The Impact of Exercise Restriction in Athletes with Hypertrophic Cardiomyopathy

2016 ◽  
Vol 26 (4) ◽  
pp. 346
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
The Impact ◽  
Exercise Restriction

Exercise in Hypertrophic Cardiomyopathy: Restrict or Rethink??

2021 ◽  
Author(s):  
Adaya Weissler Snir ◽  
Kim A. Connelly ◽  
Jack M. Goodman ◽  
David Dorian ◽  
Paul Dorian
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Animal Studies ◽  
Critical Evaluation ◽  
Sports Participation ◽  
Potential Benefits ◽  
Underlying Mechanisms ◽  
Exercise Induced ◽  
And Function ◽  
The Impact ◽  
Exercise Restriction

The detailed physiological consequences of aerobic training, in patients with hypertrophic cardiomyopathy (HCM) are not well understood. In athletes and non-athletes with HCM, there are two hypothetical concerns with respect to exercise: exercise-related worsening of the phenotype (e.g. promoting hypertrophy, fibrosis), and/or triggering of arrhythmia. The former concern is unproven and animal studies suggest an opposite effect, where exercise has been shown to be protective. The main reason for exercise restriction in HCM is fear of exercise-induced arrhythmia. Whilst the safety of sports in HCM has been reviewed, even more recent data suggest a substantially lower risk for sudden cardiac death (SCD) in HCM than previously thought, and there is an ongoing debate about restrictions of exercise imposed on individuals with HCM. This review outlines the pathophysiology of HCM, the impact of acute and chronic exercise (and variations of exercise intensity, modality, and athletic phenotype) in HCM including changes in autonomic function, blood pressure, cardiac dimensions and function, and cardiac output, and the underlying mechanisms that may trigger exercise-induced lethal arrhythmias. It provides a critical evaluation of the evidence regarding risk of SCD in athletes and the potential benefits of targeted exercise prescription in adults with HCM. Finally, it provides considerations for personalized recommendations for sports participation based on the available data.

Worldwide differences in primary prevention implantable cardioverter defibrillator utilization and outcomes in hypertrophic cardiomyopathy

2021 ◽  
Author(s):  
Victor Nauffal ◽  
Peter Marstrand ◽  
Larry Han ◽  
Victoria N Parikh ◽  
Adam S Helms ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Primary Prevention ◽  
Implantable Cardioverter Defibrillator ◽  
Cox Proportional Hazards ◽  
Icd Implantation ◽  
Icd Therapy ◽  
Cardioverter Defibrillator ◽  
Significant Difference ◽  
Implantation Rates ◽  
The Impact

Abstract Aims  Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry. Methods and results We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89–2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76–6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28–0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74–1.97]). Conclusion  Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

The impact of diabetes mellitus on the clinical phenotype of hypertrophic cardiomyopathy

2018 ◽  
Vol 40 (21) ◽  
pp. 1671-1677 ◽  
Author(s):  
Yishay Wasserstrum ◽  
Roberto Barriales-Villa ◽  
Xusto Fernández-Fernández ◽  
Yehuda Adler ◽  
Dor Lotan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Hypertrophic Cardiomyopathy ◽  
Clinical Phenotype ◽  
The Impact

scholarly journals Hypertrophic cardiomyopathy-linked variants of cardiac myosin-binding protein C3 display altered molecular properties and actin interaction

2018 ◽  
Vol 475 (24) ◽  
pp. 3933-3948 ◽  
Author(s):  
Sahar I. Da'as ◽  
Khalid Fakhro ◽  
Angelos Thanassoulas ◽  
Navaneethakrishnan Krishnamoorthy ◽  
Alaaeldin Saleh ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Binding Protein ◽  
Clinical Severity ◽  
Actin Binding ◽  
Cardiac Myosin ◽  
C2 Domains ◽  
Cardiac Phenotype ◽  
Myosin Binding Protein ◽  
Myosin Binding ◽  
The Impact

The most common inherited cardiac disorder, hypertrophic cardiomyopathy (HCM), is characterized by thickening of heart muscle, for which genetic mutations in cardiac myosin-binding protein C3 (c-MYBPC3) gene, is the leading cause. Notably, patients with HCM display a heterogeneous clinical presentation, onset and prognosis. Thus, delineating the molecular mechanisms that explain how disparate c-MYBPC3 variants lead to HCM is essential for correlating the impact of specific genotypes on clinical severity. Herein, five c-MYBPC3 missense variants clinically associated with HCM were investigated; namely V1 (R177H), V2 (A216T), V3 (E258K), V4 (E441K) and double mutation V5 (V3 + V4), all located within the C1 and C2 domains of MyBP-C, a region known to interact with sarcomeric protein, actin. Injection of the variant complementary RNAs in zebrafish embryos was observed to recapitulate phenotypic aspects of HCM in patients. Interestingly, V3- and V5-cRNA injection produced the most severe zebrafish cardiac phenotype, exhibiting increased diastolic/systolic myocardial thickness and significantly reduced heart rate compared with control zebrafish. Molecular analysis of recombinant C0–C2 protein fragments revealed that c-MYBPC3 variants alter the C0–C2 domain secondary structure, thermodynamic stability and importantly, result in a reduced binding affinity to cardiac actin. V5 (double mutant), displayed the greatest protein instability with concomitant loss of actin-binding function. Our study provides specific mechanistic insight into how c-MYBPC3 pathogenic variants alter both functional and structural characteristics of C0–C2 domains leading to impaired actin interaction and reduced contractility, which may provide a basis for elucidating the disease mechanism in HCM patients with c-MYBPC3 mutations.

P894The association of the polymorphic variant rs1739843 of the hspb7 gene with clinical profile and outcomes in patients with hypertrophic cardiomyopathy (10 years follow-up)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Streltsova ◽  
A Gudkova ◽  
A Poliakova ◽  
S Pyko ◽  
A Kostareva
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Allele Frequency ◽  
Functional Class ◽  
Clinical Profile ◽  
Genotype Frequency ◽  
Polymorphic Variant ◽  
Control Group ◽  
Healthy Donors ◽  
The Impact ◽  
Benign Course

Abstract Purpose The aim of this study was to determine the impact of polymorphic variant rs1739843 of the hspb7 gene on clinical profile and outcomes in patients with hypertrophic cardiomyopathy (HCM). Methods The study population consisted of 108 patients with HCM ≥45 years old. The control group included 192 healthy donors. A novel disease pathway model, firstly designed in foreign outcome study (2017), was employed to assess clinical course of HCM. SNP rs1739843 of the hspb7 gene was genotyped by allele-specific real-time polymerase chain reaction (PCR) assay. Results It was found a significant increase in TT genotype frequency of rs1739843 of the hspb7 gene in patients with HCM (n=108) – 20.4%, compared with control group (n=192) – 4.2% (TT: TC+CC, odds ratio (OR) = 5.88, 95% confidence interval (CI) = 2.52–13.75, p<0.001). High prevalence of CC genotype of rs1739843 of the hspb7 gene was observed in control group – 80.2% vs 31.5% in HCM (CC: TC+TT, OR = 0.11, 95% CI = 0.07–0.19, p<0.001). The allele frequency (C: T) also differed between HCM and control groups – 55.6: 44.4% in HCM, vs 88.02: 11.98% in control group (OR = 5.88, 95% CI = 3.91–8.85, p<0.001). It was also found a significant increase in TT genotype frequency of rs1739843 of the hspb7 gene in HCM patients with benign course free of adverse pathways (n=48) – 16.7%, compared with control group (n=192) – 4.2% (TT: TC+CC, OR= 4.60, 95% CI = 1.63–12.99, p<0.001)). The allele frequency (C: T) in HCM patients with benign course free of adverse pathways was 56.3: 43.7% vs 88.02: 11.98% in control group (OR = 5.71, 95% CI= 3.44–9.49, p<0.001). The mortality rate of HCM patients with 1, 2 or 3 adverse pathways was higher compared with HCM patients with benign course free of adverse pathways. HCM patients ≥45 years old showed a significant increase in T allele frequency in cases of presence of 2 (CHF (chronic heart failure) III–IV functional class (NYHA) + AF (atrial fibrillation)) and 3 adverse pathways (CHF III-IV functional class (NYHA) + AF + SCD (sudden cardiac death) of HCM progression. Conclusions The T allele and TT genotype of rs1739843 of the hspb7 gene were more frequent in patients with HCM ≥45 years old, compared with control group. It was also found a significant increase in frequency of TT genotype and T allele of rs1739843 of the hspb7 gene in HCM patients with benign course free of adverse pathways, compared with control group. HCM progression along 2 and more adverse pathways in patients ≥45 years old has been characterized with adverse outcome. Allele T of rs1739843 of the hspb7 gene was associated with 2 and more adverse pathways of HCM progression.

THE IMPACT OF ADVANCED THERAPIES IN IMPROVING SURVIVAL TO HEART TRANSPLANT IN HYPERTROPHIC CARDIOMYOPATHY

2018 ◽  
Vol 71 (11) ◽  
pp. A681 ◽  
Author(s):  
Ethan Rowin ◽  
Barry J. Maron ◽  
Patrick Abt ◽  
Michael Kiernan ◽  
Amanda Vest ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Heart Transplant ◽  
Advanced Therapies ◽  
The Impact

scholarly journals Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics

2014 ◽  
Vol 117 (12) ◽  
pp. 1471-1477 ◽  
Author(s):  
Gerrie P. Farman ◽  
Priya Muthu ◽  
Katarzyna Kazmierczak ◽  
Danuta Szczesna-Cordary ◽  
Jeffrey R. Moore
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Sarcomeric Proteins ◽  
Motion Generation ◽  
In Vitro Motility Assay ◽  
In Vitro Motility ◽  
Cross Bridge ◽  
Significant Difference ◽  
The Impact

Familial hypertrophic cardiomyopathy (HCM) is associated with mutations in sarcomeric proteins, including the myosin regulatory light chain (RLC). Here we studied the impact of three HCM mutations located in the NH2 terminus of the RLC on the molecular mechanism of β-myosin heavy chain (MHC) cross-bridge mechanics using the in vitro motility assay. To generate mutant β-myosin, native RLC was depleted from porcine cardiac MHC and reconstituted with mutant (A13T, F18L, and E22K) or wild-type (WT) human cardiac RLC. We characterized the mutant myosin force and motion generation capability in the presence of a frictional load. Compared with WT, all three mutants exhibited reductions in maximal actin filament velocity when tested under low or no frictional load. The actin-activated ATPase showed no significant difference between WT and HCM-mutant-reconstituted myosins. The decrease in velocity has been attributed to a significantly increased duty cycle, as was measured by the dependence of actin sliding velocity on myosin surface density, for all three mutant myosins. These results demonstrate a mutation-induced alteration in acto-myosin interactions that may contribute to the pathogenesis of HCM.

scholarly journals Gender-Related Differences in Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis

Pulse ◽  
2021 ◽  
Vol 9 (1-2) ◽  
pp. 38-46
Author(s):  
Angkawipa Trongtorsak ◽  
Natchaya Polpichai ◽  
Sittinun Thangjui ◽  
Jakrin Kewcharoen ◽  
Ratdanai Yodsuwan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Hypertrophic Cardiomyopathy ◽  
Cohort Studies ◽  
Meta Analysis ◽  
Phenotypic Expression ◽  
Female Gender ◽  
Increased Risk ◽  
All Cause Mortality ◽  
The Impact ◽  
Related Mortality

<b><i>Background:</i></b> Gender-related differences in phenotypic expression and outcomes have been established in many cardiac conditions; however, the impact of gender in hypertrophic cardiomyopathy (HCM) remains unclear. We conducted a systematic review and meta-analysis to assess the differences in clinical outcomes between female and male HCM patients. <b><i>Methods:</i></b> We searched MEDLINE and EMBASE from inception to October 2020. Included were cohort studies that compared outcomes of interest including all-cause mortality, HCM-related mortality, and worsening heart failure (HF) or HF hospitalization between male and female. Data from each study were combined using the random effects model to calculate pooled odds ratio (OR) with 95% confidence interval (CI). <b><i>Results:</i></b> Eleven retrospective cohort studies with a total of 9,427 patients (3,719 females) were included. Female gender was significantly associated with an increased risk of all-cause mortality (pooled OR = 1.63, 95% CI: 1.26–2.10, <i>p</i> ≤ 0.001), HCM-related mortality (pooled OR = 1.47, 95% CI: 1.08–2.01, <i>p</i> = 0.015), and worsening HF or HF hospitalization (pooled OR = 2.05, 95% CI: 1.76–2.39, <i>p</i> ≤ 0.001). <b><i>Conclusions:</i></b> Female gender was associated with a worse prognosis in HCM. These findings suggest the need for improved care in women including early identification of disease and more possible aggressive management. Moreover, gender-based strategy may benefit in HCM patients.

scholarly journals Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

2019 ◽  
Author(s):  
Sathiya N. Manivannan ◽  
Sihem Darouich ◽  
Aida Masmoudi ◽  
David Gordon ◽  
Gloria Zender ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Exome Sequencing ◽  
Rapid Screening ◽  
Functional Study ◽  
Ventricular Muscle ◽  
Loss Of Function ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
The Impact

AbstractHypertrophic cardiomyopathy (HCM) is characterized by enlargement of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the C-terminal EF-hand (CEF) domain. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stopgain variants that lead to loss of the CEF domain are stably expressed. However, stopgain variants show impaired localization suggesting a functional role for the CEF domain. The degradation of the MYL2-fs can be rescued by inhibiting the cell’s proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither MYL2-fs nor MYL2:p.Gly162Arg supports regular cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathies.Author SummaryWe report a novel frameshift variant in MYL2 that is associated with a severe form of infantile-onset hypertrophic cardiomyopathy. The impact of the variant is only observed in the recessive form of the disease in the proband and not in the parents who are carriers of the variant. This is in contrast to other dominant variants in MYL2 that are associated with cardiomyopathies. We compared the stability of this variant to that of other cardiomyopathy associated MYL2 variants and found molecular differences in the disease pathology. We also show different protein domain requirement for stability and localization of MYL2 in cardiomyocytes. Further, we used a fly model to demonstrate functional deficits due to the variant in the developing heart. Overall, our study shows a molecular mechanism by which loss-of-function variants in MYL2 are recessive while missense variants are dominant. We highlight the use of exome sequencing and functional testing to assist in the diagnosis of rare forms of diseases where pathogenicity of the variant is not obvious. The new tools we developed for in vitro functional study and the fly fluorescent reporter analysis will permit rapid analysis of MYL2 variants of unknown significance.

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