Hypertrophic Cardiomyopathy Patients Research Articles

Myocardial perfusion improvement and mechanism after percutaneous intramyocardial septal radiofrequency ablation in obstructive hypertrophic cardiomyopathy: a study of myocardial contrast echocardiography.

The data on myocardial perfusion of the percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) for obstructive hypertrophic cardiomyopathy (HOCM) are still lacking, although PIMSRA have been proved to be of great safety and efficacy. The aim of this study was to quantitatively analyze the changes in myocardial perfusion after PIMSRA using myocardial contrast echocardiography (MCE). 27 HOCM patients treated with PIMSRA were retrospectively analyzed, and their echocardiographic parameters and perfusion parameters of MCE were collected before and 12 months after PIMSRA. A reperfusion curve was used to quantify microvascular blood volume (A), microvascular flux rate (β), and microvascular blood flow (MBF) of each segment. Then the value difference (Δ) of parameters between post- and pre-operation were calculated. Finally, the correlation between the changes in MBF and in each echocardiographic parameter was analyzed. (1) Compared with baseline, the global A, β and MBF were significantly increased in HOCM patients after PIMSRA (all P < 0.001). The β, MBF were increased in the interventricular septum (P < 0.001, respectively), and the A, β, MBF were increased in the left ventricular wall (all P < 0.001). (2) Correlation analysis showed that the ΔMBF of interventricular septum was mainly negatively correlated with the maximum interventricular septum thickness (ΔIVSTmax, r=-0.670, P < 0.001), mean interventricular septum thickness (ΔIVSTmean, r=-0.690, P < 0.001), and left ventricular mass index (ΔLVMI, r=-0.774, P < 0.001), while the ΔMBF of left ventricular wall was positively correlated with left ventricular end-diastolic volume index (ΔLVEDVI, r = 0.621, P = 0.001) and stroke volume index (ΔSVI, r = 0.810, P < 0.001). Myocardial perfusion was improved at both interventricular septum and ventricular wall in HOCM patients after PIMSRA. MCE can provide a new dimension for the efficacy evaluation to PIMSRA procedure.

A Novel Data Augmentation Method for Radiomics Analysis Using Image Perturbations.

Radiomics extracts hundreds of features from medical images to quantitively characterize a region of interest (ROI). When applying radiomics, imbalanced or small dataset issues are commonly addressed using under or over-sampling, the latter being applied directly to the extracted features. Aim of this study is to propose a novel balancing and data augmentation technique by applying perturbations (erosion, dilation, contour randomization) to the ROI in cardiac computed tomography images. From the perturbed ROIs, radiomic features are extracted, thus creating additional samples. This approach was tested addressing the clinical problem of distinguishing cardiac amyloidosis (CA) from aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM). Twenty-one CA, thirty-two AS and twenty-one HCM patients were included in the study. From each original and perturbed ROI, 107 radiomic features were extracted. The CA-AS dataset was balanced using the perturbation-based method along with random over-sampling, adaptive synthetic (ADASYN) and the synthetic minority oversampling technique (SMOTE). The same methods were tested to perform data augmentation dealing with CA and HCM. Features were submitted to robustness, redundancy, and relevance analysis testing five feature selection methods (p-value, least absolute shrinkage and selection operator (LASSO), semi-supervised LASSO, principal component analysis (PCA), semi-supervised PCA). Support vector machine performed the classification tasks, and its performance were evaluated by means of a 10-fold cross-validation. The perturbation-based approach provided the best performances in terms of f1 score and balanced accuracy in both CA-AS (f1 score: 80%, AUC: 0.91) and CA-HCM (f1 score: 86%, AUC: 0.92) classifications. These results suggest that ROI perturbations represent a powerful approach to address both data balancing and augmentation issues.

“Interstitial fibrosis is associated with left atrial remodeling and adverse clinical outcomes in selected low-risk patients with hypertrophic cardiomyopathy”

BackgroundCardiovascular magnetic resonance (CMR) extracellular volume (ECV) allows non-invasive detection of myocardial interstitial fibrosis, which may be related to diastolic dysfunction and left atrial (LA) remodeling in hypertrophic cardiomyopathy (HCM). While the prognostic role of LGE is well-established, interstitial fibrosis and LA dysfunction are emerging novel markers in HCM. This study aimed to explore the interaction between interstitial fibrosis by ECV, LA morpho-functional parameters and adverse clinical outcomes in selected low-risk patients with HCM. Methods115 HCM patients and 61 matched controls underwent CMR to identify: i) interstitial fibrosis by ECV in hypertrophied left ventricular LGE-negative remote myocardium (r-ECV); ii) LA indexed maximum (LAVi max) and minimum (LAVi min) volumes, ejection fraction (LA-EF) and strain (reservoir εs, conduit εe and booster εa), by CMR feature-tracking. 2D-echocardiographic assessment of diastolic function was also performed within 6 months from CMR. A composite endpoint including worsening NYHA class, heart failure hospitalization, atrial fibrillation and all-cause death was evaluated at 2.3 years follow-up. HCM patients were divided into two groups, according to r-ECV values of controls. ResultsPatients with r-ECV ≥29% (n = 45) showed larger LA volumes (LAVimax 63 vs. 54 ml/m2, p < 0.001; LAVimin 43 vs. 28 ml/m2, p 〈0001), worse LA function (εs 16 vs. 28%, εe 8 vs. 15%, εa 8 vs. 14%, LA-EF 33 vs. 49%, all p < 0.001) and elevated Nt-proBNP (1115 vs. 382 pg/ml, p = 0.002). LA functional parameters inversely correlated with r-ECV (εs r = −0.54; LA-EF r = −0.46; all p < 0.001) and E/e' (εs r = −0.52, LA-EF r = −0.46; all p < 0.006). r-ECV ≥29% and LAVi min >30 ml/m2 have been identified as possible independent factors associated with the endpoint. ConclusionsIn HCM diffuse interstitial fibrosis detected by increased r-ECV is associated with LA remodeling and emerged as a potential independent predictor of adverse clinical outcomes, on top of the well-known prognostic impact of LGE.

Modeling cardiomyocyte signaling and metabolism predicts genotype-to-phenotype mechanisms in hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (HCM) is a significant precursor of heart failure and sudden cardiac death, primarily caused by mutations in sarcomeric and structural proteins. Despite the extensive research on the HCM genotype, the complex and context-specific nature of many signaling and metabolic pathways linking the HCM genotype to phenotype has hindered therapeutic advancements for patients. Here, we have developed a computational model of HCM encompassing cardiomyocyte signaling and metabolic networks and their associated interactions. Utilizing a stochastic logic-based ODE approach, we linked cardiomyocyte signaling to the metabolic network through a gene regulatory network and post-translational modifications. We validated the model against published data on activities of signaling species in the HCM context and transcriptomes of two HCM mouse models (i.e., R403Q-αMyHC and R92W-TnT). Our model predicts that HCM mutation induces changes in metabolic functions such as ATP synthase deficiency and a transition from fatty acids to carbohydrate metabolism. The model indicated major shifts in glutamine-related metabolism and increased apoptosis after HCM-induced ATP synthase deficiency. We predicted that the transcription factors STAT, SRF, GATA4, TP53, and FoxO are the key regulators of cardiomyocyte hypertrophy and apoptosis in HCM in alignment with experiments. Moreover, we identified shared (e.g., activation of PGC1α by AMPK, and FHL1 by titin) and context-specific mechanisms (e.g., regulation of Ca2+ sensitivity by titin in HCM patients) that may control genotype-to-phenotype transition in HCM across different species or mutations. We also predicted potential combination drug targets for HCM (e.g., mavacamten plus ROS inhibitors) preventing or reversing HCM phenotype (i.e., hypertrophic growth, apoptosis, and metabolic remodeling) in cardiomyocytes. This study provides new insights into mechanisms linking genotype to phenotype in familial hypertrophic cardiomyopathy and offers a framework for assessing new treatments and exploring variations in HCM experimental models.

Clinical characteristics and outcomes of alcohol septal ablation in the era of transcatheter valve interventions.

The clinical efficacy and safety of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) have been well-established; however, less is known about outcomes in patients undergoing preemptive ASA before transcatheter mitral valve replacement (TMVR). The goal of this study is to characterize the procedural characteristics and examine the clinical outcomes of ASA in both HCM and pre-TMVR. This retrospective study compared procedural characteristics and outcomes in patient who underwent ASA for HCM and TMVR. In total, 137 patients were included, 86 in the HCM group and 51 in the TMVR group. The intraventricular septal thickness (mean 1.8 vs. 1.2 cm; p < 0.0001) and the pre-ASA LVOT gradient (73.6 vs. 33.8 mmHg; p ≤ 0.001) were higher in the HCM group vs the TMVR group. The mean volume of ethanol injected was higher (mean 2.4 vs. 1.7 cc; p < 0.0001). The average neo-left ventricular outflow tract area increased significantly after ASA in the patients undergoing TMVR (99.2 ± 83.37 mm2 vs. 196.5 ± 114.55 mm2; p = <0.0001). The HCM group had a greater reduction in the LVOT gradient after ASA vs the TMVR group (49.3 vs. 18 mmHg; p = 0.0040). The primary composite endpoint was higher in the TMVR group versus the HCM group (50.9% vs. 25.6%; p = 0.0404) and had a higher incidence of new permanent pacemaker (PPM) (25.5% vs. 18.6%; p = 0.3402). The TMVR group had a higher rate of all-cause mortality (9.8% vs. 1.2%; p = 0.0268). Preemptive ASA before TMVR was performed in patients with higher degree of clinical comorbidities, and correspondingly is associated with worse short-term clinical outcomes in comparison to ASA for HCM patients. ASA before TMVR enabled percutaneous mitral interventions in a small but significant minority of patients that would have otherwise been excluded. The degree of LVOT and neoLVOT area increase is significant and predictable.

The feasibility of left ventricular strain and strain rate for evaluating patients with risk factors of sudden cardiac death in hypertrophic cardiomyopathy by Feature-tracking Cardiac Magnetic Resonance.

Sudden cardiac death (SCD) represents the most severe complication of hypertrophic cardiomyopathy (HCM). However, the relationship between strain, strain rate, and risk factors in SCD risk stratification remains elusive. The study aimed to assess the attenuation of strain and strain rate in HCM by feature-tracking cardiac magnetic resonance (FT-CMR). All strain and strain rates were obtained automatically by FT, with manual adjustment of endocardial and epicardial borders. Strain indicators included left ventricular (LV) global longitudinal (GLS), circumferential (GCS), radial strain (GRS), peak diastolic-longitudinal (PD-LSR), circumferential (PD-CSR), and radial strain rate (PD-RSR). Patients were categorized into high and low-risk groups for SCD based on the 2020 American Heart Association/American College (AHA/ACC) HCM Risk-SCD model. The correlation between strain/strain rate and SCD risk factors was assessed via Spearman correlation analysis. Furthermore, a multivariate logistic regression analysis was conducted to explore the factors that influence SCD risk in HCM patients. A total of 105 HCM patients were analyzed in this study, including 38 patients in the high-risk group, and 67 patients in the low-risk group. Compared to the low-risk group, the high-risk group exhibited significantly worse strain and strain rate (p<0.001). Furthermore, both circumferential and radial strain as well as strain rate exhibited meaningful associations with risk factors for SCD. Additionally, GRS emerged as an independent risk factor for predicting heightened SCD risk in HCM patients (p<0.001). In conclusion, LV strain and strain rate based on FT-CMR can be evaluated for SCD risk and are strongly associated with SCD risk factors.

Exercise limitation in hypertrophic cardiomyopathy: combined stress echocardiography and cardiopulmonary exercise test.

The study aims to investigate exercise-limiting factors in hypertrophic cardiomyopathy (HCM) using combined stress echocardiography and cardiopulmonary exercise test. A symptom-limited ramp bicycle exercise test was performed in the semi-supine position on a tilting dedicated ergometer. Echocardiographic images were obtained concurrently with gas exchange measurements along predefined stages of exercise. Oxygen extraction was calculated using the Fick equation at each activity level. Thirty-six HCM patients (mean age 67±6years, 72% men, 18 obstructive HCM) were compared with age and sex-matched 29 controls. At rest, compared with controls, E/E' ratio (6.26±2.3 vs. 14±2.5, P<0.001) and systolic pulmonary artery pressures (SPAP) (22.6±3.4 vs. 34±6.2mmHg, P=0.023) were increased. Along with the stages of exercise (unloaded; anaerobic threshold; peak), diastolic function worsened (E/e' 8.9±2.6 vs. 13.8±3.6 P=0.011; 9.4±2.3 vs. 18.6±3.3 P=0.001; 8.7±1.9 vs. 21.5±4, P<0.001), SPAP increased (23±2.7 vs. 33±4.4, P=0.013; 26±3.2 vs. 40±2.9, P<0.001; 26±3.5 vs. 45±7mmHg, P<0.001), and oxygen consumption (6.6±1.7 vs. 6.8±1.6, P=0.86; 18.1±2.2 vs. 14.6±1.5, P=0.008; 20.3±3 vs. 15.1±2.1mL/kg/min, P=0.01) was reduced. Oxygen pulse was blunted (6.3±1.8 vs. 6.2±1.9, P=0.79; 10±2.1 vs. 8.8±1.6, P=0.063; 12.2±2 vs. 8.2±2.3mL/beat, P=0.002) due to an insufficient increase in both stroke volume (92.3±17 vs. 77.3±14.5 P=0.021; 101±19.1 vs. 87.3±15.7 P=0.06; 96.5±12.2 vs. 83.6±16.1mL, P=0.034) and oxygen extraction (0.07±0.03 vs. 0.07±0.02, P=0.47; 0.13±0.02 vs. 0.10±0.03, P=0.013; 0.13±0.03 vs. 0.11±0.03, P=0.03). Diastolic dysfunction, elevated SPAP, and the presence of atrial fibrillation were associated with reduced exercise capacity. Both central and peripheral cardiovascular limitations are involved in exercise intolerance in HCM. Diastolic dysfunction seems to be the main driver for this limitation.

Hypertrophic cardiomyopathy detection with artificial intelligence electrocardiography in international cohorts: an external validation study

Abstract Aim Recently, deep-learning artificial intelligence (AI) models have been trained to detect cardiovascular conditions, including hypertrophic cardiomyopathy (HCM), from the 12-lead electrocardiogram (ECG). In this external validation study, we sought to assess the performance of an AI-ECG algorithm for detecting HCM in diverse international cohorts. Methods and Results A convolutional neural network-based AI-ECG algorithm was developed previously in a single-center North American HCM cohort (Mayo Clinic). This algorithm was applied to the raw 12-lead ECG data of HCM patients and non-HCM controls from 3 external cohorts (Bern, Switzerland; Oxford, UK; and Seoul, South Korea). The algorithm’s ability to distinguish HCM vs non-HCM status from the ECG alone was examined. A total of 773 HCM patients and 3,867 non-HCM controls were included across 3 sites in the merged external validation cohort. The HCM study sample comprised 54.6% East Asian, 43.2% White, and 2.2% Black patients. Median AI-ECG probabilities of HCM were 85% for HCM patients and 0.3% for controls (p &amp;lt; 0.001). Overall, the AI-ECG algorithm had an AUC of 0.922 (95% CI 0.910-0.934), with diagnostic accuracy 86.9%, sensitivity 82.8% and specificity 87.7% for HCM detection. In age- and sex-matched analysis (case-control ratio 1:2), the AUC was 0.921 (95% CI 0.909-0.934) with accuracy 88.5%, sensitivity 82.8%, and specificity 90.4%. Conclusion The AI-ECG algorithm determined HCM status from the 12-lead ECG with high accuracy in diverse international cohorts, providing evidence for external validity. The value of this algorithm in improving HCM detection in clinical practice and screening settings requires prospective evaluation.

Transapical intramyocardial septal microwave ablation in treatment of hypertrophic obstructive cardiomyopathy: 12-month outcomes of a swine model

BackgroundTo date, the extended Morrow procedure is considered the gold standard treatment for patients with obstructive hypertrophic cardiomyopathy who experience severe symptoms and are unresponsive to medication treatment. We therefore aimed to perform transapical intramyocardial septal microwave ablation to reduce the thickness of the interventricular septum myocardium in a minimally invasive method.MethodsFourteen swine were divided to form either a microwave ablation group (n = 7) or a sham group (n = 7). In the microwave ablation group, a transapical microwave antenna was inserted into the septum to ablate each myocardial segment at 40 W for 1 min, while in the sham group, the same operation was performed but without power output. We used echocardiography, electrocardiogram, during the operation. And added computerized tomography, cardiac nuclear magnetic resonance during follow-up.ResultsSegment hypokinesis was observed in all swine immediately following ablation. Compared with the sham group, the thickness of ablated segments in the ablation group decreased significantly 1 month post-operation (ablation group, 5.53 ± 1.00 mm vs. 8.03 ± 1.15 mm, respectively, P < 0.01; sham group, 8.40 ± 0.94 mm vs. 8.21 ± 1.09 mm, respectively, P = 0.081), and the outcome was still observed 1 year post-operation (ablation group, 3.36 ± 0.85 mm vs. 8.03 ± 1.15 mm, respectively, P < 0.01). No perforation of the septum was observed during the procedure or follow-up, and no heart failure or sudden cardiac death occurred during postoperative feeding.ConclusionsTransapical intramyocardial septal microwave ablation can effectively and safely produce a large region of necrosis. This technique can potentially mimic surgical myectomy while avoiding cardiopulmonary bypass and median sternotomy in high-risk hypertrophic obstructive cardiomyopathy patients.

Anderson–Fabry Disease Homozygosity: Rare Case of Late-Onset Variant

Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who, in most cases, are heterozygous with delayed and variable clinical presentation caused by uneven X-chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke, or unexplained cardiomyopathy. Here, we describe a unique case of a homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly, including with alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease led to the discovery of the same variant in several members of her family. The identified variant was c.644A&gt;G, p.Asn215Ser (p.N215S), which is known to cause predominant cardiac involvement with late onset of the disease. This variant is amenable to oral therapy with the small-molecule chaperone migalastat, which was started and then interrupted due to the recurrence of the patient’s migraine and then re-initiated again after two years. During this period, the patient received enzyme replacement therapy with agalsidase beta but developed progressively worsening venous access. Our case illustrates the importance of the systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom the routine diagnostic process fails to discover Fabry disease, in particular variants with late-onset cardiac manifestations. Many of the late-onset variants are amenable to orally active therapy with migalastat, which significantly improves the comfort of the treatment. Its long-term results are being analyzed by a large international “Follow-me” registry, which was designed to verify the validity of pivotal trials with migalastat in Fabry disease.

10 Pre-clinical studies of sotagliflozin in hypertrophic cardiomyopathy

OBJECTIVES/GOALS: Study the regulatory role of sodium glucose co-transporter 1 (SGLT1) in cardiomyocytes and the therapeutic potential of sotagliflozin in hypertrophic cardiomyopathy (HCM) by (a) quantifying SGLT1 expression in HCM and (b) examining the impact of sotagliflozin on cardiac mechanics. METHODS/STUDY POPULATION: * Use Western Blot in cardiac tissue from HCM and non-HCM patients and pre-existing RNA seq and proteomics datasets to quantify SGLT1 levels in HCM. Hypothesis: SGLT1 is upregulated in HCM * Determine how SGLT1/2 inhibition by sotagliflozin will affect cardiac mechanics using living myocardial slice (LMS) preparations. A vibratome creates 200um-thick slices from (a) failing HCM heart explants, (b) septal myectomy samples from HCM patients, and (c) nonfailing rejected donor hearts. LMS are mounted on a force transducer and work-loops are stimulated under varying pre- and after-loads. Collecting baseline and post-drug work loops allows each slice to function as its own control. Hypothesis: sotagliflozin will improve diastolic mechanics by reducing stiffness in the end-diastolic pressure-volume relationship RESULTS/ANTICIPATED RESULTS: * Preliminary results from RNA seq data indicate that SLC5A1 mRNA (encoding gene for SGLT1) is significantly decreased in HCM. No proteomics study examined thus far has detected SLC5A1, indicating that overall SGLT1 levels in cardiac tissue are quite low. We will examine SGLT1 levels in our own HCM and non-HCM tissue samples with both mass-spectrometry and Western Blot. * We analyze six slices from each heart and expect 15 donor hearts and 15 HCM hearts/myectomy samples. We visualize the work loop by plotting stress/strain. Stress/strain at mitral valve closure represents exponential end diastolic pressure-volume relationship; Stress/strain at aortic valve closure represents linear end systolic pressure volume relationship. A two-sample paired t-test will compare change in stiffness and elastance. DISCUSSION/SIGNIFICANCE: This project contributes to a growing body of research surrounding the currently unknown cardioprotective mechanism of SGLT 1/2 inhibitors, furthers the technique of using living myocardial slices to study cardiac mechanics, and supports a trial examining sotagliflozin in HCM, for which disease modifying therapy remains a prevailing unmet need.

Prevalence and Predictors of Readmissions in Patients With Hypertrophic Cardiomyopathy and Atrial Fibrillation/Flutter

Atrial fibrillation/flutter (AF) is the most common dysrhythmia in patients with hypertrophic cardiomyopathy (HCM). Unexplained left ventricular hypertrophy and left ventricular outflow tract obstruction are integral components of HCM pathology which can cause increased left atrial pressure and atrial myopathy contributing to the substrate for AF. We aimed to determine the impact of AF on hospital readmissions in patients with HCM. We conducted a retrospective analysis using the 2015 to 2019 Nationwide Readmission Database to analyze the effect of AF on 30-day readmission and causes of 30-day readmission in patients with HCM. We also determined the hospital, patient, and procedure-specific independent predictors of readmission in patients with HCM and AF. Of 191,235 index HCM hospitalizations, 81,390 (42.6%) had a secondary diagnosis of AF. A total of 16.9% of patients with HCM and AF were readmitted within 30 days as compared with 14% of HCM patients without AF. The presence of AF was independently associated with a higher risk of all-cause 30-day readmission (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.17 to 1.25, p <0.001). The foremost etiology of 30-day readmission in HCM patients with AF was hypertensive heart and chronic kidney disease with heart failure, whereas the foremost etiology of 30-day readmission in HCM patients without AF was sepsis. Interventions aimed toward AF management (electrical cardioversion: adjusted HR 0.91, 95% CI 0.82 to 1.01. p = 0.074, AF ablation: HR 0.92, 95% CI 0.74 to 1.13, p = 0.409, Watchman procedure: HR 1.50, 95% CI 0.16 to 14.6, p = 0.725) during index admission did not significantly impact the 30-day readmission in HCM patients with AF. Myectomy during index hospitalization (adjusted HR 0.54, 95% CI 0.34 to 0.86, p = 0.010) was most strongly associated with a lower risk of 30-day readmission in HCM patients with AF. In conclusion, in patients hospitalized for HCM, presence of AF was associated with excess risk of 30-day all-cause readmission. Interventions aimed toward HCM management, that is, myectomy rather than interventions aimed toward AF management predicted lower readmission rate in this patient population.

Comparing long-term outcomes of septal myectomy and mitral valve replacement in hypertrophic cardiomyopathy patients: A retrospective cohort study in Iran.

Hypertrophic cardiomyopathy (HCM) affects millions of individuals worldwide. In severe cases, it can cause life-threatening conditions such as left ventricular outflow tract (LVOT) obstruction, mitral regurgitation (MR), and sudden cardiac death, making surgical treatment necessary. This study aimed to report the long-term outcomes of HCM patients undergoing septal myectomy or mitral valve replacement (MVR) and compare the results between different types of surgeries. This was a retrospective cohort study on HCM patients who underwent surgical treatment in an Iranian referral center between 2005 and 2021. Patients were divided into three groups according to the type of surgery received: septal myectomy, MVR, or a combination of both surgeries. Patient characteristics, surgical and echocardiographic features, and in-hospital and long-term outcomes were reported and compared between the three groups. A total of 102 patients with an average age of 53.3 ± 16.9 were included. Twenty-six patients had septal myectomy, 23 had MVR, and 53 had combined septal myectomy and MVR surgery. All surgeries were associated with a significant reduction in interventricular septum thickness and LVOT gradients. After a median of 6.8-year follow-up time, patients with an isolated septal myectomy had significantly lower mortality and major adverse cardiac and cerebrovascular events rates than the other groups. Isolated septal myectomy showed better long-term survival rates and can correct HCM-related MR, while MVR should be preserved only for intrinsic valve defects. More extensive studies are needed to confirm these findings and achieve a comprehensive guideline on surgical treatment of HCM.

Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localise to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52-53, localised to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four and half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in maintenance and/or regulation of sarcomeric organisation and function.

Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction.

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.

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.

The Clinical Impact of SARS-CoV-2 on Hypertrophic Cardiomyopathy.

This study aims to understand and describe the clinical impact of SARS-CoV-2 (COVID-19) infection in patients with Hypertrophic Cardiomyopathy (HCM). A data repository of over 6.6 million patients in a large metropolitan (Chicago IL) healthcare system was queried to identify adults with a history of HCM and COVID-19 infection between 2019 and 2021. Propensity score-matched analysis was performed based on age, sex, BMI, and elements of the cardiovascular history, including tobacco use, hypertension, hyperlipidemia, myocardial injury, and heart failure. Individuals with HCM and COVID-19 infection had more total hospitalizations (41.6 v 23 per 100 persons, p < 0.01), more heart-failure-related hospitalizations (24.2 v 8.7 per 100-persons, p < 0.01), more non-ST elevation myocardial injury (NSTEMI) hospitalizations (8.6 v 4.6 per 100-persons, p < 0.01), and increased mortality (10.8 v 5 per 100-persons, p < 0.01) compared to HCM patients without a history of COVID-19 infection. Patients with HCM and COVID-19 were also noted to have a higher peak CRP when compared to those without prior COVID-19 (Inter-quartile range of 9.0-106.9 v 1.8-21.3, p < 0.01). In patients with HCM, COVID-19 infection is associated with increased incidence of myocardial injury, increased number of total and heart-failure specific hospitalizations, and increased mortality.

Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients.

Individual Approach to Prescribing Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common hereditary disease of the myocardium. Sodium-glucose co-transporter 2 inhibitors are recognized as first-line drugs for the treatment of heart failure, but at the moment there is little known about their use in HCM.&#x0D; The aim. To assess the possibility of using an acute test with empagliflozin in patients with HCM with echocardiographic assessment of left ventricular outflow tract (LVOT) obstruction.&#x0D; Materials and methods. Twenty-six non-obstructive HCM patients were examined. All the patients underwent an acute test with sodium-glucose co-transporter 2 inhibitor using 10 mg of empagliflozin and echocardiographic examination before and 3 hours after administration. Twenty-four patients were included in the further analysis (2 patients were excluded due to arrhythmia). The patients were divided into two groups: group 1 included subjects with an increase in LVOT pressure after empagliflozin (12 patients), group 2 included those without an increase in the gradient (12 patients).&#x0D; Results. During the acute test, an increase in LVOT gradient occurred in 12 patients, and in 6 patients the gradient increased significantly and reached more than 30 mm Hg. The indicator at rest in patients before the test was 11.2 (10.1-19), after the test it was 12.45 (8.9-17) mm Hg (p = 0.042). The indicator at the height of the Valsalva test also increased from 15 (11-29) to 15.45 (10.4-33) mm Hg (p=0.29). Comparative analysis of clinical and echocardiographic data did not show significant difference between the groups.&#x0D; Conclusions. In some patients with HCM without signs of overt or latent obstruction at the baseline, a significant increase in LVOT pressure was noted after acute test with empagliflozin. Conducting an acute test in patients with HCM is appropriate to determine the possibility of the development of LVOT obstruction while taking the drug.

Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.