an index of hypertrophy, was 7.2(0.5) after three months of pressure overload. Subsequently the band was surgically removed, reducing the gradient to an average of 58(10) mm Hg. Balloon dilatation of the residual aortic stricture reduced the gradient further to 6(5) mm Hg. Over the ensuing six months, echocardiographic determination of left ventricular mass showed the regression in left ventricular hypertrophy. After six months, left ventricular weight to body weight ratio in the previously banded animals was significantly reduced from 7.2(0.5) to 5.3(0.2) (p less than 0.05). CONCLUSIONS: The model produced over 100% left ventricular hypertrophy, most of which regressed following removal of the pressure overload.     

Thyroxine-induced left ventricular hypertrophy in the rat. Anatomical and physiological evidence for angiogenesis

We examined anatomical and physiological responses of the left coronary vascular system to thyroxine-induced myocardial hypertrophy. Wistar-Kyoto rats (1 and 5 months old) were administered thyroxine (0.25 mg/kg per day) or the saline vehicle (sham-treated controls) for 2 months. At the ages of 3 and 7 months, each group of animals was used for one of three experimental protocols: determination of numerical capillary density in perfusion-fixed hearts, measurement of coronary reactive hyperemic responses following a 20-second coronary occlusion (peak-to-resting blood flow velocity) as an index of coronary reserve, and assessment of myocardial perfusion under resting conditions and during maximum coronary dilation (dipyridamole infusion) for the calculation of minimum coronary resistance per unit weight of the left ventricle or minimum coronary resistance of the total left ventricle. In both groups of thyroxine-treated animals, the left ventricular weight-to-body weight ratio increased by 35-40%. Capillary density of the 3- and 7-month-old Wistar Kyoto controls was 4467 +/- 352 (mean +/- SEM) and 4029 +/- 143 capillaries/mm2, respectively, but was increased significantly in the thyroxine-treated animals to 6052 +/- 409 capillaries/mm2 (3-month) and 4654 +/- 201 capillaries/mm2 (7-month). In both age control groups, the peak-to-resting blood flow velocity ratio was about 2.2. This index of coronary reserve was not changed in the thyroxine-treated animals. Myocardial perfusion measurements were limited to the 7-month-old animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of hearts with 2 types of pressure-overload left ventricular hypertrophy

Comparisons of myocardium remodeled by the 2 most common causes of left ventricular hypertrophy (LVH), hypertension and aortic constriction, are limited. We hypothesized that important differences may exist in the myocardium of hearts with these 2 origins of "pressure overload" LVH. Accordingly, we studied isolated hearts from 3 groups of Dahl salt-sensitive rats, controls, and hearts with matched amounts of LVH secondary to either hypertension or aortic constriction. Isovolumic LV function and myocardial energetics ((31)P nuclear magnetic resonance spectroscopy) were measured as coronary flow was lowered to 16% of baseline for 48 minutes. During this low-flow ischemia, isovolumic end-diastolic pressure, a measure of LV stiffness, increased to 52+/-4 mm Hg in controls and 51+/-6 mm Hg in aortic banded hearts but to only 35+/-5 mm Hg in hearts with hypertensive LVH. In all hearts, the P(i) resonance in the (31)P nuclear magnetic resonance spectrum, whose position indicates myocardial pH, split into 2 peaks during low-flow ischemia, which indicates distinct regions of pH 6.9 (moderate acidosis) and pH 6.2 (severe acidosis). Concentrations of ATP, PCr, P(i), and H(+) of the moderately acidotic region were not different among groups. However, the size of the severely acidotic region was smallest in the hypertensive LVH hearts, and in all 3 groups, the size of this region correlated (r(2)=0.65 to 0.80) with the degree of LV stiffening. We conclude that in Dahl rats, LVH secondary to hypertension protects against ischemia-induced diastolic dysfunction by minimizing the size of the region of severe acidosis.     

Left ventricular failure induced by long-term hypertension in rats

To determine whether the duration of hypertension is an essential component in the evolution of myocardial dysfunction, renal artery constriction was performed in male Fischer 344 rats at 4 months of age, and in vivo global cardiac performance of sham-operated and experimental animals was evaluated 8 months later. Systemic arterial blood pressure increased to 173 +/- 5 mm Hg 2 weeks after the arteries were clipped and remained elevated for the following 5 months. Blood pressure decreased over the remaining 3 months to a value not significantly different from control rats that were killed, 132 +/- 4 mm Hg. After 8 months of renovascular hypertension, we observed that the elevated level of systolic arterial pressure was accompanied by a distinct absence of left ventricular hypertrophy when measured at the ventricular weight level. Moreover, left ventricular end-diastolic pressure increased in hypertensive animals from 6.0 to 24.0 mm Hg while peak left ventricular pressure was identical to controls. In addition, peak +dP/dt and -dP/dt were depressed in hypertensive animals. Although stroke volume was unaltered, cardiac output in renal artery clipped animals was depressed by 34% while total peripheral resistance was elevated by 50%. Ventricular chamber remodeling in the hearts of hypertensive animals was evidenced as a 19% increase in the transverse and a 16% increase in the longitudinal axes of the left ventricle with a 27% diminution of wall thickness. Myocardial damage, in the form of myocyte loss and replacement fibrosis, increased in the hearts of hypertensive animals resulting in a ninefold augmentation in the volume fraction of collagen within the ventricular wall. These alterations in the architectural properties of chamber geometry coupled with the abnormalities in contractile performance resulted in a severe reduction in ejection fraction from 82% to 47% and a marked elevation in transmural diastolic and systolic stress in hypertensive animals. The gradient in stress across the ventricular wall, from epicardium to endocardium, revealed a direct correlation with the regional distribution of myocardial damage. In conclusion, the loading state of the myocardium, tissue injury, and myocardial fibrosis all appear to be critical determinants in the genesis of left ventricular failure in long-term pressure overload.     

Effects of chronic hypertension and left ventricular hypertrophy on the incidence of sudden cardiac death after coronary artery occlusion in conscious dogs

When acute myocardial infarction occurs in patients with hypertension and left ventricular hypertrophy (LVH), the incidence of sudden cardiac death increases markedly. Possible explanations include increased size of the occluded vascular bed secondary to more extensive atherosclerotic coronary vascular disease in the presence of hypertension, decreased coronary reserve secondary to LVH, and intrinsic electrophysiologic abnormalities in hypertrophied cardiac muscle. To explore these possibilities, we produced acute circumflex coronary occlusion during the resting, conscious state in 32 control dogs and in 28 dogs with hypertensive LVH. Before coronary occlusion, mean arterial pressure was 96 +/- 0.1 mm Hg in control dogs and 125 +/- 5 mm Hg in dogs with hypertensive LVH (p less than 0.01). The control left ventricular/body weight ratio was 4.5 +/- 0.1 g/kg, compared with 6.1 +/- 0.1 g/kg in hypertensive LVH (p less than 0.01). Cumulative mortality at 6, 24 and 48 hours was 9%, 13% and 16% in control dogs and 32%, 43% and 54%, respectively, in dogs with hypertensive LVH (all p less than 0.01 vs control). The perfusion fields of the occluded vessel defined by postmortem coronary angiography were similar in the two groups (31 +/- 2% of left ventricular mass for control vs 29 +/- 2% for hypertensive LVH). Thus, the increased incidence of sudden cardiac death after coronary artery occlusion in hypertensive LVH dogs cannot be explained by increased size of the occluded vascular bed and is probably related to the decreased coronary reserve or intrinsic electrophysiologic abnormalities that characterize pressure-induced hypertrophied cardiac muscle.     

31P magnetic resonance spectroscopy of pressure overload hypertrophy in rats: effect of reduced perfusion pressure

STUDY OBJECTIVE - The purpose of the study was to confirm the presence of abnormalities in the coronary vessels of hypertensive hearts, and to examine the effects of reduced coronary perfusion pressure. DESIGN - Rats were made hypertensive by aortic banding, after which coronary flow and myocardial energy metabolites were studied in isolated hearts at physiological (140 cm H2O) and reduced (80 cm H2O) coronary perfusion pressures and compared with normotensive controls. SUBJECTS - Wistar-Kyoto rats between 250 and 300 g were used. Left ventricular hypertrophy was generated by aortic banding in 29 rats; 8 were studied one week after banding, and 21 three weeks after banding. There were 45 controls. MEASUREMENTS and RESULTS - Energy metabolites were assessed using 31P magnetic resonance spectroscopy, standardised by high performance liquid chromatography of rapidly freeze clamped tissue. Left ventricular wall thickness was determined using two dimensional echocardiography. Coronary flow (normalised for heart weight) was reduced significantly after one and three weeks of left ventricular hypertrophy, and at either physiological or below physiological pressures. Hearts from aortic banded animals developed higher intraventricular pressure with reduced oxygen consumption when perfused at a physiological pressure, indicating increased thermodynamic efficiency. When perfused at reduced pressure, the developed pressure declined significantly in both the one week and the three week banded groups compared to normal hearts. The phosphorylation potential and intracellular pH (pHi) were not significantly lower after one week and three weeks of left ventricular hypertrophy when perfused at physiological pressure. When perfused at reduced pressure, phosphorylation potential declined significantly in both groups of hypertrophied hearts, whereas pHi declined significantly only in the three week hypertrophy group. CONCLUSIONS - There is improved thermodynamic efficiency of the hypertrophied myocardium when perfused at a physiological pressure, but when perfused at a reduced pressure, ventricular function, phosphorylation potential and pHi decline in rat hearts after three weeks of aortic constriction, indicating an impairment of coronary reserve.     

Coronary vasodilator capacity and epicardial vessel remodeling in physiological and hypertensive hypertrophy

The aim of this study was to compare resting coronary flow velocity, determinants of myocardial oxygen demand, and coronary vasodilator capacity in subjects with physiological, exercise-induced, and hypertensive left ventricular hypertrophy. Sixteen healthy sedentary men, 16 endurance athletes, and 16 hypertensive subjects (mean+/-SEM for left ventricular mass index: 94.9+/-5.5, 184.6+/-8.4, 154.4+/-9.5 g/m(2), respectively) were studied by transesophageal and transthoracic Doppler echocardiography. Coronary flow velocity in left anterior descending artery and cross-sectional area of left main artery were assessed at rest and during dipyridamole-induced vasodilation. Myocardial oxygen demand was estimated through rate-pressure product, left ventricular wall stress, and inotropic function. Coronary flow reserve and minimum coronary resistance were comparable to those of sedentary men in athletes (mean+/-SEM: 3. 23+/-0.16 versus 3.60+/-0.18 and 0.96+/-0.06 versus 1.04+/-0.04 mm Hg. s. cm(-1)), while in hypertensive subjects they were decreased and increased, respectively (mean+/-SEM: 2.31+/-0.08 and 1.21+/-0.10 mm Hg. s. cm(-1); P:<0.05 for both). Resting flow velocity was directly related to rate-pressure product in sedentary men and athletes and also to wall stress in athletes, while these correlations were absent in hypertensives. Dilation of left main artery after dipyridamole was significantly higher in athletes than in sedentary men and hypertensive subjects (mean+/-SEM for area change: 32.9+/-3.7% versus 12.8+/-2.5% and 6.4+/-3.3%; P:<0.05 and 0.01). These data indicate that vasodilator capacity of coronary microcirculation is not impaired in athletes with physiological hypertrophy, in contrast to hypertensive patients. The relationship between resting flow velocity and determinants of oxygen demand is preserved in physiological hypertrophy but missing in hypertensive hypertrophy. Furthermore, the vasodilator capacity of coronary macrocirculation is also enhanced in exercise-trained subjects.