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Introduction: In hypertrophic cardiomyopathy (HCM), atrial fibrillation (AF) has historically been regarded to have a deleterious impact on clinical course, strongly associated with progressive heart failure (HF) symptoms. However, there is a paucity of information regarding the impact of AF on HCM employing validated quality of life (QoL) surveys. Therefore, we evaluated the impact of AF on QoL utilizing patient reported outcome measures (PROMs). Methods: 218 consecutive HCM patients with or without AF at the Lahey HCM center in 2022 completed PROMs at their most recent visit evaluating HF (Kansas City Cardiomyopathy Questionnaire [KCCQ]) and AF symptoms (AF Effect on QoL [AFEQT]). Results: Among the 218 patients, 50 (23%) had a history of AF and comprise the primary study cohort. AF was diagnosed at 55 ± 10 years of age, median of 5.5 years before PROM, with 66% of patients treated with a rhythm control strategy with antiarrhythmic drug and/or AF ablation. AFEQT indicated that 52% of patients experienced no or minimal AF‐related disability, mild to moderate in 22%, and severe in 26%. There was no substantial difference in HCM phenotype in patients with no or minimal AF disability compared to those with severe disability. HF symptoms for most HCM patients with prior AF history was consistent with no or minimal (59%) or only mild (27%) disability as measured by KCCQ overall summary scores. In addition, with multivariate analysis, AF history was associated with less HF symptoms and improved QoL (OR 0.4, p = 0.02). Conclusion: In contrast to prior perceptions, HCM patients with prior AF history were less likely to incur HF symptoms impairing QoL compared to HCM patients without AF. After treatment, prior history of AF did not substantially impact current QoL. These data provide a realistic appraisal for the impact that AF has on HCM patients and also offers a measure of reassurance for this patient subgroup. [ABSTRACT FROM AUTHOR]

Background: Elevated mean pulmonary artery pressure (mPAP) is common in patients with hypertrophic cardiomyopathy (HCM) and heart failure symptoms. However, dynamic left ventricular (LV) outflow tract obstruction may confound interpretation of pulmonary hypertension (PH) pathophysiologic features in HCM when relying on resting invasive hemodynamic data alone.Research Question: Do structural changes to the lung vasculature clarify PH pathophysiologic features in patients with HCM with progressive heart failure?Study Design and Methods: Clinical data and ultrarare lung autopsy specimens were acquired retrospectively from the National Institutes of Health (1975-1992). Patients were included based on the availability of lung tissue and recorded mPAP. Discarded tissue from rejected lung donors served as control specimens. Histomorphology was performed on pulmonary arterioles and veins. Comparisons were calculated using the Student t test and Mann-Whitney U test; Pearson correlation was used to assess association between morphometric measurements and HCM cardiac and hemodynamic measurements.Results: The HCM cohort (n = 7; mean ± SD age, 43 ± 18 years; 71% men) showed maximum mean ± SD LV wall thickness of 25 ± 2.8 mm, mean ± SD outflow tract gradient of 90 ± 30 mm Hg, median mPAP of 25 mm Hg (interquartile range [IQR], 6 mm Hg), median pulmonary artery wedge pressure (PAWP) of 16 mm Hg (IQR, 4 mm Hg), and median pulmonary vascular resistance of 1.8 Wood units (WU; IQR, 2.4 WU). Compared with control samples (n = 5), patients with HCM showed greater indexed pulmonary arterial hypertrophy (20.7 ± 7.2% vs 49.7 ± 12%; P < .001) and arterial wall fibrosis (11.5 ± 3.4 mm vs 21.0 ± 4.7 mm; P < .0001), which correlated with mPAP (r = 0.84; P = .018), PAWP (r = 0.74; P = .05), and LV outflow tract gradient (r = 0.78; P = .035). Compared with control samples, pulmonary vein thickness was increased by 2.9-fold (P = .008) in the HCM group, which correlated with mPAP (r = 0.81; P = .03) and LV outflow tract gradient (r = 0.83; P = .02).Interpretation: These data demonstrate for the first time that in patients with obstructive HCM, heart failure is associated with pathogenic pulmonary vascular remodeling even when mPAP is elevated only mildly. These observations clarify PH pathophysiologic features in HCM, with future implications for clinical strategies that mitigate outflow tract obstruction. [ABSTRACT FROM AUTHOR]

Obstructive hypertrophic cardiomyopathy (oHCM) has been studied primarily in comprehensive centers of excellence. Broadening the understanding of patients with oHCM in the general population may improve identification and treatment in other settings. This retrospective cohort study identified adults with oHCM from a large electronic medical record database comprising data from 39 integrated delivery networks (IBM Explorys; observational period: January 2009–July 2019). Clinical characteristics, healthcare resource utilization (HCRU), and outcomes were reported. Of 8791 patients, 53.0% were female and the mean index age was 61.8 years. Cardiovascular drugs prescribed included beta-blockers (80.5%), calcium channel blockers (46.0%), and disopyramide (2.4%). Over time, heart failure, atrial fibrillation, and ventricular arrhythmias increased. Surgical procedures included septal myectomy (22.0%), alcohol septal ablation (0.6%), and heart transplantation (0.3%). Implantable cardioverter defibrillators were present in 11.2% of patients. After initial septal reduction therapy (SRT), HCRU increased and 550 patients (27.7%) required a reintervention. Of the overall group, 2.7% experienced sudden cardiac arrest by end of study. In conclusion, this cohort of patients with oHCM had guideline-recommended drug therapy and procedures. Despite this, heart failure, atrial fibrillation, and ventricular arrhythmias increased, and more than a quarter of patients undergoing SRT required reintervention. These unresolved issues emphasize the unmet need for new, effective therapies for patients with oHCM. [ABSTRACT FROM AUTHOR]

Background: Myocardial scar burden quantified using late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR), has important prognostic value in hypertrophic cardiomyopathy (HCM). However, nearly 50% of HCM patients have no scar but undergo repeated gadolinium-based CMR over their life span. We sought to develop an artificial intelligence (AI)-based screening model using radiomics and deep learning (DL) features extracted from balanced steady state free precession (bSSFP) cine sequences to identify HCM patients without scar. Methods: We evaluated three AI-based screening models using bSSFP cine image features extracted by radiomics, DL, or combined DL-Radiomics. Images for 759 HCM patients (50 ± 16 years, 66% men) in a multi-center/vendor study were used to develop and test model performance. An external dataset of 100 HCM patients (53 ± 14 years, 70% men) was used to assess model generalizability. Model performance was evaluated using area-under-receiver-operating curve (AUC). Results: The DL-Radiomics model demonstrated higher AUC compared to DL and Radiomics in the internal (0.83 vs 0.77, p = 0.006 and 0.78, p = 0.05; n = 159) and external (0.74 vs 0.64, p = 0.006 and 0.71, p = 0.27; n = 100) datasets. The DL-Radiomics model correctly identified 43% and 28% of patients without scar in the internal and external datasets compared to 42% and 16% by Radiomics model and 42% and 23% by DL model, respectively. Conclusions: A DL-Radiomics AI model using bSSFP cine images outperforms DL or Radiomics models alone as a scar screening tool prior to gadolinium administration. Despite its potential, the clinical utility of the model remains limited and further investigation is needed to improve the accuracy and generalizability. [ABSTRACT FROM AUTHOR]

These network medicine data illustrate the feasibility of using independent patient-patient networks to redefine HCM patient classifications for the purpose of risk assessment and HCM management, by segregating low- from high-risk subgroups among a heterogeneous disease population. Graph: Figure 1 A novel HCM patient-patient network medicine model identifies subgroups with unexpected clinical risk profiles. A novel patient-patient network medicine approach to refine hypertrophic cardiomyopathy subgrouping: implications for risk stratification. [Extracted from the article]

Hypertrophic cardiomyopathy (HCM) is considered a primary disorder of the sarcomere resulting in unexplained left ventricular hypertrophy but the paradoxical association of nonmyocyte phenotypes such as fibrosis, mitral valve anomalies and microvascular occlusion is unexplained. To understand the interplay between cardiomyocyte and nonmyocyte cell types in human HCM, single nuclei RNA-sequencing was performed on myectomy specimens from HCM patients with left ventricular outflow tract obstruction and control samples from donor hearts free of cardiovascular disease. Clustering analysis based on gene expression patterns identified a total of 34 distinct cell populations, which were classified into 10 different cell types based on marker gene expression. Differential gene expression analysis comparing HCM to Normal datasets revealed differences in sarcomere and extracellular matrix gene expression. Analysis of expressed ligand-receptor pairs across multiple cell types indicated profound alteration in HCM intercellular communication, particularly between cardiomyocytes and fibroblasts, fibroblasts and lymphocytes and involving integrin β1 and its multiple extracellular matrix (ECM) cognate ligands. These findings provide a paradigm for how sarcomere dysfunction is associated with reduced cardiomyocyte secretion of ECM ligands, altered fibroblast ligand-receptor interactions with other cell types and increased fibroblast to lymphocyte signaling, which can further alter the ECM composition and promote nonmyocyte phenotypes. [ABSTRACT FROM AUTHOR]

Background: The impact of comorbid disease states on the development of atrial and ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) remains unresolved. Objective: Evaluate the association of comorbidities linked to arrhythmias in other cardiovascular diseases (e.g., obesity, systemic hypertension, diabetes, obstructive sleep apnea, renal disorders, tobacco, and alcohol use) to atrial fibrillation (AF) and sudden cardiac death (SCD) events in a large cohort of HCM patients. Methods: A total of 2269 patients, 54 ± 15 years of age, 1392 males, were evaluated at the Tufts HCM Institute between 2004 and 2018 and followed for an average of 4 ± 3 years for new‐onset clinical AF and SCD events (appropriate defibrillation for ventricular tachyarrhythmias, resuscitated cardiac arrest, or SCD). Results: One or more comorbidity was present in 75% of HCM patients, including 50% with ≥2 comorbidities, most commonly obesity (body mass index [BMI] ≥ 30 kg/m2) in 43%. New‐onset atrial fibrillation developed in 11% of our cohort (2.6%/year). On univariate analysis, obesity was associated with a 1.7‐fold increased risk for AF (p =.03) with 12% of obese patients developing AF (3.3%/year) as compared to 7% of patients with BMI < 25 kg/m2 (1.6%/year; p =.006). On multivariate analysis, age and LA transverse dimension emerged as the only variables predictive of AF. Comorbidities, including obesity, were not independently associated with AF development (p >.10 for each). SCD events occurred in 3.3% of patients (0.8%/year) and neither obesity nor other comorbidities were associated with increased risk for SCD (p >.10 for each). Conclusions: In adult HCM patients comorbidities do not appear to impact AF or SCD risk. Therefore, for most patients with HCM, adverse disease related events of AF and SCD appear to be primarily driven by underlying left ventricular and atrial myopathy as opposed to comorbidities. [ABSTRACT FROM AUTHOR]

For 60 years, surgical myectomy has been the definitive treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM). Myectomy provides the opportunity to reverse heart failure symptoms in the vast majority of patient with low risk when performed in experienced centers and associated with extended longevity. More recently, a novel class of negative inotropic drug therapy with mavacamten has emerged offering expanded treatment options for obstructive HCM. In the recently completed phase III clinical trial, the EXPLORER-HCM about one-third of patients on mavacamten achieved the primary end-point of subjective symptomatic improvement and increased functional capacity assessed by peak VO2. Of note, outflow gradients persistent in 43% of patients on mavacamten and 50% with symptoms consistent with NYHA class II or greater. A subset of patients also experienced significant reversible systolic dysfunction. Therefore, it is timely to place into perspective the potential role of mavacamten in context of the established low risk: high benefit of surgical myectomy for treatment of heart failure. [ABSTRACT FROM AUTHOR]

Background: Quantification of myocardium scarring in late gadolinium enhanced (LGE) cardiac magnetic resonance imaging can be challenging due to low scar‐to‐background contrast and low image quality. To resolve ambiguous LGE regions, experienced readers often use conventional cine sequences to accurately identify the myocardium borders. Purpose: To develop a deep learning model for combining LGE and cine images to improve the robustness and accuracy of LGE scar quantification. Study Type: Retrospective. Population: A total of 191 hypertrophic cardiomyopathy patients: 1) 162 patients from two sites randomly split into training (50%; 81 patients), validation (25%, 40 patients), and testing (25%; 41 patients); and 2) an external testing dataset (29 patients) from a third site. Field Strength/Sequence: 1.5T, inversion‐recovery segmented gradient‐echo LGE and balanced steady‐state free‐precession cine sequences Assessment: Two convolutional neural networks (CNN) were trained for myocardium and scar segmentation, one with and one without LGE‐Cine fusion. For CNN with fusion, the input was two aligned LGE and cine images at matched cardiac phase and anatomical location. For CNN without fusion, only LGE images were used as input. Manual segmentation of the datasets was used as reference standard. Statistical Tests: Manual and CNN‐based quantifications of LGE scar burden and of myocardial volume were assessed using Pearson linear correlation coefficients (r) and Bland–Altman analysis. Results: Both CNN models showed strong agreement with manual quantification of LGE scar burden and myocardium volume. CNN with LGE‐Cine fusion was more robust than CNN without LGE‐Cine fusion, allowing for successful segmentation of significantly more slices (603 [95%] vs. 562 (89%) of 635 slices; P < 0.001). Also, CNN with LGE‐Cine fusion showed better agreement with manual quantification of LGE scar burden than CNN without LGE‐Cine fusion (%ScarLGE‐cine = 0.82 × %Scarmanual, r = 0.84 vs. %ScarLGE = 0.47 × %Scarmanual, r = 0.81) and myocardium volume (VolumeLGE‐cine = 1.03 × Volumemanual, r = 0.96 vs. VolumeLGE = 0.91 × Volumemanual, r = 0.91). Data Conclusion: CNN based LGE‐Cine fusion can improve the robustness and accuracy of automated scar quantification. Level of Evidence: 3 Technical Efficacy: 1 [ABSTRACT FROM AUTHOR]

Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine. Understanding patient-specific pathobiological pathways is a critical step for advancing precision medicine. Here the authors show that individualized protein-protein interaction networks provide key insight on patient-level pathobiology and clinically relevant pathophenotypic characteristics in a complex disease. [ABSTRACT FROM AUTHOR]

Ventricular Arrhythmias in HCM Introduction Triggers and ICD interventions of ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) offer insight into mechanisms and treatment. Methods and Results Intracardiac ICD electrograms from 71 HCM patients in the HCM I and II studies were analyzed by three individuals. Rhythms were defined as VF (polymorphic ventricular arrhythmia), VT (monomorphic ventricular tachycardia), and ventricular flutter (VFL; VT ≥ 240 bpm). Physical activity and rhythm preceding the arrhythmia were ascertained. Of 149 arrhythmias, VF was present in 74, VT in 57, and VFL in 18. In those whose activity was known, moderate or intense physical activity was associated with over 50% of the tachycardias (57 of 111). Rhythms preceding ventricular arrhythmias were often sinus tachycardia (49 of 149; 33%) or rapid atrial fibrillation (7 of 149; 5%). VF and VFL were more likely preceded by supraventricular rhythms >100 bpm (30 of 68 with VF; 44%; 12 of 16 with VFL 75%, vs. 14 of 50 with VT 28%; P = 0.001). Antitachycardia pacing (ATP) was successful in 39 of 53 (74%). Multiple shocks were more often required to terminate VFL (10 of 18; 56%) compared to VF (10 of 72; 14%) and VT (2 of 25; 8%; P < 0.0001). Of arrhythmias requiring more than one shock to terminate, 16 of 22 were preceded by sinus tachycardia and/or moderate or extreme physical activity. Conclusions Rapid supraventricular rhythms, and at least moderate activity, frequently precede VT and VF, and when they occur in these situations often require multiple ICD shocks to restore sinus rhythm. ATP is successful in terminating VT and VFL, and should be a programmed in all HCM patients with ICDs. [ABSTRACT FROM AUTHOR]

Left atrial (LA) volumes are known to be increased in hypertrophic cardiomyopathy (HCM) and are a predictor of adverse outcome. In addition, LA function is impaired and is presumed to be due to left ventricular (LV) diastolic dysfunction as a result of hypertrophy and myocardial fibrosis. In the current study, we assess the incremental effect of outflow tract obstruction (and concomitant mitral regurgitation) on LA function as assessed by LA strain. Patients with HCM (50 obstructive, 50 nonobstructive) were compared to 50 normal controls. A subset of obstructive patients who had undergone septal myectomy was also studied. Utilising feature-tracking software applied to cardiovascular magnetic resonance images, LA volumes and functional parameters were calculated. LA volumes were significantly elevated and LA ejection fraction and strain were significantly reduced in patients with HCM compared with controls and were significantly more affected in patients with obstruction. LA volumes and function were significantly improved after septal myectomy. LVOT obstruction and mitral regurgitation appear to further impair LA mechanics. Septal myectomy results in a significant reduction in LA volumes, paralleled by an improvement in function. [ABSTRACT FROM AUTHOR]