The Phenotypic Spectrum of Subclinical Sarcomere-related Hypertrophic Cardiomyopathy and Transition to Overt Disease

Abstract

Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular hypertrophy (LVH) with LV wall thickness ≥15mm in probands or ≥13mm in at-risk relatives. Although LVH is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, prior to diagnosis with HCM (G+/LVH-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LVH are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca²⁺ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including abnormal electrocardiogram, longer mitral valve leaflets, lower global E’ velocities on Doppler echocardiography and higher serum N-terminal pro-peptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and to guide the development of novel treatment strategies aimed at influencing disease trajectory.

Introduction

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder that is frequently caused by pathogenic/ likely pathogenic (P/LP) variants in genes associated with the sarcomere apparatus. Genetic testing identifies a P/LP variant in 30–40% of adults with a clinical diagnosis of HCM, but >60% of patients diagnosed during childhood or with a family history of HCM have a P/LP^1,2. The most commonly involved genes are myosin binding protein C (MYBPC3), β-myosin heavy chain (MYH7), troponin T (TNNT2) and troponin I (TNNI3) (Table 1). However, not all variant carriers (G+) demonstrate clinically overt HCM (LVH+) as the penetrance (the percentage [%] of G+ who have LVH in cross-sectional studies) and phenotypic conversion (% of G+ who develop LVH during short to medium term longitudinal follow-up) are variable; influenced by age, the specific gene, and clinical context amongst other currently unidentified genetic and environmental factors.

Table 1.

Sarcomere genes definitively associated with HCM.

Gene*	Protein	Prevalence in HCM cohorts	Cross-Sectional Penetrance in family/clinical studies†
MYBPC3	Myosin-binding protein C	30–40%	≈ 55%
MYH7	β-Myosin heavy chain	10–30%	≈ 65%
TNNT2	Troponin T	3–10%	≈ 60%
TNNI3	Troponin I	3–10%	≈ 60%
MYL2	Myosin regulatory light chain 2	<3%	≈ 65%
MYL3	Myosin essential light chain 3	<3%	≈ 30%
TPM1	α-Tropomyosin	<3%	≈ 50%
ACTC1	α-Actin	<1%	≈ 70%

^*Ordered based on prevalence (i.e., % of P/LP carriers amongst G+ participants) in clinically-based HCM cohorts.

^†Defined as the % of P/LP carriers who have LVH in cross-sectional family/clinically-based HCM studies.

Traditionally, HCM is diagnosed by the presence of unexplained LVH with maximal LV wall thickness (MWT) ≥15 mm (or ≥13mm for at-risk relatives or sarcomere variant carriers) on cardiac imaging-- echocardiography or cardiovascular MRI (CMR). Although LVH is a key feature, this binary definition of disease does not account for concurrent features that impact LV wall thickness, such as sex, ethnic background, comorbidities, or body size, leading to both under-diagnosis and over-diagnosis. The definition does not recognize that the disease is a continuum and that the absence of LVH cannot be translated to no phenotype in sarcomere variant carriers. A dichotomous cutoff also fails to encompass the complex phenotypic spectrum of HCM which extends beyond simple alteration of LV wall thickness. Furthermore, phenotypic manifestations of sarcomere variants are detectable prior to the emergence of LVH and fundamental to the pathophysiology of overt HCM. Abnormal cardiac morphology (e.g., small cavity size³), altered myocardial energetics (e.g., lower phosphocreatine-to-adenosine triphosphate [ATP] ratio on MR spectroscopy⁴), activation of pro-fibrotic pathways^5,6, electrical abnormalities (e.g., pathological Q-waves on electrocardiogram [ECG]), diastolic dysfunction (e.g., lower global E’ velocities on Doppler echocardiography⁷), abnormal Ca²⁺ signaling, and microvascular dysfunction (e.g., perfusion defects on stress CMR⁸) have all been identified in subclinical HCM. Importantly, how these early phenotypic manifestations, individually or collectively, influences the evolution to overt HCM or prognosis is not well characterized. Moreover, the factors that render sarcomere variant carriers susceptible or resilient to developing penetrant disease are not understood. Given the absence of severe remodeling and extensive fibrosis, the subclinical stage could be more amenable to therapies aimed at attenuating disease progression or, ultimately, preventing disease emergence. However, reliable metrics of early phenotypic progression and inflection points where the natural course of the disease may be altered through intervention have not been elucidated. In the light of recent advancements in developing novel disease-specific therapies (e.g., myosin inhibitors and gene-based therapy), there is pressing need to gain a comprehensive understanding of the subclinical HCM and the transition to overt disease.

We conducted a systematic review to summarize current knowledge about early phenotypic manifestations in humans with subclinical HCM who carry P/LP sarcomere gene variants in the absence of left ventricular hypertrophy (G+LVH−). We also sought to evaluate available information regarding the transition from subclinical to clinically overt disease, including factors which influence disease penetrance and expressivity.

Methods

Search Process

The review was conducted to fulfill the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria. Our review question was: “What is known about the subclinical HCM phenotype and about the transition from G+LVH− to overt HCM in humans?”. Any English-written original research published or pre-print manuscripts, meta-analyses, conference abstracts or case reports available online through electronic indexing on PubMed, Embase, Scopus, Web of Science, Google Scholar, Cochrane Library, MedRxiv, and BioRXiv providing insights about our review question were included in this study.

A systematic search of the above academic search engines was used to identify relevant eligible publications up to 1^st of March 2024. Search items were defined using the PECO (Patient/Exposure/Comparator/Outcomes) framework: (P)= (“hypertrophic cardiomyopathy”, “HCM”, “LV hypertrophy”); (E)= (“pre-phenotypic”, “prephenotypic”, “non-hypertrophic”, ”nonhypertrophic”, “pre-LVH”, “pre-clinical”, ”preclinical”, ”sub-clinical”, “subclinical”, “early disease”, “gene carrier”, “mutation carrier”, “gene positive”, “gene mutation”, “variant carrier”, “HCM carrier”); (C)= (“overt HCM”, “hypertrophic HCM”, “genotype positive HCM”, “phenotype positive HCM”); (O)= (“penetrance”, “phenotypic conversion”, “expressivity”, “age of onset”, “age of diagnosis”, “prevalence”, “manifestations”, “phenotype”, “morphological”, “structural”, “functional”, “dysfunction”, “characteristic”, “feature”, “transition to disease”, “disease progression”, “disease evolution”). We modified the search queries by including individual genes from Table 1 instead of using the generic term “gene”. We combined the categories of the PECO framework using “AND”, while grouping variations within each category were combined using “OR.” We excluded systematic and literature reviews; meta-analyses results were included. We also excluded studies which: (1) did not provide insights into subclinical HCM, (2) did not appraise the presence of variants using genotyping, (3) did not evaluate the presence of LVH with structural imaging (i.e., echocardiography or CMR), (4) were basic science studies such as human laboratory (e.g., cell cultures) or animal HCM studies, and (5) were conducted in syndromic HCM or HCM phenocopies. Despite the concordance between basic science models (e.g., mouse HCM models) and HCM in humans, not all insights derived from these studies are translational. Although excluded as part of the systematic search, selected insights of interest for future clinical trials about mechanisms and potential therapeutics from basic science studies were discussed in instances where human clinical data was lacking. Considering the absence of validated tools to assess study quality in the specific context of this review, we opted not to pursue a formal quality assessment. Nevertheless, we thoroughly critically appraised the included studies.

Results

Search results

Database searches identified 2326 articles. After screening the abstracts, 611 full text manuscripts were assessed. After applying our exclusion criteria, 91 were included in the qualitative analysis. Figure 1 presents the PRISMA flow chart.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow-chart.

Phenotypic Spectrum of Subclinical HCM

Abnormal Myocardial and Mitral Valve Morphology

Morphologic abnormalities have been consistently identified in subclinical HCM, including larger atrial volumes^9,10, bulky septomarginal trabeculum and increased septal convexity (Fig. 2A), higher prevalence of myocardial crypts^11–13 (Fig. 2B), the presence of an LV apical-basal muscle bundle¹⁴, small LV cavity size³, higher maximal septal to lateral WT ratio¹⁰, increased LV apical rotation and twist¹⁵, multiple accessory papillary muscle heads and their anterior displacement^16,17, elongated anterior mitral valve leaflets (MVL)¹⁶ (but normal posterior MVL¹⁸) (Fig. 2C) which can display systolic anterior motion¹⁹, and abnormal trabecula detected by CMR fractal analysis²⁰ (Fig. 2D). MV abnormalities may represent a primary phenotype which evolves independently of LVH and increases susceptibility to developing LVOT obstruction¹⁸. Additionally, progression to overt HCM may be more likely in G+LVH− participants with longer MV leaflets⁷. Similarly, phenotypic conversion may be higher in those with greater, although normal, LV wall thickness at initial evaluation⁹.

Figure 2.

CMR features in sarcomere variant carriers (G+ LVH–) which are not present in healthy individuals (G-LVH-) Using CMR, a broad spectrum of structural and functional abnormalities can be seen in sarcomere gene variant carriers (G+LVH−): (A) increased septal convexity using CMR structural imaging (best seen on 4C); (B) myocardial crypts in the basal LV segments on CMR structural image (best seen on 2C); (C) MV abnormalities such as leaflet elongation using CMR structural imaging (best seen on 3C); (D) increased trabeculation using fractal analysis of the cine images; (E) borderline/slightly increased T₁ on non-contrast T₁ maps; (F) myocardial perfusion defects using adenosine stress perfusion (a focal defect is presented, but defects can also be diffuse); (G) borderline/slightly increased ECV after contrast-enhanced T₁ mapping with GBCA; and (H) minimal LGE post-GBCA (LGE is absent in the vast majority). Images were obtained at 1.5T at St Bartholomew and Royal Free hospitals in London. Red arrows indicate abnormalities, while green arrows indicate normal variants.

2C/3C/4C =two/three/four chambers; bSSFP = balanced steady state free precession; CMR = cardiovascular magnetic resonance imaging; ECV = extracellular volume; FD =fractal dimension; G+= presence of sarcomere variant; LVH+ =presence of LVH; GBCA = gadolinium-based contrast agents; HCM = hypertrophic cardiomyopathy; LGE = late gadolinium enhancement; LV = left ventricle; LVH= LV hypertrophy; MOCO = motion-corrected; PSIR = phase-sensitive inversion recovery; mm=millimeter; MV = mitral valves; ms = milliseconds.

Altered Myocardial Energetics

Abnormal myocardial energetics have been detected in subclinical HCM, but it is currently unclear whether this is related to insufficient energy generation and/or inefficient usage. For example, phosphorus-31 MR spectroscopy in subclinical HCM revealed a lower phosphocreatine-to-ATP ratio in the interventricular septum compared to other LV regions⁴. In addition, sarcomere variant carriers may also have a lower myocardial external efficiency (i.e., lower work per unit of oxygen consumption), with MYH7 potentially affected more than MYBPC3 carriers, even in the presence of normal myocardial blood flow^21,22. This could be due to lower myocardial ATP levels (potentially secondary to the decoupling between the phosphocreatine kinase pathway and mitochondrial oxidative phosphorylation), altered myosin cycling rates²³, and accelerated cross bridge detachment²⁴. Currently, the impact of reduced myocardial energetics in the subclinical stage is poorly understood, and its link with disease progression remains elusive. Nonetheless, cardiac hypertrophy secondary to worsened myocardial energetics is known to occur in other genetic etiologies (e.g., mitochondrial ribonucleic acid²⁵, AMP-activated protein kinase²⁶ etc.).

Myocardial Fibrosis

Focal myocardial fibrosis as identified by late gadolinium enhancement (LGE) on CMR imaging is present in ~60% of adults¹ with overt HCM but its prevalence is lower (i.e., 40–50%) in the pediatric population²⁷. It is thought to be related to disease duration and has been associated with the extent of hypertrophy²⁸, inducible ischemia²⁹, sudden death risk³⁰, LV dilation, and systolic dysfunction³¹. Indeed, focal LGE is very rarely seen in the subclinical stage^6,27. Nonetheless, animal models of HCM have demonstrated that profibrotic pathways are upregulated before development of histological fibrosis and hypertrophy³². Focused human studies have suggested that a profibrotic state may be present in G+LVH− individuals. Increased serum levels of C-terminal pro-peptide of type I procollagen [PICP] and PICP-to-C-terminal telopeptide of type I collagen ratios⁵ (indicating more collagen synthesis than degradation leading to extracellular matrix [ECM] deposition) have been detected. Moreover, a six-peptide multiplex biomarker panel consisting mostly of ECM-related proteins was found to be elevated in overt HCM and G+LVH− compared to healthy controls³³. Additionally, in contrast to focal fibrosis, CMR studies in G+LVH− demonstrated that interstitial fibrosis may be increased. There is a longer native myocardial T₁^34,35 (Fig. 2E) and higher extracellular volume (ECV)⁶ (Fig. 2G) using myocardial mapping sequences. ECV also correlated with higher serum N-terminal pro-peptide of B-type natriuretic peptide (NT-proBNP) levels and lower e’ velocity on echocardiography, suggesting that increased ECV has physiologic relevance and leads to increased hemodynamic stress and diastolic abnormalities⁶. Thus, it has been speculated that a predisposition for developing myocardial fibrosis may be an early direct consequence of pathogenic sarcomere variants, not exclusively secondary to LVH^36,37. The absence or minimal presence of LGE in subclinical (Fig. 2H) may be a result of the limitations of using LGE to detect fibrosis (e.g., need to null against healthy myocardium) rather than signifying the absence of fibrosis or fibrotic tendencies.

From a treatment perspective, activation of transforming growth factor β (TGF-β) is thought to be one of the mediators of profibrotic processes in HCM³⁶. Inhibition of these pathways may provide an opportunity to alter the genotype-phenotype transition in variant carriers. The renin-angiotensin-aldosterone system may be involved in the fibrotic remodeling as angiotensin II upregulates TGF-β³⁸. In animal models, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and aldosterone antagonists were shown to reduce the development of hypertrophy and fibrosis^39–41. Translation to HCM in humans was investigated in the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial⁴². Valsartan appeared to improve cardiac structure and function in early-stage but clinically overt sarcomere-related HCM, however significant benefit could not be detected in a small exploratory cohort of gene variant carriers with subclinical HCM⁹.

Electrical Abnormalities

ECV expansion might explain some of the ECG abnormalities such as the presence of Q-waves, higher RS voltages sometimes meeting ECG LVH criteria (e.g., Sokolow-Lyon), and ST segment/T-wave changes identified in subclinical HCM (Fig. 3)⁴³. However, these ECG findings are non-specific as they can exist in health in certain ethnicities (e.g., African-Caribbeans) or in athletes, but can also be present in other conditions (e.g., hypertension). However, an abnormal ECG was associated with a 4-fold higher risk of developing overt HCM over 15 years in a longitudinal study⁴⁴.

Figure 3.

ECG features in sarcomere gene variant carriers (G+ LVH–). Using ECGs, a broad spectrum of electrophysiological abnormalities can be seen in sarcomere gene variant carriers (G+LVH−): (A) pathological Q-waves (>2 mm deep or >25% of the depth of the QRS complex unless in leads III or aVR); (B) tall R-waves and (C) deep S-waves sometimes meeting ECG LVH criteria (e.g., Sokolow-Lyon); (D) QRS fragmentation; (E) ST-depression; (F) T-wave inversion; and (G) giant T-waves (T-waves >1mV; usually positive but sometimes inverted).

ECG = electrocardiogram/electrocardiography; mm =millimeter; mV=millivolt. Other abbreviations as in Figure 2.

Systolic and Diastolic Dysfunction

Tissue Doppler echocardiography has identified impaired relaxation, as reflected by the lower mitral annular velocities (e’), and increased filling pressures, reflected by increased E/e’ ratio, in subclinical HCM^45–47. Additionally, G+/LVH- individuals with lower global e’ velocities⁷ appeared to be more likely to progress to overt HCM.

Besides LV stiffening secondary to ECV expansion⁶, additional proposed pathophysiological mechanisms underlying diastolic dysfunction in subclinical HCM include increased cytosolic Ca^{2+ 48}, increased myofilament Ca²⁺ sensitivity due to reduced troponin phosphorylation^49–51, smaller LV cavity size³, and altered myocardial activation as a direct result of the sarcomere variant (e.g., altered actin ATPase activity^52,53, reduced super-relaxed state of myosin^54,55, higher gliding velocity^52,56, and greater force generation^52,57). Importantly, mavacamten (a myosin ATPase inhibitor) was able to suppress the development of LVH, myocardial disarray, and fibrosis in G+LVH− animal models⁵⁸. However, the role of myosin ATPase inhibitors in human sarcomere variant carriers has not been explored in clinical trials.

Although LV ejection fraction is usually supranormal^59,60, sarcomere variant carriers have been shown to have impaired myocardial dynamics characterized by worse strain values suggesting some impairment of systolic function^10,61–63. G+LVH− individuals with higher NT-proBNP may be more likely to develop overt HCM⁶⁴.

Impaired Calcium Signaling

Increased cytosolic Ca²⁺ has been shown to precede the development of LVH in some animal models of HCM⁴⁸. Since Ca²⁺ is an inotrope, the increased Ca²⁺ signaling might also underlie supranormal systolic function^59,60 identified in subclinical HCM by CMR. Following beneficial results seen in a mouse model of HCM, diltiazem⁶⁵, a calcium-channel blocker, increased LV end diastolic diameter and reduced wall thickness in G+/LVH– in a pilot human clinical trial, suggesting a potential disease-modifying role for calcium-channel blockers if used at the subclinical HCM stage³.

Increased cytosolic Ca²⁺ may potentially lead to over-activation of calmodulin kinase, thus disinhibiting the growth factor, mammalian target of rapamycin (mTOR) and facilitating development of LVH. Indeed, mTOR inhibitors^66–69 were able to attenuate LVH development in G+LVH− animal models. However, clinical translation of mTOR inhibitors has not yet been investigated in humans.

Microvascular Dysfunction

Microvascular dysfunction is also linked to abnormal morphology and diastolic dysfunction. On a background of dysfunctional angiogenesis, even a small degree of impaired relaxation may compress the microvasculature and further reduce the capillary MBF and increase susceptibility to ischemia⁷⁰. Regionally and globally impaired myocardial perfusion on adenosine stress perfusion CMR was observed in G+LVH− individuals, suggesting microvascular dysfunction (Fig. 2F)⁸. Moreover, oxygen-sensitive CMR sequences suggested that subclinical HCM is characterized by impaired tissue oxygenation⁷¹. In response to reduced MBF, the cardiomyocytes may express hypoxia inducible factors (HIFs) which could trigger a signaling cascade translating into cardiomyocyte hypertrophy and fibroblast proliferation. A small study in pediatric HCM suggested that HIF1A upregulation was associated with a younger age of HCM onset, increased LVH and worsened diastolic dysfunction⁷². In addition, basic science studies suggest that P/LP MYBPC3 and MYH7 variants may induce HIF signaling early in the disease pathogenesis⁷³.

Discussion

Altered Pathways in Subclinical HCM

This review summarizes subtle early phenotypic manifestations that can be identified in sarcomere variant carriers before a diagnosis of HCM can be established, when LV wall thickness is normal. Thematic groups can be established, for example, both myocardial and MV morphological abnormalities have been reported in subclinical HCM, including smaller LV cavity size³, increased septal convexity, and longer MV leaflets¹⁶. Sarcomere variants may lead to the pathological activation of pro-fibrotic pathways^36,37. Indeed, increased interstitial fibrosis has been detected in G+LVH− individuals⁶ and may partly underlie the impaired relaxation and ECG abnormalities seen in the subclinical stage. Notably, ECV decreases in athletes, suggesting that physiological hypertrophy occurs without ECM expansion⁷⁴. Inefficient myocardial energetics in the subclinical state^4,21,22 has been postulated to contribute to “compensatory” hypertrophy, although robust supporting evidence is lacking. However, despite identifying early phenotypic manifestations, to date, a unifying theory has not been established to explain how sarcomere variants lead to HCM. To establish the sequence of events, a more comprehensive understanding of the pathways activated in the earliest stages of disease is needed. To map the changes which occur as sarcomere variant carriers transition to overt disease, a multidisciplinary approach integrating basic science and long-term prospective clinical studies is vital. This approach will hopefully also identify therapeutic targets that can alter the natural history of the disease, leading to the development of novel disease-modifying strategies that will slow progression or prevent the emergence of HCM.

Predicting Transition from Subclinical to Overt HCM

The transition from subclinical to clinically overt HCM is poorly captured and poorly understood. Because of this uncertainty, surveillance of at-risk relatives is currently relatively crude with lifelong clinical screening uniformly recommended, starting with first degree relatives,^{75 76} although penetrance is incomplete and risk for disease development is not equally distributed.

Previous studies have identified the affected gene² (variants in MYBPC3^77,78, MYH7^79,80, TTNT2^81,82 and TNNI3^83,84), co-existence of multiple P/LP variants⁸⁵, a positive family history², older age⁸⁶, male sex⁸⁷, ethnicity⁸⁸, higher body size⁸⁹, higher blood pressure⁹⁰, and an abnormal ECG⁴⁴ as risk factors for developing penetrant disease in the short term, however it remains unclear how these factors influence the subclinical phenotype or the pathophysiological mechanisms driving the transition from subclinical to clinically overt disease. Another study suggested that progression to HCM was more likely in G+LVH− with longer MV leaflets, lower global E’ velocities on Doppler echocardiography and higher serum NT-proBNP over a median follow-up of 3 years starting from a mean age of 16 years⁷. Additionally, individuals relatively greater but still normal septal thickness and larger left atrial volume (indexed to body surface area) at baseline may also be more likely to develop overt HCM during a 2-year longitudinal follow-up starting from a mean age of 16 years⁹. If none of these features are present, a longer interval between screenings may be reasonable. Conversely, if these features or other early phenotypic manifestations are identified, more frequent surveillance would be appropriate. Further study is needed to determine how to better tailor and individualize long term family screening.

Improving the Definition of HCM

Recognizing that the phenotype of HCM extends beyond just increased LV wall thickness is important to improve diagnosis and understanding of this complex cardiomyopathy. However, diagnostic criteria for HCM have remained unaltered for >50 years and focus only on a dichotomous threshold of maximal LV wall thickness: >15mm in probands and >13mm in sarcomere variant carriers or relatives of probands given the higher pretest probability of HCM^75,76. LV wall thickness is influenced by age, sex, ethnicity, body size, physical fitness, and the presence of co-morbidities (e.g., pressure overload)⁹¹. Accounting for demographic characteristics and comorbidities will allow us to develop more personalized and biologically relevant thresholds to define pathologic LVH. In addition to considering the totality of phenotypic manifestations, using more accurate thresholds for LVH will improve the diagnosis HCM.

Conclusions

The absence of LVH is not equivalent with the absence of a phenotype in sarcomere variant carriers. Individuals with subclinical HCM can have abnormal cardiac morphology, pro-fibrotic remodeling, myocardial tissue abnormalities, impaired relaxation, abnormal Ca²⁺ signaling, microvascular dysfunction and altered myocardial energetics. The subclinical phase of HCM provides a unique window of opportunity to interrupt disease progression, as disease modification may be more biologically feasible earlier, before cardiac remodeling is advanced, and pathophysiology entrenched. To leverage this opportunity, large-scale longitudinal studies of G+LVH− individuals are critically needed to understand disease trajectories, to identify robust, dynamic biomarkers that track disease progression or incipient transition to overt HCM, and to discover critical periods, where phenotypic progression may be intercepted. Such knowledge will also have immediate clinical impact by informing family management. Accurate stratification of risk for developing clinical HCM would reduce and appropriately focus the burden of longitudinal screening. These insights will also guide the development of disease-modifying therapies intended to prevent HCM in genetically susceptible individuals.

Nonstandard Abbreviations and Acronyms

ACMG

American College of Medical Genetics and Genomics

ATP

adenosine triphosphate

CMR

cardiovascular magnetic resonance imaging

ECG

electrocardiogram

ECM

extracellular matrix

ECV

extracellular volume

G+LVH−

the absence of left ventricular hypertrophy in sarcomere or sarcomere-related variant carriers or subclinical hypertrophic cardiomyopathy

G+LVH+

the presence of left ventricular hypertrophy in sarcomere or sarcomere-related variant carriers or overt hypertrophic cardiomyopathy

HIF

hypoxia inducible factor

LGE

late gadolinium enhancement

HCM

hypertrophic cardiomyopathy

LGE

late gadolinium enhancement

LV

left ventricle

LVH

left ventricular hypertrophy

mTOR

mammalian target of rapamycin

MV

mitral valve

MVL

mitral valve leaflets

MWT

maximal wall thickness

MYBPC3

myosin binding protein C

MYH7

β -myosin heavy chain

NT-proBNP

N-terminal pro-peptide of B-type natriuretic peptide

P/LP

pathogenic or likely pathogenic

PICP

C-terminal pro-peptide of type I procollagen

TGF-β

transforming growth factor β

TNNI3

troponin I

TNNT2

troponin T