Effects of glucose intolerance on myocardial function and collagen-linked glycation.

In experimental diabetes, diastolic dysfunction of the left ventricle has been associated with collagen-linked glycation. To determine whether less severe hyperglycemia may have similar effects, we gave alloxan to mongrel dogs (group 2) to induce impaired glucose tolerance (IGT) for comparison with normal subjects (group 1). After 6 months, hemodynamic studies were performed in the anesthetized animals. Basal heart rate, aortic pressure, and ejection fraction were comparable in the two groups, but calculated chamber stiffness was increased in group 2, associated with a reduced end diastolic volume and increased pressure. During infusion of dextran, the volume and pressure responses were similarly abnormal in group 2. In the myocardium, the collagen concentration rose with an increased interstitial distribution histologically. To assess glycation, collagen was extracted, digested with collagenase, and measured for fluorescence. Advanced glycation end products were increased in group 2 to 10.6 +/- 1.6 vs. 6.9 +/- 0.7 fluorescent units (FU)/mg collagen in group 1 (P < 0.01). To assess whether this could be pharmacologically prevented, we administered enalapril to inhibit ACE during the 6 months of glucose intolerance to group 3. This resulted in normal glycation and significant reduction in chamber stiffness increment. We gave group 4 animals aminoguanidine daily for 6 months, which prevented abnormal collagen glycation and chamber stiffness. Thus, in animals with IGT, collagen-linked glycosylation appeared to be a major factor affecting diastolic function and was shown to be amenable to pharmacological intervention.

Sarcoidosis of the uterus.

The present case of sarcoidosis of the uterus and the previously reported cases are reviewed. Uterine sarcoidosis is usually detected during the investigation of abnormal uterine bleeding in patients with prior evidence of sarcoidosis in another site. However, in several of the reviewed cases, either the uterus was the site of the initial diagnosis of sarcoidosis or its involvement was detected soon afterward. When hysterectomies were performed on patients with endometrial involvement, the myometrium was usually found to contain nonnecrotizing epithelioid granulomas. By contrast, uterine tuberculosis usually spares the myometrium. The differential diagnosis between uterine sarcoidosis and uterine tuberculosis is discussed.

Arrhythmia susceptibility and myocardial composition in diabetes. Influence of physical conditioning.

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.

Cell sodium and the induction of myocardial injury after adrenaline.

Accumulation of calcium in cardiac cells during catecholamine induced injury is considered a major pathogenetic factor but its mechanism has not been defined. During initiation of injury in an intact canine model, cell sodium was enhanced fourfold in myocardium after a local infusion of epinephrine via the left anterior descending coronary artery for a 60 min period. Tissue calcium was enhanced and a major role for the Na-Ca carrier system is suggested. Regional myocardial function, blood flow and electrocardiogram responses to toxic levels of the catecholamine have been contrasted with ischaemic injury.

Antiarrhythmic effects of aspirin during nonthrombotic coronary occlusion.

To study the action of aspirin upon the myocardium per se, independent of thrombosis, coronary occlusion with a balloon catheter was induced in 53 anesthetized dogs divided into two groups. One group (N = 20) was treated daily with aspirin (600 mg/dog) for seven days and another (N = 33) was untreated. Left ventricular hemodynamics and precordial ECG mapping were used to assess the influence of myocardial ischemia over a four hour period. There were no significant differences in left ventricular function or extent of injury as judged by ECG mapping between the two groups. However, there was a significant decrease in the incidence of ventricular fibrillation in the treated dogs (5% vs 39%). Serial plasma samples for free fatty acid determination showed a significant rise in the untreated group. Aspirin blocked the FFA increment in the treated animals. Tissue samples from the ischemic area of left ventricle exhibited a significant reduction of the sodium and water increments, as well as a lesser potassium loss in the treated animals compared to the controls and may have been the basis for the lower incidence of arrhythmias. Since infusion of 51Cr labelled platelets showed no myocardial accumulation of platelets in either group, microthrombi did not appear to contribute to the observed differences.

Relation of platelets to catecholamine induced myocardial injury.

To test the thesis that myocardial injury, induced by catecholamines, is ischaemic in origin due to platelet accumulation in the coronary microvasculature, sustained left intracoronary and systemic infusion of catecholamines in toxic dosage was given to dogs previously infused with autologous 51Cr-labelled platelets. Subsequent determination of tissue radioactivity and electrolytes, as well as electronmicrography, indicated that the induced myocardial injury was not related to microvascular occlusion by platelets.

Altered myocardial function and collagen in diabetic rhesus monkeys on atherogenic diet.

We have demonstrated that in rhesus monkeys, 18 months of diabetes alters the end-diastolic pressure, end-diastolic volume relations without hypertrophy. Accumulation of collagen in the myocardial interstitium was the apparent basis for abnormal left ventricular performance. Neither collagen concentration nor left ventricular performance were signigicantly affected by dietary lipid composition. These myocardial abnormalities occurred at a stage when coronary atherosclerosis was limited. However, the relative influence of coronary atherosclerosis and myocardial alterations during more prolonged lipid feeding remains to be determined.

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.

The effects of tolbutamide on the myocardium in experimental diabetes.

The effects of chronic tolbutamide treatment were examined in a diabetic animal model in which abnormal myocardial function and composition have previously been demonstrated. Eight diabetic dogs were given tolbutamide 250 mg/day orally and compared with seven untreated diabetics, five healthy dogs receiving tolbutamide, and eight normal controls. After one year, resting hemodynamic studies in the intact anesthetized state showed that treated diabetic dogs had a significantly higher left ventricular end-diastolic pressure of 12.1+/-1.3 mm Hg associated with normal end-diastolic volume, compared to 6.1+/-0.8 mm Hg in untreated diabetics (P less than 0.01) and 6.3+/-0.5 in normals. Stroke work and ejection fraction were similar to normals. Acute volume expansion revealed a larger rise of left ventricular end-diastolic pressure in treated and untreated diabetics than normals, without a significant stroke volume response in treated diabetics. Enhanced stiffness of myocardium appeared to be related to interstitial accumulation of periodic acid-Schiff staining material, further intensified in treated diabetics by triglyceride accumulation observed on electron microscopy and by chemical analysis. Thus treatment of diabetes with tolbutamide, despite improved glucose tolerance, effected further reduction of left ventricular function and altered morphology of myocardium.

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.