scholarly journals Pathogenic Mechanisms of Hypertrophic Cardiomyopathy beyond Sarcomere Dysfunction

2021 ◽  
Vol 22 (16) ◽  
pp. 8933
Author(s):  
Chun Chou ◽  
Michael T. Chin
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Large Scale ◽  
Complex Disease ◽  
Cardiac Fibrosis ◽  
Cardiovascular Disorder ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signals ◽  
Sequencing Studies

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray, and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset, and complications. While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. Furthermore, large-scale genome sequencing studies revealed that many genes previously reported as causative of HCM in fact have little or no evidence of disease association. These findings thus call for a re-evaluation of the sarcomere-centered view of HCM pathogenesis. Here, we summarize our current understanding of sarcomere-independent mechanisms of cardiomyocyte hypertrophy, highlight the role of extracellular signals in cardiac fibrosis, and propose an alternative but integrated model of HCM pathogenesis.

scholarly journals Pathogenic Mechanisms of Hypertrophic Cardiomyopathy Beyond Sarcomere Dysfunction

2021 ◽  
Author(s):  
Chun Chou ◽  
Michael T. Chin
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Large Scale ◽  
Complex Disease ◽  
Cardiac Fibrosis ◽  
Cardiovascular Disorder ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Extracellular Signals ◽  
Sequencing Studies

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset and complications. While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. Furthermore, large scale genome sequencing studies revealed that many genes previously reported as causative of HCM in fact have little or no evidence of disease association. These findings thus call for a re-evaluation of the sarcomere-centered view of HCM pathogenesis. Here, we summarize our current understanding of sarcomere-independent mechanisms of cardiomyocyte hypertrophy, highlight the role of extracellular signals in cardiac fibrosis, and propose an alternative but integrated model of HCM pathogenesis.

scholarly journals MYBPC3 Haplotype Linked to Hypertrophic Cardiomyopathy in Rhesus Macaques (Macaca mulatta)

2020 ◽  
Vol 70 (5) ◽  
pp. 358-367
Author(s):  
Robert F Oldt ◽  
Kimberly J Bussey ◽  
Matthew L Settles ◽  
Joseph N Fass ◽  
Jeffrey A Roberts ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Complex Disease ◽  
Rhesus Macaques ◽  
Amplicon Sequencing ◽  
Cardiovascular Disorder ◽  
Left Ventricular ◽  
Risk Haplotype ◽  
Wide Range

In humans, abnormal thickening of the left ventricle of the heart clinically defines hypertrophic cardiomyopathy (HCM), a common inherited cardiovascular disorder that can precede a sudden cardiac death event. The wide range of clinical presentations in HCM obscures genetic variants that may influence an individual's susceptibility to sudden cardiac death. Although exon sequencing of major sarcomere genes can be used to detect high-impact causal mutations, this strategy is successful in only half of patient cases. The incidence of left ventricular hypertrophy (LVH) in a managed research colony of rhesus macaques provides an excellent comparative model in which to explore the genomic etiology of severe HCM and sudden cardiac death. Because no rhesus HCM-associated mutations have been reported, we used a next-generation genotyping assay that targets 7 sarcomeric rhesus genes within 63 genomic sites that are orthologous to human genomic regions known to harbor HCM disease variants. Amplicon sequencing was performed on 52 macaques with confirmed LVH and 42 unrelated, unaffected animals representing both the Indian and Chinese rhesus macaque subspecies. Bias-reduced logistic regression uncovered a risk haplotype in the rhesus MYBPC3 gene, which is frequently disrupted in both human and feline HCM; this haplotype implicates an intronic variant strongly associated with disease in either homozygous or carrier form. Our results highlight that leveraging evolutionary genomic data provides a unique, practical strategy for minimizing population bias in complex disease studies.

scholarly journals Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis

2017 ◽  
Vol 232 (3) ◽  
pp. 437-450 ◽  
Author(s):  
Rachel V Richardson ◽  
Emma J Batchen ◽  
Adrian J W Thomson ◽  
Rowan Darroch ◽  
Xinlu Pan ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Cell Types ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Primary Driver ◽  
Ventricular Fibrosis

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types.

scholarly journals Role of deformation imaging in left ventricular non-compaction and hypertrophic cardiomyopathy: an Indian perspective

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
A. J. Ashwal ◽  
Sudhakar Rao Mugula ◽  
Jyothi Samanth ◽  
Ganesh Paramasivam ◽  
Krishnananda Nayak ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Left Ventricular ◽  
Deformation Imaging ◽  
Indian Perspective

scholarly journals Baseline clinical features in a large-scale registration survey of patient with hypertrophic cardiomyopathy throughout Japan: J-HCM registry study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Kubo ◽  
H Takano ◽  
M Takayama ◽  
Y.L Doi ◽  
Y Minami ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Clinical Features ◽  
Clinical Characteristics ◽  
Large Scale ◽  
Risk Group ◽  
Nyha Class ◽  
Left Ventricular ◽  
Registry Study ◽  
Icd Implantation ◽  
Successful Recovery

Abstract Background Hypertrophic cardiomyopathy (HCM) is a most prevalent primary myocardial disorder with heterogeneous clinical features. However, there have been few studies on clinical features of HCM as a prospective cohort. In 2015, we established a large-scale registration survey of patients with HCM throughout Japan, named J-HCM registry study. Purpose The aim of this study was to clarify the clinical features of Japanese patients with HCM. Methods J-HCM registry study is a prospective, multicenter investigation, consisting of 24 hospitals. This time, we present the baseline clinical characteristics in this survey. Results Total 1484 patients were registered. The ages at registration and at diagnosis were 65±15 and 56±17 years, respectively, and 806 patients (54%) were men. Majority of the patients (95%) was NYHA class I or II. With regard to subtypes of HCM, there were 526 patients (36%) in the HCM with left ventricular (LV) outflow tract obstruction, 126 patients (8%) in the mid-ventricular obstruction, 57 patients (4%) in the end-stage phase characterized by LV ejection fraction <50%, and 197 patients (14%) in apical HCM. At registration, 80 patients (6%) had prior successful recovery from sustained ventricular tachycardia or ventricular fibrillation, 162 patients (11%) suffered from heart failure hospitalization, and 64 patients (4%) had history of embolic event. Regarding invasive treatment, 160 patients (10%) had prior septal reduction therapy and 162 patients (11%) had ICD implantation. According to the 2014 European Society of Cardiology Guidelines on sudden cardiac death (SCD) prevention, the study patients were divided into 3 categories by the HCM Risk-SCD calculator: patients distribution, 4% in the high risk group (≥6% calculated HCM Risk-SCD at 5 years), 7% in the intermediate risk group (4% to <6%), 69% in the low risk group (<4%), and 16% in the patients with extreme characteristics (Figure 1). Conclusions In this multicenter registration survey of patients with HCM, the baseline clinical characteristics were almost similar to several retrospective large-scale cohorts in Western countries except older age and less symptomatic state. This study will provide important knowledge regarding management of HCM. Figure 1 Funding Acknowledgement Type of funding source: None

Abstract 15632: Phenotypic Overlap Between Left Ventricular Noncompaction and Hypertrophic Cardiomyopathy: A Case Report

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ethan Senser ◽  
Madison Hawkins ◽  
Eric M Williams ◽  
Lauren Gilstrap
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Mri ◽  
Genetic Diagnosis ◽  
Lateral Wall ◽  
Anterior Wall ◽  
Left Ventricular ◽  
Ventricular Noncompaction ◽  
History Of ◽  
Clinically Significant

Introduction: Left ventricular non-compaction (LVNC) is characterized by extensively trabeculaed myocardium adjacent to normal compacted myocardium of the left ventricle (LV). Hypertrophic cardiomyopathy (HCM) typically appears as diffuse or segmental LV hypertrophy, with or without outflow tract obstruction. Cardiac sarcomere mutations are present in most HCM cases and have also been identified in LVNC. Whether or not there is clinically significant phenotypic overlap between the two diseases is less well understood. We present a case of known HCM that met criteria for both LVNC and HCM by cardiac MRI. Case: A 49-year old man with HCM due to a c.3742_3759dup variant in MYBPC3 presented to clinic after an episode of syncope and ICD firing. In clinic, the device was interrogated and he was found to have had ventricular flutter which was successfully treated with one shock and a new, high (>20%) burden of premature ventricular beats. An echocardiogram showed a stable ejection fraction at 42%, mild concentric LV hypertrophy without obstruction and a newly dilated LV with an end diastolic diameter of 7.1cm (previously 6.2cm). A cardiac MRI was performed ( Figure ) and showed LV noncompaction and diffuse transmural and mid myocardial hyperenhancement/fibrosis of the septum, basilar lateral wall, anterior wall, and distal right ventricle consistent with patient's long-standing history of hypertrophic cardiomyopathy. Discussion: This case highlights the phenotypic overlap between HCM and LVNC by cardiac MRI. Had this patient not already carried a genetic diagnosis of HCM, he would likely have been diagnosed with LVNC based on this cardiac MRI. The phenotypic overlap in these diseases raises questions about ICD guidelines, the role of anticoagulation and prognosis.

scholarly journals Endogenous T1ρ cardiovascular magnetic resonance in hypertrophic cardiomyopathy

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Elizabeth W. Thompson ◽  
Srikant Kamesh Iyer ◽  
Michael P. Solomon ◽  
Zhaohuan Li ◽  
Qiang Zhang ◽  
...  
Keyword(s):  
Cardiovascular Magnetic Resonance ◽  
Hypertrophic Cardiomyopathy ◽  
Magnetic Resonance ◽  
Extracellular Volume ◽  
Relaxation Times ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Short Axis ◽  
Spearman's Rho ◽  
Spearman’S Rho

Abstract Background Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular wall thickness, cardiomyocyte hypertrophy, and fibrosis. Adverse cardiac risk characterization has been performed using late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV). Relaxation time constants are affected by background field inhomogeneity. T1ρ utilizes a spin-lock pulse to decrease the effect of unwanted relaxation. The objective of this study was to study T1ρ as compared to T1, ECV, and LGE in HCM patients. Methods HCM patients were recruited as part of the Novel Markers of Prognosis in Hypertrophic Cardiomyopathy study, and healthy controls were matched for comparison. In addition to cardiac functional imaging, subjects underwent T1 and T1ρ cardiovascular magnetic resonance imaging at short-axis positions at 1.5T. Subjects received gadolinium and underwent LGE imaging 15–20 min after injection covering the entire heart. Corresponding basal and mid short axis LGE slices were selected for comparison with T1 and T1ρ. Full-width half-maximum thresholding was used to determine the percent enhancement area in each LGE-positive slice by LGE, T1, and T1ρ. Two clinicians independently reviewed LGE images for presence or absence of enhancement. If in agreement, the image was labeled positive (LGE + +) or negative (LGE −−); otherwise, the image was labeled equivocal (LGE + −). Results In 40 HCM patients and 10 controls, T1 percent enhancement area (Spearman’s rho = 0.61, p < 1e-5) and T1ρ percent enhancement area (Spearman’s rho = 0.48, p < 0.001e-3) correlated with LGE percent enhancement area. T1 and T1ρ percent enhancement areas were also correlated (Spearman’s rho = 0.28, p = 0.047). For both T1 and T1ρ, HCM patients demonstrated significantly longer relaxation times compared to controls in each LGE category (p < 0.001 for all). HCM patients also showed significantly higher ECV compared to controls in each LGE category (p < 0.01 for all), and LGE −− slices had lower ECV than LGE + + (p = 0.01). Conclusions Hyperenhancement areas as measured by T1ρ and LGE are moderately correlated. T1, T1ρ, and ECV were elevated in HCM patients compared to controls, irrespective of the presence of LGE. These findings warrant additional studies to investigate the prognostic utility of T1ρ imaging in the evaluation of HCM patients.

Supplementary role of left ventricular global longitudinal strain for predicting sudden cardiac death in hypertrophic cardiomyopathy

2021 ◽  
Author(s):  
Hyun-Jung Lee ◽  
Hyung-Kwan Kim ◽  
Sang Chol Lee ◽  
Jihoon Kim ◽  
Jun-Bean Park ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Sudden Cardiac Death ◽  
Risk Score ◽  
Primary Endpoint ◽  
Cardiac Death ◽  
Longitudinal Strain ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
C Statistic

Abstract Aims We investigated the prognostic role of left ventricular global longitudinal strain (LV-GLS) and its incremental value to established risk models for predicting sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). Methods and results LV-GLS was measured with vendor-independent software at a core laboratory in a cohort of 835 patients with HCM (aged 56.3 ± 12.2 years) followed-up for a median of 6.4 years. The primary endpoint was SCD events, including appropriate defibrillator therapy, within 5 years after the initial evaluation. The secondary endpoint was a composite of SCD events, heart failure admission, heart transplantation, and all-cause mortality. Twenty (2.4%) and 85 (10.2%) patients experienced the primary and secondary endpoints, respectively. Lower absolute LV-GLS quartiles, especially those worse than the median (−15.0%), were associated with progressively higher SCD event rates (P = 0.004). LV-GLS was associated with an increased risk for the primary endpoint, independent of the LV ejection fraction, apical aneurysm, and 2014 European Society of Cardiology (ESC) risk score [adjusted hazard ratio (aHR) 1.14, 95% confidence interval (CI) 1.02–1.28] or 2011 American College of Cardiology/American Heart Association (ACC/AHA) risk factors (aHR 1.18, 95% CI 1.05–1.32). LV-GLS was also associated with a higher risk for the composite secondary endpoint (aHR 1.06, 95% CI 1.01–1.12). The addition of LV-GLS enhanced the performance of the ESC risk score (C-statistic 0.756 vs. 0.842, P = 0.007) and the 2011 ACC/AHA risk factor strategy (C-statistic 0.743 vs. 0.814, P = 0.007) for predicting SCD. Conclusion LV-GLS is an important prognosticator in patients with HCM and provides additional information to established risk stratification strategies for predicting SCD.

Abstract 16383: Inhibition of Egfr Signalling Promotes Maladaptive Cardiac Remodelling in Hypertensive Heart Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Susanna Cooper ◽  
Zoe Haines ◽  
Viridiana Alcantara Alonso ◽  
Joshua J Cull ◽  
Feroz Ahmad ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mrna Expression ◽  
Left Ventricular ◽  
Egfr Inhibitors ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Egfr Ligands ◽  
Cardiac Adaptation

Introduction: Epidermal growth factor (EGF) receptors (EGFRs: ERBB1-4) are activated by a family of ligands (e.g. EGF, Hb-EGF, EREG, TGFa), signaling through ERK1/2 and Akt to promote cell division and cancer. Antibody-based inhibition of ERBB2 in breast cancer can cause heart failure, but the role of other receptors and EGFR ligands in the heart, and potential cardiotoxicity of generic EGFR inhibitors is unclear. Hypothesis: We hypothesize that EGFR ligands play an important role in cardiac adaptation to hypertension, acting through EGFRs to promote adaptive remodelling. Methods & Results: EGF ligand/receptor mRNA expression was assessed in human failing hearts and normal controls (n=12/8). EGFRs were expressed at similar levels, but ligand expression differed with significant up- or downregulation of EGF/Hb-EGF vs EREG/TGFa, respectively, in failing hearts (p<0.05). EGF potently activated ERK1/2 and Akt (assessed by immunoblotting) in neonatal rat cardiomyocytes, leading to hypertrophy (p<0.05, n=4). The anti-cancer drug afatinib inhibits EGFRs. To assess the role of EGF signaling in cardiac adaptation to hypertension in vivo , C57Bl/6J mice (n=6) were treated with 0.8 mg/kg/d angiotensin II (AngII; 7d) ± 0.45 mg/kg/d afatinib. AngII promoted cardiac hypertrophy with increased left ventricular (LV) wall thickness (WT) and decreased LV internal diameter (ID; assessed by echocardiography). Afatinib enhanced AngII-induced hypertrophy with significantly increased WT:ID ratios (1.30-fold and 1.54-fold in diastole and systole, respectively; p<0.05) but inhibited AngII-induced increases in Nppb mRNA expression and cardiomyocyte cross-sectional area (208.80±9.78 vs 161.10±3.87μm 2 ; p<0.05). In contrast, Col1a1 mRNA expression was enhanced by afatinib, along with interstitial and perivascular fibrosis (3.21±0.38 vs 5.61±0.46, 0.98±0.06 vs 1.45±0.18 % area; p<0.05). Conclusion: EGFR signaling is modulated in human heart failure, promotes cardiomyocyte hypertrophy and is required for cardiac adaptation to hypertension. Since EGFR inhibition in hypertension prevents adaptive cardiomyocyte hypertrophy whilst promoting fibrosis, EGFR inhibitors are likely to cause cardiac dysfunction and be cardiotoxic in hypertensive patients.

Abstract 507: Activation of the Classically Pro-Apoptotic Death Receptor 5 Promotes Physiological Hypertrophy and Cardiomyocyte Survival

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Toby Thomas ◽  
Miles Tanner ◽  
Laurel Grisanti
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Fibrosis ◽  
Death Receptor ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Death Receptor 5 ◽  
Tnf Α ◽  
Cardiomyocyte Survival

Heart failure is hallmarked by a combination of cardiomyocyte hypertrophy and death. Apoptosis, one of the primary mechanisms of cell death, occurs through finely tuned extrinsic or intrinsic pathways. Of the mediators involved in extrinsic apoptotic signaling, some have been extensively studied, such as tumor necrosis factor ((TNF)-α), while others have been relatively untouched. One such receptor is Death Receptor 5 (DR5) which, along with its ligand TNF-Related Apoptosis Inducing Ligand (TRAIL), have recently been implicated as a biomarker in determining the progression and outcome in patients following multiple heart failure etiologies, suggesting a novel role of DR5 signaling in the heart. These studies suggest a potentially protective role for DR5 in the heart; however, the function of TRAIL/DR5 in the heart has been virtually unstudied. Our goal was to explore the role of TRAIL/DR5 in cardiomyocyte hypertrophy and survival with the hypothesis that DR5 promotes cardiomyocyte survival and growth through non-canonical mechanisms. Mice treated with the DR5 agonist bioymifi or a DR5 agonist antibody, MD5-1, were absent of cell death, while an increase in hypertrophy was observed without a decline in cardiac function. In isolated cardiomyocytes, this pro-hypertrophic phenotype was determined to operate through MMP-dependent cleavage of HB-EGFR, leading to transactivation of EGFR and ERK1/2 signaling. To determine the role of DR5 in heart failure, a chronic catecholamine administration model was used and DR5 activation was found to decrease cardiomyocyte death and cardiac fibrosis. ERK1/2, a well characterized pro-survival, pro-hypertrophic kinase is activated in the heart with DR5 agonist administration and may represent the mechanistic link through which DR5 is imparting cardioprotection. In summary, DR5 activation promotes cardiomyocyte hypertrophy and survival and prevents cardiac fibrosis via a non-canonical MMP-EGFR-ERK1/2 pathway. Taken together, these studies identify a previously undetermined role for DR5 in the heart and identify novel therapeutic target for the treatment of heart failure.

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