Search Results (247)

Over the past four decades, cardioprotective research has revealed an extraordinary complexity of cellular and molecular mechanisms capable of mitigating ischemia/reperfusion injury (IRI). Among these, ischemic conditioning has emerged as one of the most influential discoveries: brief episodes of ischemia followed by reperfusion activate protective programs that reduce myocardial damage. These effects can be elicited locally (pre- or postconditioning) or remotely (remote conditioning), acting mainly through paracrine signaling and mitochondria-linked kinase pathways, with both early and delayed windows of protection. We have contributed to clarifying the roles of mitochondria, oxidative stress, prosurvival kinases, connexins, extracellular vesicles, and sterile inflammation, particularly via activation of the NLRP3 inflammasome. Despite robust preclinical evidence, clinical translation of these approaches has remained disappointing. The challenges largely stem from experimental models that poorly reflect real-world clinical settings—such as advanced age, comorbidities, and multidrug therapy—as well as the reliance on surrogate endpoints that do not reliably predict clinical outcomes. Nevertheless, interest in multi-target protective strategies remains strong. New lines of investigation are focusing on emerging mediators—such as gasotransmitters, extracellular vesicles, and endogenous peptides—as well as targeted modulation of inflammatory responses. Future perspectives point toward personalized cardioprotection tailored to patient metabolic and immune profiles, with special attention to high-risk populations in whom IRI continues to represent a major clinical challenge. Full article

Background: Intravenous thrombolysis (IVT) is the standard treatment for ischemic stroke within 4.5 h of symptom onset. However, a significant proportion of patients present beyond this window. This study aims to evaluate the efficacy and safety of IVT beyond the 4.5 h window in selected patients. Methods: A systematic literature search was conducted across PubMed, Cochrane Library, and Google Scholar from inception to April 2025. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results: A total of 12 RCTs were included, with 3236 patients. Compared to controls, IVT significantly improved excellent functional outcomes [OR: 1.40; 95% CI: 1.21–1.62] and good functional outcomes [OR: 1.26; 95% CI: 1.06–1.50] at 90 days. IVT also improved recanalization [OR: 2.47; 95% CI: 1.96–3.12], reperfusion [OR: 2.20; 95% CI: 1.26–3.84], and early neurological improvement [OR: 1.91; 95% CI: 1.12–3.26]. However, it was associated with a significantly higher risk of symptomatic intracranial hemorrhage (sICH) [OR: 2.17; 95% CI: 1.25–3.79], any ICH [OR: 1.49; 95% CI: 1.09–2.04], and type-II parenchymal hemorrhage (PH) [OR: 2.14; 95% CI: 1.19–3.83]. No significant difference was observed in systemic hemorrhage, 90-day all-cause mortality, 7-day mortality, or 90-day intervention-related mortality (p > 0.05). Conclusions: IVT beyond 4.5 h improves neurological outcomes in patients with ischemic stroke without increasing overall mortality or systemic bleeding, though it raises the risk of sICH, any ICH, and type-II PH. Further large RCTs are needed to confirm these findings and guide clinical practice. Full article

Background/Objectives: Ischemic postconditioning (IP) is a well-established intervention that mitigates this damage by activating endogenous cardioprotective pathways. However, the presence of comorbidities such as dyslipidemia can disrupt these protective mechanisms and abolish the infarct-sparing effect typically induced by IP. In this context, identifying pharmacological strategies to restore cardioprotection is of clinical relevance. This study aimed to evaluate whether N-acetylcysteine (NAC), a glutathione precursor with antioxidant properties, can restore the infarct-limiting effect of IP compromised by HFD-induced oxidative stress. Methods: Male mice were fed a control diet (CD) or HFD for 12 weeks. NAC (10 mM) was administered in drinking water for 3 weeks before ex vivo myocardial ischemia/reperfusion (I/R) injury (30 min ischemia/60 min reperfusion). In IP groups, six cycles of brief I/R were applied at the onset of reperfusion. Infarct size, ventricular function, redox status (GSH/GSSG), lipid profile, and histology were evaluated. Results: NAC improved the lipid profile (HDL/non-HDL ratio) and enhanced the infarct-sparing effect of IP in CD-fed mice. In HFD-fed mice, NAC restored the efficacy of IP, significantly reducing infarct size (HFD-I/R-NAC: 39.7 ± 4.5% vs. HFD-IP-NAC: 26.4 ± 2.0%, p < 0.05) without changes in ventricular function. The ratio of oxidized/reduced glutathione (GSSG/GSH) is depicted. Under basal conditions, the hearts of mice fed an HFD exhibited a shift towards a more oxidized state compared to the control diet CD group. In the I/R protocol, a significant shift towards a more oxidized state was observed in both CD and HFD-fed animals. In the IP protocol, the GSSG/GSH ratio revealed a tendency to basal values in comparison to the I/R protocol. The analysis indicates that animals subjected to I/R and IP protocols in conjunction with NAC show a tendency to reach basal values, thus suggesting a potential for the reduction in ROS. Conclusions: NAC treatment mitigates oxidative stress and restores the cardioprotective effect of ischemic postconditioning in a model of early-stage atherosclerosis. These findings support NAC as a potential adjunct therapy to improve myocardial resistance to reperfusion injury under dyslipidemic conditions Full article

Background: Ischemia–reperfusion injury (IRI) is a key contributor to graft dysfunction in kidney transplantation. Cell-free mitochondrial DNA (mtDNA) is increasingly recognized as a damage-associated molecular pattern (DAMP) and biomarker in IRI, but its prognostic role in living donor kidney transplantation (LDKT) remains unclear. Methods: This post hoc analysis of the VAPOR-1 study evaluated urinary mtDNA (UmtDNA) in 57 LDKT recipients. MtDNA levels (ND1, ND6, and D-loop) were measured at five early timepoints post-transplantation using qPCR. Associations between early UmtDNA and long-term graft function, defined by estimated glomerular filtration rate (eGFR) at 1, 12, and 24 months, were analyzed. Results: Higher UmtDNA levels in the first urine after reperfusion were significantly associated with improved eGFR at 12 months and a positive change in eGFR between month 1 and 24. These associations were not attributable to urine creatinine levels or mitochondrial copy number. Conclusions: In this LDKT cohort, elevated early UmtDNA may reflect a well-functioning graft capable of clearing systemic mtDNA rather than ongoing tubular injury. These findings suggest that the biological interpretation of mtDNA as a biomarker is context-dependent and call for careful reconsideration of its role in early transplant monitoring. Full article

Background: Antegrade root cardioplegia remains the most popular strategy for myocardial protection during coronary artery bypass graft (CABG) performed with cardiopulmonary bypass (CPB) and aortic cross clamp. In patients with depressed left ventricular function, however, especially if associated with severe multiple coronary stenosis, increased pharmacological and/or mechanical support in the early post-CPB period is often required to support left ventricular recovery. In this study, we analyzed the results of a myocardial protection strategy that includes selective infusion of cardioplegia through each venous graft followed by warm reperfusion distal to each coronary anastomosis until complete removal of the aortic clamp (total antegrade cardioplegia infusion and warm reperfusion = TAWR) to improve early postoperative recovery in patients with depressed left ventricular function undergoing multi-vessel CABG. Methods: Out of 97 patients undergoing CABG using the TAWR strategy for myocardial protection, 32 patients presented with depressed left ventricle function (EF < 40%) and multi-vessel coronary diseases requiring ≥2 vein grafts and were enrolled as Group A. Combined primary outcomes and postoperative early and late left ventricle recovery (including spontaneous rhythm recovery, inotropic support and postoperative troponin release) were analyzed and compared with those of 32 matched patients operated on using standard antegrade root cardioplegia and limited warm reperfusion through LIMA graft (SAWR) enrolled as Group B. Results: Two patient died in hospital (in-hospital mortality 3.1%) with no statistical differences between the two groups. In Group A 27 patients (90%) had spontaneous recovery of idiopathic rhythm compared to 17 (53%) in group B (p = 0.001). Early inotropic support was required in nine patients (28%) of group A and seventeen patients (53%) of group B (p = 0.041). Furthermore, in eight patients (25%) of group A and seventeen (53%) of group B (p = 0.039) inotropic support was continued for >48 h. Conclusions: The TAWR strategy seems to significantly improve early postoperative cardiac recovery in patients with left ventricle depression undergoing multi-vessel CABG, when compared with SAWR strategy and could therefore be considered the strategy of choice in this subset of patients. Full article

Surgical myocardial revascularization, regardless of the technique used, causes ischemia–reperfusion injury (IRI) in the myocardium mediated by inflammation and degradation of the endothelial glycocalyx (EG). We investigated the difference between on-pump and off-pump techniques in terms of the concentration of proinflammatory interleukin (IL)-18 and the EG degradation products syndecan-1 and hyaluronic acid measured by ELISA in the peripheral and cardiac circulation during open heart surgery and in the early postoperative period. The concentration of IL-18, C-reactive protein (CRP), and cardiac troponin T (cTnT) and the leukocyte count increased statistically significantly in revascularized patients at 24 and 72 h after revascularization compared to the beginning of the procedure and was always statistically significantly higher in on-pump patients. Syndecan-1 and hyaluronic acid only increased in on-pump patients 24 and 72 h after revascularization. IL-18 correlated positively with syndecan-1 and CRP only in the pump setting and with the number of leukocytes in both revascularization regimens 24 and 72 h after the surgery. cTnT and hyaluronic acid did not correlate with IL-18. Our results suggest that IL-18 plays an important role in the early inflammatory response in patients during open heart surgery and in the early postoperative period, leading to additional damage to the EG, while it is probably not responsible for myocardial necrosis. It could serve as a biomarker to identify high-risk patients and as a therapeutic target to reduce inflammation and EG degradation. In addition, measurement of IL-18 could help improve the treatment, recovery, and outcomes of patients after heart surgery. Full article

Background: Among patients with congenital heart disease, particularly those with a history of undergoing the Fontan operation, pregnancy presents a significant maternal–fetal risk, especially when complicated by severe valvular dysfunction. Lung reperfusion syndrome (LRS) is a rare but life-threatening complication occurring following valve intervention. Multidisciplinary management, including by Cardio-Obstetrics teams, is essential for optimizing outcomes in such high-risk cases. Methods: We present the case of a 37-year-old pregnant patient with previously repaired tetralogy of Fallot (via the Fontan procedure) who presented at 24 weeks gestation with worsening severe pulmonary stenosis and right-ventricular dysfunction. The patient had been lost to cardiac follow-up for over a decade. She experienced recurrent arrhythmias, including supraventricular and non-sustained ventricular tachycardia, prompting hospital admission. A multidisciplinary team recommended transcatheter pulmonic valve replacement (TPVR), performed at 28 weeks’ gestation. Results: Post-TPVR, the patient developed acute hypoxia and hypotension, consistent with Lung Reperfusion Syndrome, necessitating intensive cardiopulmonary support. Despite initial stabilization, progressive maternal respiratory failure and fetal compromise led to an emergent cesarean delivery. The neonate’s neonatal intensive care unit (NICU) course was complicated by spontaneous intestinal perforation, while the mother required intensive care unit (ICU)-level care and a bronchoscopy due to new pulmonary findings. She was extubated and discharged in stable condition on postoperative day five. Conclusions: This case underscores the complexity of managing severe congenital heart disease and valve pathology during pregnancy. Lung reperfusion syndrome should be recognized as a potential complication following TPVR, particularly in pregnant patients with Fontan physiology. Early involvement of a multidisciplinary Cardio-Obstetrics team and structured peripartum planning are critical to improving both maternal and neonatal outcomes. Full article

Objectives: Contrast-induced acute kidney injury (CI-AKI) remains a frequent and serious complication after cardiac catheterization. Sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, plays a central role in renal protection against ischemia-reperfusion injury, inflammation, and vascular dysfunction. We aimed to investigate whether serum SIRT1 levels could serve as an early diagnostic biomarker for CI-AKI. Methods: This prospective case-control study included 50 patients undergoing elective percutaneous coronary intervention (PCI) for stable angina. Serum SIRT1 levels were measured at baseline, 24 h, and 72 h post-PCI. The occurrence of CI-AKI was defined by a standard rise in serum creatinine, and patients were stratified accordingly. Results: Although SIRT1 levels tended to be lower in patients who developed CI-AKI (n = 17) compared to those without (n = 33), the differences were not statistically significant at any time point (p > 0.05). However, a significant between-group difference was observed in the 72-h change in SIRT1 levels (Δ0–72 h, p = 0.037), with a greater decline in the CI-AKI group. Multivariable logistic regression also revealed a trend-level inverse association between 72-h SIRT1 levels and CI-AKI (β = −0.536, p = 0.099). Conclusions: While SIRT1 is biologically plausible as a renal protective factor, our findings suggest that serial SIRT1 measurement may offer added value as a dynamic biomarker rather than a static diagnostic tool. Confirmatory trials incorporating serial SIRT1 measurements may help translate this molecular signal into clinically actionable tools for early detection of CI-AKI. Full article

Background: Cardiogenic shock (CS) is a life-threatening complication of ST-elevation myocardial infarction (STEMI) and remains the leading cause of in-hospital mortality, with rates ranging from 5 to 10% despite advances in reperfusion strategies. Early identification and timely intervention are critical for improving outcomes. This study investigates the utility of machine learning (ML) models for predicting the risk of CS during the early phases of care—prehospital, emergency department (ED), and cardiology-on-call—with a focus on accurate triage and prioritization for urgent angiography. Results: In the prehospital phase, the Extra Trees classifier demonstrated the highest overall performance. It achieved an accuracy (ACC) of 0.9062, precision of 0.9078, recall of 0.9062, F1-score of 0.9061, and Matthews correlation coefficient (MCC) of 0.8140, indicating both high predictive power and strong generalization. In the ED phase, the support vector machine model outperformed others with an ACC of 78.12%. During the cardiology-on-call phase, Random Forest showed the best performance with an ACC of 81.25% and consistent values across other metrics. Quadratic discriminant analysis showed consistent and generalizable performance across all early care stages. Key predictive features included the Killip class, ECG rhythm, creatinine, potassium, and markers of renal dysfunction—parameters readily available in routine emergency settings. The greatest clinical utility was observed in prehospital and ED phases, where ML models could support the early identification of critically ill patients and could prioritize coronary catheterization, especially important for centers with limited capacity for angiography. Conclusions: Machine learning-based predictive models offer a valuable tool for early risk stratification in STEMI patients at risk for cardiogenic shock. These findings support the implementation of ML-driven tools in early STEMI care pathways, potentially improving survival through faster and more accurate decision-making, especially in time-sensitive clinical environments. Full article

Brain ischemia-reperfusion (IR) injury is a critical pathological process that leads to extensive neuronal death, with hippocampal pyramidal cells, particularly those in the cornu Ammonis 1 (CA1) subfield, being highly vulnerable. Until now, human olfactory mitral cell resistance to IR injury has not been directly studied, but olfactory dysfunction in humans is frequently reported in systemic vascular conditions such as ischemic heart failure and may serve as an early clinical marker of neurological or cardiovascular disease. Mitral cells, the principal neurons of the olfactory bulb (OB), exhibit remarkable resistance to IR injury, suggesting the presence of unique molecular adaptations that support their survival under ischemic stress. Several factors may contribute to the resilience of mitral cells. They have a lower susceptibility to excitotoxicity, mitigating the harmful effects of excessive glutamate signaling. Additionally, they maintain efficient calcium homeostasis, preventing calcium overload—a major trigger for cell death in vulnerable neurons. Mitral cells may also express high baseline levels of antioxidant enzymes and their activities, counteracting oxidative stress. Their robust mitochondrial function enhances energy production and reduces susceptibility to metabolic failure. Furthermore, neuroprotective signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated antioxidative responses, further bolster their resistance. In addition to these intrinsic mechanisms, the unique microvascular architecture and metabolic support within the olfactory bulb provide an extra layer of protection. By comparing mitral cells to ischemia-sensitive neurons, key vulnerabilities—such as oxidative stress, excitotoxicity, calcium dysregulation, and mitochondrial dysfunction—can be identified and potentially mitigated in other brain regions. Understanding these molecular determinants of neuronal survival may offer valuable insights for developing novel neuroprotective strategies to combat IR injury in highly vulnerable areas, such as the hippocampus and cortex. Full article

Background: While early risk stratification in STEMI is essential, the threat of cardiogenic shock (CS) persists after revascularization due to reperfusion injury and evolving instability. However, risk prediction in later phases—after revascularization—is less explored, despite its importance in guiding intensive care decisions. This study evaluates machine learning (ML) models for dynamic risk assessment in interventional cardiology and cardiac intensive care unit (CICU) phases, where timely detection of deterioration can guide treatment escalation. Methods: We retrospectively analyzed clinical and procedural data from 158 patients diagnosed with STEMI complicated by cardiogenic shock, treated between 2019 and 2022 at the Cardiology Department of the University Emergency Hospital of Bucharest, Romania. Machine learning models—Random Forest (RF), and Quadratic Discriminant Analysis (QDA)—were developed and tested specifically for the interventional cardiology and CICU phases. Model performance was evaluated using area under the receiver operating characteristic curve (ROC-AUC), accuracy (ACC), sensitivity, specificity, and F1-score. Results: In the interventional phase, RF and QDA achieved the highest accuracy, both reaching 87.50%. In the CICU, RF and QDA demonstrate the best performance, reaching ACCs of 0.843. QDA maintained consistent performance across phases. Relevant predictors included reperfusion strategy, TIMI flow before percutaneous coronary intervention (PCI), Killip class, creatinine, and Creatine Kinase Index (CKI)—all parameters routinely assessed in STEMI patients. These models effectively identified patients at risk for post-reperfusion complications and hemodynamic decline, supporting decisions regarding extended monitoring and ICU-level care. Conclusions: Predictive models implemented in advanced STEMI phases can contribute to dynamic, phase-specific risk reassessment and optimize CICU resource allocation. These findings support the integration of ML-based tools into post-PCI workflows, enabling earlier detection of clinical decline and more efficient deployment of intensive care resources. When combined with earlier-stage models, the inclusion of interventional and CICU phases forms a dynamic, end-to-end risk assessment framework. With further refinement, this system could be implemented as a mobile application to support clinical decisions throughout the STEMI care continuum. Full article

Sickle cell disease (SCD) is a monogenic blood disorder characterized by abnormal hemoglobin S production, which polymerizes under hypoxia conditions to produce chronic red blood cell hemolysis, widespread organ damage, and vasculopathy. As a result of vaso-occlusion and ischemia-reperfusion injury, individuals with SCD have recurrent pain episodes, infection, pulmonary disease, and fall victim to early death. Oxidative stress due to chronic hemolysis and the release of hemoglobin and free heme is a key driver of the clinical manifestations of SCD. The net result is the generation of reactive oxygen species that consume nitric oxide and overwhelm the antioxidant system due to a reduction in enzymes such as superoxide dismutase and glutathione peroxidase. The primary mechanism for handling cellular oxidative stress is the activation of antioxidant proteins by the transcription factor NRF2, a promising target for treatment development, given the significant role of oxidative stress in the clinical severity of SCD. In this review, we discuss the role of oxidative stress in health and the clinical complications of SCD, and the potential of NRF2 as a treatment target, offering hope for developing effective therapies for SCD. This task requires our collective dedication and focus. Full article

Antibody-mediated rejection is a critical factor in acute and chronic allograft rejection, with Human Leukocyte Antigen as the primary target of the humoral immune response in kidney transplants. In addition to HLA antibodies, non-HLA Abs also play a significant role in AMR. These non-HLA Abs, which can target either autoantigens or alloantigens, may be present pre-transplantation or develop post-transplant. They are associated with various types of allograft injury. The major non-HLA Abs include those directed against the angiotensin II type 1 receptor, endothelin type A receptor, and MICA, as well as other antigens such as vimentin, collagens, and anti-endothelial cell antibodies. Factors such as ischemia, reperfusion injury, and calcineurin inhibitor toxicity can trigger the pathogenic activity of these Abs. The mechanisms underlying non-HLA Ab production are not yet fully understood but are thought to involve endothelial injury and the exposure of neoantigens. Research indicates that these non-HLA Abs can cause graft injury through both complement-dependent and complement-independent pathways. However, detecting non-HLA Abs remains a challenge due to the lack of reliable diagnostic tools. Current treatment strategies for managing the effects of pathogenic non-HLA Abs include intravenous immunoglobulin, plasmapheresis, rituximab, and bortezomib. Early identification of high-risk patients and timely intervention are crucial to preventing graft failure. This review examines the development, mechanisms, and clinical significance of non-HLA Abs in kidney transplantation, highlighting the need for improved diagnostic methods and tailored therapeutic approaches. Full article

Acute Kidney Injury (AKI) is a severe clinical condition featured by a rapid decrease in kidney function in a short period of time. AKI, which is often secondary to sepsis, ischemia-reperfusion and drug toxicity, is associated to high morbidity and mortality. Moreover, it contributes to the development of chronic kidney disease (CKD), due to maladaptive or incomplete repair mechanisms, resulting in renal fibrosis. Small non-coding RNA has recently emerged as a novel biomarker for the early detection and treatment of AKI. In particular, microRNAs (miRNAs) are non-coding RNA molecules of 21–25 nucleotides regulating the expression of protein-coding genes through sequence-specific recognition. Due to their high stability in biological fluids, such as urine and plasma, they can be reliably analyzed and quantified, and for this reason they can be considered potential diagnostic and therapeutic biomarkers. Specifically, miRNAs have been demonstrated to predict AKI before the increase in creatinine levels, thus improving the management of this syndrome. In this review, we provide a comprehensive overview of the role of urinary and plasma miRNAs in the early detection and treatment of AKI. Full article

Introduction: Postreperfusion syndrome (PRS) is associated with complications following liver transplantation (LT). Mannitol may play a role in attenuating PRS as a free radical scavenger. This study aimed to evaluate the association between intraoperative mannitol administration and the incidence of PRS and postoperative acute kidney injury (AKI) in LT. Methods: A retrospective analysis of adult liver-only transplantation between August 2019 and January 2023 at the Mount Sinai Hospital was performed. Patients in the mannitol group received 25G of the drug intravenously prior to reperfusion. Any recipients with pre-existing renal diagnoses were excluded. Demographic, laboratory, intraoperative, and hospital course data were extracted from an institutional data warehouse. Multivariable logistic regressions were used to evaluate the association between mannitol administration and PRS, AKI, early allograft dysfunction, and postoperative cardiac complications. Negative binomial regression was used to evaluate the association with postoperative length of stay (LOS) and ICU LOS. Results: 495 LT cases were included. A total of 81 patients received mannitol before graft reperfusion, while 414 patients did not. The incidence of PRS in patients who received mannitol was 13% and 17% for those who did not receive mannitol (p = 0.53). Additionally, 79% of patients who received mannitol experienced AKI at 7 days, compared to 73% in those who did not receive mannitol (p = 0.48). In the multivariable regression models, mannitol administration was not associated with decreased incidence of PRS or postoperative AKI. It was, however, associated with increased postoperative cardiac complications (risk-adjusted odds ratio 2.70, 95% confidence interval 1.15–6.14, p = 0.02). Conclusions: Mannitol administration during LT was not an effective therapy for reducing PRS or postoperative AKI. Full article