© 2014, Wiley Periodicals, Inc. DOI: 10.1111/echo.12548

Echocardiography

Impact of Azelnidipine and Amlodipine on Left Ventricular Mass and Longitudinal Function in Hypertensive Patients with Left Ventricular Hypertrophy Hirohiko Motoki, M.D., Ph.D.,* Jun Koyama, M.D., Ph.D.,* Atsushi Izawa, M.D., Ph.D.,* Takeshi Tomita, M.D., Ph.D.,* Yusuke Miyashita, M.D., Ph.D.,* Masafumi Takahashi, M.D., Ph.D.,† and Uichi Ikeda, M.D., Ph.D.* *Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan; and †Division of Bioimaging Sciences, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan

Background: The impact of long-acting calcium channel blocker (CCB) administration on serial changes in left ventricular (LV) function and morphology in hypertensive patients with LV hypertrophy remains unclear. This study attempted to clarify this impact by comparing the effects of administration of azelnidipine with that of amlodipine using conventional and speckle tracking echocardiography. Methods: An equal number (16) of 32 hypertensive patients was prospectively assigned to a group administered 5 mg of amlodipine/day or a group administered 16 mg of azelnidipine/day. LV function and morphology was examined by conventional and speckle tracking echocardiography at baseline and at 1, 3, 6, and 12 months after treatment initiation. Results: Both groups were found to have experienced a significant decrease in systolic blood pressure by 1 month after treatment initiation; a significant reduction in septal thickness and LV mass index at 6 and 12 months. Transmitral flow E/A ratio and early diastolic mitral annular velocity at lateral wall significantly improved at 12 months. On the other hand, a significant improvement of global longitudinal strain was observed earlier than the above indexes at 3, 6, and 12 months. Ar-A duration difference was significantly decreased at 3 months. The global circumferential strain improved significantly at 3 months, but there were no significant changes in mid-/apical circumferential and radial strains throughout the study period. Conclusion: Azelnidipine has beneficial effects on LV mass regression, transmitral flow, tissue Doppler, and LV longitudinal strain that are comparable to those of amlodipine on the same parameters. (Echocardiography 2014;31:1230–1238) Key words: left ventricular hypertrophy, left ventricular mass, strain–strain rate Left ventricular hypertrophy (LVH) is a cardinal manifestation of preclinical cardiovascular disease that strongly predicts myocardial infarction, stroke, and cardiovascular death in hypertensive patients.1–4 The findings of several studies suggest that regression of hypertensive LVH is associated with improved prognosis.5,6 Regarding the form of treatment, previous research has indicated that no significant differences exist between the effects of ACE-I and those of newer, long-acting calcium channel blockers (CCBs) on LVH.7,8 Analysis of tissue Doppler imaging (TDI) has demonstrated reduced systolic long-axis function and reduced contractile reserve during exercise Address for correspondence and reprint requests: Jun Koyama, M.D., Ph.D., Department of Cardiovascular Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Fax: +81-263-37-2573; E-mail: [email protected]

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in hypertensive patients with isolated diastolic dysfunction.9,10 Although TDI is a valuable tool in the assessment of regional myocardial function, several technical limitations are associated with its use, such as angle dependency, high noise to signal ratio, and high measurement variability. A newly developed method of speckle tracking echocardiography (STE) is able to overcome these crucial limitations, making it possible to evaluate different components of complex cardiac motions, namely longitudinal, circumferential, and radial deformation. Both azelnidipine and amlodipine, 2 long-acting CCBs, have been found to significantly inhibit LV macrophage infiltration and LV fibrosis in animal models. However, azelnidipine has been found to have a greater inhibitory effect on these parameters as compared to amlodipine.11 We investigated serial improvement in LV mass and function after initiation of azelnidipine

Impact of Calcium Channel Blocker on Hypertensive LVH

therapy, a relatively new long-acting CCB, in hypertensive patients with LVH and compared it with that after initiation of amlodipine therapy, a commonly prescribed CCB, in the same type of patients using conventional and STE. Materials & Methods: Study Population: Thirty-two consecutive hypertensive patients with LVH who had been diagnosed with essential hypertension on the basis of history, physical examination, and laboratory findings (systolic blood pressure [BP] > 140 mmHg and/or diastolic BP > 90 mmHg) were prospectively enrolled in this study. LVH was determined by the echocardiographic criteria of (1) LV mass index (LVMI) > 115 g/m2 in men or >95 g/m2 in women and (2) relative wall thickness (RWT) >0.42.12 All patients met these echocardiographic criteria as well as the criterion of absence of clinical evidence of heart failure; coronary artery disease; congenital or valvular heart disease; or any systemic disease such as diabetes mellitus or connective tissue disorders that had the potential to induce changes in LV structure and function. The exclusion criterion was prior treatment with CCBs or antihypertensive agents within 6 months of study initiation. Patients with atrial fibrillation were also excluded from the study. Prior to commencement, approval for this study was obtained from the relevant institutional review board and written informed consent was obtained from all patients. All study procedures were conducted in accordance with Declaration of Helsinki guidelines.13 Study Protocol: The study began with M-mode, two-dimensional (2D), and Doppler echocardiography of all prospectively enrolled 32 patients to assess baseline cardiac function. After initial assessment, an equal number of patients (16) was randomly assigned to a group administered 5 mg of amlodipine/day and to a group administered 16 mg of azelnidipine/day. All 32 patients underwent follow-up examination with conventional echocardiography, TDI, and STE 1, 3, 6, and 12 months after initial assessment. Conventional Echocardiographic Examination: All participants were examined by standard 2D and Doppler echocardiography using a commercially available machine (Vivid-7, GE Vingmed Ultrasound AS, Horten, Norway) with a 1.5– 4.0 MHz (M4S) transducer. Parasternal and apical projections were obtained according to the recommendations of the American Society of Echocardiography (ASE).14 LVEF was derived

using Simpson’s modified biplane method and LV mass estimated using the area length formula in accordance with ASE documentation on LV quantification.15 LVMI was then calculated using the following formula: LVMI = LV mass/body surface area. RWT was estimated using the following formula: RWT = (septal wall thickness + posterior wall thickness)/LV end-diastolic diameter. Pulsed Doppler echocardiography of the transmitral and pulmonary venous flow velocities were performed, positioning a sample volume at the level of the mitral tips and the right upper pulmonary vein 1 cm below the ostium in the apical fourchamber view. The sample volume was then placed in the area of the anterior mitral valve leaflet to record the outflow and the transmitral flow profiles simultaneously to calculate isovolumic relaxation time. The offline analyses of transmitral flow and pulmonary venous flow were performed with the use of dedicated software (EchoPAC PC Dimension BT 8.0, GE Vingmed Ultrasound AS). Three consecutive beats were measured and averaged for each measurement. Peak velocities of early(E) and late-filling (A) waves, duration of A-wave, the E/A ratio, and deceleration time of the E-wave were measured from transmitral flow velocities, and the peak velocities of the systolic (S), diastolic (D), and A waves (Ar), duration of Ar, and the D/S ratio were also measured from pulmonary venous flow. The time difference between Ar and mitral A-wave duration (Ar-A) was calculated to detect age-independent variable of diastolic dysfunction.16 Tissue Doppler Imaging: Pulsed-wave TDI recordings from the septal and lateral mitral annulus were obtained from the apical four-chamber view. A sample volume of 5 mm was placed over the mitral annulus and the average of 3 consecutive cardiac cycles of peak systolic (s′), peak early diastolic (e′), and peak late diastolic (a′) velocities were measured. E/e′ was also calculated to estimate LV filling pressure. Speckle Tracking Imaging: All echocardiographic recordings were obtained in digital format and stored on magneto-optical disks for offline analysis (EchoPAC Dimension BT 8.0). The apical four-chamber, two-chamber, and long- and short-axis views (at basal, mid, and apical planes) were scanned to evaluate LV strain. Gain setting and pulse repetition frequency were adjusted and sector size and depth optimized to obtain a high frame rate (80–98 frames/sec). The endocardium was traced in an optimal frame around the end systole, from which a region of

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interest was automatically selected to approximate the myocardium between the endocardium and the epicardium. The region of interest width was adjusted to fit the wall thickness. The 2D strain was measured as previously described.17,18 The global longitudinal strain was calculated using automated function imaging software (EchoPAC Dimension BT 8.0) from 3 apical views. Statistics: Numerical variables were expressed as mean value
standard deviation (SD). Statistical analysis of difference between the groups was performed using the Student’s t test. Proportions were compared using contingency table analysis. A mixed model repeated measures analysis of variance was used to compare drug effects over time. The model produced estimated marginal means of the value at each time point and statistical significance tests between specific time points within or between the 2 drug treatments at different time points using Bonferroni correction. All statistical analyses were performed with a commercially available software program (SPSS, version 21.0, SPSS Inc. Chicago, IL, USA). A difference was considered significant if it reached a A (n = 3/4) Mean E/e′

1M

Baseline

Azelnidipine

Mitral Annular Velocity Parameters by Tissue Doppler at Baseline,1, 3, 6, and 12 Months (M) after Treatment

TABLE III

Impact of Calcium Channel Blocker on Hypertensive LVH

1235

1236

51.1
15.0 47.4
17.4

GLS = global longitudinal strain; GCS = global circumferential strain; MRS = mean radial strain (6 segments). *P < 0.001 versus pre. †P < 0.001 versus 1 M by post hoc (Bonferroni) test.

0.446

0.152 0.160 0.819 49.8
16.0 51.1
14.6 49.4
12.1 44.9
18.7 47.3
15.8 49.5
13.8 52.9
12.8

0.401

MRS (apex)

55.2
12.4

0.245

0.238 0.498

0.072 50.1
17.0

52.0
17.1 51.7
19.1

57.6
12.6 57.5
14.1

51.8
19.3 52.2
15.7

46.6
14.7 51.4
14.7

49.8
18.9 51.7
15.2

57.3
13.6 53.2
15.0

52.1
14.7 56.3
16.0

51.9
15.1

53.3
14.4

55.2
13.2

47.5
15.8

47.9
14.3

MRS (base)

20.4
4.8 19.6
3.8 GCS (apex)

MRS (mid)

0.318

0.860 0.059 0.713 20.2
2.9 20.3
4.0 20.5
3.7 20.1
2.7 17.1
11.6 19.3
3.8 19.5
4.0

0.337

19.5
5.5 18.2
5.4

20.8
4.8

0.359 0.453 20.5
3.9 20.5
3.8 20.3
5.2 19.4
4.3 17.3
9.9 18.5
4.2 18.5
3.8

0.879

GCS (mid)

20.5
5.0

0.007