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Effect of Mibefradil on Left Ventricular Diastolic Function in Patients with Congestive Heart Failure

Muntinga, H.*; van der Vring, J.*; Niemeyer, M.*†; van den Berg, F.*; Knol, H.§; Bernink, P.*; van der Wall, E.; Blanksma, P.; Lie, K.

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Journal of Cardiovascular Pharmacology: May 1996 - Volume 27 - Issue 5 - p 652-656
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Abstract

As a result of myocardial infarction, congestive heart failure can develop; due primarily to diastolic dysfunction or to a combination of diastolic and systolic dysfunction of the left ventricle (1-3). Diastolic dysfunction, in this context, implies that the left ventricle is not able to accept blood at low pressures (1,4,5). Pulmonary congestion can thus develop (1,4,5). The use of calcium antagonists for the treatment of stable angina in patients with such a condition can be hazardous because of a potential deterioration of systolic function (6-8). This may not necessarily be true in the case of second- and third-generation calcium antagonists, which might actually benefit diastolic function in coronary artery disease (2,8,9).

Mibefradil, a calcium antagonist from a new chemical structural class of benzimidazolyl-substituted tetraline derivatives, has been shown to possess strong antianginal properties (10). In addition, no deterioration of systolic function has been reported in patients with chronic stable angina pectoris or in rats with chronic myocardial infarction (10,11). To date, no reports concerning the effects of mibefradil on systolic and diastolic left ventricular function in patients with chronic heart failure have been published. The effects of mibefradil on diastolic left ventricular function in patients with congestive heart failure due to earlier myocardial infarction were investigated in the present study.

PATIENTS AND METHODS

Fifteen patients with chronic congestive heart failure (NYHA class II or III) were included in the study. More than 3 months before the study, all patients had myocardial infarction that resulted in a left ventricular ejection fraction (EF) ≤40%. Exclusion criteria included unstable angina pectoris; clinically significant valvular disease, including mitral regurgitation; hypertrophic obstructive or dilated cardiomyopathy; moderate or uncontrolled hypertension; clinically significant arrhythmias or bradycardia; and first- or higher degree atrio-ventricular (AV) block.

Study design

On day 1 of investigation, patients were randomized in a double-blind design for their study medication, which was either placebo (group I, 5 patients) or mibefradil (group II, 10 patients). Patients receiving mibefradil were randomly assigned in pairs to different dose groups. Six patients received mibefradil in the relatively low doses of 6.25, 12.5, and 25 mg/day (group IIA). The remaining 4 patients received the higher doses of 50 and 100 mg/day mibefradil (group IIB). They then underwent multigated nuclear angiography at ≈10 a.m. Three hours later (1 p.m.), they underwent a second nuclear angiography. For the next 7 days, patients received their study medication once daily. On day 8, a multigated nuclear angiogram was made before and 3 h after ingestion of the last study tablet (10 a.m. and 1 p.m.). During nuclear angiography, resting systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were also obtained. Mean arterial pressure (MAP) was then calculated.

Nuclear angiography

Some of each patient's red blood cells were labeled with 99m technetium-pertechnetate after intravenous administration of stannous pyrophosphate. The total dosage range was 550-740 MBq. Left ventricular function was evaluated by radionuclide angiography with a γ-camera (Siemens Orbiter) with an all-purpose parallel-hole collimator, interfaced with a Pinnacle computer (Medasys, Ann Arbor, MI, U.S.A.). Multigated images supine rest position were obtained in the left anterior oblique view with a caudal tilt, so that both left and right ventricles appeared separated. Only a 5% cycle-length window with forward gating was accepted (12). Acquisition was completed after 150,000 counts per frame of 20 ms. Temporal smoothing was achieved with five Fourier harmonics (13,14).

Measurements

From the systolic part of the left ventricular time-activity curve (TAC) we measured the EF and the peak ejection rate (PER). The diastolic parameters included the peak filling rate (PFR) and the time to peak filling rate (t-PFR). PFR was normalized to end-diastolic volume as well as stroke volume. Atrial contribution (AC) was measured as a percentage of the diastolic filling volume.

Statistical analysis

Measured data are mean ± 1 SD unless otherwise stated. For statistical analysis a model of repeated measures analysis of variance was used since the same variable was obtained on several occasions. In this design, the variability due to differences between subjects can be eliminated from the experimental error. A p-value < 0.05 was considered statistically significant. We tested the differences in the means with the various mibefradil dosages. In the case of an immediate effect of mibefradil on the tested parameters, we would expect a third-order polynomial for group II, which would be more pronounced in group IIB patients, who received the higher dosage. In the case of a delayed medication effect, we would expect a linear change in the parameters of group II.

RESULTS

Patients

The patients' baseline characteristics are shown in Table 1. All calcium antagonists and β-blocking agents were withdrawn at least 5 half-lives before trial. All other oral medication was continued. At baseline, there were no statistically significant differences among the three groups.

Effects of mibefradil on MAP, HR, and EF

Table 2 shows the effects of mibefradil on HR, MAP, and EF. HR was decreased by mibefradil (p < 0.05). The bradycardic effect was evident only after 1-week treatment in the high-dose group (Fig. 1). Mibefradil had no effect on SBP, DBP, MAP, EF, or PER.

Effects of mibefradil on the diastolic nuclear angiographic parameters

Effects of mibefradil on the diastolic nuclear angiographic parameters are summarized in Table 3. Mibefradil had no statistically significant effect on PFR, both when normalized to end-diastolic counts or to stroke counts (Fig. 2A and B). Mibefradil had no effect on AC (Fig. 3) or t-PFR.

DISCUSSION

We investigated the effects of mibefradil on diastolic left ventricular function in patients with heart failure and decreased EF due to previous myocardial infarction. We assessed diastolic function by measuring various indexes (PFR, t-PFR, and AC) of diastole using nuclear angiography. We also measured several indexes of systolic function by this technique (EF and PER).

The interpretation of diastolic parameters in patients with systolic dysfunction is complex. Not only physiological variations such as HR and BP can influence the outcome of measurements on diastolic function (13,15-17), but methodological aspects such as gating mode and normalization parameters in radionuclide angiography must also be taken into account in the study of diastolic parameters (12-14,17,18). Interpretation of these parameters must therefore be made with great caution. In standardized conditions, however, diastolic parameters in patients with systolic dysfunction are likely to be reproducible.

Our data show that mibefradil had a statistically significant effect on HR, especially in the dosages of 50 and 100 mg/day. No such effect was noted at dosages of 6.25-100 mg/day on either systolic or diastolic parameters or BP.

In previous studies of patients with chronic heart failure, adverse reactions of short-term treatment with calcium antagonists on systolic function had been emphasized (6-8). The observed systolic deterioration may not occur in treatment with second-generation calcium antagonists, however (7,8). These results are in agreement with ours, which showed no statistically significant effect of mibefradil on EF or PER.

The effect of calcium antagonists in heart failure on diastolic function has not been extensively reported but a stabilizing and beneficial effect has been recorded in several studies (1-3,9); an effect probably due either to the negative chronotropic or to the coronary vasodilator properties of calcium antagonists (1,9). Negative chronotropic properties afford more time for production of increased left ventricular filling, whereas vasodilation achieves a better balance between myocardial oxygen demand and supply. This is likely to be an important mechanism in the improvement of diastolic function in patients with coronary artery disease after coronary angioplasty or bypass surgery (19,20) and could also be an important mechanism in the improvement of diastolic function after administration of oral calcium antagonists in patients with recent myocardial infarction and decreased left ventricular systolic function (9). Coronary vasodilation was also observed in anesthetized dogs during ischemia after intravenous mibefradil administration (21). Moreover, in stable angina in humans, mibefradil proved effective in doses of 50, 100, and 200 mg/day (10). Whether vasodilation plays a role in chronic heart failure due to old myocardial infarction remains uncertain.

Our present data showed no evidence of improvement or worsening of diastolic function after short-term mibefradil administration in patients with severely decreased systolic function, possibly because it was administered in relatively low doses. However, neither was any direct effect on PFR noted in group IIB. The combined data suggest that short-term administration of the new calcium antagonist mibefradil is relatively safe in patients with coronary artery disease and decreased left ventricular function. Long-term mibefradil treatment of patients with heart failure remains to be investigated, however. The mechanism of the unfavorable effects of calcium antagonists in long-term treatment of patients with heart failure is probably multifactorial (8). Mibefradil probably has less negative inotropic effect than most calcium antagonists (11). However, the possible role of unfavorable neurohormonal activation in patients with heart failure when treated with mibefradil is not yet clear. Therefore, more research is needed in a larger study group, with adequate doses for the treatment of angina pectoris, to allow more definite conclusions on the safety of mibefradil in patients with heart failure to be drawn.

As compared with a control group of patients who received placebo medication, patients receiving mibefradil exhibited a clear statistically significant effect of the drug on HR, but no effect on BP or systolic and diastolic left ventricular function. We conclude therefore that short-term administration of mibefradil in patients with heart failure due to previous myocardial infarction is probably safe.

Acknowledgment: The authors wish to thank H. Louwes and H. Schuurman from the Department of Nuclear Medicine of the Martini Hospital in Groningen for their technical support.

FIG. 1
FIG. 1:
. Heart rate (HR) on day 1 before and 3 h after medication intake and after 1 week of treatment before and 3 h after the last medication intake. Mibefradil caused a statistically significant decrease in HR (p < 0.05). Placebo (ovals), low-dose mibefradil (inverted triangles), high-dose mibefradil (triangles).
FIG. 2
FIG. 2:
. Peak filling rate (PFR), normalized to end-diastolic volume (EDV) (A) and to stroke volume (SV) (B) on day 1 before and 3 h after medication and after 1 week of treatment before and 3 h after the last medication intake. Mibefradil had no statistically significant effect on either parameter. Placebo (ovals), low-dose mibefradil (inverted triangles), high-dose mibefradil (tringles).
FIG. 3
FIG. 3:
. Atrial contribution to diastolic filling (AC). On day 1 before and 3 h after medication and after 1 week of treatment before and 3 h after the last medication intake. Mibefradil had no statistically significant effect on this parameter. Placebo (ovals), low-dose mibefradil (inverted triangles), high-dose mibefradil (triangles).

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Keywords:

Calcium antagonists; Mibefradil; Heart failure; Diastolic function

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