Shirley Krikler

Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes

In thirty patients with stable angina and positive exercise tests, ambulatory ST segment monitoring was used to record episodes of transient myocardial ischaemia during daily life. All patients had four consecutive days of monitoring and in 20 patients long-term variability was assessed by repeated 48 hour monitoring and exercise testing over 18 months. There were 1934 episodes of rectilinear or downsloping ST-depression (911, 1 mm; 638, 2 mm; 385, greater than 3 mm) in 446 days of recording, of which only 470 (24%) were accompanied by angina. Positron tomography showed evidence of regional myocardial ischaemia during both symptomatic and asymptomatic ST depression. On average, heart rate at the onset of both symptomatic and asymptomatic ST episodes was significantly lower than the rate at the onset of ST depression during exercise testing (98 +/- 20.5 vs 124 +/- 17 beats/minute). Heart rate rose by more than 10 beats in the minute preceding ST depression in only 23% of episodes. Over 18 months, 8 (40%) patients exhibited marked variability in the number of daily ST episodes. Variability of ST depression was consistently underestimated by symptoms and not reflected by exercise testing. Thus, patients with stable angina showed frequent, variable, and often asymptomatic electrocardiographic evidence of ischaemia. Heart rate increase was not common before myocardial ischaemia, suggesting that, in such patients, transient impairment in coronary supply may be at least as important as excessive increase in demand in the genesis of ischaemia during daily life.

Nifedipine and propranolol: A beneficial drug interaction

The antianginal effects of two active drugs, nifedipine and propranolol, alone in combination, were compared with those of placebo in a double-blind clinical trial that included 16 patients with chronic stable angina triggered by exertion. A low dose and a high dose of the active drugs were used (nifedipine, 30 and 60 mg/day; propranolol, 240 and 280 mg/day). Precordial exercise mapping and continuous electrocardiographic recordings were used to assess objective response to therapy, and the patients were asked to keep a diary of episodes of chest pain and consumption of nitroglycerin tablets for subjective appraisal. Both frequency of chest pain and nitroglycerin consumption were significantly reduced by each of the active drugs when compared with placebo, and the combination of nifedipine and propranolol added significantly to the effectiveness. Reductions in area of ischemia and number of episodes of ST segment depression on 48-hour ambulatory electrocardiographic monitoring corroborated the efficacy of each active treatment with respect to placebo. Nearly 60 percent of all episodes of ST segment depression were painless and responded to the active treatment in the same manner as did the episodes associated with chest pain. Side effects were mild and all treatments were well tolerated. The objective methods used allowed for clear-cut differentiation of treatment effects with the various regimens. Although the two drugs alone were significantly more effective than placebo, their combination provided an even greater improvement (p less than 0.005), and therefore it appears to be a safe and effective form of treatment for chronic stable angina.

Analysis of ST-Segment Changes in Normal Subjects: Implications for Ambulatory Monitoring in Angina Pectoris

Continuous monitoring of the electrocardiogram in patients with angina pectoris and coronary artery disease (CAD) has shown episodes of asymptomatic ST-segment depression, suggesting frequent silent myocardial ischemia during normal daily life. Interpretation of this new finding depends on whether similar changes occur in normal subjects. Frequency-modulated ambulatory electrocardiographic recordings were performed in 80 asymptomatic normal volunteers (20 from each decade between 20 and 50 years and, 20 more than 50 years old) and in 20 patients with noncardiac pain, negative exercise and provocative tests and angiographically normal coronary arteries. Treadmill exercise testing was performed in all subjects more than 40 years old. Episodes of T-wave change were identified in 53 subjects. Five subjects younger than 40 years had episodes of ST elevation that were prolonged; they usually occurred at night. In 3 patients they could be reproduced by postural change. Only 2 subjects, both older than 40 years had planar ST depression during tachycardia; one of these subjects had a positive exercise test response. No patient with normal coronary arteries had significant ST depression. Tachycardia was frequently associated with upsloping ST depression (36%), which was more common in younger subjects: Five subjects also showed isolated single complexes with ST depression during baseline instability. With use of frequency-modulated recordings, transient ST depression of 0.1 mV or greater that lasted 80 ms or longer and more than 30 seconds in duration, was rare in a normal population. This finding supports the use of this signal to follow the activity of CAD out of the hospital, specifically in patients with typical angina and proved CAD.

A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy

OBJECTIVES The aim of this study was to determine whether therapy with a beta-adrenergic or calcium channel blocking agent can improve the functional capacity and quality of life of patients with mild or moderately symptomatic hypertrophic cardiomyopathy. BACKGROUND Both beta-blockers and calcium channel blockers may alleviate symptoms in hypertrophic cardiomyopathy, but previous studies have been performed in hospitalized patients or have been open studies without control subjects. METHODS A randomized, double-blind crossover trial of nadolol, verapamil and placebo, administered for periods of 4 weeks each, was performed in 18 patients with mild or moderately symptomatic hypertrophic cardiomyopathy (10 men, 8 women; mean age +/- SD 39 +/- 17 years). A detailed symptom assessment, bicycle exercise testing, echocardiography and Holter monitoring were performed in each period. RESULTS Two patients withdrew from the study owing to symptomatic sinus bradycardia during nadolol therapy. Neither drug improved maximal oxygen consumption (placebo 26 +/- 8, verapamil 23 +/- 6, nadolol 21 +/- 7 ml/kg per min; p = 0.1). Peak exercise work load was reduced by > or = 10 W in 13 patients (81%) during nadolol therapy and in 4 patients (25%) during verapamil therapy (p = 0.005, nadolol vs. verapamil). Despite the effects on exercise capacity, 13 patients (81%) preferred drug treatment (8 verapamil, 5 nadolol) over placebo (p = 0.001). Verapamil improved reported performance at work compared with nadolol (p = 0.01) and tended to improve other measures of health-related behavior and symptoms compared with nadolol and placebo. CONCLUSIONS In patients with mild or moderately symptomatic hypertrophic cardiomyopathy, exercise capacity was not improved by nadolol or verapamil, and individuals were more often impaired by nadolol than with verapamil. Nevertheless, many patients derived symptomatic benefit from drug therapy, especially with verapamil.

Cigarette Smoking and the Treatment of Angina with Propranolol, Atenolol, and Nifedipine

To determine whether cigarette smoking affects the results of drug treatment for angina, we studied 10 cigarette smokers with angina who were given placebo, nifedipine (60 mg per day), propranolol (240 mg per day), and atenolol (100 mg per day), each for one week. The four-week double-blind study was repeated with the same randomly determined order of drug sequences, after all 10 subjects had stopped smoking. Before and after the subjects stopped smoking, all three drugs significantly reduced the frequency of angina, as measured with angina diaries, and improved the results of maximal exercise testing and 48-hour ambulatory monitoring of ST segments (P less than 0.01). However, during the nonsmoking phase of the study, there was an overall decline in the frequency of angina and an improvement in performance on exercise testing (P less than 0.05) as compared with the smoking period, although the results of 48-hour ambulatory monitoring remained unchanged. The improvement after patients stopped smoking was greater during treatment with nifedipine than during administration of the other two drugs or placebo. Blood levels of propranolol were increased when patients stopped smoking; levels of nifedipine and atenolol were unchanged. Our data show that smoking had direct and adverse effects on the heart and interfered with the efficacy of all three anti-anginal drugs, but with nifedipine the most.

Placebo controlled trial of xamoterol versus digoxin in chronic atrial fibrillation.

Thirteen patients in chronic atrial fibrillation with a normal resting heart rate but with exercise tachycardia and episodes of bradycardia were randomised to treatment periods of two weeks on xamoterol (200 mg twice daily), low dose digoxin, or placebo, in a blind crossover study. The results (mean SEM) of symptom scores, a treadmill exercise test, and 24 hour ambulatory electrocardiographic monitoring were obtained. Xamoterol improved symptom scores and controlled exercise heart rate better than digoxin. Xamoterol was better than digoxin or placebo in reducing the heart rate response to exercise and tended to improve exercise duration. Xamoterol, by reducing the daytime maximum hourly heart rate and increasing the night time minimum hourly heart rate, significantly reduced the difference between the two compared with placebo. In contrast, digoxin tended to reduce both the maximum and minimum hourly heart rates through day and night. Both the frequency and duration of ventricular pauses were reduced by xamoterol but tended to increase with digoxin. Xamoterol reduced both the circadian variation in ventricular response to atrial fibrillation and exercise tachycardia by modulating the heart rate according to the prevailing level of sympathetic activity. These changes were translated into symptomatic benefit for the patients studied.

Effects of lisinopril on cardiorespiratory, neuroendocrine, and renal function in patients with asymptomatic left ventricular dysfunction.

OBJECTIVE--To determine the cardiac, renal, and neuroendocrine effects of lisinopril in men with untreated, symptom free left ventricular systolic dysfunction. DESIGN--A randomised, double blind cross over trial with six week treatment periods to compare lisinopril (10 mg/day) and matching placebo. SETTING--Hospital outpatient department. PATIENTS--Patients with pronounced systolic dysfunction on cross sectional echocardiography due to myocardial infarction at least six months previously, without angina and with no or minimal breathlessness. Eighteen men were identified of whom 15 completed the study. INTERVENTIONS--Lisinopril (10 mg) or placebo given once daily by mouth. MAIN OUTCOME MEASURES--Primary: oxygen consumption at peak exercise. Secondary: resting cardiac function as measured by radionuclide ventriculography and echocardiography, renal function estimated radioisotopically, and plasma indices of neuroendocrine activity. RESULTS--Compared with placebo, lisinopril increased (mean (SD)) peak oxygen consumption during exercise (19.8(3.1) ml/kg/min v 21.4(3.2) ml/kg/min; p < 0.003). Lisinopril did not improve indices of cardiac function at rest. It reduced plasma concentrations of angiotensin II (median values 7 pg/ml to 5 pg/ml; p < 0.02), aldosterone (median values 113 pg/ml to 66 pg/ml; p < 0.05) and atrial natriuretic peptide (median values 69 pg/ml to 40 pg/ml; p < 0.04), but noradrenaline and antidiuretic hormone concentrations did not change. Renal blood flow increased and glomerular filtration rate declined. CONCLUSIONS--Even before the onset of heart failure lisinopril improves the cardiopulmonary response to exercise in patients with systolic ventricular dysfunction.

Angiotensin-converting enzyme inhibitors, left ventricular dysfunction, and early heart failure

A study was undertaken to examine the effects of the angiotensin-converting enzyme inhibitor lisinopril on exercise performance in 18 patients with major impairment of left ventricular systolic function. The study was a randomized, double-blind, crossover design, and patients received treatment with either once-daily lisinopril (2.5-10 mg) or placebo for a period of 6 weeks. A total of 15 patients completed the study. Compared with placebo, lisinopril had no significant effect on supine or standing blood pressure or heart rate. Although lisinopril had no effect on exercise duration during a low-intensity exercise protocol, in patients undergoing a high-intensity exercise protocol, there was a trend toward improved exercise time and peak oxygen consumption improved significantly. In addition, treatment with lisinopril resulted in an increase in renal blood flow and a reduction in glomerular filtration rate. Moreover, administration of once-daily lisinopril 10 mg resulted in a decrease in plasma concentrations of angiotensin II, aldosterone, and atrial natriuretic peptide, and an increase in plasma concentrations of active renin.

Comparative study of the effect of nifedipine versus diltiazem on exercise performance, serum propranolol levels, and ST-segment abnormalities in patients with chronic stable angina taking propranolol

Twelve patients (10 men and 2 women), mean age 60.6 years (range 50 to 75), with stable angina pectoris were administered propranolol until beta blockade was evident. Treadmill exercise testing was performed, 24-hour ambulatory electrocardiograms were recorded, and serum propranolol levels were assessed at 1 and 2 hours after dosing with propranolol alone, and after 2 weeks of combined therapy with either nifedipine, 10 or 20 mg, or diltiazem, 60 or 120 mg, administered every 8 hours. Patients were assigned to treatment regimens in randomized, double-blind, crossover fashion. At the time of exercise testing, maximal exercise time, time to angina, peak exercise heart rate and systolic blood pressure and time to 1 mm of ST-segment depression were measured. The rate-pressure product was also calculated. Maximal exercise time increased from 708 +/- 140 seconds with propranolol alone to 795 +/- 156 seconds after combined propranolol-nifedipine therapy (p less than 0.05), and to 790 +/- 107 seconds (p less than 0.05) after propranolol-diltiazem therapy. Time to onset of angina increased from 472 +/- 191 seconds with propranolol alone to 564 +/- 123 seconds (p = NS) after propranolol-nifedipine treatment and to 607 +/- 197 seconds (p less than 0.05) after propranolol-diltiazem treatment. Peak exercise heart rate remained unchanged with propranolol-nifedipine therapy (103 +/- 16 beats/min vs 104 +/- 17 with propranolol alone). However, with propranolol-diltiazem therapy, peak exercise heart rate significantly decreased to 95 +/- 14 beats/min (p less than 0.05); peak systolic blood pressure and rate-pressure products were comparable on all treatment regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of PY 108-068, A new calcium channel blocker, for angina pectoris

The efficacy of PY 108-068 (75 and 150 mg/day), a new dihydropyridine calcium antagonist, was compared with placebo for treatment of chronic stable angina. Twelve patients were studied in a placebo-controlled, double-blind, randomized, crossover trial of 2 weeks each. Antianginal efficacy was assessed by the number of episodes of angina and nitroglycerin tablets consumed during each 2-week period, as well as the number of episodes of ischemia during 48-hour ambulatory monitoring and the area and severity of ST-segment depression during 16-point precordial exercise mapping. Nitroglycerin consumption (mean +/- standard error of the mean) decreased from 6.1 +/- 2.9 with placebo to 1.8 +/- 1.5 with 75 mg/day of PY 108-068 (p less than or equal to 0.03) and to 3.6 +/- 2.3 with 150 mg/day of PY 108-068 (p less than or equal to 0.01 vs placebo, difference not significant vs 75 mg/day of PY 108-068), whereas episodes of angina were reduced significantly only by the high dose (p less than or equal to 0.03) (11.1 +/- 3.9 with placebo, 6.3 +/- 2.4 with 75 mg/day of PY 108-068 and 8.1 +/- 3.4 with 150 mg/day of PY 108-068). The low dose alone significantly reduced ST-segment depression during exercise testing (p less than or equal to 0.03) (29.6 +/- 3.6 with placebo, 23.1 +/- 5.6 with 75 mg/day of PY 108-068 and 24.4 +/- 5.0 with 150 mg/day of PY 108-068), whereas neither dose significantly altered the number of episodes of ischemia during ambulatory monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)