Single-nucleus RNA/ATAC-seq in early-stage HCM models predicts SWI/SNF-activation in mutant-myocytes, and allele-specific differences in fibroblasts.

Hypertrophic cardiomyopathy (HCM) is associated with phenotypic variability. To gain insights into transcriptional regulation of cardiac phenotype, single-nucleus linked RNA-/ATAC-seq was performed in 5-week-old control mouse-hearts (WT) and two HCM-models (R92W-TnT, R403Q-MyHC) that exhibit differences in heart size/function and fibrosis; mutant data was compared to WT. Analysis of 23,304 nuclei from mutant hearts, and 17,669 nuclei from WT, revealed similar dysregulation of gene expression, activation of AP-1 TFs (FOS, JUN) and the SWI/SNF complex in both mutant ventricular-myocytes. In contrast, marked differences were observed between mutants, for gene expression/TF enrichment, in fibroblasts, macrophages, endothelial cells. Cellchat predicted activation of pro-hypertrophic IGF-signaling in both mutant ventricular-myocytes, and profibrotic TGFß-signaling only in mutant-TnT fibroblasts. In summary, our bioinformatics analyses suggest that activation of IGF-signaling, AP-1 TFs and the SWI/SNF chromatin remodeler complex promotes myocyte hypertrophy in early-stage HCM. Selective activation of TGFß-signaling in mutant-TnT fibroblasts contributes to genotype-specific differences in cardiac fibrosis.

Acute coronary syndrome in patients with hemophilia: a delicate balancing act.

Therapeutic advances have resulted in increased life expectancy in patients with hemophilia. Consequently, the prevalence of coronary artery disease in this population is increasing. Little is known about the optimal management of acute coronary syndrome in these patients. Current guidelines for the management of this condition are based mainly on expert opinion and generally recommend administration of the clotting factor prior to the anticoagulant, antiplatelet, and interventional therapies. We report a case that illustrates the potential harm that may come from this approach: evolution of non-ST-segment elevation acute coronary syndrome into ST-elevation acute coronary syndrome during the administration of recombinant clotting factor. We review available literature and describe the refined informatics-based guidelines for managing acute coronary syndrome in patients with hemophilia we developed in response to the presented clinical case. We propose adopting this novel informatics-based approach, which aids in the identification and early treatment of these patients, operationalizes timely involvement of hematology experts, and gathers data for further study.