Heart Failure as a Consequence of Hypertrophic Cardiomyopathy

Overview

Henri Liouville, a French pathologist, described the first case of hypertrophic cardiomyopathy (HCM) in 1869. The patient was an elderly woman with symptoms of heart failure, a ventricular wall thickness of 3.5 to 4 cm and left ventricular outflow tract (LVOT) obstruction. Dr. Liouville described the LVOT obstruction as “Rétrécissement cardiaque sous aortique,” which literally translates to subaortic cardiac. Since this initial description, there has been considerable interest in the unusual clinical and pathological manifestations of HCM.

Alexander Schmincke described diffuse muscular “hyperplasia” at the LVOT and pointed out the vicious cycle of left ventricular hypertrophy and outflow tract obstruction, perpetuating each other. Robert L. Levy and William C. Von Glahn described HCM as “Cardiac Hypertrophy of Unknown Etiology in Young Adults” in 1933. William Evans reported the familial nature of “idiopathic cardiomegaly” in 1949 and constructed the first documented pedigree of a family with HCM. Donald Teare also noted the familial nature of HCM in a young adult patient with severe cardiac hypertrophy. J.A.P. Paré and colleagues described the autosomal dominant mode of inheritance of HCM in a large French-Canadian family, whose genetic mutation was identified by Christine Seidman and colleagues three decades later.

Lord Russell Brock in England and Andrew Glenn Morrow and Eugene Braunwald in the United States recognized the dynamic nature of LVOT obstruction in HCM and concluded that the obstruction was due to “systolic narrowing of the LVOT resulting from massive muscular hypertrophy.” Dr. Braunwald and colleagues coined the term “idiopathic hypertrophic subaortic stenosis.” They also described the unique hemodynamic feature known as the Brockenbrough phenomenon and characterized left ventricular diastolic dysfunction as a major feature of HCM, independent of LVOT obstruction. These observations led Dr. Morrow and colleagues to introduce trans-aortic surgical myectomy in the 1960s, which is known as the Morrow operation.

Advances in echocardiographic imaging led to the next phase of discoveries in HCM and the description of asymmetric septal hypertrophy (ASH) and the assessment of LVOT obstruction by Doppler imaging. Echocardiography soon emerged as the most commonly used imaging tool in diagnosing HCM, the assessment of its severity, the detection of diastolic dysfunction, and the estimation of the LVOT gradient. Likewise, tissue Doppler and spectral imaging modalities provided valuable information on regional myocardial contraction and relaxation abnormalities as well as diastolic function. These imaging modalities also offer utilities in the preclinical and early identification of family members who carry the causal mutations for HCM.

The seminal discovery of the first causal mutation in familial HCM by Drs. Christine and Jon Seidman in 1990 ushered in the era of molecular genetics. The discovery, which was made in the original French-Canadian family described by Paré 30 years earlier, shifted the paradigm of HCM from being an “obscure” disease to primarily a genetic disease of sarcomere and sarcomere-associated proteins. The genetic discoveries brought forth the routine applications of genetic testing in the diagnosis and management of patients with HCM.

Ulrich Sigwart introduced alcohol septal ablation for the reduction of LVOT obstruction in three patients who reported marked and rapid improvement in their symptoms. The technique commonly known as percutaneous alcohol septal ablation has become an alternative modality to Morrow’s procedure for the treatment of selected symptomatic HCM patients with LVOT obstruction who are refractory to medical therapy.

Progress in diagnosis and management of patients with HCM has continued unabated. Notable among the recent progresses is the use of defibrillators (implantable cardioverter-defibrillator, [ICD]) in prevention of sudden cardiac death (SCD) in HCM as an effective intervention, particularly in the secondary prevention of SCD. In recent years a number of randomized clinical trials, albeit small-scale initial phase II and III studies, with new pharmacological agents have been initiated and are expected to pave the way for larger-scale efficacy studies. The findings could expand our pharmacopeia beyond the β blockers, which were established by Dr. Braunwald and colleagues, as the cornerstone of medical therapy for HCM more than half a century ago. Finally, development of new patient-specific and genetic-based therapies are being developed, which might fulfill the goal of tailoring the treatment to the individual patient.

Definition

HCM could be defined as a genetic disease of cardiac myocytes that grossly manifests with cardiac hypertrophy; often asymmetric, and a nondilated left ventricle with a preserved or increased ejection fraction ( Fig. 23.1 ). Thus, by definition, cardiac hypertrophy caused by loading conditions is excluded. Cardiac hypertrophy is commonly concentric but occasionally involves a specific left ventricular wall or apex. It is asymmetric with a predominant involvement of the interventricular septum in about quarter of the cases.

Epidemiology

HCM is a relatively common disease with an estimated prevalence of 1:500 (0.16% to 0.29%) in the world population. Population frequency of HCM might be higher than that estimated based on the expression of cardiac hypertrophy with a wall thickness of 15 mm or greater, as expression of hypertrophy is age-dependent and often absent in the young individuals. It is estimated that approximately 50% of those with the underlying causal HCM mutations develop HCM by the third decade of life, ∼75% by the fifth decade of life, and 95% by 50 years of age. Because of the age-dependent penetrance of HCM mutations, HCM is more prevalent in the older populations, estimated at 0.29% (44/15,137) in the 60-year-old individuals who have had an echocardiogram.

In the clinical diagnosis of HCM, phenocopy conditions should be considered, which might be present in 5% to 10% of those with the clinical diagnosis of HCM, particularly the children. In addition, the presence of concomitant conditions leading to increased load, such systemic arterial hypertension, could complicate the clinical diagnosis, hence estimating the true prevalence of HCM. A genetic-based diagnosis might facilitate the accurate diagnosis of HCM in such cases ( see also Chapter 24 ).

Molecular Genetic Basis of Hypertrophic Cardiomyopathy

HCM, a classic single gene disorder, is a familial disease in approximately two-thirds of cases and with an autosomal dominant pattern of inheritance. HCM with an autosomal recessive or an X-linked mode of inheritance is rare. The latter typically raises the possibility of a phenocopy condition, such as Fabry disease.

Pioneering studies by Christine and Jon Seidman have led to the discovery of the first causal gene for HCM, namely the MYH7 gene, which encodes sarcomere protein β-myosin heavy chain (MYH7), in the French-Canadian family that was originally described by Paré. Subsequently, additional causal genes, including MYBPC3 , TNNT2 , TPM1 , and TNNI3 , which encode myosin-binding protein C proteins, cardiac troponin T, α-tropomyosin, and cardiac troponin I, respectively ,were mapped and identified. Given that the well-established causal gene for HCM encodes sarcomere proteins, HCM is considered primarily a disease of sarcomere protein ( Fig. 23.2 ). Since the initial discoveries, over a dozen causal genes encoding sarcomere proteins and sarcomere-associated proteins, and thousands of mutations for HCM have been identified ( Table 23.1 ).

The list of established causal genes for HCM includes ACTC1 (cardiac α-actin), MYL2 (myosin light chain 2), MYL3 (myosin light chain 3), and CSRP3 (muscle LIM protein). In addition, TTN (titin), TCAP (telethonin), MYOZ2 (myozenin 2), TRIM63 (ubiquitin E3 ligase tripartite motif protein 63 or MuRF1), and FHL1 (four and a half LIM domain 1) also are likely causal genes for HCM. Finally, mutations in TNNC1 (cardiac troponin C), MYH6 (myosin heavy chain or α-myosin heavy chain), PLN (phospholamban), CAV3 (caveolin 3) , ALPK3 (α kinase 3) , and JPH2 (junctophilin 2) have been associated with HCM.

It is evident that HCM is a genetically heterogeneous disease. MYH7 and MYBPC3 are the two most common causal genes and together are responsible for approximately half of the familial HCM. TNNT2 , TNNI3 , and TPM1 are relatively uncommon causes of HCM and collectively are responsible for less than 10% of the HCM cases. The remainder of the causal genes are even less common. Overall, the known causal genes account for about two-thirds of the HCM cases.

The majority of the causal mutations are missense mutations. Premature truncating mutations are rare with the exception of MYBPC3 mutations, which are often insertion/deletion and frameshift mutations, leading to premature truncation of the encoded protein. The frameshift mutations are often transcribed into unstable mRNAs, which are targeted for degradation by the nonsense-mediated decay (NMD). Similarly, whenever a premature truncated protein is expressed it is typically degraded by the ubiquitin proteasome system (UPS), leading to haploinsufficiency. Rare deletion mutations in MYH7 , TNNT2, and others also have been reported.

Population frequency of a specific HCM mutation is low and most mutations are either rare or private mutations. A notable exception is the p.Arg502Trp mutation in MYBPC3 , which has been reported to occur in ∼2.4% of HCM patients. Likewise, the p.Val762Asp mutation in the MYBPC3 gene has been reported in 3.9% of the Japanese population. A few hot spots for mutation also have been reported. Moreover, mutations do not exhibit an aggregation in a specific domain of the encoded protein, with the exception of mutations in MYH7 , which show a predilection toward the globular head and hinge region of the protein, albeit mutations in the rod domain of MYH7 , which have also have been described. Finally, MYH7 and MYBPC3 are the two most common causal genes in apical HCM.

The causal gene in approximately one-third of HCM remains unknown. The so-called missing causal genes typically pertain to the sporadic cases, where establishing the causality of the genetic variants unambiguously is exceedingly challenging if not impossible. This is in contrast to large families where the causal genes and mutations could be unambiguously identified through cosegregation and linkage analysis. The difficulty in identifying the “missing causal genes” in the sporadic cases, is in part intrinsic to genetic diversity of the humans, as each genome comprises about 4 million genetic variants, including about 11,000 nonsynonymous, and several thousand pathogenic variants. In addition, the majority of the genetic variants is rare and population-specific, which makes it challenging to identify the responsible causal variant in a sporadic case. In addition, genetic variants exert a gradient of effect sizes, ranging from large and disease causing to clinically negligible. Those with large effect sizes are expected to exhibit a high penetrance, cause familial disease where the variant cosegregates with inheritance of the phenotype. In contrast, variants with moderate effect sizes exhibit incomplete or low penetrance in a familial setting and are often found in sporadic cases. Therefore, unambiguous ascertainment of genetic causality in such situations is difficult.

Finally, a subset of HCM, estimated to be about 5%, is caused by compound mutations in the same gene or two different genes. Double mutations seem to be associated with a more pronounced phenotype. Likewise, a small subset of HCM might be caused by multiple pathogenic variants, and hence, might be oligogenic in nature.

Pathogenesis

The mechanistic molecular pathways connecting the causal mutations to the ensuing clinical and phenotypic features of HCM are diverse ( Fig. 23.3 ). The mechanistic events could be sequentially categorized into three groups, based on the proximity of the genetic mutations, as follows:

• Proximal effects of the causal mutations, namely transcription and translation of the mutant proteins;

• Effects of the mutations on sarcomere structure and function, such as assembly and ATPase activity;

• Molecular pathways that are activated in response to structural and functional defects in the myofilaments/sarcomeres and link the mutations to the phenotypic features, such as trophic and mitotic factors.

Each set of the mechanistic categories entail a diverse array of events, likely reflecting the underpinning biological effects of the involved codon and protein. The mechanisms are likely to differ for HCM caused by mutations in genes other than those coding for the sarcomere proteins, including phenocopy conditions.