Assessing the Applicability of Cardiac Myosin Inhibitors for Hypertrophic Cardiomyopathy Management in a Large Single Center Cohort.

Background: Cardiac myosin inhibitors (CMIs), including Mavacamten and Aficamten, have emerged as a groundbreaking treatment for hypertrophic cardiomyopathy (HCM). The results from phase 2 and 3 randomized clinical trials for both drugs have showed promising outcomes. However, the highly selective patient recruitment for these trials raises questions about the generalizability of the observed positive effects across broader patient populations suffering from HCM. Methods: A retrospective cohort study at University Hospital Heidelberg included 404 HCM patients. Baseline assessments included family history, electrocardiograms (ECGs), and advanced cardiac imaging, to ensure the exclusion of secondary causes of left ventricular hypertrophy. Results: Among the HCM patients evaluated, only a small percentage met the inclusion criteria for recent CMI trials: 10.4% for EXPLORER-HCM and 4.7% for SEQUOIA-HCM. The predominant exclusion factor was the stringent left ventricular outflow tract (LVOT) gradient requirement. Conclusions: This study highlights a significant discrepancy between patient demographics in clinical trials and those encountered in routine HCM clinical practice. Despite promising results from the initial randomized clinical trials that led to the approval of Mavacamten, the selected patient population only represents a small part of the HCM patient cohort seen in routine clinics. This study advocates for further expanded randomized clinical trials with broader inclusion criteria to represent diverse primary HCM patient populations.

Improving sudden cardiac death risk stratification in hypertrophic cardiomyopathy using established clinical variables and genetic information.

BACKGROUND AND AIMS: The cardiac societies of Europe and the United States have established different risk models for preventing sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). The aim of this study is to validate current SCD risk prediction methods in a German HCM cohort and to improve them by the addition of genotype information. METHODS: HCM patients without prior SCD or equivalent arrhythmic events ≥ 18 years of age were enrolled in an expert cardiomyopathy center in Germany. The primary endpoint was defined as SCD/-equivalent within 5 years of baseline evaluation. 5-year SCD-risk estimates and recommendations for ICD implantations, as defined by the ESC and AHA/ACC guidelines, were analyzed. Multivariate cox proportional hazards analyses were integrated with genetic findings as additive SCD risk. RESULTS: 283 patients were included and followed for in median 5.77 years (2.92; 8.85). A disease-causing variant was found in 138 (49%) patients. 14 (5%) patients reached the SCD endpoint (5-year incidence 4.9%). Kaplan-Meier survival analysis shows significantly lower overall SCD event-free survival for patients with an identified disease-causing variant (p < 0.05). The ESC HCM Risk-SCD model showed an area-under-the-curve (AUC) of 0.74 (95% CI 0.68-0.79; p < 0.0001) with a sensitivity of 0.29 (95% CI 0.08-0.58) and specificity of 0.83 (95% CI 0.78-0.88) for a risk estimate ≥ 6%/5-years. By comparison, the AHA/ACC HCM SCD risk stratification model showed an AUC of 0.70 (95% CI 0.65-0.76; p = 0.003) with a sensitivity of 0.93 (95% CI, 0.66-0.998) and specificity of 0.28 (95% CI 0.23-0.34) at the respective cut-off. The modified SCD Risk Score with genetic information yielded an AUC of 0.76 (95% CI 0.71-0.81; p < 0.0001) with a sensitivity of 0.86 (95% CI 0.57-0.98) and specificity of 0.69 (95% CI 0.63-0.74). The number-needed-to-treat (NNT) to prevent 1 SCD event by prophylactic ICD-implantation is 13 for the ESC model, 28 for AHA/ACC and 9 for the modified Genotype-model. CONCLUSION: This study confirms the performance of current risk models in clinical decision making. The integration of genetic findings into current SCD risk stratification methods seem feasible and can add in decision making, especially in borderline risk-groups. A subgroup of patients with high SCD risk remains unidentified by current risk scores.

RBM20-Related Cardiomyopathy: Current Understanding and Future Options.

Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice regulators, such as RNA-binding motif protein 20 (RBM20) determine the physiological mRNA landscape formation, and rare variants in the RBM20 gene explain up to 6% of genetic dilated cardiomyopathy (DCM) cases. With ample knowledge from RBM20-deficient mice, rats, swine and induced pluripotent stem cells (iPSCs), the downstream targets and quantitative effects on splicing are now well-defined and the prerequisites for corrective therapeutic approaches are set. This review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy. Promising therapeutic strategies are presented and put into context with the pathophysiological characteristics of RBM20-related diseases.