scholarly journals Genetic Determinant of Familial Dilated Cardiomyopathy and Genotype-Targeted Therapeutic Strategy

2020 ◽  
Author(s):  
Jing Zhong ◽  
Li-Ping Li ◽  
Jian-Feng Zhou ◽  
Yong-He Ding
Keyword(s):  
Dilated Cardiomyopathy ◽  
Therapeutic Strategy ◽  
Individualized Medicine ◽  
Systolic Dysfunction ◽  
Disease Diagnosis ◽  
Left Ventricular ◽  
Familial Dilated Cardiomyopathy ◽  
Left Ventricular Dilation ◽  
Improve Patient ◽  
Targeted Therapeutic

Dilated cardiomyopathy (DCM) is a myocardium disease characterized by left ventricular dilation and systolic dysfunction. Genetic susceptibility contributes significantly to the disease progression in familial DCM. Mutations in more than fifty different genes have been identified to cause DCM, accounting for up to 50% of familial DCM cases. Elucidation of genetic basis for the remaining familial DCM probands promises to substantially increase the efficiency of genetic testing for early disease diagnosis and intervention. Dissecting genetic pathways linked to DCM and related pathogenic mechanisms can provide valuable insights into the understanding of disease pathophysiology that can be leveraged for development of genotype-targeted therapeutic strategy. Here, we review genetic variants, with a focus on affected genes most commonly implicated in DCM, and highlight their underlying pathophysiological mechanisms of action. We discuss recent progress on gene-based therapeutic strategy which holds the opportunities to implement individualized medicine and ultimately to improve patient outcome in the future.

scholarly journals Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

2020 ◽  
Vol 9 (9) ◽  
pp. 2770 ◽  
Author(s):  
Charles Tharp ◽  
Luisa Mestroni ◽  
Matthew Taylor
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Diastolic Dysfunction ◽  
Therapeutic Target ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Post Translational Modifications ◽  
Left Ventricular Dilation ◽  
Molecular Springs

Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin’s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin’s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin’s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.

scholarly journals Altered expression of genes for Kir ion channels in dilated cardiomyopathy

2013 ◽  
Vol 91 (8) ◽  
pp. 648-656 ◽  
Author(s):  
Viktoria Szuts ◽  
Dalma Ménesi ◽  
Zoltán Varga-Orvos ◽  
Ágnes Zvara ◽  
Nazanin Houshmand ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Expression Profiles ◽  
Systolic Dysfunction ◽  
Gene Expression Profiles ◽  
Left Ventricular ◽  
Altered Expression ◽  
Molecular Alterations ◽  
Expression Of Genes ◽  
Gene Coding ◽  
Left Ventricular Dilation

Dilated cardiomyopathy (DCM) is a multifactorial disease characterized by left ventricular dilation that is associated with systolic dysfunction and increased action potential duration. The Kir2.x K+ channels (encoded by KCNJ genes) regulate the inward rectifier current (IK1) contributing to the final repolarization in cardiac muscle. Here, we describe the transitions in the gene expression profiles of 4 KCNJ genes from healthy or dilated cardiomyopathic human hearts. In the healthy adult ventricles, KCNJ2, KCNJ12, and KCNJ4 (Kir2.1–2.3, respectively) genes were expressed at high levels, while expression of the KCNJ14 (Kir2.4) gene was low. In DCM ventricles, the levels of Kir2.1 and Kir2.3 were upregulated, but those of Kir2.2 channels were downregulated. Additionally, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97) anchoring molecule exhibited a 2-fold decline with increasing age in normal hearts, and it was robustly downregulated in young DCM patients. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM.

scholarly journals Torsion Mechanics as an Indicator of More Advanced Left Ventricular Systolic Dysfunction in Secondary Mitral Regurgitation in Patients with Dilated Cardiomyopathy: A 2D Speckle-Tracking Analysis

Cardiology ◽  
2018 ◽  
Vol 139 (3) ◽  
pp. 187-196 ◽  
Author(s):  
Elena Kinova ◽  
Natalia Spasova ◽  
Angelina Borizanova ◽  
Assen Goudev
Keyword(s):  
Mitral Regurgitation ◽  
Dilated Cardiomyopathy ◽  
Speckle Tracking ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Functional Mitral Regurgitation ◽  
Compensatory Mechanism ◽  
Structural Wall ◽  
Group 2 ◽  
Group 1

Left ventricular (LV) twist serves as a compensatory mechanism in systolic dysfunction and its degree of reduction may reflect a more advanced stage of disease. Aim: The aim was to investigate twist alterations depending on the degree of functional mitral regurgitation (MR) by speckle-tracking echocardiography. Methods: Sixty-three patients with symptomatic dilated cardiomyopathy (DCM) were included. Patients were divided according to MR vena contracta width (VCW): group 1 with VCW <7 mm (mild/moderate MR) and group 2 with VCW ≥7 mm (severe MR). Results: There were no differences in LV geometry and function between groups. Group 2 showed lower endocardial basal rotation (BR) (–2.04° ± 1.83° vs. –3.23° ± 1.83°, p = 0.012); epicardial BR (–1.54° ± 1.18° vs. –2.31° ± 1.22°, p = 0.015); endocardial torsion (0.41°/cm ± 0.36°/cm vs. 0.63°/cm ± 0.44°/cm, p = 0.033) and mid-level circumferential strain (CSmid) (–6.12% ± 2.64% vs. –7.75% ± 2.90%, p = 0.028), when compared with group 1. Multivariable linear regression analysis identified endocardial BR, torsion and CSmid, as the best predictors of larger VCW. In the ROC curve analysis, endocardial BR and CSmid values greater than or equal to –3.63° and –9.35%, respectively, can differentiate patients with severe MR. Conclusions: In DCM patients, torsional profile was more altered in severe MR. Endocardial BR, endocardial torsion, and CSmid, can be used as indicators of advanced structural wall architecture damage.

P595Characteristics of the right ventricle in patients with nonischemic dilated cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Becker ◽  
C P Allaart ◽  
M Wubben ◽  
J H Cornel ◽  
A C Van Rossum ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Right Ventricular ◽  
Dilated Cardiomyopathy ◽  
Ventricular Function ◽  
Left Atrial ◽  
Systolic Dysfunction ◽  
Underlying Mechanism ◽  
Left Ventricular ◽  
End Diastolic Volume ◽  
Nonischemic Dilated Cardiomyopathy

Abstract Background In nonischemic dilated cardiomyopathy (DCM), diagnosis and prognosis is based on left ventricular function. Although concomitant right ventricular (RV) dysfunction is frequently observed, the underlying mechanism is currently not fully understood. Purpose We aimed to describe the characteristics of right ventricular function in DCM patients with cardiac magnetic resonance (CMR) imaging using cine and late-gadolinium enhancement (LGE) imaging. Methods Patients with DCM and left ventricular (LV) dysfunction (ejection fraction (EF) <50%) on LGE-CMR were included prospectively. LV and RV volumes and function were quantified and RV systolic dysfunction was defined as RV ejection fraction (RVEF)<45%. The presence and pattern of LGE were assessed visually and the extent was quantified using the full-width half maximum method. Septal midmyocardial LGE pattern was defined as midwall striae or hinge-point myocardial hyperenhancement. Moreover, left atrial (LA) volumes were calculated using the bi-plane area-length method. Results The study included 214 DCM patients (42% female, age 58±14 years) with a mean LVEF of 34±12% and RVEF of 46±12%. RV systolic dysfunction was present in 39% and was associated with the presence of septal midwall LGE (OR 1.96 (95% CI 1.09–3.54) p=0.026). In patients with RV dysfunction, LV dilation was more severe (LV end diastolic volume (EDV) 242±97mL vs. 212±58mL, p=0.011) and LVEF was lowere (26±12% vs. 39±8%, p<0.001) (figure A). There was a weak correlation between septal LGE amount and LVEDV and RVEDV (respectively r=0.36, p=0.003 and r=0.35, p=0.005) In patients with RV dysfunction, left atrial volumes were enlarged (56±23mL/m2 vs. 46±14mL/m2, p<0.001) and LA emptying fraction was moderately correlated to RVEF (figure B), also after exclusion of patients with a history of atrial fibrillation. RVEF in DCM patients Conclusion In DCM, reduced RVEF predominantly occurred in patients with a) LVEF lower than 30%, b) septal midwall enhancement, indicating progressive LV remodeling, c) LA dilation and d) LA dysfunction. This suggests that RV dysfunction in advanced DCM is drive by LV diastolic dysfunction resulting in increased afterload of the RV.

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