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Original Article

Cilnidipine Improves Left-Ventricular Midwall Function Independently of Blood Pressure Changes in Chinese Patients With Hypertension

Ma, Zhi-yong MD, PhD; Li, Li MD, PhD; Zhong, Xue-zhen MD; Tan, Hong-wei MD, PhD; Wang, Rong MD; Wang, Ying PhD; Zhang, Wei MD, PhD; Zhang, Yun MD, PhD

Author Information
Journal of Cardiovascular Pharmacology: January 2007 - Volume 49 - Issue 1 - p 33-38
doi: 10.1097/FJC.0b013e31802bfdee
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Abstract

INTRODUCTION

Left-ventricular (LV) systolic dysfunction predicts morbidity and mortality.1,2 LV systolic performance assessed by conventional methods, LV ejection fraction (EF) and endocardial fractional shortening (eFS), has been found to be normal or even supernormal in many patients with hypertension.3,4 However, experimental studies suggest that systolic function is depressed in hypertrophy and tended to involve the measurement of myocardial myofibril function.5,6 This paradox may be explained by the fact that in the presence of abnormal LV geometry, as often occurs in hypertensive subjects, EF does not accurately describe the contractile behavior of myocardium.

It is often assumed that the inner and outer parts of the LV wall thicken equally during systole. However, myocardial shortening in subendocardial layers is greater than that in subepicardial layers.7 Therefore, a theoretical midpoint in the wall shows relative migration toward the epicardium throughout contraction (Figure 1). There may therefore be a discrepancy between shortening at the endocardium and the midwall, and this has prompted recent interest in the measurement of midwall fractional shortening (mFS).7,8 There also are anatomic reasons why assessment of shortening at the midwall level may be preferred: circumferentially orientated fibers predominate here, unlike at the subendocardium and subepicardium, where most fibers are longitudinally orientated.9 So, LV midwall fiber shortening has been proposed as a more physiologically appropriate index of myocardial performance in systemic hypertension.8 mFS was impaired in the early stage of hypertension,8,10 and depressed mFS is a strong, independent predictor of adverse cardiovascular events.1,2 Little is known, however, about whether LV midwall systolic performance is reduced in Chinese patients with mild to moderate hypertension. Thus, initially, mFS among our patient population was compared with that of normotensive subjects.

FIGURE 1
FIGURE 1:
Epicardial migration of theoretical midwall fiber during systole.

Cilnidipine is a long-acting calcium channel blocker, which blocks not only L-type Ca2+ channels in blood vessel, but also the N-type Ca2+ channels in sympathetic nerve endings.13 Clinical studies demonstrate that cilnidipine is an effective antihypertensive drug and has been found to improve LV diastolic dysfunction.14 However, its effect on LV systolic function is unclear; thus our study also aimed to examine the effect of cilnidipine on LV midwall systolic function in Chinese patients with mild to moderate hypertension.

MATERIALS AND METHODS

Patients

Forty patients of either sex with essential hypertension were recruited from the cardiovascular outpatient clinic of QiLu Hospital, Shandong University. Enrollment criteria were as follows: (1) age range from 18 to 65 years, and (2) diastolic blood pressure (BP) between 95 and 109 mm Hg and systolic BP <180 mm Hg after a 2 week placebo run-in period. Exclusion criteria were as follows: (1) history and/or signs of cardiovascular complications (eg, heart failure, myocardial infarction, stroke, and/or angina pectoris) or major target-organ damage (eg, serum creatinine >1.5 mg/dL), (2) major cardiovascular or noncardiovascular disease besides hypertension, (3) pregnancy or lactation, (4) contraindications to the antihypertensive study drug(s), (5) conditions that would prevent the collection of technically adequate echocardiograms (eg, obesity or pulmonary emphysema), and (6) atrial fibrillation or other major arrhythmias.

Study Design

Patients undergoing existing antihypertensive therapy stopped all antihypertensive therapy, and all subjects underwent a 2 week placebo run-in period. During the 2 week placebo run-in period, each patient made 3 visits to the clinic. At the end of the run-in period, 37 patients (34 male, 3 female) were enrolled. Baseline BP was taken as the value obtained at the third visit just before the commencement of antihypertensive therapy. Each patient underwent a baseline echocardiography study. After the third visit, patients began a regimen of 5 milligrams per day of cilnidipine. If diastolic BP remained “uncontrolled” (>90 mm Hg) after 2 weeks, the dosage would be increased to 10 milligrams per day. After 8 weeks, an echocardiography study was repeated.

The control group consisted of 30 healthy subjects (25 male, 5 female) without a history of cardiac disease or systemic hypertension and having normal findings on physical examination, chest roentgenography, electrocardiography, and echocardiography. They also underwent an echocardiography study.

The study was approved by the Ethics Committee of QiLu Hospital, Shandong University, and all subjects gave informed consent.

Blood Pressure

BP was measured in an office setting by the conventional cuff method with a mercury manometer. Patients remained seated for at least 15 minutes before BP was measured, and measurement was taken in the morning before daily intake (ie, 8:00-10:00 AM). Three successive BP readings were obtained at averaged 2 minute intervals.

Echocardiography

Two-dimensionally guided M-mode echocardiograms were obtained as previously described with a Hewlett-Packard Sonos 7500 (Andovor, MA, USA) phased-array system by 1 operator who had no information of the study. All measurements were made according to American Society of Echocardiography guidelines.15 Three consecutive cardiac cycles were measured, and average values were obtained. LV mass (LVM) was calculated using Devereux's formula,16 and the LV mass index (LVMI) was obtained by dividing the LVM by body surface area.

Calculations

The following parameters were derived from the M-mode diastolic measurements of the interventricular septum (IVS), LV internal diameter (LVID), and posterior wall (PWT) and the systolic measurements of LV internal diameter (LVIDs) and posterior wall (PWTs).

Endocardial fractional shortening (eFS%) is calculated as follows:

Stroke volume was derived from diastolic and systolic LV volumes calculated with Teicholz's formula. Stroke volume = [7/(2.4 + LVID) × LVID3] − [7/(2.4 + LVIDs) × LVIDs3]

Ejection fraction (EF%) was also derived:

mFS was calculated by using a modified ellipsoidal model of LV geometry. This analysis has been previously described in detail.8 Briefly, 2 myocardial shells are constructed, which are set to have equal thickness in diastole. Assuming conservation of the volumes of each individual shell and of the LV wall throughout the cardiac cycle, particularly at diastole and systole, yields:

where H is the shell thickness, d is diastole, and s is systole. Because the 2 shells are constructed to have equal thickness in diastole, Hd = (PWTd + IVSd)/2, where PWT is the posterior wall thickness and IVS is the thickness of ventricular septum. During systole, the inner shell thickens more than the outer shell and there is epicardial migration of the midwall line (Figure 1). This can be demonstrated by solving the equation given earlier for Hs. mFS can then be calculated as follows:

Circumferential end-systolic wall stress (cESS) at the level of the minor axis was determined by the method of Gaasch et al17 and used as a measure of myocardial afterload. By using a cylindrical model and cuff systolic BP measured at the end of the echocardiogram, cESS is calculated from the following equation:

Calculated mFS was then compared with the value predicted from a linear relation obtained from a population of normotensive employed adults.8: Predicted mFS= 20.01 − 0.002 × cESS Then the afterload-corrected mFSc was expressed as a percentage of predicted shortening.

Statistics

Data are expressed as mean ± standard deviation (X ± SD). Student's t test was used to compare differences between groups, and the chi-square statistic was used for categorical variables. The changes in the measured variable with drug treatment were determined by 2-tailed paired Student's t test. Spearman's rank correlation coefficient was used to assess relationships between changes of mFS and BP. All statistical analyses were performed by software SPSS 11.0, and P < 0.05 was considered statistically significant.

RESULTS

Clinical Data

Clinical data for the patients with hypertension compared with normotensive control subjects are listed in Table 1. There were no differences between groups in terms of age, sex, body mass index, and heart rate (HR). After cilnidipine treatment, systolic and diastolic BP decreased significantly; HR didn't change.

TABLE 1
TABLE 1:
Clinical Characteristics of Patients With Hypertension and Control Subjects

LV Geometry and Systolic Performance of Patients With Hypertension and Control Subjects

LV geometry measures were significantly higher in the hypertensive group at baseline and after 8 weeks. EF and eFS were also significantly higher in the hypertensive group. However, mFS was lower in the hypertensive group at baseline, and after 8 weeks mFS increased to a similar level to the control group (Table 2).

TABLE 2
TABLE 2:
LV Geometry and Systolic Performance of Patients With Hypertension and Control Subjects

Effects of Cilnidipine on LV Geometry and Systolic Performance of Patients With Hypertension

LV geometry measures and conventional LV chamber systolic indices (EF, eFS) did not change after 8 weeks of treatment. However, cilnidipine significantly improved mFS and mFSc to a level similar to that of the control group (Table 2, Figures 2 and 3). Furthermore, changes of mFS showed no correlations with changes of systolic and diastolic BP (Figures 4 and 5).

FIGURE 2
FIGURE 2:
Effects of cilnidipine on LV myocardial function measured at midwall of patients with hypertension. mFS, midwall fractional shortening. *P < 0.05 compared with control group, †P < 0.01 compared with baseline.
FIGURE 3
FIGURE 3:
Effects of cilnidipine on LV myocardial function measured at midwall of patients with hypertension. mFSc, afterload-corrected mFS. *P < 0.05 compared with control group, †P < 0.01 compared with baseline.
FIGURE 4
FIGURE 4:
Relationship between the changes of mFS and the changes of systolic and diastolic blood pressure after treatment with cilnidipine.
FIGURE 5
FIGURE 5:
Relationship between the changes of mFS and the changes of systolic and diastolic blood pressure after treatment with cilnidipine.

DISCUSSION

Effects of Cilnidipine on Blood Pressure and Heart Rate

In our 37 Chinese patients with mild to moderate hypertension, once-daily administration of cilnidipine (5-10 mg) decreased the resting BP without any change in HR in patients with essential hypertension. This is similar to several previous studies. Hoshide et al18 found 8-16 weeks of treatment with cilnidipine but not amlodipine significantly decreased the ambulatory BP level without causing an increase in HR. In a 7day treatment, cilnidipine did not change heart rate or any indices of power spectral components of ambulatory HR records.19 These studies indicated that cilnidipine could block the L-type Ca2+ channels to decrease BP and block the N-type Ca2+ channels in sympathetic nerve endings to notcause reflex tachycardia.

LV Midwall Myocardial Function in Hypertension

Previous studies have found that, although conventional LV chamber function (EF, eFS) was normal or supranormal in many patients with hypertension, LV midwall systolic function (mFS) was impaired in the early stage of hypertension8,10; patients with different LV geometric patterns have different mFS, and mFS was lower, especially in patients with LVH8,11,20; reduced mFS is associated with impaired LV relaxation12 and impairment of coronary capacity21; and mFS is an independent predictor of cardiovascular risk in hypertension.1,2

In our 37 Chinese patients with mild to moderate hypertension, although conventional LV chamber function (EF, eFS) was higher compared with the control group, mFS was lower in the hypertensive group at baseline, and after 8 weeks of treatment mFS increased to a similar level to the control group. This was not a result of the increased afterload; when stress-shortening relationships were taken into account by comparing actual and predicted mFS, actual mFS was still significantly depressed. These results confirmed previous observations.8,7,10 A possible explanation for normal LV chamber function in the presence of depressed midwall function in hypertension is that because the inner layer of the ventricle thickens more than the outer layer, a thickened inner layer provides significantly more inward movement compared with the inner layer of a normal ventricle. This allows total wall shortening to remain normal despite a depression in fiber shortening (ie, the change in LV geometry allows the chamber function to remain normal).8,22

mFS Tracking Changes in Myocardial Performance With Antihypertensive Therapy

The primary aim of our study was to assess the effects of cilnidipine on midwall function in a respectively short term. With significant BP reduction, LV geometry measures and conventional LV chamber systolic indices (EF, eFS) did not change after 8 weeks of cilnidipine treatment. However, cilnidipine significantly improved LV myocardial function measure (mFS) to a level similar to that of the control group. This suggested that mFS was more sensitive than conventional measures of LV systolic function in tracking changes in myocardial performance with antihypertensive therapy. This is similar to several previous studies. In the LIFE23 study, antihypertensive therapy increased LV mFS and contractility with a small decrease in LV chamber function. Schussheim24 et al found that calcium channel blockers could improve stress-adjusted and absolute midwall function with no significant changes in conventional measures of LV chamber function. In patients with LV hypertrophy (LVH), tight blood pressure control could regress LVH and improve midwall systolic function.24 However these studies suggested that improvement of LV midwall function is dependent on normalization of LV geometry or on regression of LVH in a long time BP control22-25 But in our study, although LV geometry and LV mass did not change in a respectively short-term treatment, cilnidipine also improved LV midwall systolic shortening, which suggested that improvement of mFS might be prior to changes of LV geometry and LV mass.

It is somewhat interesting that an improvement in mFS showed no correlations with reductions of systolic and diastolic BP. It is important when cardiac systolic function is assessed that this is conducted in parallel with afterload because this can influence shortening independently of myocardial factors. In the present study, cardiac afterload was considered through assessment of circumferential end-systolic wall stress.20 The normal relationship between mFS and circumferential wall stress was examined in 156 normal subjects.8 When stress-shortening relationships were directly examined by expressing the observed mFS as a percentage of predicted shortening derived from the circumferential end-systolic stress data, the corrected shortening also had improved to a similar level to the control group by the end of the study. It suggested that cilnidipine could improve myocardial systolic function independently of BP reduction. The mechanism may be a result of the following: (1) inhibiting the influx of Ca2+ by blocking L-type calcium channels, relieving the intracellular Ca2+ overload13; (2) increasing coronary blood flow and coronary capacity21; and (3) blocking N-type Ca2+ channel, suppressing sympathetic activity.13

Study Limitations

A potential limitation in this study is small population size and a respectively short term, precluding meaningful multivariate analysis to determine if the changes in mFS are independently linked to reduction in LV geometric patterns. So, such an analysis as part of a larger study powered to study clinical end points will help ascertain the independent clinical contribution of mFS as a sensitive, noninvasive marker of early hypertensive heart disease.

CONCLUSIONS

Midwall fractional shortening is more reliable and sensitive than conventional LV systolic function measures in assessment of LV systolic function and tracking changes in myocardial performance with antihypertensive therapy; cilnidipine can improve LV systolic function (mFS) independent of BP reduction.

Acknowledgment

This study was partly supported by the Natural Science Foundation (Y2005C32) from the Department of Science and Technology of Shandon Province, China.

References

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Keywords:

essential hypertension; midwall fractional shortening; left-ventricular systolic function; cilnidipine

© 2007 Lippincott Williams & Wilkins, Inc.