Pulmonary arterial hypertension (PAH) is characterized by molecular heterogeneity, which has limited personalized approaches to treatment selection. In this study, the authors assembled a novel pipeline that leveraged pulmonary artery endothelial cell biopsies acquired at the point of care to build individualized interactomes that served as the basis for a systems pharmacology analysis. Concordance between the molecular targets of a prescribed PAH pharmacotherapy class and interactome topology was associated with improved clinical outcomes using a retrospective in silico trial design. These data suggest that clinically actionable individualized treatment selection is feasible in PAH with relevance to other complex cardiovascular diseases.
Systolic heart failure is increasingly recognized as a disease of impaired cardiac energy metabolism. Here, the authors show that cardiac myosin super-relaxation (an energy-conserving myosin state) is destabilized in failing human myocardium. Importantly, this loss of energy conservation is associated with elevated post-translational modifications (phosphorylation and acetylation) rather than gross structural changes in thick filament organization. Hence, targeting post-translational modifications signaling pathways opens new therapeutic opportunities.
Ankyrin-B (AnkB), encoded by ANK2, is essential for ion channel localization in the heart. We investigated its role in regulating sinoatrial node (SAN) responses to autonomic input. AnkB-haploinsufficient (AnkB+/-) mice showed baseline bradycardia, heightened SAN response to β-adrenergic stimulation, and increased heart rate variability. These mice exhibited reduced ICa,L and SAN sarcoplasmic reticulum Ca2+ content, unchanged IK,ACh density, but impaired IK,ACh desensitization. AnkB interacts with GIRK1/4 subunits, and its loss in cardiomyocyte-specific knockout mice reduced GIRK1 membrane localization. Our findings support that AnkB deficiency disrupts autonomic regulation of SAN function through downregulation of ICa,L and the reduction in IK,ACh desensitization.
Bioelectrical impedance (BI) is gaining significant attention for its potential in cardiovascular health monitoring and early disease detection. On the basis of the principles of tissue conductivity and body composition, BI operates by applying a low-amplitude alternating current through the body and measuring the resulting impedance. Different BI techniques, such as body composition assessment, impedance cardiography, transthoracic impedance, and electrical impedance tomography, use these measurements to estimate several clinically relevant parameters such as intracellular and extracellular fluid volumes, cell membrane integrity, cardiac output, stroke volume, systemic vascular resistance, and overall body composition. Because of its portability, safety, and ease of use, BI is increasingly used in cardiovascular health, particularly for monitoring heart failure, evaluating fluid balance, and assessing vascular health. In this review, we describe the basic principles and the evolution of bioimpedance techniques, highlight their current clinical applications in the field of cardiology, and discuss the ongoing developments and future perspectives of this promising tool.
We investigated how inflammatory fibroblasts (IFs) contribute to acute viral myocarditis, a dangerous inflammatory heart disease often caused by infections like coxsackievirus B3 (CVB3). Using CCL2-mCherry reporter mice, we tracked IF kinetics during CVB3 infection and discovered that their activity peaks on day 3 of myocarditis and is characterized by the production of Th1, Th2, and Th17 chemokines rather than typical profibrotic genes. We identified IL-1β as the most potent activator of this inflammatory state. We generated PDGFRαcreIL1r1fl/fl mice to specifically delete IL-1 signaling in fibroblasts. This targeted deletion reduced total cardiac inflammation by 45%-specifically lowering monocytes, T cells, and NK cells-without affecting viral clearance. By confirming the presence of IFs in endomyocardial biopsies from human patients, we have shown that fibroblast-specific IL-1 signaling is a critical driver of disease and a potential therapeutic target.
Bioprosthetic heart valves made from glutaraldehyde-fixed animal pericardium are widely used for valve replacement but are prone to early degeneration arising from the interplay of thrombosis, inflammation, and calcification. Current chemical treatments passivate the tissue surface but do not address these biological processes. This study introduces a plasma polymerized nanoparticle (PPN) platform that enables rapid, uniform coating of bioprosthetic pericardium and provides binding sites for active drug functionalization. Using PPNs, we immobilized the anticoagulant apixaban, the selective NLRP3-inflammasome inhibitor MCC950, or the anticalcification compound phytic acid directly onto valve tissue. These functionalized coatings reduced thrombosis in vitro and limited fibrosis and calcification in a 28-day rat subcutaneous model, demonstrating the capacity of PPNs to conjugate different small molecules to target multiple mechanisms of valve deterioration. Importantly, PPN coatings did not alter leaflet mechanics or hemodynamic performance when applied to a commercial transcatheter valve. This versatile coating platform represents an important advance in bioprosthetic valve technology with significant implications for their performance.
Mitochondrial health is essential for maintaining cardiac function, and mitophagy—the selective degradation of damaged mitochondria—is central to maintenance of mitochondrial quality. In this review, we focus on the role of mitophagy in atherosclerotic disease, exploring both canonical and noncanonical pathways. We aim to highlight how proper regulation of mitophagy supports cardiac health, while imbalances in this process can contribute to the onset and progression of cardiovascular conditions. In addition, we examine the cardioprotective potential of mitophagy in the context of disease and discuss its close relationship with mitochondrial dynamics, particularly as they relate to both macrovascular and microvascular dysfunction. Finally, we identify current gaps in knowledge and outline key questions that remain for the field to address, with the goal of guiding future research in this critical area of cardiovascular biology.
Rheumatic heart disease (RHD) remains the leading cause of acquired valvular heart disease in low- and middle-income countries, affecting an estimated 40 million individuals and disproportionately affecting children and young adults in endemic regions. No pharmacological intervention has been shown to modify valvular disease progression in established RHD. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardioprotective effects across multiple cardiovascular conditions, prompting interest in their potential applicability to RHD. This hypothesis-generating review synthesizes current evidence on the molecular and cellular pathology of RHD and evaluates the mechanistic plausibility of SGLT2 inhibitor effects in this context. Evidence derived largely from non-rheumatic valve disease and experimental models suggests that SGLT2 inhibitors may attenuate oxidative stress, inflammatory cytokine signaling, transforming growth factor-β-driven fibrosis, and mitochondrial dysfunction; processes implicated in valvular remodeling. Mechanotransduction cascades and osteogenic calcification pathways, characterized primarily in calcific aortic valve disease, are biologically plausible but remain uncharacterized in RHD tissue. Whether these mechanisms are operative within the postinflammatory, immune-mediated rheumatic valve environment remains uncertain and represents an important avenue for future research. Validation of SGLT2 expression in rheumatic valve tissue, mechanistic testing in etiologically relevant models, and early-phase clinical trials tailored to endemic health system realities are essential prerequisites before any therapeutic claims can be advanced. This review outlines the translational pathway needed to determine whether this hypothesis warrants clinical development.
Reduced left atrial (LA) strain is associated with cerebral small vessel disease (CSVD). In memory clinic patients without atrial fibrillation, LA reservoir strain and LA conduit strain were significantly associated with white matter hyperintensity volume and cerebral microinfarcts. From plasma proteomic profiling of 1,441 proteins, we identified 23 proteins significantly associated with LA reservoir strain, 425 with LA conduit strain, 199 with white matter hyperintensity volume, and 247 with cerebral microinfarcts. Among them, 13 proteins were commonly associated with both LA strain and CSVD, with 8 proteins showing evidence of significant mediation effects for the association between LA strain and CSVD. The mediators included tumor necrosis factor receptor superfamily member (TNFRSF)-11A, TNFRSF1B, TNFRSF10B, cystatin-C, nectin-4, insulin-like growth factor-binding protein, CD27, and brorin. Partial correlation network analysis also supported TNFRSF11A and insulin-like growth factor-binding protein as highly interconnected proteins in this study population. These plasma proteins may offer pathobiological clues linking LA dysfunction to CSVD.
This study reports a congenital heart disease, characterized by ventricular wall thinning and septal defects, caused by a heterozygous missense mutation (R755 W) in the glycolytic gene PFKP (platelet isoform of phosphofructokinase-1). The pathogenic mechanism involves the PFKP mutation impairing enzyme activity, which inhibits cardiomyocyte proliferation and leads to the thinning of the compact myocardium. In the mouse model, we found that administering the downstream metabolite, fructose-1,6-bisphosphate, reversed the myocardial hypoplasia in fetal mice, providing proof-of-concept for in utero intervention. Clinically, we successfully prevented the transmission of the disease using preimplantation genetic testing, resulting in the birth of a healthy infant.
