Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve.

The relations between left ventricular mass, mass to volume ratio, systolic wall stress and myocardial oxygen consumption were analyzed in 187 patients with chronic heart disease. The degree of left ventricular hypertrophy is determined by mass, the mass to volume ratio, and pressure and, hence, systolic wall stress. For each condition an inverse relation exists between mass to volume ratio and peak systolic wall stress. In chronic heart disease at least two types of inappropriate left ventricular hypertrophy may occur: (1) low stress hypertrophy with an increased mass to volume ratio, normal left ventricular function and normal or reduced oxygen consumption (MVO₂), whereas (2) high stress hypertrophy has a normal or low mass to volume ratio, impaired left ventricular function and an increased MVO₂. The range of systolic wall stress was 100 to 450 × 10³, dynes/cm² and reflects the stress that could be altered by inotropic interventions and changes in systolic pressure. A similar reserve capacity is present for both the metabolic and the coronary reserves. Total left ventricular oxygen consumption is related to total left ventricular mass. This relation is influenced by the degree of viability of left ventricular mass, by the mass to volume ratio and by inotropic interventions. Left ventricular oxygen consumption per viable mass unit (MVO₂) is significantly correlated with the systolic force per unit cross-sectional area of the left ventricular wall, that is, to left ventricular systolic wall stress.It is concluded that peak systolic wall stress represents one of the major determinants of myocardial oxygen consumption and of ventricular performance. It closely relates to the appropriateness of left ventricular hypertrophy, which may be defined by the relation between systolic pressure, mass to volume ratio and peak systolic wall stress.     

Physiologic concentrations of beta-lipotropin stimulate lipolysis in rabbit adipocytes

The proopiocorticomelanotropin (POMC) sequence beta-lipotropin stimulates glycerol release from incubated rabbit adipocytes at a minimal concentration of 10(-9) mol/L. However, when lipolysis inhibiting substances (eg, fatty acids and adenosine) and contaminating peptide degrading activity are continuously removed by fat cell perifusion, the sensitivity is increased to 10(-13) and partly to 10(-14) mol/L beta-lipotropin. This higher sensitivity of the perifused adipocyte could also be demonstrated with alpha-MSH (from 5 X 10(-10) to 10(-13) mol/L). The restimulation of glycerol release was shown for both peptides. We conclude that POMC peptides might be involved in the regulation of lipolysis since the minimal effective concentrations are near to plasma concentrations.     

Influence of polyunsaturated fats and fat restriction on serum lipoproteins in humans

This study was designed to determine the effects of polyunsaturated fats and of reducing intake of total fat on serum lipids, lipoproteins, and apolipoproteins. Twenty-two normolipidemic women living in a nunnery were given a reference diet (fat/carbohydrate $\text{42}\text{46\%}$ of energy, $\text{P}\text{S}$ ratio 0.16), a polyunsaturated diet ($\text{42}\text{46\%}\text{,}\text{P}\text{S}\text{1.0}$), and a low-fat, polyunsaturated diet ($\text{32}\text{56\%}\text{,}\text{P}\text{S}\text{1.0}$) for 6 weeks each. Serum and lipoprotein lipids were determined by standard procedures, apolipoproteins either by laser immunonephelometry or by rocket immunoelectrophoresis. Consumption of the polyunsaturated diet decreased cholesterol and apolipoprotein B levels in VLDL (?33.1% and ?23.8%) and in LDL (?13.5% and ?8.8%) without affecting HDL. Consumption of the low-fat, polyunsaturated diet resulted in a reincrease of VLDL triglycerides, but not of VLDL cholesterol. Concentration of VLDL apolipoprotein B further fell (?41.6%) and that of apolipoprotein E decreased (?25.9%), resulting in an increased VLDL lipid/apolipoprotein mass ratio. This study indicates that responses to therapeutic polyunsaturated diet are lowered levels of VLDL and LDL, but unchanged levels of HDL. Additional restriction of dietary fat intake alters the VLDL composition with a decrement in apolipoprotein E enriched VLDL particles.     

Impaired beta-adrenergic stimulation in the uninvolved ventricle post-acute myocardial infarction: reversible defect due to excessive circulating catecholamine-induced decline in number and affinity of beta-receptors

Left ventricular infarction (AMI) was produced in experimental animals and the contractile response to isoproterenol was tested in the isolated perfused heart preparation. Adenylate cyclase activity, phosphodiesterase activity, and beta-receptor binding characteristics were determined in a sarcolemmal preparation of the right ventricle of the same hearts. Three days post-AMI the dose-response curve for isoproterenol of right ventricular dP/dtmax was significantly depressed, while the inotropic effect of histamine was not impaired. Stimulation of adenylate cyclase activity by isoproterenol was reduced by 70% in the membrane preparation, whereas histamine and NaF stimulation rates were unaltered; phosphodiesterase activity was unchanged. In contrast, beta-receptor binding studies with [3H]-DHA1 indicated 74% loss and 10 times lowered affinity (KD) of the remaining beta-receptors, while specific [3H]-QNB1 binding was unchanged. All of the above alterations were prevented by pretreatment with reserpine or metoprolol. It is concluded that these abnormalities in the nonischemic surviving myocardium post-AMI are the result of specific reversible damage of sarcolemmal beta-receptors due to excessive levels of circulating catecholamines.     

Relationship between extent of coronary artery disease and correlative risk factors.

An analysis was made of correlative factors which might be related to the angiographically measured extent of coronary artery disease in 140 patients. All patients presented with clinically important chest pain. Thirty-three had a normal coronary arteriogram. The extent of the atheromatous process was measured precisely at angiography by three different techniques. A coronary score, based on the percentage of luminal narrowing, was found to be best suited for the analysis. The most important contributory factors to the severity of atherosclerosis was duration of clinical history, number of previous myocardial infarctions, and male sex, but more specifically elevation of serum cholesterol and diabetes mellitus. Cigarette smoking, obesity, hypertension, a family history of atherosclerosis, and elevated serum triglycerides had a positive influence but this was not statistically significant.     

Influence of left ventricular function and severity of coronary artery disease on exercise-induced pulmonary thallium-201 uptake

Pulmonary uptake of thallium-201 during exercise was measured in 58 patients with coronary artery disease and compared with the results from 21 patients with normal coronary arteries and 5 normal volunteers. A quantitative method was used to assess the pulmonary thallium uptake relative to cardiac activity (heart/lung ratio). This ratio was calculated for exercise and for redistribution imaging. The mean exercise heart/lung ratio for the group with coronary artery disease was 1.43 +/- 0.36 SD (n = 58); and for the "normal" group was 2.76 +/- 0.41 (n = 26) (P less than 0.001). Increased pulmonary uptake after exercise in the coronary disease group was reversible (mean redistribution heart/lung = 1.96 +/- 0.37 SD; P less than 0.001). The exercise heart/lung ratio differed significantly between groups with single-, two- and three-vessel disease; patients with and without prior infarction; and patients with exercise-induced ST segment depression and elevation. Linear regression analysis between ejection fraction calculated from equilibrium radionuclide angiography at rest and the exercise heart/lung ratio in the coronary artery disease group gave the equation: exercise heart/lung = 0.857 +/- 0.014 ejection fraction for n = 58; r = 0.695; P less than 0.001. It would appear that the exercise heart/lung ratio is a simple and valuable non-invasive index which should be used as part of routine thallium scan interpretation to provide additional information on left ventricular function after exercise and as an indicator of the severity of obstructive coronary artery disease.     

Analysis of coronary responses to nifedipine alone and in combination with intracoronary nitroglycerin in patients with coronary artery disease

Left coronary artery (CA) dilation responses to nifedipine and nitroglycerin (NTG) were studied in patients with CA disease. Quantitative angiography was used to measure the diameter of CAs before and after nifedipine (10 mg buccal) and the addition of NTG (200 μg) given into the left CA. Ninety-three CA segments were measured. The CA diameter was unchanged in 60 segments after nifedipine and was increased in only 27. Diameters of six other segments decreased. The average percentage of dilation of the various CA segments after nifedipine ranged from ?2% to 14%. After NTG, CA dilation compared with control diameters occurred in 84 of the 93 segments. Only eight CA segments were unchanged and one other decreased. The average percentage of dilation of the various CA segments after NTG ranged from 8% to 35% compared with control diameters. Compared with diameters observed after nifedipine, NTG caused dilation in 82 of 93 CA segments; 10 appeared unchanged and one decreased. The diameter of eight coronary stenoses was also measured and was increased in three after nifedipine. After NTG the diameter of six of the eight stenoses increased compared with control diameter, and in four of the six that showed dilation, the diameter was larger than after nifedipine alone. These data suggest that nifedipine does not cause appreciable dilation of epicardial CA in patients with coronary disease. The capacity of NTG to induce dilation appears preserved after nifedipine. Although dilation of epicardial CAs and coronary stenoses was not apparent after nifedipine in our patients at rest, it is possible that nifedipine's clinically beneficial effects are mediated in some patients through prevention of increases in coronary tone.     

Immune reactions in infective endocarditis. II. Relevance of circulating immune complexes, serum inhibition factors, lymphocytotoxic reactions, and antibody-dependent cellular cytotoxicity against cardiac target cells

Circulating immune complexes (IC) were detected in 35 out of 41 patients (85%) with infective endocarditis of known bacterial origin in contrast to only 9 out of 20 patients (45%) with endocarditis but negative blood cultures (p less than 0.05). Peak IC levels of 33.25 +/- 24.33 micrograms/ml in the early period fell significantly to 8.38 +/- 13.37 micrograms/ml after antibiotic treatment (p less than 0.001). High levels of IC coincided with relative hypocomplementemia. Erythrocyturia was observed in 51 of 58 IC-positive patients demonstrating peripheral sequelae of circulating IC. Incidence and concentrations of IC correlated neither with the mere presence of the rheumatoid factor nor with the titers of antimyolemmal antibodies, nor with antibody mediated cytolysis in the presence of complement. Serum inhibition factors (SIF) and E-rosette inhibitory factors (RIF) were not demonstrated, indicating that IC in endocarditis do not suppress phytohemagglutinin-induced lymphocyte proliferation or the E-rosetting of T cells. Significant lymphocytotoxicity against heterologous cardiac target cells without serum (LC) could be demonstrated in 11 out of 23 patients (48%) with endocarditis as compared to its absence in controls (n = 33, p less than 0.01). In assays of antibody-dependent cellular cytotoxicity (ADCC), either enhancement or blocking of lymphocytotoxicity by autologous serum or both was observed. The modulation of lymphocytotoxicity was most likely due to antimyolemmal antibodies, to IC, or to both, although effects of other serum factors cannot be ruled out completely.     

Clinical and hemodynamic evaluation of coronary collateral vessels in coronary artery disease

To appraise the functional significance of coronary collateral vessels, 78 consecutive patients with angina pectoris and at least 75 per cent obstruction in a major coronary vessel were studied clinically, hemodynamically, and angiographically and by stress testing. Forty-eight of them (62 per cent) had coronary collateral vessels. When patients with collaterals were compared with those without, the severity of angina pectoris and the number of positive treadmill ECG's were not statistically different. The patients with collaterals had a greater incidence of past myocardial infarction, $\text{33}\text{48}$ (68 per cent) vs. $\text{8}\text{30}$ (27 per cent) (P = 0.001); more extensive obstructive disease angiographically, 8.0 ± 0.4 vs. 6.3 ± 0.5 (P = 0.05); more abnormal pacing ventricular function curves, $\text{22}\text{23}$ (96 per cent) vs. $\text{9}\text{15}$ (60 per cent) (P = 0.01); and a greater incidence of left ventricular contraction abnormalities, $\text{43}\text{48}$ (90 per cent) vs. $\text{16}\text{30}$ (53 per cent) (P = 0.025).Patients who have coronary artery disease and collateral vessels cannot be distinguished from their counterparts without collaterals on a clinical basis except for a greater incidence of myocardial infarction in the former. Present evidence implies that collateral vessels may protect the patient by delaying the onset of angina pectoris, but when angina occurs these patients have more extensive coronary artery disease and greater myocardial dysfunction. In addition, collaterals, although not preventing, may limit the extent of myocardial infarction and reduce immediate mortality. The prognosis from the onset of angina pectoris may be worse in those patients with collateral vessels, however, because of their more extensive disease.     

Hemodynamic and myocardial energetic changes induced by the new cardiotonic agent,AR-L 115, in patients with coronary artery disease

AR-L 115 has been shown to improve left ventricular (LV) pump function in patients with advanced congestive cardiomyopathy by the intravenous and oral routes. Since AR-L 115 effects on myocardial oxygen consumption (MV?O₂) and coronary blood flow (CSF) are unknown, the hemodynamic, myocardial metabolic, and ECG responses to AR-L 115 (2 mg/kg bolus) were monitored at 9-, 14-, and 9-minute intervals in seven patients with coronary disease, exhibiting ischemia during pacing stress only. Maximal responses occurred at the fourteenth minute after AR-L 115. There were (average) increases in cardiac index by 30%, heart rate by 19%, CSF by 39%, MV?O₂ by 34%, and LV $\text{dp}\text{dt}$ max by 27%. There were (average) decreases in peak LV systolic pressure by 13%, LV end-diastolic pressure by 42%, systemic vascular resistance by 34%, and in coronary vascular resistance by 37%. All changes were significant (p < 0.05). Myocardial lactate extraction, stroke work index, and stroke index remained unchanged (p > 0.05). The modes increase in MV?O₂ is possibly explained by the increase in contractility being partially offset by reductions in LV preload and afterload. AR-L 115-improved LV pump function was accompanied by moderate increases in MV?O₂ and CSF but without evidence of myocardial ischemia.     

Ventricular function at rest, during leg raising and physical exercise before and after aortocoronary bypass surgery.

In nine patients with coronary heart disease contractility indexes during isovolumic contraction and during the ejection phase were measured simultaneously, using an angiographic catheter-tip manometer. Regional wall motion at rest, after leg raising and during physical exercise (bicycle ergometer) was analyzed using the hemiaxis method. Five weeks after aortocoronary bypass surgery these examinations were repeated. Preoperatively left ventricular end-diastolic pressure increased from 21 to 37 mm Hg after leg raising. The velocity of mean circumferential fiber shortening (VCF) and of regional shortening in the anterior wall decreased significantly. All patients discontinued physical exercise due to angina pectoris. Left ventricular end-diastolic pressure increased from 21 to 39 mm Hg during exercise. Large hypokinetic and akinetic areas developed, especially in the anterior wall. Velocity of fiber shortening of the anterior wall decreased from 1.43 to 0.76/sec. End-diastolic volume remained unchanged, but end-systolic volume increased significantly. In six patients with patent grafts surgery had a beneficial effect. Angiograms at rest revealed no significant postoperative changes; however, after leg raising and physical exercise, ventricular function was greatly improved over the preoperative performance. Velocity of fiber shortening in the anterior wall increased significantly from 0.76 to 2.56/sec, mean VCF from 1.11 to 2.12 circumferences/sec, maximal rate of rise of left ventricular pressure from 2,302 to 4,280 mm Hg/sec and peak velocity of contractile elements (Vpm) from 27.8 to 55.7/sec. The mean functional improvement in individual wall segments was 500 percent. Ejection fraction increased from 54 percent to 76 percent. End-diastolic volume remained unchanged while end-systolic volume decreased from 67 to 33 ml/1.73 m² (P < 0.002). In three patients occlusion of the bypass graft or myocardial infarction occurred intraoperatively. Their postoperative findings at rest and during exercise were unchanged from the preoperative values. After successful bypass surgery ventricular function at rest did not change, but during exercise, a marked improvement in overall and in regional ventricular function was found.