The purpose of this study is to evaluate whether exercise trainig for 12 weeks prevents the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Symptom-limited treadmill exercise with thallium-201 myocardial single photon emission computed tomography (SPECT) was performed one and 13 weeks after PTCA in 18 patients with exercise training and in 20 patients with-out. For quantitative analysis, the average count of region of interest in the hypoperfused area on the polar map was calculated. A percentage tl uptake was determined by dividing average count of the hypoperfused area by that of a normal reference area at an initial image (%IU) and a delayed image (%DU). A percentage redistribution (%RD) was obtained by subtracting %IU from %DU as the parameter of residual ischemia in the hypoperfused area. Total treadmill exercise duration and maximal pressure rate product 13 weeks after PTCA increased significantly (p<0.01) in the trained group, whereas there was no significant change in the untrained group. %DU increased significantly (p<0.01) in the trained group, whereas there was no significant change in the untrained group. %RD decreased significantly (p<0.01) in the trained group, whereas there was no significant changes in the untrained group. The restenosis rates at the third month after PTCA was 17% (3/18) in the trained group and 40% (8/20) in the untrained group. These findings suggest that in patients with coronary artery disease exercise training improves myocardial perfusion by preventing the progression of coronary artery stenosis after PTCA.

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The effects of endothelin (ET) on the function of cultured human umbilical vein endothelial cells (HUVEC) and that of human platelets were investigated with reference to endothelium-derived relaxing factor (EDRF) and PGI₂. Considering the platelets, ET had no effect on platelet-rich plasma (PRP) aggregation, the generation of thromboxane A₂ ([TXA₂]) from platelets, and cytosolic free calcium ion concentration ([Ca⁺⁺]_i), cAMP content ([cAMP]_i) or cGMP con-tent ([cGMP]_i) in platelets. In contrast, the addition of the solution in which HUVEC had been incubated with ET to PRP produced a decrease in PRP aggregation, [TXA₂], and [Ca⁺⁺]_i, and an increase not only in [cAMP]_i but also in [cGMP]_i in platelets. In the HUVEC pretreated with acetylsalicylic acid (aspirin), this increase of [cGMP]_i Was not affected, but the HUVEC-mediated decrease in PRP aggregation, [TXA₂], and [Ca⁺⁺]_i induced by ET were not completely abolished. However, the pretreatment of HUVEC with a combination of aspirin and L-NG-monomethyl arginine (LNMMA) as an inhibitor of EDRF completely abolished the HUVEC-mediated decrease in PRP aggregation, [TXA₂] and [Ca⁺⁺]_i induced by ET, and also abolished the enhancement of [cGMP]_i and [cAMP]_i in platelets. The PGI₂ Of HUVEC was enhanced by ET with no changes in [Ca⁺⁺]_i, [cAMP]_i and [cGMP]_i. The ET-induced enhancement was remarkably attenuated by pretreating the HUVEC with aspirin, but not with LNMMA. We conclude that ET attenuates the aggregation of platelets through a decrease in [TXA₂] by an increase in [cAMP]_i Via the increase in PGI₂ Of HUVEC, and by an increase in [cGMP]_i Via EDRF.

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To understand the mechanism leading to progressive pulmonary hypertension, we investigated the time course of vascular response to an acutely repetitive pulmonary microembolism in dogs by using pulmonary vascular impedance. In a normal state, the mean pulmonary arterial pressure (mPAP) was transiently increased by emboli, and the impedance moduli of 0 Hz (=Rin), 1.5 Hz and 3 Hz were slightly increased. A four-element electrical vascular model showed the transient increase in peripheral pulmonary vascular resistance (R₂) and inertia, and reduction in compliance (C). In contrast, in a state of a slight pulmonary hypertension, mPAP was continuously increased by the same amount of emboli, and the impedance moduli of both 0 Hz and 3 Hz were significantly increased. By a four-element model, a severe increase in R₂ and reduction in C were observed, and these changes continued. Therefore, although the vascular response to pulmonary microembolism basically depends on the degree of mechanical obstruction, this response is thought to be modulated by the responsiveness of pulmonary vessels at that time, which is involved in the alteration in the local characteristics of pulmonary vessels, and/or the recruitment of a new blood flow.

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We examined the hearts of 97 WKY/NCrj rats, a strain which spontaneously develops congenital cardiac malformations, by means of echocardiography with a pulsed Doppler ultrasound, and compared the results with those of 20 WKY/Ta rats and 30 normal Wistar rats. Dissection of these WKY/NCrj rats revealed a ventricular septal defect (VSD) in 20 and pulmonary valve dysplasia (PVD) in 41, both VSD and PVD occurring together in 18. VSD was readily diagnosed in vivo by the jet flow signal derived from the left-to-right shunt near the mernbranous portion, with a sensitivity of 85% and a specificity of 99%. Ultrasound imaging revealed overriding of the aorta and right ventricular (RV) hypertrophy in 18 of the 20 rats with VSD. Of the 20 rats with VSD, 10 had a systolic high-velocity jet across the RV outflow indicating an infundibular stenosis. PVD was commonly accompanied by a pulmonary regurgitation signal, with severe cases showing intensified echo and low excursion of the cusps. The regurgitation signal showed a good diagnostic value for PVD with a sensitivity of 82% and a specificity of 85%. In the remaining 54 WKY/NCrj rats without VSD or PVD, the ratio of mean left ventricular (LV) wall thickness to cavity dimension, the fractional shortening of the LV dimension, and the septal to LV free wall thickness ratio were all abnormally high, and the motion of the ventricular septum was reduced in most of the cases compared with that of the other two strains. All these features resemble the hypertrophic cardiomyopathy seen in humans, which further promises that the rats should be a useful model for the controversial disease.

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It is well known that failing hearts show diminished responsiveness (desensitization) to catecholamines. In this study, 2 different animal models were used to investigate the alterations in the hormone sensitive cardiac adenylyl cyclase system in a congestive heart failure. In the first model, cardiomyopathic Syrian hamsters (BIO53.58), we found reduced activity of the catalytic protein of adenylyl cyclase; this reduction was more prominent in an older animals (28-week-old vs 16-week-old). At both ages, the amount of inhibitory GTP-binding protein (G_i) was markedly increased in BIO53.58 compared to control healthy hamsters. Moreover the increased G_i Was shown to be fully functional in the inhibitoty pathway of the adenylyl cyclase system. In the second model, chronically norepinephrine-infused rats, we found a decrease in B-adrenergic receptor density at an early stage of injection (3 days), while the activity of catalytic protein decreased beyond 14 days of injection, and the amount of G_i increased after 7 days of injection. These results suggest that increased plasma catecholamine concentrations in the setting of congestive heart failure might be a major trigger for qualitative and quantitative alterations observed in various components of cardiac adenylyl cyclase system, and that GTP-binding proteins and catalytic protein of adenylyl cyclase are involved in the mechanism of desensitization especially after chronic in vivo stimulation of adrenergic receptors.

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Sympathetic activations may deteriorate myocardial failure due to progression of myocardial cell injury. In the present study, to test whether microtubules, calcium ion (Ca²⁺) sensitive cytoskeltons, are disrupted by norepinephrine (NE) and whether beta-adrenoceptor antagonist could attenuate the disruption of microtubules, structures of microtubules are studied in rat hearts with continuous subcutaneous infusions of norepinephrine. In the sham operated rats the microtubules stained by immunohistochemical technique showed normal network structures. A low dose of NE infusion (2/μg/kg/h) for 6 h resulted in a minimal change in microtubule structures. However, infusion for 24 h of NE (2 μg/kg/h) and a large dose of NE infusion (20 /μg/kg/h) for 6h caused disruptions of microtubules in small patchy lesions (8±3%, 12±4% of area, respectively). A large dose of NE infusion for 24 h increased systolic blood pressure from 116±6 to 152±4mmHg and increased plasma NE concentration from 430 ± 40 to 17100 ± 3700 pg/ml and further disrupted the network of microtubules in 40±6% of the total area. Propranolol (500 /μg/kg/h) markedly attenuated NE-induced disruptions of microtubules. Disruptions of microtubules may be one of the underlying mechanism of deterioraion of myocardial failure in chronic heart failure in which sympathetic activity is markedly activated.

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Whether cardiac hypertrophy is a compensatory response or a cause of decompensation has been an interesting and important controversy in cardiology. The purpose of this study is to assess qualitative and quantitative changes in biological factors involved in the evolution and the development of right ventricular hypertrophy (RVH) and right ventricular failure in response to pressure overload in rats with pulmonary hypertension induced by monocrotaline injection, and to clarify the process from compensation to deterioration in cardiac hypertrophy biochemically and morphologically. Significant RVH was produced in rats at 2 weeks after single subcutaneous injection of monocrotaline, and signs of right ventricular failure became obvious at 4 weeks as RVH became more severe. In the right ventricle of these rats, we found that: 1) myosin isoenzymes shifted from V1 to V3 both at 2 and 4 weeks; 2) total collagen content increased, and type III and type V collagens increased with a relative decrease in type I collagen at both 2 and 4 weeks; 3) intracellular Ca²⁺ transient recorded from isolated myocytes showed a lower peak and slower descent slope compared to those of control rats; 4) ultrastructural changes observed by scanning electron microscopy at 1 and 2 weeks disappeared gradually as heart failure developed, and degeneration or destruction of mitochondria or sarcoplasmic reticulum became remarkable at 3 and 4 weeks. These findings suggest that cardiac hypertrophy might be an ominous sign of cardiac failure rather than a benign adaptive process, at least in this model.

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To elucidate mechanisms of adaptation and maladaptation in heart failure. abnormalities of left ventricular function and their relationships to myocardial contractile protein were studied in the Syrian hamster Bio 14.6. Left ventricular and heart weights were both increased in 20-week-old cardiomyopathic hamsters, indicating cardiac hypertrophy as a compensatory mechanism to the disease process of cardiomyopathy. However further increase in the left ventricular weight was not observed in older (40-week-old) cardiomyopathic hamsters. On the other hand left ventricular volume and volume/mass ratio were increased progressively. Correspondingly, V₃ type myosin was increased and myosin sliding velocity was decreased. Left ventricular function of cardiomyopathic hamsters evaluated using an isovolumically beating perfused heart preparation was depressed, and this functional impairment was also progressive. Chronic administration of metoprolol, a β-blocking agent, induced further increase in left ventricular volume and mass without changing left ventricular function and myosin isozyme pattern. Thus In cardiomyopathic hamsters, left ventricular function progressively deteriorates in spite of a variety of adaptive mechanisms, and remodeling occurs. β-blocking agents may modify this process.

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We examined the effect of age on capacity for myocardial hypertrophy, pressure-generating ability and coronary circulation after imposition of pressure-overload. Marked right ventricular and cellular hypertrophy was observed I week after pulmonary artery constriction in the developmental phase of rats (2 months of age) and after 3 weeks in the young-adult rats (7 months). In old rats (18 months) similar increases in peak right ventricular pressure did not produce significant hypertrophy even after 3 weeks. The right ventricular hypertrophy at the organ and cell levels in response to pressure-overload decreased with age. In vivo pressure-generating ability, which was determined by maximum isovolumic pressure during pulmonary artery occlusion, correlated with the degree of myocardial hypertrophy in each age group. During the ascending aortic constriction experiment the age-associated diminution in hypertrophic response was also observed in the left ventricle. Coronary dilator capacity, which was determined after brief ischemia in an isolated, blood-perfused, beating but nonworking heart model, was decreased in the presence of myocardial hypertrophy in young-adult rats (7 months) and in the absence of significant myocardial hypertrophy in old rats (18 months). The age-associated diminution in capacity for myocardial hypertrophy, pressure-generating ability and maladaptation in the coronary circulation may explain the higher incidence of heart failure or increased vulnerability of the myocardium to ischemic episodes during hemodynamic stress in aged patients.

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To evaluate the role of endogenous atrial natriuretic peptide (ANP) in patients with congestive heart failure (CHF), the relationship between plasma ANP and cyclic guanosine monophosphate (cGMP) levels and the prognosis of patients with CHF was examined. In patients with chronic mild to moderate CHF, there was a positive correlation between plasma ANP and cGMP levels (r=0.81, p<0.001). However, there was no significant correlation between these plasma levels in patients with chronic severe CHF, in whom the cGMP concentration reached a plateau in spite of high levels of ANP. The ANP extraction level and the cGMP production level in the pulmonary and systemic circulation correlated significantly in patients with mild CHF. In contrast, there was no significant correlation between the 2 parameters in patients with severe CHF, and the molar ratios of cGMP production to ANP extraction in the pulmonary and systemic circulation were significantly lower than those in patients with mild CHF. In 44 patients with chronic severe CHF who were followed up over 2 years, plasma ANP levels provided more sensitive and specific prognostic information than any other parameters. These results indicate that ANP receptors coupled to guanylate cyclase may be down-regulated in patients with chronic severe CHF, suggesting that high plasma ANP levels as a prognostic predictor may be associated with limitations of compensation by endogenous ANP.

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To evaluate the blood flow distribution during exercise, 51 patients with chronic heart failure underwent ergometer exercise testing measuring cardiac output and leg blood flow. At the given workrate (10 watts and 25 watts) cardiac index (L/min/m²) was significantly lower in NYHA class III patients than class I patients (at 10 watts, 4.08± 1.05 in class I, 4.01 ±1.29 in class II and 3.00±0.89 in class III, p<0.05; I vs III), while leg blood flow (L/min/m²) was similar among 3 groups (at 10 watts, 1.19±0.32, 1.29±0.25 and 1.16±0.29, ns). Consequently, residual blood flow (L/min/m²) was significantly lower in class III than class I (at 10 watts, 2.89±.92 and 2.78±1.27 and 1.84±0.71, p<0.05: I vs III). The results at 25 watts were similar. Serum noradrenaline was significantly higher in class III patients than class I patients at both 10 and 25 watts. We concluded that in severe heart failure, agreater blood flow is distributed to the working leg muscle as compared with less severe heart failure. And such an increased distribution of blood flow to working leg plays a role to compensate an insufficient cardiac output response in patients with severe heart failure.

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In congestive heart failure (CHF), excessive vasoconstriction is present, which is due to overactive vasoconstrictor mechanisms although vasodilator mechanisms may be impaired. In the present study, we examined vasodilation in CHF by measuring forearm blood flow with a strain gauge plethysmograph. Patients with CHF had higher forearm vascular resistance than normal control subjects. Patients with CHF had decreased forearm vasodilation in response to intra-arterial infusions of atrial natriuretic peptide (ANP) and acetylcholine, but not in response to sodium nitroprusside or nitroglycerin. Oral captopril did not alter the degree of forearm vasodilation during handgrip exercise. These results suggest that endothelium-dependent and ANP-induced forearm vasodilation is impaired in patients with CHF but the decreased vasodilation is not due to impaired vascular smooth muscle responsiveness to a vasodilator. The renin-angiotensin system does not seem to play a major role in the main-tenance of vascular resistance during exercise in CHF.

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To assess the compensatory change in oxygen uptake (VO₂) kinetics during exercise in patients with heart failure, we performed cardiopulmonary exercise testing using a cycle ergometer in 29 cardiac patients and 18 normal subjects. The work rate increased linearly (1w/6sec) after a 4 min, 20w warm-up. The ratio of increase in VO₂ to increase in work rate (ΔVO₂/Δ WR) was determined by linear regression of VO₂ plots. Cardiac output by dye dilution method and plasma norepinephrine concentration (NE) were measured at rest and 20w warm-up. VO₂ at rest and at 20w warm-up and ΔVO₂/ΔWR decreased significantly with increasing severity in NYHA functional classification. ΔVO₂/ΔWR showed significant negative correlation to the difference in NE levels at rest and at 20w (r=-0.69, p<0.001). The delta values of arteriovenous O₂ content difference, calculated using Fick's principle, and cardiac index from rest to 20w warm-up failed to show significant relationship to ΔVO₂/ΔWR. These results suggest that the decrease in VO₂ requirement in heart failure patients is due probably to blood redistribution during exercise as a compensatory mechanism for exercise intolerance.

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We evaluated changes in left ventricular (LV) preload and the Doppler-derived transmitral late to early diastolic peak velocity ratio (A/E ratio) during the exercise in 27 patients with ischemic heart disease. After the exercise, A/E ratio de-creased in 16 patients with a remarkable elevation in LV preload, and increased in 11 with a mild elevation. Further, Doppler transmitral flow in conjunction with pulmonary venous flow and hemodynamic parameters were analyzed in 11 dogs during a worsening course of heart failure induced by dextran infusion. The relationship of A/E ratio to LV end-diastolic pressure showed a quadratic curve concave to the pressure axis. A/E ratio, an index expressing left atrial (LA) contribution to LV filling, returned to that seen before volume loading under the condition of cardiac dysfunction. Pulmonary venous reflux fraction determined as the ratio of peak velocity of pulmonary venous reflux during LA systole to the sum of systolic and diastolic peak velocities of pulmonary venous antegrade flow, did not increase here. In this situation, blood could not be ejected from the left atrium into the left ventricle and even into the pulmonary veins during LA contraction. Finally. LV filling was not compensated by the left atrium, and LA booster pump function itself was deteriorated.

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Compensation for heart failure can be influenced by cardiac loads due to organ failure. This investigation studied the effect of secondary organ failure on the hemodynamics of acute heart failure. Of 106 patients with acute heart failure due to myocardial infarction or dilated cardiomyopathy, 49 (46%) patients had secondary organ failure, either kidney, liver, brain or blood. Their acute heart failure was sustained for significantly longer than that of 57 patients without organ failure. A transient but severe decompensation induced secondary organ failure, although the left ventricular ejection fraction was not different from that of the control without heart failure. Hypervolemia in cases of renal failure, bradycardia in loss of consciousness, hyperdynamic state in anemia and low blood pressure in liver dysfunction caused the sustained acute heart failure. These results suggested that secondary organ failure might occur in 46% of patients with acute heart failure, and might disrupt compensation by different kinds of hemodynamic loads in low cardiac function.

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