Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiovascular diseases, with a prevalence between 1:200 and 1:500, affecting more than 20 million people worldwide [1]. Although the majority (∼75%) of HCM patients have normal life expectancy without limiting symptoms, the natural history of the disease includes ominous events such as atrial fibrillation and stroke, infective endocarditis, heart failure (HF) to the worst scenario represented by sudden cardiac death (SCD). HF can develop over time mainly through three different phenotypes: left ventricular (LV) obstruction (obstructive HCM), non-obstructive HCM with a normal or preserved ejection fraction (LVEF), “end-stage” HCM or hypokinetic-dilated evolution (ES-HCM) [1].

The major determinants of the most ominous outcomes, namely, all-cause death, SCD, hospitalization for HF, and HF progression, have been largely researched and studied over time and only partially identified and characterized. To date, the role of myocardial fibrosis (MF), microvascular dysfunction, end-stage evolution, and LV apical aneurism has been clearly demonstrated to be associated and to cause adverse outcome.

However, the role of multiple gene mutations (sarcomeric and not sarcomeric) before of larger and systematic studies had been largely debated [2]. In 2010, Girolami et al. [3] were able to demonstrate in a large cohort of HCM patients (∼490) that the presence of multiple sarcomere gene mutations correlates with the development of HF, ES-HCM evolution, and SCD. The characteristics linked to multiple mutations and worse outcome were young age, extensive MF, and great impairment of microvascular function due to adverse remodeling of the coronary arteriole wall [3]. Four years later, a multicenter international study on 150 patients confirmed that double and or triple sarcomere gene mutations were present in 13% of ES-HCM evolution [4]. Taken together, both these large studies strengthened the hypothesis that a “genetic burden” exists and plays a significant role in determining the outcome of HCM.

Furthermore, the advent of novel techniques of next-generation DNA sequencing able to easily study the whole exome and even the whole genome increased the detection power of multiple pathogenic mutations translating into more accurate HCM diagnosis. A recent study [5] demonstrated that the whole-genome sequencing applied to HCM improved the yield of genetic testing, in particular, used as a first-line genetic test identified pathogenic variants in 42% of patients tested and an additional 9% of gene-elusive HCM patients with pathogenic variants in deep intronic regions of MYBPC3 (causing a splice-gain) when compared to protein-coding exons only analysis.

In this issue of cardiology, Zhao et al. [6] systematically and retrospectively studied 719 HCM Asian patients, using exome sequencing (both partial and whole); after excluding phenocopies and patients with other ion channel gene variations, they focused their attention on calcium-channel and sarcomere gene mutations in HCM, considering in their final analysis 371 HCM patients. The authors showed that in this cohort – followed in mean for 62 months – a calcium-channel gene mutation added to a sarcomere gene mutation, found in ∼10% of the studied population (i.e., 36/371), was significantly associated with a worse primary outcome, i.e., a combined of all-cause death, SCD, hospitalization for HF, and progression to more symptomatic and severe HF (NYHA III and IV). More attentive analysis of the split end-points demonstrated that the adverse outcome has been driven mainly by a progression to more severe HF, whereas this combination of mutations had no significant impact on the other end-points.

The authors were also able to characterize the phenotype of HCM patients that showed progression of HF and to link calcium-channel gene mutations to a higher prevalence of LV obstruction driven by a higher degree of septal hypertrophy and a more severe SAM. This finding is interesting in light of the existing literature, which has demonstrated that different mutations in sarcomere genes are associated with heterogenous distribution of LV hypertrophy not only in sarcomeric HCM (i.e., sigmoidal, reverse-curve, apical, etc.) [7] but also among the phenocopies of HCM such as cardiac amyloidosis in which different transthyretin mutations are associated with different distributions of “pseudo-hypertrophy” [8, 9].

The progression to more severe HF has also been indirectly linked to another phenotype which is adverse remodeling and ES-HCM evolution. Indeed, the study of Zhao et al. [6] clearly shows that a “higher LVEF,” i.e., >61%, has been associated with better outcome (driven by both SCD and HF). Previously, Olivotto et al. [10] demonstrated that LVEF between 50% and 60% is associated with adverse remodeling in HCM and represents the phase that precedes the evolution to ES-HCM (i.e., defined by an LVEF <50%). ES-HCM has clearly proven to cause adverse outcome, i.e., both all-cause and CV mortality driven by a higher rate of SCD and HF death; indeed, its mortality is 11.1% per year versus 1.2% per year of the HCM general population. The hallmark of end-stage evolution is an extensive MF and the presence of coronary microvascular dysfunction. A previous study on a large series of ES-HCM explanted hearts – before heart transplantation – provided the first detailed quantification and characterization of MF in these hearts showing that more than one-third of the LV myocardium is substituted by fibrosis both interstitial and scar-like [11]. The same study documented the existence of a severe coronary microvascular pathology characterized by intimal hyperplasia and media hypertrophy that causes myocardial ischemia and that there is a tight proximity between areas of MF and abnormal coronary arterioles. Several studies showed a link between multiple sarcomere gene mutations to both microvascular ischemia – caused by pathology of small coronary vessels – and a larger amount of MF [12]. Furthermore, genes that encode for extracellular matrix proteins have been involved and the possibility that calcium-channel gene mutations play a role in the pathogenesis of ES evolution is opened by this study.

However, the Zhao et al. [6] research is limited because cardiac magnetic resonance has not been systematically performed to quantify both interstitial and scar-like MF (by T1 mapping and late gadolinium enhancement). Another important limitation of this cohort is the lack of data about LV strain. This measurement is more sensitive and more informative than LVEF alone, and it offers especially an added value in HF across the full spectrum of LVEF not only for prognosis stratification but also for diagnosis [13]. Its role is of paramount importance in patients with LV hypertrophy both when they present HF with mildly reduced LVEF and HF with preserved LVEF because alone it can distinguish HCM from cardiac amyloidosis (LV strain in the apex is compromised in HCM vs. normal or spared in amyloidosis). Moreover, patients with mutation both in the sarcomere genes and in the calcium-channel genes potentially can have a more compromised LV strain even when the LVEF is higher than 50%.

Another finding of the authors is the association of QTc interval prolongations and conduction block as left bundle branch block with calcium-channel gene mutations. Despite a possible involvement of calcium channels suggested by their role in myocardial cell depolarization, SCD has not been significantly increased by the presence of double mutations in this cohort. Therefore, this study does not suggest a role of calcium-channel gene mutations in arrhythmic death; however, further studies are needed especially in light that previous international studies documented that prolonged QTc interval, QRS duration ≥120 ms, and pseudo-STEMI pattern are independent predictors of SCD and major CV events and that a relation with mutations in sodium-channel gene (such as rare variants of the SCN5A gene) has been hypothesized [14].

Finally, Zhao et al. [6] confirmed the existence of sex differences within HCM patients with double mutations; indeed, females were shown to have less LV hypertrophy and higher LVEF and to be a predictor of SCD. These data can be partially explained by previous studies that documented a higher association of MF and female sex but are largely unknown. However, it is evident that myocardial remodeling and physiopathology can have significant differences between sexes being influenced by different mechanisms triggered by hormones as it happens in HF and other CV and non-CV diseases [15].

In conclusion, HCM is a genetically driven disease; although, over the last 30 years, the most studied and characterized mutations are that of sarcomere genes, only the recent advent in the clinical practice of the whole exome and whole-genome sequencing is unveiling to both researchers and clinical cardiologists the complex interplay between sarcomere genes and other gene mutations The different combinations of mutations that involve different ion channel genes, extracellular matrix protein genes, fibroblast genes, and many others are able to modify not only the phenotypical expression but also the outcome of the disease and its impact both on survival and on quality of life. Therefore, after the discovery of our galaxy (sarcomere gene mutations), the new horizon is the discovery of the universe (multiple gene mutations).

The authors have no conflict of interest to declare related to this manuscript.

This work has been supported by the Italian Ministry of Health Ricerca – Corrente – IRCCS MultiMedica.

G. Galati conceived, wrote, and revised the manuscript. O. Germanova and R.F.E. Pedretti read, critically revised the manuscript, contributed to the content, and approved the final version of the manuscript.

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