Search Results (321)

Autoimmune myocarditis frequently progresses to inflammatory cardiomyopathy through dysregulated immune–stromal interactions. This study employs single-nuclei RNA-sequencing (snRNA-seq) to profile 46,233 cardiac nuclei from the experimental autoimmune myocarditis (EAM) mouse model at four timepoints: day 0 (healthy), day 14 (inflammation), day 21 (acute inflammation), and day 40 (late cardiac remodelling). Single-nuclei RNA profiling identified 18 transcriptionally distinct cell populations. Global cell–cell communication analysis revealed a dramatic peak of intercellular signalling at day 14 (5907 interactions), with fibroblast subpopulations and macrophages as dominant hubs, followed by partial resolution at day 21 (2264 interactions) and renewed remodelling at day 40 (4862 interactions). Subclustering of the macrophage compartment identified five subpopulations: Mac-TLF, Mac-MHCII, Mac-rMHCII, Mac-ResL, and Classical Monocytes. Tissue-resident macrophages (Mac-TLF, CCR2-) dominated at healthy state (~55%) but were rapidly depleted at day 14, coinciding with a dramatic influx of recruited CCR2⁺ macrophages (Mac-rMHCII), which expanded to over 70% of the compartment and maintained dominance through day 40. At inflammation (day 14), the expanded Mac-rMHCII subpopulation displayed a strongly pro-inflammatory signature (Il1b, Ankrd1, Stat2, Parp14, Apoe), and the overall macrophage compartment was enriched for cytokine response, Fc-gamma receptor, and Notch signalling pathways, while downregulating homeostatic and mitochondrial metabolic programmes, potentially contributing to impaired efferocytosis and cardiomyocyte dysfunction. Macrophage-centred communication networks expanded markedly at day 14 (1047 interactions), with resting fibroblasts (FB-R) as the primary signalling partner, driving pro-inflammatory stromal activation marked by upregulation of Ccl2, Ccl7, and Csf2. Intra-macrophage subcluster communication also intensified at this timepoint (447 interactions). These findings delineate the temporal and functional heterogeneity of cardiac macrophages during EAM progression and identify key immune–stromal interactions driving pathological cardiac remodelling. The coexistence of pro-inflammatory and transitional reparative macrophage subsets highlights the limitations of broad immunosuppression and supports precision strategies targeting CCR2-mediated recruitment, the SPP1 signalling axis, and macrophage–fibroblast crosstalk as therapeutic avenues in myocarditis and its progression. Full article

Immune-mediated myocardial injury is an important yet underrecognized manifestation of systemic rheumatic diseases and represents a biologically heterogeneous process extending beyond traditional cardiovascular complications such as pericardial disease or accelerated atherosclerosis. This review aimed to summarize current evidence regarding the molecular mechanisms underlying autoimmune myocardial injury and propose an integrated pathogenic framework. A structured narrative review of the literature was performed, focusing on molecular and cellular mechanisms, disease-specific pathogenic pathways, advances in cardio-immunology, and contemporary diagnostic approaches in autoimmune myocardial disease. Current evidence indicates that myocardial injury in rheumatic diseases results from complex interactions involving autoantibody-mediated injury, immune complex deposition, endothelial dysfunction, coronary microvascular dysfunction, dysregulated innate and adaptive immunity, oxidative stress, mitochondrial dysfunction, immunometabolic reprogramming, and regulated cardiomyocyte death. These mechanisms contribute to heterogeneous clinical manifestations, including myocarditis, arrhythmias, inflammatory cardiomyopathy, and heart failure. An integrated immune–microvascular–immunometabolic framework may represent a central mechanism driving myocardial injury and progression to inflammatory cardiomyopathy, supporting earlier diagnosis, improved risk stratification, and the development of precision therapeutic strategies. Full article

Sudden cardiac death (SCD) in athletes often represents the first manifestation of an underlying inherited cardiovascular disorder exposed by adrenergic stress, altered calcium cycling, mechanical loading, and metabolic demand during intense exercise. This review focuses on the molecular architecture that links genotype to arrhythmogenic phenotype in athletes, emphasizing sarcomeric force generation and energetic inefficiency in hypertrophic cardiomyopathy, desmosomal failure and Hippo/Wnt/transforming growth factor-beta (TGF-β) signaling in arrhythmogenic cardiomyopathy, and ion-channel and calcium/calmodulin-dependent protein kinase II (CaMKII)calcium handling abnormalities in inherited channelopathies. This review further examines how exercise-induced physiological remodeling intersects with these pathways through insulin-like growth factor-1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling, mitochondrial biogenesis, oxidative stress, inflammatory signaling, and epigenetic regulation. Attention is given to the molecular basis of genotype-positive/phenotype-negative states, variable penetrance, and exercise-mediated disease expression. Finally, the integration of molecular biology with genomic data, polygenic risk, and emerging digital phenotyping is discussed to refine mechanism-based risk stratification and identify future therapeutic targets for prevention of SCD in athletes. Full article

Sirtuins are an evolutionarily conserved family of nicotinamide adenine dinucleotide (NAD⁺)-dependent enzymes that regulate aging, cellular stress responses, and metabolic homeostasis. In mammals, seven isoforms (SIRT1–SIRT7) differ in subcellular localization, substrate specificity, and enzymatic activity, allowing them to control genomic stability, mitochondrial function, redox balance, inflammation, apoptosis, autophagy, and cell proliferation. Increasing evidence links sirtuin dysregulation to age-related chronic diseases, particularly cardiovascular disease (CVD). This review provides an integrated overview of the structure, enzymatic functions, localization, and biological specialization of mammalian sirtuins, with an emphasis on their roles in physiological aging and cardiovascular homeostasis. We discuss the involvement of individual sirtuins in major cardiovascular pathologies, including metabolic cardiomyopathy, myocardial ischemia–reperfusion injury (IRI), cardiac hypertrophy, fibrosis, heart failure, atherosclerosis, coronary artery disease, and hypertension. Particular focus is placed on SIRT1, SIRT3, and SIRT6, which emerge as key regulators of endothelial integrity, mitochondrial quality control, oxidative stress, inflammatory signaling, and myocardial remodeling. We also highlight the context-dependent and sometimes dual effects of other sirtuin isoforms in CVD. Finally, we summarize current therapeutic strategies targeting sirtuins, including activators, NAD⁺-boosting approaches, and selective inhibitors, and discuss the main challenges for future clinical translation in cardiovascular medicine, including precision, isoform-specific intervention design strategies, and long-term clinical implementation. Full article

Eicosanoids and their receptors act as key regulators of inflammation, calcium homeostasis, mitochondrial function, and cardiomyocyte survival, thereby contributing to the onset and progression of cardiac dysfunction. This review aims to summarize the evidence to underscore the pivotal role of eicosanoids and their receptors in the pathophysiology of cardiomyopathy, analysing the potential protective activity of traditional and natural compounds to counteract cardiovascular disease onset and progression. Among eicosanoid receptors, prostaglandin E2 receptor 3 (EP3), prostaglandin E2 receptor 4 (EP4), chemoattractant receptor expressed on type 2 helper T cells (CRTH2), and thromboxane prostanoid (TP) emerge as critical modulators with distinct and often opposing effects on cardiac physiology. While EP3 and CRTH2 are predominantly associated with detrimental outcomes such as impaired contractility and enhanced apoptosis, EP4 signalling consistently demonstrates cardioprotective properties, including improved calcium handling and preservation of mitochondrial integrity. These findings highlight the therapeutic potential of selectively targeting eicosanoid receptor pathways to mitigate cardiac remodelling and dysfunction. In parallel, increasing attention has been directed toward natural bioactive compounds as complementary strategies for cardioprotection. Polyphenols, flavonoids, carotenoids, and other nutraceuticals exert beneficial effects through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, often intersecting with eicosanoid signalling pathways. Their ability to modulate oxidative stress and inflammatory responses suggests a promising role in preventing or attenuating cardiomyopathy, particularly in metabolic and drug-induced contexts. Future research should focus on well-designed clinical trials, a deeper characterization of receptor-specific signalling networks, and the development of targeted therapies that combine pharmacological and nutraceutical approaches. Overall, a better understanding of eicosanoid-mediated mechanisms may open new ways for cardiomyopathy prevention and treatment, ultimately improving patient outcomes and reducing the burden of cardiovascular disease. Full article

Due to the complex pathophysiology and serious outcomes of autoimmune myocarditis, we sought to determine whether ethanolic lemon balm extract (LBE) could attenuate disease progression and development of dilative cardiomyopathy (DCM). EAM was induced in Dark Agouti rats by immunization with porcine myosin. Fifty animals were allocated to five groups: healthy controls, untreated EAM, and EAM treated with LBE (50, 100, or 200 mg/kg) for six weeks. Hemodynamic parameters were monitored, and echocardiography assessed cardiac structure and function. Inflammatory, oxidative, fibrotic, and apoptotic markers were analyzed. Immunological profiling revealed that LBE significantly decreased proinflammatory cytokines (IL-1, IL-6, TNF-α, IL-4, IL-17) while restoring anti-inflammatory IL-10 levels (p < 0.05). Antioxidant activity was confirmed by reduced levels of O₂⁻, H₂O₂, and TBARS, accompanied by significant increases in SOD, CAT, and GSH activity (p < 0.05), and upregulation of SOD1 and SOD2 gene expression. Additionally, LBE (200 mg/kg) markedly reversed fibrotic remodeling through suppression of TGF-β expression and collagen deposition, as shown by Sirius Red staining, and mitigated apoptosis by modulating Bax/Bcl-2 balance and reducing TUNEL-positive cells. Collectively, these findings suggest that LBE exerts strong cardioprotective effects in EAM by regulating inflammatory, oxidative, fibrotic, and apoptotic pathways, thereby preventing myocarditis progression toward DCM. Full article

Background: Pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor with potent antioxidant and anti-inflammatory properties, has been shown to protect against cardiac injury. However, its therapeutic potential in diabetic cardiomyopathy (DCM) induced by Type 2 diabetes mellitus (T2DM) and the underlying mechanisms remain poorly understood. Methods: A T2DM mouse model was established via a high-fat diet and low-dose STZ. We investigated the cardioprotective effects of 12-week oral PQQ administration, assessing fasting blood glucose, oral glucose tolerance, cardiac function, myocardial histopathology, blood biochemistry, mitophagy, and NLRP3 inflammasome activation. In vitro experiments using AC16 cardiomyocytes exposed to palmitic acid and high glucose were also conducted. Results: Results showed PQQ significantly improved cardiac function, attenuated remodeling, and reduced proinflammatory cytokines in mice with T2DM, regulated key mitophagy-related proteins (Parkin, Beclin-1, LC3B-II, p62), and downregulated NLRP3 inflammasome pathway components (Caspase-1, NLRP3, IL-1β, IL-18). In vitro experiments demonstrated that PQQ reduced reactive oxygen species (ROS) production, improved mitochondrial membrane potential, promoted mitophagy, and inhibited NLRP3 inflammasome-mediated pyroptosis. Conclusions: PQQ alleviates DCM in mice with T2DM by improving mitochondrial quality control, promoting mitophagy, and subsequently inhibiting NLRP3 inflammasome-mediated pyroptosis, highlighting its potential as a promising therapeutic agent for T2DM-associated cardiomyopathy. Full article

Diabetic cardiomyopathy (DC) is a serious health issue. MicroRNA-155b expression dysregulation might be involved in the fibrotic cycle in DC. L-Arginine (l-arg) is reported to have a preferable impact on the cardiovascular system. We aimed to understand the pathogenesis of DC and to detect the potential protective effect of l-arg through modulation of apoptosis, inflammation, fibrosis, and miR-155b expression. This study comprised four groups of forty adult male rats (10 rats in each group): diabetics, l-arg diabetics, l-arg, and controls. Blood glucose, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), body weight, and cardiac hypertrophy index (HW/BW ratio) were assessed. Echocardiographic assessment of left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) was done. Expressions of toll-like receptor-4 (TLR4), pro-inflammatory interleukin 1 beta (IL-1β), interleukin 6 (IL-6), anti-inflammatory interleukins (IL-4, IL-13), apoptotic markers (bcl-2, bax) and microRNA-155b were measured by real-time PCR. Myocardial light, electron microscopic and morphometric studies were performed. Results showed a significant decrease in cardiac hypertrophy (HW/BW = 0.0030 ± 0.0002 mg/g), echocardiographic parameters (LVEF = 54.12 ± 1.628% and LVFS = 20.40 ± 0.541%), hemodynamic parameters (HR = 411.0 ± 9.684 bpm, SBP/DBP = 84 ± 4.998/60 ± 3.062 mmHg) and downregulation of the expression of IL-4, IL-13, IL- 1β, IL-6 and TLR4 in the l-arg diabetic group compared to diabetic rats. Additionally, restoration of normal appearance of most cardiac myofibrils, intact blood vessels, decreased cardiac fibrosis and upregulation of bax expression were observed. Expression of microRNA-155b increased by 0.007 for each gram increase in blood glucose (>1.45, it showed 100% specificity and 96.7% sensitivity). In conclusion, microRNA-155b upregulation is associated with enhancement of the transcription of inflammatory cytokines and apoptotic genes. L-arginine may be a useful protective strategy for DC through modulation of apoptosis, inflammation, and fibrosis, in addition to regulating the expression of miR-155b. Full article

Background: Septic cardiomyopathy (SCM) is a fatal sepsis-induced dysfunction. While Pueraria (Pue) exhibits protective effects in sepsis, its regulatory role regarding programmed cell death (PCD) in SCM remains unclear. This study aimed to identify Pue’s PCD-related targets in SCM and construct a validated diagnostic model. Methods: We analyzed 14 PCD modalities across seven GEO transcriptomic datasets. A robust machine learning framework integrating 171 algorithm combinations built a diagnostic signature. The immune landscape was profiled using single-cell RNA sequencing and enrichment analyses. Experimental validation utilized SCM patient blood samples and heart tissues from an LPS-induced murine model. Results: Nine PCD patterns were significantly altered in SCM. Intersection analysis and machine learning identified five core Pue targets: STAT3, RIPK2, GM2A, ALOX5, and DPP4. A diagnostic model constructed with these genes achieved high AUCs across all datasets. Single-cell analysis revealed cell-type-specific expression within the myocardial immune landscape. Differential expression of these five genes was validated in both human and animal samples, correlating significantly with cardiac function indices. Conclusions: Our results demonstrate that Pueraria mitigates SCM and restores cardiac function by modulating the expression of core PCD-related targets. These targets are closely associated with the localized inflammatory response, providing potential therapeutic avenues for SCM. Full article

Arrhythmogenic cardiomyopathy (ACM) is a genetic myocardial disorder marked by progressive cardiomyocyte loss, fibro-fatty replacement, ventricular arrhythmias, and risk of sudden cardiac death. Traditionally considered a structural and electrical disease driven by desmosomal dysfunction, emerging evidence redefines ACM as an inflammatory cardiomyopathy in which immune activation plays a central role. This review integrates genetic, molecular, experimental, and clinical data to highlight inflammation as a unifying feature of ACM. Desmosomal gene variants impair cell adhesion and also activate cardiomyocyte-intrinsic inflammatory pathways, including nuclear factor of kappa B (NFκB) and glycogen synthase kinase 3β (GSK3β) signaling, promoting cytokine release, immune cell recruitment, and fibrotic remodeling. Preclinical studies suggest inflammation precedes structural changes, indicating it may be an initiating event rather than a secondary response. Clinical and pathological findings support this model, with inflammatory infiltrates, circulating cytokines, and autoantibodies observed across disease stages. These processes often present as episodic “hot phases” resembling myocarditis, thus complicating diagnosis. The inflammatory landscape involves both innate and adaptive immunity, along with stromal and neuronal remodeling, contributing to arrhythmogenesis through gap junction disruption, calcium-handling abnormalities, and fibrosis. Environmental factors such as exercise, stress, and metabolic disturbances further modulate inflammatory pathways and disease expression. Therapeutically, this evolving perspective supports immunomodulatory approaches, including inhibition of NFκB, GSK3β, and cytokine signaling. Early clinical data on immunosuppressive and cytokine-directed therapies are promising, especially during active inflammatory phases, while gene-based strategies specifically address the underlying genetic defects. In conclusion, ACM should be recognized as an inflammatory cardiomyopathy shaped by interactions between genetic susceptibility and immune dysregulation. Integrating genetic and immunologic profiling may improve diagnosis, risk stratification, and treatment, ultimately leading to refined personalized therapeutic strategies. Full article

Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent class III histone deacetylase, functions as a central metabolic sensor and stress-responsive regulator in the cardiovascular system. Unlike its well-characterized role in atherosclerosis, SIRT1 exerts multifaceted protective effects directly on cardiac tissue. This review synthesizes recent advances in understanding SIRT1-mediated cardioprotection across a spectrum of heart diseases, including myocardial ischemia/reperfusion (I/R) injury, heart failure (HF), diabetic cardiomyopathy (DCM), cardiac hypertrophy, aging-related cardiac dysfunction and circadian rhythm disruption. Mechanistically, SIRT1 orchestrates antioxidant defense through nuclear factor erythroid 2-related factor 2 (Nrf2) and Forkhead box O (FoxO) transcription factors activation, suppresses inflammatory signaling via nuclear factor kappa B (NF-κB) deacetylation, inhibits apoptosis by targeting p53, promotes autophagic flux and mitophagy, regulates mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and controls ferroptosis via the Nrf2/glutathione peroxidase 4 (GPX4) axis. Preclinical studies demonstrate that natural compounds (resveratrol, quercetin, curcumin, ginsenosides, tanshinone IIA, bergenin, swietenine) and synthetic SIRT1 activators (SRT1720, anilinopyridine derivatives) attenuate cardiac injury and improve function. Moreover, SIRT1 serves as a prognostic biomarker in HF and diabetic patients. However, context-dependent dual roles, where excessive SIRT1 expression may be detrimental, underscore the need for precise modulation. Challenges remain in achieving cardiac-specific targeting, optimizing NAD⁺ availability, and translating preclinical findings into clinical practice. Future research should integrate multi-omics approaches, single-cell transcriptomics, and precision medicine strategies to unlock the therapeutic potential of SIRT1 in cardiac diseases. Full article

Ischemic heart disease (IHD) remains the leading cause of chronic heart failure (HF) worldwide, yet the biological processes underlying this transition are not fully elucidated. Growing evidence indicates that chronic, low-grade inflammation acts as a pivotal link between ischemic injury and progressive myocardial dysfunction. Our review is the most up-to-date and structured synthesis on the pathophysiological pathways, biomarkers, and therapeutic implications of subclinical inflammation in patients with IHD at risk of developing HF. Following acute or repetitive ischemic episodes, persistent immune activation—mediated through interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)—promotes endothelial dysfunction, microvascular instability, and extracellular matrix remodeling. These mechanisms culminate in ventricular stiffness, diastolic impairment, and adverse structural remodeling, even when left ventricular ejection fraction is preserved. Biomarkers such as Galectin-3, cancer antigen 125 (CA125), and high-sensitivity C-reactive protein (hsCRP) provide valuable insight into the interplay between fibrosis, congestion, and systemic inflammatory load, supporting early detection of subclinical myocardial injury. Advanced imaging modalities, including strain echocardiography and cardiac magnetic resonance imaging (MRI) mapping, enhance the phenotypic characterization of inflammatory cardiomyopathy. Understanding and targeting these inflammatory pathways may open new avenues for precision-based prevention and treatment, ultimately improving outcomes across the IHD–HF continuum. Full article

HIV-associated cardiomyopathy is a significant cause of morbidity and mortality among people living with HIV, contributing to heart failure, arrhythmia, and sudden cardiac death. Despite its clinical importance, its individual-patient clinical spectrum has not been systematically synthesized. We conducted a systematic review of published English-language case reports and small case series describing cardiomyopathy in HIV-infected individuals. Etiologies were classified using a framework distinguishing cardiomyopathy arising from uncontrolled HIV from that occurring despite virologic control. Stratified analyses examined temporal trends and geographic differences. We identified 99 patients (75 male, 20 female, 4 unspecified) from 27 countries (80% high-income). Median age was 35 years (IQR 28–45). Among 52 patients with CD4 data, median was 154 cells/µL (IQR 84–391); 52% had CD4 < 200. Systolic dysfunction was present in 94% with echocardiographic data. Uncontrolled HIV phenotypes predominated (64%), but controlled phenotypes (21%)—including drug-induced cardiomyopathy (n = 19, predominantly zidovudine-associated) and autoimmune or inflammatory mechanisms (n = 13)—were substantial. Mortality declined across eras: 65% pre-ART, 32% early ART, 21% modern ART. Recovery occurred in 58%. HIV-associated cardiomyopathy is heterogeneous with improving outcomes across treatment eras. Systematic etiologic evaluation is warranted in all affected patients. The near absence of data from sub-Saharan Africa represents a critical gap. Full article

Heart failure (HF) has traditionally been regarded as a primary myocardial disorder in veterinary medicine. However, accumulating evidence suggests that HF represents a systemic syndrome characterized by dynamic multiorgan interactions. In human cardiovascular research, cardiorenal and cardiointestinal paradigms have reshaped disease conceptualization, yet comparable integrative frameworks remain underdeveloped in veterinary cardiology. Naturally occurring canine HF—particularly myxomatous mitral valve disease and dilated cardiomyopathy—offers a clinically relevant translational platform in which systemic remodeling unfolds within an intact physiological lifespan. This review proposes a systems-based perspective that integrates spontaneous canine HF with controlled in vivo experimental models. We outline four main pathways of interaction: (1) the heart–gut axis, wherein reduced perfusion can influence inflammation and disruption of the intestinal barrier; (2) the heart–bone axis, wherein endocrine factors like osteoprotegerin and osteocrin can impact remodeling of the cardiovascular system; (3) the heart–vascular endothelium axis, wherein inflammatory signaling and dysfunction of the vascular endothelium are hallmarks; and (4) the neurocardiac axis, which reflects an imbalance in the autonomic nervous system. Emerging regenerative and organelle-based strategies—including mesenchymal stem cell therapy and mitochondrial transplantation—are discussed within this multiorgan framework. Rather than focusing solely on cardiac contractility, these approaches may function as systemic inflammatory modulators, and endothelial, metabolic, and autonomic pathways. Canine HF can be better understood as a multiorgan network condition; reframing it in this way can help researchers in the field of translational cardiology create more comprehensive diagnostic and treatment plans. 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