Clinical Hypertrophic Cardiomyopathy Research Articles

Long-Term Outcomes After Septal Reduction Therapies in Obstructive Hypertrophic Cardiomyopathy: Insights From the SHARE Registry.

Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined. Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome. Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P<0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P<0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P<0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction. Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF.

Association of Fibrate use with clinical expression of hypertrophic cardiomyopathy.

An association between obesity, metabolic abnormalities and clinical hypertrophic cardiomyopathy (HCM) expression has been reported. We investigated whether managing dyslipidaemia with fibrates could affect the clinical expression of HCM. We screened patients who used fibrates between 2010 and 2017 from a nationwide database. After excluding patients with a history of HCM, we identified fibrate-user group (n=412823). We then constructed a 1:1 matched cohort of fibrate-naïve participants (n=412823). After a 1year lag period, we identified the incident HCM cases for the following 5years. During a median follow-up period of 3.96years, we identified 454 incident clinical HCM cases. After adjusting for covariates, fibrate use was associated with a lower risk of clinical HCM expression [hazard ratio (HR) 95% confidence interval (CI): 0.763 (0.630-0.924)]. In subgroup analyses, fibrate use was associated with a reduced risk of clinical HCM expression in patients with a body mass index ≥25kg/m2 and those with abdominal obesity [HR (95% CI): 0.719 (0.553-0.934) and 0.655 (0.492-0.872)], but not in those without obesity. Fibrate use was also associated with lower risks of incident clinical HCM in patients with triglyceride levels ≥150mg/dL and those with metabolic syndrome [HR (95% CI): 0.741 (0.591-0.929) and 0.750 (0.609-0.923)], but not in their counterparts. Regarding lifestyle behaviours, fibrate use appeared to provide more prognostic benefits in patients who currently smoked, consumed alcohol or did not engage in regular physical activities. The use of fibrates is associated with a lower incidence of clinical HCM expression. This association was also more prominent in those with obesity, unhealthy metabolic profiles and poor lifestyle behaviours.

Phenotypic spectrum of the first Belgian MYBPC3 founder: a large multi-exon deletion with a varying phenotype.

Variants in the MYBPC3 gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in MYBPC3 (del exon 23-26) in several probands. We aimed to assess the presence of a common haplotype and to describe the cardiac characteristics, disease severity and long-term outcome of mutation carriers. Probands with HCM caused by a pathogenic deletion of exon 23-26 of MYBPC3 were identified through genetic screening using a gene panel encompassing 59 genes associated with cardiomyopathies in a single genetic center in Belgium. Cascade screening of first-degree relatives was performed, and genotype positive relatives were further phenotyped. Clinical characteristics were collected from probands and relatives. Cardiac outcomes included death, heart transplantation, life-threatening arrhythmia, heart failure hospitalization or septal reduction therapy. Haplotype analysis, using microsatellite markers surrounding MYBPC3, was performed in all index patients to identify a common haplotype. The age of the founder variant was estimated based on the size of the shared haplotype using a linkage-disequilibrium based approach. We identified 24 probands with HCM harbouring the MYBPC3 exon 23-26 deletion. Probands were on average 51 ± 16years old at time of clinical HCM diagnosis and 62 ± 10 years old at time of genetic diagnosis. A common haplotype of 1.19Mb was identified in all 24 probands, with 19 of the probands sharing a 13.8Mb haplotype. The founder event was estimated to have happened five generations, or 175-200years ago, around the year 1830 in central Flanders. Through cascade screening, 59 first-degree relatives were genetically tested, of whom 37 (62.7%) were genotype positive (G+) and 22 (37.3%) genotype negative (G-). They were on average 38 ± 19years old at time of genetic testing. Subsequent clinical assessment revealed a HCM phenotype in 19 (51.4%) G+ relatives. Probands were older (63 ± 10 vs. 42 ± 21years; p < 0.001) and had more severe phenotypes than G+ family members, presenting with more symptoms (50% vs. 13.5%; p = 0.002), arrhythmia (41.7% vs. 12.9%, p = 0.014), more overt hypertrophy and left ventricular outflow tract obstruction (43.5% vs. 3.0%; p < 0.001). Male G+ relatives more often had a HCM phenotype (78.6% vs. 34.8%; p = 0.010) and were more severely affected than females. At the age of 50, a penetrance of 78.6% was observed, defined as the presence of HCM in 11 of 14 G+ relatives with age ≥50years. Overall, 20.3% of all variant carriers developed one of the predefined cardiac outcomes after a median follow-up of 5.5years with an average age of 50 (±21) years. A Belgian founder variant, an exon 23-26 deletion in MYBPC3, was identified in 24 probands and 37 family members. The variant is characterized by a high penetrance of 78.6% at the age of 50years but has variable phenotypic expression. Adverse outcomes were observed in 20.3% of patients during follow-up.

Mortality in hypertrophic cardiomyopathy is unrelated to genotype

Abstract Background Hypertrophic cardiomyopathy (HCM) patients with a pathogenic variant are presumed to have worse prognosis than patients without a pathogenic mutation. However, the genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and relationship between genotype status and outcomes have not been completely resolved. Objective We assessed a large international HCM cohort to define the natural history and clinical consequences of genotype status. Methods Consecutive patients (n=1468) with established clinical HCM diagnosis underwent genetic testing focused on HCM-related genes. Patients with pathogenic or likely pathogenic variants were considered genotype positive (G+), and those without definite disease-causing mutation or a variant of uncertain significance (VUS) were considered genotype negative (G-). Patients were followed for 9.6 ± 8.2 years for clinical outcomes. Results Of 1468 HCM patients, 1156 (79%) were G - and 312 (21%) were G+. Over the follow-up 116 (10%) G- patients died at 70 ± 14 years, including in 26 (2.2%) from HCM-related causes. HCM-related mortality was not significantly different in G- patients (0.3%/year) as compared to G+ patients (0.3%/year) when adjusted for age (HR 0.93, 95% CI 0.38-2.30, p=0.87). All-cause mortality was not different among these groups (0.7%/year G- vs. 0.6%/year G+) when adjusted for age (HR 0.62, 95% CI 0.3-1.2, p=0.14) or comorbidities (HR 0.78, 95% CI 0.46-1.31, p=0.35). Rate of progression to advanced heart failure NYHA class III/IV in nonobstructive patients was not different in G- (4%/ year) vs. G+ (3%/year, HR 1.20, 95% CI 0.63-2.26, p=0.58). Sudden death events (appropriate ICD shocks, aborted cardiac arrest and sudden death) were more frequent in G+ patients (1.7%/year) than in G- patients (0.5%/year), albeit of borderline statistical significance when adjusted for age and SD risk factors (HR 1.58, 95% CI 1.00-2.49, p=0.05). Conclusions In this large consecutive genotyped cohort, all-cause and HCM-related mortality was unrelated to genotype status. Substantial proportion of G- patients experienced progressive HF, at a similar rate when compared to G+ patients. Although G- patients had less frequently SD events, genotype negative status could not be considered benign.FiguresTable

Abstract 16660: Precision Diagnosis of Hypertrophic Cardiomyopathy: A New Definition of Inappropriate Hypertrophy

Introduction: The definition of hypertrophic cardiomyopathy (HCM), unaltered for 50 years, requires unexplained left ventricular hypertrophy with a maximum wall thickness (MWT) ≥15mm in probands. However, this doesn’t consider age, sex and body-size which is inadequate for a precision therapy era. Aim: To develop a personalised definition of inappropriate hypertrophy using cardiac MRI and evaluate potential care implications. Methods: Healthy reference cardiac MRIs from the Framingham Heart Study, UK Biobank, and multiple healthy volunteer studies were analysed by a validated AI algorithm. Generalized additive mixed models accounting for age, sex, and body surface area (BSA) established a personalized hypertrophy threshold for MWT (&gt;95% prediction interval) and conditional Z-scores. We assessed the discordance in HCM diagnosis between a “≥15mm” and “personalized hypertrophy” threshold applied to the UK Biobank and clinical HCM cohorts. Results: In healthy subjects (n=5,255), 36% of MWT variation was explained by age, sex and BSA. In the UK Biobank (n=44,690), using ≥15mm, there is a substantial sex skew; 8% of males and 1% of females are classified as hypertrophic. With a personalized threshold, this reduces to 3% of males and 2% of females classified as hypertrophic. 17% of subjects have a predicted hypertrophy threshold of 15mm (with 46% predicted ≤ 14mm, 37% predicted ≥16mm). In clinical HCM cohorts (n=1,854) across 5 centres in 4 countries (UK, USA, Italy, Portugal), females had thinner hearts (17.7 vs 19.1mm; p&lt;0.001) but more relative hypertrophy evidenced by greater deviation (Z-scores) from their predicted MWT (5.4 vs 5.1; p=0.05). Conclusion: We propose a new, personalised definition for hypertrophy that mitigates for significant age, sex and BSA confounding inherent in a 15mm cut point. We have identified potential for under/over diagnosis in a population cohort and suboptimal risk stratification in smaller, younger and/or female HCM patients.

Circulating MicroRNAs Identify Early Phenotypic Changes in Sarcomeric Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. Pathogenic germline variation in genes encoding the sarcomere is the predominant cause of disease. However diagnostic features, including unexplained left ventricular hypertrophy, typically do not develop until late adolescence or after. The early stages of disease pathogenesis and the mechanisms underlying the transition to a clinically overt phenotype are not well understood. In this study, we investigated if circulating microRNAs (miRNAs) could stratify disease stage in sarcomeric HCM. We performed arrays for 381 miRNAs using serum from HCM sarcomere variant carriers with and without a diagnosis of HCM and healthy controls. To identify differentially expressed circulating miRNAs between groups, multiple approaches were used including random forest, Wilcoxon rank sum test, and logistic regression. The abundance of all miRNAs was normalized to miRNA-320. Of 57 sarcomere variant carriers, 25 had clinical HCM and 32 had subclinical HCM with normal left ventricular wall thickness (21 with early phenotypic manifestations and 11 with no discernible phenotypic manifestations). Circulating miRNA profile differentiated healthy controls from sarcomere variant carriers with subclinical and clinical disease. Additionally, circulating miRNAs differentiated clinical HCM from subclinical HCM without early phenotypic changes; and subclinical HCM with and without early phenotypic changes. Circulating miRNA profiles did not differentiate clinical HCM from subclinical HCM with early phenotypic changes, suggesting biologic similarity between these groups. Circulating miRNAs may augment the clinical stratification of HCM and improve understanding of the transition from health to disease in sarcomere gene variant carriers.

Abstract 14861: Decisional Factors Affecting Genetic Testing Uptake Among Black Adults With Hypertrophic Cardiomyopathy

Introduction: Black adults are underrepresented in hypertrophic cardiomyopathy (HCM) research and experience disparities in HCM - related variant interpretation due to a lack of diversity in genomic reference databases. This is compounded by lower HCM genetic testing utilization among this population. The objective of the qualitative study was to explore decisional factors affecting genetic testing use among a sample of Black adults with HCM. Methods: We used purposive sampling to recruit adults with clinical HCM and had undergone clinical genetic testing for HCM, self-identified as Black/African American, and were receiving care at a large urban academic center. Semi-structured individual interviews were conducted and inductive qualitative content analysis was performed to identify themes related to decisional factors for HCM genetic testing utilization. Quantitative descriptive analysis included demographics and genetic literacy evaluation via the Rapid Estimate of Adult Literacy in Genetics (REAL-G) Results: The sample included 30 individuals (15, 50% women), mean (SD) age 48.8 (17.2) years. Ten (33.3%) individuals had likely-pathogenic/pathogenic variants on clinical genetic testing. REAL-G scores were median (IQR) 62.5 (61;63), signifying a high-school literacy level. Almost half (46.7%) of participants reported finding at least some difficulty paying for basic necessities. The most common themes in decision-making regarding genetic testing utilization included out-of-pocket test costs and a positive relationship with HCM providers, followed by self-care and family concerns. Additional themes emerged concerning individual paths to an HCM diagnosis, including seeing multiple providers and navigating layers of the healthcare system, prior to evaluation by an HCM specialist. Conclusions: This study identified decisional facilitators regarding genetic testing use among a cohort of Black adults with HCM. Future work may focus on identifying barriers and designing interventions to improve genetic testing utilization in this population.

Human versus machine: does artificial intelligence add value to identification of hypertrophic cardiomyopathy in pediatric patients?

Abstract Introduction An abnormal increase in left ventricular thickness is a hallmark of hypertrophic cardiomyopathy (HCM). Although standard measures of left ventricular voltage abnormalities on electrocardiograms (ECGs) have high false positive rates and poor correlation to left ventricular thickness, ECGs continue to be part of most screening programs. We developed a machine learning model for HCM classification from ECG in a pediatric cohort and compared its efficacy to that of clinician specialists. Purpose To compare clinician-based predictions of HCM to a machine learning model trained to classify pediatric patients with HCM utilizing 12-lead ECG. Methods ECGs from patients &amp;lt;19 years with HCM, including those with HCM gene mutations, were compared to those from age- and sex-matched controls with normal heart structure and function on echocardiogram. Patients with a known history of primary causes of left ventricular hypertrophy such as aortic stenosis or glycogen storage disease were excluded. A cascaded convolutional neural network was developed combining a residual neural network with a 2-layer dense neural network with 10-fold cross validation. The performance of the machine learning based HCM classification was compared to that of two independent clinicians. Results Analytic sample included data from 82 patients with clinical HCM compared to 91 healthy control subjects. The machine model AUC was 0.89 (0.84–0.94). Clinician inter-rater reliability was 0.8. The clinicians had a higher specificity (97% vs 82%) but lower sensitivity (50% vs 78%) than the machine learning model. Compared to clinician-classification, the positive predictive value was lower in the machine model (82% vs 93%). Conclusion In this preliminary study, machine learning classification of HCM utilizing 12-lead ECG had greater sensitivity than that of clinician interpretation. Machine learning may play a role in screening and diagnosis, including in subjects with normal-appearing ECG. Evaluation of its utility in a larger cohort is needed. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Le Bonheur Children's Hospital

Assessing health-related quality-of-life in patients with symptomatic obstructive hypertrophic cardiomyopathy: EQ-5D-based utilities in the EXPLORER-HCM trial

Aims To assess the effects of mavacamten on health-related quality-of-life (HRQoL) in symptomatic obstructive hypertrophic cardiomyopathy (HCM) and estimate health utilities by New York Heart Association (NYHA) functional class. Materials and methods Patients with symptomatic obstructive HCM were randomized to 30 weeks of mavacamten or to placebo treatment, with or without beta-blocker or calcium channel blocker monotherapy, in EXPLORER-HCM (ClinicalTrials.gov identifier: NCT03470545). Health utility was measured using the EuroQoL 5-dimension 5-level (EQ-5D-5L) index score with the US value set. The 30-week changes in EQ-5D-5L index score and EuroQoL visual analog scale (EQ-VAS) score were compared between the two arms using linear regression, and the proportions of patients with a meaningful improvement were compared using logistic regression. The meaningful change thresholds were estimated using both distribution- and anchor-based approaches. Mean utilities by NYHA class were estimated for each arm using a generalized estimating equation. Results Compared with placebo (N = 89), patients receiving mavacamten (N = 96) had significantly greater 30-week improvement in EQ-5D-5L index score (mavacamten = 0.084; placebo = 0.009; adjusted difference = 0.073 [95% confidence interval = 0.027–0.118]) and EQ-VAS score (mavacamten = 8.5; placebo = 0.7; adjusted difference = 7.5 [95% confidence interval = 1.8–13.2]), and a significantly higher proportion of these patients showed meaningful improvement in EQ-5D-5L index score and EQ-VAS score. Both outcomes were correlated with the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS) and HCM Symptom Questionnaire Shortness-of-Breath (HCMSQ SoB) subscore, two patient-reported anchor variables. Additionally, mean utilities significantly decreased with higher NYHA functional class (values for NYHA class I, II, and III/IV – mavacamten = 0.950, 0.866, and 0.708; placebo = 0.952, 0.850, and 0.704). Conclusions Compared with placebo, mavacamten significantly improved EQ-5D-5L index score and EQ-VAS score – and thus HRQoL – among patients with symptomatic obstructive HCM. Patients with a higher NYHA functional class had a lower health utility value.

Obesity and metabolic health status are determinants for the clinical expression of hypertrophic cardiomyopathy.

We sought to investigate the association of obesity and metabolic health status with the incidence of clinical hypertrophic cardiomyopathy (HCM) diagnosis in the general population. Our goal was to identify modifiable risk factors to attenuate clinical expression of HCM, enabling management evolution from a mostly passive strategy of risk stratification to a proactive strategy of modifying disease expression. Using nationwide population-based data from the Korean National Health Insurance Service, 28,679,891 people who were free of prevalent HCM and who underwent health examinations between 2009 and 2015 were followed until 31 December 2016. The primary outcome was clinical HCM that was defined as incident diagnosis of HCM during the follow-up, after a blanking period of 12 months. Over a median follow-up of 5.2 years, 0.027% (n = 7851) of the study participants were diagnosed as incident HCM. The incidence rate per 1000 person-years was 0.059. A significant association was found between body mass index (BMI) and the incidence of clinical HCM after multivariate adjustment, with a hazard ratio per 1 kg/m2 increase in BMI of 1.063 (95% confidence interval 1.051-1.075). Metabolically unhealthy participants had a greater incidence of HCM than metabolically healthy participants, regardless of obesity status. The effect of BMI was more pronounced in several subgroups, including participants with no hypertension, those aged less than 65 years and men. We found that individuals with obesity and/or metabolic abnormalities had a significantly higher incidence of clinical HCM diagnosis than their counterparts. Efforts to manage obesity and metabolic abnormalities may be important in modifying clinical expression of HCM.

Analysis of three-chamber view conventional and tagged cine MRI in patients with suspected hypertrophic cardiomyopathy.

To investigate the potential value of adding a tagged three-chamber (3Ch) cine to clinical hypertrophic cardiomyopathy (HCM) magnetic resonance imaging (MRI) protocols, including to help distinguish HCM patients with regionally impaired cardiac function. Forty-eight HCM patients, five patients with "septal knuckle" (SK), and 20 healthy volunteers underwent MRI at 1.5T; a tagged 3Ch cine was added to the protocol. Regional strain, myocardial wall thickness, and mitral valve leaflet lengths were measured in the 3Ch view. In HCM, we found a reduced tangential strain with decreased diastolic relaxation in both hypertrophied (p = 0.003) and remote segments (p = 0.035). Strain in the basal septum correlated with the length of the coaptation zone + residual leaflet (r = 0.48, p < 0.001). In the basal free wall, patients with SK had faster relaxation compared to HCM patients with septal hypertrophy. The 3Ch tagged MRI sequence provides useful information for the examination of suspected HCM patients, with minimal additional time cost. Local wall function is closely associated with morphological changes of the mitral apparatus measured in the same plane and may provide insights into mechanisms of obstruction. The additional strain information may be helpful when analyzing local myocardial wall motion patterns in the presence of SK.

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models.

Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation-bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti-TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage

Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations.

A missense mutation within the C6-domain of cMyBP-C results in cardiac enlargement and depressed ventricular function

Cardiac myosin-binding protein-C (cMyBP-C) plays a key role in determining the force and kinetics of myocardial contraction, primarily by binding to either myosin subfragment-2 or actin or both. By modulating the probability of myosin cross-bridge binding to actin, cMyBP-C normally acts to govern the kinetics of force development and relaxation. To determine the effects on cardiac morphology and function due to a novel cMyBP-C W792R missense mutation associated with clinical hypertrophic cardiomyopathy in humans. We generated cMyBP-C-W792R heterozygous and homozygous knock-in mice to investigate the structural and functional phenotypes associated with a missense mutation within the C6-domain of cMyBP-C. Compared to wild-type, homozygous W792R knock-in hearts exhibited significant ventricular and atrial dilation. While the W792R mutant protein was expressed at equivalent levels as in wild-type mice, the extent of phosphorylation of the mutant cMyBP-C protein was markedly reduced. Measurements of steady-state force and cross-bridge cycling kinetics showed that homozygous cMyBP-C W792R skinned myocardium exhibited a significant increase in the Ca2+-sensitivity of force and accelerated cross-bridge cycling kinetics (ktr) at maximal levels of Ca2+-activation, compared to WT myocardium. Cardiac function, as assessed by transthoracic echocardiography, revealed depressed indices of systolic and diastolic ventricular function in the homozygous W792R KI mice. These results demonstrate that a mutation within the mid-region of cMyBP-C can disrupt the dynamic regulation between myosin and actin that is normally governed by cMyBP-C, thereby leading to aberrant cardiac enlargement and commensurate diminution of in vivo ventricular function.

Robust semi-automated quantification of cardiac MR perfusion using level set: Application to hypertrophic cardiomyopathy patient data

BackgroundRecently there have been several clinical MR perfusion studies in patients with hypertrophic cardiomyopathy (HCM) who may suffer from myocardial ischemia due to coronary microvascular dysfunction. In these studies, data analysis relied on a manual procedure of tracing epicardial and endocardial borders. The goal of this work is to develop and validate a robust semi-automated analysis method for myocardial perfusion quantification in clinical HCM data. MethodDynamic multi-slice stress perfusion MRI data were acquired from 18 HCM patients. The proposed semi-automated method required user input of two landmark selections: LV center point and RV insertion point. Automated segmentations of the endocardial and epicardial borders were performed in three short-axis slices using distance regularized level set evolution on RV, LV, and myocardial enhancement frames. ResultsThe proposed automated epicardial border detection method resulted in average radial distance errors of 7.5%, 9.5%, and 11.6% in basal, mid, and apical slices, respectively, when compared to manual tracing of the borders as a reference. In linear regression analysis, the highest correlation of myocardial upslope measurements was observed between the manual method and the proposed method in the anterolateral section (r=0.964), and the lowest correlation was observed in the inferoseptal section (r=0.866). ConclusionThe proposed semi-automated method for myocardial MR perfusion quantification is feasible in HCM patients who typically show (1) irregular myocardial shape and (2) low image contrast between the myocardium and its surrounding regions due to coronary microvascular disease.

Impact of the papillary muscles on cardiac magnetic resonance image analysis of important left ventricular parameters in hypertrophic cardiomyopathy.

PurposeThe use of cardiac magnetic resonance (CMR) analysis has increased in patients with hypertrophic cardiomyopathy (HCM). Quantification of left ventricular (LV) measures will be affected by the inclusion or exclusion of the papillary muscles as part of the LV mass, but the magnitude of effect and potential consequences are unknown.MethodsWe performed Cine-CMR in (1) clinical HCM patients (n = 55) and (2) subclinical HCM mutation carriers without hypertrophy (n = 14). Absolute and relative differences in LV ejection fraction (EF) and mass were assessed between algorithms with and without inclusion of the papillary muscles.ResultsPapillary muscle mass in group 1 was 6.6 ± 2.5 g/m2 and inclusion of the papillary muscles resulted in significant relative increases in LVEF of 4.5 ± 1.8 % and in LV mass of 8.7 ± 2.6 %. For group 2 these figures were 4.0 ± 0.9 g/m2, 3.8 ± 1.0 % and 9.5 ± 1.8 %, respectively. With a coefficient of variation of 4 %, this 9 % difference in LV mass during CMR follow-up will be considered a change, while in fact the exact same mass may have been assessed according to two different algorithms.ConclusionsIn clinical HCM patients, CMR quantification of important LV measures is significantly affected by inclusion or exclusion of the papillary muscles. In relative terms, the difference was similar in subjects without hypertrophy. This underscores a general need for a uniform approach in CMR image analysis.

Incidentally Detected Myocardial Cleft: Cardiac Computed Tomography and Magnetic Resonance Imaging Findings

Myocardial clefts are congenital anomalies, usually localized in the basal inferior wall of the left ventricle and mid-apical segments of the interventricular septum. The patients with genetic mutations related to hypertrophic cardiomyopathy showed significant elevation in the incidence of myocardial cleft. Also there is a significant correlation between the myocardial clefts and the carriers of hypertrophic cardiomyopathy gene mutations without clinical signs . Magnetic resonance imaging allows us to diagnose the myocardial clefts of the healthy individuals as well as the patients and closely follow up for clinical hypertrophic cardiomyopathy. Here we present the cardiac computed tomography and magnetic resonance imaging findings of a case with myocardial cleft.

Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers.

Phenotypic heterogeneity and incomplete penetrance are common in patients with hypertrophic cardiomyopathy (HCM). We aim to improve the understanding in genotype-phenotype correlations in HCM, particularly the contribution of an MYL2 founder mutation and risk factors to left ventricular hypertrophic remodelling. We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G > A [p.(Glu22Lys)] mutation and a common founder haplotype. In this unique cohort, we investigated factors influencing phenotypic outcome in addition to the primary mutation. The mutation alone showed benign disease manifestation with low penetrance. The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers (P = 0.0005). The most prominent risk factor was hypertension, observed in 71% of mutation carriers with HCM and an additional risk factor. The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers. However, the presence of an additional risk factor for hypertrophy, particularly hypertension, adds to the development of HCM. Early diagnosis of risk factors is important for early treatment of MYL2 mutation carriers and close monitoring should be guaranteed in this case. Our findings also suggest that the presence of hypertension or another risk factor for hypertrophy should not be an exclusion criterion for genetic studies.

QRS Fragmentation and QTc Duration Relate to Malignant Ventricular Tachyarrhythmias and Sudden Cardiac Death in Patients with Hypertrophic Cardiomyopathy.

QRS fragmentation (fQRS) and prolonged QTc interval on surface ECG are prognostic in various cardiomyopathies other than hypertrophic cardiomyopathy (HCM). The association between fQRS and prolonged QTc duration with occurrence of ventricular tachyarrhythmias or sudden cardiac death (VTA/SCD) in patients with HCM was explored. One hundred and ninety-five clinical HCM patients were studied. QTc duration was derived applying Bazett's formula; fQRS was defined as presence of various RSR' patterns, R or S notching and/or >1 additional R wave in any non-aVR lead in patients without pacing or (in)complete bundle branch block. The endpoints comprised SCD, ECG documented sustained VTA (tachycardia or fibrillation) or appropriate implantable cardioverter defibrillator (ICD) therapies (antitachycardia pacing [ATP] or shock) for VTA in ICD recipients (n = 58 [30%]). QT prolonging drugs recipients were excluded. After a median follow-up of 5.7 years (IQR 2.7-9.1), 26 (13%) patients experienced VTA or SCD. Patients with fQRS in ≥3 territories (inferior, lateral, septal, and/or anterior) (p = 0.004) or QTc ≥460 ms (p = 0.009) had worse cumulative survival free of VTA/SCD than patients with fQRS in <3 territories or QTc <460 ms. fQRS in ≥3 territories (ß 4.5, p = 0.020, 95%CI 1.41-14.1) and QTc ≥460 ms (ß 2.7, p = 0.037, 95%CI 1.12-6.33) were independently associated with VTA/SCD. Likelihood ratio test indicated assessment of fQRS and QTc on top of conventional SCD risk factors provides incremental predictive value for VTA/SCD (p = 0.035). Both fQRS in ≥3 territories and QTc duration are associated with VTA/SCD in HCM patients, independently of and incremental to conventional SCD risk factors.

Preclinical alterations in cardiac energetics amongst sarcomere mutation carriers in hypertrophic cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) is characterised by reduced myocardial tissue oxygenation (assessed using blood oxygen level dependent (BOLD) CMR imaging) during stress, as well as reduced myocardial perfusion reserve (MPRI) due to coronary microvascular dysfunction. In HCM gene carriers without the HCM phenotype, it has been suggested that only oxygenation is impaired. [1] It remains unclear whether this relates to early cardiac remodelling/ diastolic dysfunction, or whether oxygen consumption is intrinsically altered with sarcomere mutations. We sought to assess the BOLD signal change during vasodilator stress in a homogenous group of MYPBC3 positive HCM patients (some with clinical HCM, and some with no phenotypic features of HCM), and normal controls.