Variant Of Hypertrophic Cardiomyopathy Research Articles

Abstract 4120375: Penetrance and Phenotype Conversion Rate of Genetic Hypertrophic Cardiomyopathy in an Academic Biobank

Introduction: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition with incomplete penetrance and variable expressivity. Given the increasing prevalence of sequencing and current guidelines on secondary finding disclosure, HCM P/LP alleles are increasingly being returned to patients who undergo genetic testing for other reasons. Whether individuals carrying P/LP HCM variants discovered in a genome-first context have progressive endophenotypes indicative of HCM remains poorly understood. Methods: To evaluate the penetrance and phenotype conversion rate of adults with P/LP HCM variants, we leveraged the Massachusetts General Brigham Biobank (MGBB), which consists of 36,417 participants with genotyping array and clinical data. Primary images of the earliest and latest TTE studies were reviewed for measurements of the posterior wall (PW), interventricular septum (IVS), and left ventricular morphology. Phenotype-positive (P+) status was defined by a PW or IVS thickness of at least 13 mm. Results: P/LP HCM variants were identified in 42 (0.1%) individuals with mean (SD) age 50.0 (16.6) years and 21 (50%) female sex. The most common HCM variants were in MYBPC3 (44%) and MYH7 (40%), followed by TNNI3(7%), MYL3 (7%), and TNNT2 (2%). Among the 42 genotype-positive (G+) individuals in MGBB, 17 (40%) had pre-existing HCM diagnoses prior to genomic return of results (gRoR). In contrast, 25 (60%) G+ individuals lacked a prior HCM diagnosis, among whom gRoR prompted TTE studies in 13 patients, revealing evidence of HCM in 9 individuals. Among the 42 G+ patients, 25 (58%) patients had completed at least two TTE studies, with a median [IQR] of 6 [3-9] TTE studies per patient, across a span of 10 [7-15] years follow-up. At the time of first TTE, 16 (64%) patients were P+ while 9 (36%) were P-. No G+, P- individuals converted to P+ over 10 years follow-up, nor was there any significant change in IVS or PW thickness. In contrast, individuals who were P+ at the initial TTE exhibited thickening PW (25% increase, CI 97.5% of 6 to 44) and IVS (26% increase, CI 97.5% of 4 to 49) over 8 years follow-up. Conclusion: In a genome-first approach, we identified 42 individuals in the MGBB with a P/LP HCM variant, among whom 60% lacked a prior clinical diagnosis of HCM. Targeted phenotyping revealed that nearly half of this newly identified group were P+. Over a median of 10 years follow-up, we observed a 0% phenotype conversion rate among G+, P- adult carriers of HCM variants.

Association between impaired left ventricular global longitudinal strain and B-type natriuretic peptide in obstructive hypertrophic cardiomyopathy

Abstract Background Left ventricular global longitudinal strain (LV-GLS) is considered valuable in explaining impaired left ventricular contractility in hypertrophic cardiomyopathy (HCM) with preserved ejection fraction and is associated with worse outcome. Elevated B-type natriuretic peptide (BNP) is a biomarker of increased LV wall stretch and a risk factor of heart failure, mortality, and other adverse cardiovascular events. However, relationship between GLS and BNP has not received sufficient attention in the obstructive variant of HCM. Purpose This study aimed to determine the association between echocardiographic LV-GLS and plasma BNP in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods A total of 145 consecutive patients (32% females) with symptomatic HOCM were enrolled in the retrospective study. HOCM was defined with a maximum end-diastolic wall thickness ≥15mm without other etiologies for LV hypertrophy, and peak LV outflow tract (LVOT) gradient ≥30mmHg. The echocardiographic parameters regarding LV geometry, loading conditions, and GLS were evaluated according to guidelines. Patients were divided into two groups according to absolute GLS values (greater or lower than median LV-GLS). Patient baseline clinical data, echocardiographic parameters, and BNP were compared. Univariate and multivariable regression analysis were applied to identify the independent determinator of LV-GLS. Results The median value of LV-GLS of this study cohort was -13.4%. Eighty-one patients (47.6±13.4 years-old) had a |GLS|≥13.4% and 64 individuals (48.7±12.6 years-old) had a |GLS|<13.4%. No differences were found in age, gender, physical examinations, LVEF, cardiovascular comorbidities, or active medications between the two groups, except for body mass index (BMI). Patients with |GLS|≥13.4% had statistically lower BMI (24.58±2.42 vs. 26.00±3.12kg/m², p=0.030). BNP was found significantly elevated in patients with |GLS|<13.4% when compared with individuals with |GLS|≥13.4% {median (IQR); 550.05 (214.50, 899.35) vs. 182.40 (78.90, 479.90)pg/mL, p=0.004}. In univariate regression analysis, decreased |GLS| was associated with male gender, maximum and mean LV wall thickness, peak LVOT gradient, reduced mitral annular e’ velocity, elevated BNP and cardiac troponin I. In multivariable regression analysis, GLS was found independently associated with mean LV wall thickness and BNP. Conclusions In patients with symptomatic HOCM with preserved ejection fraction, impaired LV-GLS was found to be associated with plasma BNP and mean LV wall thickness, independent of gender, age, loading conditions, LVEF, or LVOT gradient. Reduced GLS may be a more sensitive surrogate in assessing increased myocardial wall tension or stretch, rather than LV contractility in these patients. Therefore, the interpretation of GLS in HOCM should shift away from systolic interest toward emphasizing its potential value in risk stratification of diastolic heart failure with preserved LVEF.Figure 1

Utility of Cardiac Computed Tomography in the Diagnosis of Apical Hypertrophic Cardiomyopathy: A Case Series

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the left ventricular myocardium. Apical HCM is a less common variant of HCM where the hypertrophy is limited to the apical segments and can be challenging to diagnose based on traditional echocardiography alone. Patients with HCM can present with exertional angina. We present a series of four different cases, where patients were advised computed tomography (CT) coronary angiography for the evaluation of coronary artery disease. While CT coronary angiography excluded obstructive coronary artery disease, a detailed evaluation of the retrospective electrocardiogram-gated CT coronary angiography data helped in establishing the diagnosis of apical HCM in these patients. We discuss the importance of a systematic analysis of cardiac CT for diagnosing HCM variants and highlight the utility of reconstructed static and cine CT images which are readily available from the data obtained during retrospective gated CT coronary angiography for diagnosing HCM.

Multinational experience with next-generation sequencing: opportunity to identify transthyretin cardiac amyloidosis and Fabry disease.

Sarcomeric hypertrophic cardiomyopathy (HCM) must be differentiated from phenotypically similar conditions because clinical management and prognosis may greatly differ. Patients with unexplained left ventricular hypertrophy require an early, confirmed genetic diagnosis through diagnostic or predictive genetic testing. We tested the feasibility and practicality of the application of a 17-gene next-generation sequencing (NGS) panel to detect the most common genetic causes of HCM and HCM phenocopies, including treatable phenocopies, and report detection rates. Identification of transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD) is essential because of the availability of disease-specific therapy. Early initiation of these treatments may lead to better clinical outcomes. In this international, multicenter, cross-sectional pilot study, peripheral dried blood spot samples from patients of cardiology clinics with an unexplained increased left ventricular wall thickness (LVWT) of ≥13 mm in one or more left ventricular myocardial segments (measured by imaging methods) were analyzed at a central laboratory. NGS included the detection of known splice regions and flanking regions of 17 genes using the Illumina NextSeq 500 and NovaSeq 6000 sequencing systems. Samples for NGS screening were collected between May 2019 and October 2020 at cardiology clinics in Colombia, Brazil, Mexico, Turkey, Israel, and Saudi Arabia. Out of 535 samples, 128 (23.9%) samples tested positive for pathogenic/likely pathogenic genetic variants associated with HCM or HCM phenocopies with double pathogenic/likely pathogenic variants detected in four samples. Among the 132 (24.7%) detected variants, 115 (21.5%) variants were associated with HCM and 17 (3.2%) variants with HCM phenocopies. Variants in MYH7 (n=60, 11.2%) and MYBPC3 (n=41, 7.7%) were the most common HCM variants. The HCM phenocopy variants included variants in the TTR (n=7, 1.3%) and GLA (n=2, 0.4%) genes. The mean (standard deviation) ages of patients with HCM or HCM phenocopy variants, including TTR and GLA variants, were 42.8 (17.9), 54.6 (17.0), and 69.0 (1.4) years, respectively. The overall diagnostic yield of 24.7% indicates that the screening strategy effectively identified the most common forms of HCM and HCM phenocopies among geographically dispersed patients. The results underscore the importance of including ATTR-CA (TTR variants) and FD (GLA variants), which are treatable disorders, in the differential diagnosis of patients with increased LVWT of unknown etiology.

Myocardial edema measured by T2 mapping is an independent predictor of ventricular arrhythmias in hypertrophic cardiomyopathy

Abstract Introduction Clinical outcome of patients with hypertrophic cardiomyopathy (HCM) largely depends on ventricular arrhythmias. Parametric T2 mapping from Cardiac MRI (CMR) was found to be a measure of myocardial edema. We sought to study whether elevated T2 values on CMR in patients with hypertrophic cardiomyopathy (HCM) might predict ventricular arrhythmias (VA) and adverse clinical outcome. Methods Consecutive patients with HCM (n = 59) and healthy volunteers (n = 21) underwent 3 Tesla CMR. T2 mapping values were independently analyzed by 2 independent readers and presented using a 16-segment AHA model. VA was recorded by 24-hour Holter monitoring and/or during exercise stress test. Composite outcome was defined as ventricular tachycardia (VT) per Holter and/or ergometry, admission due to arrhythmias, ICD insertion and all-cause mortality. Statistical analysis was a t-test for VA and multi-variant logistic regression model adjusted for age and gender. Results Septal and apical variants of HCM were found in 42 and 17 patients, respectively. We found good interobserver agreement in T2 values (ICC=0.92, 95% CI 0.86 - 0.96, p value <0.001). The 3rd tertile of T2 values (48 ± 8 msec) was significantly associated with VA 92% vs. 57 and 40% in lower tertiles, p = 0.02. Logistic regression analysis showed the 3rd tertile was an independent predictor of composite outcome (VT per Holter and/or ergometry, admission due to arrhythmias, ICD and all-cause mortality) OR 95% CI = 22.8 (1.4 - 361.6), p = 0.026. ROC analysis to find best cut-off of T2 for prediction of outcome showed AUC 0.7 (Figure 1). Conclusion Elevated T2 is an independent predictor of VA and adverse outcome in HMC patients. These results suggest the impact of myocardial edema in myocardial disease activity in HCM.ROC analysis to find best cut-off of T2

Gene-echocardiography: refining genotype-phenotype correlations in hypertrophic cardiomyopathy.

This study aims to clarify the association between hypertrophic patterns and genetic variants in hypertrophic cardiomyopathy (HCM) patients, contributing to the advancement of personalized management strategies for HCM. A comprehensive evaluation of genetic mutations was conducted in 392 HCM-affected families using Whole Exome Sequencing. Concurrently, relevant echocardiographic data from these individuals were collected. Our study revealed an increased susceptibility to enhanced septal and interventricular septal thickness in HCM patients harbouring gene mutations compared with those without. Mid-septal hypertrophy was found to be associated predominantly with myosin binding protein C3 (MYBPC3) variants, while a higher septum-to-posterior wall ratio correlated with myosin heavy chain 7 (MYH7) variants. Mutations in MYH7, MYBPC3, and other sarcomeric or myofilament genes (troponin I3 [TNNI3], tropomyosin 1 [TPM1], and troponin T2 [TNNT2]) showed a relationship with increased hypertrophy in the anterior wall, interventricular septum, and lateral wall of the left ventricle. In contrast, alpha kinase 3 (ALPK3)-associated hypertrophy chiefly presented in the apical region, while hypertrophy related to titin (TTN) and obscurin (OBSCN) mutations exhibited a uniform distribution across the myocardium. Hypertrophic patterns varied with the type and category of gene mutations, offering valuable diagnostic insights. Our findings underscore a strong link between hypertrophic patterns and genetic variants in HCM, providing a foundation for more accurate genetic testing and personalized management of HCM patients. The novel concept of 'gene-echocardiography' may enhance the precision and efficiency of genetic counselling and testing in HCM.

Abstract P1025: Hsp70 Co-chaperones Regulate Sarcomeric Proteostasis In Hypertrophic Cardiomyopathy

Significance: Recent Genome Wide Association Studies (GWAS) identified non-sarcomeric variants in hypertrophic cardiomyopathy (HCM) with three of the top 10 variant loci in or near genes that encode for co-chaperones of HSP70: BAG3, DNAJC18 and HSPB7. These variants are also present in dilated cardiomyopathy (DCM), but have an opposing effect on cardiac function, leading us to hypothesize that GWAS variants in HSP70 co-chaperones can affect the proteostasis of contractile proteins in the HCM heart. As a first step, we determined the effects each HSP70 co-chaperone knockdown (KD) had on sarcomeric and z-disc protein expression and the poly-ubiquitinated state of cardiomyocyte-specific proteins. Methods and Results: Transduction of human iPSC-CMs (iPSC-CMs) with adenoviral vectors driving shRNA expression against BAG3, DNAJC18, HSPB7, or scramble (control) yielded transduction efficiencies > 75% and >80% reduction in target transcript 4 days post-transduction. BAG3 KD increased poly-ubiquitinated proteins by 38+/-9% (p<0.001) and reduced steady state expression of sarcomeric and z-disc proteins, including: MyBP-C (p<0.0001), actin (p<0.0001), cardiac troponin I (p<0.05), tropomyosin (TPM1) (p<0.01), myosin light chain 3 (MYL3) (p<0.0001), filamin C (p<0.05), and alpha-actinin-2 (p<0.0001). DNAJC18 KD increased poly-ubiquitinated protein by 66+/-17% (p<0.01) but did not impact sarcomere protein expression. Conversely, HSPB7 KD reduced poly-ubiquitinated proteins by 21+/-7% (p<0.01) and increased protein expression of MyBP-C (p<0.01), TPM1 (p<0.05), and myosin light chain 2 (p<0.05). DNAJC18 KD increased BAG3 and HSPB7 protein expression levels by ~2-fold (p<0.001) without increasing transcript levels, suggesting BAG3 and HSPB7 may be protein clients of DNAJC18. Conclusions: HSP70 co-chaperones that have an established genetic association with human HCM play an important role in cardiomyocyte proteostasis. Multiple sarcomeric and z-disc proteins appear to be clients of BAG3, while BAG3 and HSPB7 themselves may be clients of DNAJC18. Targeting this axis could be therapeutic for patients with HCM that possess genetic variants in sarcomeric proteins.

Abstract P2049: Myosin Heavy Chain-7 E848G Mutation-induced Sarcopenia And Hypocontractility In Induced Pluripotent Stem Cell Model Of Hypertrophic Cardiomyopathy Are Rescued By Muscle Ring Finger 1 Ablation

Hypertrophic cardiomyopathy (HCM) presents with idiopathic left ventricular hypertrophy and occasionally systolic dysfunction. In a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of HCM, we previously reported the pathogenic MYH7 E848G variant increased hiPSC-CM size and impaired contractility. To elucidate the mechanisms by which the E848G variant causes HCM, we now examined cardiac tissue from a MYH7 wt/E848G patient. We found reduced expression of the following sarcomeric proteins: β-myosin heavy chain (βMHC) (97.8 ± 1.1% reduction), α-sarcomeric actinin (αSA) (84.8 ± 7.3%), and ventricular myosin light chain (MLC-1v) (45.9 ± 13.9%) relative to healthy patient tissue. Isogenic MYH7 wt/E848G hiPSC-CMs also had reduced protein expression of βMHC (22.8%) and αSA (24.5%) relative to MYH7 wt/wt hiPSC-CMs and unchanged mRNA expression. These results suggest MYH7 E848G HCM induces broad sarcomere component deficiency. We tested hiPSC-CM contractility using single cell traction force microscopy (TFM) and engineered heart tissues (EHT). Single isogenic MYH7 wt/E848G hiPSC-CMs had lower maximum twitch force (80 ± 12 nN) than MYH7 wt/wt hiPSC-CMs (150 ± 20 nN) by TFM. Isogenic MYH7 wt/E848G EHTs had lower maximum twitch force (118.9 ± 23.7 μN) than MYH7 wt/wt EHTs (287.4 ± 27.7 μN). Because MuRF1, an E3 ubiquitin-protein ligase, is known to target βMHC for proteasomal degradation, we hypothesized MuRF1 mediates the sarcopenic and hypocontractile phenotype. Genetic ablation of TRIM63 (encoding MuRF1) significantly reduced MYH7 wt/E848G hiPSC-CM cell size by flow cytometry (6.8 ± 1.7%). MYH7 wt/E848G TRIM63 -/- hiPSC-CMs increased protein expression of βMHC (154.7 ± 51.9%), αSA (44.9 ± 25.6%), and MLC-1v (246.9 ± 57.3%) relative to MYH7 wt/E848G TRIM63 +/+ hiPSC-CMs. MYH7 wt/E848G TRIM63 -/- had significantly higher maximum twitch force by TFM (133 ± 14 nN) and EHTs (178.2 ± 9.8 μN) than MYH7 wt/E848G TRIM63 +/+ by TFM (67 ± 8.0 nN) and EHTs (118.9 ± 23.7 μN). Our results implicate sarcopenia in the pathogenesis of MYH7 E848G HCM and identify MuRF1 as a potential novel therapeutic target for HCM. Further study will determine if these findings are generalizable to other pathogenic HCM variants in MYH7 and other sarcomeric genes.

Age and Sex Differences in the Genetics of Cardiomyopathy

Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling.Graphical Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.

PO-03-087 PROGNOSIS OF HYPERTROPHIC CARDIOMYOPATHY IN JAPANESE PATIENTS WITH AN IMPLANTABLE CARDIOVERTER DEFIBRILLATOR -FOCUS ON APICAL HYPERTROPHIC CARDIOMYOPATHY

Patients with hypertrophic cardiomyopathy (HCM) are at high risk of lethal arrhythmias, and implantable cardioverter defibrillators (ICDs) are widely used for prevention of sudden cardiac death (SCD). Apical HCM is a phenotype variant of HCM, with hypertrophy predominantly affecting apex, that was initially described 30 years ago. Apical HCM patients may have different clinical prognosis compared with other subsets of HCM. In previous studies, apical HCM patients seem to have a more benign prognosis than other types of HCM. However, little is known about the long-term outcomes of apical HCM patients and there are many unclear points. Moreover, there are few reports about the clinical prognosis in apical HCM patients with an ICD. The aim of this study is to identify the difference between the prognosis of apical and the other types of HCM patients with an ICD. We retrospectively analyzed the database of our ICD clinic. All subjects underwent ICD implantation between October 2006 and September 2018. We classified HCM patients into LV outflow tract obstruction (LVOTO) and midventricular obstruction (MVO), apical HCM and other non-obstructive types. We divided all the patients into apical and other types of HCM, and examined their background, incidence of appropriate ICD therapies, hospitalization for heart failure, electrical storm and cardiac death. A total of consecutive 64 Japanese HCM patients with an ICD (follow-up period, 86±24 months; age, 65±14 years; male sex, 83%; left ventricular ejection fraction, 56±14%; LV max wall-thickness, 19±7mm) were enrolled in this study. We classified them into 14 apical HCM and 50 other types of HCM patients. The clinical characteristics and major events of these patients are shown in the Figure. During the follow-up periods, there were no significant differences in the incidence of electrical storm, hospitalization for heart failure and cardiac death between the 2 groups (p=0.11; p=0.60; p=0.39). Appropriate ICD therapies occurred in 6 of 14 (43%) patients with apical HCM and 5 of 50 (10%) patients with other types of HCM (p=0.010). Appropriate ICD therapy was more prevalent in patients with apical HCM, compared to patients with other types of HCM. Aggressive intervention such as catheter ablation for ventricular tachycardia and ventricular fibrillation may be considered in patients with apical HCM. Further studies are needed to clarify the manifestations and long-term outcome of apical HCM patients.

Prevalence, characteristics, and natural history of apical phenotype in a large cohort of patients with hypertrophic cardiomyopathy

BackgroundApical hypertrophic cardiomyopathy (ApHCM) is a variant of hypertrophic cardiomyopathy (HCM) with distinct imaging and clinical characteristics. Data on the prognosis of this HCM subgroup appear conflicting. Our study aims to clarify the natural history of ApHCM and identify predictors of outcomes. Materials and methodsA total of 856 patients with HCM were retrospectively examined. ApHCM was defined as asymmetric left ventricular hypertrophy confined predominantly at the apex, either isolated (pure ApHCM type) or with co-existent hypertrophy of the interventricular septum (mixed ApHCM). Echocardiographic, clinical, and survival data were compared between individuals with ApHCM and non-ApHCM. ResultsA total of 143 (16.7%) patients were diagnosed with ApHCM. Compared with non-ApHCM, subjects with apical HCM were diagnosed at an older age and had better echocardiographic indices and more comorbidities at baseline. Apical aneurysms were more prevalent among the ApHCM phenotype (6.3% vs. 1.7%, p = 0.003). During a mean follow-up of 6 ± 3 years, ApHCM was characterized by lower all-cause, cardiovascular, heart failure-related mortality, and ventricular arrhythmic events compared with non-ApHCM. Multivariate analysis identified atrial fibrillation and HCM risk-sudden cardiac death (SCD) as independent predictors of the composite outcome of overall mortality and hospitalizations for cardiovascular reasons (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.9-9.5 for atrial fibrillation and HR 1.2, 95% CI 1.02-1.3 for HCM risk-SCD) in ApHCM. ConclusionsApHCM exhibited a lower rate of all-cause mortality and arrhythmic events in the middle-aged population of patients with HCM. Atrial fibrillation and HCM risk-sudden cardiac death were independent predictors of a composite of overall mortality and cardiovascular hospitalizations among those with ApHCM.

Abstract 15058: Critical Reappraisal of Genetic Variants in Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is a disease characterized by genotypic and phenotypic heterogeneity. Correct classification of genetic variation is critical for clinical interpretation. Herein, variants of uncertain significance (VUS) pose a dilemma in clinical practice, limiting physicians’ decision making and causing anguish to patients and family members. Furthermore, with increasing knowledge and changing guidelines, continuous reassessment is crucial to maintain usefulness in practice. This study sought to assess contemporary variant classification in a large cohort of patients with HCM. Methods: Retrospective analysis of all patients with HCM seen at Mayo Clinic and all patients with a variant in one of 8 genes with strong disease association for HCM were included. Genetic test reports were obtained from electronic health records along with their original variant classification assigned by either a commercial or research laboratory. Reassessment of variant pathogenicity was performed using the 2015 ACMG guideline criteria. Population frequency was obtained using Gnomad. Co-segregation presence or absence was determined by family history and co-segregation studies. Combined Annotation Dependent Depletion (CADD) was used as computational evidence of genetic deleterious effects for single nucleotide variants. Results: Between 2003 to 2019, a total of 1,782 patients underwent laboratory or commercial HCM genetic testing. Of these, 787 (44%) had positive genetic test with a variant at least 1 of the 8 genes. The original pathogenic classification was obtained for 754 patients. Of those, 430 (57%) variants where within the gene MYBPC3, 244 (32%) within MYH7 and 80 (11%) within either ACTC1, MYL2, MYL3, TINNI3, TNNT2 or TPM1. Overall, 222 patients (29%) originally had one or more variants classified as a VUS. Upon reassessment, 120 (54%) were reclassified as either pathogenic (33%), likely pathogenic (58%), benign (5%) or likely benign (3%). Conclusion: Periodic reassessment for HCM genetic variants, especially VUS, is critical for adequate patient care and management. Cascade screening could decrease patients’ uncertainty regarding their prognosis and management.

Abstract 15675: Mid-Ventricular Hypertrophic Cardiomyopathy Presenting With Minoca

Background: Mid-ventricular hypertrophic obstructive cardiomyopathy (HOCM) is an uncommon form of cardiomyopathy that is linked to an apical aneurysm, increasing the risk of sudden death. Cases: We described four patients who presented with chest pain or SOB. Troponin elevation, acute myocardial infarction on cardiac MRI and absence of obstructive coronary disease confirmed the diagnosis of MINOCA. Echo revealed a pressure gradient between the apical and basal chambers of the left ventricle. Cardiac MRI showed mid-ventricular HOCM and mid-cavity obliteration with akinetic apical chamber LGE revealed areas of sub-endocardial or transmural myocardial infarction at the level of obstruction and at the apical segments distal to the obstruction. The presence of myocardial edema on tissue mapping in the same area suggested acute myocardial injury (Figure). Discussion: The pathogenesis of development of apical myocardial scarring and aneurysm formation in mid-ventricular HOCM remains unknown. Other variant of hypertrophic cardiomyopathy shows mid-myocardial foci of scar inside the hypertrophied segments, indicating fibrosis. Whereas in our patients, the LGE revealed a sub-endocardial or transmural infarct (myocardial infarction pattern) - an uncommon pattern in other hypertrophic cardiomyopathy variants. This pattern and elevation of troponin during the acute phase of illness supports the hypothesis that apical aneurysm is due to apical myocardial ischemia in mid-ventricular HOCM. Tissue characterization and pattern of scar by cardiac MRI in these patients could be useful in understanding the pathophysiology of this type of HOCM.

Abstract 14417: Implications of Atrial Fibrillation on Clinical Outcomes of Patients With Hypertrophic Obstructive Cardiomyopathy

Introduction: Atrial fibrillation is a comorbidity often seen in patients with hypertrophic cardiomyopathy (HCM); however, contemporary data on its prevalence and clinical implications in the obstructive variant of HCM is scarce. Hypothesis: We sought to study the outcomes and implications of atrial fibrillation among patients hospitalized with hypertrophic obstructive cardiomyopathy (HOCM). Methods: Patients with a principal discharge diagnosis of HOCM between 2016 and 2019 were identified in the National Readmissions Database. Among those, patients with and without a diagnosis of atrial fibrillation were categorized. HOCM hospitalizations with atrial fibrillation were matched 1:1 fashion to HOCM without atrial fibrillation. Results: Of the 40,516 HOCM hospitalizations, 14,637 (36.12%) had a secondary diagnosis of atrial fibrillation. Propensity score-matched comparison between HOCM with and without atrial fibrillation (Figure 1) showed higher cardiogenic shock (2.69% vs. 1.98%, p-value <0.01), and acute stroke (3.85% vs 2.91%, p-value <0.01) as compared with HFpEF without atrial fibrillation (Table 1). Total charges were higher in HOCM with atrial fibrillation compared to patients without atrial fibrillation ($ ($86,392.6 vs. $83,762.21). The 30 days all-cause readmission rate among patients admitted with HOCM with AF was higher than those without AF (15.91% vs 14.80, p-value <0.01). Conclusions: In patients with HOCM presence of atrial fibrillation was associated with higher cardiogenic shock and acute stroke.

Prognosis of hypertrophic cardiomyopathy in Japanese patients with an implantable cardioverter defibrillator -focus on apical hypertrophic cardiomyopathy

Abstract Background Patients with hypertrophic cardiomyopathy (HCM) are at high risk of lethal arrhythmias, and implantable cardioverter defibrillators (ICD) are widely used for prevention of sudden cardiac death (SCD). Apical HCM is a phenotype variant of HCM, with hypertrophy predominantly affecting apex, that was initially described 30 years ago. Apical HCM patients may have different clinical prognosis compared with other subsets of HCM. In previous studies, apical HCM patients seem to have a more benign prognosis than other types of HCM. However, little is known about the long-term outcomes of apical HCM patients and there are many unclear points. Moreover, there are few reports about the clinical prognosis in apical HCM patients with an ICD. Objective The aim of this study is to identify the difference between the prognosis of apical and the other types of HCM patients with an ICD. Methods We retrospectively analyzed the database of our ICD clinic. All subjects underwent ICD implantation between October 2006 and September 2018. We classified HCM patients into LV outflow tract obstruction (LVOTO) and midventricular obstruction (MVO), apical HCM and other non-obstructive types. We divided all the patients into apical and other types of HCM, and examined their background, incidence of appropriate ICD therapies, hospitalization for heart failure, electrical storm and death. Results A total of consecutive 64 Japanese HCM patients with an ICD (follow-up period, 86±24 months; age, 65±14 years; male sex, 83%; left ventricular ejection fraction, 56±14%; LV max wall-thickness, 19±7mm; LV apical aneurysm, 9.4%; 5-year risk of SCD, 4.4±2.1) were enrolled in this study. We classified them into 14 apical HCM and 50 other types of HCM patients. The clinical characteristics and major clinical events of these patients are shown in the Table 1. During the follow-up periods, there were no significant differences in the incidence of electrical storm, hospitalization for heart failure and death between the 2 groups (p=0.11; p=0.60; p=0.39). Appropriate ICD therapies occurred in 6 of 14 (43%) patients with apical HCM and 5 of 50 (10%) patients with other types of HCM (p=0.010). The risk factors of patients with apical HCM patients are shown in Table 2. Conclusions Appropriate ICD therapy was more prevalent in patients with apical HCM, compared to patients with other types of HCM. Aggressive intervention such as catheter ablation for ventricular tachycardia and ventricular fibrillation may be considered in patients with apical HCM and higher score of 5-year risk of SCD. Further studies are needed to clarify the manifestations and long-term outcome of apical HCM patients. Funding Acknowledgement Type of funding sources: None.

Cardiac Multislice Computed Tomography in the Detection of Phenotypic Polymorphism of Hypertrophic Cardiomyopathy

Background. Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease with a prevalence of 1 case per 500 people and is the most common cause of sudden cardiac death in young patients. As clinical manifestations and electrocardiographic data are nonspecific and diverse, noninvasive imaging techniques play a key role in the detection of HCM and the understanding of its pathophysiology.
 The aim. To evaluate the possibilities of ECG-synchronized cardiac multislice computed tomography (MSCT) as a highly informative diagnostic tool for assessing the morpho-functional state of the heart in patients with HCM.
 Materials and methods. This was a retrospective analysis conducted at the National Amosov Institute of Cardiovascular Surgery from January 2020 to December 2021. We examined 221 cardiac MSCT scans of patients who underwent the examination to assess the spread of myocardial hypertrophy. Particular attention was paid to the presence of crypts at different levels of the left ventricle (LV), anatomical features of the mitral valve and subvalvular apparatus. The presence of systolic pulling of the anterior mitral valve to the interventricular septum, myocardial mass, LV end-diastolic, LV end-systolic volumes and the corresponding indices of body surface area, ejection fraction were determined and calculated during the functional analysis. Additionally, the anatomy and patency of the coronary arte­ ries were assessed. The studies were performed on a 640-slice Canon Aquilion One CT scanner with retrospective ECG gating and subsequent image processing. The studies were transferred to a workstation for review and evaluation by a team of radiologists.
 Results. The mean patient age was 46 ± 23 years, 48% were male. Mean maximal LV wall thickness was 19 mm (range 16–34). In 159 patients (71.9%), there was an asymmetric form of HCM with a predominant thickening of the anterior and anteroseptal segments of the left ventricle at the basal and midventricular levels. Fifty-four (24.4%) patients had symmetric form of HCM. The midventricular form of HCM was detected in 4 patients (1.8%). Apical form of HCM was detected in 3 patients (1.3%). One patient was diagnosed with a tumor-like variant of HCM (0.5%). In 198 patients (89.6%), systolic anterior motion of the mitral valve to the interventricular septum was found. In 95 cases (42.9%), morphological abnormality, abnormality of the number or attachment of the papillary muscles were detected. Forty-eight myocardial crypts were detected in 44 patients (21.7%). In 194 patients (87.7%), patent coronary arteries without signs of stenosis were found, 68 patients (30.7%) had 74 myocardial bridges (33.4%).
 Conclusions. HCM is a genetic heart disease with enormous phenotypic diversity. Due to its high spatial resolution, cardiac MSCT is an accurate diagnostic tool, which allows to assess the morphofunctional state of the LV, mitral valve, subvalvular apparatus, as well as to analyze the anatomy and narrowing of coronary arteries in patients with HCM.

The Involvement of ALPK3 in Hypertrophic Cardiomyopathy in East Asia.

ObjectiveALPK3 is associated with a recessive form of pediatric cardiomyopathy accompanied by musculoskeletal and craniofacial abnormalities. Heterozygous truncating variants in this gene (ALPK3tv) have recently been confirmed as a cause of autosomal dominant hypertrophic cardiomyopathy (HCM). Whether ALPK3 is also implicated in HCM in East Asia and the effect of missense variants in ALPK3 on HCM remains unresolved.MethodsWe compared the frequency of rare deleterious variants in ALPK3 in a study cohort comprised of 793 HCM cases of East Asian descent to that in the controls subset of Genome Aggregation Database (gnomAD). Gene burden test was used to assess this association. The involvement of these variants in HCM was further validated by independent cohort. The clinical characteristics and prognoses of these carriers were compared with sarcomere-positive and negative patients.ResultsRare deleterious variants in ALPK3 were significantly enriched in HCM compared with gnomAD controls (truncating: 4/793 vs. 4/4523, P = 0.02; missense: 25/793 vs. 46/4523, P = 2.56e-5). Replication in an independent cohort provided more supporting evidence. Further comparisons revealed that ALPK3 carriers displayed more severe hypertrophy in interventricular septum (IVS) and apex, as well as greater maximal left ventricular wall thickness, relative to sarcomere negatives.ConclusionHeterozygous rare variants in ALPK3, both missense and truncating variants, are associated with HCM in East Asians.

Signal-to-Noise Analysis Can Inform the Likelihood That Incidentally Identified Variants in Sarcomeric Genes Are Associated with Pediatric Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and can predispose individuals to sudden death. Most pediatric HCM patients host a known pathogenic variant in a sarcomeric gene. With the increase in exome sequencing (ES) in clinical settings, incidental variants in HCM-associated genes are being identified more frequently. Diagnostic interpretation of incidental variants is crucial to enhance clinical patient management. We sought to use amino acid-level signal-to-noise (S:N) analysis to establish pathogenic hotspots in sarcomeric HCM-associated genes as well as to refine the 2015 American College of Medical Genetics (ACMG) criteria to predict incidental variant pathogenicity. Methods and Results: Incidental variants in HCM genes (MYBPC3, MYH7, MYL2, MYL3, ACTC1, TPM1, TNNT2, TNNI3, and TNNC1) were obtained from a clinical ES referral database (Baylor Genetics) and compared to rare population variants (gnomAD) and variants from HCM literature cohort studies. A subset of the ES cohort was clinically evaluated at Texas Children’s Hospital. We compared the frequency of ES and HCM variants at specific amino acid locations in coding regions to rare variants (MAF < 0.0001) in gnomAD. S:N ratios were calculated at the gene- and amino acid-level to identify pathogenic hotspots. ES cohort variants were re-classified using ACMG criteria with S:N analysis as a correlate for PM1 criteria, which reduced the burden of variants of uncertain significance. In the clinical validation cohort, the majority of probands with cardiomyopathy or family history hosted likely pathogenic or pathogenic variants. Conclusions: Incidental variants in HCM-associated genes were common among clinical ES referrals, although the majority were not disease-associated. Leveraging amino acid-level S:N as a clinical tool may improve the diagnostic discriminatory ability of ACMG criteria by identifying pathogenic hotspots.

The Role of Cardiovascular Magnetic Resonance Imaging in the Evaluation of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, affecting 1 out of 500 adults globally. It is a widely heterogeneous disorder characterized by a range of phenotypic expressions, and is most often identified by non-invasive imaging that includes echocardiography and cardiovascular magnetic resonance imaging (CMR). Within the last two decades, cardiac magnetic resonance imaging (MRI) has emerged as the defining tool for the characterization and prognostication of cardiomyopathies. With a higher image quality, spatial resolution, and the identification of morphological variants of HCM, CMR has become the gold standard imaging modality in the assessment of HCM. Moreover, it has been crucial in its management, as well as adding prognostic information that clinical history nor other imaging modalities may not provide. This literature review addresses the role and current applications of CMR, its capacity in evaluating HCM, and its limitations.

813 The added value of transthoracic three dimensional echocardiography in apical hypertrophic cardiomyopathy

Abstract We present the case of a 73-year-old patient with a recent diagnosis of hypertrophic cardiomyopathy (HCM). He was asymptomatic and has no family history of sudden cardiac death (SCD), syncope or ventricular arrhythmias. An echocardiogram performed at the moment of diagnosis (2020), showed left ventricular (LV) asymmetric apical hypertrophy with maximal wall thickness of 21 mm. Cardiac magnetic resonance (CMR) confirmed LV apical hypertrophy with mid-ventricular obliteration, and late gadolinium enhancement in the apical segments, without wall motion abnormalities present at rest. According to 2014 ESC guidelines, his calculated risk score for sudden cardiac death was low (1.23% at 5 years). On 2021, a comprehensive transthoracic echocardiographic examination including advanced techniques (three-dimensional echo-3DE-, and two-dimensional speckle-tracking-2DSTE) was done as part of his routine follow-up in our cardiomyopathy outpatient clinic. The echo study showed an asymmetric pattern of LV hypertrophy with a maximal wall thickness of 21 mm at the level of the anterolateral apical segment, normal LV volumes (end-diastolic volume 55 mL/m2) and ejection fraction (69%) by 3DE. LV longitudinal strain analysis by 2DSTE showed impaired LV myocardial deformation mainly at the apical LV segments (GLS = −13.6%). There was evidence of dynamic intracavitary obstruction (maximal gradient 32 mmHg at rest and raised to 52 mmHg during Valsalva manoeuvre). 3DE views of the LV (both multi-slice display and 3D rendered image) allowed to avoid foreshortening of the LV apical views, and to appreciate the actual wall motion at the real LV apex. They revealed a LV apical aneurysm which was not detected in the conventional LV-focused apical 2D views (Figure 1A and B). Apical hypertrophic cardiomyopathy (ApHCM) is a variant of HCM that is characteristic of focal thickening of the LV apical myocardium and was reported to have a more benign course than other non-apical forms. However, the presence of LV aneurysm in ApHCM patients is associated with an increased risk for ventricular arrhythmias, sudden cardiac death and thromboembolism. Accordingly, the detection of apical LV aneurysms has significant impact on patient management. Guidelines recommend the use of contrast echocardiography or CMR when the apical region of the LV is suboptimally visualized by conventional 2D echocardiography. However, contrast echocardiography may still be affected by apical foreshortening resulting in suboptimal accuracy, as it is a 2D technique. On the other end, CMR may be contraindicated or not widely available for routine yearly follow-up for all HCM patients requiring regular imaging follow-up. Our clinical case emphasizes the added value of 3DE to increase the sensitivity of transthoracic echocardiography in detecting apical LV aneurysms in patients with apical HCM with important clinical implications for the management of the patient. 813 Figure 1(A) 2D 4chamber-view showing maximal wall thickness in the apical segments (21 mm) with apical obliteration. At a first evaluation, apical aneurism is not easily detected. (B) 4D rendering of the apex showing the apical aneurism.