Studies have suggested a genetic susceptibility to Takotsubo syndrome. In this case-control genome-wide association study, we examined genetic risk variants associated with the condition. We identified 2 single-nucleotide polymorphisms, rs2073526 and rs1614887, highly expressed in the heart, with suggested association. Both were associated with several corresponding genes with an expression quantitative trait locus in the heart, with potential mechanistic pathways in metabolism and inflammation.
Dyslipidemia, marked by elevated low-density lipoprotein cholesterol, is a major risk factor for coronary heart disease. Mouse experimental systems, such as Ldlr-/- mice that develop atherosclerosis and metabolic disorders when fed a high-fat diet (HFD), are crucial for studying disease mechanisms and identifying potential biomarkers. Using recent nanoparticle-dependent enrichment of plasma proteins and mass spectrometry, we quantified 5,080 plasma proteins from Ldlr-/- mice fed a chow or HFD for 3 or 6 months. Proteins with sustained enrichment in HFD were indicative of liver cell subtypes, whereas proteins that increased from 3 to 6 months were indicative of inflammation and endothelial activation. Proteins/genes from human cardiovascular genomic and proteomic studies were also detected in the plasma and aorta including MMP12, LPL, and HP that increased with HFD. These data provide many avenues for understanding disease pathology and uncovering novel molecular contributors to cardiovascular diseases.
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.
Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired cardiac contractility. AC01, a small-molecule ghrelin receptor agonist, enhances contractility in cardiomyocytes. This study evaluated the in vivo hemodynamic effects of AC01 in a mouse HFrEF model and in cynomolgus monkeys. In HFrEF mice, intravenous AC01 significantly increased cardiac output, stroke volume, and ejection fraction versus vehicle, without any apparent detriment to diastolic function. Pressure-volume loop analysis demonstrated load-independent inotropic effects. In monkeys, oral AC01 increased cardiac output and stroke volume while reducing heart rate, without lowering central aortic pressure. These effects were sustained over 14 days of oral dosing. Additionally, AC01 improved autonomic balance by increasing parasympathetic and decreasing sympathetic activity. Overall, AC01 produced rapid, consistent, and sustained improvements in systolic function across species, supporting its potential as a novel, load-independent inotropic therapy for heart failure.
Patients with and without obstructive coronary artery disease (oCAD) experience heterogeneous cardiovascular risk, and coronary computed tomography angiography (CCTA) high-risk plaque features are not universally available. This study evaluated whether circulating proteomic profiles clarify plaque biology and improve risk assessment. Proteomic profiling of 572 proteins was performed in PROMISE (N = 1,724), with validation in Dan-NICAD (N = 2,743) and UK Biobank (N = 53,018). A high-risk composite phenotype (HRCP) combined oCAD, high stenosis or plaque burden, high coronary calcium, and high-risk plaque features. Thirty-seven proteins were independently associated with HRCP and were mapped to inflammatory, metabolic, and proteolytic pathways; 7 were also associated with major adverse cardiovascular events, including lipoprotein lipase and cathepsin D. While the 37-protein score added little discrimination beyond clinical factors, it improved reclassification (net reclassification index = 0.13, P < 0.001), suggesting proteomic profiles may complement clinical models while elucidating disease biology and highlighting cathepsin D as a potential therapeutic target.
Myocardial autoimmune responses result in distinctive cardiac diseases and are associated with poor clinical outcomes. Autoantibodies (AAbs) play a crucial role in myocardial humoral autoimmunity by targeting endogenous tissue, or "self-antigens." Myocardial tissue injury or myocyte disarray caused by AAbs triggers a cascade of defensive immunological responses that may lead to worsening biventricular remodeling. However, over the past decade, the concept of AAbs in myocardial diseases has shifted from viewing AAbs as uniformly deleterious to a more nuanced explanation of AAbs influencing downstream intracellular pathways with multiple possible outcomes. This paradigm shift arose from technological advances such as large language models for accelerated epitope screening and high-throughput protein assays that uncover complex autoimmune cross-reactivity and downstream intracellular signaling pathways. In this contemporary review article, we critically appraise the latest translational data on the role of AAbs in myocardial disease and provide a framework to encourage scientific endeavors in the development of new therapeutics for cardiomyopathies.
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.
