Sarcomeric Hypertrophic Cardiomyopathy Research Articles

Patterns of Left Ventricular Remodelling in Children and Young Patients with Hypertrophic Cardiomyopathy.

Introduction: The aim of this study was to evaluate the age at onset, clinical course, and patterns of left ventricular (LV) remodelling during follow-up in children and young patients with hypertrophic cardiomyopathy (HCM). Methods: We included consecutive patients with sarcomeric or non-syndromic HCM below 18 years old. Three pre-specified patterns of LV remodelling were assessed: maximal LV wall thickness (MLVWT) thickening; MLVWT thinning with preserved LV ejection fraction; and MLVWT thinning with progressive reduction in LV ejection fraction (hypokinetic end-stage evolution). Results: Fifty-three patients with sarcomeric/non-syndromic HCM (mean age 9.4 ± 5.5 years, 68% male) fulfilled the inclusion criteria. In total, 32 patients (60%) showed LV remodelling: 3 patients (6%) exhibited MLVWT thinning; 16 patients (30%) showed MLVWT thickening; and 13 patients (24%) progressed to hypokinetic end-stage HCM. Twenty-one patients (40%) had no LV remodelling during follow-up. In multivariate analysis, MLVWT was a predictor of the hypokinetic end-stage remodelling pattern during follow-up (OR 1.17 [95%CI 1.01-1.36] per 1 mm increase, p-value 0.043), regardless of sarcomeric variants and New York Heart Association class. Two patients with sarcomeric HCM, showing a pattern of MLVWT regression during childhood, experienced progression during adolescence. Conclusions: Different patterns of LV remodelling were observed in a cohort of children with sarcomeric/non-syndromic HCM. Interestingly, a pattern of progressive MLVWT thinning during childhood, with new progression of MLVWT during adolescence, was noted. A better understanding of the remodelling mechanisms in children with sarcomeric HCM may be relevant to defining the timing and possible efficacy of new targeted therapies in the preclinical stage of the disease.

HYPERTROPHIC CARDIOMYOPATHY AND MYBPC3 VARIANT - A CLINICAL CASE

Abstract Introduction Hypertrophic cardiomyopathy is a primary pathology of the cardiac muscle. Sarcomeric forms of hypertrophic cardiomyopathy (HCM) often have autosomal dominant transmission. A pathogenetic or likely pathogenetic mutation affecting genes encoding sarcomeric proteins is present in 30-60% of cases. In this study, we present a case of a family affected by hypertrophic cardiomyopathy with a mutation classified as of uncertain significance in the MYBPC3 gene. Clinical Case Mr. AA, 74 years old, attended the cardiomyopathy outpatient clinic of our hospital in June 2021 due to worsening heart failure with an hypertrophic phenotype. His medical history reported an increase in the thickness of the interventricular septum (IVS) since 1985. In 2015, the patient underwent pacemaker implantation for symptomatic 2:1 atrioventricular block associated with syncope and complete left bundle branch block. Since 2016, he had paroxysmal atrial fibrillation complicated by an ischemic stroke in 2019 with subtherapeutic INR. Cardiac magnetic resonance imaging (MRI) or genetic evaluation had never been performed. During the visit, the patient reported that his sister (AG, 73 years old) had undergone tests due to diffuse negative T waves findings in a previous ECG, revealing the presence of a long myocardial bridge of the left anterior descending artery (LAD). No family history of sudden cardiac death was reported. The echocardiogram of AA showed LV hypertrophy (septal wall thickness/posterior wall thickness 18/15 mm, respectively) with an ejection fraction of 36%. Suspecting sarcomeric HCM, a genetic test (TruSight One Expanded Illumina) was performed, revealing two variants of uncertain significance in heterozygosity in the CACNA1C - Calcium Voltage-Gated Channel Subunit Alpha1 C gene (c.2460G>C p.(Lys820Asn)) and MYBPC3 gene (c.2030C>T p.(Pro677Leu)). After a few months, AG presented MRI results suggestive of HCM apical variant (Figure 1). The genetic consultant recommended family screening, and the pedigree is shown in Figure 2. All carriers of the CACNA1C mutation had a negative phenotype. AG's son, IF, 56 years old, carriers of MYBPC3 mutation, presented an MRI compatible with early-stage HCM (Figure 3). His son, carriers of MYBPC3 mutation as well, is now awaiting a cardiac MRI. Conclusions In the family presented here, the MYBPC3 variant (c.2030C>T p.(Pro677Leu)) appears to be correlated with the development of sarcomeric hypertrophic cardiomyopathy. Registry studies with a large sample size are desirable to accurately classify variants of uncertain significance, which are becoming more common due to the widespread use of genetic tests.

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.

Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt Disease.

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.

Anderson-Fabry disease management: role of the cardiologist.

Anderson-Fabry disease (AFD) is a lysosomal storage disorder characterized by glycolipid accumulation in cardiac cells, associated with a peculiar form of hypertrophic cardiomyopathy (HCM). Up to 1% of patients with a diagnosis of HCM indeed have AFD. With the availability of targeted therapies for sarcomeric HCM and its genocopies, a timely differential diagnosis is essential. Specifically, the therapeutic landscape for AFD is rapidly evolving and offers increasingly effective, disease-modifying treatment options. However, diagnosing AFD may be difficult, particularly in the non-classic phenotype with prominent or isolated cardiac involvement and no systemic red flags. For many AFD patients, the clinical journey from initial clinical manifestations to diagnosis and appropriate treatment remains challenging, due to late recognition or utter neglect. Consequently, late initiation of treatment results in an exacerbation of cardiac involvement, representing the main cause of morbidity and mortality, irrespective of gender. Optimal management of AFD patients requires a dedicated multidisciplinary team, in which the cardiologist plays a decisive role, ranging from the differential diagnosis to the prevention of complications and the evaluation of timing for disease-specific therapies. The present review aims to redefine the role of cardiologists across the main decision nodes in contemporary AFD clinical care and drug discovery.

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography

BackgroundVentricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. ObjectivesThe purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. MethodsThis was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. ResultsCompared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). ConclusionsIn the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.

Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation. Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring an HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7-R403Q) or cardiac troponin T (TNNT2-R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance the relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin's effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed, electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current. SGLT2i (canagliflozin > dapagliflozin > empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction 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.

Abstract 12135: Quality of Life in Early-Stage Hypertrophic Cardiomyopathy: A Secondary Analysis of the VANISH Trial

Background: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) showed valsartan improves LV remodeling in early-stage HCM, but its effects on quality of life (QOL) are unknown. A better understanding of QOL may impact patient wellness. Aims: Describe baseline QOL in early-stage HCM. Assess the impact of valsartan on QOL in early-stage HCM. Methods: We evaluated QOL using age-adjusted versions of the Pediatric Quality of Life Inventory in VANISH participants (ages 8-45): 166 with early-stage HCM, 34 with subclinical HCM (sarcomere variant present but normal LV wall thickness/no HCM diagnosis). Demographic, imaging, CPET, and biomarker correlates of baseline QOL were studied. The impact of valsartan on QOL was analyzed in the early-stage HCM cohort. Results: Participants with early-stage HCM reported good baseline QOL, better than an earlier published healthy validation cohort but diminished compared to subclinical participants (mean overall/physical/psychosocial scores 85/87/84 for early-stage, 90/92/89 subclinical, 82/84/81 earlier validation cohort). Race and ethnicity influenced QOL, with non-white and Hispanic participants reporting lower scores (Table 1). Valsartan improved physical QOL (p=0.03), with suggestion of differential effect by sex and pubertal status, but limited power to detect effect modification (Figure 1). Conclusion: Baseline QOL is lower in patients with early-stage HCM compared to subclinical participants despite NYHA I status. Non-white and Hispanic participants and those with lower baseline peak VO 2 may have lower quality of life. Valsartan treatment improved physical QOL.

Angiotensin receptor blockers in patients with hypertrophic cardiomyopathy: A comparison of VANISH and INHERIT randomized trials

To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM). We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results. No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up (P=.4). With the exception of tissue Doppler systolic (s') velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM. Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial.

Prevalence of myocarditis and its contribution to the course of primary myocardial hypertrophy

Aim. To assess the incidence of myocarditis in patients with primary myocardial hypertrophy and to study its contribution to the disease course.Material and methods. The study included 100 patients with primary left ventricular myocardial hypertrophy, 52 men and 48 women (mean age, 51,5±15,7 years; followup period 10,4 [2,1; 36,1] months). All patients underwent electrocardiography, 24-hour electrocardiographic monitoring, echocardiography, as well as DNA analysis (n=96), myocardium pathological study (n=29), cardiac magnetic resonance imaging (n=31), cardiac multislice computed tomography (n=26), assessment of anti-cardiac antibodies (n=43), free light chain level in serum and urine by immunofixation method (n=10); 99mTc-pyrophosphate myocardial scintigraphy (n=5); biopsy of the rectal mucosa and/or subcutaneous fat for amyloid (n=9).Results. In 68%, true (sarcomeric) hypertrophic cardiomyopathy (HCM) was diagnosed, in 16% — amyloidosis with cardiac involvement, in 10% — storage diseases, in 3% — neuromuscular diseases, in 2% — myocardial hypertrophy was combined with severe restriction (mixed phenotype), and in 1% — LEOPARD syndrome. Concomitant myocarditis was diagnosed in 30% of patients. In HCM, myocarditis was detected in 31% of cases. These patients had a significantly higher heart failure class (heart failure class 3 [2; 3] vs 2 [1; 3], p=0,026) and mortality (33,3% vs 6,4%, p=0,01). In amyloidosis, the incidence of myocarditis was 31,3%. In these patients, ventricular tachycardia was observed significantly more often: 80,0% vs 18,2% (p=0,036). The prevalence of concomitant myocarditis in the subgroup of storage diseases was 30%: 2 patients with Fabry disease and 1 patient with Danon disease. Of the three patients with neuromuscular diseases, myocarditis was diagnosed in 1. In the subgroups with the restrictive phenotype and LEOPARD syndrome, no cases of myocarditis were recorded. Treatment of myocarditis made it possible to stabilize the patients' condition.Conclusion. Concomitant myocarditis led to heart failure progression, worsening ventricular arrhythmias and, as a consequence, an increased risk of sudden cardiac death. It is necessary to actively diagnose and treat myocarditis in patients with primary myocardial hypertrophy.

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.

Proteomic and phosphoproteomic analyses of myectomy tissue reveals difference between sarcomeric and genotype-negative hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetically heterogenous condition with about half of cases remaining genetically elusive or non-genetic in origin. HCM patients with a positive genetic test (HCMSarc) present earlier and with more severe disease than those with a negative genetic test (HCMNeg). We hypothesized these differences may be due to and/or reflect proteomic and phosphoproteomic differences between the two groups. TMT-labeled mass spectrometry was performed on 15 HCMSarc, 8 HCMNeg, and 7 control samples. There were 243 proteins differentially expressed and 257 proteins differentially phosphorylated between HCMSarc and HCMNeg. About 90% of pathways altered between genotypes were in disease-related pathways and HCMSarc showed enhanced proteomic and phosphoproteomic alterations in these pathways. Thus, we show HCMSarc has enhanced proteomic and phosphoproteomic dysregulation observed which may contribute to the more severe disease phenotype.

Differentiating primary sarcomeric hypertrophic cardiomyopathy from Noonan syndrome: can the electrocardiogram be of use?

Noonan syndrome is a multi-system genetic disorder and patients may suffer from hypertrophic cardiomyopathy. Previous studies have identified electrocardiographic features that may support a diagnosis of Noonan syndrome. In this two-centre retrospective study, we analysed typical Noonan syndrome-related electrocardiographic features in 30 patients with Noonan syndrome with hypertrophic cardiomyopathy and compared these with the electrocardiographic features in 15 children with sarcomeric hypertrophic cardiomyopathy. Typical Noonan syndrome-related electrocardiographic features are a negative aVF, small left precordial R-waves, large right precordial S-waves, and abnormal Q-wave. We also analysed electrocardiographic features of hypertrophic cardiomyopathy: ST-segment abnormalities and T-wave abnormalities. A negative aVF was seen in 83% of patients with Noonan syndrome-related hypertrophic cardiomyopathy in contrast to 27% of patients with primary sarcomeric hypertrophic cardiomyopathy (p < 0.001). An extreme QRS axis in the north-west was seen only in patients with Noonan syndrome-related hypertrophic cardiomyopathy. This QRS axis deviation is likely to be determined by the Noonan syndrome-related hypertrophic cardiomyopathy and not by the type of hypertrophic cardiomyopathy. There were no differences between the two groups in the frequency of large right precordial S-waves and small R-waves in the left precordial leads V5 and V6. However, an abnormal R/S ratio was more often seen in patients with Noonan syndrome-related hypertrophic cardiomyopathy (p < 0.001). Pathologic Q-waves were seen statistically more frequently in patients with sarcomeric hypertrophic cardiomyopathy (p = 0.009). The occurrence of ST-segment and T-wave pathology did not statistically differ between the two groups. Electrography can be of use in differentiating sarcomeric hypertrophic cardiomyopathy from Noonan syndrome-related hypertrophic cardiomyopathy.

Abstract P2071: Mutation-Specific Calmodulin-Kinase II Activation In Hypertrophic Cardiomyopathy

Autophosphorylation of Calmodulin-Kinase IIδ (CaMKIIδ) at Thr-287 leads to autoactivation such that kinase activity is autonomous of Ca 2+ /CaM. In the heart, CaMKIIδ functions to regulate Ca 2+ homeostasis by targeting Ca 2+ handling proteins, including phospholamban (PLB). In sarcomeric hypertrophic cardiomyopathy (HCM), disruption of Ca 2+ homeostasis and aberrant autoactivation of CaMKIIδ has been linked to disease progression. We have previously shown that the pathogenic role of autonomous CaMKIIδ in HCM is mutation-specific. Transgenic mice expressing the HCM mutation R92W in cardiac troponin T (cTnT) exhibited an increase in autonomous CaMKIIδ while cTnT-R92L mice did not. The potentially clinically relevant mechanism(s) underlying this mutation specificity are unresolved. We hypothesize that a potential trigger of autonomous CaMKIIδ is accelerated myofilament Ca 2+ dissociation kinetics. We have previously shown that cTnT-R92W accelerates Ca 2+ dissociation, while cTnT-R92L decelerates Ca 2+ dissociation. Here, we extended our study to include cTnT-I79N and cTnT-R94H to determine if Ca 2+ dissociation rates can be linked to autonomous CaMKIIδ activity and thus provide a potential novel target in HCM. Our data show that cTnT-I79N accelerates Ca 2+ dissociation, and cTnT-R94H decelerates Ca 2+ dissociation, similar to our earlier findings. To determine whether the mutation-specific changes in Ca 2+ dissociation alter CaMKIIδ activity, transgenic mice expressing cTnT-R94H and cTnT-I79N were probed for autophosphorylated CaMKIIδ and Thr-17 phosphorylated PLB. At 2 months, PLB phosphorylation is unchanged in cTnT-R94H and cTnT-I79N mice. At 4 months, cTnT-I79N mice exhibit a trending increase in autonomous CaMKIIδ and cTnT-R94H mice exhibit a modest increase, similar to cTnT-R92W positive controls. These trends are matched by PLB phosphorylation levels. At 6 months, cTnT-R94H mice exhibit normal autonomous CaMKIIδ levels. While future and ongoing work will explore changes in myocellular Ca 2+ homeostasis in more depth, these preliminary data suggest that, unlike cTnT-R94H mice, cTnT-I79N mice exhibit elevated autonomous CaMKIIδ and these mutation-specific differences may underlie observed phenotypic variation in patients.

Systolic anterior motion of the anterior mitral valve leaflet begins in subclinical hypertrophic cardiomyopathy.

Anterior mitral valve leaflet (AMVL) elongation is detectable in overt and subclinical hypertrophic cardiomyopathy (HCM). We sought to investigate the dynamic motion of the aorto-mitral apparatus to understand the behaviour of the AMVL and the mechanisms of left ventricular outflow tract obstruction (LVOTO) predisposition in HCM. Cardiovascular magnetic resonance imaging using a 1.5 Tesla scanner was performed on 36 HCM sarcomere gene mutation carriers without left ventricular hypertrophy (G+LVH-), 31 HCM patients with preserved ejection fraction carrying a pathogenic sarcomere gene mutation (G+LVH+), and 53 age-, sex-, and body surface area-matched healthy volunteers. Dynamic excursion of the aorto-mitral apparatus was assessed semi-automatically on breath-held three-chamber cine steady-state free precession images. Four pre-defined regions of interest (ROIs) were tracked: ROIPMVL: hinge point of the posterior mitral valve leaflet; ROITRIG: intertrigonal mitral annulus; ROIAMVL: AMVL tip; and ROIAAO: anterior aortic annulus. Compared with controls, normalized two-dimensional displacement-vs.-time plots in G+LVH- revealed subtle but significant systolic anterior motion (SAM) of the AMVL (P < 0.0001) and reduced longitudinal excursion of ROIAAO (P = 0.014) and ROIPMVL (P = 0.048). In overt and subclinical HCM, excursion of the ROITRIG/AMVL/PMVL was positively associated with the burden of left ventricular fibrosis (P < 0.028). As expected, SAM was observed in G+LVH+ together with reduced longitudinal excursion of ROITRIG (P = 0.049) and ROIAAO (P = 0.008). Dyskinesia of the aorto-mitral apparatus, including SAM of the elongated AMVL, is detectable in subclinical HCM before the development of LVH or left atrial enlargement. These data have the potential to improve our understanding of early phenotype development and LVOTO predisposition in HCM.

Left Atrial Strain Imaging by Speckle Tracking Echocardiography: The Supportive Diagnostic Value in Cardiac Amyloidosis and Hypertrophic Cardiomyopathy.

Background: Left atrial (LA) function is crucial for assessing left ventricular filling in various cardiovascular conditions. Cardiac Amyloidosis (CA) is characterized by atrial myopathy and LA function impairment, with diastolic dysfunction up to restrictive filling pattern, leading to progressive heart failure and arrhythmias. This study evaluates LA function and deformation using speckle tracking echocardiography (STE) in patients with CA compared to a cohort of patients with sarcomeric Hypertrophic Cardiomyopathy (HCM) and a control group. Methods: We conducted a retrospective, observational study (from January 2019 to December 2022) including a total of 100 patients: 33 with ATTR-CA, 34 with HCMs, and 33 controls. Clinical evaluation, electrocardiograms, and transthoracic echocardiography were performed. Echocardiogram images were analyzed in post-processing using EchoPac software for LA strain quantification, including LA-reservoir, LA-conduit, and LA-contraction strain. Results: The CA group exhibited significantly impaired LA function compared to HCMs and control groups, with LA-reservoir median values of -9%, LA-conduit -6.7%, and LA-contraction -3%; this impairment was consistent even in the CA subgroup with preserved ejection fraction. LA strain parameters correlated with LV mass index, LA volume index, E/e', and LV-global longitudinal strain and were found to be associated with atrial fibrillation and exertional dyspnea. Conclusions: LA function assessed by STE is significantly impaired in CA patients compared to HCMs patients and healthy controls. These findings highlight the potential supportive role of STE in the early detection and management of the disease.

Echocardiographic and Etiopathogenic Features of Hypertrophic Cardiomyopathy: Casablanca University Hospital Experience

Hypertrophic cardiomyopathy (HCM) is the most common non-ischemic cardiomyopathy with a prevalence of 1:500 in the general population, based on the recognition of the phenotype. HCM is defined by the presence of increased left ventricular (LV) wall thickness that is not solely explained by abnormal loading conditions and the phenotype also includes disorganized myocyte arrangement, fibrosis, small-vessel disease, and abnormalities of the mitral valve apparatus. In particular to this pathology, we have conducted a one-year prospective study to determine clinical, echocardiographic features and etiopathogenic aspects of hypertrophic cardiomyopathy in the Casablanca university hospital. The results concluded that 50% of the causes was due to amyloidosis 35%, sarcomeric HCM and 15% Fabry disease in which 2 cases were related with pregnancy. Transthoracic echocardiography and cardia MRI plays an important role in HCM diagnosis and prognosis.

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.

BS-452758-1 SUPPRESSION-REPLACEMENT GENE THERAPY REVERSE REMODELS THE INTRACELLULAR CALCIUM HANDLING DISEASE PHENOTYPE OF TNNT2-MEDIATED HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM), characterized by otherwise unexplained left ventricular hypertrophy, has a prevalence of 1:500. Pathogenic variants in TNNT2-encoded cardiac troponin T causes a thin filament subtype of sarcomeric HCM. A key cellular feature of the pathological remodeling in TNNT2-mediated HCM involves dysregulation of intracellular calcium handling in ventricular cardiomyocytes (CMs). To develop a TNNT2 “suppression-replacement (SupRep)” gene therapy to reverse the intracellular calcium perturbations associated with thin filament, sarcomeric HCM using induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) derived from a patient with TNNT2-R288P-mediated HCM. Custom-designed TNNT2 targeting shRNAs were tested for knockdown (KD) efficiency using TSA201 cells and RT-qPCR. A dual-component SupRep TNNT2 gene therapy was created by cloning into a single construct a custom-designed TNNT2 shRNA that produced greatest KD (suppression) and a “shRNA-immune” (shIMM) TNNT2 cDNA (replacement). Patient-specific TNNT2-R288P and CRISPR/Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated from a patient with HCM. The intracellular calcium indicator, Fluo-4, was used to detect intracellular free calcium. Our lead TNNT2-shRNA had an 80% KD efficiency of TNNT2. TNNT2-R288P iPSC-CMs treated with TNNT2-SupRep showed a similar KD efficiency. Compared to the IC iPSC-CMs, the TNNT2-R288P iPSC-CMs showed increased irregular events (30.4% vs. 10.9%, p<0.0001), prolonged calcium transient duration 90 (CTD90, 1.01 ± 0.03 s vs. 0.89 ± 0.02 s, p<0.0001) and prolonged peak to 90% decay time (0.57 ± 0.02 s vs. 0.49 ± 0.01 s, p=0.0012). Compared to untreated cells, transfection with TNNT2-SupRep gene therapy, the TNNT2-R288P iPSC-CMs showed a decrease in irregular events (30.4% vs. 14%, p<0.0001), shortened CTD90 (1.01 ± 0.03 s vs. 0.91 ± 0.01 s, p=0.003), and shortened peak to 90% decay time (0.57 ± 0.02 s vs. 0.50 ± 0.02 s, p=0.02). There was no significant difference in irregular events, CTD90, or peak to 90% decay time between TNNT2-R288P iPSC-CMs treated with TNNT2-SupRep and IC iPSC-CMs. Here, we provide the first proof-of-principle SupRep gene therapy for TNNT2-mediated HCM. TNNT2-SupRep gene therapy almost fully restored the impaired intracellular calcium handling properties of TNNT2-R288P patient-derived iPSC-CMs back to the normal state achieved by the CRISPR/Cas9 gene-edited cure.