Early impairment of coronary flow reserve and increase in minimum coronary resistance in borderline hypertensive patients

OBJECTIVE: To evaluate relations between coronary flow velocity and myocardial oxygen demand at rest, as well as coronary vasodilator capacity and flow reserve, in asymptomatic subjects with borderline hypertension as compared to normotensive controls and patients with sustained high blood pressure (HBP) and without left ventricular hypertrophy (LVH). SUBJECTS AND METHODS: Forty-two asymptomatic males were studied: 13 healthy normotensive volunteers; 12 subjects with borderline HBP and 17 asymptomatic subjects with sustained systemic hypertension. Coronary flow velocity in left anterior descending artery and coronary flow reserve were assessed by transesophageal echo-doppler at baseline and during intravenous adenosine infusion. Left ventricular mass, peak systolic wall stress (PSWS; Pa), and midwall fractional shortening (MFS; %) were obtained from M-mode images of the left ventricle in transthoracic long-axis view and in transesophageal transgastric view. RESULTS: Coronary flow velocity at baseline was not significantly different in the three groups, despite significantly higher rate-pressure product (RPP) in the hypertensive groups as compared with controls. Only in control subjects, was resting coronary flow velocity significantly correlated with RPP (y = 4279 + 200x, r = + 0.58, P < 0.05) and PSWS (y = 17.2 + 5.1 x, r = + 0.62, P < 0.05). Coronary reserve was 3.5 +/- 0.65 in controls and significantly lower (P < 0.05) in borderline hypertensive (2.87 +/- 0.46) and in sustained hypertensive subjects (2.66 +/- 0.56). Minimum coronary resistance was significantly increased in both hypertensive groups (1.30 +/- 0.29 and 1.39 +/- 0.48 mmHg/s per cm) as compared to normotensive controls (0.93 +/- 0.20 mmHg/s per cm, P < 0.01). CONCLUSIONS: In asymptomatic subjects with borderline hypertension and without LVH, a significant reduction in coronary flow reserve is already detectable and appears almost entirely related to an impaired coronary vasodilator capacity rather than to an increased myocardial oxygen demand.     

Effect of volume-overload hypertrophy on the coronary circulation awake dogs

Inadequate coronary reserve is present in left ventricular hypertrophy secondary to hypertension. Since this abnormality might be due in part to vascular hypertrophy of coronary resistance vessels in response to chronic hypertension, we studied a model of ventricular hypertrophy without hypertension. Volume-overload hypertrophy was produced by creating complete heart block in mongrel dogs; 6 to 7 weeks later the dogs were studied in the awake state. The thirteen dogs with chronic heart block had a 49% increase (P less than 0.05) in left ventricular mass compared with eight control dogs. The major findings in this study were: 1) at rest, coronary blood flow (microsphere technique) per unit weight of left ventricle was not increased in dogs with hypertrophy; and 2) the minimal coronary vascular resistance per unit weight of left ventricle calculated during iv adenosine infusion at a rate that produced maximal vasodilatation was not significantly higher in dogs with left ventricular hypertrophy than in controls (16.4 +/- 1.0 vs 14.7 +/- 1.5 kPa . litre-1 . min . 100 g, respectively). Minimal coronary vascular resistance of the entire left ventricle was significantly less in dogs with hypertrophy than controls (13.0 +/- 0.8 vs 17.3 +/- 1.7 kPa . litre-1 . min, respectively). This data suggests that vascular hypertrophy of coronary resistance vessels related to chronic hypertension may be the cause of the increased minimal coronary vascular resistance seen in dogs with pressure-overload left ventricular hypertrophy.     

Homogeneously Reduced Versus Regionally Impaired Myocardial Blood Flow in Hypertensive Patients: Two Different Patterns of Myocardial Perfusion Associated With Degree of Hypertrophy

Objectives. The aim of this study was to quantitatively measure regional and global myocardial blood flow and coronary reserve in hypertensive patients without coronary artery disease and to assess the correlation with left ventricular mass.Background. The effect of left ventricular hypertrophy on regional vasodilating coronary capability in arterial hypertension is controversial, and no quantitative method has been applied to assess a possible correlation.Methods. Positron emission tomography was performed in 50 untreated hypertensive patients and 13 normotensive subjects. Blood flow at baseline and after dipyridamole was globally and regionally measured by using nitrogen-13 ammonia; coronary reserve and resistance were calculated. Left ventricular mass was assessed by two-dimensional echocardiography.Results. In hypertensive patients, flow at baseline was similar to that of normotensive subjects (p = 0.21), but values were reduced after pharmacologic vasodilation (p < 0.05). This impairment of maximal coronary flow was not correlated with left ventricular mass (p = 0.13). Among hypertensive patients, we identified a group with a homogeneous distribution of perfusion and a group with a heterogeneous flow pattern. Flow was globally reduced in the former group, but it was abnormal only at the site of perfusion defects in the latter. Patients with regional defects showed the highest likelihood of having an increased left ventricular mass.Conclusions. In arterial hypertension, left ventricular mass is not correlated with global myocardial blood flow. Nevertheless, patients with ventricular hypertrophy are likely to show a heterogeneous flow pattern with regional defects and almost normal blood flow in nonaffected regions. In hypertensive patients with a homogeneous perfusion pattern during stress, myocardial blood flow frequently shows a diffuse reduction.     

Hemodynamic consequences of left ventricular hypertrophy in spontaneously hypertensive rats.

Compared with hearts from normotensive rats isolated, perfused hearts from spontaneously hypertensive rats exhibit a rightward shift of the Frank-Starling curve in the lower range of filling pressures, that is, up to 10 mm Hg. The extent of this shift is proportional to the degree of left ventricular hypertrophy. This is suggested to be a consequence of an altered relation between end-diastolic pressure and end-diastolic tension of the progressively more thick-walled left ventricle. Furthermore, the cardiac function curves revealed that maximal cardiac performance is apparently better in spontaneously hypertensive rats than in normotensive rats at increased levels of afterload. Therefore, left ventricular hypertrophy in established hypertension seems to contribute to adjustment of cardiac performance to the enhanced pressure work in hypertension; however, this occurs at the expense of a rightward shift of the Frank-Starling curve. In spontaneously hypertensive rats studied in vitro, coronary vascular resistance per unit weight of tissue was increased at maximal dilation, as was maximal pressor response. This may reflect the same type of structural vascular adaptation that occurs in most systemic vascular beds in hypertension and that contributes to maintenance of increased vascular reactivity and flow resistance in both hypertensive patients and spontaneously hypertensive rats. Apparently as a consequence of this adaptation, splanchnic nerve stimulation at an increasing rate caused exaggerated increases in resistance in anesthetized hypertensive rats by comparison with findings in normotensive rats. However, the effect of capacitance vessel constriction on stroke volume caused by splanchnic nerve stimulation was less pronounced in hypertensive rats. This relative “hyporeactivity” of the capacitance vessels also suggests an altered relation between cardiac filling pressure and stroke volume of the hypertrophied left ventricle in the spontaneously hypertensive rat.     

Coronary blood flow during the development and regression of left ventricular hypertrophy in renovascular hypertensive rats

Left ventricular (LV) coronary flow (CF) was determined by left atrial injection of microspheres in conscious rats during the development and after the reversal of LV hypertrophy in 2-kidney, 1-clip Goldblatt hypertension. Two groups of untreated renal hypertensive rats (RHR) were studied, the first (RHR₁, n = 17) at 10 weeks and the second (RHR₂, n = 9) at 24 weeks after clipping. Beginning 9 weeks after clipping, 2 other groups were treated either with captopril (40 to 60 mg/kg/day) in drinking water (RHR-C, n = 8) or left nephrectomy (RHR-N, n = 9) and followed for 15 weeks. Sham-operated animals followed for similar periods of time served as controls (Sham-1, n = 12, as a control for RHR₁, and Sham-2, n = 11, as a control for RHR₂). In all groups, LV mass increased or decreased in close correlation with changes in arterial blood pressure, and minimal total LV coronary resistance remained unchanged. The development of hypertrophy was associated with a tendency toward reduction in CF reserve (defined as maximal CF/unit mass); this flow reserve was restored with reversal of hypertrophy. The importance of the relation between pressure and LV mass as a determinant of CF reserve was investigated in a second study in which this relation was changed by altering the periods of captopril therapy; in these cases, CF reserve correlated significantly with the ratio of arterial pressure to LV mass (r = 0.76, n = 12, p < 0.01). The results suggest that maintenance of CF reserve in LV hypertrophy depends on an appropriate balance between arterial pressure and LV mass, and might be disturbed by antihypertensive therapy that leaves LV hypertrophy unchanged.     

Relations among impaired coronary flow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensive patients without obstructive coronary artery disease

Invasive Doppler catheter-derived coronary flow reserve, echocardiographic measurements of left ventricular hypertrophy and intravenous dipyridamole-limited stress thallium-201 scintigraphy were compared in 48 patients (40 were hypertensive or diabetic) with clinical ischemic heart disease and no or minor coronary artery disease. Abnormal vasodilator reserve (ratio less than 3:1) occurred in 50% of the study group and markedly abnormal reserve (less than or equal to 2:1) occurred in 27%. Coronary vasodilator reserve was significantly lower (2.2 +/- 0.8 versus 3.5 +/- 1.3, p = 0.003) and indexed left ventricular mass significantly higher (152.6 +/- 42.2 versus 113.6 +/- 24.0 g, p = 0.0007) in patients with a positive (n = 11) versus a negative (n = 32) thallium perfusion scan. Coronary flow reserve was linearly related in coronary basal flow velocity as follows: y = -0.17x + 4.59; r = -0.57; p = 0.00002. The decrement in flow reserve was not linearly related to the degree of left ventricular hypertrophy. Abnormal vasodilator reserve subsets found in hypertensive patients were defined on the basis of basal flow velocity, indexed left ventricular mass and clinical factors. In this series, diabetes did not cause a detectable additional decrement in flow reserve above that found with hypertension alone. These findings demonstrate that thallium perfusion defects are associated with depressed coronary vasodilator reserve in hypertensive patients without obstructive coronary artery disease. Left ventricular hypertrophy by indexed mass criteria is predictive of which hypertensive patients are likely to have thallium defects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of exercise on coronary circulation in left ventricular hypertrophy caused by hypertension

Exercise is known to promote myocardial vascularity. We therefore studied whether it could prevent coronary abnormalities of hypertensive left ventricular (LV) hypertrophy. Female Sprague-Dawley 1 clip-2 kidneys Goldblatt hypertensive rats (RHR) and their appropriate controls (Sham-SH), were either made to swim (RHR-SW, SH-SW) or kept sedentary (RHR-SED, SH-SED) for 9 weeks. Maximal coronary blood flow (LV CBF, ml/min/gm) and minimal coronary resistance after carbochrome (total LVCR/LV mmHg/ml/min), an index of the functional cross sectional area (CSA) of coronary resistance vessels, were determined in conscious rats by microspheres. Results (m +/- SD) (n = 12 in all groups): (Table: see text). Exercise increased functional coronary CSA in normotensive rats only. This beneficial effect did not occur in hypertension, probably because of functional changes in the coronary vessels of RHR.     

Myocardial perfusion during long-term angiotensin-converting enzyme inhibition or beta-blockade in patients with essential hypertension

Hypertension is associated with reduced coronary vasodilatory capacity, possibly caused by structural changes in the coronary resistance vessels. Because vasodilatory treatment may correct abnormal structure better than nonvasodilating treatment, we compared whether long-term angiotensin-converting enzyme (ACE) inhibition has a greater effect on coronary reserve and cardiovascular structure than beta-blockade in patients with essential hypertension. Thirty previously untreated hypertensive patients were randomized in a double-blind design to treatment for 1 year with either perindopril (4 to 8 mg per day, n=15) or atenolol (50 to 100 mg per day, n=15) and furthermore compared with normotensive controls. Cardiac output and left ventricular mass were measured with echocardiography and resistance artery structure was determined in vitro. Using positron emission tomography, myocardial perfusion (MP) was determined at rest and during dipyridamole-induced hyperemia while still on medication. Perindopril reduced left ventricular mass by 14+/-4% (P<0.01), peripheral vascular resistance by 12+/-6% (P<0.01), and media thickness-to-lumen diameter ratio of resistance arteries by 16+/-4% (P<0.05), whereas atenolol had no effect. Resting MP was decreased both by perindopril (-11+/-4%, P<0.01) and by atenolol (-25+/-4%, P<0.01) in parallel to the reduction in rate pressure product. Hyperemic MP was unaltered by perindopril (+2+/-6%, P=NS), but reduced by atenolol (-32+/-5%, P<0.01). Compared with atenolol, perindopril treatment resulted in higher coronary reserve (P<0.05). We conclude that compared with beta-blockade, ACE inhibition increases coronary reserve and results in regression of hypertensive resistance artery structure and left ventricular hypertrophy. Vasodilating may thus be superior to nonvasodilating treatment in repairing the hypertensive myocardial microcirculation.     

Failure of swimming exercise to improve capillarization in cardiac hypertrophy of renal hypertensive rats

Female Sprague-Dawley rats were made hypertensive by the two kidney/one clip Goldblatt procedure, while control animals were sham-operated. One week later, half of the animals were subjected to a moderate swimming exercise and the other half remained sedentary. Thus, four experimental groups, each consisting of 14 rats, were formed: control animals that were exercised or kept sedentary and corresponding renal hypertensive animals either exercised or sedentary. In hypertensive rats, a significantly increased left ventricular weight and reduced coronary reserve were found. Cardiac hypertrophy in hypertensive rats was characterized by a lower number of capillaries on a tissue cross-section, larger heterogeneity of the capillary net, and a less uniform orientation of capillaries in space. Total length of capillaries in the hypertrophic hearts increased significantly, but less than the increase in cardiac weight, resulting in reduced capillary length density. Chronic swimming for 2 hr/day for a period of 6 weeks, subsequent to a 4-week acclimation period, did not significantly influence any of the investigated indexes of capillaries from hypertrophic hearts. In the normotensive rats, chronic swimming resulted only in a moderate increase in total capillary length associated with a small increase in the left ventricular weight of similar degree. Thus, chronic exercise in normotensive rats induced a moderate increase in total capillary length per left ventricle, while it did not alleviate impaired capillarization of hypertrophic hearts from hypertensive rats.     

Morphometry of canine coronary arteries, arterioles, and capillaries during hypertension and left ventricular hypertrophy

The mechanisms responsible for the increase in minimal coronary vascular resistance per unit mass of myocardium in animals with chronic hypertension and left ventricular hypertrophy remain unidentified. Because increases in wall thickness of resistance vessels in some vascular beds in response to hypertension may decrease luminal diameter, we hypothesized that similar changes may occur in the coronary vasculature. To test this hypothesis, we performed hemodynamic and morphometric studies on eight dogs with renovascular hypertension (one kidney, one clip) of 6 weeks' duration, and in six normotensive dogs. Hypertension evoked a 27% increase in left ventricular mass and was associated with a 67% increase in left ventricular minimal coronary vascular resistance per 100 g calculated from coronary perfusion measured with microspheres during adenosine infusion. The vasculature was fixed via perfusion of glutaraldehyde and tissue samples from the left ventricle were embedded in Epon. Wall:lumen ratios, determined by light microscopy, of coronary arteries and arterioles were similar in hypertensive and normotensive dogs. Lumen diameters of large epicardial arteries (greater than 640 microns) of hypertensive dogs increased significantly so that wall:lumen ratios were normal despite an increased medial thickness. Ultrastructural analysis, however, showed an enhancement of the relative extracellular compartment of the tunica media of large coronary arteries of hypertensive dogs: 36.4 +/- 3.4% vs. 26.5 +/- 1.6% (mean +/- SEM). Capillary numerical density and surface area (surface area:tissue volume) were significantly lower in the endomyocardium, while capillary volume density (volume:tissue volume) was lower in the midmyocardium and endomyocardium of hypertensive dogs compared to normotensives.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphologic, hemodynamic and coronary perfusion characteristics in severe left ventricular hypertrophy secondary to systemic hypertension and evidence for nonatherosclerotic myocardial ischemia.

Patients with the clinical diagnosis of ischemic heart disease who were found to be free of significant coronary artery atherosclerotic disease (n = 150) underwent coronary vasodilator reserve testing, 2-dimensional echocardiography, and dipyridamole limited-stress thallium testing. After exclusions (predominantly for technically poor coronary artery Doppler signals or suboptimal echocardiography), 100 patients formed the study population. The purpose was to characterize typical cardiac and coronary artery findings in hypertensive patients with severe left ventricular (LV) hypertrophy (n = 15) and to investigate the evidence for myocardial ischemia unrelated to coronary atherosclerosis in early and advanced hypertensive heart disease. Normotensive and hypertensive control groups without LV hypertrophy (n = 12 and 34, respectively) were used for comparison. Severe LV hypertrophy was defined as LV mass index greater than or equal to 50% above established gender specific norms using 2-dimensional-directed M-mode echocardiography and the cube equation corrected to agree with necropsy estimates of mass. Clinical characteristics more often associated with severe LV hypertrophy were black race (67%), diabetes mellitus (33%), proteinuria (47%) and elevated creatinine (1.5 +/- 0.9 mg/dl). Baseline electrocardiograms and dipyridamole limited-stress thallium scans were highly likely to be abnormal (94 and 73%, respectively). Both eccentric and concentric cardiac hypertrophies were found in the severe group. Ejection fraction was significantly lower (0.51 vs 0.68, p = 0.002) and basal coronary flow velocity higher (12.0 vs 5.0 cm/s, p = 0.0004) among these patients when compared with normotensive control patients. Coronary flow reserve did not differ between control groups but was significantly depressed in patients with severe LV hypertrophy (2.5 vs 3.9, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of perindopril on left ventricular hypertrophy, coronary reserve and mechanical properties of the papillary muscle of the rat with renovascular arterial hypertension

We investigate the effect of a new angiotensin-converting enzyme inhibitor: Perindopril (IRIS) on regression of left ventricular hypertrophy (LVH), coronary blood flow and mechanical performance of isolated papillary muscle in renovascular hypertensive (Goldblatt 2 kidneys-1 clip) Sprague-Dawley male rats. Sham operated rats (G1) and half of hypertensive rats (G2) were studied after 8 weeks. The other half of 8 weeks long hypertensive rats (G3) were treated during 8 weeks with Perindopril in drinking water at a dosage adjusted to maintain blood pressure (BP) measured with tail cuff method under 140 mmHg. The study of each rat included 1) coronary blood flow and resistance measurements under resting conditions and after coronary dilation by carbochrome infusion (9 mg/kg) using left atrial injection of radioactive microspheres (method of Wicker and Tarazi) 2) the study of mechanical performance of the isolated papillary muscle 3) weight of left ventricle after separation of septum and free wall whose subendocardial and subepicardial layers were counted separately. Results (mean +/- SD): (table; see text) MAP: mean pressure. LV/BW: left ventricular mass (mg) per gram of body weight; CR (C): minimal coronary resistance after carbochrome (mmHg/ml/min/100 mg); DL/Dt: peak velocity of shortening at L max preload; Vrelax: peak velocity of relaxation; THR: time of half relaxation; p less than 0.05; p less than 0.01 compared to SHAM. In this model, hypertension induced a 50 p. 100 LVH whose regression was nearly complete after 8 weeks of treatment with Perindopril. Minimal coronary resistance after carbochrome were higher in hypertensive rats compared to sham and return to normal after regression of LVH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between left ventricular midwall function and coronary vasodilator capacity in arterial hypertension

In systemic hypertension, depressed left ventricular midwall shortening predicts an adverse outcome and is associated with increased left ventricular relative wall thickness, which has been proposed as an independent predictor of cardiovascular risk and reduced coronary reserve. This study was designed to investigate whether depressed midwall shortening is associated with more critical impairment of coronary function and with exercise-induced myocardial ischemia. Sixty untreated hypertensive patients without coronary artery stenosis and 20 normotensive volunteers underwent exercise ECG testing, standard and transesophageal echocardiography to assess the occurrence of exercise-induced myocardial ischemia, left ventricular mass, geometry, and midwall shortening, and coronary vasodilator capacity. Compared with hypertensive patients with normal midwall shortening, those with depressed function (n=15) had higher minimum coronary resistance (1.19+/-0.27 versus 1.39+/-0.20 mm Hg/cm per second, P<0.01) and prevalence of exercise-induced myocardial ischemia (36 versus 67%, P<0.05). Within the hypertensive group, midwall shortening was inversely related to minimum coronary resistance (r=-0.42, P<0.01). Compared with patients with an exercise ECG test negative for myocardial ischemia, those with a positive test result (n=26) had higher minimum coronary resistance (1.13+/-0.21 versus 1.38+/-0.27 mm Hg/cm per second, P<0.01) and lower midwall shortening (104+/-16 versus 93+/-14%, P<0.01). We conclude that hypertensive patients with depressed midwall shortening have more severe impairment of coronary function and a higher prevalence of exercise-induced myocardial ischemia as compared with hypertensive patients with normal midwall shortening. These findings suggest that a decrease in myocardial performance may be related, at least in part, to chronic intermittent myocardial ischemia caused by a critical impairment of coronary vasodilator capacity.     

Coronary Hemodynamics in Diabetic Spontaneously Hypertensive Rats

We investigated the coronary hemodynamics in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats 4 and 20 weeks after Streptozotocin or vehicle injection. The hemodynamic parameters were measured at rest and during maximal coronary vasodilation with dipyridamole. Streptozotocin, 40 or 60 mg/kg, produced moderate or severe diabetes in both strains, but resulted in a mortality of 11.3 or 40.8% in SHR alone. The left and right ventricular weights were decreased with no change in their ratios to body weight in both strains. Severely diabetic SHR and WKY revealed hypotension, bradycardia, an increased cardiac index and decreased total peripheral resistance index at both weeks. Moderately diabetic SHR revealed similar changes except for an unaltered cardiac index. Short-term severely diabetic SHR alone displayed an in-creased basal bi-ventricular coronary flow (per u n i t mass). The maximal coronary flow was unaltered i n any group by diabetes. The left ventricular transmural flow distribution was also unaltered i n any group. However, severe diabetes i n SHR diminished a coronary flow reserve (maximal minus basal flow) of the l e f t ventricle a t 4 weeks, and that of both ventricles a t 20 weeks. Thus, the severity and duration of diabetes had a strain-related influence on the systemic and coronary hemodynamics, w i t h deaths and a reduced coronary flow reserve i n SHR alone. The minimal coronary vascular resistance i n both ventricles (per u n i t mass) showed no increase i n each group by diabetes, suggesting no overalldecrease i n functional cross-sectional area of the coronary vasculature.     

Coronary vasodilator capacity and hypertension-induced increase in left ventricular mass

An increase in left ventricular mass represents a compensatory response of hypertensive heart to augmented loading conditions. The concept of inappropriate mass has been proposed to define an increase in left ventricular mass higher than needed to compensate for increased workload. To assess whether inappropriate left ventricular mass is associated with more severe impairment of coronary vasodilator capacity, 64 untreated middle-aged hypertensive patients without significant coronary artery stenosis and 14 normotensive volunteers comparable for age and gender were studied by transthoracic and transesophageal echocardiography to evaluate left ventricular mass, geometry, and coronary flow velocity response to adenosine. Thirty-three patients had appropriate and 31 had inappropriate increase in left ventricular mass, whereas all normotensive control subjects had appropriate left ventricular mass. Compared with control subjects, minimum coronary resistance (0.87+/-0.18 mm Hg per second/centimeter) was increased in both hypertensive subgroups, more in those with inappropriate left ventricular mass (1.34+/-0.23 versus 1.19+/-0.23 mm Hg per second/centimeter, P<0.01), who also exhibited lower afterload-corrected midwall shortening and ratio of peak early and peak late velocities of transmitral flow profile. In hypertensive patients, minimum coronary resistance was related positively to absolute and relative left ventricular wall thickness (r=+0.33 and +0.35, both P<0.01) and negatively to midwall shortening and ratio of peak early and peak late velocities of transmitral flow (r=-0.32 and -0.31, both P<0.02). Thus, in the hypertensive heart, a deviation of left ventricular mass from values compensatory for increased cardiac workload is associated with lower coronary vasodilator capacity, depressed left ventricular wall mechanics, and abnormal left ventricular diastolic filling pattern.     

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.     

Effects of long-term cardiac hypertrophy on coronary vasodilator reserve in SHR rats

The effects of long-term left ventricular (LV) hypertrophy on coronary vascular reserve have not been extensively investigated. To test the hypothesis that the duration of LV hypertrophy may modulate coronary vascular reserve, a newly developed pulsed Doppler flowmeter was used to compare the characteristics of coronary reactive hyperemia in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The data suggest that coronary reactive hyperemic responses in the rat are markedly different from those in larger animals and humans, e.g., peak/rest blood flow velocity ratio and the repayment/debt area ratio were 30 to 50% of those observed in larger laboratory animals. Because minimal coronary vascular resistance is similar in the rat and larger animals, the relatively high myocardial oxygen consumption at rest and consequent high myocardial blood flow at rest probably account for the alteration of coronary reactive hyperemia in the rat. In SHR rats, the characteristics of coronary reactive hyperemia decreased during developing (3-month-old) and peak (7-month-old) LV hypertrophy compared with those in their age-matched WKY controls. However, in 12-month-old SHR rats with stable LV hypertrophy, the coronary reactive hyperemic response was similar to that of 12-month-old WKY rats. Mean arterial pressures were significantly elevated in each of the 3 SHR groups. These data suggest a significant decrement in coronary vascular reserve during actively developing and peak LV hypertrophy, but the decrement disappears during stabilized hypertrophy. These studies suggest that the duration of LV hypertrophy may modulate the interaction between pathologic increases in cardiac mass and growth of the coronary vasculature.     

Coronary flow velocity reserve is diminished in hypertensive left ventricular hypertrophy

BACKGROUND: Dipyridamole stress transesophageal echocardiography (STEE) is a feasible method for the evaluation of coronary flow velocity reserve (CFR). AIM: The aim of the present study was to investigate CFR in hypertensive patients with or without left ventricular hypertrophy (LVH). METHODS: The study comprised 73 patients with a negative coronary angiogram (29 men and 44 women). Three different groups were compared: normotensive patients, hypertensive patients without LVH and hypertensive patients with LVH. RESULTS: CFR was significantly decreased in patients with hypertension with LVH as compared to normotensive cases (2.19+/-0.50 vs 2.71+/-1.10; p<0.05). CFR of hypertensive patients without LVH was only slightly reduced as compared to normotensive cases (2.44+/-0.81 vs 2.71+/-1.10; p=ns). In hypertensive patients with LVH, the LV mass and LV mass index were inversely related to CFR (r = -0.481 and -0.477, p<0.05, respectively). CONCLUSIONS: CFR is diminished in patients with hypertension. The degree of CFR reduction is related to the extent of LVH.     

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)