Hypertrophic Cardiomyopathy Risk Research Articles

Left atrial and left ventricular strain in feature-tracking cardiac magnetic resonance for predicting patients at high risk of sudden cardiac death in hypertrophic cardiomyopathy.

Sudden cardiac death (SCD) represents the most severe complication of hypertrophic cardiomyopathy (HCM). The risk stratification of SCD in patients with HCM remains a subject of ongoing debate, and the utility of left atrial (LA) and left ventricular (LV) myocardial strain for risk stratification of also SCD remains uncertain. Through use of feature-tracking cardiac magnetic resonance (FT-CMR), this study aimed to investigate the attenuation of LA and LV strain in HCM and to assess their predictive value in SCD. This retrospective and cross-sectional study included patients with HCM who underwent 3.0 T cardiac magnetic resonance (CMR) at a single institution. Feature-tracking strain analysis was conducted to obtain the strain rate (SR) and LV strain and to evaluate LV function. LA strain was measured during different functional phases including left atrial reservoir strain (LARS), LA conduit strain (LACS), and LA booster strain. All patients were categorized into high- and low-risk groups for SCD as defined by the 2020 American Heart Association/American College HCM implantable cardioverter defibrillator class of recommendation algorithm. Comparison between the two groups was conducted using the independent samples t test and the nonparametric rank sum test. Multivariate logistic regression analysis was performed to further identify the factors influencing SCD risk in HCM. Compared with those in the low-risk group, patients in the high-risk group had lower left ventricular ejection fraction (LVEF), LV stroke volume index (LVSVI), and LA stroke volume index (LASVI) but a higher LV end-systolic volume index (LVESVI), LV maximum wall thickness, and late gadolinium enhancement (LGE) (P<0.001). LV strain, SR, and LA strain all showed significant differences between the high- and low-risk groups (LARS: P=0.04; LACS: P=0.02; all other P values <0.001). The LV global circumferential strain (LVGCS) had a strong negative correlation with LVEF in patients with HCM (r=-0.76; P<0.001). Multivariate analysis showed that LV global radial strain (LVGRS) and LARS could be used for categorizing the patients into the high-risk group [LVGRS: odds ratio (OR) =0.69; 95% confidence interval (CI): 0.55-0.87, P<0.001; LARS: OR =1.39; 95% CI: 1.02-1.90, P=0.03]. The combined LVGRS-LARS model exhibited a superior diagnostic value for high risk of SCD [area under the curve (AUC) =0.95; 95% CI: 0.90-1.00; P<0.001] compared to LARS alone (AUC =0.63; 95% CI: 0.51-0.76; P=0.04). LA and LV strain measured by FT-CMR can accurately identify those patients with HCM at a high risk of SCD. This approach may prove considerably value in guiding early therapeutic intervention with implantable cardioverter-defibrillators (ICDs) to prevent adverse clinical outcomes.

Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.

Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital-twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. Computational models of human HCM cardiomyocytes, tissue and ventricles were used to simulate outcomes of phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n=12 cells, N=5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N=28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarisation, and (iii) ischaemia, impaired repolarisation, and diffuse fibrosis.HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of c.a. 75,000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia-fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.

Role of Biomarkers of Myocardial Injury to Predict Adverse Outcomes in Hypertrophic Cardiomyopathy.

Serum troponins and CK-MB (creatine kinase-MB) are readily detectable and reliable cardiac-specific biomarkers of subclinical myocardial injury. This study explores the roles of cTnI (cardiac troponin I) and CK-MB in hypertrophic cardiomyopathy (HCM). This study included 1045 patients with HCM who had baseline cTnI and CK-MB measurements at Fuwai Hospital between 1999 and 2019. Patients were excluded if they had undergone percutaneous coronary intervention or coronary artery bypass grafting, or had renal failure. Five end points were studied: all-cause death, cardiovascular death, noncardiovascular death, sudden cardiac death, and other cardiovascular death. Cox regression was used to assess the associations of cTnI and CK-MB levels with outcomes. Nine hundred seventy patients with available follow-up data were finally analyzed (mean age, 49.3 years; 36.4% female). During the median 4.3-year follow-up period, 87 patients reached the end points. Higher cTnI (per 0.05 ng/mL increase) and CK-MB (per 1 IU/L increase) levels were associated with increased risks of all-cause death (cTnI: adjusted hazard ratio [HR], 1.038, P<0.001; CK-MB: adjusted HR, 1.021, P=0.004), cardiovascular death (cTnI: adjusted HR, 1.040, P<0.001; CK-MB: adjusted HR, 1.025, P=0.006), and sudden cardiac death (cTnI: adjusted HR, 1.045, P<0.001; CK-MB: adjusted HR, 1.032, P=0.001). Patients with elevated levels of both cTnI and CK-MB had worse prognoses than patients with an elevated level of either biomarker alone and patients who did not have an elevated level of either biomarker. Addition of the binary indicator elevation of both cTnI and CK-MB significantly improved the discrimination and reclassification abilities of the standard HCM Risk- sudden cardiac death model (C statistics: P=0.002; net reclassification improvement, 0.652; integrated discrimination improvement, 0.064). Comprehensive evaluations of biomarkers of myocardial injury, cTnI and CK-MB, have considerable value for predicting adverse outcomes among patients with HCM. Routine cTnI and CK-MB assessments may help to guide implantable cardioverter defibrillator implantation for primary prevention in HCM.

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88). We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Revisiting Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Current Practice and Novel Perspectives.

Sarcomeric hypertrophic cardiomyopathy (HCM) is a prevalent genetic disorder characterised by left ventricular hypertrophy, myocardial disarray, and an increased risk of heart failure and sudden cardiac death. Despite advances in understanding its pathophysiology, treatment options for HCM remain limited. This narrative review aims to provide a comprehensive overview of current clinical practice and explore emerging therapeutic strategies for sarcomeric HCM, with a focus on cardiac myosin inhibitors. We first discuss the conventional management of HCM, including lifestyle modifications, pharmacological therapies, and invasive interventions, emphasizing their limitations and challenges. Next, we highlight recent advances in molecular genetics and their potential applications in refining HCM diagnosis, risk stratification, and treatment. We delve into emerging therapies, such as gene editing, RNA-based therapies, targeted small molecules, and cardiac myosin modulators like mavacamten and aficamten, which hold promise in modulating the underlying molecular mechanisms of HCM. Mavacamten and aficamten, selective modulators of cardiac myosin, have demonstrated encouraging results in clinical trials by reducing left ventricular outflow tract obstruction and improving symptoms in patients with obstructive HCM. We discuss their mechanisms of action, clinical trial outcomes, and potential implications for the future of HCM management. Furthermore, we examine the role of precision medicine in HCM management, exploring how individualised treatment strategies, including exercise prescription as part of the management plan, may optimise patient outcomes. Finally, we underscore the importance of multidisciplinary care and patient-centred approaches to address the complex needs of HCM patients. This review also aims to encourage further research and collaboration in the field of HCM, promoting the development of novel and more effective therapeutic strategies, such as cardiac myosin modulators, to hopefully improve the quality of life and outcome of patients with sarcomeric HCM.

Quantitative Late Gadolinium Enhancement Cardiac Magnetic Resonance and Sudden Death in Hypertrophic Cardiomyopathy: A Meta-Analysis

BackgroundQuantitative late gadolinium enhancement (LGE) cardiac magnetic resonance provides important prognostic information for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). However, it has not been fully integrated into clinical practice. ObjectivesThe purpose of this study was to assess the prognostic value of LGE extent in predicting SCD in adults with HCM across different methods of quantification, thresholds, and patients’ clinical profile. MethodsThe authors searched PubMed, Web of Science, and Cochrane Library for studies investigating the prognostic value of LGE% in predicting SCD in HCM. Pooled ORs were calculated with 95% CIs. The optimal threshold was determined using a multiple cutoffs model. ResultsEleven studies were included in the meta-analysis with a total of 5,550 patients and a median follow-up time of 5.2 years. Two studies quantified LGE manually, 7 studies used the 6 SD technique, 1 study used the 4 SD technique, and 1 study the 2 SD technique. There was no statistically significant difference in predicting SCD between these 4 methods (P = 0.443). Optimal cutoff could be determined only for the 6 SD technique. LGE 10% was the optimal threshold of the 6 SD technique with sensitivity 0.73 and specificity 0.67. ConclusionsThe different LGE quantification techniques have comparable accuracy in predicting SCD. When the more extensively studied 6 SD technique is used, LGE 10% is the optimal cutoff and can effectively restratify intermediate-risk patients. LGE extent can improve HCM risk stratification, but it is unlikely to become a standalone tool.

Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the MESA.

Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown. Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts. The SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume (P=0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume (P=0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 (P=7.3×10-22). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1-mediated α-smooth muscle actin and collagen expression. Common genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging-based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.

Advanced searching for hypertrophic cardiomyopathy heritability in real practice tomorrow.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease associated with morbidity and mortality at any age. As studies in recent decades have shown, the genetic architecture of HCM is quite complex both in the entire population and in each patient. In the rapidly advancing era of gene therapy, we have to provide a detailed molecular diagnosis to our patients to give them the chance for better and more personalized treatment. In addition to emphasizing the importance of genetic testing in routine practice, this review aims to discuss the possibility to go a step further and create an expanded genetic panel that contains not only variants in core genes but also new candidate genes, including those located in deep intron regions, as well as structural variations. It also highlights the benefits of calculating polygenic risk scores based on a combination of rare and common genetic variants for each patient and of using non-genetic HCM markers, such as microRNAs that can enhance stratification of risk for HCM in unselected populations alongside rare genetic variants and clinical factors. While this review is focusing on HCM, the discussed issues are relevant to other cardiomyopathies.

Radiomics of Late Gadolinium Enhancement Reveals Prognostic Value of Myocardial Scar Heterogeneity in Hypertrophic Cardiomyopathy

BackgroundLate gadolinium enhancement (LGE) scar burden by cardiac magnetic resonance is a major risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). However, there is currently limited data on the incremental prognostic value of integrating myocardial LGE radiomics (ie, shape and texture features) into SCD risk stratification models. ObjectivesThe purpose of this study was to investigate the incremental prognostic value of myocardial LGE radiomics beyond current European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) models for SCD risk prediction in HCM. MethodsA total of 1,229 HCM patients (62% men; age 52 ± 16 years) from 3 medical centers were included. Left ventricular myocardial radiomic features were calculated from LGE images. Principal component analysis was used to reduce the radiomic features and calculate 3 principal radiomics (PrinRads). Cox and logistic regression analyses were then used to evaluate the significance of the extracted PrinRads of LGE images, alone or in combination with ESC or ACC/AHA models, to predict SCD risk. The ACC/AHA risk markers include LGE burden using a dichotomized 15% threshold of LV scar. ResultsSCD events occurred in 30 (2.4%) patients over a follow-up period of 49 ± 28 months. Risk prediction using PrinRads resulted in higher c-statistics than the ESC (0.69 vs 0.57; P = 0.02) and the ACC/AHA (0.69 vs 0.67; P = 0.75) models. Risk predictions were improved by combining the 3 PrinRads with ESC (0.73 vs 0.57; P < 0.01) or ACC/AHA (0.76 vs 0.67; P < 0.01) risk scores. The net reclassification index was improved by combining the PrinRads with ESC (0.25 [95% CI: 0.08-0.43]; P = 0.005) or ACC/AHA (0.05 [95% CI: −0.07 to 0.16]; P = 0.42) models. One PrinRad was a significant predictor of SCD risk (HR: 0.57 [95% CI: 0.39-0.84]; P = 0.01). LGE heterogeneity was a major component of PrinRads and a significant predictor of SCD risk (HR: 0.07 [95% CI: 0.01-0.75]; P = 0.03). ConclusionsMyocardial LGE radiomics are strongly associated with SCD risk in HCM and provide incremental risk stratification beyond current ESC or AHA/ACC risk models. Our proof-of-concept study warrants further validation.

Inequities in Treatments and Outcomes Among Patients Hospitalized With Hypertrophic Cardiomyopathy in the United States.

Background Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiac disease. In small studies, sociodemographic factors have been associated with disparities in septal reduction therapy, but little is known about the association of sociodemographic factors with HCM treatments and outcomes more broadly. Methods and Results Using the National Inpatient Survey from 2012 to 2018, HCM diagnoses and procedures were identified by International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification (ICD-9-CM and ICD-10-CM) codes. Logistic regression was used to determine the association of sociodemographic risk factors with HCM procedures and in-hospital death, adjusting for clinical comorbidities and hospital characteristics. Of 53 117 patients hospitalized with HCM, 57.7% were women, 20.5% were Black individuals, 27.7% lived in the lowest zip income quartile, and 14.7% lived in rural areas. Among those with obstruction (45.2%), compared with White patients, Black patients were less likely to undergo septal myectomy (adjusted odds ratio [aOR], 0.52 [95% CI, 0.40-0.68]), or alcohol septal ablation (aOR, 0.60 [95% CI, 0.42-0.86]). Patients with Medicaid were less likely to undergo each procedure (aOR, 0.78 [95% CI, 0.61-0.99] for myectomy; aOR, 0.54 [95% CI, 0.36-0.83] for ablation). Women (aOR, 0.66 [95% CI, 0.58-0.74]), patients with Medicaid (aOR, 0.78 [95% CI, 0.65-0.93]), and patients from low-income areas (aOR, 0.77 [95% CI, 0.65-0.93]) were less likely to receive implantable cardioverter-defibrillators. Women (aOR, 1.23 [95% CI, 1.10-1.37]) and patients from towns (aOR, 1.16 [95% CI, 1.03-1.31]) or rural areas (aOR, 1.57 [95% CI, 1.30-1.89]) had higher odds of in-hospital death. Conclusions Among 53 117 patients hospitalized with HCM, race, sex, social, and geographic risk factors were associated with disparities in HCM outcomes and treatment. Further research is required to identify and address the sources of these inequities.

Contribution of artificial intelligence and left atrial strain in the prediction of sudden cardiac death in hypertrophic cardiomyopathy. Results of a multicentric cohort

Sudden cardiac death (SCD) remains a serious outcome in hypertrophic cardiomyopathy (HCM), with an estimated incidence of 1%/year. Its risk prediction stays challenging for clinicians. Implantation of cardioverter-defibrillator is recommended with a strong level of evidence when the HCM risk score is over 6%. However, the ESC HCM risk score is criticized for its moderate diagnostic performance (C-index 0,70), and its low sensibility. Recent studies suggest that low PALS (peak atrial longitudinal strain) is associated with poor prognosis in HCM. Artificial intelligence, wich is experiencing an unprecedented boom, may be an interesting tool in association to left atrial strain in Prognostication. This preliminar study aimed to evaluate the value of the left atrial strain coupled with artificial inteligence algorythm in the prediction of suddent cardiac death in hypertrophic cardiomyopathy. This restrospective multi-center cohort (Marseille la Timone, Bordeaux and Rennes) included 431 patients with sarcomeric HCM from 2007 to 2018. The average follow-up time was 57 months. The primary endpoint was all cause death, ventricular arythmias, recovered SCD and internal electric shock. Analyses were entrusted to the LIS laboratory specialized in Computer Science at Aix-Marseille University. Sixty-six percent of men composed the cohort with a mean age of 52 ± 16 yo. Sarcomeric mutations were found in 52% of them, the mean left ventricular ejection fraction was 63 ± 16, 23% had significant ventricular obstruction. The mean PALS was 25 ± 12%. In the multivariate analysis, PALS 4 chamber, left ventricular global longitudinal strain and syncope were associated with the primary endpoint, (respectivly HR 2,48 IC95% [1,09–5,63]; P 0,030; HR 1,13 IC95% [1,03–1,25]; P 0,012; HR 0,95 IC95% [0,92–0,99]; P: 0.023). The random Forrest algorithm was able to successfully classify the patient (occurrence of primary endpoint or not) in 92,2% of the cases. Left atrial strain coupled with the Random Forrest algorithm could offer an interesting implementative value for the prediction of sudden cardiac death in hypertrophic cardiomyopathy. Further analysis are required to define its sensibility and specificity.

Targeting co-chaperones of HSP70 to modulate Myosin Binding Protein C turnover in hypertrophic cardiomyopathy.

Rationale: Hypertrophic Cardiomyopathy (HCM) is an inherited cardiovascular disease that affects 1 in 500 people. Over half of familial HCM cases arise from MyBP-C haploinsufficiency, thus stabilizing MyBP-C protein expression is an appealing therapeutic approach. Recently, two GWAS studies identified multiple HCM risk alleles. Three of the top 10 are localized near or in gene loci that code for HSP70 co-chaperones, highlighting the important role of the HSP70 system in HCM. Hypothesis: Co-chaperones of HSP70, (BAG3, DNAJC18, and HSPB7) regulate the expression and stability of sarcomeric and z-disc proteins, specifically MyBP-C. Methods/Results: Proximity labeling was performed to identify which components of the HSP70 co-chaperone network interact with or lie in close proximity to MyBP-C. Human iPSC-CMs (hiPSC-CMs) were transduced with a Turbo-ID-MYBPC3 adenoviral (AdV) construct, treated with biotin, and biotinylated proteins were captured by streptavidin beads. HSPA1A (i.e. HSP70), BAG3, DNAJC13, HSPB7, HSPB1, and CRYAB were identified by mass spectrometry as proximity proteins to wild-type MyBP-C but were absent in controls (AdV-MyBP-C without Turbo). hiPSC-CMs were transfected with AdV-shRNA to knock down HSP70 co-chaperone expression (BAG3, DNAJC18, or HSPB7). DNAJC18 was included because of the risk allele identified in GWAS, even though DNAJC18 was not identified as a direct interactor with MyBP-C during proximity labeling. Adv transfection efficiency was &gt; 70% (p&lt;0.0001) and resulted in a &gt;75% decrease (p&lt;0.01) in co-chaperone transcript expression and a &gt;50% decrease (p&lt;0.001) in protein. BAG3 knockdown decreased the steady state protein expression of MyBP-C (p&lt;0.0001) and a majority of other sarcomeric proteins. Utilizing a cycloheximide (CHX) chase assay to measure protein ½ life, MyBP-C protein degradation was greatly accelerated by BAG3 knockdown compared to scrambled shRNA 24 hours post-CHX (p&lt;0.0001). DNAJC18 knockdown had no significant effects on steady state protein expression of MyBP-C or other sarcomeric proteins, while HSPB7 knockdown increased MyBP-C (p&lt;0.01), myosin (p&lt;0.01), tropomyosin (p&lt;0.05), and myosin light chain 2 (p&lt;0.05) protein compared to scrambled shRNA. DNAJC18 and HSPB7 knockdown each increased BAG3 protein expression (p&lt;0.01), while BAG3 knockdown reduced DNAJC18 protein (p&lt;0.0001) but had no effect on HSPB7. Conclusion: MyBP-C interacts with and is stabilized by BAG3. MyBP-C may also be a direct client for HSPB7, but further studies are needed. Knockdown experiments of DNAJC13, HSBP1 and CRYAB, identified as proximity proteins of MyBP-C by Turbo-ID, are also underway. The HSP70 co-chaperone network may serve a therapeutic target to normalize MyBP-C levels in the context of MyBP-C haploinsufficiency. Institutional Start Up Funds This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Novel insights into diminished cardiac reserve in non-obstructive hypertrophic cardiomyopathy from four-dimensional flow cardiac magnetic resonance component analysis.

Hypertrophic cardiomyopathy (HCM) is characterized by hypercontractility and diastolic dysfunction, which alter blood flow haemodynamics and are linked with increased risk of adverse clinical events. Four-dimensional flow cardiac magnetic resonance (4D-flow CMR) enables comprehensive characterization of ventricular blood flow patterns. We characterized flow component changes in non-obstructive HCM and assessed their relationship with phenotypic severity and sudden cardiac death (SCD) risk. Fifty-one participants (37 non-obstructive HCM and 14 matched controls) underwent 4D-flow CMR. Left-ventricular (LV) end-diastolic volume was separated into four components: direct flow (blood transiting the ventricle within one cycle), retained inflow (blood entering the ventricle and retained for one cycle), delayed ejection flow (retained ventricular blood ejected during systole), and residual volume (ventricular blood retained for >two cycles). Flow component distribution and component end-diastolic kinetic energy/mL were estimated. HCM patients demonstrated greater direct flow proportions compared with controls (47.9 ± 9% vs. 39.4 ± 6%, P = 0.002), with reduction in other components. Direct flow proportions correlated with LV mass index (r = 0.40, P = 0.004), end-diastolic volume index (r = -0.40, P = 0.017), and SCD risk (r = 0.34, P = 0.039). In contrast to controls, in HCM, stroke volume decreased with increasing direct flow proportions, indicating diminished volumetric reserve. There was no difference in component end-diastolic kinetic energy/mL. Non-obstructive HCM possesses a distinctive flow component distribution pattern characterised by greater direct flow proportions, and direct flow-stroke volume uncoupling indicative of diminished cardiac reserve. The correlation of direct flow proportion with phenotypic severity and SCD risk highlight its potential as a novel and sensitive haemodynamic measure of cardiovascular risk in HCM.

Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy.

A large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy and ventricular septal defects. This study sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to diseases of the IVS, hypertrophic cardiomyopathy, and ventricular septal defect. We estimated the cross-sectional area of the IVS from the 4-chamber view of cardiac magnetic resonance imaging in 32 219 individuals from the UK Biobank which was used as the basis of genome wide association studies and Mendelian randomization. Measures of IVS cross-sectional area at diastole were a strong proxy for the 3-dimensional volume of the IVS (Pearson r=0.814, P=0.004), and correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. Seven loci with clear genomic consequence and relevance to cardiovascular biology were uncovered by genome wide association studies, most notably a single nucleotide polymorphism in an intron of CDKN1A (rs2376620; β, 7.7 mm2 [95% CI, 5.8-11.0]; P=6.0×10-10), and a common inversion incorporating KANSL1 predicted to disrupt local chromatin structure (β, 8.4 mm2 [95% CI, 6.3-10.9]; P=4.2×10-14). Mendelian randomization suggested that inheritance of larger IVS cross-sectional area at diastole was strongly associated with hypertrophic cardiomyopathy risk (pIVW=4.6×10-10) while inheritance of smaller IVS cross-sectional area at diastole was associated with risk for ventricular septal defect (pIVW=0.007). Automated estimates of cross-sectional area of the IVS supports discovery of novel loci related to cardiac development and Mendelian disease. Inheritance of genetic liability for either small or large IVS, appears to confer risk for ventricular septal defect or hypertrophic cardiomyopathy, respectively. These data suggest that a proportion of risk for structural and congenital heart disease can be localized to the common genetic determinants of size and shape of cardiovascular anatomy.

Benefits, harms, and costs of newborn genetic screening for hypertrophic cardiomyopathy: Estimates from the PreEMPT model

PurposePopulation newborn genetic screening for hypertrophic cardiomyopathy (HCM) is feasible, however its benefits, harms, and cost-effectiveness are uncertain. MethodsWe developed a microsimulation model to simulate a US birth cohort of 3.7 million newborns. Those identified with pathogenic/likely pathogenic variants associated with increased risk of HCM underwent surveillance and recommended treatment, whereas in usual care, individuals with family histories of HCM underwent surveillance. ResultsIn a cohort of 3.7 million newborns, newborn genetic screening would reduce HCM-related deaths through age 20 years by 44 (95% uncertainty interval [UI] = 10-103) however increase the numbers of children undergoing surveillance by 8127 (95% UI = 6308-9664). Compared with usual care, newborn genetic screening costs $267,000 per life year saved (95% UI, $106,000 to $919,000 per life year saved). ConclusionNewborn genetic screening for HCM could prevent deaths but at a high cost and would require many healthy children to undergo surveillance. This study shows how modeling can provide insights into the tradeoffs between benefits and costs that will need to be considered as newborn genetic screening is more widely adopted.

Predictive value of left atrial strain analysis in adverse clinical events in patients with hypertrophic cardiomyopathy: a CMR study

BackgroundA subset of patients with hypertrophic cardiomyopathy (HCM) will experience adverse clinical events such as heart failure (HF), cardiovascular death, and new-onset atrial fibrillation (AF). Current risk stratification methods are imperfect and limit the identification of patients at high risk for HCM. This study aimed to evaluate the role of cardiac magnetic resonance (CMR)-derived left atrial strain parameters in the occurrence of adverse clinical events in patients with HCM.MethodsLeft atrial (LA) structural, functional, and strain parameters were evaluated in 99 patients with HCM and compared with 89 age-, sex-, and BMI-matched control subjects. LA strain parameters were derived from CMR two- and four-chamber cine images by a semiautomatic method. LA strain parameters include global longitudinal strain (GLS) and global circumferential strain (GCS). The LA GLS includes reservoir strain (GLS reservoir), conduit strain (GLS conduit), and booster strain (GLS booster). Three LA GLS strain rate (SR) parameters were derived: SR reservoir, SR conduit, and SR booster. The primary endpoint was set as a composite of adverse clinical events, including SCD, new-onset or worsening to hospitalized HF, new-onset AF, thromboembolic events, and fatal ventricular arrhythmias.ResultsLA GLS, GLS SR and GCS were impaired in HCM patients compared to control subjects (all p < 0.001). After a mean follow-up of 37.94 ± 23.69 months, 18 HCM patients reached the primary endpoint. LA GLS, GLS SR, and GCS were significantly lower in HCM patients with adverse clinical events than in those without adverse clinical events (all p < 0.05). In stepwise multiple Cox regression analysis, LV SV, LA diameter, pre-contraction LAV (LAV pre-ac), passive LA ejection fraction (EF), and LA GLS booster were all independent determinants of adverse clinical events. LA GLS booster ≤ 8.9% was the strongest determinant (HR = 8.9 [95%CI (1.951, 40.933)], p = 0.005). Finally, LA GLS booster provided predictive adverse clinical events value (AUC = 0.86 [95%CI 0.77–0.98]) that exceeded traditional outcome predictors.ConclusionLA strain assessment, a measure of LA function, provides additional predictive information for established predictors of HCM patients. LA GLS booster was independently associated with adverse clinical events in patients with HCM.

1059 FAMILIAL RISK OF DILATED AND HYPERTROPHIC CARDIOMYOPATHY: A NATIONAL FAMILY STUDY IN SWEDEN

Abstract Aims To determine the familial incidence of dilated (DCM) and hypertrophic cardiomyopathy (HCM) in first-, second- and third-degree relatives of affected individuals. Methods and results In this population-based multigenerational cohort study, full-siblings, half-siblings, and cousin pairs born to Swedish parents between 1932 and 2015 were included and register-based DCM and HCM diagnoses among relatives were ascertained. Adjusted odds ratios (ORs) for DCM and HCM were calculated for relatives of individuals with DCM and HCM compared with relatives of individuals without DCM and HCM for reference. Total study population included 6,334,979 subjects and consisted of 5,577,449 full-siblings, 1,321,414 half-siblings, and 3,952,137 cousins. Overall, 10,272 (0.16%) unique individuals were diagnosed with DCM and 3,769 (0.06%) with HCM. Of these, 7,716 (75.12%) and 2,375 (63.01%) were males, respectively. Familial risk odds ratios (ORs) for DCM were 5.35 (95% confidence intervals (CI): 4.85-5.90) for full-siblings, 2.68 (95%CI:1.86-3.87) for half-siblings, and 1.72 (95%CI:1.12-2.64) for cousins of affected individuals. The ORs for HCM were 42.44 (95%CI:37.66-47.82) for full-siblings, 32.70 (95%CI:21.32-50.15) for half-siblings, and 36.96 (95%CI:29.50-46.31) for cousins of affected individuals. In sex-stratified analysis, relatives of affected females were found more likely to be affected than were relatives of affected males, with stronger aggregation observed for HCM. Conclusions Familial risk of HCM and DCM is high and associated with genetic resemblance, with strongest aggregations observed in relatives of affected females with HCM, whereas this association was distinctly attenuated for DCM. The finding of a Carter effect, more pronounced in HCM, suggests a multifactorial threshold model of inheritance.

The impact of adrenoceptor-1 gene polymorphism on structural and functional features in patients with hypertrophic cardiomyopathy

Abstract Background The adrenergic system plays a central role during the clinical course of hypertrophic cardiomyopathy (HCM) and hence beta-blocker therapy is the first-line treatment option according to current guidelines. Previous studies demonstrated variable cellular response to an adrenergic stimulus due to adrenoceptor-1 (ADRB-1) gene polymorphism in several patient groups including hypertension and dilated cardiomyopathy. Moreover, the impact of beta-blockers is also variable in these patients. Purpose We aimed to investigate the impact of ADRB-1 gene polymorphism on structural and functional features among patients with HCM. Methods In this study, we investigated the roles of Arginin389Glycine and Glycine49Serine polymorphism. Patients with a clear diagnosis of HCM according to current guidelines were included. Structural features including maximal wall thickness, interstitial fibrosis and left ventricular/atrial volumes were obtained using cardiac MRI and transthoracic echocardiography. Functional features including heart rate, blood pressure, left ventricular outflow obstruction were also recorded. The risk of sudden cardiac death was calculated using the HCM risk score. The impact of beta-blocker therapy on heart rate and blood pressure were also compared. Results After the exclusion of patients, 147 patients were included in the study. 77% of the study population were male and the mean age was 49.5 years. The hypertrophic segment was septum in 83% of the study population. The mean maximum wall thickness was 20 mm (19–23). With respect to Ser49Gly polymorphism, Serine homozygotes demonstrated higher late-gadolinium enhancement and indicator of interstitial fibrosis (p: 0.007). In concordance with higher LGE, the presence of fragmented QRS on surface ECG (p: 0.026) and a higher prevalence of non-sustained ventricular tachycardia (p: 0.016) in these patients were observed. The risk of sudden cardiac death was also higher in Ser49 homozygotes (p: 0.041). However, with respect to Arg389Gly gene polymorphism, there was no significant difference between Arg389 homozygotes, Arg389Gly heterozygotes and Gly389 homozygotes in terms of structural and functional features. The vast majority of patients reported improved functional capacity and decreased shortness of breath during the follow-up regardless of ADRB-1 gene polymorphism which is objectively validated by decreased pro-BNP levels in all patients. Conclusion Our results indicated that ADRB-1 gene polymorphism, particularly Ser49Gly gene polymorphism may have a significant role during the clinical course of HCM. Since Ser49 homozygote patients demonstrated higher interstitial fibrosis and a higher risk of sudden cardiac death, further studies are required to determine the significance of Ser49Gly gene polymorphism in HCM patients. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Bilimsel Arastırma Projesi (BAP) - Istanbul University - Cerrahpasa, Cerrahpasa Medical School

Ventricular activation time as a marker for complex ventricular arrhythmias, sudden cardiac death and ICD implantation in hypertrophic cardiomyopathy

Abstract Background Identification of patients with hypertrophic cardiomyopathy (HCM) who are at high risk of sudden cardiac death (SCD) is essential, as life-threatening ventricular arrhythmias (VAs) can be effectively prevented with an implantable cardioverter defibrillator (ICD). Risk stratification using HCM Risk-SCD score is recommended in the 2014 ESC guidelines for the management of patients with HCM. However, the role of electrocardiogram (ECG) in risk stratification is less well established. Purpose We investigated the association between the ventricular activation time (VAT), an ECG marker of the duration of ventricular depolarization, with the HCM Risk-SCD score, the presence of complex VAs, the implantation of an ICD and ICD-therapy for VAs. Methods Patients with a history of HCM, documented by echocardiography, were studied. The 12-lead ECG and echocardiography were performed on the same day. On ECG, we evaluated the VAT in milliseconds, between the onset of the QRS complex to the peak of R wave on V5 or V6 precordial ECG leads. A careful personal and family history for unexplained syncope and SCD was obtained, respectively. The presence of non-sustained ventricular tachycardia (NSVT) and ICD therapy were assessed either with 48h ECG recording or ICD interrogation. HCM Risk-SCD score was calculated by the corresponding ESC online calculator. Statistical analysis was performed using the SPSS software. Results Thirty-three patients with HCM were included (mean age 51±12 years, 78.8% male). According to the HCM Risk-SCD score, HCM patients were divided into three groups: low-risk (&amp;lt;4, 45.5%), intermediate-risk (4 to &amp;lt;6, 24.2%) and high-risk (&amp;gt;6, 30.3%) for SCD. Approximately half of the HCM patients had episodes of NSVT (48.5%) and an ICD (48.5%). Ventricular activation time was significantly prolonged in high-risk group compared either with intermediate-risk (74±24.5 vs 48.7±16.4, p=0.006) or low-risk (74±24.5 vs 44.3±12.6, p&amp;lt;0.001). HCM patients with NSVT had a significantly prolonged VAT compared with those without NSVT (62.19±25.2 vs 47.06±15.3, p=0.022). Moreover, HCM patients with an ICD had a higher VAT than those without an ICD (62.1±25.2 vs 47±15.3, p=0.003). VAT was also significantly prolonged in the group with appropriate ICD therapy for VAs compared with that without ICD therapy (82.8±22.1 vs 52.2±16.4, p=0.007). Finally, there was a significant positive correlation between VAT and NSVT (r=0.352, p=0.044), history of syncope (r=0.604, p&amp;lt;0.001), HCM risk-SCD score (r=0.493, p=0.004), ICD implantation (r=0.508, p=0.003) and ICD therapy (r=0.648, p=0.007) for VAs while there was not a correlation with the family history of SCD. Conclusion Prolongation of VAT is associated with NSVT, HCM risk score for SCD, ICD implantation and ICD therapy for VAs in patients with HCM and it seems to be a novel, easy to measure, ECG marker for risk stratification. Funding Acknowledgement Type of funding sources: None.

Cellular determinants of arrhythmic risk in hypertrophic cardiomyopathy

The most devastating consequence of HCM is sudden cardiac death (SCD) due to ventricular fibrillation. The positive correlation between the extent of late gadolinium enhancement and the arrhythmic risk in HCM suggests that ventricular arrhythmias originate from the fibrotic regions. However, recent data suggest that enhanced cellular automaticity (early- or delayed-afterdepolarizations, EADs or DADs-) may be clinically more relevant in promoting ventricular arrhythmias in patients. Aiming to better understand the cellular and molecular mechanisms of arrhythmogenesis in HCM and to establish a reliable arrhythmic risk stratification in patients, we performed a translational study in HCM patients who underwent surgical myectomy, by combining a clinical follow-up study with in vitro assessments of cellular arrhythmogenicity. We retrospectively studied 61 HCM patients who underwent surgical myectomy. At the time of surgery, fresh ventricular tissue was collected and used to isolate single ventricular cardiomyocytes (CMs), which were used for patch-clamp and Ca 2+ imaging experiments to assess the occurrence of EADs and DADs. Patients were followed up for a median time of 8 years and the occurrence of non-sustained ventricular tachycardia (NSVT) or life-threateningarrhythmic events (LAE) was monitored. EADs occurred in CMs from 36% of patients and were associated with prolonged action potential duration. DADs occurred in 24% of patients and were associated with abnormalities of intracellular Ca 2+ handling. The occurrence of NSVT/ LAE in patients strongly correlated with the presence of DADs in cardiomyocytes. The presence of pro-arrhythmic changes appears to be necessary for arrhythmia generation in HCM and seems to be related with specific alterations at ECG level, that might be used as clinical arrhythmia predictors in HCM patients. Fibrosis per se is not a major predictor of arrhythmias in HCM but may contribute to generate sustained arrhythmias in the presence of substantial cellular triggers (DADs).