Effect of angiotensin-converting enzyme inhibitor therapy in mitral regurgitation with normal left ventricular function.

Mitral regurgitation (MR) is a common, frequently asymptomatic valvulopathy that can ultimately lead to left ventricular failure. With the objective of forestalling MR progression, a prospective, placebo controlled, double-blind study was conducted. It measured the effectiveness of lisinopril, an angiotensin-converting enzyme inhibitor, in reducing the echocardiographic signs of MR severity over a one-year period. Severe coronary disease was excluded by stress echocardiography. Treatment effectiveness was estimated to be proportional to the reduction in MR fraction and cardiac chamber dimensions, compared with baseline, according to intention-to-treat analysis. A final patient population of 23 asymptomatic adults aged 53.3 +/- 2.4 years (mean +/- SEM), with moderate, organic MR and normal left ventricular function was selected from the echocardiographic database. All baseline patient characteristics were comparable in the two treatment groups, including the MR fraction (55 +/- 3%). Twelve patients received lisinopril (18 +/- 1 mg) and 11 received placebo. After one year of treatment, a statistically significant difference in the MR fraction was observed between the two groups. For the lisinopril group the MR fraction dropped by 6.4 +/- 3.5% and for the placebo group it increased by 3.7 +/- 3.2% versus baseline (P < 0.05). No differences in left atrial or ventricular dimensions were observed. The study drug was stopped in four patients after one patient presented with rapid atrial fibrillation and angina while three patients were intolerant to lisinopril. Only one patient receiving placebo was taken off therapy. In conclusion, treatment with lisinopril indicates some reduction in the severity of chronic moderate MR in asymptomatic patients with normal left ventricular function. This approach appears to be safe, but side effects are not uncommon, warranting regular follow-up.

Angiotensin-converting enzyme inhibition in myocardial infarction--Part 1: Clinical data.

There is an increasing body of clinical trial evidence to support the use of angiotensin-converting enzyme (ACE) inhibitors in the management of patients following myocardial infarction (MI). Enthusiasm for the use of ACE inhibitors in the acute phase of MI had previously been tempered by the adverse results of an early trial. However, exciting new information is available from several large, randomized studies that has not only quelled those initial concerns but also attests to the efficacy of using this class of medication in the first 24 h after an acute MI. A Canadian National Opinion Leader Symposium was held in November 1995 to review the results of the major ACE inhibitor clinical trials and to discuss key issues and controversies surrounding their use in acute MI. The focus of this paper, the first of two parts, is on the results of the major ACE inhibitor clinical trials.

Angiotensin-converting enzyme inhibition in myocardial infarction--Part 2: Clinical issues and controversies.

Over the past 10 years, several clinical studies have concluded that, in patients already receiving conventional therapies, angiotensin-converting enzyme (ACE) inhibitors further reduce the risk of death following myocardial infarction (MI). Post-MI ACE inhibitors have proven to be effective as long term therapy in high risk patients as well as when used for much shorter periods in a broad patient population. However, while considerable mortality data have been collected, the effects of ACE inhibitors post-MI on other cardiovascular outcomes have not been as well documented. In addition, a number of issues regarding the most effective use of these agents remain unresolved. This paper, the second of two parts, focuses on the clinical issues and controversies surrounding the use of ACE inhibitors following acute MI. The effects of ACE inhibitors on the outcomes of sudden death, nonsudden death, recurrent angina, mitral regurgitation and left ventricular dysfunction are reviewed and potential mechanisms of action are proposed. In addition, ACE inhibitor therapy is discussed in terms of patient selection criteria, choice of agent, optimal dosing regimen, concomitant use of other therapies and relative costs of treatment. Finally, potential mechanisms of action of ACE inhibitors are proposed for each of the outcomes examined.

Predictors of survival of in-hospital cardiac arrest.

A prospective study was conducted of all cases of attempted resuscitation following cardiac arrest occurring over a period of one year in a tertiary care teaching hospital. Analysis was made of the effects on survival of preselected variables of patients and circumstances of arrest. In 125 cases for which resuscitation was attempted, 49 attempts (39%) were initially successful. Twenty-three patients were discharged from hospital (18% overall survival). The most potent predictors of successful resuscitation were early successful resuscitation (less than 20 mins), age less than 75 years, and cardiac arrest in proximity to an acute ischemic cardiac event (less than 48 h). Survival to discharge was extremely poor when the arrest was unwitnessed (zero of 20 cases) or when the arrest occurred on medical or surgical wards (two of 62 cases). Such low efficacy indicates that reassessment of policy regarding the administration of cardiac resuscitation to patients in hospital is warranted.

Assay of glyceryl trinitrate, isosorbide dinitrate, and their metabolites in plasma by large-bore capillary column gas-liquid chromatography.

Two large-bore capillary columns, one with dimethyl polysiloxane (HP-1) as the stationary phase and the other with phenyl (50 per cent) methyl (50 per cent) polysiloxane (DB-17), were used to develop gas-liquid chromatographic (GLC) assays for measuring isosorbide dinitrate (ISDN), glyceryl trinitrate (GTN), and their metabolites. ISDN, isosorbide-2-mononitrate (2-ISMN), and isosorbide-5-mononitrate (5-ISMN) in plasma, ranging in concentration from 1 to 300 nM, and GTN, glyceryl-1,2-dinitrate (1,2-GDN), and glyceryl-1,3-dinitrate (1,3-GDN), ranging in concentration from 3 to 60 nM in plasma, were analysed on both columns. GLC analysis yielded baseline resolution of the analytes. The method using the dimethyl polysiloxane column gave a lower limit of detectability for GTN of 0.75 nM (signal/noise (s/n) = 2), and the procedure using the phenyl-methyl column provided a lower limit of detectability for ISDN of 81 pM (s/n = 2). The large-bore column GLC procedures exhibited shorter retention times for both ISDN and GTN than those previously reported for capillary-column assays. The chromatographic resolution of analytes and column efficiency of the large-bore capillary columns were comparable to the results previously found using capillary-column GC. The assays for ISDN and GTN have been shown to be appropriate for pharmacokinetic studies in volunteers and patients. We determined that the HP-1 column is appropriate for the analysis of GTN and metabolites, and the DB-17 column is suitable for analysis of ISDN and its metabolites. We conclude that the use of large-bore capillary columns provides rapid and reliable GLC assays for organic nitrates.

Diltiazem dose responses in sustained therapy for stable angina pectoris.

Fifteen patients with stable effort angina were treated for 2 weeks with each of diltiazem 120 mg, 240 mg, 360 mg or placebo in a double-blind crossover protocol. The frequency of angina was decreased from 7.2 +/- 1.1 (mean +/- S.D.) episodes per 2 weeks with placebo to 5.9 +/- 5.2 (N.S.), 4.1 +/- 1.1 (p less than 0.01) and 1.5 +/- 0.8 (p less than 0.005) with 120 mg, 240 mg and 360 mg diltiazem respectively. Similar decreases occurred in nitroglycerin consumption. Ten hours after the last dose of each treatment period, each patient was challenged with 120 mg diltiazem. Treadmill exercise testing was carried out at 0, 1, 2, 4 and 8 hours. Time to onset of angina and 0.1m V ST depression increased at 1 hour, was maximal at 2 and 4 hours, and remained elevated at 8 hours. Two weeks of sustained treatment with diltiazem did not alter the responses in treadmill performance to 120 mg diltiazem. Hemodynamic changes were consistent with decreased myocardial oxygen demand and increased myocardial oxygen supply by diltiazem. There was no significant attenuation of hemodynamic response with sustained therapy. Trough plasma levels of diltiazem at 10 hours following the last dose of sustained therapy varied in a dose-dependent manner. However, corresponding exercise tolerances were identical regardless of the plasma level. Peak drug levels at 4 hours following 120 mg aldo did not correlate with exercise performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial exercise testing in patients with effort angina: variable tolerance, fixed threshold.

To investigate the frequency and mechanism of variable threshold angina, seven treadmill exercise tests were performed in each of 28 patients with stable effort angina and exercise-induced ST segment depression. Each patient had tests at 8 AM on 4 days within a 2 week period and on 1 of these days had three additional tests at 9 AM, 11 AM and 4 PM. Time to 1 mm ST depression increased from 277 +/- 172 seconds on day 1 to 319 +/- 186 seconds on day 2, 352 +/- 213 seconds on day 3 and 356 +/- 207 seconds on day 4 (p less than 0.05). Rate-pressure product at 1 mm ST depression remained constant. Similarly, time to 1 mm ST depression increased from 333 +/- 197 seconds at 8 AM to 371 +/- 201 seconds at 9 AM and to 401 +/- 207 seconds at 11 AM and decreased to 371 +/- 189 seconds at 4 PM (p less than 0.01). Again, rate-pressure product at 1 mm ST depression remained constant. The standard deviation for time to 1 mm ST depression, calculated as a percent of the mean for each patient's seven tests and then averaged for the entire group, was 22 +/- 11%. The standard deviation for rate-pressure product at 1 mm ST depression, calculated in the same way, was significantly less at 8.4 +/- 2.8% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose response effects of diltiazem on treadmill tolerance in chronic stable angina: a randomized double-blind, placebo-controlled crossover trial.

Sixteen patients with stable angina underwent treadmill exercise on 4 separate days prior to and at 1, 2, 4 and 8 hours following a single dose of 30 mg, 60 mg or 90 mg of diltiazem or identical placebo. Prolongation of exercise time to the onset of angina, 0.1 mV ST depression and to maximal exercise developed within 2 hours, peaked at 4 hours and persisted for 8 hours. Time to angina at control with placebo and 90 mg of diltiazem was 399 +/- 176 and 368 +/- 193 seconds respectively (X +/- SD) and 4 hours post drug was 474 +/- 216 and 635 +/- 209 seconds respectively (p less than 0.001). The pressure-rate product at angina 4 hours following 90 mg of drug was higher than after placebo (189 +/- 48 and 168 +/- 44 mmHg-1 X 10(-2) respectively). Heart rate increased (127 +/- 24 vs. 117 +/- 19 bpm) while systolic pressure was unchanged (147 +/- 17 and 142 +/- 21 mmHg). During submaximal exercise at a fixed work load, diltiazem, 90 mg, decreased heart rate from 114 +/- 14 to 97 +/- 18 bpm (p less than 0.005), systolic blood pressure from 148 +/- 19 to 135 +/- 18 mmHg (p less than 0.005) and rate-pressure product from 169 +/- 37 to 131 +/- 36 mmHg-1 X 10(-2) (p less than 0.005). Peak diltiazem plasma levels occurred at 4 hours, being 37 +/- 34, 74 +/- 67 and 106 +/- 68 ng/ml for 30, 60 and 90 mg respectively. Drug levels paralleled increased exercise tolerance when mean data were considered; however, correlation on an individual basis was poor.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitroglycerin-induced coronary vasoconstriction.

Nitroglycerin is routinely used during coronary angiography for its vasodilating effects. An unusual case is described in which nitroglycerin induced severe coronary artery spasm. Interpretation of coronary angiograms after nitroglycerin should be made with caution.

The impact of an ECG computer analysis program on the cardiologist's interpretation. A cooperative study.

Nine experienced electrocardiographers and the ECG computer program developed in the Veterans Administration (AVA 4.0) were evaluated against ECG-independent evidence of 180 patients' true diagnoses. A cross section of cardiac abnormalities was included. Each reader was given the 12-lead and orthogonal 3-lead ECG. The impact of ECG computer reports on the interpretations by the nine readers was evaluated by comparing their interpretations before and after the addition of a computer report. Using only high probability statements, the average accuracy of ECG diagnosis by the nine readers was 54%. It increased to 62% when the computer report was added. Computer interpretation was correct in 76%. It was shown that the Bayesian classification method together with multivariate analysis, used in the VA program, are mainly responsible for the improvement in diagnostic accuracy.

Exercise and the asymptomatic individual: assessment and advice.

With the current popularity of physical fitness, the family physician is often asked to advise asymptomatic individuals who wish to undertake an exercise program. In the majority of cases, adequate assessment consists of a thorough history and physical examination, along with a few simple investigations, including a resting electrocardiogram. Exercise stress testing of asymptomatic individuals produces an unacceptably high frequency of false-positive results, and its use should be restricted to those patients with cardiac symptoms or major cardiac risk factors. The potential benefits of a longterm commitment to regular exercise should be discussed with the patient and guidance provided on the optimal form of exercise program for that individual. Exercise must not be considered in isolation. Other major cardiovascular risk factors should be sought and dealt with appropriately.

Effects of barbiturate anesthetics and ketamine on the force-frequency relation of cardiac muscle.

The effects of ketamine and barbiturates (pentobarbital, thiopental, methohexital) were studied in an isolated rabbit Langendorff preparation. All agents tested depressed contractility. Ketamine, as well as the lipophilic barbiturates (thiopental, methohexital), caused a relatively greater depression at higher pacing rates such that the force-frequency relation was reversed. Pentobarbital did not reverse Bowditch. The effects of barbiturates on Bowditch correlated directly with lipid solubility, suggesting that their rate-related effects are due to perturbation of the membrane lipid bilayer. Disruption of hydrogen bands between polar membrane components may also be involved. The time course of the effect of thipental at high pacing rates was slower, both in onset and recovery, than at low rates. At a pacing rate of 1 Hz, maximal depression of contraction developed within 5 min. However, at 2.5 Hz, contractility continued to decline for up to 30 min. After 5 min of perfusion with thiopental, Bowditch was still positive, but by 30 min it was reversed. These temporal differences in thipental effects suggest that different mechanisms may dominate in the support of contractility at different ranges of heart rate.

The impact of the computer-reported vectorcardiogram on the cardiologist interpreter of the scalar electrocardiogram.

The purpose of this study was to determine if the computer-reported vectorcardiogram (VCG) had a notable impact on the cardiologist interpreter of the 12-lead scalar electrocardiogram (ECG). Three cardiologists read 100 12-lead scalar ECGs and four months later again read the same tracings while having available the VCG computer report. The diagnosis was altered in 25% of the repeated interpretations. Forty-five per cent of these had only minor changes and can probably be disregarded. Major or significant changes occurred in 14% of the records, and 80% of these were apparently attributable to the computer report. It was concluded that the use of a computer-assisted interpretation of a VCG may enhance the uniformity and consistency of the cardiologist's interpretation of the scalar ECG.

Problems in management of the pregnant patient with rheumatic heart disease and valve prosthesis.

The clinical course, through pregnancy and delivery, of a 30-year-old woman with rheumatic heart disease and a prosthetic mitral valve is presented. Despite maternal development of congestive cardiac failure and atrial fibrillation, the delivery of a healthy infant was achieved. The problems encountered during pregnancy and delivery in patients with rheumatic heart disease and prosthetic valves are discussed. These include the management of long-term anticoagulant therapy, prophylaxis against rheumatic fever and subacute bacterial endocarditis, impaired cardiac function, atrial fibrillation, breast feeding, and contraception as they relate both to the mother and the fetus and infant.

Electrocardiographic changes in precordial leads during selective coronary angiography.

Precordial electrocardiographic leads V1, V2, V5, V6, and limb leads I and II were recorded simultaneously utilizing radio transparent electrodes and wire leads during coronary angiography in 35 patients with obstructive coronary disease and in 17 subjects with normal coronary angiograms. The pattern of electrocardiographic changes produced by injection of contrast material into either the right or left coronary artery was similar in both groups of patients. During injections into the left coronary artery a leftward shift of the QRS occurred. Injections into the right coronary artery also produced a leftward shift of depolarization forces but, in addition, the QRS became inferiorly directed more consistently than during left coronary injections. The changes produced by angiography in the pattern of repolarization consisted of a marked increase in T wave amplitude and the transient appearance of large U waves. The changes in T waves were consistently opposite in direction to those of the QRS. The polarity of the U wave coincided with that of the T wave in the majority of cases. No consistent differences in the pattern of electrocardiographic changes were observed in subjects with a dominant right coronary artery from those with a dominant left system nor in subjects with normal coronaries from those with occlusive coronary disease.

Antigenic differences in (Na+, K+)-ATPase preparations isolated from various organs and species.

Antisera to purified (Na+, K+)-ATPase raised in rabbits and in sheep were purified by an absorption procedure employing purified canine kidney (Na+, K+)-ATPase. The antibodies were fractionated into two components, one which inhibited catalytic activity, and a second which inhibited ouabain binding. Under certain conditions, the fraction that inhibited ouabain binding also inhibited catalytic activity, and the effectiveness of both was dependent to some extent on the ligands present in the incubation medium. Thus, both antibody fractions appeared to detect conformations of the enzyme that depended upon ligand-induced perturbations. When the antibody raised against catalytic activity was incubated with erythrocyte membrane fragments, an inhibition of the (Na+, K+)-ATPase occurred, but only minimal or no effect on potassium influx or on digoxin-induced inhibition of potassium flux in intact erythrocytes was noted. In a similar experiment, however, the antibody against ouabain binding significantly inhibited potassium influx, suggesting specificity in terms of the macromolecular surfaces of the pump which were exposed to the external medium. We concluded that there may be organ and species differences among (Na+, K+)-ATPase preparations. Antibodies prepared in rabbits and sheep were fractionated by absorption to dog brain enzyme. Both the antibody fraction which bound to the brain enzyme and that which did not bind inhibited the dog kidney (Na+, K+)-ATPase, but only the former inhibited dog brain (Na+, K+)-ATPase. When the two fractions were recombined, inhibition was restored to the extent of the unfractionated antibody.

Effects of an antibody to a highly purified Na+, K+-ATPase from canine renal medulla: separation of the "holoenzyme antibody" into catalytic and cardiac glycoside receptor-specific components.

An antiserum was prepared against a highly purified Na(+), K(+)-adenosine triphosphatase (ATP phosphohydrolase, EC 3.6.1.3). Purification and fractionation yielded two globulin components, one of which appears specific for a digitalis glycoside receptor site or binding conformation and the other for a catalytic site or conformation.