Igor E. Konstantinov

Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a katp channel-dependent mechanism

Background. We assess whether remote ischemic preconditioning (rIPC) of the recipient can modify ischemia-reperfusion (IR) injury in the donor heart following orthotopic heart transplantation from brain dead donors and to examine potential mechanisms of protection. Methods. Sixteen pigs weighing from 26 to 34.2 (mean 29.2) kg, randomized to control group (n=5), ischemic preconditioning (rIPC) group (n=6), and to receive rIPC with prior glibenclamide administration (Glib + rIPC) group (n=5) underwent orthotopic heart transplantation with the support of hypothermic (32°C) cardiopulmonary bypass (CPB). The hearts were harvested from donor animal rendered brain dead by balloon compression via a craniotomy. Preconditioning of the recipients was induced by four 5-min cycles of lower limb ischemia. Myocardial infarction (MI) was induced following heart transplantation by 30 min of left anterior descending (LAD) artery occlusion following by 2 hr of regional reperfusion. The extent of myocardial infarction was assessed by triphenyltetrazolium (TTC) staining. Results. Preconditioning of the recipient reduced the mass of MI (6.75±6.3 g in rIPC vs. 18.1±5.8 g in control, P=0.01), MI to area at risk (ARR) mass ratio by 57% (15.6%±15.2% vs. 36.3%±13.4%, P=0.04). The protective effect of preconditioning was abolished by pretreatment with glibenclamide. Conclusions. Remote ischemic preconditioning of the recipient, decreases ischemia-reperfusion injury in the brain dead donor heart following orthotopic heart transplantation via a Katp channel-dependent mechanism. This study suggests that a circulating effector persists after the rIPC stimulus is applied, and excludes an ongoing afferent neurogenic mechanism of cardioprotection.

Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils.

OBJECTIVES Preconditioning of cells or organs by transient sublethal ischemia-reperfusion (IR), termed ischemic preconditioning (IPC), protects the cell or organ from a subsequent prolonged ischemic insult. The mechanisms of this effect remain to be fully elucidated. We have recently reported that IPC of a forearm results in alterations in gene expression profiles of circulating polymorphonuclear leukocytes. The goal of the current study was to determine if the observed changes in gene expression lead to functional changes in neutrophils. METHODS We examined the effect of repetitive transient human forearm ischemia (three cycles of 5 min ischemia, followed by 5 min of reperfusion) on the function of circulating neutrophils. Neutrophil functions were examined before, after 1 d, and after 10 d of daily transient forearm ischemia. To modulate IR-induced inflammation the neutrophils were stimulated with N-formyl-methionyl-leucyl phenylalanine (FMLP) and lipopolysaccharide (LPS). RESULTS Neutrophil adhesion was significantly decreased on day 1 and remained low on day 10 (P = 0.0149) without significant change in CD11b expression. Phagocytosis was significantly suppressed on day 10 compared with day 0 (P < 0.0001). Extracellular cytokine levels were low in the absence of an exogenous stimulus but stimulation with LPS induced significant changes on day 10. We observed a trend in reduction of apoptosis on day 1 and day 10 that did not reach statistical significance (P < 0.08). CONCLUSION This study indicates that repetitive IPC of the forearm results in substantial alterations in neutrophil function, including reduced adhesion, exocytosis, phagocytosis, and modified cytokine secretion.

Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study.

Objectives: To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB). Design: Randomised study with an experimental model of CPB (3 h CPB with 2 h of cardioplegic arrest). Twelve 15 kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6 h. Intervention: rIPC was induced by four 5 min cycles of lower limb ischaemia before CPB. Main outcome measures: Troponin I, glial protein S-100B, lactate concentrations, load-independent indices (conductance catheter) of systolic and diastolic function, and pulmonary resistance and compliance were measured before and for 6 h after CPB. Results: Troponin I increased after CPB in both groups but during reperfusion the rIPC group had lower concentrations than controls (mean area under the curve −57.3 (SEM 7.3) v 89.0 (11.6) ng·h/ml, p  =  0.02). Lactate increased after CPB in both groups but during reperfusion the control group had significantly more prolonged hyperlactataemia (p  =  0.04). S-100B did not differ between groups. Indices of ventricular function did not differ. There was a tendency to improved lung compliance (p  =  0.07), and pulmonary resistance changed less in the rIPC than in the control group during reperfusion (p  =  0.02). Subsequently, peak inspiratory pressure was lower (p  =  0.001). Conclusion: rIPC significantly attenuated clinically relevant markers of myocardial and pulmonary injury after CPB. Transient limb ischaemia as an rIPC stimulus has potentially important clinical applications.

Outcomes of the Arterial Switch Operation for Transposition of the Great Arteries: 25 Years of Experience

BACKGROUND Studies on long-term outcomes of the arterial switch operation (ASO) for transposition of the great arteries (TGA) are uncommon. Thus, we sought to determine the long-term outcomes for patients after ASO performed at a single institution over a 25-year period. METHODS From 1983 to 2009, 618 patients underwent the ASO for TGA and were reviewed retrospectively. RESULTS Overall early mortality was 2.8%. Risk factors for early death on multivariate analysis were resection of left ventricular outflow tract obstruction at time of ASO (p = 0.001), weight less than 2.5 kg at time of ASO (p < 0.001), associated aortic arch obstruction (p = 0.043), and the need for postoperative extracorporeal membrane oxygenation (p < 0.001). Mean follow-up time was 10.6 years (range 2 months to 26.1 years). Late mortality was 0.9%. Reintervention was significantly higher (p < 0.001) in patients with ventricular septal defect or arch obstruction versus those without them (25.2% and 23.4% vs 5.9% at 15- year follow-up). Risk factors for late reintervention were left ventricular outflow tract obstruction at time of ASO (p < 0.001) and a greater circulatory arrest time (p < 0.001). Freedom from at least moderate neoaortic valve regurgitation for the entire cohort was 98.7% (95% confidence interval 96.8 to 99.5%) at 20 years. Mild neoaortic regurgitation was seen in 25.6% of patients at mean follow-up. All patients were free of arrhythmia and heart failure symptoms at last follow-up. CONCLUSIONS The ASO can be performed with good long-term results. Patients with associated ventricular septal defect and aortic arch obstruction warrant close follow-up.

Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance.

OBJECTIVES This study examined survival after surgical palliation in children with single-ventricle physiology. BACKGROUND Contemporary surgical outcomes for the entire population of newborns undergoing single-ventricle palliation are unclear. METHODS In a single-center review of 499 consecutive patients undergoing univentricular palliation from 1990 to 2008, predictors of mortality were determined using multivariate risk analysis, stratified for each post-operative stay and interim states. RESULTS After 2000, the population comprised more patients with dominant right ventricle (66% vs. 36%) and hypoplastic left heart syndrome (HLHS) (47% vs. 13%). Median age at bidirectional cavopulmonary shunt (BCPS) decreased from 15 months (10 to 22 months) before 2000 to 4 months (3.3 to 9 months) thereafter. Survival rates at 1, 5, and 10 years were, respectively, 82% (95% confidence interval [CI]: 79% to 85%), 74% (95% CI: 70% to 78%), and 71% (95% CI: 67% to 75%). Throughout the study, atrioventricular valve regurgitation (hazard ratio [HR]: 1.8; p = 0.008), not having transposition (HR: 2.0; p = 0.013), and heterotaxia (HR: 2.0; p = 0.026) were predictors of mortality. The most potent risk factor was right ventricular (RV) dominance (HR: 2.2; p = 0.001) because of its impact before BCPS. HR for death in patients with RV dominance went from 2.8 (95% CI: 1.4 to 5.7; p = 0.005) before BCPS to 1.0 (95% CI: 0.5 to 2.1; p = 0.98) thereafter. Survival of patients with RV dominance, adjusted for the risk factors noted here, improved over the study period (p = 0.001). CONCLUSIONS Considerable mortality is still observed during the first years of life among patients with single ventricle. RV dominance is the most important risk factor for death but only before BCPS.

Remote Ischemic Conditioning: Evolution of the Concept, Mechanisms, and Clinical Application

Abstract  Remote ischemic conditioning is a novel concept of protection against ischemia‐reperfusion injury. Brief controlled episodes of intermittent ischemia of the arm or leg may confer a powerful systemic protection against prolonged ischemia in a distant organ. This conditioning phenomenon is clinically applicable and can be performed before—preconditioning, during—perconditioning, or after—postconditioning prolonged distant organ ischemia. The remote ischemic conditioning may have an immense impact on clinical practice in the near future. (J Card Surg 2010;25:127‐134)

A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage

Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.

Effects of intermittent lower limb ischaemia on coronary blood flow and coronary resistance in pigs

Aim:  Intermittent limb ischaemia prior to cardiac ischaemia is a cardioprotective stimulus. This study was to investigate whether this peripheral stimulus had any effects on basal coronary blood flow and resistance, and to explore its potential mechanisms by studying the effect of femoral nerve transection and Katp blockade by glibenclamide.

Remote Ischemic Preconditioning (RIPC) Modifies Plasma Proteome in Humans

Remote Ischemic Preconditioning (RIPC) induced by brief episodes of ischemia of the limb protects against multi-organ damage by ischemia-reperfusion (IR). Although it has been demonstrated that RIPC affects gene expression, the proteomic response to RIPC has not been determined. This study aimed to examine RIPC induced changes in the plasma proteome. Five healthy adult volunteers had 4 cycles of 5 min ischemia alternating with 5 min reperfusion of the forearm. Blood samples were taken from the ipsilateral arm prior to first ischaemia, immediately after each episode of ischemia as well as, at 15 min and 24 h after the last episode of ischemia. Plasma samples from five individuals were analysed using two complementary techniques. Individual samples were analysed using 2Dimensional Difference in gel electrophoresis (2D DIGE) and mass spectrometry (MS). Pooled samples for each of the time-points underwent trypsin digestion and peptides generated were analysed in triplicate using Liquid Chromatography and MS (LC-MS). Six proteins changed in response to RIPC using 2D DIGE analysis, while 48 proteins were found to be differentially regulated using LC-MS. The proteins of interest were involved in acute phase response signalling, and physiological molecular and cellular functions. The RIPC stimulus modifies the plasma protein content in blood taken from the ischemic arm in a cumulative fashion and evokes a proteomic response in peripheral blood.

Surgical valvotomy and repair for neonatal and infant congenital aortic stenosis achieves better results than interventional catheterization.

OBJECTIVES This study sought to compare outcomes after surgical valvuloplasty and balloon dilation of the aortic valve in neonates and infants. BACKGROUND Surgical techniques of aortic valve repair have improved and there is today controversy on the best approach to treat neonatal congenital aortic valve stenosis. METHODS Retrospective review of data and follow-up of 123 consecutive neonates and infants (35 females, 88 males) undergoing intervention for congenital aortic stenosis. RESULTS From 1977 to 2009, 123 consecutive neonates (<30 days) and infants (31 days to 1 year) underwent relief of congenital aortic stenosis. Median age at procedure was 27 days (6 to 76 days). Twenty-year survival was 80 ± 7%. Fifty-four patients required a re-intervention and freedom from re-intervention was 55 ± 6% at 10 years and 40 ± 6% at 20 years. By multivariate analysis, having the relief of stenosis by balloon valvuloplasty and undergoing initial treatment as a neonate were predictive of re-intervention. Freedom from re-intervention at 5 years was 27% after balloon valvuloplasty versus 65% after surgery. At latest follow-up, an additional 16 patients had moderate or severe stenosis and 8 had regurgitation. Freedom from re-intervention or stenosis was 39 ± 5% at 15 years. By multivariate analysis, balloon valvuloplasty (p < 0.001) and treatment as a neonate (p = 0.003) were again predictive of stenosis or re-intervention. Thirty-five patients ultimately needed a valve replacement. Significant predictor of the requirement of valve replacement was unicuspid aortic valve (p < 0.001). Freedom from valve replacement was 55 ± 7% at 20 years. CONCLUSIONS Surgical valvuloplasty remains the best approach to treat neonates and infants with congenital aortic stenosis. After surgery, a higher proportion of patients remain free of re-intervention than after interventional catheterization and the relief of their stenosis lasts longer.