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.

Antithrombotic Medication and Major Complications After Mechanical Aortic Valve Replacement.

Patients with mechanical aortic valve replacement (AVR) require lifelong vitamin K antagonist (VKA) therapy for stroke and systemic embolism prevention. However, VKA treatment predisposes patients to various types of bleeding. In the present study, we sought to assess the success of antithrombotic therapy and the occurrence and timing of strokes and bleeding events after mechanical AVR. A total of 308 patients who underwent isolated mechanical AVR were included in the study, and follow-up data were completed for 306 patients (99.4%). The median follow-up time was 7.3 (interquartile range 4.2 to 10.9) years. The risk for major bleeding was 5-fold compared with major stroke (6.2% vs 1.3% and 20.9% vs 4.0%, respectively; events rates 3.1 vs 0.5 per 100 patient-years, respectively) at 30-day and long-term follow-up, indicating good efficacy but inadequate safety of stroke prevention. At the time of the early postoperative major bleeding, the international normalized ratio was under the therapeutic range in 73.7% of the patients. However, most patients were on triple antithrombotic treatment consisting of subcutaneous enoxaparin, VKA, and a tail effect of discontinued aspirin. During the long-term follow-up, the most common site of bleeding was gastrointestinal (41.7%), followed by genitourinary bleeding (23.3%) and intracranial hemorrhage (18.3%). Furthermore, mortality was relatively high, with a 10-year survival estimate of 78.3%. In conclusion, although ischemic stroke is a well-identified adverse event after mechanical AVR, it seems that major bleeding is a frequent clinically relevant complication during perioperative and long-term follow-up. This finding underscores the recognition and management of modifiable bleeding risk factors.

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.

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.

Retrospective observational analysis of a coronary artery bypass grafting surgery patient cohort: Off-pump versus on-pump.

Objectives: To determine whether surgical technique has an effect on prognosis in coronary artery bypass grafting (CABG). Design: Retrospective observational. Setting: Single center. Participants: All the off-pump (OPCABG) and on-pump (ONCABG) patients at Turku University Central Hospital in 2018. Interventions: None. Measurements and main results: After propensity score matching, perioperative, 1-year and 3-year mortality did not differ between the groups. The ONCABG patients received more allogenic red blood cells (1.3 vs. 0.6 units, p = 0.020), autologous red blood cells (564 vs. 285 ml, p < 0.001) and crystalloids (3388 vs. 2808 ml, p < 0.001), and had higher postoperative values of troponin T (581 vs. 222, p = 0.001) and lactate (1.69 vs. 1.23, p < 0.001) than the OPCABG patients. Conclusions: The both techniques seem equally safe. However, there may be some benefits to avoiding using a heart-lung machine, such as lower infused fluid volumes. Myocardial damage may also be milder and postoperative hemodynamics more balanced in OPCABG patients, based on lower levels of troponin T and lactate.

Transcatheter and surgical aortic valve replacement in patients with left ventricular dysfunction.

BACKGROUND: Patients with severe aortic stenosis and left ventricular systolic dysfunction have a poor prognosis, and this may result in inferior survival also after aortic valve replacement. The outcomes of transcatheter and surgical aortic valve replacement were investigated in this comparative analysis. METHODS: The retrospective nationwide FinnValve registry included data on patients who underwent transcatheter or surgical aortic valve replacement with a bioprosthesis for severe aortic stenosis. Propensity score matching was performed to adjust the outcomes for baseline covariates of patients with reduced (≤ 50%) left ventricular ejection fraction. RESULTS: Within the unselected, consecutive 6463 patients included in the registry, the prevalence of reduced ejection fraction was 20.8% (876 patients) in the surgical cohort and 27.7% (452 patients) in the transcatheter cohort. Reduced left ventricular ejection fraction was associated with decreased survival (adjusted hazards ratio 1.215, 95%CI 1.067-1.385) after a mean follow-up of 3.6 years. Among 255 propensity score matched pairs, 30-day mortality was 3.1% after transcatheter and 7.8% after surgical intervention (p = 0.038). One-year and 4-year survival were 87.5% and 65.9% after transcatheter intervention and 83.9% and 69.6% after surgical intervention (restricted mean survival time ratio, 1.002, 95%CI 0.929-1.080, p = 0.964), respectively. CONCLUSIONS: Reduced left ventricular ejection fraction was associated with increased morbidity and mortality after surgical and transcatheter aortic valve replacement. Thirty-day mortality was higher after surgery, but intermediate-term survival was comparable to transcatheter intervention. Trial registration The FinnValve registry ClinicalTrials.gov Identifier: NCT03385915.

Objectively measured preoperative physical activity and sedentary behaviour among Finnish patients scheduled for elective cardiac procedures: baseline results from randomized controlled trial.

BACKGROUND: We investigated preoperative physical activity (PA) and sedentary behaviour (SB) in patients scheduled for elective cardiac procedures and compared them with population-based sample of Finnish adults. METHODS: Cardiac patients (n = 139) undergoing cardiac operations carried a triaxial accelerometer for seven days during the month before the procedure. Patients were categorised into four groups according to the procedure: percutaneous coronary intervention or coronary angiography (PCI-CA), coronary artery bypass grafting (CABG), aortic valve replacement (AVR) and mitral valve surgery (MVS). The raw accelerometer data was analyzed with dedicated algorithms to determine metabolic equivalents (METs, 3.5 mL/kg/min of oxygen consumption) of PA. The intensity of PA was divided into two categories: light (LPA, 1.5-2.9 METs) and moderate-to-vigorous (MVPA, ≥ 3.0 METs), while SB represented intensity < 1.5 MET without movements. SB and PA were described as daily means and accumulation from different bout lengths. Daily standing, steps and mean and peak MET-values were calculated. The results were compared between the patient groups and against the reference group from a population-based study FinFit2017. RESULTS: Cardiac patients had fewer daily steps than the FinFit population (p = 0.01), and less SB accumulating from < 20 min bouts (p = 0.002) but more from 20 to 60 min bouts (p = 0.002). Particularly, CABG group had less daily MVPA (p = 0.002) and MVPA accumulating from > 10 min bouts (p < 0.001) than the FinFit population. CONCLUSIONS: We found large differences in PA and SB between the patient groups and the FitFit population, CABG group having the worst activity profile. Also, the variation within the patient groups was wide, which should be considered to individualise the rehabilitation programs postoperatively. Trial registration clinicaltrials.gov (NCT03470246). Registered 19 March 2018, https://clinicaltrials.gov/ct2/show/NCT03470246.

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.

Spinal cord injury during selective cerebral perfusion and segmental artery occlusion: an experimental study.

OBJECTIVES: Since selective cerebral perfusion (SCP) has been used in aortic arch surgical procedures, the core temperature during lower body circulatory arrest (LBCA) has been steadily rising. Simultaneously, the use of a frozen elephant trunk (FET) graft has been increasing. The safe period of LBCA in relation to spinal cord ischaemic tolerance in combination with segmental artery occlusion by the FET procedure has not been defined. METHODS: Sixteen pigs were assigned to undergo 65 (n = 10) or 90 min (n = 6) of SCP at 28°C with LBCA in combination with occlusion of the 8 uppermost segmental arteries in the thoracic (Th) aorta (15-20 cm FET, Th8-level). The follow-up period consisted of a 6-h intensive period and a 5-day observation period. Near-infrared spectroscopy of the collateral network was used to determine spinal cord oxygenation. The neurological status of the patients was evaluated daily, and the brain and the spinal cord were harvested for a histopathological analysis. RESULTS: Five out of 6 pigs after 90 min and 1 out of 10 pigs after 65 min of LBCA died within 48 h of multiorgan failure. Of the survivors in the 65-min group, 6 out of 9 had paraparesis/paraplegia; the remaining 3 reached normal function. The lone survivor after 90 min of LBCA was paraplegic. Nadir near-infrared spectroscopy of the collateral network values at Th8 and Th10 were 34 (±5) and 39 (±4), and they were reached within 35 min of SCP in both groups. CONCLUSIONS: An extended FET graft with LBCA and SCP durations >65 min at 28°C results in a poor outcome.

Priming protects the spinal cord in an experimental aortic occlusion model.

OBJECTIVES: Paraplegia is a devastating complication in aortic aneurysm surgery. Modifying the spinal cord vasculature is a promising method in spinal cord protection. The aim of this study was to assess whether the spinal cord can be primed by occluding thoracic segmental arteries before simulated aneurysm repair in a porcine model. METHODS: Twelve piglets were randomly assigned to the priming group (6) and the control group (6). Eight uppermost thoracic segmental arteries were occluded at 5-minute intervals in the priming group before a 25-minute aortic crossclamp. In the control group, the aorta was crossclamped for 25 minutes. During the first 5 minutes, 8 segmental arteries were occluded. After the aortic crossclamping, piglets were observed under anesthesia for 5 hours and followed up 5 days postoperatively. Near-infrared spectroscopy, motor-evoked potentials, blood samples, neurology with the modified Tarlov score, and histopathology of the spinal cord were assessed. RESULTS: The median Tarlov score during the first postoperative day was higher in the priming group than in the control group (P = .001). At the end, 50% of the control animals had paraplegia compared with 0% of paraplegia in the priming group. The mean regional histopathologic score differed between the priming group and the control group (P = .02). The priming group had higher motor-evoked potentials during the operation at separate time points. The lactate levels were lower in the priming group compared with the control group (Pg = .001, Pg×t = .18). CONCLUSIONS: Acute priming protects the spinal cord from ischemic injury in an experimental aortic crossclamp model.

Sex-Specific Clinical Outcomes After Treatment of Left Main Coronary Artery Disease. A NOBLE Substudy.

Background: While female sex has been associated with worse outcomes following coronary revascularization, previous analyses in left main coronary artery (LMCA) disease have been conflicting. In addition, a signal that increased mortality may be specific to women treated with percutaneous coronary intervention (PCI) requires further investigation. Methods: Nordic-Baltic-British left main revascularization study (NOBLE) was a randomized trial comparing PCI to coronary artery bypass surgery (CABG) in patients with LMCA disease. The primary endpoint was a composite of all-cause mortality, nonprocedural myocardial infarction, repeat revascularization, and stroke (major adverse cardiovascular and cerebrovascular events [MACCE]). We report the 5-year sex-specific outcomes. Results: Of 1184 patients analyzed, 256 (22%) were female and 928 (78%) were male. There were no significant within-sex differences in baseline characteristics, disease location, or complexity between those treated with PCI and those with CABG. The 5-year MACCE rates were 29% and 15% in females and 28% and 20% in males treated with PCI and CABG, respectively. Within both sexes, there was an increased risk of MACCE with PCI compared with CABG, but no difference in all-cause mortality. On multivariate analysis, female sex was not an independent predictor of MACCE. Conclusions: Following the treatment of LMCA disease, long-term outcomes favored CABG over PCI in both sexes. Importantly, there was no difference in all-cause mortality in females or males at 5 â€‹years.

Physical activity and sedentary behaviour in secondary prevention of coronary artery disease: A review.

Comprehensive management of coronary artery disease (CAD) includes physical exercise as a part of daily lifestyle therapy. Still CAD patients generally have low physical activity (PA) and high sedentary behaviour (SB). This review summarizes the effect of exercise training and habitual PA and SB on physical fitness and quality of life (QoL) as well as on rehospitalizations and mortality in patients with stable CAD, recent acute coronary syndrome (ACS) or recent revascularization. A literature review of the influence of exercise, and PA and SB profiles in secondary prevention of CAD was performed using PubMed. All articles published between January 2001 and April 2019, meeting the inclusion criteria were considered. A total of 25 cross-sectional or prospective studies or randomized controlled trials (RCT) were included to this review. Exercise training was found to improve maximal oxygen consumption, QoL, and to reduce rehospitalizations and mortality among patients with established CAD. Remote PA interventions have not been as effective as the supervised exercise sessions in reducing the clinical endpoints. High SB, especially when combined to low PA, is associated with poor cardiorespiratory fitness and worse long-term prognosis among patients with ACS. In conclusion, exercise training and high PA are beneficial for patients with stable CAD, recent ACS or recent revascularization. High SB is associated with poor cardiopulmonary fitness and increased mortality in ACS patients. Novel tools using online applications and smart devices are promising means to offer remote guidance for PA among patients unable to participate in regular exercise sessions.

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.

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.

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).

Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial.

Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%-50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).

Remote Ischemic Preconditioning in Spinal Cord Protection: A Surviving Porcine Study.

Surgical repair of thoracic aorta can compromise blood flow of the spinal cord. To mitigate spinal cord ischemia (SCI) additional protection methods are needed. In experimental studies remote ischemic preconditioning (RIPC) has proven to be an effective method of protecting organs from ischemia. The aim of the study was to assess efficacy of RIPC in spinal cord protection in a chronic porcine model. Sixteen piglets were assigned into the RIPC group (8) and the control group (8). RIPC was performed using blood pressure cuff in a 5-minute ischemia followed by a 5-minute reperfusion repeating cycles 4 times. The left subclavian artery and all segmental arteries above diaphragm were ligated at 5-minute intervals to accomplish SCI. The follow-up comprised a 4-hour intensive monitoring and a 7-day recovery phase. Blood samples were obtained, motor-evoked potentials and near-infrared spectroscopy (NIRS) of longitudinal back muscles were measured. Paraplegia was assessed every day postoperatively. Histopathological analysis of the spinal cord was performed after 7 days. NIRS values 4 hours after SCI were higher in the RIPC group, 45.5 (44.5-47.0), than in the control group, 41.5 (40.5-44.0) (P = 0.042). Nadir value of NIRS was 43.4 (39.3-46.0) in the RIPC group and 38.9 (38.-40.0) in the control group (P = 0.014). On the first postoperative day the RIPC group reached modified Tarlov score of 3 (2-3) vs 2 (1-2) in the control group (P = 0.024). RIPC hastens the recovery from SCI during the first postoperative day.

Moderate hypothermia with remote ischaemic preconditioning improves cerebral protection compared to deep hypothermia: a study using a surviving porcine model.

OBJECTIVES: The optimal temperature management of hypothermic circulatory arrest is still controversial. Moderate hypothermia preserves cerebral autoregulation and shortens cardiopulmonary bypass (CPB) duration. However, moderate hypothermia alone has inferior organ protection to deep hypothermia, so adjuncts that increase the ischaemic tolerance are needed. Thus, we hypothesized that a combination of remote ischaemic preconditioning (RIPC) and moderate hypothermia would be superior to deep hypothermia alone. METHODS: Sixteen pigs were randomized to either RIPC or control groups (8 + 8). The RIPC group underwent 4 cycles of transient hind limb ischaemia. The RIPC group underwent cooling with CPB to 24°C, and the control group underwent cooling with CPB to 18°C, followed by a 30-min arrest period and subsequent rewarming to 36°C. Measurements of cerebral metabolism were made from sagittal sinus blood samples and common carotid artery blood flow. The permissible periods of hypothermic circulatory arrest were calculated based on these measurements. Neurological recovery was evaluated daily during a 7-day follow-up, and the brain was harvested for histopathological analysis. RESULTS: Six pigs in the RIPC group reached normal neurological function, but none in the control group reached normal neurological function (P = 0.007). The composite neurological score of all postoperative days was higher in the RIPC group than in the control group [55 (52-58) vs 45 (39-51), P = 0.026]. At 24°C, the estimated permissible periods of hypothermic circulatory arrest were 21 (17-25) min in the RIPC group and 11 (9-13) min in the control group (P = 0.007). CONCLUSIONS: RIPC combined with moderate hypothermia provides superior cerebral protection.