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To investigate and to compare the protective action of verapamil, nifedipine and diltiazem on the acutely infarcting myocardium, we studied effects on cellular damage and mechanical function in the isolated working rat heart preparation subjected to left main coronary artery ligation. First, the fall in the ventricular fibrillation threshold (VFT) was diminished by all three agents, but non-specific effects of these agents were operating at least in part. All three compounds afforded substantial dose-dependent reduction of lactate dehydrogenase release, which was taken as an index of cellular damage, and preserved ATP stores in the infarcting myocardium. The range of effective concentrations was small and close to doses which produced atrioventricular conduction disturbances (verapamil, diltiazem) or LV pump failure (nifedipine). It is argued that these concentrations may be therapeutically relevant, whereas the concentration of a β-adrenoceptor antagonist agent required comparably to inhibit enzyme release was supra-therapeutic (metoprolol 10−4M). There are substantial differences between such animal models and the situation in acute myocardial infarction in man, where preliminary data show benefits both forβ-adrenergic blockade by sotalol and for calcium antagonism by nifedipine. [ABSTRACT FROM PUBLISHER]

A 14-year-old boy with proved varicella developed severe, intractable heart failure with the clinical features of congestive cardiomyopathy. Detailed investigations failed to disclose any alternative aetiological factor. It is proposed that varicella myocarditis was the cause of the acute congestive cardiomyopathy found in this patient. [ABSTRACT FROM PUBLISHER]

Acute severe myocardial ischemia and evolving myocardial infarction cause neural stimulation, increased levels of circulating catecholamines, and release of catecholamines from storage depots in the left ventricle, with consequent exposure of injured myocardial cells to relatively high concentrations of catecholamines during the transitional period in which myocyte injury becomes progressively more severe. beta-Adrenergic receptor numbers may be increased in the ischemic myocardium within 15-35 minutes of coronary artery occlusion and are associated with intact or enhanced coupling with the adenylate cyclase enzyme and elevated levels of cyclic adenosine monophosphate (AMP); their stimulation may mediate ventricular fibrillation. The administration of beta-adrenergic blockers before or within the first few minutes after coronary artery occlusion prevents or attenuates the development of ventricular fibrillation. beta-Receptor numbers are increased in the ischemic myocardium at 60 minutes of coronary artery occlusion but are uncoupled from the adenylate cyclase enzyme at the level of the G protein and/or catalytic unit. However, with reperfusion after 60 minutes of coronary artery occlusion, the increase in ischemic-region beta-adrenergic receptor numbers persists, and adenylate cyclase responsiveness to beta-receptor stimulation is restored. If a catecholamine is administered, increases in cyclic AMP and activated phosphorylase occur in ischemic-reperfused myocardium. These data indicate that beta-adrenergic mechanisms may play an important role in arrhythmogenesis and may contribute to myocyte injury during severe and intense myocardial ischemia and evolving myocardial infarction.

The antiarrhythmic effect of alpha 1-adrenoceptor antagonists during myocardial ischemia and reperfusion remains controversial. The potential antiarrhythmic properties of indoramin, an alpha 1-antagonist, were assessed in the isolated perfused rat heart during regional ischemia and during sustained reperfusion. Coronary artery ligation (CAL) decreased the ventricular fibrillation threshold (VFT) of control hearts from 9.1 +/- 1.3 (pre-CAL, mean +/- SEM) to 2.1 +/- 0.5 mA 15 min post-CAL (p less than 0.0001). Perfusion with indoramin 10(-8) M (alpha 1-receptor antagonistic concentration) started 5 min prior to CAL did not prevent the fall in VFT after CAL. Indoramin 10(-6) M prevented the fall in VFT after CAL relative to the control group. Indoramin 10(-5) M markedly increased the VFT before CAL from 9.9 +/- 1.0 to 28.6 +/- 2.9 mA (p less than 0.0001) and prevented the fall in VFT after CAL. During reperfusion, indoramin 10(-5) M decreased the incidence of spontaneous ventricular fibrillation (VF) to 1 of 6 vs. 6 of 6 in the control group (p less than 0.02). Indoramin 10(-5) M preserved adenosine triphosphate in the reperfused myocardium: 2.82 +/- 0.06 vs. 2.16 +/- 0.21 mumol/g in the control group (p less than 0.05). Specific alpha 1-antagonist properties of indoramin did not appear to be involved in the antiarrhythmic effects.

The English literature contains 101 reported cases of cardiac fistula following penetrating thoracic trauma. We describe an additional 10 cases seen during a 7 year period. Six patients had ventricular septal defects, another a ventricular septal defect together with a ventriculo-atrial defect, two patients had aorta--right ventricular fistulous and the final patient, a right coronary artery--right atrial fistula. This series demonstrates several interesting features. First, the mode of clinical presentation in four of the 10 patients was remarkable, because despite severe cardiac injury they initially had neither symptoms nor signs of cardiac decompensation. Second, only two of the seven patients hospitalized immediately after the injury presented with cardiac murmurs suggestive of cardiac fistula formation, whereas the remaining five exhibited cardiac murmurs 1 to 21 days after initial cardiovascular examination. Third, concomitant traumatic valvular lesions occurred frequently (five of 10 cases) but usually were not clinically detectable because of the similarity and dominance of the fistulous murmur. Fourth, it was confirmed that the type of cardiac fistula occurring most commonly following penetrating cardiac trauma was a ventricular septal defect and that conservative management of small ventricular septal defects is compatible with a prolonged asymptomatic course. Finally, attention is drawn to the frequent association of aortic incompetence with aorta--right heart fistulas and the tendency for these fistulas to produce congestive cardiac failure.

A 40-year old man presented with pulmonary symptoms and a right-sided haemorrhagic pleural effusion. Tuberculosis and carcinoma, both primary and secondary, were excluded as a cause. Chronic pancreatitis was diagnosed on the basis of a 5-year history of repeated episodes of alcohol-induced epigastric pain and suggestive findings on endoscopic retrograde cholangiopancreatography. The chronic pancreatitis became acute during hospitalization. The disproportionate elevation of the pleural fluid amylase level in comparison with the serum amylase level provided definitive evidence that the pleural effusion was a complication of pancreatitis.

Only 1 case of systemic lupus erythematosus (SLE) has been documented in a South African Black man. We report 3 further patients, 1 each from Cape Town, Durban and East London, diagnosed between 1978 and 1982. All 3 patients fulfilled the revised American Rheumatism Association criteria for the classification of SLE.

Early experiments with the calcium antagonist verapamil showed that it could inhibit the transsarcolemmal influx of calcium ions induced by isoproterenol in ventricular myocardium without inhibiting the effect of beta stimulation to increase tissue cyclic AMP. Current views of the effects of the beta-receptor-adenylate cyclase-cyclic AMP system of the calcium channel suggest that both calcium antagonists and beta-adrenoceptor antagonists should inhibit transsarcolemmal calcium influx if calcium is the third messenger of beta-agonist catecholamines. When high concentrations of circulating catecholamines are added to normal isolated hearts, two of the effects include increased vulnerability to ventricular fibrillation and high rates of enzyme release. These effects are antagonized by beta-adrenoceptor inhibitors and by calcium antagonists, which suggests a classical second (cyclic AMP) and third (calcium) messenger effect. In the presence of coronary artery ligation, the ventricular fibrillation threshold falls and enzyme release is enhanced. Both effects are associated with an increased tissue cyclic AMP level in the ischemic zone and are susceptible to calcium antagonist procedures. Neither effect can be fully stopped by beta-adrenoceptor antagonism. Therefore the evidence from this model with coronary artery ligation favors the views that 1) cyclic AMP accumulates in ischemic tissue by a process not fully susceptible to inhibition by beta-adrenoceptor antagonists; and 2) calcium ions are associated with the development of ventricular fibrillation and enzyme release by a process susceptible to inhibition by calcium antagonist agents such as verapamil, nifedipine, and diltiazem.

Twenty-five cases of non-insulin-dependent diabetes mellitus in the young were investigated for autonomic dysfunction by simple electrophysiological tests to assess the integrity of the cardiovascular reflexes. The mean age of the group at the onset of symptomatic diabetes mellitus ws 27 +/- 0,7 years, and that at the time of investigation for autonomic dysfunction ws 34 +/- 1,3 years. Nine patients had clinical evidence of peripheral neuropathy, while only 3 of the 25 had symptoms of autonomic neuropathy. Fourteen patients showed an abnormality during one or more tests for autonomic function, and of this group 9 had unequivocal evidence of autonomic neuropathy. Only 3 patients displayed both sympathetic and parasympathetic impairment of autonomic function, being the only patients exhibiting symptoms of autonomic impairment. The remaining patients with autonomic dysfunction showed only parasympathetic dysfunction. This study demonstrates that subclinical autonomic neuropathy is not an uncommon occurrence in cases of non-insulin-dependent diabetes mellitus in the young and emphasizes the need for a greater awareness of this complication.

This study examines the arrhythmogenic action of alpha 1 and alpha 2-adrenoceptor stimulation in the isolated perfused rat heart. The alpha 1-agonist methoxamine in the presence of the beta 1-antagonist atenolol 10(-6) M decreased the ventricular fibrillation threshold in the normoxic rat ventricular myocardium: VFT values (mA): Control 11.2 +/- 0.5; methoxamine 10(-6) M 4.9 +/- 0.9 (P less than 0.01 vs control); methoxamine 10(-5) M 3.5 +/- 0.5 (P less than 0.01 vs control). The alpha 1-antagonist prazosin 10(-8) M prevented the methoxamine-induced fall in ventricular fibrillation threshold. The alpha 2-agonist BHT 933 (azepexole) in the presence of atenolol 10(-6) M produced no alteration in the ventricular fibrillation threshold. Methoxamine 10(-6) M to 10(-5) M had a positive inotropic effect with increased left ventricular pressure development, myocardial oxygen consumption and QT-interval; however, tissue levels of cyclic AMP remained unchanged. Methoxamine 10(-6) M did not alter heart rate, coronary flow rate or deplete tissue levels of adenosine triphosphate, phosphocreatine or glycogen. The enhanced vulnerability to ventricular fibrillation induced by methoxamine could be demonstrated only at supraphysiological extracellular calcium concentrations (2.5 mM) but not at physiological calcium concentrations (1.25 mM). The arrhythmogenic and inotropic effect of methoxamine 10(-6) M was prevented by inhibition of transsarcolemmal Ca2+ ion influx by nisoldipine 10(-8) M or by inhibition of release of Ca2+ from sarcoplasmic reticulum by ryanodine 10(-9) M to 10(-8) M. Thus in isolated normoxic rat heart preparations, activity of the alpha 1-receptor appears to mediate ventricular arrhythmogenesis but only in the setting of myocardial calcium overload. The arrhythmogenic effect of alpha 1-stimulation may be due to increased transsarcolemmal calcium influx and enhanced release of calcium from the sarcoplasmic reticulum; increased myocardial oxygen consumption secondary to greater left ventricular pressure development may contribute in part.

Despite the widespread use of glutaraldehyde-preserved porcine xenografts, severe short-term calcification of these valves has been infrequently reported. This report describes four cases of glutaraldehyde-preserved porcine xenografts in the mitral valve position in which severe calcification occurred within 17 to 25 months of implantation. All four patients were children, aged 13 to 15 years. The clinical presentation in all four cases occurred at a late stage when there was severe xenograft obstruction, with acute symptoms of cardiac decompensation in the presence of pulmonary hypertension and right heart failure. There was rapid cardiac deterioration resulting in a low output state and episodic pulmonary edema necessitating urgent mitral valve replacement. In only one case was there clear auscultatory evidence of severe mitral stenosis. Calcification of these xenografts occurred in the presence of normal serum calcium levels and was not related to infective endocarditis. Histologic examination of the calcified xenografts strongly suggested dystrophic calcification resulting from primary collagen degeneration. The exact cause is unclear, but it appears that glutaraldehyde-preserved porcine xenografts may produce severe short-term calcification with acute hemodynamic deterioration necessitating urgent valve replacement and that this accelerated calcification may be a complication in young persons,

Recent evidence suggests that catecholamine-induced myocardial damage may be due to the cardiotoxic property of its non-physiological metabolite, adrenochrome. We investigated whether catecholamine-mediated myocardial damage is the result of catecholamine stimulation per se or the consequence of physiological or non-physiological metabolites. In the Langendorff perfused rat heart, fresh epinephrine (10(-6) M) solution increased cumulative lactate dehydrogenase (LDH) release when the perfusion pressure was 100 cm but not 65 cm, 3640 +/- 665 v. control 545 +/- 45 mIU/g/35 min respectively (P less than 0.01). In the left atrial perfused rat heart working against a hydrostatic pressure of 100 cm, fresh epinephrine (10(-6) M) solution produced the greatest increase in cumulative LDH release, 9346 +/- 1806 v. control 472 +/- 47 mIU/g/45 min respectively (P less than 0.01). Beta 1 but not alpha 1 adrenergic stimulation provoked enzyme leakage. Beta-adrenoceptor antagonism with atenolol 10(-5) M prevented catecholamine-induced leakage. Physiological metabolites of epinephrine viz metanephrine 10(-6) M, dihydroxymandelic acid 10(-6) M, vanillylmandelic acid 10(-6) M, and the non-physiological metabolite adrenochrome 10(-6) M to 10(-4) M did not increase the cumulative LDH release over 45 min. When adrenochrome 10(-4) M was perfused for 120 min enzyme release occurred, albeit only a third of that induced by epinephrine 10(-6) M over 45 min. We demonstrate that epinephrine-induced myocardial cellular damage is due to the direct effect of catecholamine stimulation acting on the beta-adrenergic receptor. The amount of left ventricular work appears to determine the extent of cellular damage. Physiological metabolites and the non-physiological metabolite, adrenochrome are not responsible for catecholamine-induced myocardial cellular damage. Epinephrine 10(-6) M caused a positive inotropic effect, whereas adrenochrome 10(-4) M induced contractile failure. Contractile failure was due to a negative inotropic effect and coronary artery vasoconstriction. Adrenochrome induces myocardial cellular damage and contractile failure but only in a concentration of 10(-4) M, this concentration does not appear to have pathophysiological relevance.

Insulin-dependent diabetes mellitus (IDDM) with onset below 35 years of age was studied in 52 Black and 38 Indian patients. IDDM accounted for approximately 10.4% and 1.1% of diabetes in the respective racial groups. The mean age and body weight in the Black and Indian diabetics were 27.6 years and 24.7 years, and 60.2 kg and 54.7 kg, respectively. The duration of diabetes in the majority of Blacks was 1-4 years, and that in Indians 5-9 years. The initial presentation in more than 80% of the patients was acute, with severe keto-acidosis in 15%. A positive family history of diabetes was obtained in more than 50% of Indians and in less than 6% of Blacks. Complications were present in 33% of Indian patients and were related to the duration of illness and dose of insulin required. Basal growth hormone, cortisol, cholesterol and triglyceride concentrations in serum were higher in Indians than in Blacks, but the differences were not significant. The disease was unrelated to excess alcohol intake or to pancreatic calcification.

A patient with a 3-year history of serologically confirmed articular systemic lupus erythematosus (SLE), who developed uncontrolled heart failure due to aortic incompetence and who was successfully treated by aortic valve replacement, is described.

Calcium antagonists are an important new modality in cardiovascular therapy. Tiapamil, a congener of verapamil, is undergoing clinical and laboratory evaluation. We have undertaken experimental studies on the anti-arrhythmic properties of tiapamil, and on the intravenous use of this agent in patients with acute myocardial infarction. Reasons are given for suggesting that tiapamil warrants further clinical evaluation, after which it may join the more established calcium antagonists as a valuable therapeutic agent.

Non-insulin-dependent diabetes mellitus (NIDDM) with onset below 35 years of age was studies in 43 Indian and 9 Black patients. NIDDM was diagnosed in 10.0% and 1.6% of diabetes in the respective racial groups. The mean age of the patients was 35.4 years and the mean duration of diabetes 7.5 years. Nearly 50% of patients were significantly obese, and more than 50% had a positive family history of diabetes. In all patients the diabetes was symptomatic at presentation, although frequently insidious in onset. In all cases the symptoms could be controlled without insulin therapy. Despite persistence significant hyperglycaemia in several patients, ketosis did not occur at any stage. Complications were detected in 40% of the Indian and 22% of the Black patients, but were unrelated to the duration of diabetes or severity of hyperglycaemia. Basal insulin levels and postglucose insulinaemic responses were lower in the Black than the Indian diabetes.

Coronary artery disease (CAD) was investigated by selective coronary cine angiography in 94 White, 59 Indian and 17 Black patients, and correlated with plasma cholesterol and triglyceride levels and glucose tolerance. CAD was found in 94%, 97% and 82%, and hypercholesterolaemia in 68%, 61% and 50% of the Whites, Indians and Blacks respectively. In the White group, cholesterol levels correlated with both frequency and severity of CAD. Hypertriglyceridaemia occurred in 44% of the White, 47% of the Indian, and 23% of the Black group, but did not correlate with the extent of CAD in any. Diabetes was detected in 56% of the Whites and 47% of the Indians, but was absent in all the Blacks tested. Hypercholesterolaemia appeared to be the only risk factor common to all racial groups.

We hypothesized that the antiarrhythmic efficacy of propranolol during acute myocardial ischemia could be dose related. Propranolol was administered in two equally divided doses 30 min before and 10 min after ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Only the lowest dose of propranolol, i.e., 0.1 mg/kg intravenously (i.v.) (plasma level 22 +/- 2 ng/ml) decreased the incidence of ventricular fibrillation (VF), i.e. 3 of 12 versus 16 of 20 in control group (p less than 0.01). VF incidence with propranolol 0.5 or 3 mg/kg was 4 of 6 and 8 of 9, respectively (both NS vs. control group). Propranolol 0.1 mg/kg did not change left ventricular (LV) blood flow. Propranolol 3 mg/kg reduced blood flow in the peripheral ischemic myocardium to 13.2 +/- 1.2 versus 19.2 +/- 1.4 ml/100 g/min in control group (p less than 0.01), and in the midischemic zone to 4.4 +/- 0.5 versus 7.0 +/- 0.9 ml/100 g/min in control group (p less than 0.001). Propranolol 0.1 mg/kg prevented a disparity of levels of cyclic AMP from arising between ischemic and non-ischemic myocardium, whereas propranolol 3.0 mg/kg did not. Furthermore, LV mechanical function was suppressed by propranolol 3 mg/kg. Only the lowest dose of propranolol (i.e., 0.1 mg/kg) decreased the incidence of VF in this model.