Hypertrophic cardiomyopathy (HCM) is the most common inheritable disease of the myocardium that is caused by genetic mutations of sarcomeric myofilaments [1, 2]. HCM is a global disease with a prevalence of 1:500 in the general adult population, equally affecting both men and women [3]. HCM carries a significant risk for diastolic heart failure, ventricular arrhythmias, and sudden cardiac death (especially in competitive athletes) [4]. HCM can be clinically diagnosed with two-dimensional echocardiography showing maximal left ventricular end-diastolic (LVED) wall thickness of $\ge$15 mm in the absence of pressure overload in adults [5, 6]. Genetic testing and family history of HCM can be helpful in patients who do not meet echocardiographic LVED wall thickness criteria [7].

Angiotensin II triggers the production of several trophic and pro-fibrotic factors that lead to myocardial hypertrophy and interstitial fibrosis [8]. Theoretically, angiotensin II receptor blockers (ARBs) should diminish the progression of LV hypertrophy and fibrosis by decreasing levels of pro-fibrotic factors. In addition, genetic studies of the renin-angiotensin-aldosterone system systems reported that genetic polymorphisms might influence the phenotypic changes observed in HCM [8]. In the past, randomized controlled trials (RCTs) failed to report any additional benefit of ARB therapy as compared to standard medical therapy consisting of negative inotropic agents including beta-blockers and non-dihydropyridine calcium channel blockers [2, 9, 10, 11, 12]. A previously published meta-analysis by Liu et al. [13] comprising those RCTs also concluded no net benefits of ARBs on ventricular hypertrophy in hypertrophic cardiomyopathy.

In a recent multicenter RCT performed by Ho et al. [14], valsartan has shown promising results in attenuation of phenotypic expression of disease in patients with HCM. They reported that that valsartan not only attenuated the progression but also improved the prognosis as it decreased type I collagen synthesis and secondary to renin-angiotensin-aldosterone system activation, which is associated with systolic dysfunction by breaking through the aldosterone.

Given the clinical importance of this topic and in light of the newer data, we performed this updated systematic review and meta-analysis aiming to evaluate the effectiveness of ARB’s therapy in patients with HCM.

This review was carried out according to the guidelines provided in Preferred Reporting Items for Systematic Reviews and Meta-Analysis [15, 16] (Supplementary Table 1 and Supplementary Table 2, Supplementary Material). The study protocol was registered in OSF Registries with DOI: 10.17605/OSF.IO/DAS7C.

We conducted an updated systematic review and meta-analysis to compare the efficacy of ARB therapy in patients with HCM. Our results showed that ARB therapy was associated with a greater reduction in LV mass and systolic blood pressure as compared to the control group consisting of either placebo or standard non-ARB medication. There was no difference found in LA volume, LVEF, LV thickness, Ea, E/A ratio, and LV fibrosis between ARB and control groups.

The Role of renin-angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEi) and ARB, has been well documented in the prevention and potential reversal of myocardial remodeling secondary to hypertension [21, 22]. Conversely, aldosterone antagonists are another class of RAS inhibitors that have been implied to enhance cardiac remodeling and cause atrial fibrillation at higher dosages by increasing collagen synthesis and cardiac myocytes apoptosis [23]. Current European Society of Cardiology and American Heart Association guidelines for the management of HCM recommend initiation of RAS inhibitors in patients with LVEF 50% as part of guideline-directed medical therapy for heart failure (Class I recommendation, Level of evidence ‘C’). [7]. At present, ARB therapy is not mentioned as part of the routine medical management of patients with HCM in the absence of other indications such as reduced (50%) LVEF [7]. Previously available data failed to show the efficacy of ARB therapy in patients with established HCM [2, 9, 10, 11, 12, 20]. Of note, many of these studies had several limitations, including smaller sample size and a shorter duration of follow-up (up to one year) [13].

Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial began in April 2014 intending to test a novel strategy of disease modification in patients with sarcomeric HCM [14, 24]. The VANISH study showed improved HCM composite scores that incorporated overall cardiac structure and function [14, 24]. It is noteworthy that despite yielding a lower composite score for patients with sarcomeric HCM, individual reduction in LV mass and SBP were not significant in the ARB group of VANISH trial [14, 24]. In contrast, our pooled analysis of all RCTs did reveal a significant reduction in LV mass and SBP in the ARB group. This can be explained by the overall larger sample size and the addition of newer data from VANISH trial with early initiation of ARB and longer follow-up duration (two years). VANISH trial [14] had many fundamental differences in the study design as compared to other RCTs; (1) VANISH trial [14] included patients with confirmed sarcomeric HCM as compared to other trials who did not specify HCM etiology, (2) VANISH trial [14] included patients at a younger age (mean age 20–30 years versus 40–65 years in other RCTs), (3) VANISH trial [14] included patients with milder disease expression (LV wall thickness 16 mm versus 21 mm in other RCTs). It is also worth mentioning that despite being at higher risk for sudden cardiac death, most patients with HCM live a normal life with minimal to absent clinical manifestations [5, 25]. It is extremely challenging to prove the effectiveness of a treatment for such conditions with a wide spectrum of phenotypic manifestations and a relatively benign clinical course in most patients. VANISH trial [14] also showed that the most striking treatment benefits were seen in patients who were started on valsartan therapy in the early phase of HCM phenotypic expression.

It is historically reported in the literature that increased circulating angiotensin-II levels are associated with increased expression of TGF-$\beta$ that in turn leads to interstitial fibrosis of various organs, including myocardium, vascular smooth muscle, liver, and kidneys [26, 27, 28, 29]. It is unknown at this time if a certain ARB agent or dosage is superior in decreasing TGF-$\beta$ levels and halting myocardial hypertrophy and fibrosis. Our analysis includes just one RCT that used candesartan [20] in the ARB group, two RCTs [12, 14] used valsartan, whereas the remaining four RCTs [2, 9, 10, 11] opted to use losartan in HCM patients assigned to the ARB group. Amongst included studies, candesartan was administered at a dose ranging from 8–32 mg per day, valsartan dose ranged from 80–320 mg per day, and losartan was utilized in a dose range from 50 to 100 mg per day [2, 9, 10, 11, 12, 14, 20]. This difference in dose range was reported to be secondary to variability in patient tolerance and difference in study protocols.

Patients with HCM and evidence of left ventricular outflow tract (LVOT) obstruction are often treated with structural interventions including septal myomectomy or transcatheter alcohol ablation of septal hypertrophy (TASH) [30]. TASH is an alternative to septal myectomy and offers the same long and short-term mortality rate. However, compared to septal myectomy, TASH had a greater risk of right bundle branch block and applying permanent pacemakers and increased the demand for further septal reduction therapy [31].

Our study is an updated meta-analysis, including one additional study. First, our meta-analysis results are substantially different from the previous meta-analysis performed by Liu et al. [13] showing a significant reduction in LV mass in the ARB group. Secondly, the previous meta-analysis did not report systolic blood pressure, LV fibrosis, Ea, E/A ratio, and LA volume fibrosis as potential outcomes. Lastly, our analysis further emphasizes the importance of a larger sample size and longer follow-up duration for future trials studying the effectiveness of medical therapy for HCM.

There are a few potential limitations in our review. First, our study population was very heterogeneous, belonging to different age groups, and at different stages and severity of HCM phenotypes. Also, all included RCTs in our meta-analysis used MRI for the measurements of the endpoints, except Penicka et al. [20] used TTE. Despite echocardiography being a more feasible and affordable screening tool, magnetic resonance imaging provides more information and three-dimensional data and can diagnose the missed or query cases by ECHO [32]. Second, underlying genetic mutations were not specified by included studies except Ho et al. [14] that included only patients with sarcomeric HCM leading to the limited applicability of our data to HCM with specific genotypes. Third, the control groups were treated with standard medical therapy instead of placebo by two studies [11, 12] as compared to the other studies included in our analysis. Fourth, the included articles did not evaluate the circulating angiotensin II, catecholamines, or markers of oxidative stress and did not assess ACE nor angiotensin II type 1 receptor genetic polymorphisms. Those parameters could provide a deeper understanding of the effect of ARB in patients with HCM. Lastly, the longest follow-up duration was one year for most studies except Ho et al. [14] that reported two years of follow-up data leading to the limited applicability of our results over a longer follow-up period. We performed sensitivity analysis by removing Ho et al. [14] and Penicka et al. [20] as solutions to the above limitations, but the results were insignificant. Therefore, further research with a homogenous population is still needed.

In patients with HCM, ARBs are associated with significantly lower LV mass and a significant reduction in SBP as compared to non-ARB medication or placebo. Therefore, initiation of ARB therapy should be considered early in the disease course for patients with HCM. However, further RCTs using larger sample sizes and longer follow-up duration should be conducted to assess the validity and applicability of this study.

BA and KSA designed the research study. HR and FL performed the research. SA and PS provided help and advice on data collection and extraction. KSA and BA analyzed the data. SA and BA wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

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This research received no external funding.

The authors declare no conflict of interest.