Search Results for: Nelle donne lo stress danneggia la salute dell’intestino

Circulation, Volume 150, Issue Suppl_1, Page A4144014-A4144014, November 12, 2024. Introduction:Lower socioeconomic status (SES) associates with greater MACE risk in part via stress-related mechanisms. Further, a higher polygenic risk score for neuroticism (nPRS), a marker linked to stress sensitivity and chronic stress conditions, is associated with greater MACE risk. Moreover, individuals with higher nPRS are more susceptible to the cardiovascular impacts of lower SES. Yet, it remains unknown whether individuals with higher nPRS experience greater adverse changes in autonomic and inflammatory intermediaries of stress in the setting of lower SES and whether these changes contribute to MACE risk. Accordingly, we tested the hypotheses that: 1) lower SES links to MACE risk via lower heart rate variability (HRV) and higher C-reactive protein (CRP), and 2) lower SES has a greater impact on HRV and CRP among those with higher nPRS.Methods:Individuals (N=18093; median age 64 years; 54% female) with nPRS and SES data were identified in the Mass General Brigham Biobank. SES was assessed as the median income of an individual’s residential zip code with lower income defined as the lowest tertile. Higher nPRS was defined as values ≥ population median. MACE data was collected for 10 years following enrollment using ICD-10 codes. CRP (N=4117) and HRV (N=4412) data were collected from available clinical lab values and electrocardiograms, respectively, with HRV assessed as the standard deviation of all normal RR intervals.Results:In the full cohort, both HRV and CRP mediated the relationship between lower SES and MACE risk (p

Circulation, Volume 150, Issue Suppl_1, Page A4146892-A4146892, November 12, 2024. Background:Takotsubo cardiomyopathy (TCM) is a unique and reversible heart condition typically triggered by intense emotional or physical stress. Meanwhile, Cirrhosis, a chronic liver disease, is associated with increasing inflammation and oxidative stress, which can potentially worsen cardiovascular problems. In this study, we aimed to study the impact of cirrhosis on outcomes in TCM.Methods:A retrospective analysis was performed using the NIS database 2016 -2020 and the International Classification of Diseases, Tenth Revision codes to identify patients > 18 years old with the principal diagnosis of Takotsubo cardiomyopathy. The effect of cirrhosis was studied on in-hospital mortality and secondary outcomes such as cardiogenic shock, ventricular arrhythmia (VA), acute respiratory and acute kidney injury (AKI), as well as resource utilisation. Categorical variables were compared using the chi-square test, and continuous variables were compared using the t-test—multivariable regression analyses adjusted for demographics, hospital-level characteristics, and relevant comorbidities.Results:We identified a total of 190,025 patients with TCM. Of these, 3,335 (1.76%) patients had liver cirrhosis, with notably higher prevalence of diabetes (33.6%), CKD (20.7%), anemia (10.2%), and major depressive disorder (25.6%) in the cirrhosis group. A higher incidence of in-hospital mortality (12.9% vs. 6.3%, p

Circulation, Volume 150, Issue Suppl_1, Page A4143729-A4143729, November 12, 2024. Post-traumatic stress disorder (PTSD) is associated with hypertension and increased heart rate, which are risk factors for cardiovascular disease including thoracic aortic aneurysms. A connection between stress and aortopathy has been suggested, yet mechanisms linking the two remain unknown. We hypothesize that PTSD-induced mechanical signals alter thoracic aortic wall homeostasis, which can predispose to aortopathy. C57BL/6 mice underwent traumatization consisting of inescapable foot shock, single prolonged stress, and single housing. PTSD phenotype was assessed through behavioral testing for the DSM-V PTSD criteria. Group-housed control mice did not undergo the traumatization but were subjected to behavioral testing. Z-scores for each behavioral test were generated and mice with z-scores above the 85% confidence interval on all criteria were considered to have a PTSD-like phenotype. This protocol yielded a PTSD phenotype in 30% of mice mimicking the human proportion of PTSD development following a traumatic experience. PTSD mice had significantly higher systolic blood pressures (PTSD (n=10), 149 ± 7mmHg; control (n=10), 123 ± 9mmHg, p

Circulation, Volume 150, Issue Suppl_1, Page A4141265-A4141265, November 12, 2024. Background:Congenital heart disease (CHD) is a common congenital anomaly with lesions requiring intervention before initial hospital discharge defined as critical CHD (CCHD). Advances in prenatal detection, surgical, and post-operative care have improved early survival of patients with CCHD, yet long-term survival is limited. Fetal echocardiography has improved diagnosis and characterization of CCHD, and prenatal palliative care (PC) consult can improve shared decision making, communication, and parental stress of patients with life-limiting conditions. We hypothesized that the utilization of prenatal PC consults for patients with CCHD would be low (

Circulation, Volume 150, Issue Suppl_1, Page A4129523-A4129523, November 12, 2024. Introduction:Patients with diabetes are at higher risk of chronic limb-threatening ischemia (CLTI), a severe form of peripheral artery disease (PAD) causing restricted blood flow to the lower limbs due, in part, to impaired angiogenesis. However, the role of microRNAs (miRNAs) in diabetic CLTI remains poorly understood. By integrating plasma miRNA sequencing data from PAD patients with diabetes with a diabetic CLTI mouse model, we have recently identified the conserved miRNA miR-1282 that is in cis-antisense orientation to SERF2, a gene associated with amyloid aggregation. Therefore, we hypothesize that miR-1282 orchestrates endothelial angiogenesis and proteostasis during diabetic CLTI.Methods:Using miR-1282 overexpression or SERF2 knockdown studies, we characterized mouse orthologs of human miR-1282 and SERF2 for angiogenesis, apoptosis, protein aggregation, and oxidative stress in diabetic mouse skeletal muscle endothelial cells (ECs). In vivo, miR-1282 mimics were delivered intramuscularly to assess their impact on blood flow recovery, angiogenesis, and protein aggregation. Mechanistic insights in ECs were gained via RNA-seq, predictive algorithms, and proteomic analyses.Results:miR-1282 inhibited the expression of its cis-antisense target SERF2 by 98%. miR-1282 is a hypoxia-induced endothelial-enriched miRNA, and its expression was inversely correlated with SERF2 expression. miR-1282 levels were markedly reduced after femoral artery ligation (FAL) in diabetic db/db mice. Overexpression of miR-1282 or SERF2 knockdown enhanced angiogenesis and reduced protein aggregation, apoptosis, and oxidative stress in both normal and hypoxic conditions in vitro. Delivery of miR-1282 mimics in db/db mice improved blood flow recovery by 108% and angiogenesis by 98%, and reduced protein aggregation by 48% and tissue necrosis. Coupling RNA-seq profiling and prediction algorithms of ECs upon miR-1282 overexpression or SERF2 knockdown revealed EREG, BAG5, CASP3, ARG1, and HSP90AA1 as potential downstream regulators. Pathway enrichment analysis implicated inhibition of endothelial apoptosis, ER stress, and protein stability among the most dysregulated processes.Conclusion:A novel mouse ortholog of human miR-1282 augments endothelial functions and diminishes protein aggregation in diabetic CLTI via suppression of its cis-antisense target SERF2. These findings uncover new potential therapeutic targets in treating diabetic CLTI.

Circulation, Volume 150, Issue Suppl_1, Page A4144145-A4144145, November 12, 2024. Background: Mavacamten reduces left ventricular outflow tract gradients (LVOTg), improves symptoms and increases exercise capacity in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients. We investigated the potential myocardial mechanical basis for improved exercise capacity in these patients.Methods:We evaluated symptoms, exercise capacity in metabolic equivalents (METs), LVOTg at rest, at Valsalva and peak-exercise, and global left ventricular longitudinal strain (GLS) at rest and peak-exercise in patients before and during mavacamten therapy.Results:oHCM patients at a single tertiary center (n=22, 56% female, mean age 64 ± 12 years) were evaluated pre- and post-mavacamten initiation (Table). Mean duration of treatment was 22 ± 14 weeks. There was significant improvement in NYHA class – proportion of NYHA I increased from 0 to 64% and NYHA II and III decreased from 77 to 34% and 23 to 5%, respectively (Figure B). All patients underwent a symptom-limited Bruce protocol treadmill stress echocardiogram and there was a significant improvement in exercise capacity pre- vs. on-mavacamten (7.6± 3.4 vs. 8.6± 3.4 METs, respectively, p 0.01). There was a significant decrease in LVOTg at rest, at Valsalva and post-exercise (47 ± 43 vs. 9.8 ±6 mmHg, 82 ± 46 vs 20 ± 19 and 114 ± 54 vs. 43 ± 40 mmHg, respectively, all p < 0.001). Rest GLS did not change pre- vs. on-Mavacamten (15 ± 3 vs. 16 ± 3%, p 0.07). However, peak-exercise GLS improved significantly (16 ± 4 vs. 18 ± 4%, pre vs. on-mavacamten, p < 0.01) (Figure A).Conclusion:Mavacamten-induced augmentation of exercise strain may be the mechanical basis for exercise capacity improvements in oHCM. Rest GLS non-significantly increased on mavacamten. Our results will need validation in a larger cohort.

Circulation, Volume 150, Issue Suppl_1, Page A4136700-A4136700, November 12, 2024. Hemorrhagic shock(HS) results from significant blood loss, leading to insufficient oxygen delivery, which causes metabolic changes and multi-organ dysfunction.The HS-related acute kidney injury developed by the patient are mainly due to alteration in Na/K ATPase.In previous O-GlcNAcylomic studies, we identified the Na/K ATPase as potentially O-GlcNAcylated.O-GlcNAcylation, a post-translational modification, plays a role in various cellular processes, such as cell survival and stress response.O-GlcNAcylation may have beneficial effect in shock situations.The objective of this study is to ascertain whether Na/K ATPase is O-GlcNAcylated and to elucidate its potential role during HS.Hemorrhagic shock was induced by an exsanguination of rats.They were then randomly treated or not with an O-GlcNAcase inhibitor, the NButGT(10mg/kg), to increase O-GlcNAc level.Blood pressure and heart rate were monitored throughout the experiment.Blood samples were collected for complete blood analysis, including biochemistry and gas measurements. kidneys were immediately frozen for histological and biochemical studies.To study the O-GlcNAcylation of Na/K ATPase an immunoprecipitation and Wheat Germ Agglutinin(WGA) based lectin affinity gel electrophoresis were used. HEK cells were treated with or without NButGT(100µM,6 hours) and/or ouabain(Na/K ATPase inhibitor) and a colorimetric kit was assessed to study O-GlcNAcylation impact on Na/K ATPase activity.O-GlcNAc levels increased by 2 folds in heart and kidney due to the NButGT treatment(p

Circulation, Volume 150, Issue Suppl_1, Page A4141935-A4141935, November 12, 2024. Background:Tyrosine kinase inhibitors (TKIs), such as sunitinib, are highly effective in treating cancers. However, they have severe cardiovascular (CV) side effects that include cardiotoxicity via cardiomyocyte injury and death resulting in myocardial dysfunction. There are no FDA-approved drugs to prevent or treat cardiotoxicity, which have been linked mechanistically to mitochondrial dysfunction and oxidative stress, highlighting the need for new therapeutics. Two recognized CV protective pathways are the particulate guanylyl cyclase A receptor (GC-A)/cGMP and the Mas receptor (MasR)/cAMP pathways. We recently engineered NPA7 a novel peptide that activates both pathways.Aim:Here we investigated NPA7’s ability to protect against sunitinib-induced cardiotoxicity in human cardiomyocytes (HCMs) and defined its role on mitochondrial function.Methods:HCMs were treated with DMSO or sunitinib (10 µM) together with PBS or NPA7 (10 µM). Intracellular reactive oxygen species (ROS) was assessed by DHE staining. CCK8 assay was performed to measure cell viability. TOM20 staining were performed by immunofluorescence and the mitochondrial length was analyzed. The protein levels of mitochondrial dynamics markers (fission: MFF, Fis1; fusion: OPA1 and MFN1) proteins were measured by western blot. Cell surface area was assessed by phalloidin staining with mRNA levels of hypertrophic gene markers (NPPA and MYH7) in HCMs using real-time PCR.Results:Sunitinib increased DHE staining and intracellular ROS in HCMs, which was decreased with NPA7 treatment. NPA7 enhanced HCM cell viability in the presence of sunitinib. TOM20 staining showed a marked reduction in mitochondrial length in sunitinib group, compared to DMSO group, whereas NPA7 treatment rescued mitochondria length (DMSO= 6.15 ± 0.94 μm, Sunitinib= 2.42 ± 0.63 μm, NPA7= 5.4 ± 1.19 μm; P < 0.05). Moreover, NPA7 inhibited mitochondrial fission protein levels (MFF and Fis1) and increased mitochondrial fusion protein levels (OPA1, MFN1) in HCMs treated with sunitinib. Sunitinib treatment notably increased HCM cell surface area and hypertrophic gene markers (NPPA and MYH7), whereas NPA7 abolished these markers of hypertrophy.Conclusions:We report, for the first time, that NPA7 protects against sunitinib induced oxidative stress, mitochondrial fragmentation, hypertrophy and cell death in HCMs. These data support a novel therapeutic approach against TKI-induced cardiotoxicity with NPA7 to which no therapies exist.

Circulation, Volume 150, Issue Suppl_1, Page A4146699-A4146699, November 12, 2024. Background:Growing evidence suggests that blunted blood pressure and heart rate responses to acute psychological stress independently associate with an increased risk of adverse outcomes in individuals with CHD, but assessment of mental stress reactivity in clinical settings is resource intensive. An alternative approach is to passively measure stress physiology at home with wearables, which is easier to translate into clinical practice. We tested the hypothesis that blunted mental-stress hemodynamic reactivity in the lab is associated with digital biomarkers of autonomic inflexibility at home.Methods:We conducted a mental stress test in 239 participants (age < 60 years) with an MI within 8 months. Participants underwent a speech stressor task in front of an audience to induce mental stress, during which blood pressure and heart rate were measured repeatedly during a baseline 15-minute rest period and 5-minute stress challenge. Participants went home with a 7-day Holter monitor to measure autonomic function. We examined vagal autonomic inflexibility with deceleration capacity (DC), a digital biomarker calculated via phase rectified signal averaging of heart rate intervals. We also examined low frequency (LF) heart rate variability (HRV), an indirect measure of baroreceptor sensitivity. We measured mean values from 5-minute windows during sedentary periods only to avoid confounding due to physical activity. We used multivariable linear regression models to adjust for potential confounding due to age, beta-blockers, and sex.Results:The mean age was 52 years, 51% were black, and 36% were women. Lower DC most strongly associated with a blunted change in heart rate during acute mental stress challenge (adjusted p

Circulation, Volume 150, Issue Suppl_1, Page A4147433-A4147433, November 12, 2024. Background:In adults with hypertrophic cardiomyopathy (HCM), left ventricular outflow tract (LVOT) obstruction and reduced left atrial strain (LAS) predict heart failure and cardiac event risk. However, data in children are limited.Hypothesis:LVOT gradient and LAS together determine cardiac outcome risk in children and young adults with HCM.Methods:All HCM patients with exercise stress echocardiography (ESE) from 2014-2022 at a single center were included. Patients were stratified by LVOT gradients: Group 1 (n=44, rest/exercise gradients < 30mmHg); Group 2 (n=41, rest < 30mmHg; exercise ≥ 30mmHg); Group 3 (n=29, rest/exercise ≥ 30mmHg). Composite cardiac outcome included cardiac syncope, non-sustained/sustained ventricular tachycardia, cardiac arrest, NYHA heart failure class ≥ II, heart transplantation, and HCM-related death. LA reservoir (LASr) and conduit (LAScd) strain were analyzed with TOMTEC AutoStrain LA. Cumulative incidence of composite outcome by LVOT group was estimated by Kaplan-Meier method. Multivariable Cox regression was used to evaluate the effect of adding LAS to a model containing only LVOT group. Model discrimination was assessed using the concordance (c) index.Results:114 patients (32%F, median age 17 years) formed the cohort. At median 2.1 years follow-up [IQR: 1.0, 3.4] composite cardiac outcome risk was higher in Group 3 vs. 2 (HR=4.97, p=0.013, Figure 1). Composite cardiac outcome risk was lower in Group 1 vs. 2, but not significant (HR=0.70, p=0.66). Adjusting for LVOT group, lower LASr and LAScd were associated with greater cardiac outcome risk (per 5% LAS decrease: LASr HR=1.56, p=0.008; LAScd HR=1.77, p=0.002, Table 1). C index increased with inclusion of LASr or LAScd in the model (Table 1).Conclusion:In one of the largest young HCM cohorts evaluated with ESE, cardiac outcome risk increased with resting LVOT obstruction and reduced LA strain. LA strain demonstrated additive value for prediction of cardiac outcomes in children.

Circulation, Volume 150, Issue Suppl_1, Page A4119267-A4119267, November 12, 2024. Background:Sarcoidosis, a systemic granulomatous inflammatory disorder can involve various organs, including the heart but isolated bi-atrial cardiac involvement is rare. Advanced cardiac imaging especially in atypical presentations, can aid in early diagnosis.Case:A 59 year-old man with history of biopsy-proven pulmonary sarcoidosis presented with non exertional chest pain for 2 months. EKG, cardiac enzymes, and Initial echocardiogram(TTE) was unremarkable. Stress echocardiogram ruled out myocardial ischemia. CT scan noted mediastinal lymphadenopathy consistent with known sarcidosis. In absence of other explainable etiolgies for chest pain, Cardiac MRI was done and showed preserved biventricular function, subepicardial enhancement in the basal inferior, inferolateral, and anterolateral walls. The enhancement raised suspicion for CS. However, symptoms resolved spontaneously, cardiac workup paused and he was monitored conservatively with serial Echocardiogram(TTE) until onset of dyspnea 3 years later. Repeat TTE and EKG then noted newly enlarged left atrium and atrial tachycardia. Further testing with Cardiac positron emission tomographic imaging with F-18 fluorodeoxyglucose (FDG-PET CT) showed abnormal myocardial uptake in both atrial posterior walls but no ventricular involvement, indicative of isolated bi-atrial inflammation in CS. He was treated with prednisone and methotrexate. Successful symptom and inflammation resolution on FDG-PET CT occurred in 3 monthsDiscussion:CS is rare and seen clinically in about 5% and diagnosed postmortem in 25% of sarcoidosis cases. Symptoms vary widely, with potential for severe heart complications. Left ventricle and interventricular septum are commonly involved, but isolated bi-atrial involvement is rare. Early diagnosis aided by Cardiac MRI and FDG-PET CT is crucial. Prednisone is mainstay of treatment, often combined with methotrexate. Cases of concurrent atrial CS involvement and bi-atrial fibrosis with Left ventricular hyperenhancement are documented, but this is the first known report of isolated bi-atrial hyperenhancement on FDG-PET CT for CS. This case highlights the need for symptom correlation with clinical and imaging follow-up, especially in atypical presentations.

Circulation, Volume 150, Issue Suppl_1, Page A4141282-A4141282, November 12, 2024. Transcatheter valve replacement has become the preferred treatment for high-risk elderly patients considering the advantages of less invasive surgical trauma and faster postoperative recovery. Transcatheter heart valves (THVs) primarily made of glutaraldehyde-crosslinked pericardial materials pose a risk of thrombosis and calcification, and are subjected to additional stress during catheter delivery, which leads to poor durability. Herein, we constructed a novel transcatheter tissue engineered heart valve for in situ regeneration through functional modification of cystamine (CySA) and pentagalloylglucose (PGG) on decellularized porcine pericardium (DPP), referred to as CySA/PGG-PP. A dynamically reversible fiber network structure was formed by the modification of CySA and PGG, resulting in excellent resistance to enzymatic degradation and crimping stability of CySA/PGG-PP. The distinctive capability of CySA to catalyze the production of endogenous nitric oxide (NO) provided CySA/PGG-PP with a long-term NO release system that inhibited platelet adhesion and activation to improve hemocompatibility. Proteomics analysis revealed that the improvement of hemocompatibility might be mediated by protein phosphorylation and arachidonic acid metabolism-related pathways. Furthermore, we found that CySA/PGG-PP exhibited significant recellularization and tissue remodeling in a rat abdominal aortic implantation model, accompanied by a mild inflammatory response and no calcification. The positive results in vivo might be regulated by genes associated with cell adhesion and differentiation, extracellular matrix organization, and TGF-β signaling pathway, as revealed by RNA sequencing. Consequently, the instructive transcatheter tissue-engineered valve overcomes the limitations of existing THVs with the aim of significantly improving valve durability for clinical therapy.

Circulation, Volume 150, Issue Suppl_1, Page A4134707-A4134707, November 12, 2024. Introduction:Epicardial adipose tissue (EAT) is a metabolically active tissue associated with cardiometabolic disease. EAT likely has local paracrine inflammatory and atherogenic effects on coronary vessels, but the metabolic underpinnings related to systemic metabolic pathways has not been evaluated.Hypothesis:We hypothesized that metabolic markers of lipid and fatty acid oxidation will be positively associated with volume of EAT.Methods:In a biomarker substudy of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) clinical trial which randomized participants to computed tomography angiography (CTA) vs. stress testing, we analyzed 1542 participants randomized to the CTA arm with available plasma at baseline. CTA phenotyping of EAT volume indexed to body surface area (cm3/m2) was determined using a validated deep-learning algorithm. Comprehensive metabolomic profiling was performed on plasma samples using mass spectrometry. Principal components analysis (PCA) was used for dimensionality reduction of 571 named metabolites. Linear regression tested the association of metabolomic factors with EAT. Univariate models were adjusted for multiple comparisons and multivariate models were adjusted for age, race and ethnicity, sex, diabetes, BMI, LDL-C, HDL-C and metabolic syndrome.Results:Of 82 PCA-derived metabolomic factors, 16 were associated with EAT in univariate models and nine were associated with EAT in multivariate models (p=0.001-0.046); 116 individual metabolites heavily loaded within these factors were significantly associated with EAT volume in multivariate models (Figure 1). This included three linoleic acid derivatives, six cholesterol esters, and glycine that were inversely associated with EAT volume (p

Circulation, Volume 150, Issue Suppl_1, Page A4146993-A4146993, November 12, 2024. Introduction:Anthracyclines (AC), a class of chemotherapeutic drugs, are used to treat various cancers, including breast cancer (BC). However, AC cause dose-dependent cardiac toxicity. Practice guidelines list pre-existing cardiomyopathy as a risk factor for cancer therapy-related cardiac dysfunction (CTRCD), but there is a lack of data on cardiotoxicity risk in patients with left ventricular (LV) hypertrabeculation without LV hypertrophy/dilation. We present a patient with LV hypertrabeculation who developed LV dysfunction after AC chemotherapy for BC.Description of Case:A 55-year-old woman diagnosed with multicentric invasive ductal carcinoma (IDC) of the right breast, stage IIA (cT3 cN1 cM0), grade 2, ER+/PR+/HER2-, was treated with neoadjuvant Paclitaxel for 3 months. Before AC-based chemotherapy, stress cardiac MRI due to residual post-COVID-19 dyspnea showed LV hypertrabeculation with a non-compacted/compacted ratio of 2.3, LVEF 56%, and no delayed enhancement. Transthoracic echocardiography (TTE) reported an LVEF of 52% with GLS of -17%. The patient’s electrocardiogram (ECG) showed normal sinus rhythm, and NT-pro BNP levels were

Circulation, Volume 150, Issue Suppl_1, Page A4125025-A4125025, November 12, 2024. Background:Chronic stress is associated with cardiovascular disease (CVD) in part through neural mechanisms that potentiate inflammation. Disrupted social connections are associated with higher chronic stress. As such, we hypothesized that: 1) previously married (divorced, separated) individuals have higher major adverse cardiovascular event (MACE) risk compared to married individuals and 2) that greater activation of stress-related neural-immune mechanisms contributes to this relationship.Methods:Participants (N=75,638) enrolled in the Mass General Brigham Biobank were studied. Marital status and MACE were identified using survey data and ICD-10 codes, respectively. A subset (N=1,121) underwent clinical18F-FDG-PET imaging, enabling assessment of stress-related neural activity as the ratio of the amygdala to prefrontal cortex activity (AmygAc). Clinical high-sensitivity C-reactive protein (hs-CRP) levels were assessed in another subset of the cohort (N=10,358). Linear and Cox regression and mediation analyses were used.Results:Among participants (median age 62 years; 53% female), 2,978 subjects developed MACE after Biobank enrollment. Previously married (vs. currently married) individuals had greater MACE risk (HR 1.33 [95% CI: 1.20,1.57], p=

Circulation, Volume 150, Issue Suppl_1, Page A4134837-A4134837, November 12, 2024. Background:Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation and cardiac repair post myocardial infarction, however, its role on mitochondrial function in I/R injury remains unknown.Research Questions:The purpose of this study is to explore the potential effects and mechanisms of CHK1 on mitochondrial homeostasis during myocardial I/R injury.Methods:To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/knock-in mouse models were generated. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism of CHK1. The interaction between CHK1 and SIRT1 was explored using truncated plasmids.Results:CHK1 was downregulated in myocardium post I/R and neonatal mouse cardiomyocytes (NMCMs) post oxygen-glucose deprivation/re-oxygenation (OGD/R).In vivo, CHK1 overexpression protected against myocardial I/R injury, while heterogenous CHK1 knockout exacerbated cardiomyopathy.In vitro, CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266-390 domain of CHK1 interacted with the 160-583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown partially attenuated the protective role of CHK1 in I/R injury.Conclusions:Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.