Henry A. Oldewurtel

Evidence for Cardiomyopathy in Familial Diabetes Mellitus

Recent epidemiologic studies have suggested that cardiac disease in common in diabetics and may often have a noncoronary basis. To examine the status of the left ventricle, 17 adult-onset diabetics of familial type without hypertension or obesity underwent hemodynamic study and were compared to 9 controls of similar age. Of the 17, 12 subjects had no significant occlusive lesions by coronary angiography. From this group eight without heart failure had a modest, but significant, elevation of left ventricular end-diastolic pressure. End-diastolic and stroke volumes were reduced, but ejection fraction and mean rate of fiber shortening were within normal limits. The left ventricular end-diastolic pressure/volume ratio was significantly higher than controls. Afterload increments effected a significant increase of filling pressure compared to normals without a stroke volume response, consistent with a preclinical cardiomyopathy. Four patients with prior heart failure had similar but more extensive abnormalities. None had local dyskinesia by angiography, and lactate production was not observed during pacing-induced tachycardia. Left ventricular biopsy in two patients without ventricular decompensation showed interstitial collagen deposition with relatively normal muscle cells. These findings suggest a myopathic process without ischemia. Postmortem studies were performed in 11 uncomplicated diabetics. Nine were without significant obstructive disease of the proximal coronary arteries, and the majority succumbed with cardiac failure. On left ventricular sections, none had evident luminal narrowing of the intramural vessels. All nine exhibited periodic acid-Schiff-positive material in the interstitium. Collagen accumulation was present in perivascular loci, between myofibers, or as replacement fibrosis. Multiple samples of left ventricle and septum revealed enhanced triglyceride and cholesterol concentrations, as compared to controls. Thus, a diffuse extravascular abnormality may be a basis for cardiomyopathic features in diabetes.

Altered Myocardial Function and Metabolism in Chronic Diabetes Mellitus without Ischemia in Dogs

Myocardial disease in diabetes mellitus is usually attributed to coronary atherosclerosis. To examine the influence of uncomplicated diabetes on the left ventricle, a mild noninsulin-requiring diabetes was produced in male mongrel dogs after three intravenous doses of alloxan were administered at monthly intervals. There was a persistent decline in glucose tolerance and a reduced insulin content in the pancreas of each alloxan-diabetic dog at the termination of the experiment. The dogs were anesthetized for hemodynamic and metabolic studies after approximately 11 months. Left ventricular end-diastolic volume and cardiac output were measured by the indicator-dilution method. An increase in afterload with moderate aortic pressure elevations elicited a significant rise in end-diastolic volume and stroke volume in normal control dogs. In diabetes, despite a similar end-diastolic pressure response, the end-diastolic volume and the stroke volume responses were significantly less than those in control dogs. During acute volume expansion of the ventricle with saline, the end-diastolic pressure increment in diabetic dogs was twice that in control dogs. These responses were attributed to an increased stiffness of the left ventricle that was apparently due to accumulation of glycoprotein (measured by periodic acid-Schiff staining) in the interstitium. Since similar abnormalities were observed in dogs with diabetes occurring spontaneously and were absent when the pancreatic effects of alloxan were inhibited in a separate group of dogs, the pathogenetic role of alloxan via a direct action on myocardium was excluded. Analysis of lipids in the left ventricle revealed elevated triglyceride and cholesterol concentrations despite normal plasma levels. During infusion of 14C-1-oleic acid, cardiac oxidation appeared to be normal, but fatty acid incorporation, which was predominantly into phospholipid in the control dogs, was diverted to triglyceride in the diabetic dogs. Since an aberration of de novo synthesis was not found during studies with 14C-acetate, triglyceride accumulation was attributed to altered intracellular metabolism, perhaps related to glycerol phosphate acyl transferase activity. The basis for cholesterol accumulation was less clear, since neither 14C-acetate nor 14C-oleate incorporation into sterol was enhanced. Myocardial ischemia was excluded on the basis of patency of coronary arteries and normal coronary blood flow, myocardial cation content, and mitochondrial morphology. Thus, it was concluded that chronic diabetes mellitus can alter myocardial composition and function independent of vascular effects.

Ventricular function in noncardiacs with alcoholic fatty liver: role of ethanol in the production of cardiomyopathy

Since many patients with cardiomyopathy have a history of chronic ethanolism often associated with malnutrition, we have evaluated left ventricular (LV) function in alcoholics with fatty liver, who had no clinical evidence of cardiac or nutritional disease. During an afterload test of LV function the pressor response to angiotensin evoked a threefold rise of enddiastolic pressure in the alcoholic group which was substantially greater than the 4 mm Hg rise in control subjects. The stroke volume and stroke work response in the noncardiac alcoholic was significantly less than in controls. Diminished LV function was corroborated in the noncardiac alcoholic at rest, using a contractility index. To evaluate the dose-response relationship of ethanol in the production of cardiac malfunction, two groups of noncardiac alcoholic subjects were studied acutely at low and moderate dose levels. After 6 oz, ventricular function, myocardial blood flow, and metabolism were not significantly affected. After 12 oz, there was a progressive rise of end-diastolic pressure and decrease of stroke output at a mean blood alcohol level of 150 mg/100 ml, reverting toward control by 4 hr. The coronary effluent transiently evidenced leakage of cell constituents, despite an increase of coronary blood flow, suggesting a direct but reversible cardiac injury. Myocardial extraction of triglyceride was enhanced, whereas FFA uptake was reduced. A possible role of myocardial triglyceride accumulation in heart muscle was considered in pathogenesis. Chronic ingestion of 16 oz of Scotch daily by an alcoholic subject while on a normal diet produced, after 12 wk, a progressive increase of heart rate and size, circulation time, and venous pressure, and a ventricular diastolic gallop. Normal values were restored within 7 wk after interrupting alcohol. These several studies suggest that the cumulative effects of repeated ingestion of ethanol in intoxicating doses can produce diminished LV function before clinical evidence of cardiac abnormality, or heart disease not necessarily related to malnutrition.

Myocardial composition and function in diabetes. The effects of chronic insulin use.

This study was undertaken in an animal model of mild diabetes to determine if provision of chronic insulin replacement during postprandial hyperglycemia may modify the abnormalities of myocardium. Group 1 served as controls with normal glucose tolerance by intravenous testing. Two additional groups were made diabetic -with low doses of alloxan. Diabetic animals of Group 2 were untreated (re = 8). Group 3 animals (re = 6) received regular insulin daily to reduce postprandial hyperglycemia. After one year with maintained body weight, the animals were studied in the intact anesthetized state using the indicator dilution technique for left ventricular volume determinations. Basal left ventricular function and contractility were similar to normals in both diabetic groups. During intraventricular infusion of saline, end-diastolic pressure roue to higher levels in untreated diabetes (14.8 ± 2 mm Hg) than normals (8.8 ± 0.84), despite similar basal levels. Insulin treatment was associated with higher filling pressures than in group 1 as well as reduced end-diastolic volume response. Collagen concentrations were enhanced an average of 50% in layers from the inner to outer myocardium in both untreated and treated diabetics, associated with sodium and water accumulation. Since hypertrophy was not present, the diminished compliance appeared related to increased collagen levels. On electron microscopy, the subcellular organelles of the cardiac cell appeared normal in both diabetic groups. Thus, collagen accumulation and abnormal myocardial function in this model of diabetes is not affected by control of postprandial hyperglycemia, but a potential role for sustained hormone replacement is not excluded.

Ventricular Arrhythmias and K+ Transfer during Myocardial Ischemia and Intervention with Procaine Amide, Insulin, or Glucose Solution*

To assess the relation of ventricular arrhythmias to myocardial K(+) movement during ischemia, we placed an electrode catheter in the left anterior descending coronary artery for thrombus production in intact anesthetized dogs. (85)Kr injections distal to the thrombus permitted serial coronary blood flow measurements. Animals of Group I with a moderate flow reduction exhibited no arrhythmia or myocardial egress of K(+). In Group II, marked flow reduction was accompanied by an injury potential and loss of K(+) from the ischemic site, before and during ventricular tachycardia. Therapeutic interventions were performed in animals having the same degree of ischemia as Group II. Systemic procaine amide in Group III interrupted the tachycardia and egress of K(+), despite persistent ischemia. Group IV did not respond to intracoronary insulin with K(+) uptake, as did normal dogs, and progressed to fibrillation. During the production of hyperglycemia in Group V, myocardial loss of K(+) ceased with maintenance of sinus rhythm. Hemodynamic factors did not appear to have a major role in the genesis of the arrhythmia.Since intracoronary infusion of K(+) in normal dogs similarly altered repolarization and produced fibrillation, it would appear that during ischemia egress of K(+) before development of the arrhythmia indicates a major role of the ion in pathogenesis. This view is supported by the myocardial loss of K(+) and arrhythmia induced in normal dogs by strophanthidin and by the fact that pharmacologic regulation of K(+) loss is associated with correction of the arrhythmia, despite persistence of low blood flow.

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.

Relation of microcirculatory thrombosis to thrombus in the proximal coronary artery: effect of aspirin, dipyridamole, and thrombolysis.

Abstract A study was designed to determine the distribution of platelets in the microcirculation of the myocardium following experimental platelet thrombosis in a major coronary vessel. Determination was made by means of 51 Cr-labelled platelets and histologic examination. The results suggest that thrombosis in a major coronary artery is associated, at least in the first hours following its occurrence, with the presence of platelet thrombi in the microcirculation of the ischemic area. Pretreatment with aspirin or dipyridamole minimized significantly the extent of microcirculatory thrombosis without affecting the thrombus in the proximal coronary artery. A thrombolytic agent given after thrombus formation had a similar effect upon microcirculatory thrombosis remaining also independent of its effect upon proximal coronary artery thrombosis. There was a decrease in incidence of arrhythmias and mortality rate in the group of animals pretreated with aspirin and dipyridamole.

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 ECGs. 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.

Progression of myocardial abnormalities in experimental alcoholism

Abstract To determine those characteristics of left ventricular functional and metabolic alterations in chronic ethanolism that may be time-dependent, up to 36 percent of total daily calories as ethanol was fed to dogs for an average of 18 months (study group 1) or 52 months (study group 2). The short- and long-term study groups were fed the same diet with vitamin supplements and were compared with simultaneously studied control animals. Left ventricular function was assessed in the intact anesthetized dogs using the thermodilution method for end-diastolic volume and stroke volume determinations. During preload increments with saline solution, a significantly greater increase in end-diastolic pressure was observed in both groups receiving ethanol as compared with the control animals; this increase was associated with reduced end-diastolic and stroke volume. However, the responses were similar in the short- and long-term study groups. Increased left ventricular collagen was the apparent basis for the compliance abnormality, but neither variable differed in the groups receiving ethanol. In contrast, the first derivative of ventricular pressure (dP/dt) normalized for preload and afterload, an index of left ventricular contractility, and the velocity of the contractile element (Vce) were significantly reduced only in the long-term study group while tissue calcium was normal. When chromium-51-EDTA was used as an extracellular marker, accumulation of water and sodium in myocardial cells was observed only in the long-term study group, without a reduction of cell potassium. In view of the dilatation of sarcoplasmic reticulum observed on electron microscopy, It is postulated that distortion of the tubular membranes may limit the rate of calcium availability to contractile protein and thus diminish contractile function in chronic alcoholism.

Myocardial function and coronary blood flow response to acute ischemia in chronic canine diabetes.

To examine the influence of preexistent diabetes mellitus on left ventricular performance and coronary blood flow responses to acute ischemia, mild normoglycemic diabetes was induced in nine mongrel dogs after three doses of alloxan, (20 mg/kg, iv), at monthly intervals. Hemodynamic measurements and coronary blood flow (85Kr clearance) were obtained before and after the onset of ischemia. This was produced by occlusion of the proximal left anterior descending coronary artery via a balloon-type catheter in nine intact anesthetized diabetic dogs and 10 nondiabetic dogs. During the 1st hour of ischemia in the diabetic group, the end-diastolic pressure rose from 7 ± 1.1 (mean ± SE) mm Hg to 23.8 ± 2.3 without a significant increase of end-diastolic volume. In controls end-diastolic pressure rose from 8.6 ± 1.1 mm Hg to 15.3 ± 1.4, and end-diastolic volume was significantly increased, so that the ratio of end-diastolic pressure and volume was significantly higher in the diabetic group (P < 0.005). Although indices of contractility did not differ, stroke volume and work reductions were significantly greater in diabetics, despite the fact that coronary blood flow was reduced to a similar extent. Size of the ischemic areas appeared comparable as judged by distribution of dye injected distal to the occlusion. Since potassium loss and sodium gain in the inner and outer layers of ischemic tissue did not differ between the two groups, the intensity of ischemia seemed similar. Glycogenolysis was unimpaired in the diabetic ischemic muscle but triglyceride levels remained elevated. Morphologically the diabetic myocardium was characterized by a diffuse accumulation of periodic acid-Schiffpositive glycoprotein in the interstitium, which was thought to limit diastolic filling of the ischemic ventricle and to contribute to the substantial reduction of ventricular performance.