Search Results (1,702)

Cardiovascular diseases remain the leading cause of mortality worldwide, and one of the key mechanisms driving the development of heart failure is pathological remodeling of the myocardium. This process involves complex structural, cellular, and metabolic alterations in which the immune system and its interactions with cardiomyocytes and fibroblasts play a central role. The aim of this work was to present the current state of knowledge on immunometabolism in cardiac remodeling and to discuss its pathophysiological relevance and therapeutic potential. This review focuses on the metabolism of cardiac macrophages, highlighting the differences between the pro-inflammatory (M1) and reparative (M2) phenotypes and their impact on inflammation, fibrosis, and myocardial regeneration. The roles of major metabolic pathways, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, are discussed, as well as the importance of the NLRP3 inflammasome and efferocytosis in regulating the inflammatory response. Furthermore, the review briefly incorporates recent insights into neutrophil, T cell, and regulatory T cell (Treg) metabolism and their contributions to inflammation, repair, and fibrotic remodeling. Particular attention is also given to cardiac fibroblasts and their metabolic reprogramming during fibrosis, with emphasis on the pivotal role of transforming growth factor-β (TGF-β) signaling. The review further discusses the role of microRNAs as mediators of intercellular communication integrating immunological and metabolic signals. The work is complemented by a discussion of therapeutic perspectives, including modulation of macrophage metabolism, fibrogenic signaling pathways, mitochondrial function, and miRNA-based therapies. Immunometabolism emerges as a promising research field whose further exploration may contribute to the development of novel, more precise strategies for the treatment of cardiovascular diseases. Full article

Congenital Long QT Syndrome (LQTS) is a hereditary cardiac channelopathy defined by delayed ventricular repolarization and an elevated risk of life-threatening ventricular arrhythmias. Recent echocardiographic studies using speckle-tracking and strain imaging have identified subtle abnormalities in ventricular and atrial mechanics among LQTS patients, including reduced global longitudinal strain, impaired diastolic function, enlarged left atrial volumes and a consistently negative electromechanical window. These findings challenge the traditional concept of LQTS as solely an electrical disease and support evolving evidence of a subclinical cardiomyopathic phenotype. Left atrial remodeling, although less studied, may represent an underrecognized component of LQTS with potential implications for arrhythmia vulnerability and diastolic dysfunction. This review summarizes current evidence on electromechanical and structural cardiac involvement in congenital LQTS, highlights its diagnostic and clinical implications, and outlines future directions for research in this evolving field. Full article

Ceramides are central bioactive sphingolipids that regulate diverse cellular processes, including membrane organization, energy metabolism, and stress signaling. Emerging evidence has implicated that ceramide dysregulation is associated with the onset and progression of heart failure. This review introduces the understanding of ceramide metabolism, focusing on its biosynthesis, and functional roles in cardiomyocytes. In addition, the contribution of systemic ceramides derived from circulating lipoproteins and peripheral tissues to cardiovascular risk is also discussed. In parallel, it is highlighted that cardiomyocyte-intrinsic ceramide synthesis plays physiological and pathological roles in the heart. Particularly, excessive ceramide accumulation is detrimental for cardiac function, through multiple mechanisms, such as lipotoxic effects, mitochondrial impairment, inflammation, and cell death. The current review discusses the potential diagnostic and therapeutic strategies targeting ceramide metabolism, as well as the open questions about ceramide association with heart disease. Full article

Cardiac fibrosis is a central determinant of heart failure progression and arises from pathological remodeling characterized by fibroblast activation, myofibroblast differentiation, and excessive extracellular matrix deposition. In contrast, physiological remodeling permits adaptive cardiac growth without net fibrosis. Pregnancy represents an underexplored physiological model of reversible cardiac remodeling. In response to hemodynamic load, the maternal heart undergoes hypertrophic growth that resolves postpartum, constituting a natural paradigm of fibrosis-resistant cardiac adaptation. Pregnancy and lactation are accompanied by profound endocrine and immune reprogramming of maternal tissues. We propose that this hormonal milieu orchestrates coordinated crosstalk among endothelial cells, fibroblasts, and immune cell populations to suppress profibrotic pathways and preserve extracellular matrix homeostasis. Candidate regulators include estrogen, progesterone, prolactin family peptides, relaxin, oxytocin, and components of the renin–angiotensin–aldosterone system. During the postpartum and lactational period, prolactin and oxytocin may further promote reverse remodeling. These hormones likely act by modulating local cytokine and growth factor networks that otherwise drive fibroblast activation. By focusing on non-myocyte cardiac cells and extracellular matrix dynamics, this review positions pregnancy as a translational model to uncover endogenous anti-fibrotic mechanisms and identify novel therapeutic strategies for cardiac fibrosis. Full article

Acute coronary syndromes (ACS) remain time-critical clinical emergencies in which early diagnosis and accurate risk stratification determine management and outcomes. Although symptoms, electrocardiography, and high-sensitivity cardiac troponin (hs-cTn) provide a reliable framework for detecting myocardial injury, they offer limited insight into plaque instability, thromboinflammatory activity, vascular repair, and post-infarction remodeling. In this narrative review, we examine the biological rationale and current clinical evidence supporting brain-derived neurotrophic factor (BDNF) as a candidate biomarker in ACS, with particular attention to pre-analytical, analytical, and phenotypic sources of heterogeneity. Available studies show that circulating BDNF concentrations vary substantially according to biological matrix, timing of sampling, ACS subtype, and assay methodology, which likely contributes to inconsistent findings across cohorts. Overall, current evidence does not support BDNF as a diagnostic alternative to hs-cTn in rule-in or rule-out pathways. However, BDNF may have value in biological phenotyping and risk stratification by reflecting platelet activation, endothelial dysfunction, inflammatory signaling, and remodeling processes after ACS. Further progress will require standardized pre-analytical procedures, separate assessment of mature BDNF and proBDNF, serial sampling, and validation in large multicenter studies. Full article

The cardiac extracellular matrix (ECM) is a dynamic, mechanically active network continuously shaped and interpreted by cardiomyocytes, fibroblasts, and macrophages. Interdependent mechanosensing, force transmission, and ECM remodeling functions create multicellular feedback loops that control tissue stiffness, alignment, maturation, and fibrotic remodeling. Together, these biomechanical processes create reciprocal signaling pathways in which cellular behavior modifies the ECM while the ECM’s mechanics concurrently shape cellular phenotype and function. This review explores cell–ECM mechanoreciprocity, a physiologic framework that unifies cell-sensing mechanotransduction, mechano-electrical coupling, and ECM-based biochemical signaling with cell-driven ECM remodeling. We propose three interconnected feedback loops that integrate biochemical and mechanical cues across cell types: load amplification, structural alignment, and immune regulation. We discuss how advanced two- and three-dimensional engineered cardiac systems incorporating tunable and dynamic mechanical cues can be used to model these interactions. We address the limitations of existing experimental platforms and the need for better models to fully recapitulate in vivo complexities. Understanding and recreating these reciprocal mechanical interactions will provide essential frameworks for disease modeling and therapeutic development while reducing reliance on in vivo studies. Full article

Myocardial infarction (MI) triggers a robust inflammatory response that is essential for tissue repair but, when excessive or prolonged, drives pathological cardiac remodelling and heart failure. Colony-stimulating factor 2 (CSF2) signalling has been implicated in driving pro-inflammatory macrophage activation post-MI. Here, we investigated the role of macrophage-specific CSF2 receptor alpha (CSF2RA) signalling in post-MI remodelling using a tamoxifen-inducible genetic mouse model and permanent coronary artery ligation. Macrophage-specific Csf2ra deficiency significantly improved left ventricular systolic function post-MI without altering cardiac fibrosis burden. Functional improvement was associated with enhanced collagen scar maturation, characterised by an increased proportion of mature collagen fibres, and with accumulation of anti-inflammatory, pro-reparative macrophages within the infarct. These macrophage changes were accompanied by increased fibroblast density, consistent with altered macrophage–fibroblast crosstalk. Collectively, these findings identify macrophage-intrinsic CSF2RA signalling as a critical regulator of inflammatory resolution and scar maturation after MI and provide mechanistic support for the rationale of selective CSF2RA inhibition as a therapeutic strategy to limit adverse cardiac remodelling and improve post-infarction recovery. Full article

Objectives: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, and cardiometabolic comorbidity, have been increasingly associated with cognitive impairment and dementia. These associations, however, remain underexplored and underappreciated in middle-aged individuals with AF. This study aimed to explore the associations of early cognitive impairment with the presence of cardiometabolic comorbidities and potential associations with echocardiographic markers in middle-aged patients with and without AF. Methods: Between 2023–2024, fifty-six consecutive outpatients with a diagnosis of AF aged 45–65 years underwent clinical evaluation, transthoracic echocardiography, and comprehensive neuropsychological assessment using the Montreal Cognitive Assessment (MoCA) and the Consortium to Establish a Registry for Alzheimer’s Disease battery (CERAD). A control group of 58 age group-matched individuals without known cardiometabolic disease was included in comparative cognitive analyses. Results: Patients with AF and cardiometabolic comorbidities demonstrated early cognitive deficits, particularly in episodic memory and visuospatial functions, detectable even in individuals with normal MoCA scores, compared with the control group. However, no associations were observed between cognitive performance and conventional echocardiographic parameters in the group with AF. Conclusions: This study corroborated prior evidence of an association between cardiometabolic impairment and subtle cognitive impairment, but did not identify a specific contribution of echocardiography markers. More extensive and sensitive biomarkers of left atrial structure and function may be required to detect harmful associations with subtle cognitive impairment in middle-aged individuals. Further prospective studies, with a more balanced control for comorbidities, are warranted to clarify the clinical relevance of atrial structural remodeling in this context. Full article

Background: Trace elements function as essential micronutrients involved in oxidative balance, mitochondrial activity, and cardiovascular metabolism. Cigarette smoking represents a significant source of toxic metals and may disrupt systemic trace element homeostasis. Alterations in micronutrient and metal balance may contribute to oxidative stress, endothelial dysfunction, and myocardial remodeling, which are central mechanisms in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). This study aimed to investigate whether smokers with HFpEF exhibit distinct hair trace element profiles compared with smokers without HFpEF. Methods: In this prospective pilot study, scalp hair samples were collected from adults undergoing clinical evaluation for suspected cardiovascular disease. Trace element concentrations were determined using inductively coupled plasma mass spectrometry (ICP-MS). Participants were first stratified according to smoking status and subsequently, within the smoker subgroup, according to HFpEF diagnosis based on the Heart Failure Association Pre-test assessment, Echocardiography and natriuretic peptide score (HFA-PEFF) algorithm. Differences in trace element concentrations were analyzed using appropriate statistical tests, with multiple-comparison correction using the Benjamini–Hochberg false discovery rate (FDR). Active smoking was defined as ≥10 cigarettes per day for at least 1 year, and cumulative exposure was quantified in pack-years. Results: Fifty-eight participants were included, including 27 active smokers. In unadjusted analyses, several trace elements differed between smokers with HFpEF and those without HFpEF, including vanadium, lithium, aluminum, and copper. However, after FDR correction, only copper remained significantly elevated in smokers with HFpEF (q = 0.004). Hair copper concentrations were markedly higher in the HFpEF group compared with smokers without HFpEF. These differences were observed alongside echocardiographic features consistent with diastolic dysfunction and structural cardiac remodeling. Conclusions: In this hypothesis-generating pilot study, smokers with HFpEF demonstrated elevated hair copper concentrations, suggesting disturbances in trace element and micronutrient homeostasis. Altered copper metabolism may reflect oxidative stress-related cardiometabolic remodeling associated with HFpEF. These findings raise the hypothesis that cardiometabolic phenotype, rather than smoking exposure alone, may modulate trace element homeostasis in HFpEF; however, causal relationships cannot be established. Full article

Non-infectious cardiac failure in feedyard cattle has become more frequently diagnosed. There is limited research assessing gross and histologic lesions in grossly abnormal hearts of harvested cattle. Cases were stratified by heart score (HS) using a scale of 1–5, with 1 representing a normal heart and 5 representing severely remodeled ventricles. Cattle were evaluated for gross lesions of the heart, lung, and liver. Samples collected from each animal for histology included cardiac (n = 4), pulmonary (n = 4), and hepatic (n = 1) tissues. Histologic evaluation scored cardiac and hepatic fibrosis and necrosis, embedded myocardial protozoal cysts (EMPCs) were quantified, and pulmonary lesions were categorized based on histologic patterns. Of 103 cases, 40 had normal HSs (NHSs) (1 or 2), and 63 had abnormal HSs (AHSs) (3, 4, or 5). There were 64 cases with normal lung deflation scores, and 39 cases with abnormal lung deflation scores. At least one cardiac section contained EMPCs in 67 cases. Cattle with abnormal lung deflation scores were more likely to have an AHS (0.76 ± 0.07, p ≤ 0.01) compared with cattle with normal deflation scores (0.52 ± 0.06). Cattle with EMPCs present in at least one cardiac section were more likely to also have an AHS (0.73 ± 0.05, p ≤ 0.1) compared with cattle without EMPCs (0.39 ± 0.08). No histological findings for the lungs or liver were associated with abnormal heart score; however, lung deflation and EMPCs were associated with abnormal heart score. Full article

Phospholipid transfer protein (PLTP) is a lipid transfer protein classically studied in the context of plasma lipoprotein metabolism, high-density lipoprotein (HDL) remodeling, and cardiovascular disease risk. PLTP facilitates phospholipid transfer between lipoproteins and regulates HDL particle size and composition through interactions with apolipoprotein A-I and apolipoprotein A-II. While its systemic roles in cholesterol handling, reverse cholesterol transport, and inflammatory signaling are well established, the cell-autonomous functions of PLTP within cardiomyocytes remain poorly defined, particularly in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Extensive experimental and clinical studies demonstrate that PLTP enhances ABCA1-dependent cholesterol efflux primarily by stabilizing ABCA1 at the plasma membrane and by promoting the generation of lipid-poor apolipoprotein A-I and pre-β HDL particles, which serve as efficient cholesterol acceptors; the magnitude of these effects depends on cellular context, PLTP expression levels, and the availability of lipid acceptors. PLTP expression is metabolically regulated and widely distributed across tissues, including macrophages and other non-hepatic cells, supporting roles beyond circulating lipoprotein remodeling. Altered PLTP activity has been linked to atherosclerosis, cardiovascular disease, and inflammatory pathways, underscoring its relevance to cardiac pathophysiology. Emerging evidence further suggests that intracellular cholesterol distribution, rather than total cholesterol content alone, critically influences mitochondrial membrane composition, bioenergetics, and stress signaling in cardiomyocytes. These observations raise the possibility that PLTP-regulated lipid flux may indirectly shape mitochondrial function by modulating cellular cholesterol homeostasis. This review synthesizes current knowledge of PLTP biology, cholesterol metabolism, and lipoprotein remodeling, and integrates these concepts with emerging frameworks in cardiomyocyte lipid metabolism and mitochondrial physiology. We highlight human iPSC-derived cardiomyocytes as a strategic and translationally relevant platform to investigate PLTP’s non-canonical, cell-intrinsic roles, identify critical knowledge gaps, and propose future directions for elucidating how PLTP may influence mitochondrial function in human cardiac cells. Full article

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, underscoring the need to better define the molecular mechanisms that govern cardiovascular homeostasis and disease progression. Among post-transcriptional regulators, microRNAs have emerged as important modulators of endothelial function, vascular smooth muscle cell plasticity, cardiomyocyte integrity, and cardiac fibroblast activity. This narrative review examines how microRNAs orchestrate molecular networks linking cellular homeostasis to inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, fibrosis, angiogenesis, and pathological remodeling across major cardiovascular cell types. It further discusses how these regulatory programs are reflected in specific cardiovascular diseases, including atherosclerosis, hypertension, acute myocardial infarction, heart failure, and arrhythmias. In addition, the review addresses the growing relevance of circulating and extracellular vesicle-associated microRNAs as candidate biomarkers for diagnosis, prognosis, and disease monitoring, as well as their therapeutic potential through mimics, inhibitors, antagomirs, and emerging delivery systems. Finally, current translation barriers are considered, including methodological heterogeneity, limited tissue specificity, delivery challenges, safety concerns, and the need for large-scale clinical validation. Overall, microRNAs are presented as integrative regulators connecting cardiovascular cell biology with disease mechanisms and clinical applications. Full article

Arterial stiffness has traditionally been interpreted as a marker of vascular ageing and cumulative blood pressure exposure. Increasing evidence, however, indicates that it should be viewed as an active determinant of cardiovascular loading conditions rather than a passive epiphenomenon. By accelerating pulse wave velocity and altering the timing of wave reflection, large artery stiffening increases central systolic pressure, augments late systolic load, and facilitates the transmission of pulsatile energy to the microcirculation. These hemodynamic alterations shape ventricular remodeling, influence ventricular–vascular coupling, and contribute to organ vulnerability even when brachial blood pressure appears adequately controlled. In this review, population-based observations and mechanistic human studies are integrated to position arterial stiffness as a stage-dependent dimension of cardiovascular disease. Community data illustrate its association with different blood pressure phenotypes and early cardiac structural changes, whereas evidence from advanced heart failure settings helps contextualize arterial stiffness within states of marked autonomic activation. Taken together, this perspective suggests that arterial stiffness is not merely a marker of cumulative damage, but a mediator that contributes to disease progression across clinical stages and, in practical terms, a phenotyping dimension along the trajectory from hypertension to heart failure. Full article

Peripartum cardiomyopathy (PPCM) is a pregnancy-associated form of systolic heart failure that develops when hemodynamic, metabolic, and hormonal stress of late gestation exceeds maternal cardiac adaptive capacity. While vascular, inflammatory, and genetic contributions have been implicated in PPCM, the integrated molecular programs connecting pregnancy-related stress to cardiomyocyte failure remain poorly defined. To elucidate these mechanisms, we performed a transcriptome-wide RNA seq of left ventricles from females with PPCM and non-failing female normal donor controls. Differential expression analysis identified 2891 genes with altered expressions (1491 upregulated, 1400 downregulated; fold change ≥ 2, FDR < 0.05). Ingenuity pathway analysis (IPA) revealed the activation of protein ubiquitination pathways, EIF2 signaling, mitochondrial dysfunction, and apoptosis pathways. Upstream regulator analysis indicated the suppression of mitochondrial protease CLPP (Z = −4.075) and activation of COPS5 (Z = +5.982) and TEAD1 (Z = +5.00), delineating dual regulatory modules of disease remodeling. Integrated network analysis demonstrated a loss of protein quality control and survival signaling with the activation of stress response and translational repression programs. This signifies a collapse of proteostasis and maladaptive adaptation. Collectively, these data define PPCM as a disorder of failed proteostasis and impaired translational homeostasis. Our analysis provides a systems-level framework connecting PPCM to ventricular dysfunction with potential therapeutic targets in mitochondria, protein quality-control, integrated stress–response, and COP9 signaling pathways. Full article

Cirrhosis is no longer viewed solely as an isolated hepatic disorder but rather as a complex multisystemic disease that affects cardiovascular, renal, pulmonary, metabolic, and immune systems. One of its most clinically relevant but under-recognized consequences is cardiac dysfunction, manifesting as cirrhotic cardiomyopathy, portopulmonary hypertension, right ventricular (RV) failure, and impaired myocardial strain. Oxidative stress (OS) has recently emerged as a fundamental mechanistic link between hepatic fibrogenesis and myocardial remodeling, acting through mitochondrial injury, NADPH oxidase activation, nitric oxide dysregulation, iron-mediated ferroptosis, and inflammatory cytokines. These alterations lead to diastolic dysfunction, autonomic imbalance, myocardial fibrosis, electrophysiological abnormalities (including QTc prolongation), and impaired RV–pulmonary artery coupling. Redox biomarkers such as malondialdehyde (MDA), NOX2-derived peptides, GSH/GSSG ratio, sST2, NT-proBNP, and 8-isoprostanes hold promise in detecting early subclinical cardiac involvement in cirrhosis. Novel antioxidant therapies, including mitochondrial-targeted molecules, NOX inhibitors, and ferroptosis blockers, may improve myocardial remodeling and hemodynamic stability. This review explores the central role of redox imbalance in the cardiohepatic syndrome and its potential utility in diagnosis, monitoring, and therapy. Full article