Effect of cilnidipine on left ventricular function in hypertensive patients as assessed by tissue Doppler Tei index

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Abstract

Tissue Doppler Tei index is pointed to be more effective in the evaluation of global cardiac function than systolic and diastolic measurements alone in various heart diseases. This study was designed to assess the effect of cilnidipine on left ventricular function in hypertensive patients by using this index. A group of 40 hypertensives (mean age 55±8 years, range: 35–65) and 16 controls (mean age 52±9 years, range: 36–65) were included. Hypertensives were classified into non-left ventricular hypertrophy (NLVH) group (25 patients) and left ventricular hypertrophy (LVH) group (15 patients), and treated with cilnidipine for 2 months. Before and after treatment, the participants were examined by echocardiography. Tissue Doppler Tei index was calculated as diastolic time interval measured from end of late diastole to origin of early diastole (a′) minus systolic Sm duration (b′) divided by b′, that is Tei index=(a′–b′)/b′. Thirty-seven hypertensive patients finished the treatment. Tei index was significantly higher in NLVH and LVH groups than in control group, and in LVH group than in NLVH group (0.44±0.07 vs 0.28±0.06, P<0.001; 0.51±0.13 vs 0.28±0.06, P<0.001; 0.51±0.13 vs 0.44±0.07, P<0.05). After treatment, Tei index was significantly decreased (0.40±0.11 vs 0.46±0.10, P<0.0001); systolic blood pressure and diastolic blood pressure were also decreased significantly. In conclusion, Tei index is impaired in hypertensives before development of ventricular hypertrophy and impairment is more prominent in hypertrophy. Cilnidipine can improve left ventricular function. Tissue Doppler Tei index is gaining importance in evaluating LV function after drug intervention in hypertensive patients.

Introduction

Hypertension is an important risk factor for myocardial infarction and stroke.1, 2 Many studies indicate that left ventricular (LV) diastolic function has been impaired in the early stage of hypertension.3, 4, 5 Pulsed Doppler transmitral flow and tissue Doppler imaging were the most widely used methods to evaluate LV diastolic function in clinical practice3, 4, 5, 6, 7, 8. Recently, several studies demonstrate diastolic dysfunction and systolic dysfunction frequently coexist in hypertensives.9, 10 Therefore, it is of utmost importance to find an independent predictor that will unmask LV dysfunction in hypertension.11

Recently, a Doppler-derived index (referred to as Tei index, or myocardial performance index) that combines systolic and diastolic time interval has been developed to assess global cardiac function.12, 13, 14 As originally described by Tei,13 the time intervals used to calculate the index are measured using pulsed-wave Doppler velocity spectra of ventricular inflow and outflow. However, the inability to measure the interval between the end and onset of mitral inflow and the ejection time simultaneously is a limitation of conventional Tei index.15, 16 Tissue Doppler imaging (TDI) is a new ultrasound technique that selectively calculates and displays online myocardial velocity information derived from the Doppler shifts created by cardiac motion.17 Studies that use Tei index derived from TDI demonstrated that TDI Tei index correlated with conventional Tei index very well.16, 18

Cilnidipine is a long-acting calcium channel blocker, which blocks not only L-type Ca2+ channel in blood vessel but also the N-type Ca2+ channel in sympathetic nerve endings.19, 20 Clinical studies demonstrate that cilnidipine is an effective antihypertensive drug.21, 22

The purpose of present study was to assess the effect of cilnidipine on LV function by TDI Tei index.

Materials and methods

Subjects

We selected consecutively for the present study 40 ambulatory patients with mild to moderate hypertension (34 men, six women, mean age 55±8 years) who visited our hospital from March 2004 to October 2004. Inclusion criteria were as follows: outpatients of either sex, aged from 18 to 65 years, with mild to moderate hypertension (diastolic blood pressure (DBP)>90 mm Hg and <110 mm Hg, systolic blood pressure (SBP)>140 mm Hg and <180 mm Hg). Patients with secondary hypertension, dilated cardiomyopathy, left bundle branch block, right bundle branch block, pre-excitation syndrome and other arrhythmias on electrocardiogram, diabetes, liver or kidney disease, cancer, major cardiovascular complication (myocardial infarction or unstable angina within 6 months, congestive heart failure), and having any other diseases with a poor prognosis were excluded from the study. Sixteen healthy subjects (12 men, four women) without a history of cardiac disease or systemic hypertension, and having normal findings on physical examination, chest roentgenography, electrocardiography and echocardiography served as controls.

Study protocol

Informed consent was obtained from all subjects based on a protocol approved by Ethics Committee of QiLu Hospital Shandong University. After 2 weeks of placebo, the participants meeting the entry criteria were treated with cilnidipine 5 mg daily for 2 months. If the medicine had not reduced diastolic pressure to <95 mm Hg after 2 weeks of treatment, the dose would be doubled. The participants were asked to visit our hospital every 2 weeks, and had their blood pressure and heart rate (HR) measured. The side effect was also recorded.

Two-dimensional, M-mode, pulsed Doppler echocardiography

All the patients were examined in the left lateral decubitis with a Hewlett–Packard Sonos 7500 (Andovor, MA, USA) phased-array system equipped with tissue Doppler technology by one operator who had no information of the study at the end of placebo period and after 2 months of treatment. Measurements of LV diameter in end diastole, LV diameter in end systole, interventricular septum and LV posterior wall thickness in end diastole were recorded from M-mode readings according to the recommendation of the American Society of Echocardiography.23 Left ventricular mass (LVM) was calculated using Devereux's formula,24 and the LV mass index (LVMI) was obtained by dividing the LVM by body surface area. Left ventricular hypertrophy was considered present when LVMI>116 g/m2 in men or 104 g/m2 in women.8 For the pulsed Doppler echocardiography studies, the sample volume was placed between anterior and posterior mitral leaflet tips to record the LV inflow patterns, and the maximum amplitudes of the early diastolic wave (E) and late diastolic wave (A) were estimated; the E/A ratio were then calculated. The E-wave deceleration time (EDT) was also estimated.

Tissue Doppler echocardiography

The pulsed-wave TDI was performed by activating the tissue Doppler function in the same machine. The filter setting was kept low, and gains were adjusted at the minimum optimal level to minimize noise and eliminate the signals produced by the transmitral flow. A 2 mm sample volume was used. From the apical four-chamber view, sample volume was placed at the lateral corner of the mitral annulus. The resulting velocities were recorded at a sweep speed of 100 mm/s and stored on VHS videotape for later playback and analysis. More than 10 cardiac cycles were recorded and five consecutive beats were used for calculation, and the values were averaged to account for variation in heart rate.

From the videotaped recordings, we measured peak velocities during systole (Sm), early diastole (Em) and late diastole (Am). The time interval from the end to the onset of mitral annulus velocity pattern during diastole (a′) was measured. The duration of the Sm (b′) was measured from the onset to the end of Sm. Isovolumetric relaxation-time (IVRT′) was calculated by subtracting the interval d′ from the interval c′ (IVRT′=c′–d′). Isovolumetric contraction time (IVCT′) was calculated by subtracting IVRT′ from (a′–b′) (IVCT′=(a′–b′–IVRT′). The c′ was the duration from R-wave to onset of Em, and the d′ was the duration from R-wave to cessation of Sm. The Tei index was calculated as (a′–b′)/b11, 16 (Figure 1).

Figure 1
figure1

Schema of tissue Doppler imaging velocity spectra representing the time interval used for calculation of TDI Tei index. Interval a′ extends from the end to the onset of mitral annulus velocity during diastole. Interval b′ extends from the beginning to the end of systolic mitral annulus motion. The Tei index is equal to (a′–b′)/b′. TDI, tissue Doppler imaging; ECG, electrocardiography.

The control subjects were also examined by the same echocardiographic protocol.

Statistical analysis

Values are expressed as mean±s.d. The differences among three groups were evaluated by one-way analysis of variance. The changes in the measured variable before and after 2-month treatment were evaluated by Student's paired t-test. All statistical analyses were performed using software from SPSS Inc., and the differences were considered significant at P<0.05.

Results

Of 40 patients enrolled in the trail, three dropped out (one because of headache and two because of failure to appear at the visit), whereas 37 (33 men, four women) completed the study. Non-left ventricular hypertrophy (NLVH) group included 25 patients and left ventricular hypertrophy (LVH) group included 15 patients. The main results of the study are shown in Tables 1, 2, 3, 4 and 5 and Figures 2, 3.

Table 1 Demographic data of controls and hypertensive patients
Table 2 Echocardiographic parameters of controls and hypertensives before treatment
Table 3 Comparison of Tei index between controls and hypertensives before treatment
Table 4 Changes of LV function after treatment with cilnidipine for 2 months
Table 5 Changes of Tei index after treatment with cilnidipine for 2 months
Figure 2
figure2

TDI Tei index among three groups (1.00=LVH group, 2.00=NLVH group, 3.00=control group); *P<0.001 compared with control group; ΔP<0.05 compared with NLVH group. LVH, left ventricular hypertrophy; NLVH, non-left ventricular hypertrophy; TDI, tissue Doppler imaging.

Figure 3
figure3

TDI Tei index at baseline and after 2 months treatment with cilnidipine (1.00=baseline, 2.00=2-month treatment) *P<0.0001 compared with baseline. TDI, tissue Doppler imaging.

There were no differences among groups in terms of age, and HR. Systolic and diastolic blood pressure were elevated in NLVH and LVH groups. Left ventricular mass index was higher in LVH group than in Control and NLVH groups (Table 1).

Em and Em/Am were highest in the control group and lowest in the LVH group with a significant difference between NLVH and LVH groups (P<0.05, P<0.01). E/A was lower in NLVH and LVH group, (P<0.001) than in control group, with no difference between NLVH and LVH groups, A was higher in NLVH and LVH groups than in control group (P<0.05) (Table 2).

TDI Tei index was found to increase from control group to LVH group (P<0.001), with a significant difference between NLVH and LVH groups (P<0.05). a′ was longer in LVH group than in control group (P<0.05). b′ was shorter in NLVH and LVH groups than in control group (P<0.01, P<0.05). Isovolumetric relaxation-time′ and IVCT′ were longer in NLVH and LVH groups than in control group (P<0.01, P<0.001) (Table 3, Figure 2).

After 2-month treatment with cilnipdipine, SBP and DBP were significantly decreased (P<0.0001) with no changes in HR in hypertensives. E, E/A, Em and Em/Am were significantly increased after treatment (P<0.01, P<0.0001) (Table 4).

After treatment, TDI Tei index was significantly decreased (P<0.0001); IVRT′ was decreased (P<0.01) (Table 5, Figure 3).

Discussion

To the best of our knowledge, this study was the first to use TDI Tei index in evaluating the effect of antihypertensive drug on LV function. The results of the present study illustrated that TDI Tei index is a safe, feasible and sensitive index for assessment of global ventricular function, after 2 months of treatment with cilnidipine, TDI Tei index was significantly decreased, indicating cilnidipine can improve LV function.

There is a substantial body of evidence that abnormalities of LV diastolic properties may occur in the presence of normal ejection fraction,3, 4 often yielding the conclusion that abnormalities in LV diastolic function may precede or be independent of systolic dysfunction. However, studies that use midwall fractional shorting instead of EF as an index of systolic function found depressed LV systolic performance occuring coincidently with impaired diastolic function.5, 9, 10 For the process of producing ‘external’ work during systole is energetically balanced by an ‘internal’ work during diastole, which is able to restore the energy spent during systole to pump blood into arterial tree.5 Accordingly, when diastolic dysfunction occurred, it should also be reflected in systole, and vice versa. Therefore, the ideal index to evaluate myocardial performance should be a non-invasive integrated assessment of systolic and diastolic function that does not artificially uncouple each other.11

The present study showed that E/A, Em and Em/Am were lower in hypertensive patients and Em, Em/Am were the lowest in LV hypertrophical patients, which demonstrate that there is diastolic dysfunction in hypertensive patients. The prolonged mitral annulus myocardial IVCT′ found in NLVH and LVH group of present study may represent an early marker of LV systolic dysfunction, and this means our patients were not in early stage of hypertensive heart disease.3

Tei index was recently proposed as a potentially useful predictor of global myocardial performance, and it was defined as the sum of IVCT and IVRT divided by the ejection time. Tei index was reported to be simple, reproducible and independent of HR and blood pressure.25 Tissue Doppler imaging Tei index was used to evaluate LV function in patients with dilate cardiomyopathy,16 myocardial infarction18 and hypertension.11 In those disease states, Tei index was found to be higher than in normal subjects, and TDI Tei index correlated well with traditional Tei index. It is reported that the normal value of TDI Tei index range from 0.29–0.36.11, 16, 18 The present study illustrates that TDI Tei index is higher in hypertensives, and more prominent in LVH group, but E/A shows no difference between NLVH and LVH groups, which suggests that TDI Tei index is a sensitive parameter for evaluation of global ventricular function before developing ventricular hypertrophy. The present study also supports the opinion that systolic dysfunction coexists with diastolic dysfunction in hypertensives.

After 2-month treatment, SBP and DBP were significantly decreased, with no changes in HR. Tissue Doppler imaging Tei index was lower than pretreatment, and the parameters that reflect LV diastolic function such as E/A, EDT, Em, Em/Am, IVRT′ were improved. However, parameters of transmitral blood flow are affected by several factors, including volume states, left atrial pressure, age and rate of myocardial relaxation26, 27 and those parameters cannot reflect systolic function coincidently. As addressed before, LV diastolic dysfunction and systolic dysfunction often coexist in hypertensives. Tei index, which combined systolic and diastolic function, appeared to be a useful parameter in evaluating LV function.11, 28 It is likely that a decrease in IVRT′ contributes more to a change in Tei index after cilnidipine treatment than a decrease in IVCT′ or an increase in b′. So the improvement of LV function is relatively more owing to improvement in LV diastolic function after treatment. The study of Palloshi et al.29 showed that treatment with carvedilol for 3 months, in patients with heart failure, decreased Tei index significantly, and improved the NYHA class, but there were no changes in EF. In the present study, EF showed no change after treatment; this may be because EF is not a sensitive parameter as midwall fraction shorting to reflect LV systolic dysfunction5, 9, 10

Wang et al.30 reported that Em strongly related to prognosis in hypertensive patients with echocardiographic evidence of LV hypertrophy. In our study, Em was lower in LVH group than in NLVH group, after 2 months of treatment, Em increased significantly in hypertensive patients and Tei index that reflects diastolic and systolic function decreased. This means cilnidipine can improve LV function, and perhaps it can lower down the mortality and morbidity of cardiovascular events in hypertensive patients, but this needs to be further investigated. Taken all the result together, it seems TDI is a useful method, not only can it assess cardiac function but can also provide information of prognosis.

Various factors are thought to be responsible for the abnormal LV relaxation in hypertensive patients. Those include ventricular hypertrophy induced by chronic pressure overload, increased the concentration of intracellular Ca2+, 31 exaggerated accumulation of fibrillar collagens type I and type III occurs throughout the free wall and interventricular septum32 and decreased coronary flow reserve.33 After treatment with cilnidipine for 2 months, blood pressure was significantly decreased, whereas parameters that reflect LV diastolic function and TDI Tei index improved, suggesting that cilnidipine can improve LV function in hypertensive patients, which is in accordance with the previous study.7, 21, 22 The mechanism may be due to (1) cilinidipine decreasing afterload effectively; (2) inhibiting the action of Ca2+ ATPase in membranes, relieving the intracellular Ca2+ overload; (3) increasing coronary blood flow; (4) blocking N-type Ca2+ channel and (5) suppressing sympathetic activity.16

In this study, lateral corner of mitral annulus was used in measuring tissue Doppler time intervals. The longitudinal systolic shorting of LV is reflected by the motion of the mitral annulus towards the cardiac apex in systole, whereas its recoiling away from the apex is the result of diastole. Recording the mitral annulus motion has the advantage that it is devoid of trabeculea, and myocardial dropouts, and therefore is less dependent on echo quality. The major advantage of pulsed-wave mitral annulus velocity measurements is that the ultrasound beam is parallel to the LV contraction. The tissue motion of lateral corner of mitral annulus is not affected by the function of right ventricle, and study has demonstrated that TDI Tei index of lateral corner correlates well with conventional Tei index when compared with TDI Tei index of septal corner of mitral annulus.16

Our study has several limitations. The conventional Tei index was not measured simultaneously. The contraction of LV along its short axis, caused by circumferential fibre was not taken into consideration. Also, midwall fraction shorting was not measured as an index of LV systolic function. The study's population was relatively small and the follow-up period was short. We need further studies containing large samples to address this issue and to investigate the effect of other drugs on LV function.

In conclusion, TDI Tei index is a safe, feasible and sensitive parameter in evaluating LV function in hypertensives and cilnidipine can improve LV function after a short-term treatment. Evaluation of hypertensives with TDI Tei index may guide interventions directed towards saving systolic and diastolic functions before LVH develops.

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Correspondence to L Li.

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Keywords

  • tissue Doppler imaging
  • Tei index
  • left ventricular function
  • cilnidipine

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