Chronic stress-induced cardiac hypertrophy remains a critical precursor to heart failure, with current therapies limited by incomplete mechanistic targeting. Cyclin-dependent kinases (CDKs), pivotal regulators of cell cycle and stress signaling, are emerging therapeutic targets in cardiovascular pathologies. Using bioinformatics analysis of human hypertrophic cardiomyopathy data sets (GSE5500, GSE136308) and a murine transverse aortic constriction (TAC) model, we investigated the therapeutic effects of the CDK inhibitor R547 (10 mg/kg, intraperitoneal every 3 days) on pressure overload-induced cardiac remodeling. Cardiac function was assessed by echocardiography, while molecular mechanisms were probed through proteomics and pathway analyses. CDKs were significantly upregulated in heart tissues of human heart failure and TAC mice. R547 treatment attenuated cardiac hypertrophy (↓37.7% cardiomyocyte cross-sectional area; P < 0.001) and fibrosis (↓70.8% collagen volume fraction; P < 0.05) versus TAC controls. Echocardiographic improvements included preserved left ventricular ejection fraction (66 ± 2.1% vs. 81 ± 4.9% in TAC; P < 0.05) and reduced ventricular wall thickening. Mechanistically, R547 concurrently inhibited PI3K/AKT/mTOR hypertrophic signaling and TGF-β/Smad3 fibrotic pathways, with corresponding downregulation of ANP, BNP, β-MHC, and collagen I. This study identifies CDK-driven signaling as a nodal regulator of pressure overload cardiomyopathy. The dual inhibition of PI3K/AKT and TGF-β/Smad3 pathways by R547 demonstrates superior efficacy in mitigating both structural and functional deterioration, positioning it as a promising multifactorial therapy for cardiac hypertrophy.

Previously, we showed that vasorelaxant effects of trans-4-methoxy-β-nitrostyrene (T4MN) in rat aorta were mediated through stimulation of the soluble guanylate cyclase (sGC) pathway. The present study tested the hypothesis that bonding of the methoxy electron-donor group at the meta-position instead of the para-position into the aromatic moiety might enhance the interaction of the nitroderivative with sGC. For this purpose, vascular effects of the trans-3-methoxy-β-nitrostyrene (T3MN) were studied in rat aorta. In endothelium-intact preparations, T3MN was 100 times more potent as a vasorelaxant than its stereoisomer, T4MN. T3MN-induced vasodilatory effects remained unaffected by indomethacin, MDL-12,330A or glybenclamide but were significantly reduced by endothelium removal, L-NAME, ODQ, LY294002, TEA, 4-AP, and apamin. Under Ca2+-free conditions, T3MN was unresponsive to transient contractions evoked by caffeine, whereas it inhibited contractions induced by (i) the protein kinase C activator phorbol 12-myristate 13-acetate, (ii) the tyrosine phosphatase inhibitor sodium orthovanadate, (iii) exogenous calcium influx via receptor- or voltage-operated Ca2+ channels and (iv), in an ODQ-preventable manner, those evoked by PHE or Ca2+ influx through stores-operated Ca2+ channels activated by thapsigargin-induced Ca2+ store depletion. In conclusion, T3MN induced a potent vasorelaxant effect that seems to be mediated partly by an endothelium-dependent mechanism involving activation of the Akt/eNOS/NO pathway and partly by an endothelium-independent mechanism through activation of the sGC/cGMP/PKG pathway in vascular smooth muscle, leading to inhibition of Ca2+ influx from the extracellular milieu and IP3-sensitive intracellular Ca2+ release as well as activation of potassium channels.

Cardiometabolic complications represent a leading cause of morbidity and mortality among cancer survivors, who increasingly face a dual burden of residual oncologic risk and rising cardiovascular (CV) vulnerability. The shared pathophysiologic mechanisms linking cancer, dyslipidemia, insulin resistance, and chronic inflammation foster an environment conducive to accelerated atherosclerosis, heart failure, and metabolic dysregulation. Hyperglycemia and hyperlipidemia, frequently coexisting in long-term cancer survivors, especially those exposed to cardiotoxic chemotherapies, hormonal therapies, or corticosteroids, are key drivers of adverse CV outcomes. Despite this recognized risk, comprehensive preventive strategies in cardio-oncology remain limited and often rely on conventional therapies insufficient to fully address the complexity of cardiometabolic disease in this population. Notably, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have emerged as powerful tools in CV risk reduction. SGLT2i have demonstrated robust benefits in heart failure, renal protection, and glycemic control, while PCSK9i provide profound and sustained reductions in low-density lipoprotein cholesterol, with emerging pleiotropic anti-inflammatory and antiatherosclerotic effects. We propose that a combinatorial strategy integrating SGLT2i and PCSK9i may offer synergistic protection against the intertwined cardiometabolic risks seen in cancer survivors. This approach targets multiple mechanistic pathways, glucose and lipid metabolism, vascular inflammation, endothelial dysfunction, and organ remodeling, potentially redefining the standard of care in high-risk cardio-oncology populations. Further clinical investigation is warranted to validate this hypothesis and establish optimal therapeutic protocols.

Cardiorespiratory fitness (CRF) in heart failure (HF) declines with age. Interleukin-1 is a proinflammatory cytokine involved in aging and HF. We aimed to determine the changes in CRF before and after treatment with anakinra, recombinant interleukin-1 receptor antagonist, in patients with HF stratified according to age younger and older than 60 years in phase II clinical trials. We analyzed data from 73 patients [37 (51%) female], 49 (67%) patients <60 years and 24 patients (33%) ≥60 years. All patients received anakinra 100 mg subcutaneously daily for a median of 4 (interquartile range from 2 to 12) weeks. We measured peak oxygen consumption (VO 2peak ) and high-sensitivity C-reactive protein (hsCRP). When compared with older patients, younger patients had higher baseline peak VO 2 [15.2 (12.4-17.7) vs. 12.4 (10.3-14.3) mL·kg -1 ·minute -1 , P = 0.001], yet no significant differences in hsCRP [6.6 (3.6-16.6) vs. 5.2 (2.7-11.2) mg/L, P = 0.18]. In both groups, anakinra decreased hsCRP [<60 years: -3.6 (-8.1 to -1.9) mg/L; P < 0.001; ≥60 years: -2.7 (-9.0 to -1.4) mg/L; P < 0.001] and increased peak VO 2peak [<60 years: +0.5 (-0.9 to 2.5) mL·kg -1 ·minute -1 ; P = 0.036; ≥60 years: +1.1 (0.2-2.3) mL·kg -1 ·minute -1 ; P < 0.001]. No significant differences in changes across time were observed between the age groups. Older patients with HF have a greater baseline impairment in CRF than younger patients despite similar levels of systemic inflammation, and they seem to have a similar improvement in CRF after treatment with anakinra. The lack of an active control group (placebo) is a significant limitation and additional studies are needed to validate and expand these findings assessing clinical outcomes.

Inflammation is increasingly recognized as a key mechanism driving impaired cardiac function and reduced cardiorespiratory fitness in heart failure. Interleukin-1 blockade with anakinra has shown consistent anti-inflammatory effects but inconclusive benefits on functional capacity in prior trials. In a pooled analysis of 73 patients, Hogwood et al reported that anakinra reduced hsCRP and modestly improved peak VO 2 across both younger (<60 years) and older (≥60 years) patients, with no difference in magnitude of benefit between age groups. These findings indicate that the functional response to IL-1 inhibition is preserved across age groups. Although the results are limited by small sample size, heterogeneous treatment duration, and lack of placebo control, they highlight the importance of age-stratified research and provide a rationale for larger randomized studies assessing long-term clinical outcomes.

Heart failure with preserved ejection fraction (HFpEF) is a prevalent and multifaceted clinical syndrome, often underdiagnosed because of its heterogeneous presentation and overlapping comorbidities. Recent randomized trials have demonstrated the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing heart failure hospitalizations and cardiovascular mortality. In this review, we analyze the main challenges of HFpEF diagnosis and discuss current diagnostic algorithms. Based on recent evidence and recommendations, we propose a possible way to simplify and accelerate the diagnostic process of HFpEF, to support an early initiation of disease-modifying therapies. An interactive web-based version of the proposed algorithm is available at www.hfpefdiagnosis.com for research or exploratory purposes.

Preeclampsia is a hypertensive disorder of pregnancy associated with substantial maternal morbidity and long-term cardiovascular risk, but the consistency of echocardiographic remodeling remains unclear. We conducted a mega-meta-analysis of left ventricular function and geometry, enabled by a large language model based suite of tools. A PROSPERO-registered review (CRD420251109103) searched PubMed, Scopus, and Embase without date limits. Synthesa AI screened more than 18,000 abstracts, extracted data, assessed risk of bias, and generated Bayesian analytic code, with all outputs validated by human reviewers. Seventy-five studies including met eligibility criteria. Preeclampsia was associated with a small but statistically significant reduction in ejection fraction (mean difference -0.87%, 95% CrI -1.58 to -0.16) and a clinically meaningful impairment in global longitudinal strain (-3.08%, 95% CrI -4.13 to -2.06). Left ventricular mass index was substantially higher in the preeclampsia group (+13.10 g/m2, 95% CrI 10.06 to 16.21), as was relative wall thickness (+0.062, 95% CrI 0.042 to 0.081), whereas fractional shortening showed no significant difference (-0.60%, 95% CrI -2.15 to +0.86). Moderator analyses revealed that BMI and parity significantly influenced strain, while gestational age at diagnosis accounted for nearly all variance in ventricular mass. This mega-meta-analysis defines a remodeling phenotype of preserved ejection fraction, impaired strain, and hypertrophic adaptation consistent with subclinical systolic dysfunction. Equally, it demonstrates the transformative role of LLM-based tools, showing that evidence syntheses of this magnitude can be automated, scaled, and standardized in ways previously unattainable.

Inclisiran, the first small interfering RNA (siRNA) lipid lowering drug, has reported muscle adverse events (MAEs), but long-term safety is unclear. This study is based on data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering the period from December 22, 2021, to December 31, 2024. MAEs signals of Inclisiran were mined by calculating reporting odds ratios (ROR) and the Bayesian confidence propagation neural network (BCPNN). Stratification analysis, serious and non-serious cases were compared, and signals were prioritized using a rating scale. Additionally, we employed mendelian randomization (MR) to investigate the causal relationship between Inclisiran and musculoskeletal system diseases. Among 4,685 adverse event reports of Inclisiran, 523 MAEs reports were found. Inclisiran has potential signals in terms of MAEs (ROR:7.51, 95%CI:6.86-8.23; IC:2.75, IC025:2.60). Inclisiran-related MAEs signal intensity was lower compared to statins (ROR:0.40, 95%CI:0.37-0.44), but higher than other PCSK9 inhibitors (ROR:5.85, 95%CI:5.26-6.50). Combination with statins/fibrates rarely increased MAE risk or signal strength. Notably, the signal between Inclisiran and MAEs can still be detected when stratified by gender, age, reporter type and serious report. Among the 7 PTs identified, muscle spasms and myalgia are of moderate clinical priority signals and should be given particular attention. MR analysis further validated that Inclisiran may be potentially associated with an increased risk of musculoskeletal system diseases. This study revealed that MAEs associated with Inclisiran. Additional laboratory and clinical monitoring should be considered for patients taking Inclisiran for timely diagnosis and management of MAEs.

Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG datasets. Unsupervised clustering categorized HF patients into LacRG-based subgroups. A LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing (scRNA-seq) expression patterns. HF mouse models were constructed and verified for LacRGs expression. In 200 HF vs. 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunological features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (AUCs: 0.999, 1.000, 0.744). scRNA-seq (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T cell, and NK cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External datasets (GSE46224, GSE116250) identified six hub gene-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. Additionally, analysis of Zenodo.4114617 further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and six hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF via immune microenvironmental mechanisms.

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease marked by extracellular matrix deposition, oxidative stress, and profound microvascular remodeling. Endothelial dysfunction, particularly via endothelial-to-mesenchymal transition (EndMT), has been implicated in fibrotic progression but remains insufficiently characterized. In this study, human pulmonary microvascular endothelial cells (HPMECs) were exposed to 5% serum from patients with IPF or healthy donors to model disease-associated vascular alterations. IPF serum stimulated a robust increase in reactive oxygen species (ROS) production and proliferation, concomitant with downregulation of endothelial markers (von Willebrand factor, CD31) and upregulation of mesenchymal markers (α-smooth muscle actin, collagen I), consistent with EndMT induction. Notably, pharmacological inhibition of NADPH oxidase (NOX) with diphenyleneiodonium markedly attenuated ROS generation, phenotypic switching, and junctional disruption observed under IPF serum exposure. Similarly, inhibition of protein kinase C (PKC) by chelerythrine suppressed ROS production and proliferative responses, implicating PKC-dependent pathways in ROS-mediated endothelial injury. Immunofluorescence analyses confirmed structural reorganization, revealing loss of endothelial junctional integrity and accumulation of mesenchymal proteins, both reversed by NOX inhibition. Together, these findings establish IPF serum-derived factors as potent drivers of endothelial oxidative stress and EndMT via NOX- and PKC-dependent mechanisms. Targeting these redox-sensitive pathways may represent a promising therapeutic strategy to mitigate vascular dysfunction, tissue remodeling, and disease progression in IPF.

Hypertension is associated with significant changes in the vascular system and is an important risk factor for cerebrovascular disease. Moreover, hypertension is a dominant determinant of heart failure, and both contribute to the development of cognitive decline and dementia. Despite these links, there is limited understanding of how hypertension and risk of heart failure influence the structure, function and mechanical properties of cerebral arterioles. We examined the effects of hypertension, alone or with predisposition for heart failure, on penetrating arterioles. Using arterioles isolated from rats with genetic hypertension, structural properties, mechanical behavior, and functional responses were characterized by pressure myography. Penetrating arterioles from spontaneously hypertensive heart failure (SHHF) rats exhibited eutrophic remodeling, reduced compliance, and increased stiffness. In contrast, penetrating arterioles from spontaneously hypertensive rats (SHR) were more compliant and less stiff despite similar structural remodeling. Increased collagen deposition in SHHF arterioles was consistent with reduced compliance, whereas SHR arterioles had unchanged collagen-elastin ratio. SHHF and SHR arterioles were functionally different when exposed to pharmacological mediators of vasomotor response. Following exposure to endothelial NMDA receptor co-agonists, glutamate and D-serine, vasorelaxation was reduced in SHHF rats but not in SHR relative to normotensive controls. In contrast, acetylcholine-induced vasorelaxation was maintained in SHHF rats but enhanced in SHR. Furthermore, sodium nitroprusside caused vasorelaxation in normotensive arterioles, whereas vasoconstriction was observed in both hypertensive strains. Therefore, penetrating arterioles undergo compensatory adaptations in hypertension, but not when there is a genetic propensity for developing heart failure.

Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge, as blood flow restoration can exacerbate tissue damage. Apelin, an endogenous peptide acting via the APJ receptor, has demonstrated cardioprotective effects in experimental models. The APJ receptor, a G-protein-coupled receptor (GPCR) widely expressed in cardiovascular tissues, mediates vasodilation, cardiac contractility, and angiogenesis. This systematic review and meta-analysis evaluates its efficacy in myocardial I/R injury. A systematic search in Medline (PubMed), Embase, Scopus, and Web of Science was conducted up to 2024, identifying rodent studies of cardiac I/R injury (Langendorff/in vivo) treated with Apelin. Studies on pre-treatment or chronic ischemia were excluded. A random-effects meta-analysis reported standardized mean differences (SMD) with 95% confidence intervals (CI), assessing heterogeneity using the I2 statistic. From 1,765 records, 26 preclinical studies met inclusion criteria. Apelin significantly improved +LVdp/dtmax, -LVdp/dtmax, LVEDP, LVESP, LVEF, LVDP×HR, CO, SV, Coronary Flow, and LVDP, but did not affect HR, MAP, LVEDV, or LVESV. It reduced infarct size, fibrosis, LDH, MDA, and apoptosis (TUNEL assay), while also reducing CK-MB and improving ATP, EC, and PCr. Meta-regression indicated most outcomes were dose-independent, although a few (e.g., MAP, TUNEL) showed dose-related responses. The risk of bias was high in most studies, and publication bias was observed for some outcomes. Apelin exerts cardioprotective effects in rodent I/R models, enhancing cardiac function and metabolism while reducing infarct size, oxidative stress, and apoptosis. Further standardized preclinical and clinical studies are warranted to optimize dosing protocols and define therapeutic applicability.

Diabetic cardiomyopathy (DCM), a global cardiovascular complication of diabetes, is characterized by concurrent diastolic and systolic ventricular dysfunction that progressively leads to heart failure, arrhythmias, and cardiogenic shock. Despite advancements in modern therapeutics, DCM continues to exhibit high mortality rates, underscoring the critical need for novel preventive and therapeutic strategies. In recent years, Traditional Chinese Medicine (TCM) has gained prominence in DCM management due to its established safety profile and emerging evidence of clinical efficacy. Current research focuses on elucidating TCM's multi-target mechanisms, particularly its regulatory effects on metabolic homeostasis, oxidative stress, and inflammatory pathways - key pathological processes in DCM progression. This review systematically investigates the latest advancements in TCM for DCM management through three principal dimensions: First, it synthesizes the etiological understanding of DCM from both TCM theory and modern medical perspectives, highlighting their complementary mechanisms in disease pathogenesis. Second, it critically evaluates the therapeutic potential of clinically validated Chinese herbal agents, focusing on their bioactive compounds that target myocardial energy metabolism and oxidative stress pathways. Third, it systematically summarizes evidence-based TCM therapeutic strategies. By consolidating existing evidence, this review aims to provide a rigorous assessment of TCM's clinical value in DCM management, while proposing standardized frameworks to facilitate deeper integration of TCM principles with evidence-based cardiology practice.

Triptolide (TP) is widely used clinically for multiple diseases, but its cardiotoxicity significantly limits its clinical applications. The underlying mechanisms of its cardiotoxicity are still unclear. Mitochondria are crucial for cellular survival and function. Here, we found that TP induced mitochondrial dysfunction and apoptosis of cardiomyocytes, which might be the key process underlying TP-induced cardiotoxicity. Moreover, the expression of prohibitin1 (PHB1) was significantly decreased after TP treatment in a time-dependent manner. Overexpression of PHB1 alleviated mitochondrial dysfunction and inhibited apoptosis of cardiomyocytes after TP treatment. Mechanistically, PHB1 might regulate mitochondrial dynamics, which maintain normal mitochondrial function. Based on the above results, PHB1 might be a potential therapeutic target for TP-induced cardiotoxicity.

This study investigates the cardioprotective potential of soluble guanylate cyclase (sGC) and its α1 subunit in myocardial ischemia/reperfusion (I/R) injury, along with the underlying mechanisms. We used a model involving Sprague Dawley rats undergoing left coronary artery I/R, complemented by H9c2 cell cultures in an anaerobic environment to simulate I/R conditions in vitro. Both loss- and gain-of-function approaches were applied to assess the role of sGC and its α1 subunit in myocardial I/R injury. Immunofluorescence microscopy, Western blotting, and RT-PCR were employed to examine how sGC and its α1 subunit influence oxidative stress and apoptosis. Our results showed that sGC and its α1 subunit were associated with reduced I/R injury severity in both in vitro and in vivo settings. Overexpression of sGC decreased cardiomyocyte apoptosis and maintained mitochondrial function during I/R, while sGC silencing heightened oxidative stress and apoptosis. Additionally, pharmacological modulation of sGC impacted signaling in the PGC-1α/UCP2 pathway. These findings demonstrate the crucial role of sGC and its α1 subunit in protecting against cardiac injury during I/R, suggesting that sGC-targeted therapies could offer promising strategies for managing myocardial damage associated with I/R injury.

Fulminant myocarditis (FM) is a critical condition with high mortality. Interleukin-1 (IL-1) is a key mediator of myocardial inflammation. We describe the case of a 19-year-old male with FM, hemodynamic deterioration refractory to standard treatment, and a marked systemic inflammatory response. The introduction of anakinra, an IL-1 receptor antagonist, led to rapid clinical, hemodynamic, and laboratory improvement. A literature review identifies other cases of severe/fulminant myocarditis with hyperinflammation that benefited from IL-1 blockade, despite heterogeneous etiologies. These data suggest that anakinra could be a valuable rescue therapeutic option in selected patients with FM and hyperinflammation. Randomized trials are needed to confirm the role of IL-1 blockade in this high-risk population, focusing on the pharmacology of the immune response.