By using a recently developed highly sensitive enzyme immunoassay method, concentrations of the 3 forms of cytoplasmic creatine kinases (CK-BB, CK-MB and CK-MM) were determined in blood samples serially taken from 18 patients who recieved mitral valve replacement. Blood CK-BB levels, 0.64 ± 0.32 ng/ml at the beginning of anesthesia, rose sharply after reperfusion reaching the peak level (23.3 ± 7.56 ng/ml) 2 hours after reperfusion, and then fell rapidly. The response of CK-BB in blood was rapider and more sensitive than that of CK-MB or CK-MM. The CK-BB concentrations were significantly higher in coronary sinus samples than in arterial samples. These results suggest that the major portion of elevate blood CK-BB level in the early phase after reperfusion are derived from the heart muscle.

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In order to clarify the possible relationship between changes in blood pressure after salt loading, membrane sodium transport and renin profile, 19 patients with essential hypertension (8 patients with low renin hypertension and 11 patients with normal renin hypertension), admitted to our hospital, were studied. We also examined the correlation of changes in intracellular sodium concentration after salt loading between erythrocytes and lymphocytes. After a control period of one week, all subjects were placed on a low salt intake for one week followed by one week of a high salt intake. Percent increases in mean blood pressure and intracellular sodium concentration in erythrocytes and in lymphocytes after salt loading were greater in low renin hypertensive patients than in normal renin hypertensives. Percent changes in intracellular sodium concentration in erythrocytes inversely correlated with those in ouabain sensitive sodium efflux rate constant and positively correlated with those in intracellular sodium concentration in lymphocytes. These results suggest that an increase in sodium chloride sensitivity of blood pressure in patients with low renin hypertension may be due to the inhibition of Na⁺-K⁺ pump in vascular smooth muscle cell membrane.

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The effect of the Chinese medicine kyushin administered orally on serum digoxin measurement was studied in an animal model. Administration of 6 pills of kyushin caused a significant increase in the serum concentration of a digoxin-like immunoreactive substance (DLIS). The DLIS concentration increased to a peak value of 1.14 ng/ml at 1 1/2 hours and declined to 0.5 ng/ml after 24 hours. A one-week administration of 10 pills of kyushin a day produced a steady-state DLIS concentration ranging from 0.91 to 1.07 ng/ml. Among the 7 different kyushin ingredients, toad venom (ch'an-su in Chinese) was the only drug that produced DLIS in the dogs' serum. The similarity in structures of digoxin and toad venom most likely plays an important role in producing a cross-reactivity of DLIS with immunoassay antibody to digoxin. Although these findings confirmation in human beings, they suggest that this nonprescription drug may seriously compromise the accuracy and interpretation of digoxin concentration measurements.

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To compare the intracellular distribution of beta-adrenoceptors in isolated myocytes of SHR with that of age-matched WKY and to examine changes in the distribution with aging, we measured the number of cell surface and total beta-adrenoceptors in 6-(young groups) and 37-week old (old groups) SHR and WKY. The number of surface beta-adrenoceptors was significantly lower in 6-week old SHR compared with that in age-matched WKY. But there was no difference in the number of total beta-adrenoceptors between the two groups. The number of surface beta-adrenoceptors in old groups was significantly reduced compared with that in the young groups, in both SHR and WKY. However, the number of total beta-adrenoceptors in the old groups did not show any difference from than in the young groups. Isoproterenol-stimulated c-AMP formation in 6-week old SHR was significantly lower than that of WKY of the same age. Isoproterenol-stimulated c-AMP formation in the old groups was significantly reduced than that of the young groups in both SHR and WKY. These results suggested that (1) there may be a difference in the intracellular distribution of cardiac beta-adrenoceptors between 6-week old SHR and WKY, (2) the intracelluar distribution of cardiac beta-adrenoceptors may be changed with aging, and (3) intracellular distribution might be related to the difference in c-AMP formation to beta-agonist.

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We measured plasma concentrations of norepinephrine, cyclic AMP, cyclic GMP, atrial natriuretic peptides (ANP) and beta-adrenoceptor density (Bmax) and affinity (Kd) of lymphocytes in patients with congestive heart failure and correlated these parameters with symptoms and hemodynamic indices. Plasma concentration of norepinephrine, cyclic AMP, cyclic GMP and ANP significantly increased in patients with congestive heart failure. Plasma concentrations of norepinephrine were related to the severity of the heart failure, plasma cyclic AMP concentrations, and pulmonary artery pressures. Cyclic AMP concentrations fell rapidly after treatment of acute left ventricular failure. Peripheral blood lymphocytes were stimulated by isoproterenol, and cyclic AMP level in lymphocytes was assayed. In normal subjects the generation of cyclic AMP after stimulation decreased with age. The response of lymphocytes in patients of NYHA classes III and IV was significantly lower than in the normal age-matched controls. A significant correlation between plasma norepinephrine concentration and increase of lymphocyte cyclic AMP was demonstrated. From these results it was suggested that beta-adrenergic receptors in congestive heart failure were desensitized. Beta receptor numbers of lymphocytes significantly decreased in NYHA class III and IV, but did not decrease in class I and II. There was no significant difference in Kd associated with congestive heart failure. Plasma concentrations of cyclic GMP also depended on the severity of heart failure and the pulmonary artery pressure, and decreased sharply with treatment, although remaining at a high value, A significant correlation between the cyclic GMP and ANP concentration was found in patients with congestive heart failure. The concentration of ANP significantly correlated with pulmonary wedge pressure and pulmonary arterial pressure and inversely correlated with cardiac index and ventricular ejection fraction. Thus, beta-adrenoceptors in congestive heart failure are down-regulated and the measurement of Bmax in lymphocytes is a useful index for the management of patients with congestive heart failure. Plasma concentration of norepinephrine, cyclic AMP, cyclic GMP, and ANP can be used as objective indices of severity of congestive heart failure.

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The relationship of plasma norepinephrine levels to the adaptational changes in ventricular-load coupling were studied at rest and during exercise in subjects with variably depressed ventricular function. Peak body oxygen consumption (V^^·O₂) and gas exchange anaerobic threshold (ATge) were measured to assess exercise capacity. Ventricular contractile properties were expressed by the slope (Ees) of the end-systolic pressure-volume relation and mechanical arterial properties were expressed by the slop (Ea) of the end-systolic pressure-stroke volume relation. Resting plasma norepinephrine was significantly elevated in patients with severe heart failure (New York Heart Association class III, IV) and correlated well with the magnitude of reduction in peak V^^·O₂ and ATge. In these patients, Ea/Ees ration was also increased and correlated with the levels of resting plasma norepinephrine. Although pump efficiency of the left ventricle progressively fell with the development of heart failure, stroke volume was maintained within normal range by virtue of a compensatory increase in end-diastolic volume. Sympathetic activity was much higher in anaerobic exercise than in aerobic exercise. However, Ees ₍ventricular contractility) remained at the same value throughout the exercise period. Thus, an increase in stroke volume during anaerobic exercise was caused more by an increase in end-diastolic volume than by an enhanced contractility. Our results suggest that the level of resting plasma norepinephrine can be a good predictor of the modulation of ventricular-load coupling in patients with heart failure and that when contractile reserve is decreased, the Frank-Starling mechanism plays an important role in the control of stroke volume.

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To elucidate the possibility of grading the severity of congestive heart failure by usingvenous characteristics, we constructed venous pressure-volume curves (PVR) and calculated venous stiffness constants (K). In addition, effects of vasoactive drugs on venous distensibility were studied. A venous pressure-volume curve could be fit well by an exponential curve (r=0.98±0.01). The PVR was shifted to the left with an increase in the clinical severity of congestive heart failure. The exponent of these curves, K, increased as the PVR was shifted to the left. K correlated with heart rate (r=0.52, p<0.01), right atrial pressure (r=0.54, p<0.02) and mean pulmonary arterial pressure(r=0.47, p<0.04). Nitroglycerin and amrinone dilated veins and decreased K by 19.6 ± 6.9% (p<0.03) and 14.0 ± 4.3% (p<0.02), respectively. Changes in K (ΔK) during the nitroglycerin and amrinone infusions correlated closely with the baseline K (ΔK=-0.41K+0.22, r=0.92, p<0.01). Therefore, the venodilating effects of these drugs were greater in patients with more severe congestive heart failure. The venous stiffness constant could be useful to grade the severity of congestive heart failure.

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Cardio-pulmonary exercise testing was performed in 99 normal subjects and 382 patients with cardiac disease in order to evaluate anaerobic threshold (AT) and related parameters as indices for assessing the severity of heart failure. AT could be determined easily during ergometer exercise testing with ramp protocol by monitoring minute ventilation (V^^·E), oxygen uptake (V^^·O₂) and carbon dioxide output (V^^·CO₂). Peak V^^·O₂ and the ratio of V^^·O₂ rising to work rate increment (ΔV^^·O₂/ΔWR) were also determined. There was good correlation between the AT determined by respiratory measurement and that determined by arterial lactic acid concentration (r=0.93, n=15). The reproducibility of AT was excellent between 2 testings with a 3-hour interval. AT (mi/min/kg) and peak V^^·O₂ (mi/min/kg) declined with age, and males showed higher values than females in both indices. % AT, determined by the predicted AT values of each age and sex, decreased as NYHA class progressed as follows: 90.2 ± 15.4% in class I, 76.9 ± 13.8% in class II, and 59.7 ± 11.9% in class III. Although ΔV^^·O₂/ΔWR was not influenced by age or sex, it also decreased as the severity of heart disease progressed. These results suggest that indices from cardiopulmonary exercise testing, especially AT, are closely related to the pathophysiology of heart failure, so that they are objective and reliable parameters for evaluation of the severity of heart failure and are sensitive enough to detect the efficacy of therapeutic intervention for heart failure.

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In a normal man sitting upright, pulmonary perfusion is several times greater in the lower lung zone than in the upper zone. This pattern may sometimes be reversed in patients with cardiac disease. Tc99m-macro-aggregated albumin pulmonary perfusion images were computerized to isocounts area images (digital perfusion images; DPI). DPI were applied to various types of cardiac disease and patterns of DPI were divided into 4 classes according to amount of nonperfused pulmonary vascular bed. C-0; normal perfusion. C-1; decrease of nonperfused pulmonary vascular bed. C-2; disappearance of nonperfused pulmonary vascular bed. C-3; decrease of pulmonary vascular bed. In 71 patients with mitral stenosis relationships between pulmonary hemodynamics during exercise and distribution of pulmonary perfusion were studied, i.e. at rest (n=71, mean pulmonary arterial pressure; 23 mmHg-cardiac index; 2.4 L/m) and during exercise C-0 (n=13.41 mmHg-5.4 L/m), C-1 (n=17, 52 mmHg-5.2 L/m), C-2 (n=27, 52 mmHg-4.5 L/m) and C-3 (n=14, 65 mmHg-3.6 L/m) respectively. In patients with congestive heart failure cardiac status was classified to 4 classes according to ejection fraction and DPI. Patients with EF less than 30% and DPI more than C-2 showed high morbidity and mortality (two years mortality 47%; 27/40). Pulmonary venous pressure increases to maintain the cardiac index (Starling's law) in class of decline in cardiac function or mitral stenosis. It was shown that increases in pulmonary venous pressure cause changes in distribution of pulmonary perfusion, which in turn works to depress the cardiac index. A decline in cardiac function and changes in the distribution of pulmonary perfusion coexist, mediated by pulmonary venous pressure and cardiac index. The distribution of pulmonary of perfusion reflects the severity of cardiac failure itself, so by using DPI the severity of cardiac failure can be easily evaluated.

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Fifty one patients (pts) with various heart disease and 6 normal subjects (N) were studied. Four of the 51 pts showed unusually high GOT values (>3000 IU) without preceding evidence of acute heart failure. myocardial infraction, of hepatitis. Of these 4 pts, either ventricular tachyarrhythmias, marked bradycardia, or rapid ventricular response with atrial fibrillation (af) were evident a few days, but hypotension and frequent arrhythmias were sustained in 3 of the 4 pts and these 3 pts died about one month later. The symptoms of the remaining one improved but he too died 9 months later of ventricular fibrillation. A postmortem histological examination revealed centrilobular necrosis of the liver cells. Thus, abnormal GOT evaluation may result from hepatic cell necrosis, which is probably due to tissue hypoperfusion caused by sever arrhythmias. Hepatic venous flow velocity (HFV) was measured in the remaining 47 pts and 6 N using a pulsed doppler echocardiogram. The HFV curve was biphasic, with the first curve corresponding to the forward flow velocity during ventricular systole (s-HFV) and the second corresponding to ventricular siastole (d-HFV). The ratio of the area under s-HFV curve to the sum of areas under s-HFV and d-HFV curves was defined as the VI ratio. In N, the VI ratio was 0.7 ± 0.06 whereas the VI ratio in pts in sinus rhythm tended to be above 0.7. This indicated that s-HFV is greater than d-HFV in N while s-HFV is less than d-HFV in pts in sinus rhythm. There was a good negative correlation (n=15: r=-0.70) between VI ratio and cardiac index (CI) in these pts, suggesting that the contribution of s-HFV to the venous return becomes greater as the cardiac function becomes more impaired. In pts with af, the VI ratio was below 0.5 and there was a good positive correlation (n=14: r=0.829 between the VI ratio and CI. This suggested that the s-HFV may be reduced due to a lack of atrial contribution in af so that contribution of d-HFV to venous return becomes greater as the cardiac function becomes more impaired. Thus, the HFV pattern may reflect the abnormality of the cardiac pump function in human beings.

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The adequacy of hepatic circulation in terms of oxygen supply-demand relation was assessed by measuring hepatic venous oxygen saturation (Shvo₂) in patients. Among those with congenital cardiac lesions (n=11), , Shvo₂ during the early postoperative period was markedly low as less than 20% in Fontan operation group (n=5) with subsequent clinical findings of acute hepatic dysfunction. Significant correlations were found between Shvo₂ values early after surgery and subsequent peak values in serum hepatic enzymes. Serum total bilirubin and prothrombin time started to deteriorate when Shvo₂ became below 30%. Cardiac index, hepatic perfusion pressure and mixed venous oxygen saturation showed positive linear correlations with Shvo₂, and central venous pressure (CVP) with an inverse relation. In chronic valvular disease 8n-28), those with NYHA class IV patients showed lower Shvo₂ (average; 47.4%) at cardiac catheterization than the others (class-I; 66.4%, class-II; 63.9%, p<0.05). These results indicate that Shvo₂ monitoring appears to be useful to assess the hepatic perfusion in terms of oxygen supply-demand relation in acute and chronic heart failure, and Shvo₂ of 30% seems to be a critical level.

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This study aims to clarify the neurohumoral regulation of cardiovascular circulatory adjustments and to analyze changes in renal function and their relationship to cardiovascular hemodynamics in the early stage of heart failure. Cardiac and peripheral (calf segment) hemodynamics, neurohumoral factors and renal function were investigated in totally 139 patients with acute myocardial infarction (AMI). Capacitance vessel constriction was observed in patients with uncomplicated AMI (Killip-I, Forrester HS-I) and constriction of capacitance and resistance vessels in patients complicated by heart failure (Killip II, Forrester HS-II) or cardiogenic shock (Killip III-IV, Forrester HS-IV). Augmented sympathoadrenal discharge significantly related to the degree of pump dysfunction (elevation of heart rate, central venous pressure, pulmonary capillary wedge pressure (PCWP) and decrease of stroke volume index (SVI)) and activation of the renin-angiotensin-aldosterone system significantly related to fall in tissue perfusion pressure (mean blood pressure and calf vascular resistance) would be a possible mechanism for these compensatory mechanisms. However these would contribute to excessive vasoconstriction in limits resulting in exercise intolerance or renal glomerular function impairment. The derangement of creatinine clearance, serum creatinine (Scr), blood urea nitrogen and β₂-microglobulin were related to Killip classification, and it was clarified that PCWP tended to elevate more in patients with preexisting renal function disturbance, and when cardiac output (CO) depressed much lower, reduction of CO per se caused more severe prerenal renal insufficiency. That is, there were significant correlations between renal function parameters and cardiovascular hemodynamics. The Cardio-Renal Subset (CRS) was originally developed according to the initial SVI and Scr, and it was demonstrated that the CRS would be of definit predictive value in early identification of high risk patients.

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Isolated ultrafiltration, hemodialysis & peritoneal dialysis (Tx) were recently used in the treatment of intractable heart failure (HF). We examined the relation between the response of HF to Tx and the residual kidney functions. Tx was carried out in 17 patients (Pts) with HF who did not respond to aggressive medical treatment. Ten Pts (R) responded to Tx and 7 Pts 8N) did not. Serum urea nitrogen (UN), creatinine (Cr), uric acid (UA9, sodium (Na), , potassium (K9, and chloride (Cl) concentrations on admission and before Tx were not different between R and N. Urine UN, Cr, Na, K and Cl on admission and before Tx were also not significantly different. Fractional sodium excretions (FENa), renal failure indices (RFI), and urine/plasma Cr rations 8U/P Cr) on admission were 2.0 ± 1.6, 2.7 ± 2.2, and 30.5 ±20.0 in R and 5.9 ± 4.2, 8.2 ± 6.0 and 11.5 ± 3.8 in N. They were significantly different (p<0.05). However, these did not differ before and after Tx. These data show that FENa, RFI and U/P Cr might be useful indices in predicting the responsiveness of intractable HF to Tx.

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