Verapamil but not nifedipine impairs left ventricular function during exercise in hypertensive patients Calcium antagonists are popular therapeutic agents in the treatment of systemic hypertension. Although these agents have similar antihypertensive efficacy, they have varied effects on left ventricular function at rest in hypertensive patients. The effect of different calcium antagonists on left ventricular function during exercise and on exercise performance in patients with hypertension, however, is less clear. Fifteen patients with essential hypertension (diastolic blood pressure = 95 to 110 mm Hg) were enrolled in a placebo-controlled, single-blinded crossover study comparing nifedipine with verapamil for rest/exercise heart rate and blood pressure, exercise performance, and rest/exercise left ventricular function. Each drug was Utrated to achieve resting diastolic pressures less than 90 mm Hg. All patients underwent maximal exercise testing and rest/exercise gated radionuclide ventriculography at the end of 3-week placebo, nifedipine, and verapamil treatment periods. Both calcium antagonists significantly reduced blood pressure at rest and during exercise compared with placebo. Neither calcium antagonist altered resting hear t rate; however, both verapamil and nifedipine significantly reduced heart rate at maximal exercise. Verapamil but not nifedipine impaired left ventricular peak emptying rate and left ventricular peak filling rate during exercise but not at rest. Neither verapamil nor nifedipine, however, significantly altered rest or exercise global left ventricular ejection fraction (LVEF) compared with placebo. There was a trend, however, for impairment in the LVEF response to exercise (ALVEF) in the verapamil treatment group. Exercise capacity was not significantly altered by either calcium antagonist compared with placebo. Thus verapamil but not nifedipine impairs left ventricular function during exercise in hypertensive patients. The clinical relevance of this effect is unclear, since verapamil did not alter exercise performance. The effect of verapamil in hypertensive patients with impaired left ventricular function may warrant further study. (AM HEART J 1990;119:636.)

Roger C. Ashmore, MD, Linda K. Corkadel, RN, Carol L. Green, RN, and Lawrence D. Horwitz, MD. Denver, Colo. Calcium antagonists are popular therapeutic agents in systemic hypertension. These drugs promote systemic vasodilation by interfering with the mechanisms of excitation-contraction coupling in vascular smooth muscle. 1-3 Calcium antagonists also interfere with excitation-contraction coupling of cardiac muscle and cause a reduction in cardiac contractility. 4-6 The overall effect of calcium antagonists on cardiac contractility in vivo, however, is a balance between direct negative inotropic effects and indirect positive inotropic effects secondary to baroreceptor-mediated reflex sympathetic stimulation. 7, 8 From the Division of Cardiology, University of Colorado Health Sciences Center. This work was supported by the Corporate Heart Fund and by funds from Pfizer, Inc., New York, N.Y. Received for publication May 18, 1989; accepted Nov. 1, 1989. Reprint requests: Roger C. Ashmore, MD, Division of Cardiology, Box B 130, 4200 E. Ninth Ave., Denver, CO 80262. 4/1/18018

636

Different calcium antagonists are known to have varied pharmacodynamic effects in hypertensive patients at rest. Nifedipine is a potent vasodilator that significantly increases heart rate and slightly improves left ventricular systolic function, while verapamil, also a potent vasodilator, does not significantly alter heart rate or left ventricular systolic function. 7 Furthermore, in conscious dogs, verapamil but not nifedipine has been shown to impair left ventricular function during exercise. 9, 10 The varied effects of nifedipine compared with verapamil on left ventricular function during exercise may potentially cause differences in exercise performance. Although the effect of various calcium channel blockers on rest and exercise hemodynamics has been studied, 11-13 their effect on left ventricular function parameters and on exercise performance in hypertensive patients is less clear. The purpose of this study therefore was to compare two calcium antagonists with differing pharmacodynamic effects (nifedipine versus vera-

Volume 119

Verapamil/nifedipine effects on LVfunction

Number 3i Part 1

WASHOUT

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PLACEBO

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CALCIUM CALCIUM ANTAGONIST WASHOUT ANTAGONIST

l'* 7

i

11

14

I 18

TIME (WEEKS) i

= TESTING (REST/EXERCISE HEART RATE AND BLOOD PRESSURE, EXERCISE CAPACITY, AND REST/EXERCISELEFT VENTRICULAR FUNCTION).

Fig. 1. This figure outlines the design of the single-blinded, crossover study comparing nifedipine and verapamil with placebo.

pamil) in patients with mild to m o d e r a t e h y p e r t e n sion on: (1) rest/exercise h e a r t rate and blood pressure, (2) exercise capacity, a n d (3) rest/exercise left ventricular systolic and diastolic function. METHODS

Patients. Fifteen patients (10 men and 5 women, age range 34 to 65 years, mean age 47 years) with essential hypertension gave their informed consent to this study. In all patients, diastolic blood pressure was 95 mm Hg or greater (average systolic blood pressure was 148 _+ 4 mm Hg and average diastolic blood pressure was 98 + 4 mm Hg). All patients were in stage I or II of the World Health Organization (WHO) classification. Causes of secondary hypertension were excluded by routine investigations. No patient had clinically evident coronary artery disease or electrocardiographi.c criteria of left ventricular hypertrophy. Exclusion criteria included clinically significant hepatic dysfunction, creatinine greater than 2.0 mg/dl, myocardial infarction or cerebrovascular accident within the last 6 months, congestive heart failure or left ventricular ejection fraction less than 35 %, uncontrolled arrhythmias or second- or third-degree heart block, presence of orthostatic hypotension due to autonomic dysfunction, women of child-bearing potential, or previous intolerance to nifedipine or verapamil. Study design. The study consisted of a placebo-controlled, single-blinded crossover design comparing nifedipine with verapamil (Fig. 1). All patients underwent an initial pretreatment evaluation that included a 3-week placebo run-in phase with the patients not receiving any antihypertensive medications. Eligible patients entered a 3-week placebo phase followed by a 1-week testing period (rest/exercise heart rate and blood pressure and rest/exercise left ventricular function). Following baseline testing, the patients were randomized to either nifedipine or verapamil treatment groups. Patients then underwent a 3week titration period to lower diastolic blood pressure to less than 90 mm Hg. The patients randomized to nifedipine received 10 mg orally three times a day the first week while patients randomized to verapamil received 80 mg orally

three times a day. At the end of this week, if the diastolic pressure was not below 90 mm Hg, the dose of calcium antagonist was increased (nifedipine to 20 mg orally three times a day and verapamil to 160 mg). All patients achieved the desired diastolic blood pressure (