scholarly journals Unraveling the Genotype‐Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity‐Related Cardiac Defects as a Major Disease Modifier

2020 ◽  
Vol 9 (22) ◽  
Author(s):  
Edgar E. Nollet ◽  
B. Daan Westenbrink ◽  
Rudolf A. de Boer ◽  
Diederik W. D. Kuster ◽  
Jolanda van der Velden
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Disease Burden ◽  
Clinical Course ◽  
Clinical Findings ◽  
Inherited Cardiomyopathy ◽  
Genes Encoding ◽  
Disease Penetrance ◽  
Disease Modifier ◽  
Sarcomere Proteins ◽  
Recent Cohort

Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype‐phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity‐induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity‐related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation‐induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.

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.

scholarly journals Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 741 ◽  
Author(s):  
Dorsch ◽  
Schuldt ◽  
Remedios ◽  
Schinkel ◽  
Jong ◽  
...  
Keyword(s):  
Quality Control ◽  
Hypertrophic Cardiomyopathy ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Left Ventricular ◽  
Microtubule Network ◽  
Protein Levels ◽  
Tubulin Acetylation ◽  
Genes Encoding ◽  
Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were 1) several key PQC players were more abundant in HCM compared to controls, 2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, 3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCMHI, 4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and 5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.

Dextrocardia and symmetric hypertrophic cardiomyopathy with multiple mutations of genes encoding the sarcomere proteins

2015 ◽  
Vol 187 ◽  
pp. 581-584 ◽  
Author(s):  
Fang Fang ◽  
Feng-Mei Cui ◽  
Yong-Ming He ◽  
Xiang-Jun Yang ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Genes Encoding ◽  
Sarcomere Proteins

scholarly journals Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review

2021 ◽  
Vol 22 (17) ◽  
pp. 9378
Author(s):  
Syeda K. Shahzadi ◽  
Nerissa Naidoo ◽  
Alawi Alsheikh-Ali ◽  
Manfredi Rizzo ◽  
Ali A. Rizvi ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Direct Consequence ◽  
Calcium Sensitivity ◽  
Biological Processes ◽  
Functional Roles ◽  
Hereditary Cardiomyopathy ◽  
Genes Encoding ◽  
Non Coding Rnas ◽  
Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including MYH7, MYBPC3, ACTC1, TPM1, MYL2, MYL3, TNNI3, and TNNT23. Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.

scholarly journals The genetics of hypertrophic cardiomyopathy

2018 ◽  
Vol 2018 (3) ◽  
Author(s):  
Mohammed Akhtar ◽  
Perry Elliott
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Treatment Strategies ◽  
Glycogen Storage ◽  
Calcium Handling ◽  
Clinical Role ◽  
Genes Encoding ◽  
Disease Stratification ◽  
Sarcomere Proteins

Hypertrophic cardiomyopathy (HCM) is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere proteins. Other inheritable causes of the disease include mutations in genes coding for proteins important in calcium handling or that form part of the cytoskeleton. At present, the primary clinical role of genetic testing in HCM is to facilitate familial screening to allow the identification of individuals at risk of developing the disease. It is also used to diagnose genocopies, such as lysosomal and glycogen storage disease which have different treatment strategies, rates of disease progression and prognosis. The role of genetic testing in predicting prognosis is limited at present, but emerging data suggest that knowledge of the genetic basis of disease will assume an important role in disease stratification and offer potential targets for disease-modifying therapy in the near future.

scholarly journals Serial Observations and Mutational Analysis of an Adoptee with Family History of Hypertrophic Cardiomyopathy

2010 ◽  
Vol 2010 ◽  
pp. 1-4
Author(s):  
Bronwyn Harris ◽  
Jean P. Pfotenhauer ◽  
Cheri A. Silverstein ◽  
Larry W. Markham ◽  
Kim Schafer ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Family History ◽  
Mutational Analysis ◽  
Clinical Findings ◽  
Dominant Mode ◽  
Natural Mother ◽  
History Of ◽  
In Cis ◽  
Inherited Cardiac Disease

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an autosomal dominant mode of transmission. Comprehensive genetic screening of several genes frequently found mutated in HCM is recommended for first-degree relatives of HCM patients. Genetic testing provides the means to identify those at risk of developing HCM and to institute measures to prevent sudden cardiac death (SCD). Here, we present an adoptee whose natural mother and maternal relatives were known be afflicted with HCM and SCD. The proband was followed closely from age 6 to 17 years, revealing a natural history of the progression of clinical findings associated with HCM. Genetic testing of the proband and her natural mother, who is affected by HCM, revealed that they were heterozygous for both the R719Q and T1513S variants in the cardiac beta-myosin heavy chain (MYH7) gene. The proband's ominous family history indicates that the combination of the R719Q and T1513S variantsin cismay be a “malignant” variant that imparts a poor prognosis in terms of the disease progression and SCD risk.

scholarly journals Fatal Subacute Hepatic Failure in a Patient with AA-Type Amyloidosis: Case Report

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Ibrahim Altraif ◽  
Fayaz A. Handoo ◽  
Khaled O. Alsaad ◽  
Adel Gublan
Keyword(s):  
Alkaline Phosphatase ◽  
Case Report ◽  
Hepatic Failure ◽  
Clinical Presentation ◽  
Clinical Course ◽  
Clinical Findings ◽  
Systemic Amyloidosis ◽  
Hepatic Involvement ◽  
Reactive Amyloidosis ◽  
Hepatic Amyloidosis

Although systemic amyloidosis of amyloid-associated protein (AA) type (secondary or reactive amyloidosis) frequently involves the liver, it rarely causes clinically apparent liver disease. Mild elevation of alkaline phosphatase and hepatomegaly are the most common biochemical and clinical findings, respectively. We report a case of systemic amyloidosis of AA type, which clinically presented as subacute hepatic failure and resulted in a fatal clinical course in a 69-year-old man. To the best of our knowledge, this is the fifth case of hepatic amyloidosis of AA type that clinically presented as fatal subacute hepatic failure, an unusual clinical presentation for hepatic involvement by systemic AA-type amyloid.

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