Filamin C Deficiency Impairs Sarcomere Stability and Activates Focal Adhesion Kinase through PDGFRA Signaling in Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Truncating mutations in filamin C () are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell adhesion, cytoskeletal organization, sarcomere structural integrity, and likely nuclear function. Our previous study showed that the transcriptional profiles of homozygous deletions in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are highly comparable to the transcriptome profiles of hiPSC-CMs from patients with truncating mutations.

The effect of cardiac resynchronization without a defibrillator on morbidity and mortality: an individual patient data meta-analysis of COMPANION and CARE-HF.

Aims: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality for patients with heart failure, reduced left ventricular ejection fraction, QRS duration >130 ms and in sinus rhythm. The aim of this study was to identify patient characteristics that predict the effect, specifically, of CRT pacemakers (CRT-P) on all-cause mortality or the composite of hospitalization for heart failure or all-cause mortality.

Methods And Results: We conducted an individual patient data meta-analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization-Heart Failure (CARE-HF) trials.

Activation of PDGFRA signaling contributes to filamin C-related arrhythmogenic cardiomyopathy.

truncating mutations () are prevalent causes of inherited dilated cardiomyopathy (DCM), with a high risk of developing arrhythmogenic cardiomyopathy. We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We demonstrated that iPSC-CMs from two patients with different mutations displayed arrhythmias and impaired contraction.

The Sarcomeric Spring Protein Titin: Biophysical Properties, Molecular Mechanisms, and Genetic Mutations Associated with Heart Failure and Cardiomyopathy.

Purpose Of Review: The giant protein titin forms the "elastic" filament of the sarcomere, essential for the mechanical compliance of the heart muscle. Titin serves a biological spring, and therefore structural modifications of titin affect function of the myocardium and are associated with heart failure and cardiomyopathy.

Recent Findings: In this review, we discuss the current understanding of titin's biophysical properties and how modifications contribute to cardiac function and heart failure.

The Addition of a Defibrillator to Resynchronization Therapy Decreases Mortality in Patients With Nonischemic Cardiomyopathy.

Objectives: The aim of this study was to determine whether patients with heart failure with reduced ejection fraction (HFrEF) due to nonischemic etiology eligible for cardiac resynchronization therapy (CRT) benefit from an implantable cardioverter-defibrillator (ICD).

Background: It is uncertain whether CRT with an ICD (CRT-D) compared to without an ICD (CRT-P) is associated with a survival benefit in patients with nonischemic etiologies of HFrEF.

Methods: Analyses of the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial were performed, using Cox proportional hazards modeling stratified by HFrEF etiology of nonischemic cardiomyopathy (NICM) or ischemic cardiomyopathy (ICM).

Dynamic Regulation of SARS-Cov-2 Binding and Cell Entry Mechanisms in Remodeled Human Ventricular Myocardium.

Using serial analysis of myocardial gene expression employing endomyocardial biopsy starting material in a dilated cardiomyopathy cohort, we show that mRNA expression of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) cardiac myocyte receptor ACE2 is up-regulated with remodeling and with reverse remodeling down-regulates into the normal range. The proteases responsible for virus-cell membrane fusion were expressed but not regulated with remodeling. In addition, a new candidate for SARS-CoV-2 cell binding and entry was identified, the integrin encoded by .

Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies.

Cardiomyopathies affect individuals worldwide, without regard to age, sex and ethnicity and are associated with significant morbidity and mortality. Inherited cardiomyopathies account for a relevant part of these conditions. Although progresses have been made over the years, early diagnosis and curative therapies are still challenging.

Sequential analysis of myocardial gene expression with phenotypic change: Use of cross-platform concordance to strengthen biologic relevance.

Objectives: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling.

Background: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices.

Methods: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3-12 months of β-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF).

3D Carbon-Nanotube-Based Composites for Cardiac Tissue Engineering.

Heart failure is a disease of epidemic proportion and a leading cause of mortality in the world. Because cardiac myocytes are terminally differentiated cells with minimal intrinsic ability to self-regenerate, cardiac tissue engineering has emerged as one of the most realistic therapeutic strategies for cardiac repair. We have previously proven the ability of carbon nanotube scaffolds to promote cardiomyocyte proliferation, maturation, and long-term survival.

Entrepreneurialism in the Translational Biologic Sciences: Why, How, and However.

Because they are perceived as distinct from the biological sciences, entrepreneurial pursuits may be daunting to the average researcher. In this report, we explain why academic scientists and in particular translational researchers should be naturally as well as rationally attracted to entrepreneurial endeavors. We go into some detail of how entrepreneurial achievements are actually accomplished and offer a few caveats for consideration when embarking down entrepreneurial pathways.

The Cardiomyopathy Lamin A/C D192G Mutation Disrupts Whole-Cell Biomechanics in Cardiomyocytes as Measured by Atomic Force Microscopy Loading-Unloading Curve Analysis.

Atomic force microscopy (AFM) cell loading/unloading curves were used to provide comprehensive insights into biomechanical behavior of cardiomyocytes carrying the lamin A/C (LMNA) D192G mutation known to cause defective nuclear wall, myopathy and severe cardiomyopathy. Our results suggested that the LMNA D192G mutation increased maximum nuclear deformation load, nuclear stiffness and fragility as compared to controls. Furthermore, there seems to be a connection between this lamin nuclear mutation and cell adhesion behavior since LMNA D192G cardiomyocytes displayed loss of AFM probe-to-cell membrane adhesion.

Analysis of long- and short-range contribution to adhesion work in cardiac fibroblasts: an atomic force microscopy study.

Atomic force microscopy (AFM) for single-cell force spectroscopy (SCFS) and Poisson statistic were used to analyze the detachment work recorded during the removal of gold-covered microspheres from cardiac fibroblasts. The effect of Cytochalasin D, a disruptor of the actin cytoskeleton, on cell adhesion was also tested. The adhesion work was assessed using a Poisson analysis also derived from single-cell force spectroscopy retracting curves.

Race, common genetic variation, and therapeutic response disparities in heart failure.

Because of its comparatively recent evolution, Homo sapiens exhibit relatively little within-species genomic diversity. However, because of genome size, a proportionately small amount of variation creates ample opportunities for both rare mutations that may cause disease as well as more common genetic variations that may be important in disease modification or pharmacogenetics. Primarily because of the East African origin of modern humans, individuals of African ancestry (AA) exhibit greater degrees of genetic diversity than more recently established populations, such as those of European ancestry (EA) or Asian ancestry.

Exploring the elasticity and adhesion behavior of cardiac fibroblasts by atomic force microscopy indentation.

AFM was used to collect the whole force-deformation cell curves. They provide both the elasticity and adhesion behavior of mouse primary cardiac fibroblasts. To confirm the hypothesis that a link exists between the membrane receptors and the cytoskeletal filaments causing therefore changing in both elasticity and adhesion behavior, actin-destabilizing Cytochalsin D was administrated to the fibroblasts.

Pharmacogenetics of heart failure.

Purpose Of Review: Novel medical approaches and personalized medicine seek to use genetic information to 'individualize' and improve diagnosis, prevention, and therapy. The personalized management of cardiovascular disease involves a large spectrum of potential applications, from diagnostics of monogenic disorders, to prevention and management strategies based on modifier genes, to pharmacogenetics, in which individual genetic information is used to optimize the pharmacological treatments.

Recent Findings: Evidence suggests that the common polymorphic variants of modifier genes could influence drug response in cardiovascular disease in a variety of areas, including heart failure, arrhythmias, dyslipidemia, and hypertension.

The AIN-76A defined rodent diet accelerates the development of heart failure in SHHF rats: a cautionary note on its use in cardiac studies.

Previous studies from our laboratory have shown positive benefits of linoleic acid (LA) feeding for attenuation of rat heart failure (HF). However, another research group concluded LA feeding was detrimental to cardiac function, using the American Institute of Nutrition 76A (AIN) diet as a background diet for the experimental animals only. To reconcile these conflicting results and determine whether (i) AIN has effects on cardiovascular function, and (ii) AIN reverses the positive effects of LA feeding, studies were performed using spontaneously hypertensive heart failure (SHHF) rats in both a survival study with lifetime feeding of AIN (control: Purina 5001) and a 2 × 2 factorial design for 6 weeks in young male SHHF rats with background diet and LA as variables.