Importance:Cardiovascular-kidney-metabolic (CKM) syndrome represents a syndromic continuum encompassing overlapping cardiovascular, kidney, and metabolic dysfunction. Hypertension is a central driver in the pathogenesis of CKM syndrome, promoting both kidney and metabolic deterioration, but little is known about the benefits of intensive blood pressure (BP) control across CKM syndrome stages. Objective:To evaluate CKM syndrome stage-specific outcomes, safety, and net clinical benefits associated with a comprehensive intensive BP intervention. Design, Setting, and Participants:This is a post hoc, secondary analysis of a cluster randomized clinical trial, the China Rural Hypertension Control Project (CRHCP), which was conducted between May 2018 and March 2023. Participants were adults aged 40 years or older with hypertension and CKM syndrome stages 2 to 4, which were defined using standard criteria. Stage 2 indicates that the patient has a metabolic risk factor; stage 3, subclinical cardiovascular disease or predicted 10-year risk of 20% or greater; and stage 4, clinical cardiovascular disease. In this analysis, participants had a median (IQR) follow-up of 3.02 (2.97-3.06) years. Data analysis was conducted from November 2024 to June 2025. Intervention:The comprehensive BP control strategy targeted a systolic BP less than 130 mm Hg and a diastolic BP less than 80 mm Hg. The intervention was delivered by trained nonphysician practitioners. Main Outcomes and Measures:The primary clinical outcome was a composite of major adverse cardiovascular events (stroke, myocardial infarction, heart failure, or cardiovascular death). Safety outcomes included hypotension, syncope, injurious falls, and kidney adverse events. A quantitative benefit-harm analysis was conducted to estimate net benefit associated with the intervention. Results:Among 33 736 participants (mean [SD] age, 63.0 [9.2] years; 20 677 [61.3%] women), 18 662 (55.3%) had stage 2 CKM syndrome (of whom 9526 [51.0%] received the intervention), 7984 (23.7%) had stage 3 (of whom 4032 [50.5%] received the intervention), and 7090 (21.0%) had stage 4 (of whom 3713 [52.4%] received the intervention). Treatment outcomes were generally consistent across CKM syndrome stages. Intensive BP control was associated with reduced cardiovascular events across all stages: in stage 2, the hazard ratio (HR) was 0.61 (95% CI, 0.50-0.73); in stage 3, the HR was 0.71 (95% CI, 0.58-0.84); and in stage 4, the HR was 0.67 (95% CI, 0.58-0.76). The risk of all-cause mortality was also lower in stage 2 (HR, 0.73; 95% CI, 0.57-0.90) and stage 3 (HR, 0.82; 95% CI, 0.68-0.96) but not in stage 4 (HR, 1.02; 95% CI, 0.84-1.20). Risk of hypotension increased across all stages (relative risk range, 1.79-2.34), while other adverse events, including kidney events, were similar between groups, despite some numerical variation across stages. Net benefits were favorable: stage 2, 1.58 (95% CI, 1.53-1.62); stage 3, 2.53 (95% CI, 2.42-2.64); and stage 4, 2.15 (95% CI, 2.04-2.26). Conclusions and Relevance:In this post hoc analysis of a cluster randomized clinical trial, a comprehensive intervention targeting BP less than 130/80 mm Hg demonstrated a favorable benefit-to-harm profile across CKM syndrome stages, with no clear heterogeneity across CKM syndrome stages. These findings provide the first trial-based evidence to guide CKM syndrome management and support scalable strategies for this high-risk, multimorbid population. Trial Registration:ClinicalTrials.gov Identifier: NCT03527719.

BACKGROUND:Cardiovascular health (CVH), as defined by the American Heart Association, provides a multidimensional framework for cardiovascular risk assessment. An increasing number of studies have developed intervention strategies based on CVH metrics. However, the multidimensional health change patterns resulting from these interventions and their relationship with clinical outcomes remain unclear. OBJECTIVES:The purposes of this study were to characterize patterns of change in CVH after intervention and to examine how multidimensional response domains derived from Life's Simple 7 (LS7) components relate to subsequent cardiovascular outcomes. METHODS:This post hoc analysis of the China Rural Hypertension Control Project included 26,700 participants. The intervention consisted of intensive blood pressure (BP) management delivered by nonphysician community health care providers, targeting <130/80 mm Hg. Changes in CVH over 0-36 months were longitudinally characterized across the LS7 components and grouped into BP, metabolic, and behavioral domains. Associations between domain-specific change patterns and subsequent cardiovascular outcomes (36-48 months) were evaluated using Cox proportional hazards models. RESULTS:Among 26,700 participants (age 62.5 ± 9.0 years; 63.0% women), the intervention improved LS7 scores at 36 months (net difference: 0.52; 95% CI: 0.38-0.66), with cardiovascular risk reduction observed among participants with improved CVH (HR: 0.71; 95% CI: 0.54-0.89). Longitudinal analyses showed sustained separation in BP between groups, with only modest and less-differentiated changes in other components. Across multidomain patterns, the greatest reduction in cardiovascular risk was observed among participants with BP improvement plus concurrent behavioral or metabolic gains (HR: 0.57; 95% CI: 0.30-0.84), followed by BP improvement alone (HR: 0.76; 95% CI: 0.55-0.98), with no significant benefit in other patterns. Net benefit analyses showed a consistent gradient across patterns. Mediation analyses indicated that BP accounted for the majority of the observed effect (67.5%), with modest contributions from behavioral (8.0%) and minimal contributions from metabolic domains. Results were consistent across sensitivity analyses. CONCLUSIONS:In this large community-based randomized trial, a scalable intervention delivered by nonphysician providers reduced cardiovascular risk, with the benefit primarily driven by BP, alongside modest contributions from behavioral and metabolic domains. This asymmetry highlights heterogeneous, domain-specific responses and provides a quantitative framework for understanding how multifaceted interventions translate into cardiovascular outcomes. (China Rural Hypertension Control Project (CRHC); NCT03527719).

Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, yet the epigenetic mechanisms that connect stress signals to durable transcriptional remodeling are incompletely understood. The BRG1/BRM-associated factor (BAF) chromatin remodeling complexes, mammalian members of the SWItch/sucrose non-fermentable (SWI/SNF) family, regulate chromatin accessibility by repositioning nucleosomes and by cooperating with transcription factors and histone-modifying enzymes. Recent structural and functional studies classify mammalian BAF complexes into three major subtypes including canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), with distinct subunit compositions and disease-relevant genomic targeting. In this review, we synthesize evidence linking BAF-dependent chromatin remodeling to myocardial infarction, ischemia-reperfusion injury, heart failure, diabetic cardiomyopathy, cardiac hypertrophy, arrhythmia, congenital heart disease, atherosclerosis, and aortic aneurysm. We emphasize subtype and subunit specific mechanisms, including inflammatory signaling, oxidative stress responses, fetal gene reactivation, ion-channel transcription, extracellular-matrix remodeling, and post-translational regulation of BAF-associated proteins. Finally, we discuss tissue-specific delivery, context-dependent effects, and the need to target disease-relevant protein-protein interfaces, providing potentially new theoretical basis and potential research directions for the prevention and treatment of CVD.

BACKGROUND:Natto Red Yeast Rice (NRYR) is a dietary supplement used to lower blood lipid. However, evidence on its effects on regulating lipid levels is limited. OBJECTIVES:The aim of this study was to assess whether NRYR can lower low-density lipoprotein cholesterol (LDL-C) levels and regulate other lipids, both alone and in addition to simvastatin. METHODS:We enrolled 1,110 participants who were randomized into 4 groups to receive a 3-month intervention of placebo, NRYR (1,950 mg/d), simvastatin (20 mg/d), or NRYR (1,950 mg/d) plus simvastatin (20 mg/d). The primary outcome was the change in LDL-C levels after 3 months, which were evaluated using linear mixed models. The primary analyses were conducted according to the modified intention-to-treat principle. Safety outcomes were also recorded. RESULTS:Significant reductions in LDL-C levels were observed in the NRYR, simvastatin, and combination group. The differences in the absolute/percent change in LDL-C levels from baseline to 3 months were -21.02 mg/dL (95% CI: -27.98 to -14.06 mg/dL)/-13.21% (95% CI: -17.88% to -8.54%), -25.80 mg/dL (95% CI: -32.64 to -18.97 mg/dL)/-17.08% (95% CI: -21.67% to -12.50%), and -32.74 mg/dL (95% CI: -39.74 to -25.73 mg/dL)/-21.22% (95% CI: -25.92% to -16.52%), respectively, compared with placebo (all P < 0.001). Compared with simvastatin alone, adding NRYR demonstrated a significant decrease in LDL-C levels with a net absolute/percent change of -7.95 mg/dL (95% CI: -13.79 to -2.11 mg/dL; P = 0.008)/-5.05% (95% CI: -8.87% to -1.24%; P = 0.009) at 1 month, but the effect was not significant at 3 months. Adverse event rates were similar across the 4 groups. CONCLUSIONS:NRYR alone lowered LDL-C levels, and its combination with simvastatin was associated with numerically but not significantly lower LDL-C levels than using simvastatin alone. (ChiCTR2200064214, ChiCTR2200064215).

Background and aims Despite advances in treating atherosclerotic coronary artery disease (ACAD), the risk of major adverse cardiovascular events remains high. We aimed to identify potential therapeutic targets for ACAD by integrating genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses. Methods Leveraging druggable genome data, cis-eQTL/cis-pQTL from blood and coronary artery tissue, alongside GWAS summary data for coronary atherosclerosis, we performed drug-target MR to identify causal genes for ACAD at both transcript and protein levels. Phenome-wide association (PheWAS), protein-protein interaction (PPI) networks, enrichment analysis, molecular docking, and in vivo experiments were also conducted. Results MR identified 57 blood cis-eQTL, 50 blood cis-pQTL, and 5 coronary artery cis-eQTL druggable genes potentially causal for coronary atherosclerosis. Notably, CES2 and TGFA showed consistent protective associations in both cis-eQTL and cis-pQTL analyses. Genetically elevated blood CES2 and TGFA levels were significantly associated with reduced ACAD risk (p < 0.001). PheWAS revealed no significant adverse effects for TGFA targeting. PPI and enrichment analyses highlighted metabolic pathways. Ten drugs targeting CES2 and three targeting TGFA were identified; in vivo experiments confirmed that atorvastatin, simvastatin, prasugrel, and vicagrel upregulate circulating CES2, while cetuximab and panitumumab increase circulating TGFA. Conclusions Genetically elevated circulating CES2 and TGFA levels are causally associated with reduced ACAD risk. Several candidate drugs capable of modulating these proteins might offer repurposing opportunities for ACAD prevention, warranting further mechanistic and clinical validation.

BACKGROUND:Intensive blood pressure (BP) control <130/80 mm Hg could bring additional benefits for cardiovascular disease (CVD). However, it is unclear whether intensive BP control remains effective and safe in the general hypertensive population with low diastolic BP (DBP) since a J-shaped relationship between DBP and CVD was observed. METHODS:This is a post hoc analysis of the China Rural Hypertension Control Project. Mixed-effect Cox proportional regression and generalised estimating equation models were used to determine HRs of outcomes by intensive BP control, stratified by baseline DBP quartiles. The interaction between intervention and DBP levels was assessed. RESULTS:A total of 33 288 participants were divided into four categories according to baseline DBP quartiles (Q1-Q4): DBP ≤80.7 mm Hg, 80.7-87.3 mm Hg, 87.3-94.3 mm Hg and >94.3 mm Hg, respectively. Compared with usual care, the intervention group reduced cardiovascular outcomes across DBP quartiles with adjusted HRs as follows: Q1: 0.69 (95% CI 0.58 to 0.83, p<0.001), Q2: 0.60 (95% CI 0.50 to 0.71, p<0.001), Q3: 0.59 (95% CI 0.49 to 0.71, p<0.001) and Q4: 0.67 (95% CI 0.56 to 0.78, p<0.001). There was no evidence of interaction between DBP quartiles and groups (p=0.987). The intervention group had a higher risk of hypotension, which was observed when stratifying by different baseline DBP levels. Intensive BP reduction did not increase the occurrence of injurious falls, syncope or adverse kidney outcomes. CONCLUSIONS:The intensive BP intervention led by non-physician providers is both effective and safe in reducing CVD and mortality across all baseline DBP groups.

BACKGROUND:Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias. METHODS:We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation. RESULTS:Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points; P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%; P<0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points; P=0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%; P<0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred. CONCLUSIONS:In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non-ion channel-based therapeutic strategy targeting the cardiac glutamatergic system. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06501638.

DNA polymerase gamma (Polγ), the sole polymerase for mitochondrial DNA (mtDNA), emerges as a critical regulator of metabolism-associated senescence. While lysine acetylation represents a key post-translational modification (PTM) influencing mitochondrial function, its mechanistic role in Polγ-mediated vascular aging remains undefined. Through combinatorial approaches employing in vitro acetylation models and POLG D257A/D257A mice, a validated model of mitochondrial dysfunction and senescence, we identify Lys 1039 (K1039) as a novel acetylation site which was dynamically regulated during aging process. Both D257A mutation-driven hyper-acetylation of Polγ K1039 reduced human aortic smooth muscle cell (HASMC) contractility, triggering pathological hyperproliferation and mitochondrial dysfunction, collectively culminating in premature cellular senescence. Pathological stimulation or genetic manipulation inducing hyperacetylation at K1039 disrupts Polγ's binding capacity with mtDNA. This molecular deficiency manifested functionally as compromised contractile performance in HASMCs and accelerated senescence phenotypes. Based on the above foundation and POLG D257A/D257A mice model, we demonstrated that D257A mutation reduced Sirt3-Polγ complex formation constituted the pathologically relevant molecular pathway driving aberrant acetylation homeostasis and leading to the senescence. Our findings establish a previously unrecognized regulatory axis wherein Polγ acetylation status at K1039 serves as a molecular switch coordinating mtDNA homeostasis, HASMCs functionality, and senescence progression. This mechanism might explain the remarkably consistent phenotypic manifestations of Polγ-induced dysfunction across diverse tissues and aging models. This work provides fundamental insights into the epigenetic-metabolic crosstalk governing vascular aging processes, providing a unifying framework for age-related vascular pathologies.

The predictive ability of triglyceride glucose (TyG)-body mass index (BMI) for hypertension onset is unclear. We aimed to explore this relationship among Chinese individuals. We included 3,729 individuals without hypertension from rural Chinese communities who underwent at least two rounds of interviews and physical examinations (2012-2015). The endpoint was new-onset hypertension. TyG-BMI was calculated using BMI, fasting blood glucose levels, and triglyceride levels; multivariate Cox regression was used for analysis. The participants (average age: 50.12 years; men: 42.26%; age range: 35-88 years) had a mean TyG-BMI of 205.95 (standard deviation: 37.05). During a median 2.59 years of follow-up, 743 (19.92%) participants developed hypertension. This incidence differed between the low, middle, and high TyG-BMI tertiles, at 14.80%, 21.08%, and 23.89%, respectively. Cox regression revealed that a high TyG-BMI was associated with the risk of new-onset hypertension compared with the lowest tertile (adjusted hazard ratio, 95% confidence interval: middle [1.29, 1.05-1.57]; high [1.32, 1.06-1.66]). For every 1.0-standard deviation increase in TyG-BMI, the risk of new-onset hypertension increased by 10% (1.10; 1.01-1.20). Thus, a high TyG-BMI was significantly associated with the risk of developing hypertension among Chinese individuals from rural communities, indicating that TyG-BMI may serve as a predictive indicator of hypertension onset.

INTRODUCTION:Blood pressure (BP) trajectories are associated with dementia, but their relevance across neurodegenerative and metabolic backgrounds in hypertensive populations remains unclear. METHODS:We analyzed 28,135 hypertensive participants from the China Rural Hypertension Control Project to estimate BP trajectories over 4 years using latent class group-based models. A nested case-control study was designed to assess interaction effects between BP trajectories and pTau217-lipid composite indices on dementia. RESULTS:Four BP trajectories were identified. In fully adjusted models, the high-stable diastolic BP trajectory showed the strongest association with dementia (odds ratio [OR] = 2.14, 95% confidence interval [CI] 1.74-2.63), followed by high-stable systolic BP trajectory (OR = 1.75, 95% CI 1.42-2.15). In the nested case-control analysis, significant interactions between pTau217-lipid composite indices and BP trajectories (high-declining and moderate-stable) were observed in relation to dementia. DISCUSSION:High-stable BP trajectories were consistently associated with dementia, whereas the associations between high-declining and moderate-stable BP trajectories varied according to pTau217-lipid composite indices.

Cardiovascular risk in metabolic disease persists long after the initiating metabolic abnormalities are corrected, a phenomenon termed metabolic memory. The DCCT/EDIC cohort is illustrative: early glycemic control produced cardiovascular protection that peaked within a decade and left a lasting legacy. The same strategy applied after prolonged hyperglycemia, however, has not reproduced this benefit. This conceptual Review proposes a framework in which such persistent risk arises from four distinct processes: encoded epigenetic memory, irreversible structural damage, chronic input from dysfunctional organs, and delayed tissue remodeling, each with a different therapeutic logic. Persistence of these encoded marks is established most directly in immune-lineage cells; its extension to cardiomyocytes remains a working hypothesis. Only encoded memory is accessible to chromatin-directed reversal, and only before metabolic stress exhausts the erasure machinery that keeps marks revisable, a time-dependence proposed to explain why early intervention succeeds where late intervention fails. Clinical efficacy therefore may depend on engaging the substrate maintaining pathology rather than normalizing a surrogate biomarker, a substrate-alignment principle consistent with the divergent outcomes of recent cardiometabolic trials. We apply the framework to atherosclerosis, heart failure, and diabetic cardiomyopathy, grade its claims by a three-tier evidence classification, and specify testable predictions that could refute it.

BACKGROUND:Hypertension is the leading risk factor for cardiovascular disease (CVD) worldwide. Implementation-based blood pressure (BP) control programs improve BP control and reduce CVD risk, but whether their benefits persist after withdrawal of trial-supported intervention components remains uncertain, especially when intensive BP control is targeted. In CRHCP (China Rural Hypertension Control Project), a nonphysician community healthcare provider (NPCHP)-led program with the intensive target of <130/80 mm Hg reduced CVD risk during the 4-year active intervention period. We extended follow-up for an additional 3 years to assess BP control and CVD outcomes over the 7-year overall period and during the 3-year posttrial period. METHODS:CRHCP was a cluster-randomized controlled trial conducted in rural China. Eligible participants were ≥40 years of age with BP ≥140/90 mm Hg or ≥130/80 mm Hg if at high CVD risk or receiving antihypertensive treatment. We randomly assigned 326 villages 1:1 to NPCHP-led intensive BP control or usual care. During the 4-year intervention, trained NPCHPs initiated and titrated antihypertensive medications using a standardized protocol under primary care physician supervision and provided coaching on home BP monitoring, lifestyle modification, and medication adherence. The program also provided discounted or free antihypertensive medications, additional training, and performance incentives. Participants in the usual care group received local standard BP management throughout. During the 3-year posttrial period from years 4 to 7, intervention participants continued care with their original NPCHPs, with physician and hypertension specialist consultation available; discounted or free medications, additional training, and performance incentives were discontinued. The primary outcome was a composite of myocardial infarction, stroke, hospitalization for heart failure, and CVD death. Treatment effects were evaluated separately over the 7-year overall and 3-year posttrial periods with prespecified subgroup analyses. RESULTS:Between May 8 and November 28, 2018, 33 995 participants were enrolled; 31 334 entered the posttrial follow-up. At the end of the 7-year overall period, BP was 138.8/80.7 mm Hg in the intervention group versus 152.3/86.1 mm Hg in the usual care group (between-group difference, -13.5/-5.4 mm Hg; P<0.0001 for both systolic and diastolic BPs); percentage of the participants with BP <130/80 mm Hg was 33.9% versus 10.5% (P<0.0001). During the 7-year overall period, the rate of composite CVD events was 2.4% versus 3.0% per person-year in the intervention and usual care groups, respectively (hazard ratio, 0.76 [95% CI, 0.72-0.81]; P<0.0001). During the 3-year posttrial period, the corresponding rates were 3.4% versus 4.2% per person-year (hazard ratio, 0.79 [95% CI, 0.73-0.85]; P<0.0001). Posttrial effects in CVD risk reduction were generally consistent across subgroups defined by baseline age, sex, education, and antihypertensive medication use. Over the 7-year overall period, the intervention group had higher risks of hypotension (risk ratio, 1.58 [95% CI, 1.39-1.79]) and mild hypokalemia (risk ratio, 1.38 [95% CI, 1.23-1.56]; P<0.001 for both). CONCLUSIONS:Multicomponent BP management strategy with a BP target <130/80 mm Hg led by NPCHPs achieved sustained BP control and reduced CVD risk during both the 7-year overall and 3-year posttrial periods. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03527719.

BACKGROUND:Myocardial infarction (MI) remains a major cause of morbidity and mortality worldwide. MFAP5 (microfibrillar-associated protein 5) is an extracellular-matrix associated secreted glycoprotein whose cardiac function is unknown. This study aimed to explore the origin, expression, function, and potential mechanisms of MFAP5 in MI. METHODS:Single-cell analysis and immunohistochemistry were used to determine the origin and expression of MFAP5. Global MFAP5-knockout (KO) mice and adeno-associated virus 9-mediated cardiac fibroblast-specific overexpression mice were used to investigate the function of MFAP5 in vivo. RNA sequencing and ingenuity pathway analysis revealed potential mechanisms. Coimmunoprecipitation and confocal microscopy identified molecular interaction domains. rMFAP5 (recombinant MFAP5 protein) and plasmid-mediated intracellular overexpression revealed the effects of MFAP5 on cardiomyocytes under oxygen-glucose deprivation conditions. RESULTS:MFAP5 was significantly increased in both human and mouse heart tissues during MI, predominantly derived from activated cardiac fibroblasts. In vivo, MFAP5-knockout exacerbated cardiac dysfunction, enlarged infarct size and increased cardiomyocyte apoptosis during the acute phase of MI. Cardiac fibroblast-specific overexpression of MFAP5 exerted a protective effect. In vitro, MFAP5 significantly inhibited apoptosis in cardiomyocytes under oxygen-glucose deprivation stimulation. Mechanistically, MFAP5 derived from fibroblasts interacted with the extracellular EGF (epidermal growth factor) repeats of the NOTCH2 receptor on the surface of cardiomyocytes via its MBD domain, promoting shedding of the extracellular fragment of NOTCH2 and generation of the NICD2 (NOTCH2 intracellular domain). MFAP5 inhibited cardiomyocyte apoptosis by activating NOTCH2 signaling. CONCLUSIONS:Fibroblast-derived MFAP5 engages cardiomyocyte NOTCH2 to inhibit apoptosis and exerts cardioprotective effects after MI.

Abstract Doxorubicin (DOX) is a potent antineoplastic agent, but its clinical application is limited by the life‐threatening cardiotoxic effects. Poly(ADP‐ribose) polymerase 1 (PARP1) transfers ADP‐ribose groups from donor NAD+ molecules onto target substrates upon oxidative stress, which may promote apoptosis and myocardial injury. The detailed molecular pathways of PARP1 activation, however, remain unclear. Here, we found that reactive oxygen species (ROS) function as signalling molecules to promote CBP‐mediated PARP1 lactylation in an ATM‐dependent manner, which induces PARP1 PARylation and ultimate cell apoptosis. We identified CBP and SIRT1 as specific lactyltransferase and delactylase of PARP1, respectively. Besides, the lactylation of PARP1 depends on the LDHA activity and lactate production. Moreover, Myocardium‐specific CBP knockout mice decrease PARP1 lactylation and prevent doxorubicin‐induced cardiac dysfunction. Our findings unravelled that excessive oxidative stress‐induced ROS accumulation activates the ATM‐CBP‐PARP1 signalling pathway via a lactylation–PARylation cascade to promote apoptosis and myocardial injury.

This paper systematically reviews the decade-long evolution of renal denervation (RDN), analyzing its paradigm shift from anatomical ablation to targeted neuromodulation. This paper focuses on breakthroughs in renal nerve mapping pioneered by Chinese scholars, discusses the clinical value of diverse energy platforms and novel catheter designs, and addresses existing challenges such as quantification of ablation energy, therapeutic heterogeneity, and health economics. A future blueprint integrating neuroimaging navigation and artificial intelligence for precision therapy is proposed, emphasizing strategic significance of RDN in holistic hypertension management and establishing a new paradigm for autonomic neuromodulation in cardiovascular diseases.