Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies

Qu, Hui‐Qi; Feldman, Arthur M.; Hákonarson, Hákon

doi:10.1161/jaha.122.027373

Cited by 17 publications

(12 citation statements)

References 101 publications

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“…Similar gene-specific or targeted molecular treatments are expected to be developed for other genetic causes of cardiomyopathy too with the expectations of achieving disease cure or complete reversal. 77 Precision medicine depends on precision diagnostics and next to genotyping, imaging is equally important for patient selection and in assessing the efficacy of existing or novel treatments. Given its high reproducibility for volumetric measurements, CMR has a primary role in assessing the efficacy of treatment interventions and is used by clinical trials to assess soft clinical end points.…”

Section: Imaging and Genetics For Patient Selection And The Deploymen...mentioning

confidence: 99%

Imagenetics for Precision Medicine in Dilated Cardiomyopathy

Antonopoulos,

Xintarakou,

Protonotarios

et al. 2024

Circ: Genomic and Precision Medicine

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Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as DSP (desmoplakin) or FLNC (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients.

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Section: Imaging and Genetics For Patient Selection And The Deploymen...mentioning

confidence: 99%

Imagenetics for Precision Medicine in Dilated Cardiomyopathy

Antonopoulos,

Xintarakou,

Protonotarios

et al. 2024

Circ: Genomic and Precision Medicine

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“…In a group of similarly large GWAS studies, the BAG3 locus was associated with dilated cardiomyopathy [ 93 ]. Most recently, we reported that all of the known pathogenic/likely pathogenic variants affect at least one of three protein functional domains: the WW domain, the second IPV (Il-Pro-Val) domain, or the BAG domain; whereas none of the missense pathogenic/likely pathogenic variants affect the proline-rich repeat (PXXP) domain [ 7 ]. A common variant, p.Cys151Arg, associated with reduced susceptibility to dilated cardiomyopathy, demonstrated a significant difference in allele frequencies among diverse human populations, suggesting evolutionary selective pressure.…”

Section: Bag3 In Heart and Skeletal Musclementioning

confidence: 99%

“…BAG3 is one of six proteins in the BAG family. All of these proteins share a BAG domain that binds to the ATPase binding site on heat shock protein 70 (Hsp/Hsc 70), yet each appears to play a unique role in the cell [ 7 ] ( Figure 1 ). All of the BAG family of proteins are constitutively expressed but are regulated independently.…”

Section: Introductionmentioning

confidence: 99%

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Brenner

Choudhary

McCormick

et al. 2023

Cells

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BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolded proteins and damaged organelles, inhibits apoptosis, maintains the homeostasis of the mitochondria, and facilitates excitation contraction coupling through the L-type calcium channel and the beta-adrenergic receptor. High levels of BAG3 are associated with insensitivity to chemotherapy in malignant cells whereas both loss of function and gain of function variants are associated with cardiomyopathy.

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“…Sometimes there may be an overlap with other types of cardiomyopathies, which share a profound propensity for arrhythmic events. 20 The best studied gene variants and their association with the clinical phenotype and the risk of SCD are presented in Table 1, [21][22][23][24][25][26] whilst an overlapping genetic background of different types of cardiomyopathies is presented in Figure 1. Genetic testing and counselling should be offered to all patients with DCM (and other cardiomyopathies) as it can aid in diagnosis, risk assessment, prognostication and reproductive decisions, and serve to initiate cascade genetic screening of the relatives.…”

Section: Genetic Backgroundmentioning

confidence: 99%

Incidence, risk assessment and prevention of sudden cardiac death in cardiomyopathies

Polovina,

Tschöpe,

Rosano

et al. 2023

European J of Heart Fail

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Cardiomyopathies are a significant contributor to cardiovascular morbidity and mortality, mainly due to the development of heart failure and increased risk of sudden cardiac death (SCD). Despite improvement in survival with contemporary treatment, SCD remains an important cause of mortality in cardiomyopathies. It occurs at a rate ranging between 0.15% and 0.7% per year (depending on the cardiomyopathy), which significantly surpasses SCD incidence in the age‐ and sex‐matched general population. The risk of SCD is affected by multiple factors including the aetiology, genetic basis, age, sex, physical exertion, the extent of myocardial disease severity, conduction system abnormalities, and electrical instability, as measured by various metrics. Over the past decades, the knowledge on the mechanisms and risk factors for SCD has substantially improved, allowing for a better‐informed risk stratification. However, unresolved issues still challenge the guidance of SCD prevention in patients with cardiomyopathies. In this review, we aim to provide an in‐depth discussion of the contemporary concepts pertinent to understanding the burden, risk assessment and prevention of SCD in cardiomyopathies (dilated, non‐dilated left ventricular, hypertrophic, arrhythmogenic right ventricular, and restrictive). The review first focuses on SCD incidence in cardiomyopathies and then summarizes established and emerging risk factors for life‐threatening arrhythmias/SCD. Finally, it discusses validated approaches to the risk assessment and evidence‐based measures for SCD prevention in cardiomyopathies, pointing to the gaps in evidence and areas of uncertainties that merit future clarification.

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Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies

Cited by 17 publications

References 101 publications

Imagenetics for Precision Medicine in Dilated Cardiomyopathy

Imagenetics for Precision Medicine in Dilated Cardiomyopathy

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Incidence, risk assessment and prevention of sudden cardiac death in cardiomyopathies

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