Chronic ischemic heart disease: from concept to fact

The development and refinement of techniques relating the determinants of increased myocardial oxygen demand to primary or secondary manifestations of inadequate myocardial blood flow made possible certain major advances in the management of chronic ischemic heart disease over the past 25 years. These include objective and quantitative evaluation of the anatomic basis and the functional consequences of ischemic heart disease, risk stratification for patient subgroups and documentation of the effects of therapy. In addition, studies in which ischemic manifestations were shown to be dissociated from increased myocardial oxygen demand have redirected attention to the supply component of the supply to demand balance for myocardial oxygenation.Diagnostic techniques, management schemata and therapeutic evaluation methods for the electrophysiologic alterations of ischemic heart disease have matured more slowly than those for the ischemic manifestations. While the pathophysiologic concepts underlying knowledge of the ischemic manifestations of coronary artery disease were formulated 25 years ago, in the case of arrhythmias, new concepts needed to be developed to provide the direction for technologic and therapeutic advances. Although the patients at risk for serious arrhythmias and sudden cardiac events are known to be those with severe coronary artery disease, impaired left ventricular function and preexisting electrical instability as manifested by frequent and complex ventricular arrhythmias, the sensitivity and specificity for any single factor as a predictor of risk remain to be established. Similarly, methods to predict efficacy of therapy are still under development. Progress will accelerate when specific factors that predict risk are identified and the methods for measuring those factors are developed and applied to the patient in an organized and systematic manner.The thesis underlying this broad conceptional review is that the fostering of the full-time clinical investigator that occurred during the 1960s and the first half of the 1970s and the consequent systematic development and application of quantitative methods to the study of disease in human beings were major forces for the remarkable progress that has been made in the management of all aspects of cardiovascular disease.     

The metabolic effects of dichloroacetate

Dichloroacetate activates the pyruvate dehydrogenase complex of many tissues by inhibiting the kinase responsible for phosphorylation and inactivation of the complex. Dichloroacetate also activates the myocardial branched-chain α-keto acid dehydrogenase complex but apparently not by direct inhibition of the analogous kinase. Oxalate and glyoxylate, metabolites of dichloroacetate, are responsible for some in vitro effects of dichloroacetate. Dichloroacetate stimulates leucine oxidation by isolated hepatocytes because glyoxylate transaminates with leucine. Dichloroacetate inhibits lactate gluconeogenesis by hepatocytes incubated in low bicarbonate buffer because oxalate inhibits pyruvate carboxylase under such conditions. In vivo, dichloroacetate decreases blood glucose by limiting the supply of gluconeogenic precursors to the liver. This effect is a consequence of pyruvate dehydrogenase activation in peripheral tissues. Dichloroacetate lowers blood cholesterol in hyperlipidemic patients by uncertain means. Dichloroacetate has been tried experimentally in treatment of diabetes, hypercholesterolemia, and hyperlactatemia, but it has neurotoxicity, can cause cataracts, and may be mutagenic.     

New antiarrhythmic agents: amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil.

The present status, clinical experience, side effects, clinical pharmacology and electrophysiologic actions of seven new antiarrhythmic agents are reviewed. The drugs selected for comment are amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide and verapamil. Each drug has been shown to have clinical efficacy in suppressing cardiac arrhythmias.     

Evaluation of abnormal exercise electrocardiogram in apparently healthy subjects: Labile repolarization (ST-T) abnormalities as a cause of false positive responses

Long-term follow-up studies were carried out in 121 apparently healthy men with an abnormal S-T segment response to exercise—49 Indiana State policemen and 72 subjects from a large occupational health center. The mean follow-up periods were 66 months and 43 months, respectively, for the two groups of subjects. A tendency toward labile S-T or T wave abnormalities were documented during standing rest or with hyperventilation in 61 of these 121 subjects and there was only one new coronary event in this subgroup. The labile ST-T wave changes and the abnormal S-T segment responses to exercise were not consistently reproducible in these subjects, and it was not unusual to see an abnormal S-T segment response at a time when the labile repolarization changes could not be demonstrated. Many of the subjects exhibited labile ST-T wave changes only after oral glucose loading. Significant coronary artery disease was documented in 34 (57 percent) of the remaining 60 subjects during the follow-up period.Coronary cineangiographic studies, obtained in 21 of the 35 subjects from the health center who had had no evidence of labile ST-T wave abnormalities, revealed coronary arterial stenoses of 75 percent or greater in 19. A statistical analysis was carried out in the 35 subjects without labile ST-T abnormalities to determine if there were exercise test variables that would differentiate the true positive from the false positive responses. A set of criteria were identified that yielded a specificity of 92 percent, a sensitivity of 82 percent and a predictive value of 95 percent. The entire group of 72 from the health center subjects had undergone an average of 3.8 exercise tests before their referral to the authors' laboratory. A review of these records revealed that a serial conversion from a normal to an abnormal S-T segment response was not more predictive of underlying coronary artery disease than an initially abnormal test result.     

Forward stroke volume calculated from aortic valve echograms in normal subjects and patients with mitral regurgitation secondary to left ventricular dysfunction

A clinically applicable method was developed for calculating aortic valve stroke volume using the echocardiographically recorded initial and late aortic cusp separation, ejection time and amplitude of posterior aortic root motion during ejection. The formula was tested prospectively in 55 patients for whom 65 Fick [n = 26]or thermodilution [n = 39]cardiac output determinations were performed simultaneously with echocardiography. Aortic valve echograms were recorded in all patients and mitral valve echograms were also recorded in 48 of the 55 patients. Twenty patients had nonrheumatic mitral regurgitation. For the 65 studies, linear correlation (r) was excellent between the aortic valve method and Fick or thermodilution method for stroke volume (r = 0.96, standard error of the estimate [SEE]± 6 cc) and for cardiac output (r = 0.92, SEE ± 0.44 liters). Differences between cardiac output values obtained from aortic valve echograms and either Fick or thermodilution techniques ranged from −1.4 to +1.5 liters/min and were normally distributed. Ninety percent of the computed aortic valve data was within 15 percent of the Fick or thermodilution data.

Aortic valve stroke volume correlated well (r = 0.93) with stroke volume derived from mitral valve echograms in the patients without mitral regurgitation but did not correlate well (r = 0.78) in the patients with mitral regurgitation. Mitral valve stroke volume exceeded aortic valve stroke volume by more than 20 percent in 19 of the 20 patients with mitral regurgitation compared with 1 of 28 patients without mitral regurgitation. The presence or absence of ventricular dyssynergy did not alter statistical findings. Data from this study show that (1) aortic valve echograms can be used clinically to measure forward stroke volume, and (2) the difference between mitral valve and aortic valve volume should be a measure of mitral regurgitant flow.     

Left atrial myxoma infected with histoplasma capsulatum

A patient is presented in whom a left atrial myxoma was found to be infected with Histoplasma capsulatum. Histoplasmosis has not been previously associated with this tumor, nor has any fungus without preceding bacterial endocarditis and long-term antibiotic therapy. The clinical course in four previously reported cases of bacterially infected myxoma is reviewed. There have been 18 prior cases of Histoplasma endocarditis and in two the patients have survived. Their clinical presentation and response to therapy are also reviewed, and pertinent therapeutic conclusions drawn. The role of echocardiography in this patient's evaluation and the ultimate successful therapy are discussed.     

Inhibition of premature ventricular extrastimuli by subthreshold conditioning stimuli

The purpose of this study was to determine whether trains of subthreshold high frequency conditioning stimuli (333 Hz, 1 ms duration, 2 ms interval) delivered to the canine ventricle inhibited the response to a premature stimulus (S2) more effectively than did a single subthreshold conditioning stimulus. It was found that trains of conditioning stimuli (mean 1.21 mA) inhibited the response to S2 152 ms beyond expiration of the ventricular effective refractory period, whereas a single conditioning stimulus inhibited S2 only 20 ms or less beyond the ventricular effective refractory period. In late diastole, trains of conditioning stimuli failed to inhibit S2 when the train of stimuli caused ventricular depolarization or the latter occurred in response to the next sinus impulse. Trains of conditioning stimuli did not induce ventricular arrhythmias. Lidocaine or autonomic blockade did not alter the response to trains of conditioning stimuli. Trains of conditioning stimuli or a single conditioning stimulus inhibited the response to S2 only when they were delivered at the same electrode site. By lengthening the ventricular effective refractory period, trains of conditioning stimuli could prevent or terminate tachycardias, but this possibility is constrained, at present, by the spatial limitations of the technique.     

Thallium-201 myocardial scintigraphy: Improved sensitivity,specificity and predictive accuracy by application of a statistical image analysis algorithm

Exercise and 3 hour delayed redistribution thallium-201 myocardial perfusion imaging was performed in 107 patients including 87 patients with documented coronary artery disease and 20 patients with normal coronary arteriograms. A computer algorithm for statistical analysis and redisplay of the analog scintillation data was developed to augment the visual analysis of the standard analog image. The basic algorithm identified the myocardial area (pixel) with the most absolute counts and developed an appropriate standard deviation range from a table. All pixels in the area of the myocardium containing absolute counts below three standard deviation ranges (or approximately 6 standard deviations) were deleted from the final image. The remaining pixels were redisplayed in a digitized bimodal format and the image photographed. Two experienced observers compared visual analysis of the analog image alone and the analog image in conjunction with the computer-analyzed image for sensitivity, specificity and predictive accuracy in the detection of perfusion defects in patients with coronary artery disease and in normal subjects. Sensitivity in patients with coronary artery disease for the analog scintillation image alone was 79 percent (69 of 87) and with computer analysis 95 percent (83 of 87). Specificity in the patients with no coronary disease was 100 percent (20 of 20) for both techniques. The predictive accuracy of the test was 83 percent (89 of 107) for the analog image alone and 96 percent (103 of 107) for the two images combined. It is concluded that use of a computer statistical analysis algorithm of thallium-201 analog myocardial perfusion images improves the accuracy of detection of perfusion defects in patients with coronary artery disease.     

Recent advances in knowledge about beta-adrenergic receptors: application to clinical cardiology

The properties of beta-adrenergic receptors in the cardiovascular system have been studied in the past by two experimental approaches, which can be termed pharmacologic and biochemical. In the pharmacologic approach, the nature of a drug interaction with receptors is deduced from alterations in the physiologic properties of the tissue caused by administration of various concentrations of the drug. Many important concepts about beta-adrenergic receptors have come from such indirect pharmacologic studies. The biochemical approach directly assesses the interaction of drugs with beta-adrenergic receptors by studying the binding of radiolabeled antagonists and agonists with the receptor. This relatively new approach has provided a large amount of new information regarding the intrinsic properties of beta-adrenergic receptors and modification of these properties by physiologic stresses, administration of drugs and disease states. The biochemical approach has also been applied recently to the study of beta-adrenergic receptors in human beings. In the future, substantial clinically relevant new information regarding the nature of beta-adrenergic receptors in physiologic and pathologic conditions should result from application of a combination of the biochemical and physiologic approaches to studies in human beings.     

Propionibacterium acnes: pathogen in central nervous system shunt infection. Report of three cases including immune complex glomerulonephritis.

Propionibacterium acnes is a pleomorphic gram-positive anaerobic rod usually isolated as a contaminant from skin. We report three cases of P. acnes infection of central nervous system shunts for hydrocephalus. The organism was seen repeatedly on gram stain in a specimen of shunt fluid in all three cases; initially, it was regarded as a contaminant. In addition, two of the patients had precipitins to extracts of their organism. Serum from normal control subjects had no such precipitins. One of the patients had an immune-complex glomerulonephritis--an entity not previously associated with anaerobic organisms. All three patients recovered after removal of the shunt and treatment with antibiotics. P. acnes is a significant pathogen in patients with central nervous system shunts.