Daily Cardiology Research Analysis

UNLABELLED: Heart failure (HF)-associated atrial myopathy is driven by complex and poorly understood mechanisms. Emerging evidence suggests that innate immune components contribute to atrial remodeling, yet the role of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) receptors remains unclear. METHODS: NOD1 expression was characterized in atrial myocardium of HF patients (n = 36) and non-failing controls (n = 45) undergoing valve surgery, and in two porcine models of atrial myopathy with divergent ventricular phenotypes: aortic banding (AoB; preserved LVEF) and left atrial infarction (LAI; reduced LVEF). The causal role of NOD1 in atrial remodeling was assessed using genetic ( RESULTS: NOD1 was markedly upregulated in atrial myocardium of HF patients and in both porcine models, across divergent ventricular phenotypes and irrespective of documented rhythm status, correlating with structural and functional indices of atrial disease severity. Genetic NOD1 deficiency in TAC mice prevented atrial dysfunction, structural remodeling, activation of profibrotic molecular pathways and Ca²⁺ mishandling. Pharmacological NOD1 inhibition with ML-130 reproduced the protective effects on atrial structural and Ca²⁺ handling. Selective NOD1 activation with C12-iE-DAP induced atrial Ca²⁺ dysregulation through CaMKII-dependent RyR2-Ser2814 hyperphosphorylation, effects that were abrogated by CaMKII inhibition, and absent in CONCLUSIONS: These findings identify the NOD1-CaMKII-RyR2 axis as a cardiomyocyte-centered mechanism linking innate immune activation to atrial Ca²⁺ dysregulation and structural remodeling in HF, establishing NOD1 as a molecular indicator of atrial myopathy burden and a mechanism-based therapeutic target.

BACKGROUND AND AIMS: The objective of this study was to define the relationships between the circulating proteome and metabolome with cardiac structure and function in patients with breast cancer receiving cardiotoxic therapies. METHODS: Proteomics and metabolomics profiling was performed in a longitudinal, prospective cohort study of breast cancer patients receiving anthracyclines and/or trastuzumab, using the Olink Explore 3072 platform and rapid liquid chromatography-mass spectrometry, respectively. Multivariable linear mixed-effect models evaluated the contemporaneous (same visit) and lagged (subsequent visit) associations between repeated measures of individual proteins or metabolites with quantitative echocardiographic measures of cardiac structure [left ventricular (LV) mass and left atrial volume index] and function [LV ejection fraction (LVEF), longitudinal and circumferential strain, E/e', and ventricular-arterial coupling]. Cox regression and pathway enrichment analyses were conducted for biomarkers demonstrating significant associations with cardiac function. RESULTS: Across 547 breast cancer participants (median age 50 years), 203 unique proteins and 16 unique metabolites were significantly associated with measures of cardiac structure and function in contemporaneous and lagged analyses. Notably, cathepsin C was associated with LVEF [false discovery rate (FDR), P = .017], longitudinal strain (FDR, P = .046), left atrial volume index (FDR, P = .035), and incident cardiac dysfunction, defined by an LVEF decline ≥10% to <50% (hazard ratio .61, 95% confidence interval .41, .90). The 147 proteins associated with cardiac function were enriched in biological processes reflective of protein deubiquitination, protein modification by small protein removal, macromolecule catabolic processes, and global metabolic pathways. Individual metabolites significantly associated with cardiac function (LVEF, longitudinal strain) included n-acetylglutamine, aspartic acid, acetylasparagine, alanyl-alanine, and prolyl-glycine (FDR, P-value < .001), and belonged to amino acids and derivatives and peptides. CONCLUSIONS: These findings provide translational insights into cancer therapy-related cardiac dysfunction and remodelling and identify potential new biomarkers of cardiotoxicity. There is an important need for validation of these findings and a deeper understanding of the biology of these biomarkers.

Heart failure (HF) remains a pressing health concern, with rising prevalence globally. Subjectivity and ambiguity in the definition of HF and its antecedent stages have limited research, global surveillance, and prevention programs. To address this, several cardiac societies and foundations convened to standardize the definition of HF in 2021 and designated stage B or pre-HF to identify individuals at risk of developing HF. In subsequent years, substantial progress and changes have been made in aspects of preventing HF, improving HF diagnosis and management, and recognizing the importance of the affected individual's voice. Global differences and disparities in HF are better understood, as are causes and comorbidities leading to differences in care, which are also influenced by access to care. This consensus document presents the Second Universal Definition of Heart Failure, aiming to standardize terminology and facilitate a uniform approach for clinicians, researchers, health systems, and policymakers. In this definition, the classification of HF phenotypes moves away from rigid left ventricular ejection fraction cutoffs, instead grouping HF into reduced, preserved, and improved ejection fraction categories to better reflect clinical realities. A universal classification of HF causes is also proposed. The document also addresses the dynamic trajectories of HF-improvement, remission, and recovery-and highlights the impact of social determinants and geographic variation on HF risk and outcomes. By providing a comprehensive, standardized framework for HF definition and classification, this document seeks to improve prevention, early detection, and management of HF worldwide, ultimately enhancing patient care and advancing global cardiovascular health.