Effect of amlodipine on ventricular hypertrophy in hypertension patients: a systematic review and meta-analysis
Original Article

Effect of amlodipine on ventricular hypertrophy in hypertension patients: a systematic review and meta-analysis

Yi Gao1,2, Di Zhou3, Ping Yang1,2

1Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China; 2Jilin Provincial International Collaboration Research Center for Precision Medicine, Changchun, China; 3Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun, China

Contributions: (I) Conception and design: Y Gao, P Yang; (II) Administrative support: P Yang; (III) Provision of study materials or patients: Y Gao, D Zhou; (IV) Collection and assembly of data: Y Gao, D Zhou; (V) Data analysis and interpretation: D Zhou; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Dr. Ping Yang. Department of Cardiology, China-Japan Union Hospital of Jilin University & Jilin Provincial International Collaboration Research Center for Precision Medicine, No.126, Xiantai Street, Changchun 130033, China. Email: pyang@jlu.edu.cn.

Background: Left ventricular (LV) hypertrophy predicts worse cardiac outcomes. Blood pressure lowering is associated with the reduction of LV hypertrophy. This study evaluated the effect of a calcium channel blocker, amlodipine, on LV hypertrophy in patients with hypertension.

Methods: Studies were identified by conducting a literature survey in electronic databases, and study selection was carried out according to precise eligibility criteria. Meta-analyses of mean change between the follow-up and baseline values of systolic/diastolic blood pressure (SBP/DBP) and LV hypertrophy indices were performed. Meta-regression analyses were performed to examine the factors affecting changes in these indices.

Results: Twenty-three studies [involving 737 patients; age 56.4 years, 95% confidence interval (CI): 53.5–59.2; females 34%, 95% CI: 25–44%; body mass index 26.4 kg/m2, 95% CI: 24.6–28.1] were included. Amlodipine treatment led to a significant reduction in SBP (−24.9 mmHg; 95% CI: −28.3 to −21.6; P<0.0001) and DBP (−14.8; 95% CI: −16.4 to −13.3; P<0.0001), without affecting the heart rate. Amlodipine treatment also significantly reduced the LV mass index. The mean difference (MD) between the follow-up and baseline LV mass index was −12.9; 95% CI: −15.4 to −10.4 (P<0.001). This decrease in LV mass index was positively associated with the follow-up duration [meta-regression coefficient (MC): 0.392; 95% CI: 0.050–0.733; P=0.026] and baseline LV mass index (MC: 0.139; 95% CI: 0.007–0.271; P=0.040). Amlodipine treatment significantly reduced the LV posterior wall thickness, which was also positively associated with the follow-up duration. There was no significant decrease in the LV end-diastolic diameter following amlodipine treatment.

Discussion: Amlodipine treatment in patients with hypertension significantly reduced the LV mass index and LV posterior wall thickness, without notably affecting the LV end-diastolic diameter. Since many of the included studies were non-randomized, open-label, or lacking appropriate comparability, we therefore performed pooled analyses of the changes from baseline, and a comparative account could not be carried out.

Keywords: Hypertension; ventricular hypertrophy; myocardial; amlodipine

Submitted Aug 12, 2021. Accepted for publication Oct 19, 2021.

doi: 10.21037/apm-21-2455

Introduction

Left ventricular (LV) hypertrophy is an echocardiographic index that indicates the presence of high LV mass (1). An LV mass index value equal to or above the 95th percentile is considered LV hypertrophy (2), and an LV mass index of over 115 g/m2 in men and 95 g/m2 in women is used diagnose LV hypertrophy (3). LV hypertrophy develops due to the increased size of cardiomyocytes, which affects the structure and function of the LV. LV hypertrophy can be either a physiological adaptation to strenuous physical exercise that eventually regresses upon the low activity, or it can be a pathological manifestation of hemodynamic overload or gene expression leading to LV dysfunction, which can cause heart failure (4). The prevalence of LV hypertrophy in patients with hypertension varies according to the LV hypertrophy threshold cutoff (5) and ranges between 36% and 46% in patients with hypertension (6). Eccentric LV hypertrophy has been found to be more prevalent than concentric LV hypertrophy (6).

LV hypertrophy is an independent predictor of fatal or non-fatal cardiovascular disease (CVD) events, especially coronary heart disease, congestive heart failure, myocardial infarction, heart failure, stroke, or mortality. Meanwhile, the reduction of LV hypertrophy indices is associated with a reduced risk of subsequent CVD and mortality (7-9). In hypertension patients without LV hypertrophy at baseline, blood pressure lowering has been found to be associated with a 46% risk reduction of developing LV hypertrophy, whereas in patients with LV hypertrophy at baseline, intensive blood pressure treatment has been shown to make the regression of LV hypertrophy 66% more likely (10).

LV hypertrophy develops as a pathophysiological adaptation against the increased afterload in patients with hypertension (11). LV hypertrophy is a strong predictor of CVD complications in patients with essential hypertension (1). Higher hemodynamic load in hypertensive patients leads to increased LV mass, which causes eccentric or concentric LV hypertrophy or geometric remodeling. Compared with eccentric hypertrophy, the presence of concentric LV hypertrophy in hypertensive patients poses the highest risk of CVD events and mortality (12). Besides hypertension, neurohormonal agents, angiotensin II, norepinephrine, aldosterone, insulin, and other growth factors play roles in the development and promotion of LV hypertrophy (13).

Calcium channel blockers constitute an important class of antihypertensive drugs which are found efficacious in reversing LV hypertrophy (14). Dihydropyridine calcium channel blockers are reported to reduce risk of heart failure, stroke, and mortality (15). Amlodipine is a long-acting dihydropyridine calcium channel blocker, which has been used as an effective antihypertensive for over three decades. Whereas the antihypertensive effects of amlodipine are well-reviewed (16-18), there is no systematic review or meta-analysis to analyze the effects of amlodipine on LV hypertrophy. Several studies have reported the outcomes of amlodipine treatment in hypertensive patients, many of which have also evaluated its effects on LV hypertrophy indices. However, the outcomes vary across these studies. The present study aimed to evaluate the effect of amlodipine on LV hypertrophy indices in patients with hypertension by conducting a systematic review of relevant studies and performing meta-analyses of important indices to quantitatively estimate the changes observed after treatment. We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/apm-21-2455).

Methods

Eligibility criteria

The inclusion criteria were as follows: (I) studies that evaluated the efficacy of amlodipine in patients with hypertension; (II) studies that reported outcomes related to the evaluation of ventricular hypertrophy, including LV mass, LV mass index, LV posterior wall thickness, relative wall thickness, LV end-diastolic diameter, and peak early diastolic filling velocity (E) to peak filling velocity at atrial contraction (A) ratio (E/A ratio); and (III) studies that reported the values of endpoints at baseline and at latest follow-up or the changes from baseline in one or more of the aforementioned indices. However, studies were excluded if they evaluated the efficacy of amlodipine in combination with other drugs, or reported the outcomes as congress abstracts.

Literature search

The literature survey was conducted in electronic databases (Google Scholar, Ovid, PubMed, and Science Direct) using the most relevant keywords, including amlodipine, calcium channel antagonist, calcium blocker, antihypertensive, hypertension patients, ventricular hypertrophy, myocardial hypertrophy, LV mass, and echocardiography. The literature search encompassed research articles published from the date of inception of the database till June 2021. Additionally, the bibliographic sections of important research and review articles were also screened. The literature search was restricted to research articles published in the English language.

Statistical analyses

Demographic and anthropometric data, clinical and pathological data, echocardiographic and Doppler indices, study design and analytical details, outcome measures, and outcomes were extracted from the research articles of selected studies and tabulated on software datasheets. Quality assessment of the included randomized studies was performed with the Cochrane Risk of Bias Assessment Tool for Randomized Controlled Trials (Collaborative Review Group, CRG), while the Newcastle-Ottawa Scale for the Assessment of Quality of Cohort Studies was used to assess the quality of non-randomized studies. Publication bias assessment was performed with Egger’s precision test and Begg’s rank correlation test.

To measure the changes in outcome endpoints, meta-analyses of the mean difference (MD) between the follow-up and baseline values were performed. For this purpose, the mean changes and variance were calculated if these were not reported by the individual studies (19). These mean changes and their variances were then used in meta-analyses using the DerSimonian-Liard pooled method to achieve overall and subgroup estimates. Sensitivity analyses were performed where feasible. For the present study, the endpoints of interest were the mean changes in systolic/diastolic blood pressure (SBP/DBP), heart rate (HR), LV mass index, LV posterior wall thickness, LV end-diastolic diameter, and the E/A ratio. The I2 index was used to estimate inconsistencies in the outcomes between studies.

Meta-regression analyses were performed using the restricted maximum likelihood method to seek relationships between the changes in LV mass index, LV posterior wall thickness, and LV end-diastolic diameter and explanatory variables including age, follow-up duration, and baseline values of LV mass index, LV posterior wall thickness, LV end-diastolic diameter, and the E/A ratio. Meta-analyses and meta-regression were performed using Stata software (version 12; Stata Corporation, College Station, Texas, USA).

Results

A total of 23 studies (11,13,20-40) were included (Figure 1), and the data of 737 patients with hypertension were used in this meta-analysis. Important characteristics of the included studies are presented in Table S1. The age of patients in these studies was 56.4 years [95% confidence interval (CI): 53.5–59.2] (range, 46±6 to 67±4). The proportion of females in this population was 34% (95% CI: 25–44%). The body mass index of patients in these studies ranged from 23±4 to 31±7, with a weighted average of 26.4 kg/m2 (95% CI: 24.6–28.1).

Figure 1 A flowchart of the study screening and selection process.

There was no significant publication bias according to Begg’s (Adjusted Kendall score =−10±14.6; P=0.493) or Egger’s (bias coefficient −0.937; 95% CI: −2.36 to 0.49; P=0.173) tests (Figure S1). The quality of the randomized studies varied from moderate to high. A lack of blinding of personnel, participants, or outcome assessment was observed in some randomized studies (Table S2). In non-randomized prospective or retrospective studies, comparability was the main constraint (Table S3).

Nineteen studies reported the changes in SBP and DBP after amlodipine treatment. Amlodipine treatment led to a significant reduction in SBP (−24.9 mmHg; 95% CI: −28.3 to −21.6; I2=95%; P<0.0001) and DBP (−14.8 mmHg; 95% CI: −16.4 to −13.3; P<0.0001 I2=90%) overall. The change in blood pressure was similar at 3 months, 6 months, and >1 year of follow-up (Table 1). There was no significant change in the HR during amlodipine treatment at any follow-up duration point (Table 1).

Table 1

Changes in blood pressure and heart rate at different time points during amlodipine treatment

Follow-up Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats per minute)
Overall (1–36 months) −24.9 (−28.3 to −21.6); I2=95%; P<0.0001 −14.8 (−16.4 to −13.3); I2=90%; P<0.0001 −0.08 (−0.91 to 0.75); I2=15%; P=0.847
1–3 months −23.6 (−31.0 to −16.1); I2=96%; P<0.0001 −16.5 (−19.5 to −13.5); I2=91%; P<0.0001 0.84 (−0.11 to 1.79); I2=0%; P=0.084
6 months −24.8 (−30.1 to −19.5); I2=96%; P<0.000 −13.9 (−16.0 to −11.8); I2=90%; P<0.0001 −0.79 (−2.16 to 0.57); I2=21%; P=0.255
1–3 years −27.5 (−32.8 to −22.3); I2=88%; P<0.0001 −13.6 (−16.3 to −10.9); I2=80%; P<0.0001 −3.43 (−7.22 to 0.37); I2=0%; P=0.077

Eighteen studies reported the changes in LV mass index. After amlodipine treatment, the LV mass index decreased during follow-up (Table 2; Figure 2). The overall change in the LV mass index was statistically significant (−12.9; 95% CI: −15.4 to −10.4; P<0.001). Outcomes of sensitivity analyses were in agreement with the overall outcomes. A decrease in the LV mass index was positively associated with the follow-up duration (meta-regression coefficient, MC: 0.392; 95% CI: 0.050–0.733; P=0.026) as well as with the baseline LV mass index (MC: 0.139; 95% CI: 0.007–0.271; P=0.040) (Figure S2A,S2B).

Table 2

Changes in LV hypertrophy indices at different time points during amlodipine treatment

Follow-up LV mass index (g/m2) LV posterior wall thickness (mm) LV end-diastolic diameter (mm)
Overall (1–36 months) −12.9 (−15.4 to −10.4); I2=96%; P<0.0001 −0.82 (−1.00 to −0.63); I2=66%; P<0.001 −0.59 (−1.42 to 0.24); I2=85%; P=0.114
1–3 months −9.42 (−13.1 to −5.78); I2=95%; P<0.0001 −0.57 (−0.71 to −0.44); I2=15%; P<0.001 −1.24 (−2.10 to 0.40) I2=63%; P=0.004
6 months −11.4 (−13.9 to −9.0); I2=75%; P<0.0001 −1.03 (−1.23 to −0.83); I2=0%; P<0.001 −0.48 (−1.05 to 0.10); I2=4%; P=0.104
1–3 years −17.7 (−22.9 to −12.6); I2=84%; P<0.0001 −1.09 (−1.33 to −0.84); I2=10%; P<0.001 0.68 (−2.39 to 3.76); I2=87%; P=0.819
Figure 2 A forest graph showing the outcomes of the meta-analysis of changes from baseline in the left ventricular mass index.

Nine studies reported the changes in LV posterior wall thickness. Amlodipine treatment also led to a significant reduction in the LV posterior wall thickness (Figure 3). In the subgroup analysis, the change in LV posterior wall thickness increased further from 3 and 6 months to 1–3 years of follow-up (Table 2). Also, the meta-regression analysis showed that the decrease in LV posterior wall thickness was positively related to the follow-up duration (MC: 0.042; 95% CI: 0.007–0.076; P=0.021; Figure S3).

Figure 3 A forest graph showing the outcomes of the meta-analysis of changes from baseline in the left ventricular posterior wall thickness.

Eleven studies reported the changes in LV end-diastolic diameter. There was no significant decrease in the LV end-diastolic diameter after amlodipine treatment overall. In the subgroup analysis, a reduction in the LV end-diastolic diameter after amlodipine treatment was only observed in the 1–3 months follow-up subgroup (Table 2; Figure S4). The decrease in LV end-diastolic diameter was inversely associated with the duration of follow-up (−0.251; 95% CI: −0.402 to −0.100; P=0.003; Figure S5).

Furthermore, there was a trend towards an increase in the E/A ratio with the follow-up in each study, although this relationship was not statistically significant (MC: 0.072; 95% CI: −0.017 to 0.161; P=0.106; Figure 4).

Figure 4 A meta-regression scatterplot showing a trend towards an increased E/A ratio at the middle and end points of follow-up observed by individual studies. E/A, peak early diastolic filling velocity to peak filling velocity at atrial contraction ratio.

Discussion

This meta-analysis found that amlodipine treatment led to significant reductions in ventricular hypertrophy indices. The LV mass index decreased more in individuals with higher baseline LV mass index. The decrease in LV mass index and LV posterior wall thickness was positively associated with the follow-up duration, but the decrease in LV end-diastolic diameter was inversely associated with follow-up. These changes were associated with significant reductions in SBP and DBP, without a notable effect on HR. The E/A ratio increased non-significantly throughout the follow-up period.

Calcium channel blockers, in general, have been found to be associated with a considerable reduction in LV hypertrophy. In a meta-analysis of 52 randomized comparative studies with at least 6-months follow-up, Salvetti et al. found a 12.3% decrease in the LV mass index with calcium channel blockers, which was comparable to the 12.5% for angiotensin receptor blockers and 11.1% for angiotensin-converting enzyme inhibitors. They found a correlation coefficient of 0.44 (P<0.001) between the change in LV mass and SBP (14). In the present study, we observed approximately 13% reduction in the LV mass index overall, and the correlation coefficients between the change in SBP/DBP and the change in LV mass index of 0.26 (P=0.247)/0.32 (P=0.143). We also found that the correlation between the changes in the LV mass index and LV posterior wall thickness was 0.35 (P=0.239), while the correlation between the changes in the LV mass index and LV end-diastolic diameter was 0.04 (P=0.9). Significant reductions in LV mass index are also observed with other calcium channel blockers including nifedipine, felodipine, and manidipine (41-43).

Combinational use of amlodipine with other related drugs exhibits better efficacy in reversing LV hypertrophy. Amlodipine in combination with benazepril (an angiotensin converting enzyme inhibitor) has been found to decrease LV mass index by 30±26 g/m2 in comparison with 14±22 g/m2 by amlodipine monotherapy (44). In patients with hypertension and hypercholesterolemia, amlodipine in combination with atorvastatin reduced left ventricular mass index (LVMI) significantly more than amlodipine monotherapy (45). Utilizing the chronotherapeutic approach, Ikeda et al. treated hypertension patients with bed-time alpha-adrenergic receptor antagonist, doxazosin, as an add-on treatment to amlodipine and found that this intervention significantly reduced morning blood pressure and LV hypertrophy. Authors suggested that this combination can be useful for patients with metabolic syndrome or insulin resistance (46). Factors other than drug class or dosage can also affect the combinational therapies e.g., a polytherapy with amlodipine, perindopril and indapamide was more effective in reversing LV hypertrophy as triple fixed dose combination than as triple free combination (47).

The LV hemodynamic workload is affected by blood pressure levels. Among the hemodynamic and non-hemodynamic factors involved in the pathogenesis of LV hypertrophy, blood pressure is a major factor (48). After finding no significant change in LV end-diastolic diameter with amlodipine treatment, Cerasola et al. suggested that a decrease in the LV mass index could be due to the reduction in LV posterior wall thickness. On the other hand, since amlodipine treatment significantly reduced both SBP and DBP; therefore, a decrease in LV mass could be attributed to hemodynamic modifications (11). Rosendorff et al., who stabilized blood pressure before echocardiographic measurements in hypertensive patients treated with amlodipine or losartan, found that the LV hypertrophy-decreasing effects of these drugs were largely pressor dependent (34). However, the study of Fogari et al. showed that amlodipine and losartan affect the LV mass differently, while reducing blood pressure similarly. In their study, losartan was more effective than amlodipine at reducing the LV mass and LV posterior wall thickness (24). Amlodipine treatment has also been found to be associated with reduction in arterial stiffness which appear to happen via both blood pressure dependent and independent mechanisms (49).

We found that the reduction in LV mass index was positively associated with the follow-up duration and baseline LV mass index. A previous meta-analysis that evaluated the efficacy of several antihypertensive drug classes in reducing LV hypertrophy reported that the percentage change in the LV mass index was positively associated with the follow-up duration and baseline LV mass index (50). These data suggest that more changes occur in patients with a high baseline LV mass index and that therapy can provide long-term benefits. However, consideration of an adequate follow-up duration will be necessary to evaluate this observation. In the present study, the average follow-up duration was 10 months (range, 1–36 months).

Subclinical organ damage is initiated when chronic hypertension begins causing cardiac remodeling. The development of LV hypertrophy involving the growth of myocytes, increased oxidative stress, increased action of vasoactive substances, and fibrosis leads to several cardiac pathologies (51). LV mass is associated with increased myocardial oxygen consumption, reduced coronary blood flow reserve, increased atherosclerotic lesions, and arrhythmogenesis (1). It is thought that amlodipine may regress the LV mass by decreasing both the afterload and intracellular calcium ions, which can retard protein synthesis (33). Cardiomyopathic damage is associated with release of biochemical markers. A strong positive correlation has been found between serum high sensitivity cardiac troponin T (hs-cTnT) and LVMI (r=0.608; P<0.001) in patients with end-stage renal disease under dialysis (52). In a cohort of patients with chronic kidney disease without heart failure, high hs-cTnT levels were predictive of LV hypertrophy (53). In individuals without CVD from general population, hs-cTnT levels were found to be positively associated with LV mass index so that LV mass, LV mass index, and LV hypertrophy values increased with increasing quintiles of hs-cTnT levels. Moreover, hs-cTnT levels were inversely associated with diastolic function irrespective of LV mass which showed that hs-cTnT may be used as an early marker of heart disease involving diastolic dysfunction (54).

Some limitations of the present study are important to consider while interpreting the outcomes. Our meta-analyses outcomes were associated with high I2 values, which reflect high levels of inconsistency in outcomes between included studies. The included studies in this meta-analysis varied in design, ranging from retrospective to prospective and from open-label to double-blind randomized controlled trials. Different etiologies and severity of hypertension in these studies could have also impacted the outcomes. Such factors might have contributed to the high I2 values. Since many of the included studies were non-randomized, open-label, or lacking appropriate comparability, we therefore performed pooled analyses of the changes from baseline, and a comparative account could not be carried out.

Conclusions

Amlodipine treatment in patients with hypertension is associated with significant reductions in LV hypertrophy and blood pressure without affecting HR. During an average follow-up of approximately 10 months, reduction in the LV mass index increased with increasing duration of follow. These results show that amlodipine therapy can significantly reduce blood pressure and LV hypertrophy in the long term, especially in patients with higher LV hypertrophy indices at baseline.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-2455

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-2455). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: A. Kassem)

Cite this article as: Gao Y, Zhou D, Yang P. Effect of amlodipine on ventricular hypertrophy in hypertension patients: a systematic review and meta-analysis. Ann Palliat Med 2021;10(10):10768-10778. doi: 10.21037/apm-21-2455

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