Cardiac disease in diabetes.

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.

Ventricular tachyarrhythmias in regional myocardial hyperkalemia: efficacy of three antiarrhythmic agents.

Potassium chloride infusion into the left anterior descending coronary artery induces a sequence of events analogous to those occurring during acute transmural ischemia. These include ST elevation, intramural conduction delay, ventricular techyarrhythmias and fibrillation. The influence of antiarrhythmic agents in an intact anesthetized canine model have not previously been tested. We have evaluated the efficacy of lidocaine, procaine amide and practolol in animals during regional hyperkalemia. In the untreated, only 9% survided a 20 minute observation period. All three treatment groups exhibited a reduced incidence of tachycardia and 74% survived the test period. In each treatment group this was associated with a further prolongation of intramural conduction time in the affected wall. This antiarrhythmic efficacy, thought possibly to be due to transformation of unidirectional to bidirectional block, supports the view that modulation of transcellular potassium activity contributes to the control of ischemic arrhythmias.

Varied cardiac abnormalities in alcoholics.

The toxic effects of acute or chronic use of alcohol on cerebral and hepatic function have long been recognized, but it has been thought that the heart was not similarly affected. This study reexamines this traditional thought and indicates that ethyl alcohol may have chronic toxic effects on the cardiovascular system.

Origin of acetyl strophanthidin-induced ventricular arrhythmias.

To examine the origin of digitalis-induced ventricular tachycardia (VT), acetyl strophanthidin (AS) (25 mug/min) was perfused into a limited zone of myocardium in intact anesthetized dogs through a catheter placed fluoroscopically in the left anterior descending artery without ischemia. A second catheter in the great cardiac vein sampled venous effluent from this region. His and left bundle branch depolarizations were recorded and bipolar intramural electrograms from endocardial and epicardial sites within the anterior descending region were obtained. No conduction alterations preceded arrhythmia. Cardiac venous K+ rose from 3.3 +/- to 4.4 +/- 0.2 meq/liter (P less than 0.001), indicating egress from the perfused zone. 10 animals (Group 1) were sacrificed 2 min after onset of VT while 11 (Group 2) continued until fibrillation (4-14 min). All showed normal (endocardial leads to epicardial) transmural depolarization during sinus rhythm, but 10/21 demonstrated reversal, usually late during VT, including 8/11 in Group 2. Epicardial activation preceded fascicular activation and QRS. Recordings from the border and circumflex regions in 10 additional dogs (Group 3) demonstrated activation reversal only in the border zone. Myocardial K+ was reduced (mean 63 +/- 1 mueq/g) and Na+ increased (mean 41 +/- 2 mueq/g) in the perfused zone (nonperfused circumflex area K+ 72 +/- 1, Na+ 33 +/- 1 mueq/g, P less than 0.001 for both); changes were similar in inner and outer ventricular wall. In related experiments, subepicardial injections of AS induced activation reversal within the immediate area, similar to recordings during coronary infusion. Reversed transmural activation with early epicardial depolarization suggest VT arises within myocardium; electrolyte gradients between adjacent regions may be causative.

The role of ethanol in cardiac disease.

The widespread use of ethyl alcohol suggests its potential importance in clinical medicine. There is no proven therapeutic effect in cardiac patients and its role as an etiologic factor in heart disease has been disputed over the years and attributed to coexistent malnutrition. The latter factor, however, has been dissociated from ethanol use in many patients with the cardiomyopathic form of heart failure. Major support for the role of ethanol as a toxic agent when used in large amounts for a prolonged period has been obtained in various species of animals, including the subhuman primate. Abnormalities include depression of ventricular function, and metabolic and morphologic changes that parallel the changes in humans with preclinical malfunction of the heart. While the mechanism of progression to heart failure or arrhythmias is not known, several factors may be associated. These include, particularly in males, the cumulative effects of ethanol alone or after intensified drinking episodes, simultaneous exposure to trace metals in excess, and occasional specific nutritional deficiency or superimposed infection. The low prevalence of clinical nutritional deficiency in patients with alcoholic cardiomyopathy and the infrequency of heart disease in patients with cirrhosis or neuropathy supports the view that the cardiac abnormality is commonly not dependent on malnutrition. Clinical data indicate that the cessation of alcohol intake may reverse the disease or interrupt its progression in many patients. However, the pathogenic process may continue unabated in some patients who become abstinent.

Myocardial ischemia and cell acidosis: Modification by alkali and the effects on ventricular function and cation composition.

Myocardial cell pH was measured with 5, 5 dimethyl-2, 4-oxazolidinedione (DMO) in intact anesthetized dogs by a transient indicator dilution technique. Bolus injections of labeled DMO, vascular, extracellular and water indicators were made into the left anterior descending coronary artery, and blood samples were collected from the great cardiac vein. The steady state distribution of DMO between cells and plasma was calculated from the mean transit times of the indicator. Normal myocardial cell pH averaged 6.94 and changed by 58% of the concomitant alterations in plasma pH after infusions of acid or alkali. Myocardial ischemia induced by inflation of a balloon tip catheter in the left anterior descending coronary artery resulted in progressive decreases in cell pH to 6.59 by 1 hour. Infusions of sodium carbonate diminished intracellular acidosis. Hemodynamic studies during 4 hours of ischemia with blood pH at 7.55 to 7.60 indicated a significantly reduced left ventricular end-diastolic pressure and increased stroke volume by comparison with findings in animals given infusions of saline solution. Ventriculograms revealed improved wall motion in the ischemic segment after infusion of alkali. Precordial mapping showed a significant reduction in the number of leads with S-T segment elevation as well as in the sum of S-T segment elevations, but R wave amplitudes did not differ from those in control studies. Calculations of extracellular space, tissue water and cation content revealed a reduced gain of cell sodium ion and loss of cell potassium ion during ischemia after alkali treatment. The latter may account for the S-T segment responses, whereas enhanced ventricular performance may be related to reduced competition of hydrogen ion with calcium ion for binding sites on contractile protein.

Cardiac conduction abnormalities produced by chronic alcoholism.

While conduction disturbances and arrhythmias are seen frequently in alcoholic cardiomyopathy, the specific relationship of these changes to ethyl alcohol has been unclear. To investigate the long-term effects of ethanol upon cardiac conduction, alcoholism was induced in 11 male mongrel dogs for 7 to 33 (mean 14.4) months by feeding up to 36 per cent of total daily calories as ethanol while adequate nutrition was maintained. His and left bundle branch electrograms in the intact anesthetized animals were recorded along with high-speed, high-frequency ECG's. While resting left ventricular pressures, volumes, and stroke outputs were normal, H-Q time was prolonged in the alcoholic animals drinking for longer than one year (35 +/- 3 msec., normals 26 +/- 1 msec.-P less than 0.001). QRS widening (to 80 +/- 4 msec.) was also evident after one year as compared with normals (62 +/- 2 msec.-P less than 0.001), and both H-Q and QRS alterations correlated with duration of intake. These changes were less after shorter ingestion periods, could not be reproduced in normals by acute ethanol infusion, and were not associated with ventricular hypertrophy, inflammation, or necrosis. No abnormalities of atrial conduction were noted. Morphologic correlates of the conduction abnormalities included accumulation of Alcian Blue-positive interstitial material as well as dilatation and localized swelling of the nonspecialized region of the intercalated discs in ventricular muscle and Purkinje fibers. Thus, prolonged ethanol intake in the absence of evident malnutrition resulted in demonstrable intraventricular conduction abnormalities and morphologic alterations which were related to duration of ingestion, consistent with a cumulative toxic effect of ethanol.

In vivo myocardial cell pH in the dog. Response to ischemia and infusion of alkali.

Myocardial cell pH has been measured with 5,5-dimethyl-2,4-oxazolidinedione (DMO) in intact anesthetized dogs by a transient indicator dilution technique. Bolus injections of labeled DMO, vascular, extracellular, and water indicators were made into the anterior descending coronary artery, and blood samples were collected from the great cardiac vein. The steady-state distribution of DMO between cells and plasma was calculated from the indicator mean transit times, and the plasma pH. Myocardial cell pH was determined from the distribution value and plasma pH. Normal myocardial cell pH averaged 6.94. Changes in myocardial cell pH after infusions of acid or alkali. Myocardial ischemia induced by inflation of a coronary artery balloon resulted in progressive decreases in cellular pH to average values of 6.83 within the initial 15 min and to 6.59 within the interval between 20 and 70 min. Infusions of Na2CO3 tended to diminish intracellular acidosis although these infusions had little effect on the difference in pH between the myocardial cell and extracellular fluid.

Myocardial function and lipid metabolism in the chronic alcoholic animal.

In view of the variables that obscure the pathogenesis of cardiomyopathy, a study was undertaken in mongrel dogs fed ethanol as 36% of calories for up to 22 mo. Both the experimental and control groups maintained body weight, hematocrit, plasma vitamin, and protein levels. Left ventricular function was evaluated in the intact anesthetized dog using indicator dilution for end-diastolic and stroke volume determinations. During increased afterload with angiotensin, the ethanol group exhibited a larger rise of end-diastolic pressure (P<0.01), whereas end-diastolic and stroke volume responses were significantly less than in controls. Preload increments with saline elicited a significantly higher end-diastolic pressure rise in the ethanol group (P<0.01). No hypertrophy, inflammation, or fibrosis was present and it was postulated that the enhanced diastolic stiffness was related to accumulation of Alcian Blue-positive material in the ventricular interstitium. To evaluate myocardial lipid metabolism, [1-(14)C]oleic acid was infused systemically. Plasma specific activity and myocardial lipid uptake were similar in both groups. There was a significantly increased incorporation of label into triglyceride, associated with a reduced (14)CO(2) production, considered the basis for a twofold increment of triglyceride content. In addition, diminished incorporation of [(14)C]oleic acid into phospholipid was observed accompanied by morphologic abnormalities of cardiac cell membranes. Potassium loss and sodium gain, like the lipid alteration, was more prominent in the subendocardium. Thus, chronic ethanol ingestion in this animal model is associated with abnormalities of ventricular function without evident malnutrition, analogous to the preclinical malfunction described in the human alcoholic.