Pereira, Naveen

The 2025 American College of Cardiology/American Heart Association/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions acute coronary syndrome guideline focuses on strategies to reduce bleeding risk with antiplatelet therapy yet lacks any recommendation related to CYP2C19 genotyping. The impact of CYP2C19 loss‐of‐function alleles on the effectiveness of clopidogrel is well documented, and although prasugrel and ticagrelor more effectively reduce the risk for atherothrombotic events compared with clopidogrel in patients with a CYP2C19 loss‐of‐function allele, clopidogrel reduces bleeding risk without an increase in atherothrombotic events compared with prasugrel or ticagrelor in those without a loss‐of‐function allele. Accordingly, an American Heart Association Scientific Statement supports CYP2C19 genetic testing before oral P2Y 12 inhibitors are prescribed. This commentary summarizes the evidence in support of CYP2C19 ‐guided P2Y 12 inhibitor selection in the context of other 2025 acute coronary syndrome guideline recommendations and urges future guidelines to incorporate recommendations for CYP2C19 genotyping, especially for those at high bleeding risk.

Abstract Background Loss-of-function variants in TTN-encoded titin are the most common genetic cause of dilated cardiomyopathy (DCM). In addition, titin truncating variants (TTNtvs) are over-represented in early-onset atrial fibrillation (AF) and unexplained sudden cardiac arrest/death (SCA/SCD) suggesting that in rare circumstances TTNtvs may cause arrhythmias in a pre-cardiomyopathic electrical phase. Purpose To compare the prevalence of AF, sustained ventricular arrhythmias (VAs) and SCA/SCD between TTNtv-positive patients with genotype-positive but phenotype-negative (G+/P-) disease, non-dilated left ventricular cardiomyopathy (NDLVC) and DCM. Methods Retrospective review of 1,229 patients in our Arrhythmogenic/Dilated Cardiomyopathy Registry was used to identify those with TTNtvs in high proportion spliced-in (>90%) exons classified as pathogenic or likely pathogenic according to current American College of Medical Genetics and Genomics variant classification guidelines. Demographic, electrocardiographic, imaging and outcome data were extracted from the electronic record. After exclusion of those without satisfactory imaging data, each TTNtv-positive patient was classified as having G+/P- disease, NDLVC, or DCM according to the 2023 European Society of Cardiology Guidelines for the management of cardiomyopathies. The prevalence of AF, non-SCA major VA events (sustained VT and appropriate VT/VF-terminating ICD therapies), and SCA/SCD was then compared between the three left ventricular morphofunctional subgroups. Results Overall, 232 TTNtv-positive patients (mean age of 44 ± 17 years; 57% male) were included (average LVEF of 39 ± 17%; 32% with a history of AF; 23% with a history of non-SCA VA event and 6% with a history of SCA). Forty-nine (21%) were G+/P-, 45 (19%) had NDLVC, and 138 (59%) had DCM at the time of their most recent clinical evaluation. As expected, the prevalence of AF was higher in TTNtv-DCM patients when compared to both TTNtv-NDLVC [56/138 (41%) vs. 11/45 (24%); p=0.04] and G+/P- disease [56/138 (41%) vs. 5/49 (10%); p<0.001]. Similarly, the number of patients who experienced a non-SCA major VA event was higher in TTNtv-DCM than either TTNtv-NDLVC [44/138 (32%) vs. 6/45 (9%); p=0.01] or G+/P- disease [44/138 (31%) vs. 4/49 (8%); p<0.001]. Interestingly, no difference in the number of TTNtv-positive patients who experienced a SCA/SCD was observed across subgroups [2/49 (4%) for G+/P-; 2/45 (4%) for NDLVC; and 8/138 (6%) for DCM; p=ns for all comparisons]. Conclusion In patients with TTNtv substrates who were evaluated at a quaternary medical center, the prevalence of AF and major VA events correlates with left ventricular morphology/function with the greatest risk observed in those with DCM. However, the prevalence of AF and major VA events, including SCA, in TTNtv-positive patients with G+/P- and NDLVC disease is not trivial and highlights the ability of TTNtvs to present in a pre-cardiomyopathic electrical phase.

This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Background. Acute cellular rejection (ACR) remains a major cause of morbidity after heart transplantation despite advances in immunosuppression. Whole genome transcriptomic profiling offers a systems-based, unbiased approach to elucidate the molecular mechanisms underlying ACR. However, noninvasive, longitudinal biomarker assessments capable of capturing the temporal dynamics of rejection biology remain scarce. Methods. RNA sequencing of peripheral blood from heart transplant recipients before, during, and after ACR was compared with nonrejection controls. Pathway analysis was conducted using differentially expressed genes (DEGs), and a machine learning approach was applied to assess gene-based prediction of ACR. Results. A total of 235 rejection-specific significant DEGs and 863 postrejection DEGs (false discovery rate < 0.05) were identified. During ACR, DEGs were enriched for T-cell activation/differentiation, apoptosis, and B-cell receptor signaling pathways. By combining the 2 sets of DEGs, a panel of 71 common genes was identified that reflected the significant, longitudinal transcriptomic dynamics of ACR. In an elastic net machine learning–based classifier, DYNLL1 and SERF2 were identified as ACR predictive genes, and achieved a cross-validated area under the receiver operating characteristic curve of 0.63. Conclusions. Peripheral blood transcriptomics identify dynamic temporal responses in ACR including T- and B-cell pathways with potential ACR predictive genes that warrant further investigation.