This study characterizes the inhibiting effect of diltiazem and nitroglycerin on periodic contractions of isolated human coronary arteries. Isometric force of coronary ring segments from sixty-nine cadavers was recorded in a muscle bath. To quantify the experimental results, we used 3×10^-6 M prostaglandin F_2α to induce the periodic contractions of a certain force. When diltiazem was added during the periodic contractions, the amplitude of oscillations gradually decreased until eventually oscillations ceased completely. The process prior to the cessation of the oscillations was characterized mainly by the inhibition of the contraction phase. The inhibition rate at the time of the complete cessation of oscillations was 49.3±6.3% at 5×10^-7M. The time required for complete disappearance of oscillation s was dependent on the diltiazem concentration. When nitroglycerin was added during periodic contractions, the oscillations did not disappear. compared to the contraction phase, the relaxation phase was appreciably inhibited. With only 10^-7 M diltiazem, the rate of inhibition of the contraction phase was 22.07.7%, where as the preliminary treatment with 510^-8M nitroglycerin led to a complete cessation of the oscillations, and suppression of the level of the contractions to a significantly greater extent, viz. 58.75.8% (p<0.001). Therefore, it is considered more effective in the treatment and prevention of coronary spasm to use diltiazem and nitroglycerin simultaneously rather than individually.

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Contributions of late diastolic filling (slow filling and atrial systolic phases) to total filling volume in both global and regional left ventricle were analyzed using radionuclide techniques in 21 patients with isolated left anterior descending coronary artery disease without previous myocardial infarction. A computer program subdivided the image of the left ventricle into four regions at a geometric center of the area. The time-activity and its first-derivative curves of the global and regional left ventricles were computed. In the global left ventricle, the percent contributions of late diastolic filling to total filling volume were significantly increased in patients with one-vessel disease than in control subjects (20±5%, 28±4%; p<0.001). In the regional left ventricle, in patients with one-vessel disease, the percent contributions of late diastolic filling to total filling volume were significantly increased in the septal (25±5%, 34±8%; p<0.001) and in the apical regions (21±4%, 28±4%; p<0.001) which were perfused by stenosed vessel. In contrast, there were no significant differences in this value between the two groups in the normally perfused lateral region (226%, 255%; p=NS). These results indicate that the late diastolic filling makes a larger contribution to the left ventricular filling in the affected regions than in the normally perfused regions, and that the increased late diastolic filling in the affected regions are the cause for the increased late diastolic filling in the global left ventricle in patients with one-vessel disease.

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The relationship between the active Ca²⁺-binding function of the cardiac sarcoplasmic reticulum (SR) and left ventricular (LV) relaxation was studied in various stages of chronically volume overloading canine hearts induced by complete atrio-ventricular (A-V) block. Rapid kinetic measurement of the Ca²⁺-binding activity of SR was made using a dual-beam spectrophotometric assay procedure. LV hemodynamics, especially diastolic indexes, were evaluated by the pressure-volume relationship using a trans-epicardial echo-cardiographic technique. In this study the maximum Ca²⁺-binding rate of SR were impaired in eccentric hypertrophied hearts and failing hearts induced by volume overload. However, there was no significant difference of SR functional defect between the hypertrophied and the failing hearts. LV systolic properties were not influenced even by chronic volume overload. Its diastolic properties, however, were reduced with the progress of eccentric hypertrophy, and were estimated to respond more sensitively to the abnormalities of cardiac function compared with systolic properties. There was a close interrelation between the Ca²⁺-binding activity of SR on the molecular level and diastolic parameters, especially the time constant T, on the ventricular chamber level. In conclusion, the impairment of the Ca²⁺-binding activity of SR is a cause of depression of LV diastole. However, the role of SR in the occurrence of heart failure could not be clarified in this study.

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The healing process of myocardial infarction was studied with special reference to the production of collagen by the determinations of prolylhydroxylase (PHase) activity and contents of hydroxyproline (Hyp) of the collagen subfractions, i.e., neutral salt soluble (NSC), acid soluble (ASC) and insoluble collagens (ISC) in comparison with histologic observation of the proliferation of connective tissue in the canine heart. The contents of Hyp in NSC and ASC increased in the infarcted tissue 5 days after coronary ligation prior to its increase in ISC. The content of Hyp in NSC, which is a precursor of ASC and ISC, reached the maximal value at 7 days and that reached the maximal value in ASC 7 to 14 days after coronary ligation. ISC increased markedly after 14 days. PHase activity increased on the second day and attained to the highest at 5 to 7 days. Proliferation of fibroblasts paralleled with the increases in PHase activity and NSC, and an increase in collagen fiber did with the contents of ISC. From these results it is concluded that in the healing stage of myocardial infarction, PHase was activated earlier than the increase in immature collagen in the infarcted area which was observed 5 to 7 days after coronary ligation was followed by the production of mature collagen after 14 days.

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We determined the effect of the calcium antagonistic agent, diltiazem hydrochloride upon ischemia-reperfusion injury in the dog. Ischemia was produced by occluding the left anterior descending artery for 40 min. Subsequent reperfusion was accomplished for 120 min by virtue of removal of the occlusion. Sixteen of the dogs studied were randomly assigned to diltiazem (D)-treated group (n=8) and saline (S)-treated group (n=8). D in saline was intravenously infused at a concentration of 3 mcq/kg/min starting 15 min after the occlusion. Myocardial blood flow (MBF) was measured using hydrogen gas clearance method. Infarct size was quantified as percent myocardium at risk by triphenyltetrazolium chloride staining. D administration caused a slight decline in mean aortic pressure, heart rate, and heart rate × systolic blood pressure throughout the periods of occlusion and reperfusion. However, there was no significant difference observed in both groups of dogs. MBF to ischemic myocardium was not significantly enhanced by D during ischemia. After 5 min of reperfusion subepicardial MBF was increased in group S, indicating a tendency towards reactive hyperemia. After 120 min of reperfusion there was a significant reduction in subendocardial MBF in group S and the transmural blood flow ratio was 1.230.59 in group D as compared with 0.530.39 in group S (p<0.05). The infarcted area as a percentage of the risk area was considerably smaller in group D than in group S (27.53.0 vs 47.06.5%, p<0.05). D markedly reduced the elevation of tissue calcium especially in the subendocardium. These findings suggest that D reduces the ultimate infarct size through the beneficial effect on ischemia-reperfusion injury.

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A 57-year old man with severe aortic regurgitation was found to have a quadricuspid aortic valve. Aortic valve replacement was performed successfully with a St. Jude Medical prosthetic valve. On histological examination, the resected cusps showed fibrotic thickening with calcification.

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For a better understanding of the functional roles of the heart as a pump system, an analogy with an industrial fluid-pump system is beneficial. In this paper, the use of the ventricular pressure-volume relationship was shown to provide one of the most useful descriptions of the heart as a pump system. This description included the pump function of the ventricle as well as the interrelation between cardiac mechanics and energetics. In describing the heart only as a pump, Thevenin's network model consisting of a source of pressure with a series source resistance (or impedance) is useful in analysing the complex interactions of the equilibrium mechanism for determining cardiac output and arterial pressure, and the matching conditions under the ventriculo-arterial coupling during the ejection period for a given set of ventricular and arterial system parameters. The analytical results using this model explained previous experimental results by other investigators. It was also suggested that the ventriculo-arterial-coupled system appears to be matched. From the engineering point of view, it is desirable also for the ventricle as a pump to behave under such an optimum matching condition for delivering a maximum power to the arterial load.

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Implication of aortic input impedance and left ventricular coupling were investigated in three series of studies. In a clinical study, the ascending aortic flow velocity and pressure were simultaneously recorded from a multisensor catheter, and input impedance was calculated from 8 harmonics of aortic pressure and flow. Left ventricular wall stress was calculated from diameters and wall thickness of cineventriculogram and simultaneous recording of left ventricular pressure. In the experimental study, programmable artificial pulsatile pump was used to control pulsatile blood flow in dogs. The pressure-flow relationship in the arterial system had slightly convex curves toward the pressure axis with a critical turning pressure, so the arterial system had low output- high resistance and high output- low resistance characteristics. Therefore, the failed heart should inevitably eject the blood against stiffened vascular beds. Increased work load of the ventricle as expressed by sustained ventricular wall stress was determined mainly by the exaggerated late systolic pressure due to increased input resistance and increased low frequency pulsatile component of the input impedance. These findings are especially important for relieving additional work load of the ischemic heart, which have higher pressure wave reflection.

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In order to evaluate how pressure and flow at the outlet of a ventricle are determined by the interaction between the ventricle and an aortic input impedance, we examined the effects of independent changes in the peripheral resistance and in the aortic compliance using isolated canine left ventricle preparations. There was an inverse linear relationship of mean values between pressure and cardiac output under pure resistance changes when coronary flow was maintained constant. But, when the coronary perfusion pressure depended on mean aortic pressure, the relationship was no longer linear under a critical aortic pressure. When aortic compliance was increased, late systolic flow was enhanced and late systolic pressure decreased such that the stroke volume increased. The top part of the pressure-volume loop showed a configurational change from the right side down to the left side down. Changes in pressure and flow wave forms, and in the pressure-volume loop can be predicted by an electrical model in which time varying capacitance arranged in series with the internal resistance was used as a ventricular model.

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There is a distinct inverse relationship between the force and the extent or velocity of muscle shortening in isolated muscle at a constant resting muscle length or in the intact heart with the preload and inotropic state held constant. In the normal ventricle, however, preload is usually allowed to increase as the aortic pressure is augmented, and the stroke volume tends to be maintained constant. Such complex interaction between increases in preload and afterload can be analyzed by a two dimensional framework in terms of the appropriateness of the matching between afterload and the level of inotropic state as modulated by preload. The initial response to chronic volume overload consists of near maximum use of the Frank-Starling mechanism. An increase in afterload due to the wall thinning and increased chamber size does not produce a fall of wall shortening. As an eccentric hypertrophy develops with series addition of sarcomeres, a delivery of much larger stroke volume is attained without any further use of the Frank-Starling mechanism, with a optimal extent of wall shortening per unit of circumference. Acute severe pressure overloading causes an acute after load mismatch despite the maximum use of preload reserve. Subsequently, chronic adaptation takes place with development of concentric hypertrophy which returns the ventricle to the control force-velocity curve. As wall thickening accomplishes a decrease in wall stress, wall shortening also becomes normal. Thus, chronic mechanical overload is initially adjusted by an adequate hypertrophy to correct afterload mismatch. Inadequate hypertrophy results in an elevation of wall stress and produces a decrease in stroke volume with the expenditure of the preload. The long standing hypertrophy may cause substantial depression of inotropic state with over heart failure. Further study will be needed how and when the pathological process overcomes the physiological adaptations.

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After the long bypass grafting between ascending and abdominal aorta with exclusion of the aortic arch using conventional synthetic vascular graft, a considerably remarkable hemodynamic change and progressive hypertrophy of the left ventricle occurred until stabilized. In the clinical cases and animal experiments, systolic hypertension, diastolic pressure decrease and consequent pulse pressure widening were observed. Furthermore, the phase difference between flow and pressure waves approximated to zero. Elevation of the after load due to systolic hypertension and widening of pulse pressure may result in energy loss in vascular pulsation, not maintaining forward flow but increasing the left ventricular external work. Furthermore, as the peak flow approximates the peak pressure and its point situates relatively early in systole, external work and wall stress of the left ventricle are markedly elevated. All those factors mentioned above lead concentric hypertrophy of the left ventricle to normalize the wall stress. Fall in the diastolic pressure at the aortic root may decrease coronary flow to lead ischemia of the hypertrophied left ventricle. This can occasionally lead to fatal heart failure after a long postoperative period. It may be concluded that these new findings are produced by a loss of compliance (Windkessel properties) in aortic root which occurred as consequence of using conventional synthetic vascular graft with exclusion of aortic arch.

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We investigated how coronary circulation influences the ventriculo-arterial interaction. For the quantitative analysis of this interaction, we proposed a simple framework where both ventricular property and vascular property were expressed as the end-systolic pressure-volume relationship. Combining this analysis with experimental data indicated the interactive nature of ventricular function that varied with loading condition through coronary circulation. Effects of regional ischemia on the ventriculo-arterial interaction was also analyzed. The loading condition insensitivity, simplicity and adequacy of the end-systolic pressure-volume relationship of ventricle made it possible to analytically couple the ventricle with arterial system providing a useful view in understanding the complex hydraulic interaction between the ventricle and arterial system.

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Underlying mechanisms of afterload dependency of ventricular relaxation rate were studied in nine isolated canine hearts and nine open chest dogs. In isolated hearts with isobaric contraction, peak LV pressure was increased by volume loading with stroke volume unchanged, and in anethetizerd open chest dogs the afterload was altered by a manual clamp of the descending aorta to various extent under the pharmacological blockade of the autonomic nerve activity. Ventricular relaxation rate was assessed by the time constant (T) of isovolumic LV pressure decay. In hearts in situ of open chest dogs, T was progressively (p<0.01) increased as peak LV pressure increased, whereas in isolated hearts T was decreased as afterload increased (p<0.05), indicating that peak LV pressure is not a major determinant of ventricular relaxation rate. Between these two heart preparations loading sequence of the heart during contraction was characteristically different; in open chest dogs, as after load increased ejection timing was accelerated and the time of dogs, as afterload increased ejection timing was accelerated and the time of peak LV pressure (TPmax) was prolonged, whereas TPmax in isolated hearts was decreased and ejection timing was progressively delayed as an increase in afterload. Consequently, TPmax showed a high correlation with T irrespective of peak LV pressure. These result indicate that T is with T irrespective of peak LV pressure. These results indicate that T is directly dependent on loading sequence mainly regulated by ejection timing. This finding was also confirmed in open chest dog experiments in which 20 pairs of contractions with comparable peak LV pressures and LV dimensions (end-systolic and end-diastolic lengths) but characteristically different loading conditions during contraction (early maximal loading vs late maximal loading) were obtained by the manual clamp of ascending aorta; in early maximal loading conditions (TPmax: 1858 ms) T's (663 ms) were significantly (p<0.01) smaller than those (11010ms) in late maximal loading conditions (TPmax: 26111 ms). A change in loading sequence associated with afterload interventions in hearts in situ may be due to a change in compliance in peripheral arterial system. We conclude that after load dependency of ventricular relaxation rate observed in hearts in situ could be attributed to the accompanied changes in loading sequence of the heart probably due to a change in arterial compliance. The dependency of relaxation on loading sequence of the heart might be clinically important in evaluating the effect of cardiovascular agents on ventricular relaxation since these agents may largely affect the vascular compliance as well as muscular relaxation per se.

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The difference between the right (RV) and the left ventricle during progressive pressure loading is that the RV changes to cylindrical form without change in its enddiastolic pressure (EDP). We investigated this particular phase experimentally and clinically. In experimental animal studies (dogs), the gradual construction of the main pulmonary artery (PA) resulted in an elevation of RV systolic pressure (RVSP) without changes in RVEDP and PA flow (FPA). This was followed by an increase in RVEDP and a decrease in FPA. In this initial phase, the RV increased in its dimension from the free wall to the septum. In 155 clinical cases with RV pressure loading, the relationship between RVEDP and RVSP suggested that the RV compliance of the cases with chronic RV pressure loading was less than that with subacute loading. However, these studies did not supply the expected data on the phase we mentioned. In 2 patients with primary pulmonary hypertension who showed spontaneous remission during our observation, a decrease in RVSP without change in RVEDP occurred with a change in RV form detected by 2-dimensional echocardiography. These data suggested the existence of a phase in which the RV showed a character of plasticity during pressure loading, but direct documentation was not successful.

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