Dan Sapoznikov

Prevention of Myocardial Damage in Acute Myocardial Ischemia by Early Treatment with Intravenous Streptokinase

We evaluated the effectiveness of early intravenous administration of 750,000 units of streptokinase in 53 patients with acute myocardial ischemia treated by a mobile-care unit at home (9 patients) or in the hospital (44 patients). Treatment was begun an average (+/- S.D.) of 1.7 +/- 0.8 hours from the onset of pain. Non-Q-wave infarctions developed subsequently in eight patients, whereas all the others had typical Q-wave infarct patterns. In 81 per cent of the patients the infarct-related artery was patent at angiography performed four to nine days after admission. Vessel patency was independent of the time of treatment, but residual left ventricular function was time dependent. Patients treated less than 1.5 hours after the onset of pain had a significantly higher ejection fraction (56 +/- 15 vs. 47 +/- 14 per cent; P less than 0.05) and infarct-related regional ejection fraction (51 +/- 19 vs. 34 +/- 20 per cent; P less than 0.01) and a lower QRS score (5.6 +/- 4.9 vs. 8.6 +/- 5.5; P less than 0.01) than patients receiving treatment between 1.5 and 4 hours after the onset of pain. Patients treated earlier by the mobile-care unit also had better-preserved left ventricular function than patients treated in the hospital. We conclude that thrombolytic therapy with streptokinase is most effective if given within the first 1.5 hours after the onset of symptoms of acute myocardial infarction.

Down's syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase

To investigate the possible involvement of Cu/Zn-superoxide dismutase (CuZnSOD) gene dosage in the neuropathological symptoms of Downs syndrome, we analyzed the tongue muscle of transgenic mice that express elevated levels of human CuZnSOD. The tongue neuromuscular junctions (NMJ) in the transgenic animals exhibited significant pathological changes, namely, withdrawal and destruction of some terminal axons and the development of multiple small terminals. The ratio of terminal axon area to postsynaptic membrane decreased, and secondary folds were often complex and hyperplastic. The morphological changes in the transgenic NMJ were similar to those previously seen in muscles of aging mice and rats as well as in tongue muscle of patients with Downs syndrome. The findings suggest that CuZnSOD gene dosage is involved in the pathological abnormalities of tongue NMJ observed in Downs syndrome patients.

Localization of lesions in the coronary circulation.

The location of coronary artery narrowings in coronary disease (CAD) is of considerable importance in assessing the mass of myocardium at risk as well as patient prognosis. The detailed distribution of coronary lesions was mapped in 302 patients with CAD who had coronary angiography for chest pain. All identifiable coronary lesions were measured manually and the site and degree of narrowing were stored in a computer-based multisegmental model of the coronary tree. A high prevalence of CAD was found in proximal vessels and especially at, or adjacent to, proximal points of branching. In the left anterior descending coronary artery, the lesions were most prevalent immediately after the first diagonal branch and at the origin of this branch. In the right coronary artery, there was a high prevalence of narrowing between the infundibular and acute marginal branches and specifically around the origin of the right ventricular branch. In the left circumflex coronary artery, there was a predilection for narrowing in and around the origin of the first marginal branch. When a ramus intermedius was present, its origin was frequently the site of narrowing.

Determinants of Short-Period Heart Rate Variability in the General Population

Decreased heart rate variability (HRV) is associated with a worse prognosis in a variety of diseases and disorders. We evaluated the determinants of short-period HRV in a random sample of 149 middle-aged men and 137 women from the general population. Spectral analysis was used to compute low-frequency (LF), high-frequency (HF) and total-frequency power. HRV showed a strong inverse association with age and heart rate in both sexes with a more pronounced effect of heart rate on HRV in women. Age and heart rate-adjusted LF was significantly higher in men and HF higher in women. Significant negative correlations of BMI, triglycerides, insulin and positive correlations of HDL cholesterol with LF and total power occurred only in men. In multivariate analyses, heart rate and age persisted as prominent independent predictors of HRV. In addition, BMI was strongly negatively associated with LF in men but not in women. We conclude that the more pronounced vagal influence in cardiac regulation in middle-aged women and the gender-different influence of heart rate and metabolic factors on HRV may help to explain the lower susceptibility of women for cardiac arrhythmias.

Computer processing of artifact and arrhythmias in heart rate variability analysis

Analysis of heart rate variability (HRV) with Holter monitoring is often difficult due to excessive artifacts and arrhythmias. While short sudden surges are treated successfully by most methods, slow heart rate (HR) variations, nocturnal trapezoidally-shaped HR increases and special types of arrhythmias which are similar to normal HRV fluctuations may distort further time domain and spectral analysis. This paper examines the advantages and disadvantages of different methods for preprocessing of HR data. We have developed the following approach to the analysis of HRV. (1) A combination method based on the absolute difference between HR values and both the last normal HR value and an updated mean is used for removal of artifacts and arrhythmias. This method can detect both sudden surges in HR values as well as longer periods of noise combined with slow normal variations. An additional stage of wild point removal is then optionally applied. (2) Certain special problems such as large T-waves, bigeminal rhythm, slow HR variations and nocturnal trapezoidally-shaped HR increases are also identified. Although none of the algorithms can be applied successfully to all cases, the final computer analysis for preprocessing described in the present study has proved to be superior to the simplified methods which are usually used and provides more suitable data for HRV analysis.

Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: A model for tongue pathology in Down's syndrome

We examined the tongue muscles in several strains of transgenic mice carrying the human Zn-Cu superoxide dismutase (CuZnSOD) gene. The presence of the extra gene was confirmed in mated progeny and the gene product activity was measured in the tongue and found to be much higher than in normal littermate controls. Using electron microscopic morphometry, the neuromuscular junctions of the transgenic mice showed significant changes resembling excessive aging, with atrophy, degeneration, withdrawal, and sometimes destruction of the terminal axons, as well as the development of multiple small terminals. The myofibers showed little change except for slight hypertrophy and an increased variability in size. They also had more megamitochondria, fat droplets and lipofuscin bodies. Excess CuZnSOD generates H2O2 and hydroxyl radicals which affect both NMJ membranes and plasticity, and which may produce premature aging. The findings resemble those observed in tongues of patients with Downs syndrome, in whom an extra CuZnSOD gene is present as part of the trisomy of chromosome 21.

Cardiovascular risk factor clustering and ratio of total cholesterol to high-density lipoprotein cholesterol in angiographically documented coronary artery disease

High levels of cardiac risk factors tend to cluster together and act synergistically. To develop a suitable and practical marker for clustering, we evaluated 380 consecutive patients at the time of coronary angiography. Analyses of lipid, rheologic, clinical and arteriographic profiles indicated a variety of interwoven relations. Because the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol (total/HDL cholesterol) was closely related to both the presence and extent of greater than or equal to 50% diameter reduction of greater than or equal to 1 coronary arteries, it was used to divide patients into quartiles. Clustering of high- and low-level risk factors was demonstrated in the highest and lowest quartiles of total/HDL cholesterol, respectively (p less than 0.001). The highest quartile may be characterized by an only moderately elevated total cholesterol level but patients in this quartile may have a very low HDL cholesterol level, high triglycerides, a tendency toward high hemoglobin and fibrinogen levels, a history of smoking, previous myocardial infarction and multivessel disease. These results suggest that total/HDL cholesterol serves as a marker not only for obstructive coronary disease but also for a cluster of potentially modifiable risk factors.

Early heart rate variability alterations after acute myocardial infarction.

In order to assess early changes in heart rate variability, we studied 81 patients with acute myocardial infarction during the initial 24 hours after thrombolytic therapy. The standard deviation of the mean heart rate and the low (0 to 0.05 Hz), mid (0.05 to 0.20 Hz), and high (0.20 to 0.35 Hz) frequency band power were evaluated with 24-hour ECG Holter recordings. We found diminished variance in the time domain and reduced power spectrum in the frequency domain compared with a group of 41 normal subjects (p < 0.01). Patients with anterior infarction had significantly (p < 0.01) higher heart rates and lower heart rate variability values than patients with inferior infarction. Reduction in heart rate variability occurred within the first 8 hours in patients with anterior infarction; a significant fall (p < 0.03) was especially noted in the high-frequency band after a decline in ST-segment elevation. Heart rate variability alterations in patients with inferior infarction were most evident in the final 8-hour interval. These findings may be viewed in terms of sympathovagal imbalance and may be related to clinical signs of intense autonomic nervous system activity that are observed early in the course of acute anterior and inferior myocardial infarction.

Sympathetic Nervous System Function and Dysfunction in Chronic Hemodialysis Patients

Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality.

Isovolumic relaxation period in man

Isovolumic relaxation period (IRP) was measured noninvasively from the onset of the aortic component of the second heart sound on the phonocardiogram to the point of separation of the mitral leaflets on the echocardiogram. IRP was measured in 83 patients with different cardiac diseases. The duration of IRP was 58 +/- 11 msec. in normal subjects. It was prolonged in hypertension (p < 0.001), HOCM (p < 0.001), in aortic stenosis (p < 0.05), and aortic incompetence (p < 0.001), and was shortened in congestive cardiomyopathyl (p < 0.05) and mitral stenosis (p < 0.01). In patients with coronary artery disease and normal over-all systolic LV function, IRP was prolonged (p < 0.001); IRP was shortened in four patients with coronary disease who had severe LV dysfunction and severe additional mitral incompetence. IRP was related to systemic blood pressure, percentage shortening of the LV in systole, and to the mitral EF slope. It tended to increase with increasing heart rate and a regression equation was developed for predicting IRP in relation to blood pressure and heart rate in normal sbjects. There was no relation to the PR-Ac time or to isovolumic contraction time. IRP is a useful measurement of LV dynamics in early diastole.