Effect of Cyclosporine on Cytokine Production in Elective Coronary Artery Bypass Grafting: A Sub-Analysis of the CiPRICS (Cyclosporine to Protect Renal Function in Cardiac Surgery) Study.

OBJECTIVES: The augmented inflammatory response to cardiac surgery is a recognized cause of postoperative acute kidney injury. The present study aimed to investigate the effects of preoperative cyclosporine treatment on cytokine production and delineate factors associated with postoperative kidney impairment. DESIGN: A randomized, double-blind, placebo-controlled, single-center study. SETTING: At a tertiary care, university hospital. PARTICIPANTS: Patients eligible for elective coronary artery bypass grafting surgery; 67 patients were enrolled. INTERVENTIONS: Patients were randomized to receive 2.5 mg/kg cyclosporine or placebo before surgery. Cytokine levels were measured after the induction of anesthesia and 4 hours after the end of cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Tissue-aggressive (interleukin [IL]-1ß, macrophage inflammatory protein [MIP]-1ß, granulocyte colony-stimulating factor [G-CSF], IL-6, IL-8, IL-17, MCP-1), as well tissue-lenient (IL-4) cytokines, were significantly elevated in response to surgery. Changes in cytokine levels were not affected by cyclosporine pretreatment. CONCLUSIONS: Elective coronary artery bypass grafting surgery with cardiopulmonary bypass triggers cytokine activation. This activation was not impacted by preoperative cyclosporine treatment.

Myocardial injury biomarkers at point of care for early identification of primary graft dysfunction after heart transplantation.

INTRODUCTION: Primary graft dysfunction (PGD) is a leading cause of 30-day mortality following heart transplantation, and early intervention in PGD may correlate to improved survival. Our analysis aimed to determine the feasibility of measuring cardiac biomarkers from the donor heart in the early phase for use as a predictor of PGD. METHODS: Blood samples from the coronary sinus were obtained at the time of transplantation in hearts preserved by cold static storage. The samples were analyzed for CK-MB and cTnI with a point-of-care method. The primary outcome was severe PGD or the need for veno-arterial extracorporeal membrane oxygenation within 7 days, referred to as severe graft dysfunction. RESULTS: Of the total cohort (n = 63), eight patients (13%) were diagnosed with severe graft dysfunction within 7 days. Patients with high CK-MB had an increased risk for severe graft dysfunction with unadjusted Odds Ratio (OR) of 4.5 (95%CI .96-21.11 P = .057) and adjusted OR of 7.4 (95%CI 1.13-48.46, P = .037. Similar but non significant trends were observed for cTnI. CONCLUSION: By measuring CK-MB from the coronary effluent in the donor heart, it may be possible to identify patients at increased risk for severe PGD after heart transplantation.

A nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation.

Pre-clinical heart transplantation studies have shown that ex vivo non-ischemic heart preservation (NIHP) can be safely used for 24 h. Here we perform a prospective, open-label, non-randomized phase II study comparing NIHP to static cold preservation (SCS), the current standard for adult heart transplantation. All adult recipients on waiting lists for heart transplantation were included in the study, unless they met any exclusion criteria. The same standard acceptance criteria for donor hearts were used in both study arms. NIHP was scheduled in advance based on availability of device and trained team members. The primary endpoint was a composite of survival free of severe primary graft dysfunction, free of ECMO use within 7 days, and free of acute cellular rejection ≥2R within 180 days. Secondary endpoints were I/R-tissue injury, immediate graft function, and adverse events. Of the 31 eligible patients, six were assigned to NIHP and 25 to SCS. The median preservation time was 223 min (IQR, 202-263) for NIHP and 194 min (IQR, 164-223) for SCS. Over the first six months, all of the patients assigned to NIHP achieved event-free survival, compared with 18 of those assigned to SCS (Kaplan-Meier estimate of event free survival 72.0% [95% CI 50.0-86.0%]). CK-MB assessed 6 ± 2 h after ending perfusion was 76 (IQR, 50-101) ng/mL for NIHP compared with 138 (IQR, 72-198) ng/mL for SCS. Four deaths within six months after transplantation and three cardiac-related adverse events were reported in the SCS group compared with no deaths or cardiac-related adverse events in the NIHP group. This first-in-human study shows the feasibility and safety of NIHP for clinical use in heart transplantation. ClinicalTrial.gov, number NCT03150147.

The influence of ischemia and reperfusion time on outcome in heart transplantation.

Ischemia/reperfusion may lead to graft dysfunction in heart transplantation (HT). The purpose of this study was to evaluate the influence of ischemic and reperfusion time on acute cellular rejection (ACR) within the first-year post-HT and on long-term outcomes. Data were collected from 331 patients (mean age 49 ± 12 y, 28% females) who underwent HT 1988-2016. Endomyocardial biopsies obtained within the first year after HT were graded according to the 2004-ISHLT-WF. We classified the patients by ischemic time 4 hours, and of these, 31 (55%) patients had reperfusion with CPB ≥90 minutes. Ischemia >4 hours had an increased risk of ACR ≥ 2R during the first year (adjusted OR = 3.1, P = .016); however, an extended reperfusion ≥90 minutes reduced the risk (adjusted OR = 0.25, P = .024). The conditional probability of surviving 10 years post-transplant, given that the patients already survived first year, was inferior for recipients with ischemia ≥ 4 hours and reperfusion <90 minutes, 59%, compared with the other groups 83%, P = .016. Prolonged reperfusion appears to reduce the risk for ACR ≥ 2R and improve long-term survival.

Sevoflurane provides better haemodynamic stability than propofol during right ventricular ischaemia-reperfusion.

OBJECTIVES: To assess whether sevoflurane provides better haemodynamic stability than propofol in acute right ventricular (RV) ischaemia-reperfusion. METHODS: Open-chest pigs (mean ± standard deviation, 68.8 ± 4.2 kg) anaesthetized with sevoflurane (n = 6) or propofol (n = 6) underwent 60 min of RV free wall ischaemia and 150 min of reperfusion. Haemodynamic parameters and blood flow in the 3 major coronary arteries were continuously monitored. Biomarkers of cardiac ischaemia were analysed. RESULTS: Mean arterial pressure and stroke volume decreased, whereas pulmonary vascular resistance increased equally in both groups. Heart rate increased 7.5% with propofol (P < 0.05) and 17% with sevoflurane (P < 0.05). At reperfusion, left atrial pressure and systemic vascular resistance decreased with sevoflurane. While RV stroke work (mmHg·ml) and cardiac output (l·min-1) decreased in the propofol group (4.2 ± 1.2 to 2.9 ± 1.7 and 2.65 ± 0.44 to 2.28 ± 0.56, respectively, P < 0.05 both), they recovered to baseline levels in the sevoflurane group (4.1 ± 1.5 to 4.0 ± 1.5 and 2.77 ± 0.6 to 2.6 ± 0.5, respectively, P > 0.05). Circumflex and left anterior descending coronary artery blood flow decreased in both groups. Right coronary artery blood flow (ml·min-1) decreased with propofol (38 ± 9 to 28 ± 9, P < 0.05), but not with sevoflurane (28 ± 11 to 28 ± 17, P > 0.05). Biomarkers of cardiac ischaemia increased in both groups. CONCLUSIONS: Compared to propofol, sevoflurane-anaesthetized pigs showed higher RV stroke work, cardiac output and right coronary artery blood flow during reperfusion. These findings warrant a clinical trial of sevoflurane in RV ischaemia in humans.

Cyclosporine before Coronary Artery Bypass Grafting Does Not Prevent Postoperative Decreases in Renal Function: A Randomized Clinical Trial.

BACKGROUND: Acute kidney injury is a common complication after cardiac surgery, leading to increased morbidity and mortality. One suggested cause for acute kidney injury is extracorporeal circulation-induced ischemia-reperfusion injury. In animal studies, cyclosporine has been shown to reduce ischemia-reperfusion injury in the kidneys. We hypothesized that administering cyclosporine before extracorporeal circulation could protect the kidneys in patients undergoing cardiac surgery. METHODS: The Cyclosporine to Protect Renal Function in Cardiac Surgery (CiPRICS) study was an investigator-initiated, double-blind, randomized, placebo-controlled, single-center study. The primary objective was to assess if cyclosporine could reduce acute kidney injury in patients undergoing coronary artery bypass grafting surgery with extracorporeal circulation. In the study, 154 patients with an estimated glomerular filtration rate of 15 to 90 ml · min · 1.73 m were enrolled. Study patients were randomized to receive 2.5 mg/kg cyclosporine or placebo intravenously before surgery. The primary endpoint was relative plasma cystatin C changes from the preoperative day to postoperative day 3. Secondary endpoints included biomarkers of kidney, heart, and brain injury. RESULTS: All enrolled patients were analyzed. The cyclosporine group (136.4 ± 35.6%) showed a more pronounced increase from baseline plasma cystatin C to day 3 compared to placebo (115.9 ± 30.8%), difference, 20.6% (95% CI, 10.2 to 31.2%, P < 0.001). The same pattern was observed for the other renal markers. The cyclosporine group had more patients in Risk Injury Failure Loss End-stage (RIFLE) groups R (risk), I (injury), or F (failure; 31% vs. 8%, P < 0.001). There were no differences in safety parameter distribution between groups. CONCLUSIONS: Administration of cyclosporine did not protect coronary artery bypass grafting patients from acute kidney injury. Instead, cyclosporine caused a decrease in renal function compared to placebo that resolved after 1 month.

Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS): a study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study.

INTRODUCTION: Acute kidney injury (AKI) after cardiac surgery is common and results in increased morbidity and mortality. One possible mechanism for AKI is ischaemia-reperfusion injury caused by the extracorporeal circulation (ECC), resulting in an opening of the mitochondrial permeability transition pore (mPTP) in the kidneys, which can lead to cell injury or cell death. Ciclosporin may block the opening of mPTP if administered before the ischaemia-reperfusion injury. We hypothesised that ciclosporin given before the start of ECC in cardiac surgery can decrease the degree of AKI. METHODS AND ANALYSIS: Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS) study is an investigator-initiated double-blind, randomised, placebo-controlled, parallel design, single-centre study performed at a tertiary university hospital. The primary objective is to assess the safety and efficacy of ciclosporin to limit the degree of AKI in patients undergoing coronary artery bypass grafting surgery. We aim to evaluate 150 patients with a preoperative estimated glomerular filtration rate of 15-90 mL/min/1.73 m2. Study patients are randomised in a 1:1 ratio to receive study drug 2.5 mg/kg ciclosporin or placebo as an intravenous injection after anaesthesia induction but before start of surgery. The primary end point consists of relative P-cystatin C changes from the preoperative day to postoperative day 3. The primary variable will be tested using an analysis of covariance method. Secondary end points include evaluation of P-creatinine and biomarkers of kidney, heart and brain injury. ETHICS AND DISSEMINATION: The trial is conducted in compliance with the current version of the Declaration of Helsinki and the International Council for Harmonisation (ICH) Good Clinical Practice guidelines E6 (R1) and was approved by the Regional Ethical Review Board, Lund and the Swedish Medical Products Agency (MPA). Written and oral informed consent is obtained before enrolment into the study. TRIAL REGISTRATION NUMBER: NCT02397213; Pre-results.

Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency.

Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [(13)C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction.

Sevoflurane anesthesia during acute right ventricular ischemia in pigs preserves cardiac function better than propofol anesthesia.

BACKGROUND: The intention of the present study was to evaluate possible cardioprotective properties of inhalation anesthesia with sevoflurane. METHODS AND MATERIALS: A porcine, open-chest model of right ventricular ischemia was used in 7 pigs receiving inhalation anesthesia with sevoflurane. The model was earlier developed and published by our group, using pigs receiving intravenous anesthesia with propofol. They served as controls. The animals were observed for three hours after the induction of right ventricular ischemia by ligation of the main branches supplying the right ventricular free wall. RESULTS: In the sevoflurane group, the cardiac output recovered 2 hours after the induction of ischemia and intact right ventricular stroke work was observed. In the propofol group, no such recovery occurred. The release of troponin T was significantly lower than in the sevoflurane group. CONCLUSIONS: Inhalation anesthesia with sevoflurane seems superior to intravenous anesthesia with propofol in acute right ventricular ischemic dysfunction.

A porcine model for acute ischaemic right ventricular dysfunction.

OBJECTIVES: To establish an experimental model for acute ischaemic isolated right ventricular dysfunction and the subsequent haemodynamic changes. METHODS: An open-chest porcine model with ischaemic dysfunction of the right ventricle induced by ligation of the three main branches supporting the right ventricular free wall. Invasive monitoring of mean arterial blood pressure (MAP), central venous pressure (CVP), left atrial pressure (LAP) and right ventricular pressure (RVP); ultrasonic measurement of cardiac output (CO) and calculation of haemodynamic parameters such as stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and right ventricular stroke work (RVSW) using standard formulae. RESULTS: The ischaemic challenge to the right ventricle resulted in a significant (≥30%) reduction in RVSW associated with an increase (6-25%) in CVP and reduction (8-18%) in pulmonary artery pressure (PAP) despite unchanged PVR, all reflecting the failing right ventricle. There was also a significant drop in CO (14-22%) despite unchanged LAP indicating lessened transpulmonary delivery of left ventricular preload due to the failing right ventricle causing the haemodynamic compromise rather than left ventricular failure. Supraventricular and ventricular arrhythmias occurred in three and two out of seven pigs, respectively-all of which except one were successfully resuscitated with cardioversion and/or defibrillation. CONCLUSIONS: This novel open-chest porcine model of induced ischaemia of the right ventricular free wall resulted in significant haemodynamic compromise confirmed using standard haemodynamic measurements making it useful for further research on acute, ischaemic isolated right ventricular failure.

Functional and pharmacological characteristics of permeability transition in isolated human heart mitochondria.

The objective of the present study was to validate the presence and explore the characteristics of mitochondrial permeability transition (mPT) in isolated mitochondria from human heart tissue in order to investigate if previous findings in animal models of cardiac disorders are translatable to human disease. Mitochondria were rapidly isolated from fresh atrial tissue samples obtained from 14 patients undergoing Maze surgery due to atrial fibrillation. Human heart mitochondria exhibited typical mPT characteristics upon calcium overload such as swelling, evaluated by changes in light scattering, inhibition of respiration and loss of respiratory coupling. Swelling was a morphologically reversible event following transient calcium challenge. Calcium retention capacity (CRC), a quantitative measure of mPT sensitivity assayed by following extramitochondrial [Ca(2+)] and changes in respiration during a continuous calcium infusion, was significantly increased by cyclophilin D (CypD) inhibitors. The thiol-reactive oxidant phenylarsine oxide sensitized mitochondria to calcium-induced mPT. Release of the pro-apoptotic intermembrane protein cytochrome c was increased after, but not before, calcium discharge and respiratory inhibition in the CRC assay. From the present study, we conclude that adult viable heart mitochondria have a CypD- and oxidant-regulated mPT. The findings support that inhibition of mPT may be a relevant pharmacological target in human cardiac disease and may underlie the beneficial effect of cyclosporin A in reperfusion injury.