TRPC6 (transient receptor potential canonical 6) channels, encoded by the TRPC6 gene, are widely expressed in cardiomyocytes and play a critical role in maintaining intracellular Ca2+ homeostasis. Variants in TRPC6 are associated with chemotherapy-related cardiomyopathy. Specifically, the TRPC6 A404V polymorphism, with a minor (404 V) allele frequency of 12% in the general population, has been identified in patients undergoing anthracycline therapy. However, the underlying mechanisms remain largely unexplored.

Cardiovascular disease is the number 1 killer in industrialized countries, with sudden cardiac death due to ventricular arrhythmias representing a major component. To reduce sudden cardiac death, accurate risk prediction and development of effective preventive treatments remain major challenges. In this study, we explored the possibility of using a population-based computational modeling approach to perform virtual clinical trials for antiarrhythmic drug discovery and drug safety testing.

In vitro functional modeling of genetic variants has revolutionized our understanding of which variants can cause cardiac disorders, providing insights into their molecular underpinnings. This review provides an overview of high-throughput methods used for the functional assessment of variants implicated in inherited cardiac diseases. Advances in gene-editing technology now enable the efficient generation of cells expressing individual genetic variants or libraries of variants for robust functional studies. We discuss innovative assays that can evaluate dozens or hundreds of variants sequentially. For example, the electrophysiological properties of numerous cardiac ion channel variants in genes linked to inherited arrhythmias can be characterized using automated patch clamping. The mechanical properties of cardiomyocytes expressing candidate cardiomyopathy variants can be assessed using techniques such as atomic force microscopy, traction force microscopy, and impedance-based methods. Multiplexed assays of variant effect are an emerging family of techniques that use gene-specific or general assays, combined with next-generation sequencing, to characterize hundreds or thousands of pooled genetic variants. We examine the key advantages and limitations of each method and outline future goals for the field. Innovative in vitro studies of cardiac genetic variants will enhance our understanding of variant-disease relationships and improve diagnosis, screening, and treatment options for these disorders.

Takayasu arteritis (TAK) is a rare, immune-mediated large-vessel vasculitis that affects predominantly young women and carries a substantial risk of both vascular complications and long-term cardiovascular disease. Although glucocorticoids and conventional immunosuppressive therapies remain the cornerstone of treatment, relapse rates are high, and current strategies fail to adequately mitigate future cardiovascular risk. This review synthesizes evidence on current treatment strategies, unmet clinical needs, and novel approaches, including immunological and vascular-targeted therapies, and argues for a shift in management paradigm toward integrated cardiovascular risk reduction. We discuss advances in understanding the pathogenesis of TAK, highlighting the roles of innate and adaptive immunity in disease progression, and the challenges of early diagnosis and disease monitoring. We critically appraise current treatment paradigms, including glucocorticoids, conventional disease-modifying antirheumatic drugs, and biologics such as tocilizumab and tumor necrosis factor-α inhibitors, and outline emerging therapies targeting novel pathways, including interleukin-17, interleukin-12/23, Janus kinase/signal transducer and activator of transcription, and Notch-1/mammalian target of rapamycin complex signaling. We highlight the increasing recognition of cardiovascular morbidity as a major contributor to mortality in TAK and the need for integrated approaches to risk factor modification. We explore a road map for advancing management of cardiovascular disease in TAK, including comprehensive screening tools that integrate serological and imaging biomarkers to interrogate cardiovascular risk and potential therapeutic cardioprotective strategies such as sodium-glucose cotransporter 2 inhibitors and endothelin receptor antagonists. Despite recent progress, clinical management remains limited by diagnostic uncertainty, heterogeneous treatment approaches, and a paucity of high-quality randomized controlled trials. Future work should focus on interventions that target both immune-mediated vascular injury and cardiovascular disease progression. Achieving long-term disease remission while reducing cardiovascular mortality must become the primary therapeutic goal in TAK.

ACTA2 pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (α-smooth muscle actin) monomers to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the ACTA2 p.R149C variant in Acta2-/- smooth muscle cells.

Arrhythmogenic cardiomyopathy (ACM) is a fatal genetic heart disease primarily caused by mutations in desmosomal genes, leading to impaired cell-cell adhesion, ventricular arrhythmias, and progressive heart failure. Although gene therapy for specific ACM populations shows promise, it remains unclear whether mutation-agnostic pathways dysregulated across desmosomal mutations could be exploited for therapeutic intervention in this genetically broad and severe population. The reduction in expression of the ventricular gap junction protein Cx43 (connexin-43) is a common molecular alteration underlying desmosomal junctional deficits and arrhythmias, suggesting a potential common underlying mechanism and a therapeutic target for ACM. We hypothesized that restoration of Cx43 expression could be a mutation-agnostic intervention for ACM.

Pathogenic SCN5A variants are associated with inherited arrhythmias such as long-QT syndrome, Brugada syndrome, and sick sinus syndrome. While Nav1.5, an α-subunit of the cardiac sodium channel encoded by SCN5A, has been considered to function as a monomer, recent studies reveal that a reduction of sodium current in wild-type Nav1.5 can be caused by dimerization with loss-of-function mutated Nav1.5 through dominant-negative effects. However, the clinical significance of the dominant-negative effect remains unclear.

Discontinuing statin therapy before pregnancy remains challenging, especially in high-risk women. We evaluated the risks of maternal cardiovascular, gestational, and fetal outcomes associated with continuing versus discontinuing statin therapy before the last menstrual period (LMP).