scholarly journals Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy

2022 ◽  
Vol 23 (2) ◽  
pp. 871
Author(s):  
Joseph D. Powers ◽  
Natalie J. Kirkland ◽  
Canzhao Liu ◽  
Swithin S. Razu ◽  
Xi Fang ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Computational Models ◽  
Systolic Dysfunction ◽  
Longitudinal Force ◽  
Rapid Onset ◽  
Structural Defects ◽  
Actin Binding ◽  
Force Transmission ◽  
Tension Development ◽  
Filamin C

Dilated cardiomyopathy (DCM) is a life-threatening form of heart disease that is typically characterized by progressive thinning of the ventricular walls, chamber dilation, and systolic dysfunction. Multiple mutations in the gene encoding filamin C (FLNC), an actin-binding cytoskeletal protein in cardiomyocytes, have been found in patients with DCM. However, the mechanisms that lead to contractile impairment and DCM in patients with FLNC variants are poorly understood. To determine how FLNC regulates systolic force transmission and DCM remodeling, we used an inducible, cardiac-specific FLNC-knockout (icKO) model to produce a rapid onset of DCM in adult mice. Loss of FLNC reduced systolic force development in single cardiomyocytes and isolated papillary muscles but did not affect twitch kinetics or calcium transients. Electron and immunofluorescence microscopy showed significant defects in Z-disk alignment in icKO mice and altered myofilament lattice geometry. Moreover, a loss of FLNC induces a softening myocyte cortex and structural adaptations at the subcellular level that contribute to disrupted longitudinal force production during contraction. Spatially explicit computational models showed that these structural defects could be explained by a loss of inter-myofibril elastic coupling at the Z-disk. Our work identifies FLNC as a key regulator of the multiscale ultrastructure of cardiomyocytes and therefore plays an important role in maintaining systolic mechanotransmission pathways, the dysfunction of which may be key in driving progressive DCM.

Abstract 194: Characterization of Arrhythmogenic Dilated Cardiomyopathy Caused by Novel Filamin C Splice Variant in a Zebrafish Model

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Rene L Begay ◽  
Teisha J Rowland ◽  
Charles A Tharp ◽  
August Martin ◽  
Sharon L Graw ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Splice Variant ◽  
Systolic Dysfunction ◽  
Family Members ◽  
Muscle Disease ◽  
Heart Tube ◽  
Zebrafish Model ◽  
Cell Stage ◽  
Cardiac Phenotype ◽  
Filamin C

Although dilated cardiomyopathy (DCM) is a serious and frequent genetic cause of heart failure, only 30-40% of cases can be attributed to a known DCM gene mutation. To identify and confirm additional disease genes involved in DCM, we performed whole exome sequencing in two multigenerational families with DCM, both from the same geographic region of Italy, and found a novel splice variant in the gene encoding filamin-C (FLNC). Previously characterized mutations in FLNC had been primarily linked to skeletal muscle disease, although none of the affected family members displayed skeletal myopathy. To confirm and further characterize the arrhythmogenic DCM phenotype observed in family members, we performed embryonic knockdown experiments using morpholino (MO) treatment in zebrafish (Danio rerio) targeting the FLNC ortholog, filamin Cb (flncb). Following MO injection into 1-2 cell stage zebrafish embryos, 63.4% (78 of 123) of viable flncb MO-injected embryos displayed a cardiac phenotype at 72 hours post fertilization (hpf) (vs. 17.0% [30 of 177] of control MO-injected embryos; p≤0.001). Increases in mortality were observed, with 20.8% (54 of 260) of flncb MO-injected embryos surviving at 7 days post fertilization (vs. 65% [162 of 249] of control embryos; p≤0.001). The flncb MO-injected embryos demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. The flncb MO-injected embryos additionally demonstrated a lower mean stroke volume than controls (0.076 vs. 0.181 nl; p=0.015), a reduced mean cardiac output (10.8 vs. 25 nl/min; p=0.02), and an increase in the fraction of retrograde blood flow over the cardiac cycle (0.42 vs. 0.03; p=0.027). Overall, this flncb MO treatment recapitulated a DCM phenotype similar to the state caused by the human splicing variant, supporting haploinsufficiency as the mechanism leading to DCM in these families. Our findings suggest that approaches to augment endogenous filamin C protein levels may represent a viable treatment strategy that warrants exploration in future studies.

scholarly journals Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy

2020 ◽  
Author(s):  
Marianna Leopoulou ◽  
Jo Ann LeQuang ◽  
Joseph V. Pergolizzi ◽  
Peter Magnusson
Keyword(s):  
Sudden Cardiac Death ◽  
Left Ventricle ◽  
Sudden Death ◽  
Risk Stratification ◽  
Dilated Cardiomyopathy ◽  
Cardiac Death ◽  
Disease Risk ◽  
Systolic Dysfunction ◽  
Preventive Strategies ◽  
Genetic Origin

Dilated cardiomyopathy (DCM) is characterized by the phenotype of a dilated left ventricle with systolic dysfunction. It is classified as hereditary when it is deemed of genetic origin; more than 50 genes are reported to be related to the condition. Symptoms include, among others, dyspnea, fatigue, arrhythmias, and syncope. Unfortunately, sudden cardiac death may be the first manifestation of the disease. Risk stratification regarding sudden death in hereditary DCM as well as preventive management poses a challenge due to the heterogeneity of the disease. The purpose of this chapter is to present the epidemiology, risk stratification, and preventive strategies of sudden cardiac death in hereditary DCM.

Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy

2000 ◽  
Vol 107 (5) ◽  
pp. 440-451 ◽  
Author(s):  
Takuro Arimura ◽  
Takeyuki Nakamura ◽  
Shitoshi Hiroi ◽  
Manatsu Satoh ◽  
Megumi Takahashi ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Actin Binding ◽  
Binding Motif

scholarly journals A Dilated Cardiomyopathy Troponin C Mutation Lowers Contractile Force by Reducing Strong Myosin-Actin Binding

2010 ◽  
Vol 285 (23) ◽  
pp. 17371-17379 ◽  
Author(s):  
David Dweck ◽  
Daniel P. Reynaldo ◽  
Jose R. Pinto ◽  
James D. Potter
Keyword(s):  
Dilated Cardiomyopathy ◽  
Contractile Force ◽  
Troponin C ◽  
Actin Binding

514 Post-burn Malnutrition and Associated Cardiomyopathy

2020 ◽  
Vol 41 (Supplement_1) ◽  
pp. S94-S95
Author(s):  
Alexis L McQuitty ◽  
Frances Brown ◽  
Mark Talon ◽  
Robert Martinez
Keyword(s):  
Wound Healing ◽  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Perioperative Care ◽  
Systolic Dysfunction ◽  
Delayed Presentation ◽  
Myocardial Depression ◽  
Post Injury ◽  
Impaired Wound Healing ◽  
The Mean

Abstract Introduction It is known that systolic dysfunction (dilated cardiomyopathy) may occur in a high percentage of patients with large TBSA burns. The reversible myocardial depression may be due to many factors: thermal injury, sepsis, severe malnutrition. Malnutrition and delayed wound healing may occur with a combination of primary and secondary protein-energy undernutrition. Methods Serial transthoracic and transesophageal echocardiographic parameters were measured during perioperative care (ejection fraction, fractional shortening, pericardial fluid) in 8 patients with evidence of malnutrition (low BMI, low albumin and prealbumin, muscle wasting) and a delayed presentation to the hospital. Initial echocardiography was performed post-injury day 30 -142; follow-up exams were performed in some patients at 2 years post-injury. Acutely-injured patients or those with sepsis were excluded. Results From 2015–2017, echocardiographic measurements were obtained in 8 patients, ages 7–21. The presenting TBSA ranged from 30–82% and included flame injury, electrical burns, and 1 case of pemphigus vulgaris. The initial ejection fraction ranged from 12–45% in patients with a BMI range of 10–25. The mean initial albumin was 2g/dL; the mean prealbumin was 9.5mg/dL. Two patients had mild to moderate pericardial effusions, which resolved after 1 month of proper nutrition. Selenium deficiency was noted in 1 patient. Four patients required perioperative short-term dobutamine. Conclusions Patients presenting with malnutrition and impaired wound healing all had evidence of cardiomyopathy; however, the degrees of systolic dysfunction varied significantly. BMI, albumin, and prealbumin all had a strong correlation with the degree of myocardial depression. Despite the lower ejection fractions, many patients maintained an adequate cardiac index and did not require inotropic medications. With time and adequate nutrition, cardiac function improved, although many remained with mild dysfunction in the first year. Applicability of Research to Practice This case series demonstrates the continued need for early recognition of malnutrition and cardiomyopathy in this patient population and the need for early intervention. Echocardiographic diagnosis may improve acute perioperative care. In addition, future studies are needed to determine the chronic cardiac effects of reversible dilated cardiomyopathy. Nutrition, refeeding, and perioperative management require a multidisciplinary team.

scholarly journals Activated myofibroblasts promote cardiac hypertrophy and systolic dysfunction independently of cardiac fibrosis in experimental autoimmune myocarditis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
K Tkacz ◽  
A Jazwa-Kusior ◽  
F Rolski ◽  
E Dzialo ◽  
K Weglarczyk ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Dilated Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Systolic Dysfunction ◽  
Heart Weight ◽  
Type I ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Abstract Background/Introduction Heart-specific inflammation – myocarditis is a common cause dilated cardiomyopathy which is characterized by pathological tissue remodeling, ventricular stiffening, cardiomyopathy and heart failure. In experimental autoimmune myocarditis (EAM) susceptible mice immunized with alpha myosin heavy chain (αMyHC) and complete Freund's adjuvant (CFA) develop acute myocarditis driven by autoreactive CD4+ T cells that is followed by progressive fibrosis, cardiomyopathy and systolic dysfunction. Purpose The aim of the study was to investigate the role of cardiac fibroblasts and myofibroblasts in myocarditis and post-inflammatory dilated cardiomyopathy in mouse model of EAM. Methods EAM was induced in BALB/c mice by immunization with αMyHC/CFA. We used reporter mice expressing EGFP under collagen type I promoter (Coll-EGFP) and RFP under a control of α-smooth muscle actin (αSMA) promoter (αSMA-RFP) and transgenic αSMA-TK mice with ganciclovir-inducible ablation of proliferating myofibroblasts. Cardiac cells were quantified using flow cytometry. Cardiac fibroblasts (CD45-CD31-EGFP+) were sorted from healthy and myocarditis-positive (day 21) mice using BD FACSAria™ II Cell Sorter and analyzed for the whole genome transcriptomics by RNA sequencing. Echocardiography was performed on Vevo 2100 Imaging System. Cardiac fibrosis was assessed by Trichrome Massons's staining and hydroxyproline assay, whereas cardiac hypertrophy by analysing cross-sectional cardiomyocyte area. Profibrotic gene expression was assessed by qRT-PCR. Results The total number of cardiac fibroblasts (CD45-CD31-EGFP+) and the subset of myofibroblasts (CD45-CD31-EGFP+RFP+) remained unchanged at inflammatory (d21) and fibrotic stages (d40). Analysis of differentially expressed genes (min. 2x fold change, p value <0.05) pointed out activation of immune processes (mainly chemokine production), response to stress, cytoskeletal and extracellular matrix re-organization in cardiac fibroblasts in response to myocarditis. αSMA-TK mice treated with ganciclovir (from day 21) showed comparable percent of fibrotic area, but significantly reduced heart weight, decreased cardiomyocyte hypertrophy and improved ejection fraction and cardiac output at day 40 comparing to PBS-treated mice. Ganciclovir-treated mice showed also attenuated cardiac Acta2 and Srf but markedly enhanced Mmp2 expression. Conclusions In EAM model cardiac fibroblasts actively participate in proinflammatory and profibrotic responses, while activated myofibroblasts contribute to dilated cardiomyopathy development independently of cardiac fibrosis. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre (Poland)

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.

Dilated cardiomyopathy: the role of genetics, highlighted in a family with Filamin C (FLNC) variant

Heart ◽  
2021 ◽  
pp. heartjnl-2021-319682
Author(s):  
Jason N Dungu ◽  
Samantha G Langley ◽  
Amy Hardy-Wallace ◽  
Brian Li ◽  
Rossella M Barbagallo ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Significant Coronary Artery Disease ◽  
Left Ventricular ◽  
Genetic Associations ◽  
Cascade Screening ◽  
Factors Affecting ◽  
Heterogenous Group ◽  
Familial Cardiomyopathy ◽  
Artery Disease ◽  
Filamin C

Dilated cardiomyopathy (DCM) is a heterogenous group of disorders characterised by left ventricular dilatation and dysfunction, in the absence of factors affecting loading conditions such as hypertension or valvular disease, or significant coronary artery disease. The prevalence of idiopathic DCM is estimated between 1:250 and 1:500 individuals. Determining the aetiology of DCM can be challenging, particularly when evaluating an individual and index case with no classical history or investigations pointing towards an obvious acquired cause, or no clinical clues in the family history to suggest a genetic cause. We present a family affected by DCM associated with Filamin C variant, causing sudden cardiac death at a young age and heart failure due to severe left ventricular impairment and myocardial scarring. We review the diagnosis and treatment of DCM, its genetic associations and potential acquired causes. Thorough assessment is mandatory to risk stratify and identify patients who may benefit from primary prevention implantable cardioverter defibrillator therapy according to international guidelines. Genetic testing has some limitations, and is positive in only 20%–35% of DCM, but should be considered in specific cases to identify families who may benefit from cascade screening after appropriate counselling. The management of often complex familial cardiomyopathy requires specialist input for every case, and the appropriate infrastructure to coordinate investigations.

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