Effect of low-dose niacin on high-density lipoprotein cholesterol and total cholesterol/high-density lipoprotein cholesterol ratio.

Niacin significantly alters blood lipid concentrations but its use has been limited because of clinically disturbing side effects. In an attempt to circumvent these drawbacks, 55 patients with cardiovascular disease were given low-dose long-acting niacin, 1 g/d. Treatment was continued for a mean of 6.7 months and lipid values were compared with a non-treated group of 17 patients followed for a mean of 6.3 months. Lipid values did not change in the nontreated group. In the niacin-treated group total cholesterol and triglyceride levels also did not significantly change. High-density lipoprotein (HDL) cholesterol level rose 31% from 1.01 +/- 0.31 mmol/L to 1.32 +/- 0.31 mmol/L and total cholesterol/HDL cholesterol ratio was reduced 27% from 6.4 +/- 1.9 to 4.7 +/- 1.3. Despite these results, 40% of the patients left the study mainly because of side effects. Apart from one patient who developed overt diabetes, of questionable relationship to niacin, no patient developed serious side effects such as jaundice or peptic ulcer as seen with much higher doses of the drug. Although often difficult to administer to patients, niacin, particularly in low dose, deserves consideration as an inexpensive agent especially useful for elevating HDL cholesterol level and altering the total cholesterol/HDL cholesterol ratio.

Long-term follow-up after recovery from acute myocardial infarction. Observations on survival, ventricular arrhythmias, and sudden death.

A long-term 12-year follow-up of 248 patients surviving acute myocardial infarction indicated a cumulative survival of 89%, 68%, 53%, and 45% for 1, 5, 10, and 12 years, respectively. When patients were assessed with five routinely obtained clinical factors, significant prognostic stratification of high- and low-risk survival groups extended throughout the follow-up period. Sudden cardiac death was found to be twice as frequent as nonsudden cardiac death, but a significant relationship between sudden death and complex ventricular ectopic beats could not be defined. The extent of complex features of ventricular ectopic beats such as pairs, multiform, repetitive, and R-on-T was inversely related to survival. During the first year after acute myocardial infarction, frequency of ventricular ectopic beats was also inversely related to survival. A long-term effect of frequency on survival, however, could not be demonstrated.

Relationship between lipids and occlusive coronary artery disease.

Total cholesterol level, high-density lipoprotein (HDL) cholesterol level, and the ratio of total cholesterol/HDL cholesterol and triglyceride level were determined in 128 consecutive patients undergoing coronary arteriography for evaluation of chest pain. Greater than 50% occlusive coronary artery disease was more prevalent in patients with either a high total cholesterol level, triglyceride level, or total cholesterol/HDL ratio, or a low HDL cholesterol level. Closer analysis of the extent of occlusive coronary artery disease indicated that the HDL cholesterol level was a better predictor of coronary artery disease than total cholesterol or triglyceride levels. The ratio of total cholesterol/HDL cholesterol, however, had a wider discrimination in identifying patients with both single-vessel or multivessel disease. This ratio should be a useful adjunct in assessing the risk of coronary artery disease.

Early treatment of acute myocardial infarction with intravenous streptokinase. A high-risk syndrome.

Fifty-one successive patients treated with intravenous streptokinase 1.7 +/- 0.8 (mean +/- SD) hours after onset of symptoms of acute myocardial infarction were evaluated during a three-month posthospital follow-up period. Coronary angiography was performed four to nine days after the initial hospital admission. Twenty-eight patients had a second late angiogram. Forty-one patients had successful reperfusion but only 25% of all patients were without significant clinical cardiovascular manifestations during this period. Postmyocardial infarction angina pectoris occurred in 21 patients, an abnormal stress test result was present in 28 patients, eight patients developed congestive heart failure, and five patients had reinfarction. An intervention with percutaneous transluminal coronary angioplasty or coronary artery bypass graft was performed in 15 (37%) of 41 reperfused patients. A significantly higher intervention rate was present in patients treated with streptokinase within one hour following the onset of symptoms. Early reocclusion (within three months of the infarct) was noted in patients with 60% or more residual stenosis in their infarct-related coronary artery. These patients also had a significantly greater incidence of angina pectoris. Our findings indicate that early thrombolytic therapy of acute myocardial infarction preserves myocardium, and since the infarct-related artery is patent, but narrowed, the jeopardized area is responsible for a high-risk syndrome with an increased likelihood of ischemic symptoms. An early aggressive approach may be indicated, especially for patients with greater than 60% residual stenosis in their infarct-related coronary artery.

Relationship between sex hormones, myocardial infarction, and occlusive coronary disease.

An alteration in sex hormones has been considered a risk factor for myocardial infarction. In this study, estradiol (E2) and testosterone (T) levels were evaluated in healthy firefighters, patients with myocardial infarction acutely and during their convalescence, patients with no evidence of occlusive coronary artery disease on arteriography, and patients with chronic angina pectoris in whom there was at least one vessel that indicated 50% occlusive coronary artery disease. Although T levels were similar in all groups, E2 levels were substantially higher in patients with myocardial infarction and in patients with chronic angina pectoris. These results support the hypothesis that elevated estrogen levels may be a risk factor for myocardial infarction and coronary artery disease, possibly by promoting clotting or coronary spasm.

Effects of potassium chromate on atherosclerosis prevention and regression in rabbits.

The effect of intraperitoneal injections of potassium chromate on prevention and regression of atherosclerosis was observed in New Zealand White rabbits. In rabbits fed a 1% cholesterol diet for 90 days, potassium chromate injection was not associated with a significant difference in weight, serum cholesterol, total cholesterol content per 8.5 cm aorta, cholesterol content per gram of aorta or percent intima covered with plaque compared to controls. Similarly, significant differences were not seen in rabbits fed a 1% cholesterol diet for 90 days followed by 60 days of potassium chromate or distilled water injections and a standard diet. These results are in keeping with recent studies suggesting a more limited role for chromium in a variety of lipid-related disorders.

Survival after recovery from acute myocardial infarction. Two and five year prognostic indices.

A prognostic index for two year survival following recovery from acute myocardial infarction has been verified in an independent group of 105 patients. Five variables comprise the index: systolic blood pressure level on admission, highest blood urea nitrogen level in the cardiac care unit; atrial arrhythmias in the cardiac care unit; angina pectoris for more than three months or a previous myocardial infarction; and more than one ventricular ectopic beat per hour recorded on an 8 hour dynamic electrocardiogram during convalescence just prior to hospital discharge. One hundred twenty-six patients have also been followed for five or more years, and we now report a five year prognostic index. Discriminant analysis indicates that the same five variables, although weighted differently, continue to be significant for prognostic assessment and may be utilized in the identification of patients at high and lower risk.

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.

Five minute recordings of heart rate variability for population studies: repeatability and age-sex characteristics.

OBJECTIVE: To evaluate the stability of short recordings of heart rate variability (HRV) with time, and the association of HRV with age and sex. DESIGN: Five minute Holter recordings were made twice over a two month interval (tracking study). In addition, HRV was measured in a cross sectional study. SETTING: Residents of 11 Israeli kibbutzim were examined in their settlements. SUBJECTS: 32 men and 38 women (aged 31-67) participated in the tracking study and 294 (aged 35-65) were involved in the cross sectional study. MAIN OUTCOME MEASURES: Time and frequency domain analyses on Holter recordings were undertaken in two breathing conditions: spontaneous and controlled breathing (15 respirations per minute). Regression was used to assess the relations of sex, age, heart rate, and logarithmically transformed HRV indices. RESULTS: HRV measures were highly consistent with time with correlations of 0.76-0.80 for high frequency and total power. Geometric mean total power declined with age by 45% in men and 32% in women, and was lower by 24% among women than among men (all p < or = 0.005). Men had a 34% higher very low and low frequency power and a higher ratio of low to high frequency power (p < 0.001). Conversely, high frequency power in women represents a greater proportion of total power than in men. CONCLUSION: Short recordings of HRV in a non-laboratory setting are stable over months and therefore characteristic of an individual. Strong age and sex effects were evident. HRV derived from short recordings can be informative in population based studies.

Changes in sinus RR interval patterns preceding ventricular ectopic beats: assessment with rate enhancement and dynamic heart rate trends.

Changes in heart rate preceding ventricular ectopic beats may be used to identify clinical subsets of patients. We evaluated RR interval patterns preceding ventricular ectopic beats with a rate enhancement method which estimates ventricular ectopic beat dependence on the sinus RR interval preceding the ventricular ectopic beat and the dynamic heart rate trend, which is based on the slope of the five RR intervals preceding the ventricular ectopic beat. Using these two methodologies in 176 patients with frequent ventricular ectopic beats we identified several unique subsets of patients: (1) bradycardia-enhanced patients were younger with a high proportion of males and longer, more variable coupling intervals; (2) tachycardia-enhanced patients exhibited sleep suppression of ventricular ectopic beats and had shorter, less variable coupling intervals; (3) patients with predominantly no change in RR preceding the ventricular ectopic beat were significantly older, with greater prevalence of cardiovascular disease and reduced sinus RR variability, indicating decreased autonomic nervous system activity. These two methods may serve as a basis for further investigations regarding the treatment and prognosis of ventricular ectopic beats.

Pharmacodynamic effects of bezafibrate and niacin combination: implications of the mode of administration.

The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.

The effect of the mode of administration on the hypolipidaemic activity of niacin: continuous gastrointestinal administration of low-dose niacin improves lipid-lowering efficacy in experimentally-induced hyperlipidaemic rats.

The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia-Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg(-1)). Continuous administration of niacin into the duodenum at 1.66 mg h(-1) (total dose 40 mg kg(-1) day(-1)) for up to 7 days (Model A) or at 2.22 mg h(-1) over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15-25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg(-1)) has a greater lipid-lowering effect than a higher dose (200 mg kg(-1)) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.

Atherosclerosis: the importance of HDL cholesterol and prostacyclin: a role for niacin therapy.

Niacin reduces the incidence of non-fatal myocardial way infarction, confers a significant long-term survival benefit after recovery from myocardial infarction, and has had many years of study and usage by the medical community. Recent evidence suggests that via mechanisms which elevate HDL cholesterol and also release endogenous prostacyclin, niacin should be a potent agent in the long-term treatment of atherosclerosis.

Left subclavian vein puncture for insertion of Swan-Ganz catheters.

A rapid, safe, and reliable method for insertion of Swan-Ganz flow-directed, balloon-tipped catheters using the left subclavian vein is described. Experience with this method in 24 consecutive patients indicates a distinct advantage over the antecubital fossa approach: A venous cutdown is not necessary, the pulmonary artery is readily entered, fluoroscopy is not required, the patient is free to move both arms, and thrombophlebitis and infection occur infrequently. With proper attention to landmarks such as the clavicular tubercle, the procedure may be performed with facility. The major complication, pneumothorax, is minimized if mechanical ventilators are briefly disconnected during the subclavian puncture.

Simulation of ventricular arrhythmias using a re-entry model algorithm.

The present study employs a computer simulation of the timing of normal and abnormal ventricular activation according to a re-entry model. A wide variety of arrhythmia patterns similar to those obtained in clinical settings may be simulated by using an algorithm which is based on parameters such as the sinus RR interval (RR), the refractory period, the coupling interval between normal activation and re-entry and the coupling interval between one re-entry and a subsequent re-entry (CV). By varying RR and CV the results of the simulation may show transition between different types of arrhythmia such as ventricular tachycardia, bigeminy, trigeminy and more widely separated ventricular ectopic beats such as in concealed bigeminy. The algorithm provides a basis for the study of re-entry, a major mechanism in the genesis of ventricular arrhythmias.

Comparison of different methodologies of heart rate variability analysis.

Two methodological aspects of heart rate variability (HRV) are tested. Heart rate variability and RR interval variability (RRV) are compared in 109 healthy subjects using 24-h Holter recordings. Autoregressive power spectrum analysis was performed, and the power in three frequency bands was evaluated by two different methods: the peak power and the mean power within the band. The power in the low frequency (LF) and high frequency (HF) ranges showed greater changes between day and night values when RRV was analysed compared with HRV. The mid frequency (MF) range power showed no significant change at night with RRV analysis compared with a significant decrease with HRV analysis. The different pattern of changes between day and night values when using RRV or HRV analysis is explained by the non-linear nature of the relationship between RR interval and heart rate and the lower heart rate at night. Therefore, depending on the heart rate, there may be amplification or attenuation of fluctuations when transforming from one heart rate variability method to another. When comparing peak power and mean power measurements within the frequency bands, the changes in LF and MF powers were similar. However, HF mean power with RRV analysis showed less change at night than the peak power and no change with HRV analysis. The explanation lies in the fact that respiratory fluctuations at night are much more regular, resulting in a sharp high peak in the power spectrum. The peak power is therefore higher at night, whereas the total power changes much less or remains unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of regularities in heart rate variations by linear and non-linear analysis: power spectrum versus approximate entropy.

Regularity or complexity characteristics of RR interval variations have attained importance in the evaluation of a variety of pathological conditions. Regular periodic fluctuations in heart rate are considered indicators of loss of control in the cardiovascular system and of disturbances in pulmonary function. Methods to detect such loss of cardiopulmonary function have been developed mainly through linear and non-linear system analysis. Both approaches were tested in the present study. MBW, which is the ratio between maximal power spectrum (PS) amplitude and its 3-db bandwidth (BW) in the 0-0.1 Hz frequency range, was calculated and compared for different examples derived from 24 h Holter recordings and for sinusoidal function mixed with varying degrees of noise. Approximate entropy (ApEn), a measure derived from non-linear system analysis has been tested for the same data and compared with the MBW ratio. The results show that MBW effectively differentiates regular and non-regular epochs while ApEn differentiates them in a less optimal manner especially in cases where higher degrees of noise are present but regularity is still observed visually.

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.

Long-term survival after recovery from acute myocardial infarction.

Long-term prognosis following recovery from acute myocardial infarction is related to the extent of myocardial impairment. This is reflected in a variety of clinical laboratory, and electrocardiographic variables which are often routinely obtained during the hospital course of a patient with acute myocardial infarction. When these factors are utilized to produce prognostic indices, patients may be stratified into a variety of survival groups. Results now indicate that very early after the development of an acute myocardial infarction there are sufficient data for the development of a long-term prognostic assessment. This information should improve our clinical approach to the patient recovering from acute myocardial infarction.