Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy

*Davide Lazzeroni and Claudio Stefano Centorbi*

#### **Abstract**

Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is characterized by cardiac hypertrophy, unexplained by the loading conditions, a non-dilated left ventricle and a normal or increased left ventricular ejection fraction (LV-EF). Prevalence of HCM has been estimated at 0.16% to 0.29% (≈ 1:625–1:344 individuals) in the general adult population. HCM represents the most common genetic heart disease and represent an archetypical single gene disorder with an autosomal dominant pattern of inheritance and historically termed a "disease of the sarcomere". The precise mechanisms by which sarcomere variants result in the clinical phenotype have not been fully understood. Mutant sarcomere genes trigger several myocardial changes, leading to hypertrophy and fibrosis, which ultimately result in a small, stiff ventricle with impaired systolic and diastolic performance despite a preserved LV-EF. The most common differential diagnosis challenges in the presence of hypertrophic heart disease are represented by: athlete's heart, hypertensive heart and other cardiomyopathies mimicking HCM. A multimodality approach using ECG, echocardiography, CMR, cardiac computed tomography (CCT) and cardiac nuclear imaging provides unique information about diagnosis, staging and clinical profiles, anatomical and functional assessment, metabolic evaluation, monitoring of treatment, follow-up, prognosis and risk stratification, as well as preclinical screening and differential diagnosis. HCM may be associated with a normal life expectancy and a very stable clinical course. However, about a third of patients develop heart failure (HF); in addition, 5–15% of cases show progression to either the restrictive or the dilated hypokinetic evolution of HCM, both of which may require evaluation for cardiac transplantation. The clinical course of HCM has been classified into four clinical stages: nonhypertrophic, classic, adverse remodeling and overt dysfunction phenotype. No evidence-based treatments are available for non-hypertrophic HCM patients (prehypertrophic stage), on the other hand in classic HCM, adverse remodeling and overt dysfunction phenotype, pharmacological or interventional strategies have the target to improve functional capacity, reduce symptoms, prevent disease progression. Therapeutic approach mainly differs on the basis of the presence or absence of significant obstructive HCM. Adult patients with HCM report an annual incidence for cardiovascular death of 1–2%, with sudden cardiac death (SCD), HF and thromboembolism being the main causes of death; the most commonly recorded fatal arrhythmic event is spontaneous ventricular fibrillation. For this reason, SCD risk estimation is an integral part of clinical management of HCM. International guidelines suggest the evaluation of several risk factor for SCD based on personal and family history, non-invasive testing including echocardiography, ambulatory

electrocardiographic 24 hours monitoring and CMR imaging in order to identity those patients most likely to benefit implantable cardioverter-defibrillator (ICD) implantation. The present chapter summarize genetics, pathogenesis, diagnosis, clinical course and therapy of HCM as well as novel therapeutic options.

**Keywords:** hypertrophic cardiomyopathy, left ventricular hypertrophy, genetics, sudden cardiac death, heart failure, echocardiography, cardiac magnetic resonance, athlete's heart, hypertrophic phenocopies

#### **1. Introduction**

#### **1.1 Definition and epidemiology**

Cardiomyopathies are defined by structural and functional abnormalities of the ventricular myocardium that are unexplained by flow-limiting coronary artery disease or abnormal loading conditions [1]. Historically, cardiomyopathies has been subdivided into primary disease, in which the heart is the only involved organ, and secondary forms where the cardiomyopathy is a manifestation of a systemic disorder. Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is characterized by cardiac hypertrophy, unexplained by the loading conditions, a nondilated left ventricle (LV) and a normal or increased left ventricular ejection fraction (LV-EF) [2]. HCM is a disorder without a distinct geographic, ethnic or gender pattern of distribution. Prevalence of HCM has been estimated at 0.16% to 0.29% (≈ 1:625–1:344 individuals) in the general adult population [2–5]. HCM is characterized by highly variable genotype–phenotype relationship with intra- and inter-family expressivity and incomplete penetrance. Given the age-dependent expression of HCM mutations, its prevalence is expected to be higher in older subjects; in fact, HCM has been reported in 0.29% (1:333) of 60-year-old individuals undergoing echocardiography for cardiovascular evaluation. [2–5]. Moreover, a much higher estimate of 0.6% (1:167) has been suggested using more sensitive imaging methods, when family members are evaluated and when genetic testing is more widely used [6–8]. On the other hand, in children cardiac hypertrophy could result from the phenocopy conditions, which might account for 5% to 10% of the clinically diagnosed HCM cases [9–11].

#### **2. Genetics**

HCM represents the most common genetic heart disease reported in populations globally. HCM is an archetypical single gene disorder with an autosomal dominant pattern of inheritance, whereby a single mutation is usually sufficient to cause the disease, albeit with variable penetrance and expression [12]. Autosomal recessive and X-linked modes of inheritance have been described but are rare [13, 14]. Approximately 60% of patients with HCM have a clearly recognizable familial disease. On the other hand, despite the great advances of the research in the field of genetics in cardiomyopathies, to date about 40% of HCM shows negative genetic testing or variants of non-certain significance. These data suggest that even non-genetic factors could contribute to the development of HCM. Moreover, a substantial proportion of patients with HCM are currently without any evidence of a genetic etiology to their disease, including a subgroup who also have no other affected family members (named "non-familial" HCM) [15]. For these reasons, the absence of an identified causative mutation should not allow to exclude a diagnosis in the presence of diagnostic criteria for HCM. Historically, HCM was termed a

#### *Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

"disease of the sarcomere" when the first three disease genes encoding components of the contractile apparatus of heart muscle were identified [16]. However, a wide variety of non-sarcomeric genes has been associated with HCM, thus suggesting that LV hypertrophy in HCM may not be a consequence of exclusive sarcomeric mutations. Among the known causal genes (**Figure 1**), thick myofilaments proteins such as MYH7 and MYBPC3 (myosin- binding protein C) are the 2 most common, together being responsible for approximately half of the patients with familial HCM [17–20]. On the other hand, mutations in thin myofilament proteins such as TNNT2, TNNI3 (cardiac troponin I) and TPM1 (α-tropomyosin) are relatively uncommon causes of HCM and together are responsible for less than 10% of cases [19–22]. Mutations in ACTC1 (cardiac α-actin), MYL2 (myosin light chain 2), MYL3 (myosin light chain 3), and CSRP3 (cysteine and glycine-rich protein 3) are also established, albeit uncommon, causes of HCM [23–25]. Moreover, mutations in TTN (titin), TCAP (telethonin), MYOZ2 (myozenin 2), TRIM63 (ubiquitin E3 ligase tripartite motif protein 63 or MuRF1), and FHL1 (four-and-a-half LIM domains 1) also have been implicated as causes of HCM but occur typically in sporadic cases and small families [26–33]. On the other hand, mutations in TNNC1 (cardiac troponin C), MYH6 (myosin heavy chain or α-myosin heavy chain), PLN (phospholamban), CAV3 (caveolin3), ALPK3 (α kinase 3), and JPH2 (junctophilin-2) have also been reported in patients with HCM [34–39] but their causal role in HCM is less certain and has not been established unambiguously. An X-linked inheritance typically raises the possibility of a phenocopy condition, such as Fabry disease [40]. A phenocopy condition also occurs in syndromic diseases, such as the Noonan syndrome and in storage diseases, such as Anderson–Fabry disease. [41, 42]. Finally, a subset of HCM patients (≈5%) exhibits 2 (digenic) or more (oligogenic) causal mutations in the same gene or causal mutations in different genes [20, 43–51] and the severity of LV hypertrophy in subjects with

#### **Figure 1.**

*HCM genetics and pathogenetic mechanisms. Center part: A schematic structure of a sarcomere composed of thick and thin filaments and Z discs is showed along with its protein constituents. Established causal genes for HCM and their relative population frequencies are listed. Panel A-D: HCM pathogenetic pathways (not be considered in isolation since they can act in concert). Panel a: Biomechanical stress sensing pathway. Panel B: Calcium cycling and sensitivity pathway. Panel C: Energy homeostasis pathway. Panel D: Fibrotic pathway. Abbreviations: LTCC, voltage-dependent L-type calcium channel; PLB, cardiac phospholamban; RyR2, ryanodine receptor 2; SERCA2, sarcoplasmic/endoplasmic reticulum calcium ATPase 2; SR, sarcoplasmic reticulum; TGF-*β*, transforming growth factor* β*; MITO, mitochondria.*

such mutations seems to be more pronounced [44–48]. The majority of the causal mutations in HCM are missense mutations which may alter protein structure and function by changing the amino acid composition of the encoding protein. The insertion/deletion mutations induce a frameshift in the encoded protein. Likewise, the premature truncated proteins are subsequently degraded by the ubiquitin proteasome system, leading to haplo-insufficiency [19, 20, 52]. The missing causal gene in HCM might be in part because of the difficulty in ascertaining the causality of the genetic variants, in an unambiguous manner, in the sporadic cases and small families [53]. In general, genetic variants exert highly variable biological consequences, ranging from large and causal to clinically negligible [54–56]. The demonstration of an association between a candidate gene and the HCM phenotype in a discovery population is considered provisional (ie, hypothesis-generating) and requires testing for replication in an independent population.

#### **3. Pathogenesis**

The precise mechanisms by which sarcomere variants result in the clinical phenotype have not been fully understood. Mutant sarcomere genes trigger several myocardial changes, leading to hypertrophy and fibrosis, which ultimately result in a small, stiff ventricle with impaired systolic and diastolic performance despite a preserved LV-EF [57]. On the other hand, abnormal sarcomeric proteins may not be solely responsible for all of the clinical characteristics observed in patients with HCM. Diverse disease features including abnormal intramural coronary arteries, responsible for small vessel ischemia, elongated mitral valve leaflets, as well as congenital anomalies of the sub-mitral valve apparatus, appear to have no known direct association with sarcomere mutations. From a metabolic viewpoint, mutations in sarcomeric proteins generally increase myofilament activation and result in myocyte hypercontractility and excessive energy use [58] due to higher (disproportionate) mitochondrial activity (**Figure 1**). Mitochondrial impairments in the cardiac energy-sensing apparatus (e.g., AMP-activated protein kinase [AMPK]) as well as alterations in calcium handling result in a stimulation of signaling pathways (e.g., the Janus-associated kinase–signal transducers and activators of transcription [JAK–STAT] signaling pathway) that contribute to myocyte relaxation abnormalities and growth, with aberrant tissue architecture abnormalities such as myofibrillar disarray and myocardial fibrosis [59–62].

#### **4. Diagnosis**

#### **4.1 Diagnostic criteria**

In 2014 ESC Guidelines, HCM is defined by a wall thickness ≥ 15 mm in one or more LV myocardial segments - as measured by any imaging technique (echocardiography, cardiac magnetic resonance imaging (CMR) or computed tomography (CT) - that is not explained solely by loading conditions, thereby including both sarcomeric and non-sarcomeric mutations, such as other genetic disorders (inherited metabolic and neuromuscular diseases, chromosome abnormalities) genetic syndromes and non-genetic disorders (e.g. senile-TTR and AL amyloidosis) [2]. On the other hand, in 2020 AHA Guidelines, HCM is defined as a disease state in which morphologic expression is confined solely to the heart and characterized predominantly by LVH (wall thickness ≥ 15 mm) in the absence of another cardiac, systemic, or metabolic disease capable of producing the magnitude of hypertrophy

*Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Diagnosis, Clinical Course and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97033*

evident in a given patient and for which a disease-causing sarcomere (or sarcomererelated) variant is identified, or genetic etiology remains unresolved [57].

Genetic and non-genetic disorders can present with lesser degrees of wall thickening (13–14 mm). In these cases, the diagnosis of HCM requires evaluation of other features including family history, non-cardiac symptoms and signs, electrocardiogram (ECG) abnormalities, laboratory tests and multi-modality cardiac imaging [2]. More limited LVH can be diagnostic in family members of HCM patients or with a positive genetic test [57]. Children, as in adults, the diagnosis of HCM requires an LV wall thickness more than two standard deviations greater than the predicted mean (z-score: defined as the number of standard deviations from the population mean) [63]. In first-degree relatives of HCM patients with unequivocal disease (LVH ≥15 mm) the diagnosis is based on the presence of otherwise unexplained increased LV wall thickness ≥ 13 mm in one or more LV myocardial segments, as measured using any cardiac imaging technique [echocardiography, cardiac magnetic resonance (CMR) or CT].

#### **4.2 Differential diagnosis:** *"from athlete's heart to HCM phenocopies"*

The most common differential diagnosis challenges in the presence of hypertrophic heart disease are represented by: athlete's heart, hypertensive heart and other cardiomyopathies mimicking HCM.

#### *4.2.1 Athlete's heart*

HCM is the most common cause of sudden cardiac death (SCD) among athletes [64]. Systematic and endurance training can lead to physiologic LV hypertrophy thereby mimicking mild forms of HCM [64]. Distinguishing between these two forms represents an important diagnostic dilemma during athlete cardiac evaluation, thus a combination of anamnestical, clinical and instrumental data is crucial to distinguish the physiological hypertrophy seen in athlete's heart from the pathological one seen in HCM. A positive family history of SCD represent an important factor that may point towards a genetic cardiomyopathy; similarly, ECG abnormalities such as ST depression, T wave inversion, abnormal Q waves or QRS axis increase the likelihood of HCM. On the other hand, isolated positive ECG criteria for hypertrophy are not enough to suspect HCM in the athlete [64]. Even in the presence of septal thickness values suspected for mild form of HCM (ranging form 14–16 mm), in the athlete's heart echocardiogram generally presents several characteristics that are uncommon in HCM such as: normal or dilated LV volumes or normal systolic and diastolic function evaluated both with traditional methods (M-Mode or 2D) and with tissue Doppler or strain echocardiography. Moreover, a reduction in LV wall thickness after a period of deconditioning points to physiological hypertrophy [65]. In some cases, further investigations such as exercise testing (arrhythmias or abnormal blood pressure response), 24 hours ECG monitoring (arrhythmias), CMR (fibrosis) or genetic testing (causative mutations) are needed to define the presence of HCM. **Table 1** summarizes the clinical-instrumental aspects most useful in the differential diagnosis between HCM and athlete's heart.

#### *4.2.2 Hypertensive heart*

Left ventricular hypertrophy secondary to arterial hypertension can be difficult to distinguish from mild forms of non-obstructive HCM caused by sarcomeric mutations; moreover an overlap between primary and secondary LV hypertrophy could be present in up to 25% of adult HCM patients with arterial hypertension [66].


