The Clinical Course of a Genetic Dilated Cardiomyopathy

Heart failure (HF) is an important and expensive component of cardiovascular morbidity and mortality, with a rising incidence (1). Dilated cardiomyopathy (DCM) is one of its most common types, with a prevalence of 1 in 250 to 400 individuals in the general population (2). The diagnosis of DCM is based on gross organ performance, including reduced left ventricular ejection fraction (LVEF) <50% and dilated chamber dimensions (1). In approximately 50% of the cases, there is a clear etiology linked to the acquired phenotype, such as an ischemic insult, or noxious exposure such as alcohol or chemotherapeutic agents. However, the remaining 50% of patients afflicted with this progressive disease receive the unsettling label of “idiopathic,” that is, of unknown origin. Investigations into the mechanistic origins of idiopathic dilated cardiomyopathy have resulted in an increasing awareness of the genetic basis of this disease.

High throughput genomic sequencing is continuously curating the genetic tapestry of idiopathic dilated cardiomyopathy (ICM) with now over 60 genes identified (3). However, for the genetic origins to be clinically useful, an urgent need exists for population studies that elucidate each genetic variant’s phenotypic penetrance, natural history of afflicted patients and that of their families, and a correlation with mutation-specific biology. The study by Dominguez et al. (4) in this issue of the Journal is of major importance because the authors meticulously dissect the penetrance, presentation, prognosis, and histological features of a well-known genetic cardiomyopathy, specifically BAG3-associated cardiomyopathy.

The current study focuses on 129 individuals from 38 families recruited from 18 European centers, which is the largest described cohort of patients with DCM in the context of BAG3 mutations (4). At initial evaluation, 57% of the subjects manifested DCM with young age of onset of 37 years. At a median follow-up of 38 months, 12 additional patients developed DCM with an estimated penetrance of ~80% after 40 years of age. Interestingly, unlike other DCM types, BAG3-associated DCM does not have significant arrhyth-mogenicity. Worse outcomes were associated with the degree of left ventricular chamber dilation and LVEF reduction, as well as male sex. This study highlights the rapidly deteriorating prognosis associated with this type of DCM with 30% incidence of major adverse events on follow-up. In fact, despite the advances in medical management of patients with DCM in the current era, only 2 patients in the studied cohort experienced reverse ventricular remodeling as demonstrated by an improvement in LVEF. It is hard, from the current study, to estimate BAG3-associated DCM prevalence across all the enrolled European centers. At present, it is already recognized that BAG3 is a major genetic DCM locus with an estimated prevalence of 2.3% to 15% among all genetic cardiomyopathies (5).

The authors furthermore performed histological studies on specimen from 3 patients with truncating mutations in whom they performed alpha-actinin and BAG3 costaining. They identified a loss of Z-disc localization of BAG3 in DCM patients as well as presence of myofibrillar disarray. These data are useful but leave unanswered the mechanistic underpinnings of the observed histological changes. BAG3 mutations as a cause of cardiomyopathy are an evolving and fascinating story. It has been only 2 decades since the cloning and sequencing of the BAG3 gene and yet, it is continuing to challenge our understanding of how different mutations within the same gene can result in divergent HF phenotypes–from dilated to hypertrophic and restrictive cardiomyopathy (5).

The basic biology of cardiac BAG3 remains poorly understood. In the adult cardiomyocyte, transverse tubules (t-tubules) are sarcolemmal folds rich in cBIN1-regulated signaling microdomains that contain the functional units of excitation-contraction coupling (6). BAG3 has been reported to colocalize with β1-adrenergic receptor and CaV1.2 channels at the t-tubules, regulating calcium current amplitude and contraction force (7). Additionally, it has been previously shown that BAG3 binds to the actin capping protein CapZβ1, which together with Hsc70, ensures the stability of the actin network and its proper anchorage at the Z-disc (8,9). As such, there are 2 BAG3 mutations described to be associated with DCM through defective Z-disc assembly and increased susceptibility to apoptosis (8). Thus, BAG3 may have a role in cardiomyocyte structure and organization of the excitation-contraction apparatus.

Furthermore, there is an emerging role for BAG3 in the stress response of cardiomyocytes. It is well known that under mechanical or metabolic adverse stimuli, myocytes switch on stress response signaling networks. Defective function in these responses in cardiomyocytes can lead to the failure of adaptation and, hence, HF phenotype manifestation with latency. In cardiomyocytes, BAG3 serves as a chaperone modulating the activity of members of the HSP70 and HSPB protein families when the cells are subjected to proteotoxic stress (10). BAG3 thus regulates mis-folded protein clearance and ensures sarcomeric stability in the heart. The pleiotropic cytoskeleton and trafficking functions of BAG3 mimic other stress response trafficking proteins such as GJA1–20k that also have dual involvement in both actin cytoskeleton and metabolic regulation (11,12). The multitude of cellular roles for BAG3 helps us understand different phenotypic presentations of mutations when they affect functionally different parts of the BAG3 protein structure. Only with further biological understanding can effective therapies be developed. Thus, immunolocalization, such as that performed by Dominguez et al. (4), is an important data point to be followed by more mechanistic biological studies.

Current therapy of DCM epitomizes “reactive” care delivery because modern diagnostics capture mostly gross organ-level dysfunction, which oftentimes represents an advanced and irreversible stage of the disease process. The current era is a challenge to all of us to transform HF practice from reactive to preventive. To achieve this transformation, it is necessary to not only establish specific genotype-phenotype correlations, but also achieve a better understanding of the mechanistic processes that underlie the cardiomyopathies at hand. Only then can the anonymity of ICM be unraveled and the term ICM be replaced by clearly defined genetic cardiomyopathy types with specific diagnostic criteria and treatment protocols. The study by Dominguez et al. (4) represents an important step towards achieving deeper understanding of BAG3-associated CMY. For instance, the results of this study could point to more aggressive advanced HF therapies and less aggressive defibrillator approaches for patients with BAG3 mutations.

Much important work still remains for clinicians and scientists to tackle the multitude of genetic cardiomyopathy types whose natural history remains to be elucidated. The study by Dominguez et al. is an excellent precedent for the types of studies needed for all major genetic cardiomyopathies. Genomic targets discovered through modern sequencing technologies can spur investigation of the specific cellular biological pathways affected. Ultimately, personalized therapeutic solutions can be applied based on the genetic and biological signature of the particular disease.