Timothy J. Regan

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.

Arrhythmias and the “Holiday Heart”: Alcoholassociated cardiac rhythm disorders

An association between excessive alcohol use and cardiac rhythm disorders is often difficult to establish in the absence of overt cardiomyopathy. We studied 32 separate hospital admissions for dysrhythmias in 24 patients (20 men, 4 women) with heavy recent alcohol ingestion and prolonged excessive alcohol use. None had evidence of overt heart disease after treatment of arrhythmia. Episodes usually followed heavy weekend or holiday sprees, resulting in hospitalization between Sunday and Tuesday or in proximity to the year-end holidays, a relationship not observed in other alcohol-associated illnesses. Atrial fibrillation was most common, but atrial flutter, atrial tachycardia, junctional tachycardia, multiple APCs, multiple PVCs and ventricular tachycardia were also observed. Transient hypokalemia was present in four of 30. The mean PEPLVET ratio after treatment was 0.412 ± 0.014 (normal 0.299 ± 0.008, P < 0.001). High-speed ECGs showed prolongation of PRc, QRS, and QTc. At cardiac catheterization, intracardiac pressures and volumes, coronary arteriograms and ventricular wall motion were normal at rest and mean cardiac index was slightly low, but the left ventricular response to angiotensin was abnormal. Cardiac arrhythmias presenting during weekend or holiday drinking episodes are associated with conduction delays and depressed cardiac performance indicative of early cardiomyopathy and suggest a “holiday heart” syndrome.

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.

Preclinical abnormality of left ventricular function in diabetes mellitus

Abnormal cardiac muscle function has been reported in experimental diabetes mellitus from this laboratory. To examine left ventricular performance in diabetic patients without clinical evidence of myocardial ischemia or other cardiovascular disease, a noninvasive measurement of the systolic time intervals was carried out. Simultaneous recordings of the electrocardiogram, heart sounds, and carotid pulse were made in 25 diabetic subjects, 20 to 56 years of age, and compared with 37 normal subjects. The diabetic subjects had a shorter left ventricular ejection time, longer pre-ejection period, and a higher ratio of pre-ejection period/left ventricular ejection time (P less than 0.001). The isovolumic time was prolonged (P less than 0.001), while heart rate and arterial pressure were within normal limits. Abnormal function was independent of apparent duration and treatment by diet alone, insulin, or hypoglycemic agents. On the basis of available morphologic data in human and canine diabetes, an alteration of the myocardial interstitium may be the basis for this preclinical abnormality in diabetic patients.

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.

Depression of Myocardial Contractility with Low Doses of Ethanol in Normal Man

Depression of myocardial contractility after ethanol ingestion in man has previously been shown only in patients with heart disease. In the present study, normal subjects, aged 23-30 years, ingested six ounces of 43% alcohol over a two hour period (Group I, 6 subjects) or a one hour period (Group II, 5 subjects). Systolic time intervals were measured every 15 min from simultaneous ECG, phonocardiogram and carotid pulse tracings. Heart rate, total electromechanical systole and left ventricular ejection time (LVET) were not changed at any time from pre-alcohol values and, except for a small (5 mm Hg) and transient change in diastolic pressure in Group II, aortic pressures also were unchanged. However, in Group I, after 60 min, at a blood ethanol of 74 ± 3 mg%, left ventricular depression was manifested by increased pre-ejection period (PEP) from 90 ± 2 to 96 ± 3.1 msec, isovolumic time (IVT) from 44 ± 3.5 to 52 ± 4 (P < .01), and PEP/LVET ratio from 0.299 ± 0.009 to 0.323 ± 0.01 (P < .05). Further depression occurred at two hours with blood ethanol at 111 ± 6 mg%. Doubling ingestion rate (Group II) produced reduction of left ventricular performance at 30 min at a blood level of 50 ± 3 mg%. Feeding of isocaloric sucrose in 5 subjects (Group III) as a control produced a decrease in PEP, IVT, and PEP/LVET. Thus, alcohol in nonintoxicating doses elicits a depression of cardiovascular function in normal unhabituated subjects.

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.

Preclinical cardiomyopathy in chronic alcoholics: A sex difference

Alcoholic subjects differ in the incidence of cardiomyopathy. Of potential variables, sex may be important since few females are seen with cardiomyopathy, even adjusting for the lower incidence of alcoholism. To examine this question, noninvasive systolic time intervals were measured in 22 males and 14 females of similar age, heart rate, and arterial pressure, without clinical evidence of heart disease or hypertrophy. Duration and intensity of ethanol intake and the interval from last drinking episode were apparently equivalent. In male alcoholics, the left ventricular preejection period and ejection time (PEP/LVET) ratio of 0.410 +/- 0.020 was significantly higher than in the 11 normal males (0.316 +/- 0.007) (P less than 0.001). In female alcoholics, the ratio was 0.322 +/- 0.015, compared to 0.310 +/- 0.01 for 11 normal females, and was significantly less than in the male patients (P +/- 0.001). In addition prolonged intraventricular conduction by high-frequency ECG was more prevalent in the male group. To further ensure equivalency of alcoholism, patients with biopsy-proved cirrhosis were selected. In nine males, PEP/LVET was significantly higher than in the 10 females. Thus, abnormal myocardial function was evident in males but not in females, suggesting that sex is a determinant of the toxic effects of ethanol on myocardium.