The aim of this study was to evaluate the late potentials (LPs) in postoperative patients with congenital heart disease (CHD) and to study the association with the clinical characteristics in the postoperative patients with LPs. Signal averaged electrocardiogram (SA-ECG) was recorded in 119 postoperative patients aged 4 to 23 years and compared with those in age matched 49 healthy volunteers with and without right bundle branch block. Based on control data, criterias of LP were defined and altered in the presence of bundle branch block. Abnormal SA-ECGS Were not detected in the patients with non-cyanotic CHD. However, abnormal and borderline SA-ECGS were recognized in 5 (12%) of 42 patients after intracardiac operation for tetralogy of Fallot and 3 (30%) of 9 patients after Rastelli's operation. The patients with abnormal and borderline SA-ECGS Were significantly older at the time of operation, and had more frequent ventricular arrhythmias (7/8: 3/111, p<0.01) and depression of the ST-T segment on ECG (7/8: 11/111, p<0.01), compared with the normal SA-ECG group. Abnormal SA-ECGS including those of borderline patients were 50% sensitive and 96% specific for documented ventricular arrhythmias. However, there was no association between anbnormalities of SA-ECGS and cardiomegaly on chest X-ray or left ventricular ejection fraction on echocardiogram. These results indicate that prolonged exposure to hypoxia may be the main cause of the primary role in the development of LPs. And late surgical intervention may result in histological background for the development of LPs.

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To elucidate whether tissue fibronectin increases in the early stages of ather-ogenesis induced by hypercholesterolemia without mechanical trauma, we investigated sequential changes in the distribution of tissue fibronectin during fatty streak initiation and maturation in the aortas of hypercholesterolemic fat-fed rabbits. The presence of fibronectin was examined on immunoperoxidase stained tissue specimens with the aid of a microscope-photometric technique. Twenty male albino rabbits were used. Cholesterol supplemented chow (1%) was given for 4 weeks (n=6), 8 (n=5) or 14 weeks (n=5). A membrane-like layer positive for fibronectin was observed along the endothelium in the normal aorta. After 4 weeks of the cholesterol-feeding, fatty streaks were initiated in the intima, where fibronectin was more densely accumulated than the normal intima. After 8 weeks of the cholesterol-feeding, fatty streaks were expanding, associated with the dense staining for fibronectin. After 14 weeks, fibronectin was still concentrated in the endothelial layer and also in the superficial areas of the thickened intima, but decreased in the deep areas of the thickened intima where collagen and elastin appeared as bundles. The photometric data of fibronectin supported these visual observations. Thus, fibronectin appeared early and disappeared later in the intima during the process of fatty streak initiation and maturation. These findings suggest that in hypercholesterolemia without mechanical endothelial injury, fibronectin may play an important role in an early process of atherogenesis.

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To elucidate the pathogenesis of the post-ischemic vascular injury in reperfused coronary arteries, the left anterior descending coronary artery (LAD) was occluded for 30 min or 60 min in 26 dogs. After 120 min of reperfusion, vascular strips were prepared from LAD and the left circumflex coronary artery (LCX) as control, and suspended in organ chambers containing Krebs-Henseleit solution and vascular reactivity was evaluated pharmacologically. In a separate experiment, LCX-strips from 12 dogs were subjected ex vivo to blood cell-free simulated ischemia by the substitution of perfusate to hypoxic, low pH and high K⁺ for 60 min and the following 60 min of reoxygenation. Vascular responses to various agents were compared prior to and after simulated ischemia. Vascular injury was also investigated histologically with electron microscopy. As the results; significantly blunted endothelium-dependent relaxations to acetylcholine (10^-6 M) and Ca-ionophore (A-23187: 10^-6 M) in LAD-strips compared to LCX were noticed (43.7±4.8 vs 61.6±7.3%, 22.7±5.2 vs 47.9±8.4% in % relaxation, respectively). Augmented contractile response selective to endothelin was also observed in reperfused vessels (LAD) compared to control vessels (10^-9 M: 105.4± 19.5 vs 42.4± 12.3% of 20 mM-KCl induced contraction, p< 0.01). Electron microscopy revealed partial detachment and blebbing of endothelial cells in reperfused coronary arteries. Similar changes were also observed in the simulated ischemia and reoxygenation study, but the augmented response to endothelin was seen only when polymorphonuclear leukocytes (PMN) activated with phorbol myristate acetate were added. Our results suggest that endothelial injury does not essentially depend on PMN, but PMN promote augmented response to endothelin. These changes indicate that enhanced spasmogeneity is present in reperfused arteries, which may contribute to post-infarction angina and prolonged myocardial dysfunction after reperfusion.

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It has been demonstrated that the V₃ cardiac myosin isozyme has a higher efficiency and consumes less oxygen in doing mechanical work than the V₁ myosin isozyme. The purpose of the present study is to investigate the functional and metabolic responses to ischemia following reperfusion of the hypothyroid heart, in which ventricular myosin isozyme is shifted from V₁ predominance to V₃ predominance . The heart was perfused by the working heart method for 15 min, and then global ischemia was induced for 10, 20 and 30 min with pacing at a rate of 320/min until cardiac cessation. The ischemic heart was reperfused for 30 min. The extent of recovery of pressure-rate product after reperfusion, following 20 min of ischemia in the hypothyroid heart, was higher than that in the control heart (p<0.01). The level of adenosine triphosphate (ATP) declined more slowly in the hypothyroid heart than in the control heart. The level of ATP and energy charge potential in the hypothyroid heart reperfused after 20 min of ischemia were higher than those in the reperfused control heart (p<0.01, p<0.05, respectively), though they did not differ from each other in preischemia. There were no significant differences in the levels of tissue lactate between the 2 hearts during ischemia and reperfusion. The recovery rate of the coronary flow of the 2 hearts did not differ from each other significantly. These data suggest that there is a probability of the V₃ predominant heart re-covering from ischemic damage to the metabolism and cardiac function better than the V₁ predominant heart because the transformation of myocardium, due to an increase in V₃, into a slower but more efficiently working muscle results in conservation of tissue ATP during ischemia.

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Emergency coronary angiography in a 28-year-old male suffering an acute anteroseptal myocardial infarction revealed complete obstruction of the left anterior descending artery in association with multiple aneurysms of the 3 major coronary arteries. Successful intracoronary thrombolytic treatment with urokinase infusion directly into the infarct-related artery was performed 2 h after the onset. Follow-up left ventriculogram showed preservation of left ventricular wall motion. Fifty days after the infarction, he underwent aorto-coronary bypass surgery. Histological examination of the biopsy specimen obtained from the aneurysm of the distal portion of the right coronary artery revealed that the 3-layer architecture of the arterial wall had been completely lost. The wall was replaced by fibrotic tissue, with slight mononuclear cell infiltration around the small vessels, but no acute inflammatory reaction or atheromatous change was seen. In spite of the presence of the coronary risk factors of hypertension and hyperlipidemia, angiography revealed no evidence of atherosclerosis of systemic arteries. It is suggested that the coronary aneurysms in this case are possible sequelae of Kawasaki disease in childhood.

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A 57-year-old man, who had undergone aorto-coronary bypass surgery 4 years before when the shape of the ascending aorta had been normal, had a unique orange-shaped aortic root aneurysm associated with severe aortic regurgitation and congestive heart failure. Replacement of the aneurysm and the aortic valve was successfully carried out, and histopathological examination revealed that the aneurysm was caused by aortitis syndrome.

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The clinical syndrome of heart failure occurs as a consequence of the limitation of compensatory mechanisms, such as cardiac hypertrophy. To clarify transcriptional changes in specific genes in failing hearts, we examined the expression of cardiac Ca²⁺+Mg<2+>-dependent ATPase in the sarcoplasmic reticulum and transforming growth factor β genes in the ventricles of rat hypertrophied heart, and the expression of guanine nucleotide-binding protein and "fetal" contractile protein genes in the ventricles of cardiomyopathic Syrian hamsters of Bio14.6. Northern blot analysis of total cellular RNA revealed that the mRNA levels of Ca²⁺ +Mg<2+>-dependent ATPase were decreased by pressure overload and became 32% of sham in I month, and were correlated with corresponding protein levels. Transforming growth factor β mRNA, a potent activator of collagen synthesis, was increased by pressure overload. The expression levels of the Gs α mRNA, which stimulated the adenylate cyclase, in Bio14.6 ventricles were lower than the levels in ventricles of the FIB hamster strain, and de-creased as the stage of cardiomyopathy progressed. Moreover, re-expression of fetal mRNA was observed in the ventricle of cardiomyopathic Syrian hamsters of the Bio14.6 strain. These results indicate that reprogramming of cardiac gene expression both of myofibrillar and nonmyofibrillar components might occur in the failing heart.

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Coupling of myocardial β-, β1-, β2- and α -adrenoceptors (AR) to myocardial contraction was investigated in patients with various degrees of heart failure. With the use of ΔVcfc, a load independent parameter of myocardial contraction, AR mediated contraction was evaluated. β-AR mediated contraction, ΔVcfc by infusion of a β-AR agonist, isoproterenol, declined with the advancement of heart failure from 0.41 Circ/sec (NYHA I) to 0.31 (NYHA II), 0.22 (NYHA III) and 0.12 (NYHA IV). Dobutamine, a β 1-AR full agonist, mediatedΔVcfc was 92-97% of that of isoproterenol. On the other hand, terbutaline sulfate, a full agonist to β2-AR, increasedΔVcfc partially in comparison with isoproterenol; 51% in NYHA I, 52% in NYHA II, 36% in NYHA III and 17% in NYHA IV. An α 1-AR agonist, methoxamine had little effect on myocardial contractility β -AR and α-AR densities were analyzed by saturation binding isotherms of myocardial membrane fraction with ¹²⁵I-Iodocyanopindolol (ICYP) and ³H-Bunazosin, respectively. β-1 and β2-ARs were separated by competition binding of ¹²⁵ICYP with a highly selective β1 AR antagonist, CGP20712A. There was a progressive down regulation of β, β1- and β2-ARs with the advancement of heart failure. A new index was used to examine coupling of ARs to myocardial contracton; Coupling Index. The index was slightly decreased in NYHA II in β - and β1-ARs. In β2-AR, the coupling index declined as heart failure advanced from NYHA I to NYHA IV. These results indicate some mechanism(s) of uncoupling takes place in mild heart failure in β and β1-AR, while in β 2-AR uncoupling progresses from NYHA II to IV. Down regulation of all β -ARs begins from NYHA III on-wards.

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We studied mitochondrial function in relation to ATP production and its relationship with myocardial oxygen consumption (VO₂) and total mechanical energy using isolated rat hearts after 8, 12, and 24 h of hypothermic preservation. In isovolumic contraction, ventricular contractility and total mechanical energy were respectively assessed by the end-systolic elastance (Ees) and pressure-volume area (PVA). Ees significantly decreased after hypothermic ischemia, although the difference was not significant between 8 and 12 h. In contrast, VO₂ measured at each left ventricular volume increased after hypothermic ischemia. PVA and VO₂ Were found to stay in linear correlation after prolonged hypothermic ischemia, although VO₂ at null PVA and VO₂ to PVA ratios significantly increased after hypothermic ischemia, especially after 12-h ischemia. Mitochondrial oxidative phosphorylation significantly decreased after hypothermic ischemia for longer than 12 h. These results indicate that mitochondrial oxidative phosphorylation was impaired due to long time hypothermic ischemia especially after 12-h ischemia. We conclude that energy uncoupling between VO₂ and PVA in hypothermically preserved heart is attributable to disturbed mitochondrial oxidative phosphorylation and that 8 h is a critical point for efficient conversion of energy from VO₂ into PVA in rat heart.

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Left ventricular contractility and the energetic cost of contraction were assessed in various disease models in experimental animals utilizing frameworks of E_max (left ventricular contractility index) and pressure-volume area (PVA, a measure of total left ventricular mechanical energy expenditure) derived from the pressure-volume (P-V) diagram. Under various contractile conditions, PVA linearly correlates with myocardial oxygen consumption per beat (VO₂) in a load-independent manner. The reciprocal of the slope of the linear VO₂-PVA relation indicates "contractile efficiency" (the energy transduction efficiency from oxygen to total mechanical energy). It was similar between dog and rabbit hearts (about 40%) and was not significantly affected by enhanced contractility with calcium, epinephrine, or cardiac cooling, or by depressed contractility with propranolol, decreased coronary perfusion pressure, or stunned myocardium. However, in thyrotoxic rabbit hearts contractile efficiency was significantly depressed compared to normal hearts. On the other hand, the VO₂ intercept of the VO₂-PVA relation (PVA-independent VO₂), which reflects VO₂ for non-mechanical activities such as excitation-contraction coupling and basal metabolism, positively correlates with E_max' Therefore, the ratio of an increase in PVA-independent VO₂ to an increase in E_max indicates "oxygen cost of contractility". Oxygen cost of contractility was higher in stunned myocardium than in normal hearts, suggesting that the energy cost of calcium handling is elevated in stunned myocardium. Thus, using the frameworks of E_max and PVA, we can interconnect cardiac mechanics and energetics. Further, using the concepts of contractile efficiency and oxygen cost of contractility, we can approach the pathogenesis of variously altered contractile conditions.

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The effects of unloading or inotropic agent in 22 patients with dilated cardiomyopathy were assessed in terms of optimal coupling between the ventricle and arterial system. In 13 patients (group A), Iower body negative pressure (LBNP) was applied to reduce preload and nitroprusside was used to decrease afterload. In 9 patients (group B), dobutamine was used to enhance inotropic state. In all patients, the direct arterial pressure was simultaneously recorded with left ventricular echocardiogram as the pressure was elevated by pheny-lephrine. The left ventricular contractile properties were defined by the slope (Ees) of the end-systolic pressure-volume relation. The arterial system properties were expressed by the slope (Ea) of the end-systolic pressure-stroke volume relation. When the Ea/Ees ratio ranged from 0.5 to I .O, both external work and mechanical efficiency are nearly maximized, In group A, baseline ventricular-load coupling was characterized by an increase in the Ea/Ees ratio (1.96 ± 1.08) where the heart could maximize neither external work nor mechanical efficiency. Ea/Ees significantly fell to I .45 ± 0.77 with nitroprusside, while increasing to 2.37± 1.17 during LBNP. In group B, Ea/Ees was decreased from 1 .43 ± to 0.82 + 0.47 with dobutamine. It is concluded that reduction in after-load rather than preload, or augmentation of contractility could restore optimal ventricular-load coupling in patients with severe cardiac dysfunction.

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To validate the usefulness of the conductance catheter in the clinical setting, we first studied the accuracy of human left ventricular (LV) volume measured by conductance catheter in comparison with LV volume measured by biplane angiography in 19 patients with heart disease. Secondly, we made a comparison of end-systolic pressure volume relation (ESPVR) and preload recruitable stroke work (PRSW) relation in 60 patients with heart disease. Thirdly, we studied the myocardial oxygen consumption (VO₂)-pressure volume area (PVA) relation to assess contractile efficiency in 22 patients with heart disease. There was a good correlation between the corrected conductance volume (Vcc) and the angiographic volume (V angio) (Vcc=0.94 Vangio+5.4, r=0.94, P<0.001). Two relations, ESPVR and PRSW, were well described by straight lines with high correlation coefficients. However, PRSW was a more linear contractile index than ESPVR. The reciprocal of the slope of the VO₂-PVA relation was approximately 40% in the control contractile state. We conclude that the conductance catheter accurately measures LV volumes and fascilitates the assessment of ESPVR, PRSW and contractile efficiency in human LV.

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Small amplitude mechanical vibration has been reported to depress the function of the isolated left ventricle in an amplitude dependent manner. We examined, 1) contractility and preload dependency of the magnitude of functional depress-ion (VID) by applying 50 Hz, 2 mm amplitude vibration to the epicardium of the canine left ventricle and, 2) whether VID is present in the failing human ventricle. The magnitude of VID was independent of preload in the physiological range of LV volume showing peak LV pressure>75 mmHg, and VID was correlated with Emax at each inotropic state. In the in-situ condition, VID appeared only in the failing condition with a sensitive increase at a mild level of heart failure. In a study during routine cardiac catheterization (n=27), the presence of VID has been demonstrated in the human ventricle (n= 18). The magnitude of VID was correlated with ejection fraction (EF) as. VID in peak LV pressure (mmHg)=80.6- 110×EF, r=0.84, p<0.01 in patients with EF&le;0.7 (n=14). Therefore, we concluded that VID could be a clinical tool for evaluation of mild heart failure.

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Mitral flow velocity pattern in patients with left ventricular (LV) diastolic dysfunction usually includes decreased peak early diastolic filling velocity (E), slowed deceleration of the early diastolic filling wave and increased peak filling velocity at atrial contraction (A). However, the abnormal mitral flow velocity pattern can be normalized in the presence of concomitant congestive heart failure. In such cases E can be equal to or even higher than normal, its deceleration is normal or faster than normal value, and A can be normal or lower than normal value. Clinical observations in patients with severe heart failure showed that the mitral flow velocity pattern changes with vasodilating therapy, reflecting the changes in the left atrial (LA) to LV pressure difference rather than those in the absolute LA pressure or LV pressure alone. This was validated in the canine study in which levels of LV dysfunction were made by the injection of microspheres into the left coronary artery to study the interrelation among the mitral flow velocity pattern and LA and LV pressures. In this experiment, the changes in the mitral flow velocity pattern could not be explained by the changes in LA or LV pressure alone but was better explained by the changes in the LA to LV pressure difference. Not only LA-LV crossover pressure but also LA compliance seem to be important as determinants of LA pressure level in diastole. In addition to LV relaxation rate, incompleteness of relaxation, elastic recoil and LV passive elastic properties, extracardiac constraint is also considered to be an important determinant of the level of the LV diastolic pressure and hence of the mitral flow velocity pattern at least in the presence of congestive heart failure. Thus, mitral flow velocity pattern is determined by the interaction of LA and LV pressures, both of which are affected by chamber properties as well as loading conditions.

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The determinants of left ventricular early diastolic filling were assessed in 15 patients with old myocardial infarction. The left atrial pressure (LAP) and left ventricular pressure (LVP) were simultaneously measured by a Millar's multisensory micromanometer with the pulsed Doppler mitral inflow velocity at baseline and during angiotensin infusion (20 ng/kg/min). Cardiac output was measured by a thermodilution method. LV peak systolic pressure and end-diastolic pressure were significantly (p<0.001) increased during angiotensin infusion from 137±19 to 170±21 mmHg and from 13.3±5.9 to 20.4±6.2 mmHg, respectively. Cardiac index was significantly decreased during angiotensin infusion. Heart rate, diastolic time, and peak positive dP/dt were unchanged. Although the LA-LV peak pressure gradient[(LAP-LVP) max]was unchanged (from 2.8±1.0 to 3.0±1.4 mmHg), the pressure gradient interval (the interval between the first and second points of transmitral pressure crossover) was significantly (p<0.001) decreased from 154±38 to 117±26 msec during angiotensin infusion. Peak early diastolic mitral inflow velocity (peak E) and the time-velocity integral of E wave (Ei) were significantly decreased during angiotensin infusion from 51±10 to 45±11 cm/sec (p<0.002) and from 7.47±1.96 to 5.70± 1.66 cm (p<0.001), respectively. Peak E had a significant linear correlation with[(LAP-LVP) max](r=0.660, p<0.0001), while Ei had a significant linear correlation with pressure gradient interval (r=0.751, p<0.0001). Thus, LV early diastolic filling is determined not only by the LA-LV peak pressure gradient, but also by the pressure gradient interval in the diseased human LV.

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Left ventricular (LV) afterload increases after mitral valve replacement, thus it would be useful to estimate postoperative LV afterload before surgery. We tested the usefulness of an index, wall stress, obtained from preoperative end-diastolic LV dimensions and diastolic blood pressure which would represent LV afterload after surgery. The data were compared with surgical mortality and morbidity. The wall stress ranged from 98 to 220 kdynes/cm² and was 202 or higher in 3 patients who died. Five patients had wall stress above 200 kdynes/cm². Among these, intra-aortic balloon pumping (IABP) was used in 4, and 3 died. Prolonged catecholamine support for >10 days was given to all of the 4 patients, including two who died 14 and 23 days after surgery. Among 38 patients who had wall stress less than 200 kdynes/cm², none died, IABP was performed in 3 patients, and prolonged catecholamine infusion was required in 5 patients. The incidence of mortality and morbidity were significantly higher in the high stress than in the low stress group (Chi-square analysis). Left ventricular end-diastolic index was larger in the high stress than in the low stress group (p<0.05). The mass/end-diastolic volume ratio was smaller in the high stress group than in the low stress group (P<0.05). In conclusion, this new index, predictive wall stress, is useful in selecting patients who would have high mortality and morbidity.

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