Edmund H. Sonnenblick

Influence of the Thyroid State on the Intrinsic Contractile Properties and Energy Stores of the Myocardium

The intrinsic contractile properties of isolated cat papillary muscles and myocardial high energy phosphate stores were examined at three levels of thyroid activity and correlated with hemodynamic measurements in the intact animal. In addition, the relationship of thyroid state to endogenous norepinephrine stores and myocardial responsiveness to certain inotropic interventions were studied. In muscles from hyperthyroid cats, the velocity of shortening and the rate of tension development were markedly augmented, while duration of active state was decreased, compared to euthyroid muscles. These findings occurred in the presence and absence of intact norepinephrine stores and over a wide range of temperature and contraction frequency. The opposite changes occurred in muscles from hypothyroid cats. Isometric tension was slightly higher in muscles from hyperthyroid and lower in muscles from hypothyroid cats. The inotropic response to both norepinephrine and strophanthidin varied inversely with the level of thyroid state and allowed all three groups of muscles to reach a common ceiling of isometric tension regardless of thyroid state. Creatine phosphate and adenosine triphosphate stores were intact at all three levels of thyroid state. Thus, the level of thyroid activity profoundly affects the intrinsic contractile state of cardiac muscle, independent of both norepinephrine stores and alterations in high energy phosphate stores, and, in addition, modifies the responsiveness of cardiac muscle to inotropic agents.

Oxygen consumption of the heart: Newer concepts of its multifactoral determination

Abstract The development of tension and the contractile state of the myocardium are the primary determinants of myocardial oxygen consumption. Recognition of these two factors and their interrelation has served to explain a number of apparent discrepancies in the literature. Other factors, including basal myocardial oxygen consumption, activation energy and external work, also contribute to the myocardial oxygen consumption, but to a relatively minor extent. An understanding of these general principles should permit a more rational consideration of the determinants of myocardial oxygen consumption and the implications of these factors in disease states.

Altered myocardial mechanics in diabetic rats.

Diabetes mellitus is associated frequently with congestive heart failure in humans, even in the absence of associated coronary disease or hypertension. Nevertheless, the effects of the diabetic state on myocardial mechanics have not been studied. Accordingly, diabetes was induced in female Wistar rats by injection of streptozotocin (60 mg/kg). Left ventricular papillary muscles were studied 5,10, and 30 weeks later and compared with controls. Relaxation was delayed significantly and velocity of shortening was depressed at all loads. However, the passive and active force-length curves, as well as the series elastic properties, were not altered. The changes in cardiac performance were found over a range of muscle lengths, stimulus frequencies, and bath concentrations of calcium, glucose, and norepinephrine. The duration of diabetes had no major effect on the mechanical changes observed. The possible influences of drug-induced cardiac toxicity, malnutrition, and altered thyroid hormone levels have been considered; the latter two factors could not be excluded completely from having some influence on the mechanical properties of diabetic cardiac muscle. Evidence is cited showing abnor-malities in calcium uptake by sarcoplasmic reticulum and depressed actomyosin ATPase activity. Thus, a cardiomyopathic state has been produced in the rat consequent to the induction of experimental diabetes mellitus. Various mechanisms for this entity have been suggested. Circ Res 47: 922-933, 1980

Microvascular spasm in the cardiomyopathic Syrian hamster: a preventable cause of focal myocardial necrosis.

The cardiomyopathic Syrian hamster develops focal myocardial necrosis beginning at 1 month of age, which leads to eventual ventricular failure within 1 year. The pathogenesis of this myocytolytic necrosis is unknown. Based on the nature of the cell necrosis, cytochemical evidence of vascular alterations, and the sensitivity of the hamsters to catecholamines and other vasoactive substances, we believe that the cardiomyopathy may be mediated by abnormalities of the microcirculation. Nonetheless, until the present study, no significant changes have been observed in these vessels. To elucidate the pathogenesis of this disease, we perfused living cardiomyopathic hamsters with silicone rubber solutions, which revealed numerous areas of microvascular constriction, diffuse vessel narrowing and luminal irregularity. Fixed structural lesions in these vessels could not be demonstrated. Pretreatment of young hamsters with verapamil during the period when they normally develop myocardial necrosis prevented myocytolytic lesions and abolished microvascular hyperreactivity. We believe that focal, transient spasm of small blood vessels, probably secondary to vasoactive substances, may cause myocytolytic necrosis (a form of reperfusion injury) in this model. This may also be a multifactorial disease with myocellular as well as vascular abnormalities leading to myocardial degeneration. The similarity of this disease to human and experimental cardiomyopathy suggests that microvascular spasm may be a common denominator of many different cardiomyopathic syndromes.

Treatment of Chronic Congestive Heart Failure with Captopril, an Oral Inhibitor of Angiotensin-Converting Enzyme

The renin-angiotensin system is thought to maintain elevated systemic vascular resistance in heart failure. The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with stable congestive heart failure poorly controlled by digitalis and diuretics. At single daily doses of 25 to 150 mg, the cardiac index rose from 1.75 +/- 0.18 to 2.27 +/- 0.39 (mean +/- S.D.) liters per minute per square meter (P less than 0.001), and pulmonary-wedge pressure fell from 26.5 +/- 7.5 to 17.3 +/- 6.1 mm Hg (P less than 0.01). Systemic vascular resistance decreased from 2006 +/- 300 to 1393 +/- 238 dyne seconds per centimeter (P less than 0.001), and mean arterial pressure fell from 83.7 +/- 7.0 to 70.3 +/- 9.9 mm Hg (P less than 0.001) (mean +/- S.D.). Heart rate did not change appreciably. Hemodynamic alterations peaked at 90 minutes and persisted for three to four hours. Control plasma renin activity ranged from 1.1 to 7.3 ng per milliliter per hour and did not correlate with changes in hemodynamic values. Three patients on long-term treatment maintained clinical improvement. Although its mechanism of action has not been completely elucidated, captopril may prove useful in the treatment of chronic congestive heart failure.

The cellular basis of dilated cardiomyopathy in humans

The present investigation was designed to evaluate whether end-stage cardiac failure in patients affected by dilated cardiomyopathy (DC) was dependent upon extensive myocyte cell death with reduction in muscle mass or was the consequence of collagen accumulation in the myocardium independently from myocyte cell loss. In addition, the mechanisms of ventricular dilation were analysed in order to determine whether the changes in cardiac anatomy were important variables in the development of intractable congestive heart failure. DC is characterized by chamber dilation, myocardial scarring and myocyte hypertrophy in the absence of significant coronary atherosclerosis. However, the relative contribution of each of these factors to the remodeling of the ventricle is currently unknown. Moreover, no information is available concerning the potential etiology of collagen deposition in the myocardium and the changes in number and size of ventricular myocytes with this disease. Morphometric methodologies were applied to the analysis of 10 DC hearts obtained from patients undergoing cardiac transplantation. An identical number of control hearts was collected from individuals who died from causes other than cardiovascular diseases. DC produced a 2.2-fold and 4.2-fold increase in left ventricular weight and chamber volume resulting in a 48% reduction in mass-to-volume ratio. In the right ventricle, tissue weight and chamber size were both nearly doubled. Left ventricular dilation was the result of a 59% lengthening of myocytes and a 20% increase in the transverse circumference due to slippage of myocytes within the wall. Myocardial scarring represented by segmental, replacement and interstitial fibrosis occupied approximately 20% of each ventricle, and was indicative of extensive myocyte cell loss. However, myocyte number was not reduced and average cell volume increased 2-fold in both ventricles. In conclusion, reactive growth processes in myocytes and architectural rearrangement of the muscle compartment of the myocardium appear to be the major determinants of ventricular remodeling and the occurrence of cardiac failure in DC.

Control of myocardial oxygen consumption: relative influence of contractile state and tension development

Myocardial oxygen consumption was measured in 11 anesthetized, open-chest dogs in order to compare in the same heart the relative influence on oxygen usage of tension development and the contractile or inotropic state, as reflected in V(max.) the maximum velocity of shortening of the unloaded contractile elements. The isovolumetrically contracting left ventricle was studied with left ventricular volume, heart rate, and systemic perfusion rate controlled. Wall tension, contractile element velocity, and V(max) were calculated. Peak developed tension was increased at a constant V(max) by increasing ventricular volume, and the effect on oxygen consumption was determined. Oxygen utilization was then redetermined at an increased V(max) but at a constant peak developed tension by infusing norepinephrine (0.76 to 7.6 mug/min) and decreasing ventricular volume to match the tension existing before norepinephrine infusion. Oxygen consumption consistently increased with increases in both developed tension and V(max) with the following multiple regression equation relating these variables: myocardial oxygen consumption (mul/beat per 100 g in LV) = K + 0.25 peak developed tension (g/cm(2)) + 1.43 V(max) (cm/sec). These data indicate that the oxygen cost of augmentation of contractility is substantial, can be independent of any change in fiber shortening, and is similar in order of magnitude to the effect of alterations in tension development

Mitral anulus motion. Relation to pulmonary venous and transmitral flows in normal subjects and in patients with dilated cardiomyopathy.

The dynamics between mitral anulus motion, and, thus, motion of the base of the heart, and filling of the left atrium and ventricle were studied by Doppler echocardiography in 12 normal subjects and 28 patients with dilated cardiomyopathy. The normal motion of the mitral anulus is associated with two phases of inflow from the pulmonary veins. The first phase (J) of pulmonary venous inflow occurs during ventricular systole, concomitant with the descent of the mitral anulus toward the ventricular apex, the extent of which is 12.8 +/- 1.4 mm. The end of the descent of the anulus occurs at the cessation of aortic ejection. About 100 msec later, a rapid recoil of the mitral anulus toward the atrium coincides with the onset of transmitral filling. This rapid recoil contributes to the displacement of blood from the atria into the ventricles in early diastole. The second phase (K) of pulmonary venous flow begins in early diastole, with its peak occurring about 50 msec after the peak of transmitral flow. During atrial contraction, the mitral anulus moves slightly (2.4 +/- 0.7 mm) toward the atrium and then returns toward its initial position within 120 msec. This motion coincides with the A wave of transmitral flow. In patients with dilated cardiomyopathy, pulmonary venous flow and mitral anulus motion are markedly altered in comparison with normal subjects. In all patients, motion of the mitral anulus is either reduced or absent.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and morphological features of human hypertensive-diabetic cardiomyopathy

Abstract The existence of a specific cardiomyopathy secondary to diabetes mellitus is controversial. During a 2-year period, we had the opportunity to examine nine diabetic patients at autopsy who had clinically severe congestive heart failure and minimal extramural coronary artery atherosclerosis. Unexpectedly, all nine patients were found to be hypertensive. Accordingly, we initiated a detailed study of the clinical and morphological features of this group, and compared the findings to age-matched autopsied subjects with either isolated hypertension, isolated diabetes mellitus, or no heart disease. The study of the hypertensive-diabetic hearts revealed severe interstitial fibrosis, focal or confluent scars, and extensive myocytolytic activity. Comparison with the diabetic, hypertensive, and normal groups showed statistically significant differences in regard to the degree of interstitial and focal scarring, and the presence of myocytolysis. Only the hypertensive group had minimal interstitial scarring. There were no statistical differences in the small vessel changes between the four groups, although subjectively the hypertensive and hypertensive-diabetic patients had more severe disease. It is concluded that the association of diabetes mellitus and hypertension in the absence of significant coronary artery atherosclerosis may lead to a severe cardiomyopathy. Although the etiology of myocardial failure in this syndrome is uncertain, the degree of myocardial fibrosis and the frequency of myocytolytic lesions possibly related to catecholamine hypersensitivity, are potential explanations. Several studies suggesting that hypertension has adverse consequences in diabetes, as well as an animal model of hypertensive-diabetic cardiomyopathy, support our conclusion that cardiomyopathy associated with diabetes mellitus is a specific entity which may be secondary to the combined effects of diabetes and hypertension on the myocardium.

Depressed cardiac sarcoplasmic reticular function from diabetic rats.

Previous studies have demonstrated impaired contractile performance and delayed relaxation of hearts of diabetic rats. Male and female rats were made diabetic with intravenous streptozotocin and their hearts were studied 4 to 5 or 9 weeks later. Plasma glucose in female diabetics averaged 453 mg100 ml and in male diabetics 615 mg100 ml. Calcium uptake by isolated sarcoplasmic reticulum in the absence of oxalate were significantly lower in preparations from hearts of diabetic males and females than from controls. Rats pretreated with 3-0-methyl glucose before streptozotocin also had normal calcium binding by SR in the absence of oxalate. Sarcoplasmic reticulum Mg2+ ATPase and Ca2+Mg2+ (total) ATPase activities were significantly depressed in preparations from the diabetic animals. The results may partially explain the abnormalities in contraction and relaxation previously observed in hearts of diabetic animals.