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Echocardiography. 2025 Sep;42(9):e70297. doi: 10.1111/echo.70297.

ABSTRACT

BACKGROUND AND OBJECTIVES: Patients with single-ventricle physiology undergoing Fontan operations face high morbidity and mortality risks. While classic-pattern dyssynchrony (CPD) and protein-losing enteropathy (PLE) are known predictors of adverse outcomes, the role of global longitudinal strain (GLS) as an independent predictor of heart failure remains unclear.

METHODS: A retrospective cohort study of 135 Fontan-operated patients from 2014 to 2015 evaluated the predictive value of GLS alongside PLE and CPD on mortality and transplantation after 9 years. Echocardiographic data, including GLS, were analyzed using speckle tracking strain analysis in 132 patients. The primary endpoint was transplant-free survival.

RESULTS: Among 132 Fontan patients, 15 had classic-pattern dyssynchrony, 29 had protein-losing enteropathy, 37 had moderately reduced global longitudinal strain (GLS ←8% ≥-16%), and 18 had severely reduced GLS (≥-8%). Cox regression analysis showed moderately reduced GLS increased mortality risk (HR 5.8, 95% CI 1.27-26.5, p = 0.023), with severely reduced GLS showing an HR of 10.3 (95% CI 2.18-48.6, p = 0.003). These results were comparable to CPD (HR 11.5, p = 0.002) and PLE (HR 14.9, p < 0.001).

CONCLUSION: Global longitudinal strain emerged as the best independent factor for predicting long-term transplant-free survival in Fontan patients, highlighting the importance of GLS assessment in routine follow-up to identify high-risk individuals for early intervention.

PMID:40965765 | DOI:10.1111/echo.70297

Pediatr Transplant. 2025 Nov;29(7):e70180. doi: 10.1111/petr.70180.

ABSTRACT

PURPOSE: Pre-transplant (PreTX) diagnoses of congenital heart disease (CHD), including single ventricle (SV) CHD, are known to be associated with immediate post-operative morbidity and mortality. However, the impact on post-discharge health and morbidity has not been elucidated.

METHODS: The Pediatric Health Information Survey (PHIS) data was used to identify patients undergoing orthotopic heart transplantation (HT). We assessed hospital encounters for readmission, ICU care, and interventions within 1 year of heart transplantation after discharge from HT.

RESULTS: A total of 4087 patients were included in the analysis with the median age of 5.2 years. PreTX diagnosis was CHD in 28%, single ventricle CHD (SV) in 31%, cardiomyopathy, and other causes in 41%. A total of 2698 patients (66%) required hospital readmission within 1 year of discharge, of which 569 required more than two readmissions. The reason for readmission was cardiac in 22%, infectious in 35%, and non-cardiac in 43%. Using multivariable modeling, younger age, CHD, SV, Hispanic race, government insurance, longer post-TX hospital stay, longer ventilation needs, and dialysis use were associated with readmission risk (all p < 0.05). CHD and SV diagnosis, younger age, and longer post-TX stay were also risk factors for ICU-level readmission (all p < 0.05). Regression analysis showed that CHD (HR 2.7) and SV (HR 5.3) were highly predictive of reinterventions within 1 year. Lastly, the morbidity burden was calculated as days alive and outside hospital (DAOH) post TX. Younger age, SV, current era for transplantation, prolonged ventilation, and hospital stay post TX were all associated with lower DAOH.

CONCLUSION: CHD and SV have a significant impact on continued morbidity post-TX, including the need for ICU-level readmission and reinterventions. The study also identifies race and post-TX morbidities as other important risk factors for readmissions and reinterventions. We need to study and improve the optimization of patients pre-and post-TX to mitigate this significant and continued risk.

PMID:40965286 | PMC:PMC12445256 | DOI:10.1111/petr.70180

Pediatr Transplant. 2025 Nov;29(7):e70179. doi: 10.1111/petr.70179.

ABSTRACT

BACKGROUND: Advances in donor organ preservation can potentially improve pediatric lung transplant outcomes. The ISHLT recommends that organ temperatures remain between 4°C and 6°C and that inflation pressures remain between 10 and 15 cm H2O during organ preservation. During traditional ice storage, temperature and inflation pressures rapidly fall below these suggested ranges. A recently developed preservation device, the Paragonix BAROguard Donor Lung Preservation System (BG) provides precise hypothermic and barometric control, ensuring that lung inflation pressure and tissue temperatures remain stable and within the ISHLT recommended range for the duration of storage. Here, we report the first clinical use of BG in a pediatric lung transplant case.

METHODS: A lung transplant was performed on a high-risk pediatric recipient after lung preservation using the BG system. We evaluated the recipient for 187 days posttransplant during hospitalization.

RESULTS: Despite multiple significant risk factors, including neuroblastoma and hemolytic uremic syndrome complicated by thrombotic microangiopathy resulting in persistent coughing, shortness of breath, and poor oral intake, the lung transplant was successful, and the patient was discharged after 187 days.

CONCLUSIONS: The BG system can be safely utilized in pediatric lung transplantation, and BG preservation can be safely implemented in high-risk cases with poor clinical prognosis.

PMID:40965263 | DOI:10.1111/petr.70179

Cardiol Young. 2025 Sep 18:1-7. doi: 10.1017/S1047951125100541. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to evaluate school-age neurodevelopmental outcomes among children with single ventricle heart disease who underwent neonatal Norwood operation with regional cerebral perfusion compared to deep hypothermic circulatory arrest. Additionally, we aimed to identify predictors of school-age development, including early developmental measures.

STUDY DESIGN: Patients enrolled in a prospective randomised trial of infants with single ventricle heart disease undergoing the Norwood operation with either regional cerebral perfusion or deep hypothermic circulatory arrest were included. For the same cohort of patients, this study performed neurodevelopmental testing at 5 years and 10 years of age. At 5 years, a comprehensive neuropsychological evaluation was performed. At 10 years, parent report instruments were used to measure participants' behaviour and executive function.

RESULTS: Forty-one patients at 5 years of age and 33 patients at 10 years of age completed neurodevelopmental evaluation. There were no significant differences in neurodevelopmental scores between the regional cerebral perfusion and deep hypothermic circulatory arrest groups at either 5 or 10 years. At 5 years of age, the average full scale intelligence quotient (IQ) was 93.4 ± SD18.8. The Bayley Scale of Infant Development Psychomotor Developmental Index (r = 0.68, p < .0001) and mental developmental index (r = 0.64, p < .0001) at 1 year positively correlated with the full scale IQ at 5 years.

CONCLUSIONS: Neurodevelopment is delayed in patients with single ventricle heart disease. Neurodevelopmental outcomes at school age did not differ based on the perfusion strategy for the Norwood operation. Mental and psychomotor developmental indices at 1 year are predictive of early school-age measures.

PMID:40964849 | DOI:10.1017/S1047951125100541

Card Fail Rev. 2025 Aug 26;11:e23. doi: 10.15420/cfr.2025.18. eCollection 2025.

ABSTRACT

BACKGROUND: Blood troponin I (TnI) concentrations, the reasons for increases in TnI after coronary artery bypass grafting (CABG) and the effects of TnI on short- and long-term outcomes are not well understood.

METHODS: Patients undergoing off-pump CABG at Anzhen Hospital between 2011 and 2022 were reviewed. Data on peak postoperative TnI and high-sensitivity (hs) TnI were collected, and patients were divided into a high TnI group (TnI ≥10 ≥g/l or hsTnI ≥10,000 pg/ml) and low TnI group. Baseline characteristics, graft flow, perioperative outcomes and long-term mortality were compared between the two groups.

RESULTS: In all, 19,196 patients were included in the study (median age 63 years; interquartile range [IQR] 57-68 years; 14,423 (75.1%) male). Compared with the low TnI group, patients in the high TnI group were more likely to have an intra-aortic balloon pump inserted (17.8% vs. 2.9%; p<0.001), receive extracorporeal membrane oxygenation support (3.6% vs. 0.1%; p<0.001), and undergo early revascularisation (2.81% vs. 0.12%; p<0.001); the high TnI group also had more in-hospital deaths (2.7% vs. 0.2%; p<0.001). After propensity score matching, patients in the high TnI group had fewer grafts to the left circumflex artery (LCX; 0.71 ± 0.58 versus 0.81 ± 0.57; p<0.001) and right coronary artery (RCA; 0.89±0.53 versus 0.95±0.53; p=0.011), as well as less graft flow to the LCX (median 33 [IQR 21-55] versus 41 [IQR 25-67] ml/min; p<0.001) and RCA (30 [IQR 18-50] versus 35 [IQR 22-55] ml/min; p<0.001) than patients in the low TnI group. Patients with high postoperative TnI also had reduced long-term survival (HR 2.59; 95% CI [1.76-3.82]; p<0.001).

CONCLUSION: Elevated TnI following off-pump CABG may be associated with incomplete revascularisation in the LCX and RCA. It is also associated with increased early and late mortality.

PMID:40964441 | PMC:PMC12439194 | DOI:10.15420/cfr.2025.18

BMJ Case Rep. 2025 Sep 17;18(9):e266174. doi: 10.1136/bcr-2025-266174.

ABSTRACT

The acute management of patients presenting with electrical storm secondary to ventricular arrhythmias (VAs) can be quite challenging, even with traditional attempts at rhythm control. Novel approaches are necessary to incorporate contemporary diagnostic investigations and therapeutic interventions to improve outcomes. Endomyocardial biopsy is an important but underutilised diagnostic tool that can rapidly guide the selection of tailored interventions, such as cardiac transplantation and other non-pharmacological interventions, to maximise survival. In our case, a previously healthy woman in her early 50s was hospitalised for symptomatic, pleomorphic ventricular tachycardia. Early rhythm control was achieved, but VAs recurred, consistent with electrical storm. Cardiac MRI demonstrated biventricular patchy fibrosis and late gadolinium enhancement. Endomyocardial biopsy confirmed giant cell myocarditis. She continued to deteriorate, developing cardiogenic shock requiring extracorporeal membrane oxygenation followed by urgent cardiac transplantation, eventually making a full recovery. We propose a contemporary algorithm for the management of electrical storm to maximise survival.

PMID:40967662 | PMC:PMC12477422 | DOI:10.1136/bcr-2025-266174

Zhonghua Er Ke Za Zhi. 2025 Oct 2;63(10):1126-1130. doi: 10.3760/cma.j.cn112140-20250516-00421.

ABSTRACT

Objective: To evaluate the safety and clinical efficacy of enteral nutrition (EN) initiated within 24 h after heart transplantation in pediatric patients. Methods: A retrospective cohort study was conducted. Clinical data from 16 pediatric heart transplant recipients at the Seventh Medical Center of the Chinese People's Liberation Army General Hospital between October 2022 and October 2024 were collected, including demographics, anthropometric measurements, biochemical markers, cytokine levels, and clinical outcomes. Based on the timing of EN initiation, the patients were divided into EN-initiated within 24 h and EN-initiated after 24 h 2 groups. Demographic data, preoperative extracorporeal membrane oxygenation (ECMO) support, physical examination indicators, laboratory parameters, and cytokine levels were compared between groups using independent samples t-test, Mann-Whitney U test, Fisher's exact probability test. Results: The cohort comprised 16 patients (10 males and 6 females) with an age of (12.5±1.9) years. The EN-initiated within 24 h group comprised 6 cases, and the EN-initiated after 24 h group comprised 10 cases. No significant difference was observed between the two groups in age, preoperative body mass index Z-score, preoperative ECMO support, physical examination indicators, laboratory parameters (total protein, albumin, hemoglobin), or cytokine levels (all P>0.05). Compared to the EN-initiated after 24 h group, the EN-initiated within 24 h group exhibited a shorter intensive care unit stay (t=2.65,P<0.05) and shorter mechanical ventilation duration (t=2.23,P<0.05) than EN-initiated after 24 h group. Total hospitalization length had no significant difference (P>0.05). At 72 h post-transplant, the EN-initiated within 24 h group had a lower interleukin-12 P70 (t=2.46, P<0.05) and interferon-γ levels (t=2.55, P<0.05) than EN-initiated after 24 h group. Prior to discharge, the EN-initiated within 24 h group has a lower mean skinfold thickness (t=2.49, P<0.05) and lower mid-upper arm circumference (t=2.36, P<0.05) compared with the EN-initiated after 24 h group. Conclusions: Initiating EN within 24 h postoperatively is safe and feasible in pediatric heart transplant recipients. Early EN may shorten the length of intensive care unit stay and mechanical ventilation while attenuating postoperative release of inflammatory cytokine.

PMID:40962547 | DOI:10.3760/cma.j.cn112140-20250516-00421

Eur J Pharmacol. 2025 Sep 15;1006:178158. doi: 10.1016/j.ejphar.2025.178158. Online ahead of print.

ABSTRACT

Myocardial ischemia-reperfusion (I/R) injury is a significant complication post-revascularization in acute myocardial infarction, with limited effective clinical interventions. Corilagin, a natural polyphenolic compound, exhibits antioxidant and anti-inflammatory properties in various disease models. However, its effects and mechanisms in myocardial I/R injury remain unclear. This study aims to elucidate the specific mechanism by which Corilagin regulates ferroptosis through the PI3K/AKT signaling pathway, thereby laying a theoretical groundwork for the development of innovative cardioprotective agents. A myocardial I/R model was established in mice through left anterior descending (LAD) artery ligation, and Corilagin's effectiveness was assessed using echocardiography, biochemical assays, and histopathological analysis. Additionally, an in vitro H/R model with neonatal rat cardiomyocytes was employed to examine ferroptosis-related markers, oxidative stress, and mitochondrial function. Utilizing network pharmacology and molecular docking analysis, potential targets were identified and subsequently validated through pharmacological inhibition of the PI3K pathway with LY294002. The findings demonstrate that Corilagin exhibited significant cardioprotective effects against I/R injury, as evidenced by reduced myocardial injury markers, decreased infarct size, and improved cardiac function. In vitro studies revealed that Corilagin treatment enhanced cell viability, reduced ROS levels and iron content, and restored mitochondrial membrane potential. Network pharmacology and molecular docking identified PI3K as a crucial target, with subsequent activation of the PI3K/AKT pathway. Notably, PI3K inhibition abolished Corilagin's suppression of ferroptosis, underscoring its pathway-dependent action. Corilagin alleviates myocardial I/R injury by activating the PI3K/AKT pathway to suppress ferroptosis, highlighting its potential as a therapeutic candidate for clinical translation.

PMID:40962010 | DOI:10.1016/j.ejphar.2025.178158

Braz J Cardiovasc Surg. 2025 Sep 1;40(5):e20240266. doi: 10.21470/1678-9741-2024-0266.

ABSTRACT

INTRODUCTION: Prolonged aortic cross-clamping may intensify systemic inflammation after cardiac surgery. This study aimed to evaluate the effect of cross-clamp duration on systemic inflammatory response index (SIRI) and systemic immune inflammation index (SIII) in isolated coronary artery bypass grafting (CABG).

METHOD: This retrospective study included 155 patients who underwent first-time isolated CABG between January 2021 and June 2024. Patients were divided into two groups based on median cross-clamping time: Group I (≤ 64 minutes, n = 83) and Group II (> 64 minutes, n = 72). Demographic, hematologic, and biochemical data were collected. SIII was calculated as platelet × neutrophil/lymphocyte; SIRI as neutrophil × monocyte/lymphocyte.

RESULTS: The mean aortic cross-clamping time of Group I was 53 minutes (interquartile range 44 - 60 minutes) and of Group II it was 78 minutes (interquartile range 71 - 87 minutes) (P < 0.001). An increase in systemic immune inflammation index and systemic inflammatory response index values was observed in both groups at the 24th postoperative hour. Postoperative systemic immune inflammation index and systemic inflammatory response index levels were significantly higher in Group II (P < 0.05). There was a weak but significant positive correlation between aortic cross-clamping time and postoperative systemic inflammation response index (r = 0.220; P = 0.006).

CONCLUSION: Prolonged aortic cross-clamping time is associated with an increased postoperative inflammatory response. These indices may serve as biomarkers for evaluating systemic inflammation following coronary artery bypass grafting.

PMID:40961274 | PMC:PMC12443441 | DOI:10.21470/1678-9741-2024-0266

J Investig Med High Impact Case Rep. 2025 Jan-Dec;13:23247096251367580. doi: 10.1177/23247096251367580. Epub 2025 Sep 17.

ABSTRACT

Coronary-subclavian steal syndrome (CSSS) is a rare but important complication following coronary artery bypass grafting (CABG) involving the left internal mammary artery (LIMA), typically due to proximal subclavian artery stenosis. We present a 54-year-old male with prior triple-vessel CABG (LIMA to left anterior descending) who developed acute chest pain and elevated troponin levels. Electrocardiogram showed diffuse ST-segment changes. Emergent angiography revealed patent grafts but critical 90% stenosis of the left subclavian artery proximal to the LIMA origin. The lesion was successfully treated with percutaneous angioplasty and drug-eluting stent placement, resulting in the resolution of symptoms and preserved cardiac function. CSSS, though uncommon, should be considered in post-CABG patients with recurrent angina or myocardial injury despite patent grafts. Literature estimates subclavian stenosis in up to 5% of CABG candidates, yet routine screening remains inconsistent. This case highlights CSSS as a reversible cause of ischemia and underscores the value of targeted vascular imaging in selected patients.

PMID:40960285 | PMC:PMC12444056 | DOI:10.1177/23247096251367580

Front Cardiovasc Med. 2025 Sep 1;12:1633002. doi: 10.3389/fcvm.2025.1633002. eCollection 2025.

ABSTRACT

This study aimed to investigate the long-term effects of different ASD closure methods on cardiovascular events in adults. A retrospective analysis was conducted using data obtained from the Korean National Health Insurance Service, focusing on patients aged ≥20 years diagnosed with ASD between 2004 and 2015. Participants were categorized into the observation, device closure, and surgery groups. Propensity score matching (PSM) was employed to mitigate imbalances among the groups. The Cox proportional hazards model was utilized to compare the occurrence of major adverse cardiovascular events (MACE), including stroke, myocardial infarction (MI), coronary revascularization, and all-cause death. In total, 20,643 patients with ASD were included in this study. After PSM, there were 6,636 in the observation group and 3,318 each in the device closure and surgery group. Over a 5-year follow-up period, the adjusted hazard ratios for MACE were significantly lower in the surgery (0.72; 95% CI: 0.66-0.79) and device closure groups (0.85; 95% CI: 0.78-0.92) than in the observation group. Beneficial effects on stroke and all-cause mortality were observed in both intervention groups. Additionally, a beneficial effect on coronary revascularization was observed in the surgery group, whereas the impact on MI was not significantly different between the groups. ASD closure, whether by surgery or using a device, is associated with a decreased incidence of cardiovascular outcomes in adults. The benefits on cardiovascular outcomes vary with the type of closure method, underscoring the need for a tailored approach to manage ASD in adults.

PMID:40959496 | PMC:PMC12434082 | DOI:10.3389/fcvm.2025.1633002

EuroIntervention. 2025 Sep 15;21(18):e1051-e1068. doi: 10.4244/EIJ-D-24-00992.

ABSTRACT

Over the past decades, percutaneous coronary intervention (PCI) has become the most common modality for myocardial revascularisation, and it is increasingly used in patients with advanced coronary artery disease. Antithrombotic therapy, including antiplatelet and anticoagulant drugs, plays a key role and should be part of the optimal revascularisation strategy in the early phase as well as in the long-term prevention of ischaemic events. An antithrombotic therapy regimen of increased intensity and/or duration may mitigate part of the ischaemic burden associated with complex PCI. However, patients undergoing complex PCI are often at increased bleeding risk, challenging, therefore, the decision-making process. In this setting, the optimal antithrombotic treatment is still a matter of debate and has become a field of intensive research. In this state-of-the-art review, we analyse the evidence related to the different approaches regarding the periprocedural and long-term antithrombotic management of patients undergoing complex PCI. Since a "one-size-fits-all" approach cannot be justified in this clinical setting, our aim is to tailor the antithrombotic strategy to each patient's profile and PCI complexity. We discuss the type and duration of antithrombotic regimens that can be selected for patients undergoing complex PCI, with a focus on prolonged dual antiplatelet therapy, P2Y12 receptor inhibitor monotherapy, and dual pathway inhibition. We also address antithrombotic management in specific scenarios (left main disease, coronary bifurcations, chronic total occlusion) and in patients undergoing complex PCI who require oral anticoagulant therapy.

PMID:40958619 | PMC:PMC12418109 | DOI:10.4244/EIJ-D-24-00992

Catheter Cardiovasc Interv. 2025 Sep 16. doi: 10.1002/ccd.70182. Online ahead of print.

ABSTRACT

BACKGROUND: Coronary microvascular dysfunction (CMD) can be phenotyped as endogenous or classical.

AIMS: This study investigated the prognostic significance of these CMD endotypes in patients with chronic coronary syndrome after elective percutaneous coronary intervention (PCI).

METHODS: This retrospective study included 205 patients who underwent elective PCI in the left anterior descending artery (LAD). Post-PCI, coronary flow was assessed using stress transthoracic Doppler echocardiography to measure diastolic peak flow velocity (DPV) and calculate coronary flow velocity reserve (CFVR). CMD was defined as CFVR ≤ 2.0 and further classified as endogenous (resting DPV > 33 cm/s) or classical (resting DPV ≤ 33 cm/s). This cutoff was determined by the 34.6th percentile of sorted DPV values, corresponding to reduced CFVR distribution. The primary endpoint was major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction, heart failure hospitalization, and target vessel revascularization.

RESULTS: Over a median follow-up of 2.3 years, 30 patients (14.6%) experienced MACE. The cumulative incidence of MACE was significantly higher in patients with endogenous-type CMD compared to those with classical-type CMD or without CMD (p < 0.001). In multivariate Cox proportional hazard analysis, endogenous-type CMD remained an independent predictor of MACE (hazard ratio: 3.28; 95% confidence interval: 1.53-7.04; p = 0.002).

CONCLUSIONS: Endogenous-type CMD in the LAD territory following elective PCI is an independent predictor of MACE. Noninvasive phenotyping of CMD post-PCI using stress echocardiography may improve risk stratification and guide personalized management strategies for these high-risk patients.

PMID:40958560 | DOI:10.1002/ccd.70182

Medicine (Baltimore). 2025 Sep 12;104(37):e44458. doi: 10.1097/MD.0000000000044458.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is associated with an elevated risk of cardiovascular disease and necessitates repeat revascularization procedures, including percutaneous coronary intervention (PCI). However, extensive data on outcomes following PCI in this cohort remain scarce. This systematic review and meta-analysis sought to evaluate the short- and long-term cardiovascular outcomes in RA patients following PCI.

METHODS: We conducted a search of PubMed, Embase, Google Scholar, and Cochrane Central for studies published until October 2024 that compared RA and non-RA cohorts' post-PCI. The primary outcomes encompassed major adverse cardiovascular events, myocardial infarction, repeat revascularization, and overall mortality. The pooled odds ratio (OR) with 95% confidence intervals was computed utilizing random-effects models. A sensitivity analysis was conducted using a leave-one-out meta-analysis.

RESULTS: Our search identified 9 qualifying studies, encompassing nearly 1 million patients (174,229 with RA and 9771,911 without RA). Individuals with RA exhibited a markedly elevated risk of short-term stroke compared to non-RA patients (OR: 0.81, 95% CI: 0.6-1.02). Long-term follow-up found an elevated risk of myocardial infarction (OR: 1.08, 95% CI: 1.01-1.16), stroke (OR: 1.09, 95% CI: 1.07-1.11), major adverse cardiovascular events (OR: 1.12, 95% CI: 0.99-1.24), and repeat revascularization (OR: 1.09, 95% CI: 1.07-1.11) among patients with RA. The sensitivity analysis revealed no significant difference, even after the exclusion of each study.

CONCLUSION: This comprehensive meta-analysis revealed that patients with RA have markedly poorer clinical outcomes post-PCI, particularly in the long term. The results underline the necessity for tailored peri-procedural approaches and ongoing monitoring in RA patients.

PMID:40958238 | PMC:PMC12440515 | DOI:10.1097/MD.0000000000044458

Circ Res. 2025 Sep 26;137(8):1117-1132. doi: 10.1161/CIRCRESAHA.125.326758. Epub 2025 Sep 3.

ABSTRACT

BACKGROUND: In response to cardiac injury the mammalian heart undergoes ventricular remodeling to maintain cardiac function. These changes are initially considered compensatory, but eventually lead to increased cardiomyocyte apoptosis, reduced cardiac function and fibrosis which are important contributors to the development of heart failure. The small GTPase Sept4 (Septin4) has previously been implicated in the regulation of regeneration and apoptosis in several organs. However, the role of Sept4 in regulating the response of the heart to stress is unknown.

METHODS: Ten-week-old wild-type (WT) and Sept4 knockout mice were subjected to transverse aortic constriction to induce cardiac injury. Genotype-dependent differences were investigated at baseline and at 1- and 4-week postinjury time points. To definitively establish the fibroblast-specific cardioprotective effects of Sept4, we generated a fibroblast-specific Sept4 conditional knockout model.

RESULTS: Under homeostatic conditions Sept4 knockout mice showed normal cardiac function comparable with WT controls. In response to transverse aortic constriction, WT mice developed reduced cardiac function and heart failure, accompanied by an increase in cardiomyocyte apoptosis. In contrast, knockout mice were protected against injury with maintenance of normal cardiac function and reduced levels of cardiomyocyte apoptosis. Both at baseline and after transverse aortic constriction, knockout hearts exhibited decreased levels of cardiac extracellular matrix deposition and fibrosis compared with WT controls. In support of these data, the level of myofibroblast activation was lower after injury in knockout mice. Furthermore, the knockout group showed higher levels of cardiac compliance and improved diastolic function compared with WT controls. Mechanistically, we identified reduced fibrosis development due to alterations in calcineurin-dependent signaling in fibroblasts. These results were further verified in fibroblast-specific conditional Sept4 knockout mice subjected to cardiac pressure overload.

CONCLUSIONS: We identified Sept4 as an important regulator of extracellular matrix remodeling in the heart. Sept4 controls the conversion of fibroblast to myofibroblast through calcineurin-dependent mechanisms.

PMID:40960950 | PMC:PMC12466173 | DOI:10.1161/CIRCRESAHA.125.326758

Circ Res. 2025 Sep 26;137(8):1117-1132. doi: 10.1161/CIRCRESAHA.125.326758. Epub 2025 Sep 3.

ABSTRACT

BACKGROUND: In response to cardiac injury the mammalian heart undergoes ventricular remodeling to maintain cardiac function. These changes are initially considered compensatory, but eventually lead to increased cardiomyocyte apoptosis, reduced cardiac function and fibrosis which are important contributors to the development of heart failure. The small GTPase Sept4 (Septin4) has previously been implicated in the regulation of regeneration and apoptosis in several organs. However, the role of Sept4 in regulating the response of the heart to stress is unknown.

METHODS: Ten-week-old wild-type (WT) and Sept4 knockout mice were subjected to transverse aortic constriction to induce cardiac injury. Genotype-dependent differences were investigated at baseline and at 1- and 4-week postinjury time points. To definitively establish the fibroblast-specific cardioprotective effects of Sept4, we generated a fibroblast-specific Sept4 conditional knockout model.

RESULTS: Under homeostatic conditions Sept4 knockout mice showed normal cardiac function comparable with WT controls. In response to transverse aortic constriction, WT mice developed reduced cardiac function and heart failure, accompanied by an increase in cardiomyocyte apoptosis. In contrast, knockout mice were protected against injury with maintenance of normal cardiac function and reduced levels of cardiomyocyte apoptosis. Both at baseline and after transverse aortic constriction, knockout hearts exhibited decreased levels of cardiac extracellular matrix deposition and fibrosis compared with WT controls. In support of these data, the level of myofibroblast activation was lower after injury in knockout mice. Furthermore, the knockout group showed higher levels of cardiac compliance and improved diastolic function compared with WT controls. Mechanistically, we identified reduced fibrosis development due to alterations in calcineurin-dependent signaling in fibroblasts. These results were further verified in fibroblast-specific conditional Sept4 knockout mice subjected to cardiac pressure overload.

CONCLUSIONS: We identified Sept4 as an important regulator of extracellular matrix remodeling in the heart. Sept4 controls the conversion of fibroblast to myofibroblast through calcineurin-dependent mechanisms.

PMID:40960950 | DOI:10.1161/CIRCRESAHA.125.326758

Ann Clin Lab Sci. 2025 Jul;55(4):481-495.

ABSTRACT

OBJECTIVE: To investigate the effect of exosomal miR-98-5p derived from bone marrow mesenchymal stem cells (BMSCs) on cardiomyocyte injury in acute myocardial infarction (AMI) and analyze its mechanism of action.

METHODS: An AMI model in rats was established via ligation of the left anterior descending (LAD) coronary artery. Cardiac systolic function was assessed via echocardiography. Histopathological alterations in myocardial tissue were evaluated by hematoxylin and eosin (HE) staining, while the extent of myocardial infarction was determined through triphenyltetrazolium chloride (TTC) staining. Serum levels of CK-MB, cTnT, and LDH were quantified through ELISA. An AMI cell model was established by subjecting H9C2 cardiomyoblasts to hypoxic conditions. Exosomes were isolated from BMSCs, and their effects on cardiomyocyte injury were investigated. Cellular autophagy levels were examined via western blot (WB). The regulatory interplay between miR-98-5p and E2F6 was validated via a dual-luciferase reporter (DLR) assay.

RESULTS: In comparison to the Sham group, myocardial tissue in rats with AMI exhibited significant structural damage, accompanied by reduced autophagic activity and reduced expression of miR-98-5p. In comparison to the AMI + phosphate-buffered saline (PBS) group, treatment with BMSCs-derived exosomes (BMSCs-exo) markedly improved cardiac function and further enhanced autophagy in AMI rats. In vitro, cells subjected to hypoxic conditions displayed diminished viability and proliferative capacity, increased apoptosis, impaired autophagy, and decreased miR-98-5p expression relative to the control group. However, administration of BMSCs-exo restored miR-98-5p expression, mitigated cellular injury, and promoted autophagic activity. Notably, these protective influences were reversed by the addition of the autophagy inhibitor 3-methyladenine (3-MA). DLR assays confirmed a direct regulatory interaction between miR-98-5p and E2F6. Suppression of miR-98-5p resulted in the upregulation of E2F6, thereby attenuating the reparative effects of BMSCs-exo on myocardial tissue and inhibiting autophagy.

CONCLUSION: BMSCs-exo miR-98-5p ameliorates AMI-induced myocardial injury by regulating cardiomyocyte autophagy through targeting E2F6.

PMID:40962448

J Am Coll Cardiol. 2025 Sep 23;86(12):892-906. doi: 10.1016/j.jacc.2025.07.027.

ABSTRACT

BACKGROUND: Intraoperative hypotension is associated with cardiovascular complications after major noncardiac surgery, but randomized trials assessing whether intensive blood pressure management during surgery can reduce these complications have shown inconsistent results.

OBJECTIVES: The purpose of this study was to determine whether intensive intraoperative blood pressure management reduces the incidence of a composite of cardiovascular complications within 30 days after major abdominal surgery.

METHODS: In this investigator-initiated parallel-group trial, patients at 3 Chinese sites were randomly assigned (1:1) to intensive blood pressure management targeting intraoperative MAP ≥80 mm Hg (intensive strategy group) or conventional management targeting intraoperative MAP ≥ the higher of 65 mm Hg or 60% of preoperative baseline pressure (conventional strategy group). We included patients aged ≥45 years who had known cardiovascular disease or cardiovascular risk factors and were scheduled for inpatient abdominal surgery expected to last at least 2 hours. The primary outcome was a composite of myocardial injury or infarction, new-onset clinically important arrhythmias, acute heart failure, stroke, cardiac arrest, and all-cause death within 30 days of surgery.

RESULTS: Between June 30, 2020, and September 23, 2022, 1,500 patients were enrolled, of whom 1,477 were included in the modified intention-to-treat population (739 in the intensive strategy group and 738 in the conventional strategy group). Patients assigned to intensive intraoperative blood pressure management experienced a lower burden of hypotension exposure, as assessed by several measures. For example, the median cumulative duration of MAP <65 mm Hg was 1 minute (Q1-Q3: 0-7 minutes) in the intensive strategy group, compared with 8 minutes (Q1-Q3: 0-20 minutes) in the conventional strategy group. The primary composite outcome occurred in 107 of 739 patients (14.5%) in the intensive strategy group and 100 of 738 patients (13.6%) in the conventional strategy group (relative risk: 1.07; 95% CI: 0.83-1.38; P = 0.61).

CONCLUSIONS: In high-risk patients having major abdominal inpatient surgery, intensive intraoperative blood pressure management targeting a mean arterial pressure ≥80 mm Hg did not reduce the incidence of cardiovascular events compared with the conventional target of ≥65 mm Hg and 60% of the preoperative baseline.

PMID:40962376 | DOI:10.1016/j.jacc.2025.07.027

FASEB J. 2025 Sep 30;39(18):e71033. doi: 10.1096/fj.202501598R.

ABSTRACT

Myocardial ischemia/reperfusion injury (MI/R) remains a major challenge in cardiac transplantation, leading to early graft dysfunction or primary nonfunction, and eventually death. This study explores the role of annexin A4 (ANXA4), a calcium-dependent phospholipid-binding protein, in MI/R pathogenesis and investigates its underlying mechanisms. In C57BL/6J mice, ANXA4 expression was moderately increased following MI/R (induced by 45-min occlusion/24 h reperfusion) (mRNA: sham vs. MI/R = 1.00 vs. 2.42, p < 0.01; protein: 1.00 vs. 2.39, p < 0.05). To assess its functional role, AAV9 particles (1 × 1011 viral genomes per mouse) carrying ANXA4 encoding fragments were intravenously injected into mice 4 weeks before the surgery. The forced elevation of ANXA4 reduced IR-induced myocardial infarction from 41.22% to 18.23%, lowered the ventricular arrhythmias score from 10.83 to 6.00, and creatinine kinase-myocardial band (CK-MB) activity from 450 to 268 U/L. ANXA4 overexpression also inhibited cardiomyocyte apoptosis, inflammation, and oxidative stress. In vitro, ANXA4 overexpression mediated by pcDNA3.1 vector protected HL-1 mouse cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cell damage. Further high-throughput transcriptomics illustrated that ANXA4 upregulation significantly suppressed the expression of the receptor for advanced glycosylation end products (RAGE; Log2 Fold change = -3.19, p < 0.05). Mechanistically, ANXA4 repressed the transcription of RAGE by dampening the nuclear translocation of NFκB p50. Collectively, this study demonstrates that ANXA4 is upregulated in the mouse myocardium post MI/R as a compensatory response, and its overexpression alleviates MI/R- and OGD/R-induced cardiomyocyte injury by preventing NFκB p50 from binding to and initiating transcription of RAGE.

PMID:40960915 | DOI:10.1096/fj.202501598R

JAMA Cardiol. 2025 Sep 17:e253043. doi: 10.1001/jamacardio.2025.3043. Online ahead of print.

ABSTRACT

IMPORTANCE: Animal studies and meta-analysis of human observational data suggest that pneumococcal polysaccharide vaccination (PPV) could be protective against atherosclerosis; however, to the authors' knowledge, no randomized clinical trial has been conducted.

OBJECTIVE: To determine whether pneumococcal vaccination (Pneumovax [Merck Sharp & Dohme Corp]) decreases the composite primary outcome of fatal and nonfatal acute coronary syndrome and ischemic stroke in people at increased risk, with an average follow-up of 7 years after immunization.

DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, placebo-controlled, parallel-arm randomized clinical trial conducted at 6 centers across Australia. Participants were community-dwelling adults 55 to 60 years of age at baseline in 2016 to 2017, with at least 2 risk factors (obesity, hypertension, or hypercholesterolemia) for cardiovascular disease (CVD) but no prior CVD event or indication for early pneumococcal vaccination. Data were analyzed from February 2023 to December 2024 using competing risk proportional hazards regression models, stratified by sex and center.

INTERVENTIONS: Participants received either 23-valent PPV (PPV23) or placebo (saline).

MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of fatal and nonfatal myocardial infarction or ischemic stroke, ascertained via electronic medical records from emergency department, admitted patient, and mortality data collections using International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes.

RESULTS: A total of 4725 participants (mean [SD] age, 58.0 [1.7] years; 2433 male [52%]) were included in this study. There was no significant difference in the primary outcome (58 of 2366 events in the active PPV23 group compared with 64 of 2357 events in the control group, hazard ratio, 0.90; 95% CI, 0.63-1.28; P = .57). Similarly, no significant differences occurred in the exploratory outcomes of all-cause mortality, all-cause hospital presentations, and CVD-related hospital procedures. These results are tempered by the lower than expected event rate leading to low power.

CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial found that PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke, although the study was underpowered.

TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12615000536561.

PMID:40960793 | PMC:PMC12444640 | DOI:10.1001/jamacardio.2025.3043