Chaojie He

Cardiovascular–kidney–metabolic (CKM) syndrome represents a pathophysiological continuum linking metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD) through shared mechanisms, including insulin resistance, chronic inflammation, endothelial dysfunction, mitochondrial impairment, and maladaptive interorgan crosstalk. Although exerkines have emerged as key mediators of exercise-induced benefits, an integrated exerkine-centered framework spanning the CKM spectrum remains lacking. This review synthesizes current evidence on the multiorgan origins and biological roles of major exerkines, including myokines, adipokines, hepatokines, cardiokines, osteokines, lipid mediators, and extracellular vesicle–associated cargos. Moreover, extending beyond reductionist descriptions, we propose a higher-level mechanistic synthesis in which exerkines function as coordinated “signatures” across CKM phenotypes, converging on key regulatory hubs, particularly AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-mediated metabolic adaptation and the Klotho/fibroblast growth factor (FGF) axis that links renal, metabolic, and cardiovascular regulation. From a translational perspective, adiponectin, FGF21, apelin, and Klotho demonstrate the most consistent associations with cardiometabolic and renal outcomes in humans. However, clinical application remains constrained by uncertain causality, context-dependent resistance, and variability in assay performance. Overall, exerkines are best conceptualized as components of an integrated signaling network rather than isolated therapeutic targets. Meanwhile, future progress will depend on defining disease-stage-specific exerkine signatures and establishing associated causal relevance in humans.

Sepsis-induced myocardial dysfunction (SIMD) is a frequent and life-threatening complication of sepsis driven by interconnected inflammatory, oxidative, metabolic, and mitochondrial disturbances. Post-translational modifications (PTMs) have emerged as key regulators of these processes by dynamically altering protein activity, stability, localization, and signaling. This narrative review aimed to summarize the roles of major PTMs in SIMD and evaluate their potential as therapeutic targets. Relevant original studies and authoritative reviews published predominantly within the past decade were identified through targeted searches of PubMed and Web of Science and qualitatively synthesized. Current evidence indicates that phosphorylation, acetylation, ubiquitination, protein methylation, ADP-ribosylation, and palmitoylation regulate major pathways involved in myocardial inflammation, oxidative stress, mitochondrial dysfunction, metabolic reprogramming, apoptosis, and impaired contractility. Crosstalk among these modifications further integrates signaling networks, while upstream epigenetic mechanisms, including DNA methylation and N6-methyladenosine RNA modification, can influence PTM-related enzymes and downstream signaling. Experimental studies also suggest that pharmacological modulation of PTM-regulated pathways may attenuate myocardial injury; however, most mechanistic and therapeutic evidence derives from animal models and cultured cells, with limited validation in human septic myocardium. PTMs therefore represent promising mechanistic and therapeutic targets in SIMD, but systematic characterization of PTM crosstalk and rigorous human translational studies are required before PTM-directed strategies can be incorporated into clinical practice.

Heart failure with preserved ejection fraction (HFpEF) has emerged as the predominantform of heart failure (HF) worldwide and is increasingly recognized as a systemic syndrome closely linked to metabolic dysfunction. Furthermore, metabolic dysfunction–associated steatotic liver disease (MASLD), a highly prevalent yet often underrecognized comorbidity in patients with HFpEF, has attracted increasing attention. Accumulating epidemiological evidence demonstrates a significant association between MASLD and HFpEF, suggesting shared pathophysiological foundations that extend beyond coincidental coexistence. Mechanistically, MASLD contributes to the development and progression of HFpEF through a network of interconnected pathways, including chronic low-grade inflammation, insulin resistance (IR), dysregulated lipid metabolism, endothelial dysfunction, the gut–liver–heart axis, and as liver-derived mediators that influence cardiac structure and function. These overlapping mechanisms underlie the pronounced clinical and phenotypic heterogeneity of HFpEF and may help explain the limited efficacy of conventional heart failure therapies. This review summarizes current diagnostic and therapeutic strategies for HFpEF and MASLD and proposes an integrated, multiorgan framework to improve clinical recognition and management. A deeper understanding of liver–heart interactions is essential to redefining cardiometabolic disease, shifting from an organ-centric perspective toward a more integrated, mechanism-based approach.

Emerging evidence has implicated the gut microbiota in the pathogenesis and progression of numerous cardiovascular diseases. Atherosclerosis is a major pathological process that leads to many severe cardiovascular complications. Meanwhile, atherosclerosis patients may experience local and systemic inflammatory responses, with structural changes in the intestinal microbiota and increased mucosal permeability. Currently, the role of gut microbiota-derived metabolites in atherosclerosis pathology is of great concern. Relevant findings have highlighted the potential direct or indirect impacts of gut microbiota on the metabolic health of the host via the production of various metabolites. Thus, this review places an emphasis on bile acids (BAs), metabolites derived from and regulated by the gut microbiota. BAs can delay the pathological processes associated with atherosclerosis, underscoring the significance of these metabolites as an early marker for disease progression risk. In addition, we explore the potential of BA-related gut metabolites as novel therapeutic targets for atherosclerosis, and propose several promising directions for future research.

Background: Myocardial ischemia-reperfusion (I/R) injury represents the major obstacle to achieving successful therapeutic outcomes in acute myocardial infarction patients. Fat mass and obesity-associated protein (Fto), an N6-methyladenosine (m6A) RNA demethylase, has been shown to protect cardiomyocytes against oxygen-glucose deprivation/reperfusion-mediated injury by regulating annexin A1 (Anxa1) expression in vitro. The present study aims to confirm the cardioprotective role of the Fto/Anxa1 axis using in vivo myocardial I/R injury models. Methods: Wild-type (WT) and Anxa1 knockout (KO) mice underwent 30-min left coronary artery ligation and 2-h reperfusion after intramyocardial delivery of recombinant adeno-associated virus serotype 9 encoding Fto (adFto) or a control vector (adnull). The effects of Fto overexpression on cardiac function, fibrosis, apoptosis, and inflammatory response were examined using echocardiography, Masson’s trichrome staining, western blot analysis, enzyme-linked immunosorbent assay, and immunohistochemical staining. m6A-RNA immunoprecipitation-quantitative polymerase chain reaction quantified Anxa1 mRNA methylation. Results: Fto overexpression by adFto significantly improved cardiac function, reduced serum creatine kinase-myocardial band and troponin T levels, and alleviated cardiac fibrosis in I/R-injured WT mice. Mechanistically, Fto weakened I/R-induced global m6A levels and decreased m6A enrichment on Anxa1 mRNA, thereby enhancing Anxa1 expression. In Anxa1 KO mice, adFto did not confer functional or molecular benefit. Conclusions: Fto enhances Anxa1 and mitigates myocardial I/R injury with suppression of nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3 (Nlrp3)-inflammasome signaling in vivo, identifying the Fto-Anxa1 axis as a mechanistic contributor and potential therapeutic target.

Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.

Background: Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disorder that clinically manifests with sudden death and progressive heart failure. Moreover, thyroid dysfunction is associated with increased cardiovascular morbidity and mortality risks. Therefore, this study aimed to clarify whether thyroid hormones could serve as an independent predictor of adverse events in patients with HCM.Methods: The cohort consisted of 782 patients with HCM who had thyroid hormones baseline data and were admitted to the Affiliated Hospital of Jiaxing University. Patients were divided into two groups according to serum levels of free triiodothyronine (fT3): the normal fT3 and low triiodothyronine (T3) syndrome groups. Low T3 syndrome was defined as fT3 < 2.43 pmol/L with a normal thyroid‐stimulating hormone (TSH) level. Patients whose TSH levels were abnormally high or abnormally low were excluded from this study. The primary endpoint was the occurrence of sudden cardiac death (SCD) events, and the secondary endpoint was a composite of worsening heart failure (WHF) events, including heart failure death, cardiac decompensation, hospitalization for heart failure, and HCM‐related stroke. The Kaplan–Meier and Cox regression were performed for the survival analysis.Results: After a median follow‐up of 52 months, 75 SCD events and 134 WHF events were recorded. The Kaplan–Meier survival curves showed that the cumulative incidence of SCD events and WHF events were significantly higher in patients with low T3 syndrome (log‐rank p = .02 and log‐rank p = .001, respectively). Furthermore, multivariate Cox regression analysis demonstrated that low T3 syndrome is a strong predictor of SCD events and WHF events (adjusted hazard ratio [HR: 1.53, 95% confidence interval [CI]: 1.13–2.24, p < .01; HR: 3.87, 95% CI: 2.91–4.98, p < .001, respectively).Conclusions: Low T3 syndrome is highly prevalent among patients with HCM and was independently associated with an increased risk of SCD events and WHF events. The routine assessment of serum fT3 levels may provide risk stratification in this population.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with varying underlying etiologies and occurs in ~5–10% of patients with acute myocardial infarction. Sleep disorders and short sleep duration are common phenomena experienced by patients with coronary heart disease and are associated with poor clinical outcomes. However, the association between sleep quality, sleep duration, and the MINOCA prognosis is less clear.Methods: We performed a prospective observational study of 607 patients with MINOCA between February 2016 and June 2018. The mean follow-up period was 3.9 years. Sleep quality and sleep duration were measured by the Chinese version of the Pittsburgh Sleep Quality Index. The primary endpoint was all-cause mortality, and the secondary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke and heart failure hospitalization.Results: During the follow-up period, all-cause death occurred in 69 participants and 105 participants developed MACE. The Kaplan–Meier survival analysis demonstrated a significant association between poor sleep quality and all-cause mortality (log-rank P = 0.005) and MACE (log-rank P = 0.004). Multivariable Cox regression model indicated that poor sleep quality was an independent predictor of all-cause mortality as well as MACE [adjusted hazard ratio (HR) = 1.649; 95% confidence interval (CI), 1.124–2.790; P < 0.001; and adjusted HR = 1.432; 95% CI, 1.043–2.004; P = 0.003, respectively]. For sleep duration, short sleep duration (P = 0.004; and adjusted HR = 1.443; 95% CI, 1.145–1.877; P < 0.001, respectively), whereas long sleep duration was not (>8 h/d). A poorer sleep profile (including poor sleep quality and short sleep duration) was associated with a 149.4% increased risk of death (HR = 2.494; 95% CI, 1.754–4.562; P < 0.001) and a 96.7% increased risk of MACE (HR = 1.967; 95% CI, 1.442–3.639; P < 0.001) than those with neither.Conclusion: Sleep disorders were common among Chinese patients with MINOCA. Poor sleep quality and short sleep duration were independently associated with an increased risk of all-cause mortality and MACE in the MINOCA population. Meanwhile, a poor sleep profile has an additive effect with regard to cardiovascular risks; in these populations, efforts should be made to improve both sleep quality and sleep duration for secondary cardiovascular prevention.Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000040701.