Protección miocárdica

Int J Mol Med. 2025 Dec;56(6):211. doi: 10.3892/ijmm.2025.5652. Epub 2025 Oct 3.

ABSTRACT

The apelin system plays a significant role in central blood pressure regulation, but its role in the neural control of myocardial protection remains poorly understood. The present study evaluated the effects of apelin‑13 in the paraventricular nucleus (PVN) on myocardial infarction (MI). In a male rat MI model, apelin‑13 expression was decreased in PVN, while Vasopressin 1a (V1a) receptor expression was increased in both PVN and nucleus tractus solitarii (NTS) and GABAA receptor (GAR)γ2 expression was increased in NTS. Cardiac function was assessed after microinjection of apelin‑13 or gene transfer of apelin‑13 into the PVN. Apelin‑13 overexpression in PVN markedly improved MI cardiac function, as evidenced by left ventricular end‑diastolic diameter, left ventricular end‑systolic diameter, left ventricular ejection fraction and left ventricular fractional shortening, along with decreased plasma noradrenaline and increased vasopressin levels. Mechanistically, both TGF‑β/Smad signaling and Bax/Bcl‑2 expression were implicated in heart tissue. Additionally, serum levels of four parasympathetic neuropeptides (somatostatin, cholecystokinin, glucagon‑like peptide‑1 and vasoactive intestinal peptide) were elevated in parallel with cardiac function improvement. Notably, V1a receptor antagonist administration in PVN/NTS or GAR agonist treatment in NTS attenuated the cardioprotective effects of apelin‑13. These findings demonstrated that PVN apelin‑13 overexpression improves cardiac function through V1a receptors (PVN/NTS) and GARγ2 (NTS), involving both parasympathetic neuroendocrine activation and modulation of myocardial apoptotic/inflammatory pathways. The present study provided novel insights into neural mechanisms of cardiovascular regulation.

PMID:41041849 | PMC:PMC12494304 | DOI:10.3892/ijmm.2025.5652

J Soc Cardiovasc Angiogr Interv. 2025 Aug 12;4(9):103867. doi: 10.1016/j.jscai.2025.103867. eCollection 2025 Sep.

ABSTRACT

BACKGROUND: The 30-day Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) has been used to risk-stratify patients undergoing transcatheter aortic valve replacement (TAVR). Whether surgical mortality risk predicts stroke and neurocognitive outcomes following TAVR is unknown. We evaluated the association between STS-PROM and clinical outcomes, including stroke, acute brain injury on diffusion-weighted magnetic resonance imaging (DW-MRI), and cognitive decline in patients undergoing TAVR.

METHODS: Patient-level data were pooled from 4 prospective trials: (1) DEFLECT III (N = 87), (2) NeuroTAVR (N = 44), (3) REFLECT I (N = 214), and (4) REFLECT II (N = 258). All studies included patients undergoing TAVR with a protocol-mandated predischarge DW-MRI and serial cognitive and neurologic assessments. All patients were evaluated by a board-certified neurologist at baseline, postprocedure, and 30 days. Clinical outcomes, including stroke, cognitive decline (Montreal Cognitive Assessment score), death, myocardial infarction, vascular, and bleeding complications were adjudicated by the same clinical events committee. Imaging analysis was performed by a single core laboratory using identical methods. The DW-MRI measures included total lesion number, individual lesion volume, and total lesion volume. Outcomes were compared between low (STS <4), intermediate (STS 4-8), and high (STS >8) risk groups.

RESULTS: In total, 537 of 603 patients with DW-MRI and complete STS assessment undergoing transfemoral TAVR were included in this pooled analysis, of which 253 (47%) were low risk, 198 (37%) intermediate risk, and 86 (16%) high risk patients. At 30 days, high risk patients had higher rates of all-cause and cardiovascular mortality, myocardial infarction, acute kidney injury, bleeding, and vascular complications. Rates of stroke, disabling stroke, DW-MRI measures of brain injury, and cognitive decline were similar across risk categories.

CONCLUSIONS: This pooled analysis demonstrates that the STS score does not predict stroke, cognitive decline, or acute brain injury after TAVR.

PMID:41040451 | PMC:PMC12485508 | DOI:10.1016/j.jscai.2025.103867

Cardiovasc Res. 2025 Oct 3:cvaf165. doi: 10.1093/cvr/cvaf165. Online ahead of print.

ABSTRACT

AIMS: T cells drive adverse cardiac inflammation and ischemia-reperfusion injury following myocardial infarction (MI). Here, we aimed to test the extent to which T cell inhibition protected cardiac function following MI in mice.

METHODS AND RESULTS: Cardiac ischemia-reperfusion injury (CIRI), mimicking MI with successful reperfusion therapy, was induced in C57BL/6J mice via temporary surgical ligation of the left anterior descending artery. T cell inhibition was achieved using abatacept, an FDA-approved CTLA-4-Ig fusion protein. Multiple treatment strategies were assessed, ranging from prolonged treatment across 4 weeks to short-term treatment, also with delayed time-to-intervention. Cardiac function was assessed using echocardiography, including strain analysis. Impacts on the cardiac and systemic immune response were assessed using flow cytometry. CIRI-induced robust CD4+ biased T cell activation in the heart within 7 days. Treatment with abatacept significantly preserved key echocardiographic metrics of cardiac function. This treatment coincided with near-complete inhibition of the cardiac T cell response, as well as reductions in innate inflammatory cells. Collectively, this demonstrated a central mechanistic role for T cell activation post-MI with reperfusion. Evaluation of short-term intervention strategies further demonstrated sustained preservation of cardiac function even where treatment was delayed by 24 h. Mechanistically, our data indicate that over 50% of lost cardiac function post-MI with reperfusion is T cell dependent.

CONCLUSION: T cell co-stimulation leading to activation is a central driver of the cardiac immune response following MI with reperfusion. The inhibition of this axis significantly protected against CIRI and preserved cardiac function. Ultimately, we highlight T cell immunomodulation and abatacept as highly promising approaches for clinical translation.

PMID:41039954 | DOI:10.1093/cvr/cvaf165

Sci Rep. 2025 Oct 2;15(1):34400. doi: 10.1038/s41598-025-17345-y.

ABSTRACT

Indobufen is a potential antiplatelet drug; the aim of this study was to investigate the pharmacodynamic effects and potential mechanisms of indobufen in a myocardial ischemia/reperfusion (I/R) injury rat model, providing another effective option for the pharmacological prevention of myocardial infarction. In the in vivo model, rats were orally administered indobufen daily. On the fifth day, after 30 min of occlusion of the left anterior descending coronary artery, the rats were reperfused for 2 h. In the in vitro model, the drug was incubated with H9C2 cells for 24 h before the establishment of an oxygen-glucose deprivation/reperfusion (OGD/R) model. Then, the hearts of the rats were collected for TTC staining and myocardial histopathological examination. Creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels in rat plasma and cell supernatants were detected with the appropriate kits. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and apoptosis-related proteins were used to assess myocardial apoptosis. Western blotting, immunohistochemistry or immunofluorescence were used to detect the expression of p-Akt/Akt and p-eNOS/eNOS. Our results suggest that indobufen ameliorates I/R injury by reducing infarct size, attenuating oxidative stress injury, and inhibiting cardiomyocyte apoptosis. In addition, indobufen increased the expression of p-Akt and p-eNOS in myocardial tissues and H9C2 cells, and LY294002, a specific inhibitor of the PI3K pathway, reversed these protective effects. In conclusion, indobufen reduced myocardial apoptosis and oxidative stress by the PI3K/Akt/eNOS pathway, thereby attenuating MI/R injury and improving cardiac function.

PMID:41038936 | PMC:PMC12491498 | DOI:10.1038/s41598-025-17345-y

Am Heart J Plus. 2025 Sep 17;59:100619. doi: 10.1016/j.ahjo.2025.100619. eCollection 2025 Nov.

ABSTRACT

Heart failure (HF) is among the leading diagnoses for those admitted to the hospital over 65 years old in high-income countries. While there is strong evidence for the use of pharmacological interventions in the treatment of HF with reduced ejection fraction (HFrEF), there is limited evidence for a similar approach to decreasing morbidity and mortality of HF with preserved ejection fraction (HFpEF). This discrepancy highlights the importance of lifestyle change (i.e. diet) for prevention of HFpEF. Given the paucity of data on dietary predictors of HFpEF and the recent changes in diagnostic criteria, we set out to assess the associations of dietary and demographic predictors with HFpEF in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. We found that males in their fifties compared to age-matched females had worse measures of diastolic function (e' lateral: 8.47 ± 2.28 vs. 8.98 ± 2.49, p < .001) and myocardial shortening (i.e. GLS: -15.91 ± 2.73 vs -16.98 ± 3.1, p < .001). Each one point of GLS increase was associated with 12 % increase in risk of HFpEF, while HDL intake was found to be protective against HFpEF. We also found that higher dietary HDL intake when individuals were in their fifties was associated with higher (i.e. better) measures of both e' lateral and e' septal velocities. Our data indicate that GLS appears to be a robust predictor of HFpEF and is influenced by dietary behaviors across the lifespan that affect BMI in males and hypertension in females.

PMID:41035498 | PMC:PMC12483684 | DOI:10.1016/j.ahjo.2025.100619

Cardiovasc Diabetol. 2025 Oct 1;24(1):378. doi: 10.1186/s12933-025-02930-2.

ABSTRACT

BACKGROUND: Testosterone deficiency is common in men with diabetes. Effects of testosterone therapy on kidney failure and cardiovascular outcomes in diabetic men remain poorly understood. Our aim was to assess whether testosterone therapy is associated with reduced risk of acute kidney injury and kidney failure requiring replacement therapy in men with diabetes and hypogonadism compared to matched untreated men with diabetes.

METHODS: Participants were recruited from the TriNetX Research Collaborative network. We identified 26,027 diabetic men with hypogonadism treated with testosterone and matched them 1:1 using propensity score matching to 26,027 untreated diabetic men with hypogonadism. Primary outcomes were acute kidney injury and kidney failure requiring replacement therapy (dialysis or transplantation). Secondary outcomes included myocardial infarction, ischemic stroke, atrial fibrillation, and all-cause mortality. Cox proportional hazard models were used over a mean follow-up of 3.3 years.

RESULTS: Men had a mean age of 58 years (SD 12), with 71% being non-Hispanic White. Testosterone-treated men had significantly lower risk of acute kidney injury (HR: 0.93 [95% CI 0.87-0.98], p = 0.01) and kidney failure with replacement therapy (HR: 0.81 [95% CI 0.72-0.92], p = 0.001) compared to untreated men. Testosterone therapy was also associated with reduced risk of myocardial infarction (HR: 0.85 [95% CI 0.78-0.93], p < 0.0001), ischemic stroke (HR: 0.88 [95% CI 0.80-0.97], p = 0.01), atrial fibrillation (HR: 0.91 [95% CI 0.85-0.98], p = 0.01), and all-cause mortality (HR: 0.85 [95% CI 0.79-0.91], p < 0.0001).

CONCLUSIONS: In this large real-world cohort study, testosterone therapy in diabetic men with hypogonadism was associated with significant reductions in acute kidney injury, kidney failure requiring replacement therapy, major cardiovascular events, and total mortality. These findings suggest that testosterone therapy could be more readily considered for men with diabetes and hypogonadism as a potential intervention to prevent kidney injury.

PMID:41035033 | PMC:PMC12487499 | DOI:10.1186/s12933-025-02930-2

Int J Biol Macromol. 2025 Sep 29;330(Pt 1):148001. doi: 10.1016/j.ijbiomac.2025.148001. Online ahead of print.

ABSTRACT

Ganoderma lucidum polysaccharides (GLPs) are a diverse class of bioactive compounds abundantly present in the mycelia, fruiting bodies, and spores of Ganoderma lucidum (G. lucidum). In recent years, GLPs have attracted considerable attention owing to their broad pharmacological activities and favorable safety profile. Despite advances in therapeutic approaches that have improved survival rate, cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide. CVDs are characterized by a complex pathogenesis and multiple risk factors, including hyperglycemia, lipid metabolism disturbances, and chronic inflammation. Accumulating evidence has demonstrated that GLPs exhibit remarkable anti-inflammatory and antioxidant properties, while also exerting regulatory effects on glucose and lipid homeostasis. Additionally, GLPs have demonstrated therapeutic potential in ameliorating endothelial dysfunction, modulating angiogenesis, attenuating atherosclerosis, and mitigating chemical-induced cardiotoxicity. This review summarizes the fundamental pharmacological activities of GLPs and discusses their potential mechanisms in cardiovascular diseases, with the aim of providing a valuable reference for future research and clinical application.

PMID:41033521 | DOI:10.1016/j.ijbiomac.2025.148001

Xenobiotica. 2025 Oct 1:1-12. doi: 10.1080/00498254.2025.2567470. Online ahead of print.

ABSTRACT

Phytopharmacology has become a key approach for developing new therapeutic strategies by utilizing the diverse bioactive properties of plant-derived compounds to treat complex diseases, including cardiovascular disorders.Myocardial ischemia-reperfusion (I/R) injury presents a major challenge in the management of acute myocardial infarction by worsening myocardial damage through oxidative stress, apoptosis, and cellular senescence.Carvacrol, a monoterpenoid phenol present in plants such as Origanum vulgare, possesses potent antioxidant and anti-inflammatory properties.This study investigates carvacrol's cardioprotective effects in an H9C2 cardiac myoblast model of I/R injury.Cardiac myoblast cells were exposed to an ischemic buffer to simulate I/R conditions, with carvacrol administered at a sub-cytotoxic dose of 12.5 µg/ml prior to exposure. Carvacrol significantly enhanced cell viability by 77.37% restoration, reduced lactate dehydrogenase (LDH) release (from 330.5 ± 25.3 to 160.8 ± 15.7 U/ml, p < 0.01), suppressed reactive oxygen species (ROS) production, inhibited caspase-3 and -8 activities, and mitigated cellular senescence as evidenced by reduced β-galactosidase staining. Additionally, carvacrol restored the expression of the myogenin gene, which was downregulated by ischemic injury.These findings highlight carvacrol's antioxidant, anti-apoptotic, anti-senescence, and gene-regulatory properties, positioning it as a promising therapeutic candidate for mitigating myocardial I/R injury.

PMID:41030227 | DOI:10.1080/00498254.2025.2567470

Cardiovasc Diabetol. 2025 Sep 30;24(1):370. doi: 10.1186/s12933-025-02900-8.

ABSTRACT

BACKGROUND: Combination therapy with glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2i), and/or finerenone offers a strategy to reduce the risk of adverse cardiovascular and renal outcomes. This study aimed to quantify the cardiorenal benefits of combination regimens with GLP-1RA, SGLT2i, and/or finerenone versus corresponding monotherapies.

METHODS: MEDLINE and Embase were systematically searched, yielding four post hoc analyses of randomized controlled trials (RCTs) and ten observational studies that met prespecified inclusion criteria. Among RCTs, a random-effects meta-regression was performed to assess whether the effect of GLP-1RAs on cardiorenal outcomes differed based on baseline SGLT2i use. Additionally, for observational studies, random-effects meta-analyses were performed to estimate the effect of combination therapy versus monotherapy on the risk of cardiorenal outcomes.

RESULTS: Across RCTs, p for interaction was > 0.05 for major adverse cardiac events (MACE) (p = 0.730), cardiovascular (CV) mortality (p = 0.889), non-fatal myocardial infarction (MI) (p = 0.237), non-fatal stroke (p = 0.696), all-cause mortality (p = 0.682), heart failure (HF) hospitalization (p = 0.257), and renal composite outcome (p = 0.890), supporting that GLP-1RAs result in a consistent reduction in outcomes irrespective of baseline SGLT2i use. In observational trials, compared to SGLT2i monotherapy, GLP-1RA and SGLT2i combination therapy significantly reduced MACE (HR 0.59, 95% CI 0.47-0.75), MI (HR 0.73, 95% CI 0.61-0.88), stroke (HR 0.72, 95% CI 0.53-0.97), all-cause mortality (HR 0.57, 95% CI 0.48-0.67), and HF hospitalization/events (HR 0.71, 95% CI 0.59-0.86). Compared to GLP-1RA monotherapy, SGLT2i and GLP-1RA combination therapy significantly reduced CV mortality (HR 0.35, 95% CI 0.15-0.81), MI (HR 0.93, 95% CI 0.88-0.97), stroke (HR 0.92, 95% CI 0.88-0.96), all-cause mortality (HR 0.59, 95% 0.49-0.70), HF hospitalization/events (HR 0.84, 95% CI 0.81-0.88), and serious renal events (HR 0.43, 95% CI 0.23-0.80). Compared to either SGLT2i or finerenone monotherapy, SGLT2i and finerenone combination therapy significantly reduced all-cause mortality and major adverse kidney events.

CONCLUSION: Combination therapy with GLP-1RA, SGLT2i, or finerenone confers cardiorenal protection beyond monotherapy in T2D, as supported by concordant evidence from RCTs and large real-world cohorts. These findings support broader clinical adoption of dual-agent strategies but also underscore the need for dedicated prospective trials powered to assess hard clinical outcomes with dual-agent strategies.

PMID:41029853 | PMC:PMC12487346 | DOI:10.1186/s12933-025-02900-8

J Cardiothorac Surg. 2025 Sep 30;20(1):353. doi: 10.1186/s13019-025-03625-1.

NO ABSTRACT

PMID:41029744 | PMC:PMC12487582 | DOI:10.1186/s13019-025-03625-1

BMC Cardiovasc Disord. 2025 Sep 29;25(1):705. doi: 10.1186/s12872-025-05183-9.

ABSTRACT

BACKGROUND: Renal ischemic/reperfusion (I/R) injury leads to acute kidney injury with multiple organ damage. Klotho has anti-inflammatory and antioxidant capacities and protects the heart and kidneys against I/R injury. This study aimed to determine whether Klotho is involved in the cardioprotective effect of limb ischemic per-conditioning (LIPerC) during renal I/R injury.

METHODS: Sprague-Dawley rats were randomly divided into three groups: Sham, I/R underwent bilateral occlusions of the renal pedicles for 60 min followed by reperfusion for 24 h, and LIPerc + I/R, which underwent cyclic I/R of the left femoral artery performed during renal ischemia. After 24 h, plasma, urine, and kidney and heart tissue were collected. Renal and cardiac functional biomarkers, soluble Klotho, oxidative stress, and inflammatory mediators were assessed.

RESULTS: Renal I/R injury caused a decrease in soluble Klotho and increased blood urea nitrogen, creatinine, troponin I, and LDH (p < 0.01). Moreover, it established oxidative stress and histopathological changes in the kidney and myocardium. The levels of TNF-α and NF-κB were upregulated, and Klotho (p < 0.01) was downregulated in the post-I/R cardiac tissue. LIPerC improved the histopathological changes and suppressed the oxidative status and inflammation. LIPerC could not compensate for the Klotho expression in the heart tissue. However, correlations between plasma levels and heart expression of Klotho with oxidative and inflammatory signals could confirm the role of Klotho in the healing effect of LIPerC on remote cardiac injury.

CONCLUSION: LIPerC may potentially ameliorate the remote cardiac dysfunction induced by renal I/R injury by modulating oxidative and inflammatory signals associated with the Klotho protein.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12872-025-05183-9.

PMID:41023844 | PMC:PMC12482132 | DOI:10.1186/s12872-025-05183-9

Nat Commun. 2025 Sep 30;16(1):8680. doi: 10.1038/s41467-025-63749-9.

ABSTRACT

Myocardial ischemia (MI), caused by insufficient blood supply, is a pathological condition where cardiomyocytes lack oxygen and energy supply. Herein, we developed a natural photosynthetic system (HCU) consisting of chlorella pyrenoidosa (C. pyre), hyaluronic acid methacryloyl (HAMA) and degradable upconversion nanoparticles (UCNPs, NaCeF4:Yb,Tm,Zr). Upon near-infrared irradiation, HCU was photo-crosslinked in situ, thereby facilitating C. pyre photosynthetic oxygen generation within the myocardium. Concurrently, cytochrome c oxidase (CCO) in mitochondria was activated to enhance electron transport along the respiratory chain, synergistically boosting cardiac energy metabolism. Consequently, the ATP levels were elevated, and the hypoxic microenvironment was mitigated. In MI mouse models, echocardiography readings returned to normal levels, and the infarct size was significantly reduced following a 7-day treatment with HCU. Based on the photosynthetic system, this study proposes an in situ oxygen and energy metabolic regulation strategy for MI, holding certain inspiration for other ischemia diseases.

PMID:41028003 | PMC:PMC12485038 | DOI:10.1038/s41467-025-63749-9

Neoreviews. 2025 Oct 1;26(10):e660-e678. doi: 10.1542/neo.26-10-060.

ABSTRACT

Congenital diaphragmatic hernia (CDH) presents a complex challenge in neonatal care, requiring tailored pharmacological strategies to manage its distinct cardiorespiratory pathophysiology. CDH is commonly associated with pulmonary hypertension, impaired myocardial function, and adverse cardiorespiratory interactions, contributing to significant morbidity and mortality. Effective pharmacotherapy must address these interconnected factors while minimizing complications or side effects. Despite limited randomized controlled trial data specific to CDH, recent reports highlight the benefits of a precision medicine approach, focusing on individualized treatments based on evolving pathophysiology. Therapeutic interventions primarily involve pulmonary vasodilators, inotropes and vasopressors, prostaglandins, and corticosteroids; each agent has a distinct physiologic effect, and use needs to be tailored to the specific patient pathophysiology. Targeted neonatal echocardiography has emerged as a valuable tool for optimizing treatment decisions by providing real-time insights into ventricular performance and hemodynamic status. In this review, we explore the shift from a generalized pharmacological approach to targeted interventions based on evolving patient physiology. We discuss key therapeutic principles and the role of different drug classes in optimizing the management of infants with CDH throughout their intensive care journey.

PMID:41027625 | DOI:10.1542/neo.26-10-060

Am J Cardiol. 2025 Sep 28:S0002-9149(25)00590-9. doi: 10.1016/j.amjcard.2025.09.035. Online ahead of print.

ABSTRACT

Alcohol's impact on cardiovascular health is biphasic: low-to-moderate intake may appear protective, but excessive or binge drinking causes significant harm. This review examines mechanisms linking overconsumption to cardiovascular disease. Acute heavy drinking can trigger "Holiday Heart Syndrome," a transient atrial arrhythmia from electrophysiological instability, autonomic imbalance, and electrolyte shifts. Chronic excess contributes to alcoholic cardiomyopathy via oxidative stress, mitochondrial dysfunction, and impaired calcium handling. Alcohol also promotes atrial fibrillation and hypertension by inducing atrial fibrosis, neurohormonal dysregulation, and endothelial injury. Excessive intake accelerates coronary artery disease and type 2 diabetes through dyslipidemia, vascular inflammation, and insulin resistance, raising risks of stroke, heart failure, and myocardial infarction. While moderate consumption was once thought cardioprotective, emerging evidence-especially for atrial fibrillation-suggests risks may outweigh benefits. In conclusion, public health guidance increasingly emphasizes moderation, individualized assessment, and avoiding binge patterns, particularly for those with underlying cardiovascular vulnerabilities.

PMID:41027502 | DOI:10.1016/j.amjcard.2025.09.035

Phytomedicine. 2025 Sep 23;148:157317. doi: 10.1016/j.phymed.2025.157317. Online ahead of print.

ABSTRACT

BACKGROUND: Hyperlipidemia significantly exacerbates myocardial ischemia-reperfusion (I/R) injurfy through lipid metabolic dysfunction and lipotoxicity. Current evidence suggests that lipid droplet accumulation and impaired lipophagy represent critical pathological mechanisms underlying cardiac dysfunction in hyperlipidemic conditions. This study investigated the cardioprotective effects of asiaticoside (AS) against myocardial I/R injury in hyperlipidemic mice and elucidated its underlying mechanisms, emphasizing the AMPK/ORP8-mediated lipophagy pathway.

METHODS: Hyperlipidemic C57BL/6 mice were established using high-fat diet feeding and subjected to myocardial I/R injury. Mice received AS (12.5, 25, or 50 mg/kg) treatment for 4 weeks prior to surgery. In vitro experiments involved H9C2 cardiomyocytes treated with palmitic acid followed by hypoxia/reoxygenation. The role of AMPK/ORP8 signaling was evaluated using pharmacological modulators [AMPK activator (A-769662) and AMPK inhibitor (Compound C)] and genetic manipulation (ORP8 siRNA knockdown).

RESULTS: AS dose-dependently improved cardiac function parameters, reduced myocardial infarct size (LVEF and LVFS) and decreased triglyceride and cardiac injury biomarkers (cTnI, LDH, CK-MB) in hyperlipidemic I/R mice. Treatment with AS significantly reduced cardiac lipid accumulation and triglyceride content while enhancing lipophagy markers (LC3B-II and Beclin-1) and reducing p62 levels. Mechanistically, AS activated AMPK phosphorylation and upregulated ORP8 expression, which was accompanied by enhanced lipophagy flux. In H9C2 cells, AS protected against palmitic acid-induced lipotoxicity and H/R injury through AMPK/ORP8-dependent lipophagy activation. AMPK inhibition (Compound C) or ORP8 knockdown significantly attenuated AS's protective effects, while AMPK activation (A-769,662) potentiated these benefits, which were reversed to some extent by ORP8 silencing.

CONCLUSIONS: This study demonstrates that AS mitigates myocardial I/R injury in hyperlipidemic conditions by promoting lipophagy through the AMPK/ORP8 signaling axis. The AMPK/ORP8-lipophagy pathway represents a novel therapeutic target for metabolic cardiovascular diseases, and AS emerges as a promising cardioprotective agent with significant translational potential.

PMID:41027151 | DOI:10.1016/j.phymed.2025.157317

J Trace Elem Med Biol. 2025 Sep 26;92:127769. doi: 10.1016/j.jtemb.2025.127769. Online ahead of print.

ABSTRACT

BACKGROUND: Zinc is an essential nutrient implicated in cardiovascular health. This study investigates whether Zn2+ protects H9c2 cells by regulating mitochondrial biogenesis, dynamics, and calcium homeostasis via the mitochondrial calcium uniporter (MCU).

METHODS: The I/R model were established using simulated ischemia and reoxygenation as previous reported, and cells were then treated with MCU siRNA. Biochemical kits, inductively coupled plasma mass spectrometry (ICP-MS), RT-qPCR, and transmission electron microscopy were used to assess the effects of Zn2+ on cell viability, cytotoxicity, Zn2+ and ATP content, NAD⁺/NADH ratio, mtDNA copy number, and mitochondrial morphological changes following myocardial I/R. Confocal microscopy and fluorescence microscopy were used to observe the fluorescence changes of Zn2+, mitochondrial membrane potential, protein expression, and mitochondrial Ca2+. The effects of Zn2+ on protein expression levels were evaluated using molecular docking and Western blot analysis.

RESULTS: Compared to the Control group, the I/R group exhibited decreased cell viability, and increased cytotoxicity. Intracellular and mitochondrial Zn2+ levels were reduced, accompanied by mitochondrial dysfunction and an increase in mitochondrial Ca2+ content. The expression levels of mitochondrial biosynthesis proteins SIRT1, PGC-1α, NRF1, and TFAM, mitochondrial fusion proteins OPA1, MFN1, and MFN2, as well as MCUb gene and protein expression were downregulated. Conversely, the expression of mitochondrial fission proteins DRP1 and FIS1, along with MCU, MICU1, and MICU2 proteins, was upregulated. Exogenous Zn2+ treatment reversed these alterations. MCU silencing by siRNA further enhanced the protection effects of Zn2+.

CONCLUSIONS: I/R induced damage in H9c2 cells and mitochondrial dysfunction. Zn2+ protected H9c2 cells against I/R injury by regulating mitochondrial biogenesis, mitochondrial dynamics, and Ca2+ homeostasis via the MCU, with this protective effect potentially associated with the entire MCU complex.

PMID:41027049 | DOI:10.1016/j.jtemb.2025.127769

EuroIntervention. 2025 Sep 30:EIJ-D-25-00486. doi: 10.4244/EIJ-D-25-00486. Online ahead of print.

ABSTRACT

Coronary artery disease (CAD) is the leading cause of heart failure with reduced ejection fraction (HFrEF). Coronary artery bypass grafting (CABG) improves long-term mortality in HFrEF. Percutaneous coronary intervention (PCI) is often performed as an alternative to CABG in patients at high surgical risk. However, in patients with HFrEF and limited myocardial reserve, PCI may result in haemodynamic instability, increasing risk and precluding optimal revascularisation. Mechanical circulatory support (MCS) during high-risk PCI may enhance haemodynamic stability during the procedure and enable complete revascularisation. We thus performed the PROTECT IV trial to determine whether PCI with routine use of the Impella CP microaxial flow pump improves early and late outcomes in patients with HFrEF and complex CAD compared with PCI with or without use of an intra-aortic balloon pump (IABP). PROTECT IV is a prospective, multicentre, randomised, parallel-controlled, open-label, superiority trial with an adaptive design. Patients with complex CAD and left ventricular ejection fraction ≤40% (n=1,252) deemed at excessive surgical risk for bypass grafting by the Heart Team will be randomised in a 1:1 ratio to PCI with Impella CP versus PCI with or without an IABP. The primary endpoint is the composite of all-cause death, stroke, myocardial infarction, unplanned clinically driven revascularisation, durable left ventricular assist device implant or heart transplant, or other hospitalisation for cardiovascular causes at 3-year follow-up, with at least 1-year follow-up in all patients. Prespecified substudies will evaluate the impact of MCS on renal function, the procedural role of right heart catheterisation, and the utility of myocardial viability assessment. The PROTECT IV trial will determine whether routine MCS with Impella CP during high-risk PCI improves the prognosis of patients with complex CAD and HFrEF.

PMID:41024656 | DOI:10.4244/EIJ-D-25-00486

Eur J Med Res. 2025 Sep 29;30(1):903. doi: 10.1186/s40001-025-03144-8.

ABSTRACT

Myocardial infarction, a serious cardiovascular disease, is still a major cause of morbidity and mortality worldwide. Growth differentiation factor-15, a stress-responsive cytokine, has been involved in cardiac pathophysiology, but its exact role in myocardial infarction remains controversial. This study aimed to clarify the mechanisms underlying the cardioprotective effects of GDF-15 in myocardial infarction. By using a combination of in vivo and in vitro methods, including immunofluorescence staining, echocardiography, RNA sequencing, and high-resolution respirometry, we showed that GDF-15 expression is significantly upregulated in infarcted myocardium and its deficiency aggravates cardiac injury. Mechanistically, GDF-15 deficiency impairs mitochondrial function and energy metabolism under hypoxic stress, as evidenced by changes in mitochondrial membrane potential and respiratory parameters. Moreover, we identified that GDF-15 suppresses hypoxia-induced reactive oxygen species generation through activation of the AMPK signaling pathway. Therapeutic administration of exogenous GDF-15 reduces myocardial injury, hypoxic stress, and fibrosis after myocardial infarction, suggesting its potential as a therapeutic target. These findings collectively demonstrate that GDF-15 plays a crucial role in cardiac protection during myocardial infarction by regulating mitochondrial function, energy metabolism, and oxidative stress. Our results provide novel insights into the molecular mechanisms of GDF-15-mediated cardioprotection and suggest its potential as a therapeutic intervention for myocardial infarction. Future studies should focus on translational research to evaluate the clinical efficacy of GDF-15-based therapies in myocardial infarction patients.

PMID:41023695 | PMC:PMC12482560 | DOI:10.1186/s40001-025-03144-8

Nan Fang Yi Ke Da Xue Xue Bao. 2025 Sept 20;45(9):1850-1858. doi: 10.12122/j.issn.1673-4254.2025.09.05.

ABSTRACT

OBJECTIVES: To verify whether hesperetin (Hes) alleviates doxorubicin (DOX)-induced cardiotoxicity by reducing inflammation via regulating the AMPK/NLRP3 pathway.

METHODS: C57/bl6 mice and H9c2 cells treated with DOX to mimic cardiotoxicity were randomly divided into Sham (or control) group, DOX group, DOX+Hes group, DOX+Hes+compound C (CC, an AMPK inhibitor) group. Cardiac function and myocardial pathologies of the mice were evaluated, and the changes in H9c2 cell morphology and viability were assessed. Lactate dehydrogenase (LDH) activity in mouse myocardial tissues and H9c2 cells was measured using ELISA, and H9c2 cell apoptosis was detected with TUNEL staining. In both H9c2 cells and the myocardial tissues of the mice, cellular expression levels of TNF-α, IL-6 and IL-1β mRNAs and cleaved caspase-3, Bcl2, Bax, IL-1β, IL-18, p-AMPK, AMPK, p-mTOR, mTOR, NLRP3, ASC and caspase-1 proteins were detected using RT-PCR and Western blotting.

RESULTS: DOX treatment caused cell swelling, decreased cell viability and increased LDH activity in H9c2 cells, resulting also in significantly increased cell apoptosis and cleaved caspase-3 expression and decreased Bcl2/Bax ratio. The DOX-treated mice showed obvious myocardial fiber swelling and inflammatory infiltration, decreased cardiac function and significantly increased myocardial LDH activity. In H9c2 cells, DOX treatment significantly increased the mRNA expressions of TNF-α, IL-6 and IL-1β and protein expressions of IL-1β and IL-18, lowered the expressions of p-AMPK and p-mTOR, and increased the expressions of NLRP3, ASC and caspase-1. Hes treatment obviously reduced these toxic effects of DOX in H9c2 cells, but its protective effects were blocked by application of compound C.

CONCLUSIONS: Hes reduces DOX-induced cardiotoxicity by inhibiting inflammation via regulating the AMPK/NLRP3 pathway.

PMID:41022595 | PMC:PMC12479266 | DOI:10.12122/j.issn.1673-4254.2025.09.05

Am J Cardiol. 2025 Sep 27:S0002-9149(25)00595-8. doi: 10.1016/j.amjcard.2025.09.039. Online ahead of print.

ABSTRACT

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide proven cardiovascular benefits in type 2 diabetes mellitus (T2DM) and heart failure, but their effects in patients with peripheral artery disease (PAD) remain unclear. PAD is common in T2DM and increases the risk of adverse cardiovascular and limb outcomes. This meta-analysis assessed the impact of GLP-1 RAs on cardiovascular and limb-related outcomes in patients with T2DM and PAD. A systematic search of PubMed, Cochrane CENTRAL, ScienceDirect, and ClinicalTrials.gov was conducted through May 24, 2025. Primary outcomes included all-cause mortality (ACM) and cardiovascular mortality (CVM). Secondary outcomes were major adverse cardiovascular events (MACE),), myocardial infarction, stroke, major adverse limb events (MALE), glycemic control (HbA1c), body weight, and adverse events. Pooled risk ratios and mean differences were calculated using random-effects models. Six randomized controlled trials, including 7,645 participants met the inclusion criteria. GLP-1 RAs significantly reduced ACM (RR 0.83, 95% CI 0.70-0.99, p = 0.04, I² = 0%), MACE (RR 0.86, 95% CI 0.76-0.98, p = 0.02, I² = 0%), and improved HbA1c (MD -0.72%, p = 0.02), with no significant effect on weight, MALE, CVM, myocardial infarction, or stroke. In conclusion, GLP-1 RAs lower MACE and ACM in patients with T2DM and PAD but do not clearly benefit limb-specific outcomes, highlighting the need for larger, PAD-focused trials to clarify their role in limb protection.

PMID:41022246 | DOI:10.1016/j.amjcard.2025.09.039