Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting.

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%-50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool.

Elective Cardiac Procedure Patients Have Low Preoperative Cardiorespiratory Fitness.

Preoperative cardiorespiratory fitness may influence the recovery after cardiac procedure. The aim of this study was to investigate the cardiorespiratory fitness of patients scheduled for elective cardiac procedures, using a six-minute walk test, and compare the results with a population-based sample of Finnish adults. Patients (n=234) awaiting percutaneous coronary intervention or coronary angiography, coronary artery bypass grafting, aortic valve replacement or mitral valve surgery performed the six-minute walk test. VO2max was calculated based on the walk test. The patients were compared to a population-based sample of 60-69-year-old Finnish adults from the FinFit2017 study. The mean six-minute walk test distances (meters) and VO2max (ml/kg/min) of the patient groups were: 452±73 and 24.3±6.9 (coronary artery bypass grafting), 499±84 and 27.6±7.2 (aortic valve replacement), 496±85 and 27.4±7.3 (mitral valve surgery), and 519±90 and 27.3±6.9 (percutaneous coronary intervention or coronary angiography). The population-based sample had significantly greater walk test distance (623±81) and VO2max (31.7±6.1) than the four patient groups (all p-values<0.001). All patient groups had lower cardiorespiratory fitness than the reference population of 60-69-year-old Finnish adults. Particularly the coronary artery bypass grafting group had a low cardiorespiratory fitness, and therefore might be prone to complications and challenging rehabilitation after the operation.

Remote ischemic preconditioning and hypoxia-induced biomarkers in acute myocardial infarction: study on a porcine model.

Objectives. Remote ischemic preconditioning (RIPC) mitigates acute myocardial infarction (AMI). We hypothesized that RIPC reduces the size and severity of AMI and explored molecular mechanisms behind this phenomenon. Design. In two series of experiments, piglets underwent 60 min of the circumflex coronary artery occlusion, resulting in AMI. Piglets were randomly assigned into the RIPC groups (n = 7 + 7) and the control groups (n = 7 + 7). The RIPC groups underwent four 5-min hind limb ischemia-reperfusion cycles before AMI. In series I, the protective efficacy of RIPC was investigated by using biomarkers and echocardiography with a follow-up of 24 h. In series II, the heart of each piglet was harvested for TTC-staining to measure infarct size. Muscle biopsies were collected from the hind limb to explore molecular mechanisms of RIPC using qPCR and Western blot analysis. Results. The levels of CK-MBm (p = 0.032) and TnI (p = 0.007) were lower in the RIPC group. Left ventricular ejection fraction in the RIPC group was greater at the end of the follow-up. The myocardial infarct size in the RIPC group was smaller (p = 0.033). Western blot indicated HIF1α stabilization in the skeletal muscle of the RIPC group. PCR analyses showed upregulation of the HIF target mRNAs for glucose transporter (GLUT1), glucose transporter 4 (GLUT4), phosphofructokinase 1 (PFK1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), enolase 1 (ENO1), lactate dehydrogenase (LDHA) and endothelial nitric oxidate synthase (eNOS). Conclusions. Biochemical, physiologic, and histologic evidence confirms that RIPC decreases the size of AMI. The HIF pathway is likely involved in the mechanism of the RIPC.

Atrial septal defect patients have an elevated risk for infective endocarditis.

Background. It has been unclear whether simple atrial septal defect (ASD) is an independent risk factor for infective endocarditis (IE). This study aimed to untangle the risk of endocarditis in a large nationwide cohort. Methods. We acquired data from the Finnish hospital discharge register on all individuals with ASD diagnosis from 1969 to 2019. Patients with complex congenital cardiac abnormalities were ruled out. Five individualized controls from the general population were matched to the ASD patient's birth year, sex, and residence at the index date. All the patients with ICD-8, -9, or -10 diagnosis codes for IE were gathered from the hospital discharge registry. Results. Altogether, 8322 patients with ASD and 39,237 individualized controls were enrolled in the study. Median follow-up was 21.6 years (IQR 11.8-36.9) from the first hospital contact. In total, 24 (16 male) cases of infective endocarditis among ASD patients and 10 (8 male) cases among controls were diagnosed during the follow-up. The incidence of endocarditis was 0.11 per 1000 person-years in the patients with ASD and 0.011 per 1000 person-years in the controls. The adjusted risk ratio for endocarditis was 13.51 (95% CI: 6.20-29.46) in patients with ASD compared to the control cohort. Patients with ASD and endocarditis had higher long-term mortality than individualized control patients (MRR 2.25, 95% CI: 1.23-4.11). Conclusions. The incidence of IE in patients with ASD was higher than in the general population. Mortality associated with IE was higher in patients with ASD compared to controls.

Long-term outcomes of mechanical versus biological valve prosthesis in native mitral valve infective endocarditis.

Objectives. To study the long-term outcomes of mitral valve replacement with mechanical or biological valve prostheses in native mitral valve infective endocarditis patients. Desing. We conducted a retrospective, nationwide, multicenter cohort study with patients aged ≤70 years who were treated with mitral valve replacement for native mitral valve infective endocarditis in Finland between 2004 and 2017. Results. The endpoints were all-cause mortality, ischemic stroke, major bleeding, and mitral valve reoperations. The results were adjusted for baseline features (age, gender, comorbidities, history of drug abuse, concomitant surgeries, operational urgency, and surgical center). The median follow-up time was 6.1 years. The 12-year cumulative mortality rates were 36% for mechanical prostheses and 74% for biological prostheses (adj. HR 0.40; CI: 0.17-0.91; p = 0.03). At follow-up, the ischemic stroke had occurred in 19% of patients with mechanical prosthesis and 33% of those with a biological prosthesis (adj. p = 0.52). The major bleeding rates within the 12-year follow-up period were 30% for mechanical prosthesis and 13% for a biological prosthesis (adj. p = 0.29). The mitral valve reoperation rates were 13% for mechanical prosthesis and 12% for a biological prosthesis (adj. p = 0.50). Drug abuse history did not have a significant modifying impact on the results (interaction p = 0.51 for mortality and ≥0.13 for secondary outcomes). Conclusion. The use of mechanical mitral valve prosthesis is associated with lower long-term mortality compared to the biological prosthesis in non-elder native mitral valve infective endocarditis patients. The routine choice of biological mitral valve prostheses for this patient group is not supported by the results.

Perioperative Bleeding Requiring Blood Transfusions is Associated With Increased Risk of Stroke After Transcatheter and Surgical Aortic Valve Replacement.

OBJECTIVES: The authors aimed to investigate the impact of severe bleeding and use of red blood cell (RBC) transfusion on the development of postoperative stroke after surgical (SAVR) and transcatheter aortic valve replacement (TAVR), taken from the FinnValve registry. DESIGN: Nationwide, retrospective observational study. SETTING: Five Finnish university hospitals participated in the registry. PARTICIPANTS: A total of 6,463 patients who underwent SAVR (n = 4,333) or TAVR (n = 2,130). INTERVENTIONS: Patients who underwent TAVR or SAVR with a bioprosthesis with or without coronary revascularization. MEASUREMENTS AND MAIN RESULTS: The incidence of postoperative stroke after SAVR was 3.8%. In multivariate analysis, the number of transfused RBC units (odds ratio [OR], 1.098; 95% confidence interval [CI], 1.064-1.133) was one of the independent predictors of postoperative stroke. The incidence of stroke increased, along with the severity of perioperative bleeding, according to the European Coronary Artery Bypass Grafting (E-CABG) bleeding grades were as follows: grade 0, 2.2% (reference group); grade 1, 3.4% (adjusted OR, 1.841; 95% CI, 1.105-3.066); grade 2, 5.5% (adjusted OR, 3.282; 95% CI, 1.948-5.529); and grade 3, 14.8% (adjusted OR, 7.103; 95% CI, 3.612-13.966). The incidence of postoperative stroke after TAVR was 2.5%. The number of transfused RBC units was an independent predictor of stroke after TAVR (adjusted OR, 1.155; 95% CI, 1.058-1.261). The incidence of postoperative stroke increased, along with the severity of perioperative bleeding, as stratified by the E-CABG bleeding grades: E-CABG grade 0, 1.7%; grade 1, 5.3% (adjusted OR, 1.270; 95% CI, 0.532-3.035); grade 2, 10.0% (adjusted OR, 2.898; 95% CI, 1.101-7.627); and grade 3, 30.0% (adjusted OR, 10.706; 95% CI, 2.389-47.987). CONCLUSIONS: Perioperative bleeding requiring RBC transfusion and/or reoperation for intrathoracic bleeding is associated with an increased risk of postoperative stroke after SAVR and TAVR. Patient blood management and meticulous preprocedural planning and operative technique aiming to avoid significant perioperative bleeding may reduce the risk of cerebrovascular complications.

Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial.

BACKGROUND: Percutaneous coronary intervention (PCI) is increasingly used in revascularisation of patients with left main coronary artery disease in place of the standard treatment, coronary artery bypass grafting (CABG). The NOBLE trial aimed to evaluate whether PCI was non-inferior to CABG in the treatment of left main coronary artery disease and reported outcomes after a median follow-up of 3·1 years. We now report updated 5-year outcomes of the trial. METHODS: The prospective, randomised, open-label, non-inferiority NOBLE trial was done at 36 hospitals in nine northern European countries. Patients with left main coronary artery disease requiring revascularisation were enrolled and randomly assigned (1:1) to receive PCI or CABG. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, repeat revascularisation, and stroke. Non-inferiority of PCI to CABG was defined as the upper limit of the 95% CI of the hazard ratio (HR) not exceeding 1·35 after 275 MACCE had occurred. Secondary endpoints included all-cause mortality, non-procedural myocardial infarction, and repeat revascularisation. Outcomes were analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01496651. FINDINGS: Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were enrolled and allocated to PCI (n=598) or CABG (n=603), with 17 subsequently lost to early follow-up. 592 patients in each group were included in this analysis. At a median of 4·9 years of follow-up, the predefined number of events was reached for adequate power to assess the primary endpoint. Kaplan-Meier 5-year estimates of MACCE were 28% (165 events) for PCI and 19% (110 events) for CABG (HR 1·58 [95% CI 1·24-2·01]); the HR exceeded the limit for non-inferiority of PCI compared to CABG. CABG was found to be superior to PCI for the primary composite endpoint (p=0·0002). All-cause mortality was estimated in 9% after PCI versus 9% after CABG (HR 1·08 [95% CI 0·74-1·59]; p=0·68); non-procedural myocardial infarction was estimated in 8% after PCI versus 3% after CABG (HR 2·99 [95% CI 1·66-5·39]; p=0·0002); and repeat revascularisation was estimated in 17% after PCI versus 10% after CABG (HR 1·73 [95% CI 1·25-2·40]; p=0·0009). INTERPRETATION: In revascularisation of left main coronary artery disease, PCI was associated with an inferior clinical outcome at 5 years compared with CABG. Mortality was similar after the two procedures but patients treated with PCI had higher rates of non-procedural myocardial infarction and repeat revascularisation. FUNDING: Biosensors.

Infective endocarditis and outcomes of mitral valve replacement.

BACKGROUND: We investigated the long-term outcomes of mitral valve replacement (MVR) in native mitral valve infective endocarditis (IE). METHODS: Multicentre, population-based cohort register study consisted of 1233 consecutive adult patients treated with first-time MVR in Finland. Mitral valve IE was diagnosed in 170 of these patients. Propensity score matching resulted in 134 pairs with balanced baseline characteristics. The median follow-up was 6.1 years. RESULTS: Pre-operative native mitral valve IE was associated with an increased hazard of 10-year mortality (38.8% vs 30.5%; HR 2.13; CI 1.17-3.85; P = .013) after MVR. Occurrence of major bleeding was higher in IE patients (26.0%) vs non-IE patients (23.4%) during the 10-year follow-up (HR 2.80; CI 1.01-7.77; P = .048). Hospital admission duration after MVR was longer in IE patients (median 28 vs 11 days; P < .0001). Cumulative ischaemic stroke rate was similar between patient groups (12.1% in IE vs 15.1% in non-IE; P = .493). Re-sternotomy was performed in 13.4% of IE patients and 9.0% of non-IE patients (P = .261). CONCLUSIONS: Patients with native mitral valve IE have a higher risk of death and major bleeding after MVR than matched patients without IE. Results highlight the importance of complication prevention in these patients.

Age-Stratified Outcome in Treatment of Left Main Coronary Artery Stenosis: A NOBLE Trial Substudy.

BACKGROUND: In the treatment of left main coronary artery (LMCA) disease, patients' age may affect the clinical outcome after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). This study stratified the clinical outcome according to the age of patients treated for LMCA stenosis with PCI or CABG in the Nordic-Baltic-British Left Main Revascularization (NOBLE) study. METHODS: Patients with LMCA disease were enrolled in 36 centers in northern Europe and randomized 1:1 to treatment by PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST elevation myocardial infarction. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCEs), a composite of all-cause mortality, nonprocedural myocardial infarction, any repeat coronary revascularization, and stroke. Age-stratified analysis was performed for the groups younger and older than 67 years and for patients older than 80 years. RESULTS: For patients ≥67 years, the 5-year MACCEs were 35.7 versus 22.3% (hazard ratio [HR] 1.72 [95% confidence interval [CI] 1.27-2.33], p = 0.0004) for PCI versus CABG. The difference in MACCEs was driven by more myocardial infarctions (10.8 vs. 3.8% HR 3.01 [95% CI 1.52-5.96], p = 0.0009) and more repeat revascularizations (19.5 vs. 10.0% HR 2.01 [95% CI 1.29-3.12], p = 0.002). In patients younger than 67 years, MACCE was 20.5 versus 15.3% (HR 1.38 [95% CI 0.93-2.06], p = 0.11 for PCI versus CABG. All-cause mortality was similar after PCI and CABG in both age-groups. On multivariate analysis, age was a predictor of MACCE, along with PCI, diabetes, and SYNTAX score. CONCLUSIONS: As the overall NOBLE results show revascularization of LMCA disease, age of 67 years or older was associated with lower 5-year MACCE after CABG compared to PCI. Clinical outcomes were not significantly different in the subgroup younger than 67 years, although no significant interaction was present between age and treatment. Mortality was similar for all subgroups (ClinicalTrials.gov identifier: NCT01496651).

Intravenous Interferon-ß1a for the Treatment of Ischemia-Reperfusion Injury in Acute Myocardial Infarct in Pigs.

BACKGROUND: To investigate the potential of intravenously administered porcine recombinant interferon-ß1a (IFN-ß1a) for myocardial protection during acute ischemia-reperfusion (IR) injury in an experimental animal model. METHODS: Twenty-two piglets (mean ± standard deviation, 26.7 ± 1.65 kg) were assigned to either the IFN group (n = 12) or the control group (n = 10). IR injury was induced by occluding the distal left descending coronary artery for 30 minutes, with a reperfusion period of 6 h. In the IFN group, the animals received 12.5 µg IFN-ß1a intravenously repeatedly; the control group received saline solution. The levels of interleukin-6 (IL-6) and cardiac troponin I (TnI) were measured, and the amount of myocardial damage was quantified by analyzing myocardial apoptosis and the mean fluorescence intensity (MFI) of methylene blue-stained cardiac tissue. RESULTS: In the IFN group, significantly more premature deaths occurred compared with the control group (25% versus 17%, P = .013). Between the groups, the mean heart rate was higher in the IFN group (102 ± 22 versus 80 ± 20 beats per minute, P = .02). IL-6 and TnI levels were comparable between the groups, with no significant difference, and there was no difference between the study groups in myocardial apoptosis in the infarcted myocardium. The percentage of MFI differed significantly between the IFN and control groups (90.75% ± 4.90% versus 96.02% ± 2.73%, P = .01). CONCLUSION: In this acute IR injury animal model, IFN-ß1a did not protect the myocardium from IR injury, but rather increased some of the unfavorable outcomes studied.

Remote ischaemic preconditioning may prolong permissible period of hypothermic circulatory arrest in a porcine model.

Objectives. The hypothermic circulatory arrest (HCA) is still of paramount importance in aortic arch surgery, but the safe period of the arrest is limited. Remote ischaemic preconditioning (RIPC) prepares the cerebral tissue for ischaemic insult. Prolongation of the permissible period of HCA with RIPC may have a major impact on the outcome of aortic operations requiring cessation of blood flow by decreasing the rate of neurological deficits. Design. Twenty pigs were randomised into the RIPC group (n = 10) and the control group (n = 10). The RIPC group underwent four cycles of transient hind limb ischaemia. Both groups underwent cooling with cardiopulmonary bypass to 11 °C followed by a 45-minute HCA and re-warming to 36 °C. Cerebral blood flow was measured with a transit time ultrasonic flowmeter from the right common carotid artery, and the arteriovenous oxygen difference was calculated from sagittal sinus and arterial blood samples. Measurements were taken at several time points during cooling and warming. Temperature coefficient (Q10) was calculated to determine estimated permissible periods of HCA. Results. The Q10 was 2.27 (1.98-2.58) for the RIPC group and 1.87 (1.61-2.25) for the control group. The permissible period of HCA at 18 °C was 26 minutes (20-33) in the RIPC group and 17 minutes (13-25) in the control group (p = .063)(Data expressed in medians and interquartile ranges). Conclusions. RIPC tends to suppress cerebral metabolism during cooling with cardiopulmonary bypass and may prolong estimated permissible period of HCA.

Meta-analysis of the Sources of Bleeding after Adult Cardiac Surgery.

OBJECTIVE: The aim of this study was to pool data on the proportion and prognostic impact of sources of bleeding in patients requiring re-exploration after adult cardiac surgery. DESIGN: Systematic review of the literature and meta-analysis. SETTING: Multistitutional study. MEASUREMENTS AND MAIN RESULTS: A literature review was performed to identify studies published since 1990 evaluating the outcome after reoperation for bleeding or tamponade after adult cardiac surgery. Eighteen studies including 5,1497 patients fulfilled the selection criteria. Reoperation for bleeding/tamponade was performed in 2,455 patients (4.6%; 95% confidence interval [CI] 3.9%-5.2%, I2 92%). These had a significantly higher risk of in-hospital/30-day mortality compared with patients not reoperated for bleeding (pooled rates: 9.3% v 2.3%; risk ratio 3.30; 95% CI 2.52-4.32; I2 47%; 8 studies; 25,463 patients). Surgical sites of bleeding were identified in 65.7% of cases (95% CI 58.3%-73.2%; I2 94%), cardiac site bleeding in 40.9% of cases (95% CI 29.7%-52.0%; I2 94%), and mediastinal/sternum site bleeding in 27.0% of cases (95% CI 16.8%-37.3%; I2 94%). The main sites of bleeding were the body of the graft (20.2%), the sternum (17.0%), vascular sutures (12.5%), the internal mammary artery harvest site (13.0%), and anastomoses (9.9%). In metaregression, surgical site bleeding was associated with a lower risk of in-hospital/30-day mortality compared with diffuse bleeding (p = 0.003). CONCLUSIONS: Surgical site bleeding is identified in two-thirds of patients undergoing re-exploration after adult cardiac surgery. Meticulous surgical technique and systematic intraoperative checking of potential surgical sites of bleeding at the time of the original cardiac surgery may reduce the risk of such a severe complication.

Immunohistochemical Analysis of the Spinal Cord Ischemia- Effect of Remote Ischemic Preconditioning in a Porcine Model.

BACKGROUND: In experimental settings, remote ischemic preconditioning (RIPC) has shown a positive effect regarding spinal cord protection after local ischemia. In this study, we conducted spinal cord immunohistochemistry to demonstrate the protective effect of RIPC after 24 hours of the regional ischemia. Methods: Twenty piglets were randomized into an RIPC group (n = 10) and a control group (n = 10). The RIPC group underwent transient left hind limb ischemia before systematic left subclavian artery and segmental artery occlusion at the level of the diaphragm. Twenty-four hours later, the thoracic and lumbar spinal cords were harvested, and the oxidative stress markers were immunohistochemically analysed. Results: A total of 18 animals survived the 4-hour follow up (10 in the RIPC group, 8 in the control group) and 14 animals survived the 24-hour follow up (7 in each group). In the single sections of the spinal cord, the antioxidant pathway activation was seen in the RIPC group, as OGG1 and DJ-1/PARK7 activation was higher (P = .038 and P = .047, respectively). Conclusions: The results indicate that the neuroprotective effect of RIPC on the spinal cord after local ischemic insult remains controversial.

Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.

BACKGROUND: Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. METHODS: In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. FINDINGS: Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1·48 (95% CI 1·11-1·96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0066). As-treated estimates were 28% versus 19% (1·55, 1·18-2·04, p=0·0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1·07, 0·67-1·72, p=0·77) for all-cause mortality, 7% versus 2% (2·88, 1·40-5·90, p=0·0040) for non-procedural myocardial infarction, 16% versus 10% (1·50, 1·04-2·17, p=0·032) for any revascularisation, and 5% versus 2% (2·25, 0·93-5·48, p=0·073) for stroke. INTERPRETATION: The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease. FUNDING: Biosensors, Aarhus University Hospital, and participating sites.

Exploring effects of remote ischemic preconditioning in a pig model of hypothermic circulatory arrest.

OBJECTIVES: During aortic and cardiac surgery, risks for mortality and morbidity are inevitable. Surgical setups involving deep hypothermic circulatory arrest (DHCA) are effective to achieve organ protection against ischemic injury. The aim of this study was to identify humoural factors mediating additive protective effects of remote ischemic preconditioning (RIPC) in a porcine model of DHCA. DESIGN: Twenty-two pigs were randomized into the RIPC group (n = 11) and the control group (n = 11). The RIPC group underwent four 5-minute hind limb ischemia-reperfusion cycles prior to cardiopulmonary bypass and DHCA. All animals underwent identical surgical procedures including 60 min DHCA at 18 °C. Blood samples were collected from vena cava and sagittal sinus at several time points. After the 8-hour follow-up period, the brain, heart, and kidney tissue samples were collected for tissue analyses. RESULTS: Serum levels of brain damage marker S100B recovered faster in the RIPC group, after 4 hours of the arrest, (p < .05). Systemic lactate levels were lower and cardiac index was higher in the RIPC group postoperatively. Immunohistochemical cerebellum regional scores of antioxidant response regulator Nrf2 were better in the RIPC group (mean: 1.1, IQR: 0.0-2.5) compared with the control group (mean: 0.0, IQR: 0.0-0.0), reaching borderline statistical significance (p = .064). RIPC induced detectable modulations of plasma proteome and metabolites. CONCLUSIONS: The faster recovery of S100B, lower systemic lactate levels and favourable regional antioxidant response suggest possible neuronal cellular and mitochondrial protection by RIPC, whereas better cardiac index underlines functional effects of RIPC. The exact humoural factor remains unclear.

Diazoxide Attenuates Ischemic Myocardial Injury in a Porcine Model.

BACKGROUND: We hypothesized that diazoxide, a mitochondrial ATP-sensitive potassium channel opener, has cardioprotective effects during acute myocardial ischemia. Diazoxide is suggested to act through protein kinase Cε (PKCε) activation. METHODS: Twelve piglets were randomly assigned to receive intravenous infusion of diazoxide (3.5 mg/kg) with solvent or only solvent (6 animals per group) before cardiac ischemia. Myocardial ischemia was induced by occluding the left circumflex artery (LCX) for 40 minutes. The reperfusion and follow-up period lasted for three hours. Throughout the experiment hemodynamic measurements and blood samples were collected, and after the follow-up period the hearts were harvested for transmission electron microscopy (TEM) as well as histopathological and immunohistochemical analyses. RESULTS: TEM showed less ischemic damage on a cellular level in the diazoxide group (P = .004) than in the control group. Creatinine kinase MB levels (Pt*g = .030) were lower, and oxygen consumption (Pt*g = .037) and delivery (Pg = .038) were higher in the diazoxide group compared to the controls. CONCLUSION: Diazoxide preserves myocardial cellular structure and cellular function, and thus it may have benefits in treating ischemic myocardial injury.

Pharmacological Preconditioning with Diazoxide in the Experimental Hypothermic Circulatory Arrest Model.

BACKGROUND: Hypothermic circulatory arrest includes a remarkable risk for neurological injury. Diazoxide, a mitochondrial adenosine triphosphate-dependent potassium ion (K+ATP) channel opener, is known to have cardioprotective effects. We assessed its efficacy in preventing ischemic injury in a clinically relevant animal model. Methods: Eighteen piglets were randomized into a diazoxide group (n = 9) and a control group (n = 9). Animals underwent 60 minutes of hypothermic circulatory arrest at 18°C. Diazoxide (5 mg/kg + 10 mL NaOH + 40 mL NaCl) was infused during the cooling phase. Metabolic and hemodynamic data were collected throughout the experiment. After 24-hour follow-up, whole brain, heart, and kidney biopsy specimens were collected for analysis. Results: Cerebellar Cytochrome-C and caspase-3 activation was higher in the control group (P = .02 and P = .016, respectively). Antioxidant activity tended to be higher in the diazoxide group (P = .099). Throughout the experiment, the oxygen consumption ratio was higher in the control animals (Pg = .04), as were the lactate levels (Pg = .02). Cardiac function tended to be better in diazoxide-treated animals. Conclusion: Diazoxide might confer neuroprotective effect as implied by the immunohistochemical analysis of the brain. Additionally, the circulatory effects of diazoxide were beneficial, supporting its neuroprotective effect.

Review of remote ischemic preconditioning: from laboratory studies to clinical trials.

In remote ischemic preconditioning (RIPC) short periods of non-lethal ischemia followed by reperfusion of tissue or organ prepare remote tissue or organ to resist a subsequent more severe ischemia-reperfusion injury. The signaling mechanism of RIPC can be humoral communication, neuronal stimulation, systemic modification of circulating immune cells, and activation of hypoxia inducible genes. Despite promising evidence from experimental studies, the clinical effects of RIPC have been controversial. Heterogeneity of inclusion and exclusion criteria and confounding factors such as comedication, anesthesia, comorbidities, and other risk factors may have influenced the efficacy of RIPC. Although the cardioprotective pathways of RIPC are more widely studied, there is also evidence of benefits in CNS, kidney and liver protection. Future research should explore the potential of RIPC, not only in cardiac protection, but also in patients with threatening ischemia of the brain, organ transplantation of the heart, liver and kidney and extensive cardiovascular surgery. RIPC is generally well-tolerated, safe, effective, and easily feasible. It has a great prospect for ischemic protection of the heart and other organs.

Remote Ischemic Preconditioning Attenuates Oxidative Stress during Cardiopulmonary Bypass.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) is used to overcome the threat of cerebral ischemia during complex surgical operations of the heart and the aortic arch. Remote ischemic preconditioning (RIPC) has been shown to mitigate neurological damage. METHODS: We analyzed blood samples in a consecutive series of 52 piglets that underwent a 60-min period of DHCA with RIPC (the RIPC group) or without (the control group), to reveal whether the protective effect to oxidative stress could be seen by measuring serum 8-hydroxydeoxyguanosine (8-OHdG). The piglets were cannulated and cooled to 18°C using a heart-lung machine, for the DHCA. The piglets were then rewarmed to normothermic temperature. Blood sampling was taken at baseline, after 30 minutes of cooling, 2 hours postoperatively, and 8 hours postoperatively, and analyzed. 8-hydroxydeoxyguanosine (8-OHdG) from blood samples was analyzed by using Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: The serum 8-OHdG concentration was lower in the RIPC group after the cooling phase, 1.84 (1.44-2.17) ng/mL, and at 8 hours after HCA 1.48 (1.39-1.69) ng/mL, when compared with the control group, where the values were 2.14 (1.81-2.56) and 1.84 (1.62-2.44) ng/mL, respectively (P = .025) and (P = .004). CONCLUSION: Remote ischemic preconditioning lowers oxidative stress during cardiopulmonary bypass.

High number of transplanted stem cells improves myocardial recovery after AMI in a porcine model.

OBJECTIVE: The clinical data considering the bone marrow mononuclear cell (BMMNC) therapy in treatment for acute myocardial infarction (AMI) are controversial and the mechanisms remain unknown. Our objective was to study the cardiac function and changes in cytokine levels after administration of BMMNC in experimental AMI model. DESIGN: Unlabeled or Super-Paramagnetic-Iron-Oxide-labeled BMMNCs or saline was injected into myocardium of 31 pigs after circumflex artery occlusion. Ejection fraction (EF) was measured preoperatively, postoperatively and at 21 days by echocardiography. Cardiac MRI was performed postoperatively and after 21 days in 7 BMMNC animals. Serum cytokine levels were measured at baseline, 24 h and 21 days. Cellular homing was evaluated comparing MRI and histology. RESULTS: From baseline to 21 days EF decreased less in BMMNC group (EF mean control -19 SD 12 vs. BMMNC -4 SD 15 percentage points p = 0.02). Cytokine concentrations showed high variability between the animals. MRI correlated with histology in cell detection and revealed BMMNCs in the infarction area. By MRI, EF improved 11 percentage points. The improvement in EF was associated with the number of transplanted BMMNCs detected in the myocardium. CONCLUSION: BMMNC injection after AMI improved cardiac function. Quantity of transplanted BMMNCs correlated with the improvement in cardiac function after AMI.