Biomedical subjects
Publications and source records attributed to T J Regan.
The current approach to cardiac disease recognizes that the cardiovascular problems of diabetic patients have both a coronary artery atherosclerotic component and an independent myocardial component. The presence of the myocardial component has become more apparent in recent years, and a full understanding of the balance between the two components is necessary for proper treatment of the cardiac problems of patients with diabetes.
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A number of experimental and clinical studies have indicated that the process of aging and diabetes mellitus may result in alterations of cardiac function and composition. These appear to be independent of myocardial ischemia. Left ventricular diastolic compliance is diminished in both situations associated with interstitial collagen accumulation. There is also a reduction in the relaxation rate of the ventricle. In the subclinical state, the aged heart cell undergoes enlargement, but this has not been described in diabetes. In an unknown portion of patients with subclinical abnormalities, the process may advance to abnormalities of systolic function, heart failure, and arrhythmias. There is no convincing evidence that intramural small vessel disease can account for the diffuse cardiomyopathy of these two states. Management requires a particularly cautious use of cardioactive agents.
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The ability to induce alcoholic cardiomyopathy has been tested in a variety of animal species. Myocardial alterations consistent with subclinical heart disease have been produced in many of these studies through a direct effect of ethanol or its metabolites upon the heart or a neurohumoral mechanism. In the rat most studies have, however, failed to finding diminished contractility in the basal state. In long-term animals the acute left ventricular responses to isoproterenol and calcium as well as pacing were reduced. Long-term studies in mongrel dogs fed 36 per cent of calories as ethanol produced an early decrease in left ventricular diastolic compliance related to interstitial collagen accumulation. Diminished contractility developed by four years. In addition to the morphologic evidence of distorted sarcoplasmic reticulum, in vitro experiments suggest important acute effects. Each mole of ethanol is bound tightly to each mole of protein comprising the Ca-ATPase pump, which is inhibited. Impaired uptake and binding of calcium by the sarcoplasmic reticulum has been observed in chronic alcohol models at one to two day intervals following the last exposure to ethanol. In addition, the flux of calcium ion does not appear normal in terms of access to contractile protein, where the calcium regulated inhibition of the troponin interaction with myosin is impaired. Experimental studies in a canine model of alcoholism revealed that the ventricular fibrillation threshold was moderately reduced in the basal state after 18 months and was diminished further after acute exposure.
In a prospective study of 34 hospitalized patients with moderate hypophosphatemia as an isolated electrolyte abnormality, the incidence of cardiac arrhythmias has been assessed in the absence of evident cardiac disease. Holter monitoring revealed that those without arrhythmias initially, group A, remained arrhythmia-free on follow-up. Group B (n = 8) had significant arrhythmias (Lown class II or above) and differed at p less than 0.02 from 28 controls. After phosphate replacement the arrhythmias in group B improved or disappeared (p less than 0.02). Thus, in the absence of known causes of cardiac arrhythmia, hypophosphatemia can be associated with significant ventricular ectopic activity.
A pathogenic role of growth hormone in the tissue complications of diabetes has been postulated. Because collagen has been found to accumulate in myocardial interstitium in diabetes, we have undertaken a study of the relationship of plasma growth hormone levels to collagen accumulation in a canine model of chronic diabetes. Sedentary normal animals and diabetic animals were compared respectively with physically conditioned animals in which the collagen increment associated with diabetes was minimized. Basal growth hormone levels as well as increments induced by hormone release after clonidine have been related to the myocardial alteration. Myocardial collagen concentration was increased to 2.94 +/- 0.11 micrograms/mg dry weight in the sedentary diabetic animals vs. 1.97 +/- 0.07 micrograms/mg dry weight in sedentary normals (P less than 0.01), but was normal in the exercised diabetic animals after 1 year. However, levels of growth hormone in the basal state were similar in all four groups. After provocative stimulation with clonidine in the normals there was a progressive rise of growth hormone levels that was similar in the sedentary and physically conditioned animals. The diabetic groups exhibited a rise of plasma growth hormone that was not significantly higher in the nonexercised animals. Moreover the peak levels of growth hormone after clonidine were comparable. The data suggest that collagen accumulation in diabetic myocardium does not appear to be dependent on increased plasma levels of growth hormone, but a role for enhanced sensitivity to hormonal action is not excluded.
Abnormal myocardial composition in diabetes mellitus has been described, but the effects on ventricular vulnerability have not been defined. We have assessed the susceptibility to arrhythmias in a canine model after 1 yr of mild diabetes induced by alloxan. Since physical conditioning can affect metabolic abnormalities in diabetes, this intervention has also been evaluated. Group 1 served as controls and groups 3 and 4 were diabetic. Animals in the latter group as well as nondiabetic controls of group 2 were exercised on a treadmill for the last 8 mo of the experiment. After 1 yr, anesthesia was induced with chloralose for vulnerability studies. The ventricular fibrillation threshold of 24.4 +/- 1.9 mA in group 3 was significantly less than in normals (45.1 +/- 2.2). Spontaneous arrhythmias were also more prevalent in diabetics during acute ischemia (group 3-A). Increased ventricular vulnerability after epinephrine infusion was present in the sedentary diabetes despite normal ventricular function responsiveness. In a superfused preparation of myocardium, resting membrane potential and action potential amplitude were normal in diabetics, and beta-adrenergic stimulation shortened repolarization more than in controls. Myocardial collagen concentrations, which included an interfibrillar distribution on morphologic examination, were increased in group 3. In the trained diabetics of group 4 the basal vulnerability thresholds and responses to epinephrine were normal. While myocardial collagen levels were normal, cholesterol and triglyceride increments persisted. Thus, in mild experimental diabetes, enhanced susceptibility to arrhythmias exists; this susceptibility may be based on a combination of nonhomogenous collagen accumulation affecting local conduction and increased electrophysiologic sensitivity to catecholamines.
Chronic cigarette use is common in persons who habitually use other cardioactive agents that have been causally associated with heart disease. This study was undertaken to determine if cigarette use intensifies the abnormalities of myocardial function and composition observed in experimental alcoholism over an 18-month period. Young adult male beagles with tracheostomy were divided into four groups. There were 10 controls (group 1); 9 smoked seven cigarettes per day (group 2); 7 were fed ethanol as 20% of calories (group 3), and 6 received both ethanol and cigarettes (group 4). After a period of 18 months, left ventricular function was assessed under anesthesia. Heart rate, left ventricular end-diastolic pressures, and volumes (indicator dilution) did not differ in the four groups. An index of contractility derived by normalizing peak dP/dt for pre- and afterload was reduced significantly below the level of 2.41 +/- 0.7 cm/s in controls to 1.41 +/- 0.35 in group 2, 1.19 +/- 0.38 in group 3, and 1.28 +/- 0.17 in the ethanol cigarette group (each p less than 0.002). Arterial pressures were moderately elevated above group 1 in all three experimental groups without evidence of left ventricular hypertrophy. In contrast to smoking, which elicited no abnormalities of myocardial cation composition, ethanol reduced myocardial potassium and sodium in group 3 without a gain of water content. In group 4, no further decline of tissue cations was observed. Thus, cigarette use when combined with ethanol over a relatively long period produced no greater myocardial abnormalities than ethanol alone and may not be essential to the genesis of cardiomyopathy in alcoholics.
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In view of clinical interest in the efficacy of beta-adrenergic blockade during acute myocardial infarction (AMI), we have determined the long-term effect of therapy on scar formation after experimental myocardial ischemia. Intact anesthetized dogs underwent acute occlusion of the left anterior descending coronary artery, by means of a balloon catheter, which permitted monitoring of the aortic-peripheral coronary artery pressure gradient during the 4-hour period of balloon inflation. Practolol administration was begun 15 minutes after the onset of ischemia in group A. Control animals (group B) received procainamide to approximate the antiarrhythmic action of beta blockade. Only group A exhibited significant reduction in the ST segments during acute ischemia. Chronic therapy was maintained for 1 month and the mature scar formed in the myocardium was assessed after 4 months. The extent of subendocardial scar was similar in both groups but subepicardial scar formation was significantly less in group A. There was also a significant decrease in the percentage of total myocardium involved with scar in this treatment group. Although thinning of the left ventricular wall was similar for both groups in the central scar region, this process was significantly reduced at the lateral margin in group A. Thus, specific beta-receptor blockade during acute myocardial ischemia and sustained during the repair process can result in a reduced quantity and altered distribution of mature scar.
Cardiomyopathy in alcoholics is considered to be associated with a low incidence of hepatic cirrhosis. To evaluate cardiac hemodynamics in alcoholic liver disease, left ventricular function in 37 patients with hepatic cirrhosis (group II) was compared with that in 13 normal subjects (group I) matched for age, sex and cardiac size. These groups were contrasted with group III, comprising 32 alcoholics without cirrhosis who had cardiac symptoms but no cardiomegaly or heart failure. Patients with cirrhosis as a group did not differ from normal subjects (group I) in terms of left ventricular filling pressure and cardiac muscle and pump function (cardiac index). However, subgroup IIA (n = 21) had a stroke index significantly less than normal, while subgroup IIB had a significantly increased stroke index and myocardial cardial contractility with a diminished systemic arterial resistance. Similar hepatic abnormalities were present in both subgroups. In group III, left ventricular end-diastolic and aortic mean pressures were significantly elevated compared with values in normal subjects, while cardiac index and indexes of ventricular contraction and relaxation were abnormal. Further examination of patients with cirrhosis indicated that the responses to volume or pressure increments in terms of the level of stroke work for a given filling pressure were most abnormal in group IIA, approximating those of group III. Thus, although overt cardiomyopathy is infrequent in patients with cirrhosis, asymptomatic myocardial disease may assume clinical importance during volume or pressure overload.
A technique for demonstrating the substrate specificities of bacterial beta-lactamases is presented. Enzymatic degradation of beta-lactam antibiotics can be detected by cutting a wall of inoculum into the agar 3 mm from an antibiotic disc. Inactivation of the drug as it diffuses through the wall of inoculum results in distortion of the resulting inhibition zone. This procedure can be applied to the Stokes, Bauer-Kirby, International Collaborative Study (ICS) and Calibrated Dichotomous Sensitivity Test (CDS) methods so that they provide information about any detrimental effect of a pathogen on beta-lactam antibiotics, in addition to the effect the antibiotics have on the pathogen. The additional information generated by this simple procedure should increase the predictive value of in-vitro tests.
Heart failure seems to occur in adult-onset diabetics with a greater frequency than in the nondiabetic population, particularly in women. A number of such patients do not have significant occlusive disease of the major coronary arteries, or convincing small-vessel disease. A subclinical abnormality of myocardium in experimental diabetes and asymptomatic human diabetics supports the concept of a diabetic cardiomyopathy.
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The efficacy of intra-aortic balloon counterpulsation for heart failure during acute myocardial infarction has been controversial, and early intervention has been suggested as crucial. We have examined this type of therapy in the intact anesthetized dog during complete occlusion of the proximal left anterior descending coronary artery with a balloon-tipped catheter. Group 1 (n = 8) represented untreated animals undergoing four hours of ischemia. Group 2 (n = 7) consisted of animals undergoing counterpulsation with an intra-aortic balloon after 15 minutes of ischemia. Initially, stroke volume and the mean rate of left ventricular fiber shortening were similarly diminished in both groups, while filling pressure rose proportionately. After four hours, the mean rate of fiber shortening, stroke volume, and left ventricular filling pressure rose to a greater extent in untreated compared to treated animals (p less than 0.01). The degree of swelling in ischemic tissue and the number of sites with ST-segment elevation and their sums were comparable in the two groups. Thus, intra-aortic counterpulsation applied early in the course of ischemia can improve global left ventricular dysfunction without affecting the extent of myocardial injury.
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