Dilated cardiomyopathy in the era of precision medicine: latest concepts and developments

Abstract

Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and dilatation, not explained by abnormal loading conditions or coronary artery disease. The clinical presentation can vary from asymptomatic to heart failure symptoms or sudden cardiac death (SCD) even in previously asymptomatic individuals. In the last 2 decades, there has been striking progress in the understanding of the complex genetic basis of DCM, with the discovery of additional genes and genotype-phenotype correlation studies. Rigorous clinical work-up of DCM patients, meticulous family screening, and the implementation of advanced imaging techniques pave the way for a more efficient and earlier diagnosis as well as more precise indications for implantable cardioverter defibrillator implantation and prevention of SCD. In the era of precision medicine, genotype-directed therapies have started to emerge. In this review, we focus on updates of the genetic background of DCM, characteristic phenotypes caused by recently described pathogenic variants, specific indications for prevention of SCD in those individuals and genotype-directed treatments under development. Finally, the latest developments in distinguishing athletic heart syndrome from subclinical DCM are described.

Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations

“…Among these, dilated cardiomyopathy (DCM) has been estimated between 1 in 250 to 2,500 of the general population ( Hershberger et al, 2013 ). More than 50 genes have been associated with familial DCM encoding sarcomeric, cytoskeletal, nuclear and plasma membrane proteins ( Mestroni et al, 2014 ; Orphanou et al, 2021 ). A prominent locus for familial DCM is LMNA , encoding lamin A and C (lamin A/C; McNally and Mestroni, 2017 ; Peters et al, 2019 ; Schultheiss et al, 2019 ).…”

Genotype-Phenotype Correlation in Familial BAG3 Mutation Dilated Cardiomyopathy

“…BAG3 is a heat shock protein (HSP) co-chaperone that induces degradation through autophagy [ 12 ]. It is determined that BAG3 is essential for the normal production of filamin and is responsible of myocyte contraction [ 3 ]. This protein plays an important role in the heart, are released during cellular stress and their role is to stimulate the repair and degradation of protein aggregates.…”

“…This is confirmed in other studies; recently, a retrospective study showed that mutations in the BAG3 gene due to DCM were mostly associated with early onset and rapid progression of the heart failure. Furthermore, the response to treatment in this gene mutation seemed less effective than on other genetic forms of DCM [ 3 ]. Therefore, our patient is particularly at an increased risk of adverse outcomes due to risk factors, such as male sex, young age, decreased LV systolic function, and LV dilatation.…”

“…Heterozygous BAG3 pathogenic variants are rarely detected, they cause damage to the structure of myofibrils and are associated with impaired contractile function. The main risk factors for adverse outcomes in patients with DCM due to BAG3 mutation are male sex, decreased LV systolic function, and LV dilatation [ 1 , 3 ]. The largest cohort of DCM caused by BAG3 mutations revealed that this clinical situation is defined by early onset disease in most patients with a high risk of progression and a worse prognosis [ 1 ].…”

Cardiomyocyte Dysfunction in Inherited Cardiomyopathies

“…The diversity of the affected pathways adds to the complexity of DCM pathogenesis and counts for the heterogeneity in phenotype expression. Sarcomeric DCM mutations include myosin, actin, titin, troponin, and tropomyosin [ 23 ].…”