scholarly journals Multi-scale computational models of familial hypertrophic cardiomyopathy: genotype to phenotype

2011 ◽  
Vol 8 (64) ◽  
pp. 1550-1561 ◽  
Author(s):  
Stuart G. Campbell ◽  
Andrew D. McCulloch
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Computational Models ◽  
Heart Function ◽  
Myocardial Strain ◽  
Cardiac Cells ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Mutant Proteins ◽  
Multi Scale ◽  
Genes Encoding ◽  
Whole Heart

Familial hypertrophic cardiomyopathy (FHC) is an inherited disorder affecting roughly one in 500 people. Its hallmark is abnormal thickening of the ventricular wall, leading to serious complications that include heart failure and sudden cardiac death. Treatment is complicated by variation in the severity, symptoms and risks for sudden death within the patient population. Nearly all of the genetic lesions associated with FHC occur in genes encoding sarcomeric proteins, indicating that defects in cardiac muscle contraction underlie the condition. Detailed biophysical data are increasingly available for computational analyses that could be used to predict heart phenotypes based on genotype. These models must integrate the dynamic processes occurring in cardiac cells with properties of myocardial tissue, heart geometry and haemodynamic load in order to predict strain and stress in the ventricular walls and overall pump function. Recent advances have increased the biophysical detail in these models at the myofilament level, which will allow properties of FHC-linked mutant proteins to be accurately represented in simulations of whole heart function. The short-term impact of these models will be detailed descriptions of contractile dysfunction and altered myocardial strain patterns at the earliest stages of the disease—predictions that could be validated in genetically modified animals. Long term, these multi-scale models have the potential to improve clinical management of FHC through genotype-based risk stratification and personalized therapy.

scholarly journals Myosins and pathology: genetics and biology.

2002 ◽  
Vol 49 (4) ◽  
pp. 789-804 ◽  
Author(s):  
Maria Jolanta Redowicz
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myosin Heavy Chain ◽  
Inner Ear ◽  
Heavy Chain ◽  
Hair Cells ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Light Chains ◽  
Myosin Isoforms ◽  
Cardiac Myosin ◽  
Genes Encoding

This article summarizes current knowledge on the genetics and possible molecular mechanisms of Human pathologies resulted from mutations within the genes encoding several myosin isoforms. Mutations within the genes encoding some myosin isoforms have been found to be responsible for blindness (myosins III and VIIA), deafness (myosins I, IIA, IIIA, VI, VIIA and XV) and familial hypertrophic cardiomyopathy (beta cardiac myosin heavy chain and both the regulatory and essential light chains). Myosin III localizes predominantly to photoreceptor cells and is proved to be engaged in the vision process in Drosophila. In the inner ear, myosin I is postulated to play a role as an adaptive motor in the tip links of stereocilia of hair cells, myosin IIA seems to be responsible for stabilizing the contacts between adjacent inner ear hair cells, myosin VI plays a role as an intracellular motor transporting membrane structures within the hair cells while myosin VIIA most probably participates in forming links between neighbouring stereocilia and myosin XV probably stabilizes the stereocilia structure. About 30% of patients with familial hypertrophic cardiomyopathy have mutations within the genes encoding the beta cardiac myosin heavy chain and both light chains that are grouped within the regions of myosin head crucial for its functions. The alterations lead to the destabilization of sarcomeres and to a decrease of the myosin ATPase activity and its ability to move actin filaments.

scholarly journals Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy

2014 ◽  
Vol 306 (6) ◽  
pp. H807-H815 ◽  
Author(s):  
David Barefield ◽  
Mohit Kumar ◽  
Pieter P. de Tombe ◽  
Sakthivel Sadayappan
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Functional Impairments ◽  
Tissue Samples ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Genes Encoding ◽  
Heterozygous Carriers ◽  
Sarcomere Proteins ◽  
Whole Heart

The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C′-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show ∼40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 μm (+/t 68.5 ± 4.1 mN/mm2 vs. +/+ 82.2 ± 3.2) and 2.3 μm (+/t 79.2 ± 3.1 mN/mm2 vs. +/+ 95.5 ± 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 ± 0.12 vs. +/+ 2.58 ± 0.43) and E′/A′ (+/t 1.18 ± 0.05 vs. +/+ 1.52 ± 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM.

Abstract 91: Pathogenicity of Naturally Produced Fragments of Cardiac Myosin Binding Protein C and Their Effects on Heart Function and Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Md. Abdur Razzaque
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein Expression ◽  
Protein C ◽  
Heart Function ◽  
Binding Protein ◽  
Ischemia Reperfusion ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Background: Myosin binding protein C (MyBP-C) is a thick filament protein consisting of 1274 amino acid residues (149kD) and mutations in the cardiac isoform (cardiac MyBP-C; cMyBP-C) are responsible for a substantial proportion (20-35%) of identified cases of familial hypertrophic cardiomyopathy (FHC). Recently we found a 40kD fragment is produced from cMyBP-C when the heart is stressed, using a stimulus such as ischemia reperfusion injury. This fragment can be detected in both the mouse and human heart and appears to be stable. Its ability to interfere with normal cardiac function is unexplored. Methods and Results: To understand the potential pathogenicity of the 40kd fragment in vivo, we generated cardiac myocyte-specific transgenic mice (TG) using a Tet-Off inducible system to permit controlled expression in cardiomyocytes. When 40kD protein expression is induced by crossing the responder animals with tetracycline transactivator (tTA) mice, the double TG mice show protein expression and, subsequently, sarcomere dysgenesis and altered cardiac geometry. The double transgenic heart fails between 3 to 17 weeks of age. Expression, the fragment in cardiomyocytes led to development of significant cardiac hypertrophy with myofibrillar disarray and fibrosis. Subsequent analyses showed that MEK-ERK hypertrophic signaling pathways were activated. To determine the role of this pathway in the pathogenic response being generated, we subjected an experimental cohort of animals to treatment with the MAPK/ERK kinase inhibitor U0126 during pregnancy. The drug effectively improved heart function and prolonged survival as compared to the untreated control cohort. Conclusions: The data show that a 40kD fragment of cMyBP-C, which is generated during the development of heart disease in both the mouse and human, is a pathogenic fragment whose presence leads to hypertrophic cardiomyopathy and heart failure. Blockade of the MEK-ERK pathway was effective therapeutically in decreasing morbidity and increasing lifespan in the face of continued synthesis of the fragment.

1180Cardiomyocyte-specific deletion of Brd4 induces hypertrophic cardiomyopathy and suggests a novel function for the chromatin reader as co-repressor in the healthy heart

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Lbik ◽  
E Buchholz ◽  
B Mohamed ◽  
A Fischer ◽  
G Hasenfuss ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ejection Fraction ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Heart Function ◽  
Left Ventricular ◽  
Cardiac Cells ◽  
Cardiomyocyte Hypertrophy ◽  
Control Group ◽  
Wall Thickening

Abstract Introduction There is increasing evidence that epigenetic mechanisms such as histone modifications integrate stress stimuli into cellular responses during pathogenesis of heart failure (HF). The chromatin readers of the Bromo- and extraterminal domain (BET) family (BRD2, BRD3, BRD4) were reported to recognize acetylated histone tails and to promote transcription. Previously, BET inhibition by JQ1 was shown to displace BET readers from chromatin preventing pathologic remodelling after pressure overload (PO). This suggests a major role for BET proteins in HF development and demonstrates their therapeutic potential. However, JQ1 acts systemically and simultaneously inhibits all BET proteins making precise conclusions on functions of particular BET members in cardiac cells impossible. This work presents the first in vivo deletion of Brd4 in cardiomyocytes and its impact on the healthy and diseased murine heart. Purpose This study aims to analyse if deleting Brd4 in cardiomyocytes can protect the heart from pathologic remodelling after PO as observed with BET inhibition. Methods The αMHC-MerCreMer line and a conditional Brd4 allele were used to induce a knockout of Brd4 (Brd4 KO) in cardiomyocytes by tamoxifen application (i.p. 3x30 mg/kg/day) at postnatal week 5. Transverse aortic constriction (TAC) was used to induce PO in 8 weeks old mice. Global gene expression changes in Brd4 KO mice were analysed by mRNA sequencing. Results Adult Brd4 KO mice showed left ventricular (LV) wall thickening, increased LV mass, cardiomyocyte hypertrophy and mild interstitial fibrosis in comparison to control but lived for over 1 year and showed normal ejection fraction. Transcriptome analysis of Brd4 KO hearts revealed the induction of a pathologic gene program like the expression of fetal genes such as Myh7 or Acta1, Nppa, and Nppb and genes involved in extra cellular matrix organization. After TAC, Brd4 KO mice showed higher mortality with a median survival of 37 days in comparison to 132 days in the control group. However, Brd4 KO mice that survived the acute phase showed significantly higher ejection fraction than control 10 weeks after TAC. Despite the basal hypertrophy, Brd4 KO mice showed no further pathologic remodelling in response to PO and had significantly lower LV weights and diameters. Conclusions The development of concentric hypertrophy, expression of fetal genes, and fibrosis with preserved ejection fraction in Brd4 KO animals resemble typical characteristics of hypertrophic cardiomyopathy, and the increased mortality after TAC is likely due to diastolic dysfunction or arrythmias. However, surviving Brd4 KO mice show limited remodelling and partially preserved heart function suggesting cardio-protective potential as previously observed with BET inhibition. Together with relevant literature our findings suggest two distinct roles for Brd4, co-repression of hypertrophy genes in the healthy heart and their co-activation in response to stress. Acknowledgement/Funding German Research Foundation - Collaborative Research Center 1002

Role of Cardiac MRI in Detecting Familial Hypertrophic Cardiomyopathy: Review

2016 ◽  
Vol 1 (1) ◽  
pp. 4
Author(s):  
Marymol Koshy ◽  
Bushra Johari ◽  
Mohd Farhan Hamdan ◽  
Mohammad Hanafiah
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Magnetic Resonance ◽  
Genetic Disorder ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Non Invasive ◽  
Wide Range ◽  
Proper Diagnosis ◽  
Magnetic Resonance Imaging Mri ◽  
Potential Use

Hypertrophic cardiomyopathy (HCM) is a global disease affecting people of various ethnic origins and both genders. HCM is a genetic disorder with a wide range of symptoms, including the catastrophic presentation of sudden cardiac death. Proper diagnosis and treatment of this disorder can relieve symptoms and prolong life. Non-invasive imaging is essential in diagnosing HCM. We present a review to deliberate the potential use of cardiac magnetic resonance (CMR) imaging in HCM assessment and also identify the risk factors entailed with risk stratification of HCM based on Magnetic Resonance Imaging (MRI).

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