Vesa Anttila

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.

Remote Ischemic Preconditioning Protects the Brain Against Injury After Hypothermic Circulatory Arrest

Background— Ischemic preconditioning (IPC) is a mechanism protecting tissues from injury during ischemia and reperfusion. Remote IPC (RIPC) can be elicited by applying brief periods of ischemia to tissues with ischemic tolerance, thus protecting vital organs more susceptible to ischemic damage. Using a porcine model, we determined whether RIPC of the limb is protective against brain injury caused by hypothermic circulatory arrest (HCA). Methods and Results— Twelve piglets were randomized to control and RIPC groups. RIPC was induced in advance of cardiopulmonary bypass by 4 cycles of 5 minutes of ischemia of the hind limb. All animals underwent cardiopulmonary bypass followed by 60 minutes of HCA at 18°C. Brain metabolism and electroencephalographic activity were monitored for 8 hours after HCA. Assessment of neurological status was performed for a week postoperatively. Finally, brain tissue was harvested for histopathological analysis. Study groups were balanced for baseline and intraoperative parameters. Brain lactate concentration was significantly lower (P<0.0001, ANOVA) and recovery of electroencephalographic activity faster (P<0.05, ANOVA) in the RIPC group. RIPC had a beneficial effect on neurological function during the 7-day follow-up (behavioral score; P<0.0001 versus control, ANOVA). Histopathological analysis demonstrated a significant reduction in cerebral injury in RIPC animals (injury score; mean [interquartile range]: control 5.8 [3.8 to 7.5] versus RIPC 1.5 [0.5 to 2.5], P<0.001, t test). Conclusions— These data demonstrate that RIPC protects the brain against HCA-induced injury, resulting in accelerated recovery of neurological function. RIPC might be neuroprotective in patients undergoing surgery with HCA and improve long-term outcomes. Clinical trials to test this hypothesis are warranted.

Acute homing of bone marrow-derived mononuclear cells in intramyocardial vs. intracoronary transplantation

Objectives. Cell homing optimisation after transplantation is critical in myocardial infarction (MI) cell therapy. Design. Eight pigs were randomized to receiving autologous purified 111indium-labeled bone marrow mononuclear cells (BMMCs) (108 cells/2 ml) by intramyocardial (IM) (n=4) or by intracoronary (IC) (n=4) transplantation after 90 minutes occlusion of the CX-coronary artery. Dual isotope SPECT imaging was performed 2 and 24 hours postoperatively. Two animals were additionally analyzed on the sixth postoperative day. Tissue samples from the major organs were analyzed. Results. In SPECT imaging revealed that BMMCs administered using IM injection remained in the injured area. In contrast, minor proportion of IC transplanted cells remained in the myocardium, as most of the cells showed homing in the lungs. Analysis of the biopsies showed a seven-fold greater number of cells in the myocardium for the IM method and a 10-fold greater number of cells in the lungs in the IC group (p < 0.001). Conclusions. In producing persistently high cell homing at the infarction site, the IM transplantation is superior to the IC transplantation. However, the IC administration might be more specific in targeting injured capillaries and epithelial cells within the infarcted myocardium.

IS MAINTAINED CRANIAL HYPOTHERMIA THE ONLY FACTOR LEADING TO IMPROVED OUTCOME AFTER RETROGRADE CEREBRAL PERFUSION? AN EXPERIMENTAL STUDY WITH A CHRONIC PORCINE MODEL

BACKGROUND Previous studies have shown that retrograde cerebral perfusion can improve neurologic outcome after prolonged hypothermic circulatory arrest. Here we have compared two temperatures of retrograde cerebral perfusion (15 degrees C and 25 degrees C) with hypothermic circulatory arrest at systemic hypothermia of 25 degrees C to clarify whether the possible benefit of retrograde cerebral perfusion may only be due to improved cooling effect. METHODS Eighteen pigs (23-27 kg) were randomly assigned to undergo 15 degrees C retrograde cerebral perfusion at systemic hypothermia of 25 degrees C, 25 degrees C retrograde cerebral perfusion at 25 degrees C systemic hypothermia, or hypothermic circulatory arrest at 25 degrees C for 40 minutes. Flow was adjusted to maintain superior vena cava pressure at 20 mm Hg during retrograde cerebral perfusion. Hemodynamic, electrophysiologic, metabolic, and temperature monitoring were performed until 4 hours after the start of rewarming. Daily behavioral assessment was done until death or until the animals were killed on day 7. Histopathologic analysis of the brain was carried out on all animals. RESULTS Epidural temperatures were lower in the 15 degrees C retrograde cerebral perfusion group during the intervention (P <.05). In the 15 degrees C retrograde cerebral perfusion group, 4 (67%) of 6 animals survived for 7 days compared with 3 (50%) of 6 in both the 25 degrees C retrograde cerebral perfusion and hypothermic circulatory arrest groups. The median total histopathologic score was 5 in the 15 degrees C retrograde cerebral perfusion group and 7 in the 25 degrees C retrograde cerebral perfusion group (P =.04). CONCLUSIONS These findings suggest that enhanced cranial hypothermia is the major beneficial factor of retrograde cerebral perfusion when careful attention is paid to its implementation.

The Role of Cerebral Microdialysis in Predicting the Outcome after Experimental Hypothermic Circulatory Arrest

Objective –To evaluate whether and which of the cerebral microdialysis parameters are predictive of postoperative outcome after an experimental 75-min period of hypothermic circulatory arrest (HCA) in a chronic porcine model. Design –Seventy-four juvenile female pigs underwent a 75-min period of HCA at 20°C. A microdialysis catheter was placed into the cortex gray matter and brain extracellular concentrations of glucose, lactate, glycerol and glutamate were measured throughout the experiment by enzymatic methods using a microdialysis analyzer. Surviving animals were sacrificed on the 7th postoperative day and histopathological examination of the brain was performed. Results –Brain glucose concentrations were higher in animals that survived ( p = 0.017), especially from the 90-min until the 7-h interval after the start of rewarming. The blood venous concentrations of glucose were also higher among survivors, and correlated significantly with the brain glucose levels at 2-h and 4-h intervals after the start of rewarming. Higher concentrations of brain lactate, glycerol and glutamate were observed throughout the study among animals that died postoperatively. Brain glutamate and glycerol concentrations were significantly, negatively correlated with brain glucose concentrations. The lactate/glucose ratio was significantly lower among survivors during the postoperative period ( p = 0.014). Furthermore, brain glucose concentrations were higher and brain glycerol concentrations lower among the animals that did not develop brain infarction, but such differences did not reach statistical significance. Conclusion –Cerebral microdialysis is a useful tool for cerebral monitoring during experimental HCA. Low brain glucose concentrations and high brain lactate/glucose ratios after HCA are strong predictors of postoperative death. Brain glucose concentrations are negatively correlated with brain glycerol and glutamate concentrations.

Ph-stat versus alpha-stat perfusion strategy during experimental hypothermic circulatory arrest: a microdialysis study

BACKGROUND The superiority of the pH-stat to the alpha-stat acid-base strategy during cardiopulmonary bypass as a neuroprotective method during hypothermic circulatory arrest is still controversial. In the present study, brain metabolism and outcome have been evaluated in a surviving model of experimental hypothermic circulatory arrest. METHODS Twenty pigs undergoing 75-minutes of hypothermic circulatory arrest at a brain temperature of 18 degrees C were randomly assigned to the alpha-stat (n = 10) or pH-stat (n = 10) strategy during cardiopulmonary bypass. RESULTS The 7-day survival rate was 90% (9 of 10) in the pH-stat group and 10% (1 of 10) in the alpha-stat group. At the end of cooling, pH-stat strategy was associated with significantly lower brain lactate and pyruvate concentrations and brain lactate-glucose ratio. After reperfusion, brain concentrations of glycerol, lactate, pyruvate, and lactate-glucose ratio were significantly lower in the pH-stat group. This strategy was associated with a faster rise of brain tissue temperature and reoxygenation on reperfusion, which is likely secondary to improved cerebral perfusion. CONCLUSIONS During cardiopulmonary bypass before and after a period of hypothermic circulatory arrest, acid-base management according to the pH-stat principles seemed to be associated with less derangements in cerebral metabolism, lower intracranial pressures, and excellent behavioral recovery and survival outcome. Because there is strong evidence of the beneficial metabolic effects related to this method, further studies using an experimental model of combined HCA and embolic brain injury are required to exclude a possible increased risk of cerebral embolism associated with the pH-stat strategy.

Basic data from 176 studies on the immediate outcome after aortic valve replacement with or without coronary artery bypass surgery.

OBJECTIVE The aim of this study was to summarize the immediate outcome after aortic valve replacement (AVR) with or without coronary artery bypass grafting (CABG). DESIGN Systematic review and meta-analysis. SETTING University hospitals. PARTICIPANTS Participants were 683,286 patients who underwent AVR with or without CABG. Patients undergoing other major cardiac procedures were excluded from this analysis. INTERVENTIONS AVR with or without CABG. MEASUREMENTS AND MAIN RESULTS Operative mortality after AVR with or without concomitant CABG was 4.3%, stroke 2.1%, pacemaker implantation 5.9%, and dialysis 2.2%. After isolated AVR, operative mortality was 3.3%, stroke 1.7%, pacemaker implantation 3.3%, and dialysis 1.6%. Mortality was increased among very elderly (< 60 years: 3.3%, 60-69 years: 2.7%, 70-79 years: 3.8%,≥ 80 years: 6.1%, p < 0.001). Prevalence of minimally invasive AVR (mini-AVR) was associated with significantly lower operative mortality (p = 0.039, 46 studies). Mini-AVR only tended toward lower mortality when included in meta-regression analysis as a dichotomous variable (mini-AVR 4,367 patients: 2.3%, 95% CI 1.8-2.9% v full sternotomy 11,076 patients: 3.5%, 95% CI 28-4.1%, p = 0.088). Operative mortality after AVR plus CABG was 5.5% (versus isolated AVR: p < 0.001), stroke 3.0%, pacemaker implantation 3.9%, and dialysis 5.6%. Mortality was high in all age strata, particularly among very elderly (mean age < 70 years: 4.8%, mean age 70-79 years: 4.7%; mean age ≥ 80 years: 8.4%, p = 0.002). CONCLUSIONS Isolated AVR is associated with low mortality and morbidity. Coronary artery disease requiring concomitant CABG increases the operative mortality. Patients requiring AVR and CABG should be the main target of less-invasive treatment strategies.

Improved Cerebral Recovery From Hypothermic Circulatory Arrest After Remote Ischemic Preconditioning

BACKGROUND Remote ischemic preconditioning is a novel method of reducing ischemia-reperfusion injury in which a transient ischemic period of the limb provides systemic protection against a prolonged ischemic insult. This method of preconditioning has shown some potential in ameliorating ischemia-related injury in various organs and experimental settings. We hypothesized that remote ischemic preconditioning might also improve the recovery from hypothermic circulatory arrest (HCA). METHODS Twenty-four juvenile pigs underwent 60 minutes of HCA at 18 degrees C with either transient right hind leg ischemic preconditioning or no ischemic preconditioning. Preconditioning was induced by four cycles of 5-minute ischemia periods with three 5-minute reperfusion periods in between. Microdialysis and electroencephalography (EEG) data were recorded to detect any possible changes during the recovery phase. RESULTS The EEG data showed that the remote ischemic preconditioning group had significantly better EEG recovery time and a lower burst suppression ratio throughout the follow-up period. Cerebral extracellular glucose and glycerol content rose significantly immediately after HCA in the control group compared with the remote ischemic preconditioning group, and significantly higher lactate concentrations were measured in the control group at 5 and 6 hours after reperfusion, indicating a difference in cerebral metabolism. CONCLUSIONS Our data imply that remote ischemic preconditioning improves the recovery from HCA. It provides a faster recovery of cortical neuronal activity and protection against potential oxygen radical-mediated ischemia damage during and after HCA. In addition, it seems to protect from a late phase lactate and pyruvate burst, mitigating possible damage from an anaerobic metabolism phase.

A Retrospective Comparative Study of Aortic Valve Replacement with St. Jude Medical and Medtronic-Hall Prostheses: A 20-year Follow-up Study

Objective - To compare the long-term clinical outcome of patients who underwent aortic valve replacement with St. Jude Medical and Medtronic-Hall mechanical prostheses. Design - From June 1978 to June 1982, 43 Medtronic-Hall and 48 St. Jude Medical mechanical valves were implanted in 90 consecutive patients with aortic valve disease, and their clinical outcome was retrospectively assessed. Results - At 20 years in the St. Jude Medical group and in the Medtronic-Hall group the actuarial rates of overall survival were 50 and 49% ( p = NS), of cardiovascular survival 66 and 63% ( p = NS), of valve-related survival 95 and 91% ( p = NS), of freedom from major valve-related complications 83 and 45% ( p = 0.005), from major cerebrovascular events 93 and 71% ( p = 0.06), from valve thrombosis 97 and 89% ( p = NS), from aortic valve reoperation 93 and 88% ( p = NS), from major bleeding 96 and 82% ( p = 0.04), and from endocarditis 93 and 82% ( p = NS), respectively. The linearized rate of overall major aortic valve prosthesis-related complications was 3.47%/year in the Medtronic-Hall valve group and 1.53%/year in the St. Jude Medical valve group ( p = 0.003). Multivariate analysis showed that the type of prosthesis was predictive of freedom from valve-related complications ( p = 0.01; 2.849; C.I. 95%: 1.246-6.516). Conclusion - The aortic St. Jude Medical mechanical valve seems to be associated with a slightly lower rate of longterm valve-related morbidity than the aortic Medtronic-Hall mechanical valve. Because of the small patient population and the retrospective nature of the study, the choice between these two prostheses should not be made only on the basis of these findings. However, these results suggest a reappraisal for further comparative studies with such an extended follow-up.

Cold retrograde cerebral perfusion improves cerebral protection during moderate hypothermic circulatory arrest: A long-term study in a porcine model

BACKGROUND Deep hypothermic circulatory arrest is an effective method of cerebral protection, but it is associated with long cardiopulmonary bypass times and coagulation disturbances. Previous studies have shown that retrograde cerebral perfusion can improve neurologic outcomes after prolonged hypothermic circulatory arrest. We tested the hypothesis that deep hypothermic retrograde cerebral perfusion could improve cerebral outcome during moderate hypothermic circulatory arrest. METHODS Twelve pigs (23-29 kg) were randomly assigned to undergo either retrograde cerebral perfusion (15 degrees C) at 25 degrees C or hypothermic circulatory arrest with the head packed in ice at 25 degrees C for 45 minutes. Flow was adjusted to maintain superior vena cava pressure at 20 mm Hg throughout retrograde cerebral perfusion. Hemodynamic, electrophysiologic, metabolic, and temperature monitoring were carried out until 4 hours after the start of rewarming. Daily behavioral assessment was performed until elective death on day 7. A postmortem histologic analysis of the brain was carried out on all animals. RESULTS In the retrograde cerebral perfusion group, 5 (83%) of 6 animals survived 7 days compared with 2 (33%) of 6 in the hypothermic circulatory arrest group. Complete behavioral recovery was seen in 4 (67%) animals after retrograde cerebral perfusion but only in 1 (17%) animal after hypothermic circulatory arrest. Postoperative levels of serum lactate were higher, and blood pH was lower in the hypothermic circulatory arrest group. There were no significant hemodynamic differences between the study groups. CONCLUSIONS Cold hypothermic retrograde cerebral perfusion during moderate hypothermic circulatory arrest seems to improve neurologic outcome compared with moderate hypothermic circulatory arrest with the head packed in ice.