Cardiopulmonary Bypass Injury Research Articles

Cardiac Surgery-Associated Acute Kidney Injury in Cardiopulmonary Bypass: A Focus on Sex Differences and Preventive Strategies.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a high-risk complication with well-recognized increased morbidity and mortality after cardiac surgery attributable in large part to cardiopulmonary bypass (CPB) associated factors contributing to AKI including hemodilution, hypothermia, hypotension and exposure to artificial surfaces. These conditions disrupt the renal microcirculation and activate local and systemic inflammatory responses to non-pulsatile flow, and low perfusion pressure. The underlying mechanisms of CSA-AKI in CPB are not fully understood, and the incidence of CSA-AKI remains high at around 30%. Furthermore, women appear to be more vulnerable than men to the renal injury associated with CPB even though the overall incidence of cardiovascular and kidney diseases is lower in premenopausal women. Nevertheless, estrogen elicits renoprotective effects in several ways including mitigating inflammation, promoting natriuresis and endothelial protection as shown in preclinical studies. However, women have higher rates of CSA-AKI and these are exacerbated in postmenopausal women. This leads to the conundrum of whether sex, age, and hormonal status differences influence CSA-AKI. In this review, we briefly discuss the pathophysiology of CSA-AKI in CPB, and sex differences in kidney functions with a focus on the possible role of estrogen-specific effects in CPB and also possible differences in CPB in women including greater hemodilution. Further, we review strategies to prevent CSA-AKI in CPB with a highlight for potential sex-specific strategies. Improving our understanding of the impact of sex and sex hormones on CSA-AKI initiation and development will allow us to better manage the CPB strategies delivered to all patients.

The role of CD38 in ischemia reperfusion injury in cardiopulmonary bypass and thoracic transplantation: a narrative review.

Ischemia reperfusion injury (IRI) is often the underlying cause of endothelium breakdown and damage in cardiac or transplantation operations, which can lead to disastrous post-operative consequences. Recent studies of cluster of differentiation 38 (CD38) have identified its critical role in IRI. Our objective is to provide a comprehensive overview of CD38-mediated axis, pathways, and potential CD38 translational therapies for reducing inflammation associated with cardiopulmonary bypass (CPB) or thoracic transplantation and IRI. We conducted a review of the literature by performing a search of the PubMed database on 2 April 2023. To find relevant publications on CD38, we utilized the MeSH terms: "CD38" AND "Ischemia" OR "CD38" AND "Transplant" OR "CD38" AND "Heart" from 1990-2023. Additional papers were included if they were felt to be relevant but were not captured in the MeSH terms. We found 160 papers that met this criterion, and following screening, exclusion and consensus a total of 36 papers were included. CD38 is most notably a nicotine adenine dinucleotide (NAD)+ glycohydrolase (NADase), and a generator of Ca2+ signaling secondary messengers. Ultimately, the release of these secondary messengers leads to the activation of important mediators of cellular death. In the heart and during thoracic transplantation, this pathway is intimately involved in a wide variety of injuries; namely the endothelium. In the heart, activation generally results in vasoconstriction, poor myocardial perfusion, and ultimately poor cardiac function. CD38 activation also prevents the accumulation of atherosclerotic disease. During transplantation, intracellular activation leads to infiltration of recipient innate immune cells, tissue edema, and ultimately primary graft dysfunction (PGD). Specifically, in heart transplantation, extracellular activation could be protective and improve allograft survival. The knowledge gap in understanding the molecular basis of IRI has prevented further development of novel therapies and treatments. The possible interaction of CD38 with CD39 in the endothelium, and the modulation of the CD38 axis may be a pathway to improve cardiovascular outcomes, heart and lung donor organ quality, and overall longevity.

The role and regulatory mechanism of HIF-1α in myocardial injury in rats undergoing cardiopulmonary bypass

Background Hypoxia-inducible factor-1alpha (HIF-1α) is a transcription factor implicated in physiological and pathological responses to hypoxia. The present study aims to investigate the effect and mechanism of HIF-1α on cardiopulmonary bypass (CPB)-related myocardial injury, thereby conferring a theoretical basis for the clinical treatment of myocardial injury in CPB. Methods An experimental model of CPB was established in rats by surgery. Adenovirus-packaged overexpression vectors and antiagomiRNA were used to overexpress HIF-1α and NR4A1 or inhibit miR-124-3p expression in rat myocardial tissues, respectively. qRT-PCR and Western blot detected HIF-1α, miR-124-3p, and NR4A1 expression in myocardial tissues. The rat cardiac function was monitored through an echocardiogram. The rat plasma at different stages of CPB was collected, followed by the detection of IL-6, cTnT, CK-MB, and IL-1β. TUNEL staining measured apoptosis in myocardial tissues. ChIP assay analysed the enrichment of HIF-1α on the miR-124-3p promoter. The binding relationships between HIF-1α and miR-124-3p promoter sequence and between miR-124-3p and NR4A1 3'UTR sequence were confirmed by dual-luciferase reporter assay. Results HIF-1α expression had no significant change after CPB modelling. Overexpression of HIF-1α improved the cardiac function of CPB rats, decreased plasma IL-6, cTnT, CK-MB, and IL-1β levels, and reduced TUNEL-positive myocardial cells. HIF-1α was enriched on the miR-124-3p promoter and promoted miR-124-3p expression. miR-124-3p bound to NR4A1 3'UTR sequence and targeted NR4A1 expression. Inhibition of miR-124-3p or overexpression of NR4A1 partially reversed the ameliorative effect of HIF-1α overexpression on myocardial injury in CPB rats. Conclusion Overexpression of HIF-1α can improve myocardial injury in CPB rats via the miR-124-3p/NR4A1 axis.

Deficiency of Interleukin-36 Receptor Protected Cardiomyocytes from Ischemia-Reperfusion Injury in Cardiopulmonary Bypass.

BackgroundInterleukin-36 has been demonstrated to be involved in inflammatory responses. Inflammatory responses due to ischemia-reperfusion injury following cardiopulmonary bypass (CPB) can cause heart dysfunction or damage.Material/MethodsThe CPB models were constructed in IL-36R−/−, IL-36RN−/−, and wild-type SD rats. Ultrasonic cardiography and ELISA were used to evaluate the cardiac function and measuring myocardial biomarker levels in different groups. TUNEL assay was used to evaluate apoptosis. Western blot assays and RT-PCR were performed to measure the expression of chemokines and secondary inflammatory cytokines in the heart. Oxidative stress in tissue and cultured cells was assessed using a DCFH-DA fluorescence probe and quantification of superoxide dismutase activity.ResultsImproved systolic function and decreased serum levels of myocardial damage biomarkers were found in IL-36R−/− rats compared to WT rats, while worse cardiac function and cardiomyocyte IR injury were observed in IL-36RN−/− rats compared to WT rats. TUNEL staining and Western blot analyses found that cardiomyocyte apoptosis and inflammation were significantly lower in the hearts of IL-36R−/− rats compared with that of WT rats. Oxidative stress was significantly lower in IL-36R−/− rats compared to WT rats. iNOS expression was significantly reduced, while eNOS expression was increased in the hearts of IL-36R−/− rats. Silencing of IL-36R expression in vitro activated SIRT1/FOXO1/p53 signaling in cardiomyocytes.ConclusionsIL-36R deficiency in cardiomyocytes repressed infiltration of bone marrow-derived inflammatory cells and oxidative stress dependent on SIRT1-FOXO1 signaling, thus protecting cardiomyocytes and improving cardiac function in CPB model rats.

Effects of Ulinastatin on Perioperative Inflammatory Response and Pulmonary Function in Cardiopulmonary Bypass Patients.

The aim of this study was to investigate whether ulinastatin (UTL) has protective effects on perioperative proinflammatory cytokines and lung injury in cardiopulmonary bypass (CPB) patients. The study included 60 patients undergoing CPB who were randomly divided into a UTL group and a control group. Blood routine examination and inflammatory cytokines concentrations were detected after anesthetic induction (T1), immediately after aortic valve opening (T2), and 4 (T3) and 24 (T4) hours after weaning from CPB. Flow cytometry was used to detect TLR4 and HSP70 expressions. Arterial blood gas and respiratory function were analyzed at the same time points. Compared with the control group, the levels of IL-2, IL-8, TNF-α, NE, TLR4, PA - aDO2, and RI at T2 were significantly lower, whereas HSP70, PaO2, OI, Cd, and Cs were higher in the UTL group (all P < 0.05). Relative to the control group at T3, white blood cell count, TLR4, IL-2, IL-6, IL-8, TNF-α, NE, and RI decreased significantly, whereas IL-10, HSP70, PaO2, OI, and Cs increased in the UTL group (all P < 0.05). At T4, IL-2, IL-6, IL-8, TNF-α, TLR4, and PaCO2 in the UTL group were significantly lower, and PaO2, IL-10, HSP70, and Cs were higher than in the control group (all P < 0.05). Our data show strong evidence that UTL suppresses proinflammatory cytokine elevation and upregulates release of anti-inflammatory mediators, reducing pulmonary injury and improving pulmonary function after CPB.

Reply to Mohite et al.

Implantation of the HVAD has become an established therapy for left ventricular failure. However, the condition of the critically ill patient with heart failure in the ‘real world’ is often complicated by haemodynamic instability, multiple organ failure and coagulopathy and in some cases compounded by surgical trauma, cardiopulmonary bypass injury and related severe complications such as postoperative bleeding, infection and right heart failure. Therefore, the early mortality in patients with INTERMACS level I, destination therapy and biventricular support is high. A novel implantation technique through small incisions, avoiding cardiopulmonary bypass, may minimize surgical trauma and reduce complication rates and early mortality [3,4]. The device selection strategy in our VAD programme includes primary implantation of an HVAD in all small patients (mostly female), patients with a planned implantation through a lateral thoracotomy (mostly destination therapy), patients with many previous cardiac operations and patients with severely impaired right ventricular function. As all these subgroups have higher perioperative mortality, it is not surprising that our survival rate cannot match the reported survival data from studies carried out for FDA or CE mark approval under completely different conditions. Thrombosis in the LVAD pumps is a severe complication that often results in high mortality. Pump thrombosis is a gradual process; thus, early detection is crucial for successful treatment. The technical sign for thrombosis of the HVAD pump is increased power consumption due to friction. As the flow is calculated linearly from power consumption, it increases simultaneously. A calculated flow of 10 l/min or higher strongly indicates pump thrombosis. Haemolysis with increased lactate dehydrogenase and free haemoglobin levels accompany thrombus formation in the pump. Mohite et al. [1]point out that thrombolytic therapy is preferred by many for the treatment of device thrombosis. At our institution, thrombolytic therapy has not been performed; early pump thrombosis detection is followed by rapid device exchange. As the majority of pump thromboses in our series occurred early after the initial operation, we refrained from performing real thrombolytic therapy (e.g. with tissue plasminogen activator) as the risk of severe bleeding complications would have been too high. Instead, we treated a limited number of patients with tirofiban (Aggrastat); however, with limited success: only 1 patient could be discharged home without device exchange. In the most recent 179 patients since publication [2] treated according to our protocol, the device exchange rate has been almost halved to 4.5% (n= 8), with 2 deaths. Minimally invasive device exchange procedures can be performed with low early mortality and contribute to faster postoperative recovery [5, 6] and should remain an important therapeutic option for patients with pump thrombosis.

Receptor for Advanced Glycation End Products Involved in Lung Ischemia Reperfusion Injury in Cardiopulmonary Bypass Attenuated by Controlled Oxygen Reperfusion in a Canine Model

Controlled oxygen reperfusion could protect the lung against ischemia-reperfusion injury in cardiopulmonary bypass (CPB) by downregulating high mobility group box 1 (HMGB1), a high affinity receptor of HMGB1. This study investigated the effect of controlled oxygen reperfusion on receptor for advanced glycation end products (RAGE) expression and its downstream effects on lung ischemia-reperfusion injury. Fourteen canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest followed by 90 minutes of reperfusion. Animals were randomized to receive 80% FiO2 during the entire procedure (control group) or to a test group receiving a controlled oxygen reperfusion protocol. Pathologic changes in lung tissues, RAGE expression, serum interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated. The lung pathologic scores after 25 and 90 minutes of reperfusion were significantly lower in the test group compared with the control group (p < 0.001). RAGE expression, TNF-α, and IL-6 were downregulated by controlled oxygen treatment (p < 0.001). RAGE might be involved in the lung ischemia-reperfusion injury in canine model of CPB, which was downregulated by controlled oxygen reperfusion.

Intervention of rosiglitazone on myocardium Glut-4 mRNA expression during ischemia–reperfusion injury in cardio-pulmonary bypass in dogs

During cardiac pulmonary bypass (CPB), myocardial ischemia-reperfusion (I/R) induces heart glucose metabolism impairment. Our previous research showed that the decreased glucose utilization is due to decreased glucose transporter-4 (Glut-4) expression and translocation to myocyte surface membranes. This study further examined whether rosiglitazone, a synthetic agonist of peroxisome proliferator-activated receptor γ, could intervene glucose metabolism by regulating Glut-4 mRNA during I/R in dogs. Cardiac ischemia was induced by cardiopulmonary bypass for 30 or 120 min. Plasma insulin and glucose concentrations were measured at pre-bypass (control), aortic cross-clamp off (I/R) at 15, 45, and 75 min. The left ventricle biopsies were taken for the expression of Glut-4 mRNA by real-time RT-PCR. In dogs receiving 120 min ischemia, coronary arterial, venous glucose concentrations, plasma insulin levels, and insulin resistant index (IRI) were increased, but the expression of Glut-4 mRNA was decreased obviously at 15 min of reperfusion, and recovered gradually. On the other hand, these changes were relatively mild in dogs treated with rosiglitazone in cardioplegic solution and expression of Glut-4 mRNA was increased remarkably. It is concluded that the decrease in total amount of Glut-4 mRNA expression could be one of the important molecular mechanisms, which causes the myocardium insulin resistance. The longer the ischemia period, the decrease in amount of Glut-4 mRNA was more dramatic. Adding rosiglitazone into the cardioplegic solution during I/R can increase the amount of Glut-4 mRNA expression, mitigate the myocardium insulin resistance and improve the myocardium I/R injury during CPB.

Controlled oxygen reperfusion protects the lung against early ischemia-reperfusion injury in cardiopulmonary bypasses by downregulating high mobility group box 1

ABSTRACTRestricting oxygen delivery during the reperfusion phase of cardiopulmonary bypass (CPB) protects the heart, but effects on lung ischemia reperfusion (IR) in CPB are unknown. We examined whether extracellular high mobility group box 1 (HMGB1) mediated inflammation during early lung IR injury in CPB. Fourteen healthy canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest, followed by 90 minutes reperfusion. Following surgery, the animals were randomized into control (n = 7) or test (n = 7) groups. Control animals received a constant level of 80% FiO2 during the entire procedure, and the test group received a gradual increase in FiO2 during the first 25 minutes of reperfusion. In the test group, the FiO2 was initiated at 40% and increased by 10% every 5 minutes, to 80%. Histology, lung injury variables, HMGB1 expression, and inflammatory responses were assessed at baseline (T1) and at 25 minutes (T2) and 90 minutes (T3) after starting reperfusion. Treatment with controlled oxygen significantly suppressed lung pathologies, lung injury variables, and inflammatory responses (all P < .001). After lung IR injury, HMGB1 mRNA and protein expressions were significantly decreased in the controlled oxygen group (all P < .001). Controlled oxygen reperfusion is protective in the early stages of lung IR injury in a canine CPB model, and this protection is linked to HMGB1 downregulation.

Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematic review

IntroductionInduction of an inflammatory response is thought to have a significant role in the complications that follow cardiopulmonary bypass (CPB). The statin drugs are increasingly being recognized as having potent anti-inflammatory effects and hence have potential to influence an important mechanism of injury in CPB, although there is no current confirmation that this is indeed the case. Our objective was to systematically review if pre-operative prophylactic statin therapy, compared with placebo or standard of care, can decrease the inflammatory response in people undergoing heart surgery with CPB.MethodsWe performed a systematic and comprehensive literature search for all randomized controlled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylactic statin treatment prior to CPB, with reported outcomes which included markers of inflammation. Two authors independently identified eligible studies, extracted data, and assessed study quality using standardized instruments. Weighted mean difference (WMD) was the primary summary statistic with data pooled using a random effects model. Descriptive analysis was used when data could not be pooled.ResultsEight RCTs were included in the review, with the number of trials for each inflammatory outcome being even more limited. Pooled data demonstrated benefit with the use of statin to attenuate the post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-α) post-CPB (WMD [95% confidence interval (CI)] -23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml [-3.83 to -0.37] respectively). Very limited RCT evidence suggests that prophylactic statin therapy may also decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin.ConclusionsAlthough the RCT evidence may suggest a reduction in post-CPB inflammation by statin therapy, the evidence is not definitive due to significant limitations. Several of the trials were not methodologically rigorous and statin intervention was highly variable in this small number of studies. This systematic review demonstrates that there is a significant gap that exists in the current literature in regards to the potential anti-inflammatory effect of statin therapy prior to CPB.

Comparison the effects of inhalation anaesthetics and TIVA on post-perfusion injury in cardiopulmonary bypass

Comparison the effects of inhalation anaesthetics and TIVA on post-perfusion injury in cardiopulmonary bypass