Cardiovascular genetics: technological advancements and applicability for dilated cardiomyopathy.
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ABSTRACT:
SUBMITTER: Kummeling GJ
PROVIDER: S-EPMC4497982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose of reviewDilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM.Recent findingsAlthough mutations in TTN remain the most common identifiable cause of genetic DCM, there is a growing appreciation for arrhythmogenic-prone DCM due to mutations in LMNA, desmosomal genes, and the recently described FLNC gene encoding the structural filamin C protein. Mutations in RBM20 highlight the relevance of RNA splicing regulation in the pathogenesis of DCM. Although expanded genetic testing has improved access to genetic diagnostic studies for many patients, the molecular mechanisms in the pathogenesis of the disease remained largely unknown.Summary: The identification of the molecular causes and subsequent insight into the molecular mechanisms of DCM is expanding our understanding of DCM pathogenesis and highlights the complexity of DCM and the need to develop multifaceted strategies to treat the various causes of DCM.
| S-EPMC8272929 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) is defined as dilation and/or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases of familial DCM have an identifiable genetic cause. Accordingly, there is a fast-growing interest in the field of molecular genetics as it pertains to DCM. Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. In addition to standard treatment of heart failure and prevention of arrhythmias and sudden cardiac death, patients with genetic cardiomyopathy stand to benefit from gene mechanism-specific therapies.
| S-EPMC10842880 | biostudies-literature
Project description:BackgroundCoronary angiography to identify coronary artery disease has been foundational to distinguish the cause of dilated cardiomyopathy (DCM), including the assignment of idiopathic or ischemic cardiomyopathy. Late gadolinium enhancement (LGE) with cardiovascular magnetic resonance (CMR) has emerged as an approach to identify myocardial scar and identify etiology.MethodsThe DCM Precision Medicine Study included patients with left ventricular dilation and dysfunction attributed to idiopathic DCM, after expert clinical review excluded ischemic or other cardiomyopathies. Ischemic cardiomyopathy was defined as coronary artery disease with >50% narrowing at angiography of ≥1 epicardial coronary artery. CMR was not required for study inclusion, but in a post hoc analysis of available CMR reports, patterns of LGE were classified as (1) no LGE, (2) ischemic-pattern LGE: subendocardial/transmural, (3) nonischemic LGE: midmyocardial/epicardial.ResultsOf 1204 idiopathic DCM patients evaluated, 396 (32.9%) had a prior CMR study; of these, 327 (82.6% of 396) had LGE imaging (mean age 46 years; 53.2% male; 55.4% White); 178 of the 327 (54.4%) exhibited LGE, and 156 of the 178 had LGE consistent with idiopathic DCM. The remaining 22 had transmural or subendocardial LGE. Of these 22, coronary angiography was normal (13), showed luminal irregularities (3), a distant thrombus (1), coronary artery disease with <50% coronary artery narrowing (1), or was not available (4).ConclusionsOf 327 probands enrolled in the DCM Precision Medicine Study cohort who had LGE-CMR data available, an ischemic-pattern of LGE was identified in 22 (6.7%), all of whom had idiopathic DCM as adjudicated by expert clinical review.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT03037632.
| S-EPMC9117485 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) is a common cause of non-ischaemic heart failure, conferring high morbidity and mortality, including sudden cardiac death due to systolic dysfunction or arrhythmic sudden death. Within the DCM cohort exists a group of patients with familial disease. In this article we review the pathophysiology and cardiac imaging findings of familial DCM, with specific attention to known disease subtypes. The role of advanced cardiac imaging cardiovascular magnetic resonance is still accumulating, and there remains much to be elucidated. We discuss its potential clinical roles as currently known, with respect to diagnostic utility and risk stratification. Advances in such risk stratification may help target pharmacological and device therapies to those at highest risk.
| S-EPMC10057087 | biostudies-literature
Project description:Heart failure is a major health burden, affecting 40 million people globally. One of the main causes of systolic heart failure is dilated cardiomyopathy (DCM), the leading global indication for heart transplantation. Our understanding of the genetic basis of both DCM and systolic heart failure has improved in recent years with the application of next-generation sequencing and genome-wide association studies (GWAS). This has enabled rapid sequencing at scale, leading to the discovery of many novel rare variants in DCM and of common variants in both systolic heart failure and DCM. Identifying rare and common genetic variants contributing to systolic heart failure has been challenging given its diverse and multiple etiologies. DCM, however, although rarer, is a reasonably specific and well-defined condition, leading to the identification of many rare genetic variants. Truncating variants in titin represent the single largest genetic cause of DCM. Here, we review the progress and challenges in the detection of rare and common variants in DCM and systolic heart failure, and the particular challenges in accurate and informed variant interpretation, and in understanding the effects of these variants. We also discuss how our increasing genetic knowledge is changing clinical management. Harnessing genetic data and translating it to improve risk stratification and the development of novel therapeutics represents a major challenge and unmet critical need for patients with heart failure and their families.
| S-EPMC5322656 | biostudies-literature
Project description:AimsDespite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool.Methods and resultsUsing OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype-phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410× and 99.42% of the nucleotides were sequenced at least 15× read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively.ConclusionPanel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.
| S-EPMC4561350 | biostudies-literature
Project description:About 92.1 million Americans suffer from at least one type of cardiovascular disease. Worldwide, cardiovascular diseases are the number one cause of death (about 31% of all global deaths). Recent technological advancements in cardiac ultrasound imaging are expected to aid in the clinical diagnosis of many cardiovascular diseases. This article provides an overview of such recent technological advancements, specifically focusing on tissue Doppler imaging, strain imaging, contrast echocardiography, 3D echocardiography, point-of-care echocardiography, 3D volumetric flow assessments, and elastography. With these advancements ultrasound imaging is rapidly changing the domain of cardiac imaging. The advantages offered by ultrasound imaging include real-time imaging, imaging at patient bed-side, cost-effectiveness and ionizing-radiation-free imaging. Along with these advantages, the steps taken towards standardization of ultrasound based quantitative markers, reviewed here, will play a major role in addressing the healthcare burden associated with cardiovascular diseases.
| S-EPMC5808891 | biostudies-literature
Project description: Not available
| S-EPMC1235300 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM), usually diagnosed as idiopathic dilated cardiomyopathy (IDC), has been shown to have a familial basis in 20-35% of cases. Genetic studies in familial dilated cardiomyopathy (FDC) have shown dramatic locus heterogeneity with mutations identified in >30 mostly autosomal genes showing primarily dominant transmission. Most mutations are private missense, nonsense or short insertion/deletions. Marked allelic heterogeneity is the rule. Although to date most DCM genetics fits into a Mendelian rare variant disease paradigm, this paradigm may be incomplete with only 30-35% of FDC genetic cause identified. Despite this incomplete knowledge, we predict that DCM genetics will become increasingly relevant for genetics and cardiovascular professionals. This is because DCM causes heart failure, a national epidemic, with considerable morbidity and mortality. The fact that early, even pre-symptomatic intervention can prevent or ameliorate DCM, coupled with more cost-effective genetic testing, will drive further progress in the field. Ongoing questions include: whether sporadic (IDC) disease has a genetic basis, and if so, how it differs from familial disease; which gene-specific or genetic pathways are most relevant; and whether other genetic mechanisms (e.g., DNA structural variants, epigenetics, mitochondrial mutations and others) are operative in DCM. We suggest that such new knowledge will lead to novel approaches to the prevention and treatment of DCM.
| S-EPMC3118426 | biostudies-literature