Shyam Kolvekar

Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial

BACKGROUND Whether remote ischaemic preconditioning, an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing coronary artery bypass graft surgery is unknown. We did a single-blinded randomised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients. METHODS 57 adult patients undergoing elective coronary artery bypass graft surgery were randomly assigned to either a remote ischaemic preconditioning group (n=27) or to a control group (n=30) after induction of anaesthesia. Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia, induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin-T concentration was measured before surgery and at 6, 12, 24, 48, and 72 h after surgery. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00397163. FINDINGS Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6, 12, 24, and 48 h after surgery. The total area under the curve was reduced by 43%, from 36.12 microg/L (SD 26.08) in the control group to 20.58 microg/L (9.58) in the remote ischaemic preconditioning group (mean difference 15.55 [SD 5.32]; 95% CI 4.88-26.21; p=0.005). INTERPRETATION We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning, using transient upper limb ischaemia.

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery

BACKGROUND Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.).

Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial

Background: Remote ischaemic preconditioning (RIPC) induced by brief ischaemia and reperfusion of the arm reduces myocardial injury in coronary artery bypass (CABG) surgery patients receiving predominantly cross-clamp fibrillation for myocardial protection. However, cold-blood cardioplegia is the more commonly used method world wide. Objective: To assess whether RIPC is cardioprotective in CABG patients receiving cold-blood cardioplegia. Design: Single-centre, single-blinded, randomised controlled trial. Setting: Tertiary referral hospital in London. Patients: Adults patients (18–80 years) undergoing elective CABG surgery with or without concomitant aortic valve surgery with cold-blood cardioplegia. Patients with diabetes, renal failure (serum creatinine >130 mmol/l), hepatic or pulmonary disease, unstable angina or myocardial infarction within the past 4 weeks were excluded. Interventions: Patients were randomised to receive either RIPC (n = 23) or control (n = 22) after anaesthesia. RIPC comprised three 5 min cycles of right forearm ischaemia, induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg, with an intervening 5 min reperfusion. The control group had a deflated cuff placed on the upper arm for 30 min. Main outcome measures: Serum troponin T was measured preoperatively and at 6, 12, 24, 48 and 72 h after surgery and the area under the curve (AUC at 72 h) calculated. Results: RIPC reduced absolute serum troponin T release by 42.4% (mean (SD) AUC at 72 h: 31.53 (24.04) μg/l.72 h in controls vs 18.16 (6.67) μg/l.72 h in RIPC; 95% CI 2.4 to 24.3; p = 0.019). Conclusions: Remote ischaemic preconditioning induced by brief ischaemia and reperfusion of the arm reduces myocardial injury in CABG surgery patients undergoing cold-blood cardioplegia, making this non-invasive cardioprotective technique widely applicable clinically. Trial registration number: NCT00397163.

Tracking the Evolution of Non–Small-Cell Lung Cancer

BACKGROUND Among patients with non‐small‐cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early‐stage NSCLC. METHODS In this prospective cohort study, we performed multiregion whole‐exome sequencing on 100 early‐stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence‐free survival. RESULTS We observed widespread intratumor heterogeneity for both somatic copy‐number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy‐number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy‐number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10‐4), which remained significant in multivariate analysis. CONCLUSIONS Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601.)

Diffuse myocardial fibrosis in severe aortic stenosis: an equilibrium contrast cardiovascular magnetic resonance study

AIMS Haemodynamics alone do not fully explain symptoms and prognosis in clinically severe aortic stenosis (AS). Myocardial disease, specifically diffuse myocardial fibrosis (DMF), may contribute. We used equilibrium contrast cardiovascular magnetic resonance (EQ-CMR) and sought to non-invasively measure DMF in severe AS and determine its clinical significance before and after valve replacement. METHODS AND RESULTS Patients with severe AS underwent echocardiography, brain natriuretic peptide (BNP), 6 min walk test (6MWT), and EQ-CMR pre- (n = 63) at baseline and at 6 months post- (n = 42) aortic valve replacement (AVR). EQ-CMR was also performed in 30 normal controls. Baseline: patients with AS had more DMF than controls (18 vs. 13%, P = 0.007) with a wide range (5-38%) that overlapped controls. The extent of diffuse fibrosis correlated inversely with the 6MWT performance (r(2) = 0.22, P = 0.001). Those with severe diastolic dysfunction had more DMF (P = 0.01). On multivariable analysis, the predictors of performance at 6MWT were diffuse fibrosis and BNP (P = 0.003 and 0.02, respectively). Post-op: following valve replacement, morphological and functional parameters improved [6 MWT, LA area, BNP, left ventricular (LV) hypertrophy, and volumes]. LV hypertrophy regression was shown to be cell volume reduction (P < 0.001) and not fibrosis regression (P = 0.54). Of the five deaths over six-month follow-up, four occurred in patients in the highest tertile of DMF. CONCLUSION DMF as measured by EQ-CMR is elevated in severe AS vs. normal controls but with a considerable overlap. It correlates with functional capacity at baseline. LV hypertrophy regression 6 months after AVR is cellular rather than fibrosis resolution.

Postconditioning protects human atrial muscle through the activation of the RISK pathway

Ischemic postconditioning (IPost) has been demonstrated to reduce myocardial injury in patients undergoing primary coronary angioplasty for an acute myocardial infarction.Pre-clinical animal studies suggest that pro-survival protein kinases of the Reperfusion Injury Salvage Kinase (RISK) pathway such as Akt and Erk1/2 mediate the cardioprotective effect of IPost.Whether IPost can protect human myocardial tissue ex vivo and whether it recruits the RISK pathway in human myocardium are both not known. To investigate this, atrial appendages were harvested from patients undergoing cardiac surgery. From these samples atrial trabeculae were isolated and mounted on a superperfusion apparatus and subjected to 90 min of hypoxia followed by 120 min of reoxygenation at the end of which function expressed as a percentage of the recovery of baseline contractile function was determined.Atrial trabeculae were randomized to control, hypoxic preconditioning (HPre), hypoxic postconditioning comprising either four 30-s (HPost-30) or 60-s (HPost-60) episodes of alternating hypoxia and reoxygenation, and HPost in the presence or absence of UO126 (a MEK1/2 inhibitor) or LY294002 (a PI3K inhibitor).HPre and HPost-60 improved the recovery of baseline contractile function (45.4±3.2% with HPre and 45.2±2.2% with HPost-60 vs 26.7±2.1 % in control: N≥ 6/group: P<0.05), whereas HPost-30 failed to cardioprotect (28.3±3.4% with HPost-30 vs 26.7±2.1 % in control: N≥ 6/group: P>0.05). The cardioprotective effect of HPost-60 was abolished in the presence of either LY (28.1±2.5% with HPost-60+LY vs 45.2±2.2% with HPost-60: N≥ 6/group: P<0.05) or UO (32.7±1.8% with HPost-60+UO vs 45.2±2.2% with HPost-60:N=7/group: P<0.05). The kinase inhibitors alone had no effect on functional recovery (28.2±3.6% with LY and 30.1±4.8% with UO vs 26.7±2.1 % in control: N≥ 5/group: P>0.05). In conclusion, we demonstrate for the first time that postconditioning protects human myocardium ex vivo and that this effect is dependent on the activation of the RISK pathway.

The divergent roles of protein kinase C epsilon and delta in simulated ischaemia–reperfusion injury in human myocardium

Experimental studies suggest that cardioprotection can be achieved through either the activation of PKC-epsilon prior to the index ischaemic episode or the inhibition of PKC-delta at the onset of reperfusion. However, whether these PKC isoforms exert such divergent roles in human myocardium, subjected to simulated ischaemia-reperfusion injury, is unclear. Human atrial trabeculae were isolated from right atrial appendages harvested from patients undergoing elective cardiac surgery. These were subjected to 90 min of hypoxia followed by 120 min of reoxygenation, at the end of which the recovery of baseline contractile function was determined. Atrial trabeculae were randomised to receive various treatment protocols comprising a peptide activator of PKC-epsilon, a peptide inhibitor of PKC-delta and their respective inactive control peptides. Administering the PKC-delta peptide inhibitor at reoxygenation improved the recovery of function at all the concentrations tested (39.3+/-1.4% at 5 nM, 52.4+/-2.9% at 50 nM and 46.8+/-2.9% at 500 nM versus the control group, 27.5+/-1.4%: N > or = 6/group: P<0.02). Preconditioning with the PKC-epsilon peptide activator improved the recovery of function (40.0+/-0.8% at 50 nM and 49.7+/-3.1% at 500 nM versus the control group 27.5+/-1.4%: N > or = 6/group: P<0.02). This cardioprotective effect was comparable to that achieved by a standard hypoxic preconditioning protocol (52.3+/-3.2%). Interestingly, administering the PKC-epsilon activator (500 nM) at the onset of reperfusion also improved the recovery of contractile function (40.7+/-2.1% versus 27.5+/-1.5%: N > or = 6/group: P < 0.05). In human myocardium, cardioprotection can be achieved by either inhibiting PKC-delta or activating PKC-epsilon at the onset of reperfusion. In addition, PKC-epsilon activation offers cardioprotection when administered as a preconditioning strategy.

Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation

Erythropoietin (EPO) has been shown to protect against myocardial infarction in animal studies by activating phosphatidylinositol‐3 kinase (PI3K)/Akt and ERK1/2. However these pro‐survival pathways are impaired in the diabetic heart. We investigated the ability of EPO to protect human atrial trabeculae from non‐diabetic and diabetic patients undergoing coronary artery bypass surgery, against hypoxia‐reoxygenation injury.

Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality

Objective We aimed to investigate whether preoperative serum neutrophil gelatinase-associated lipocalin (sNGALpre-op) predicted postoperative acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. Methods This study was a post hoc analysis of the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patient Undergoing Coronary Artery Bypass Graft Surgery trial involving adult patients undergoing coronary artery bypass graft. Postoperative AKI within 72 hours was defined using the International Kidney Disease: Improving Global Outcomes classification. Results 1371 out of 1612 patients had data on sNGALpre-op. The overall 1-year cardiovascular and all-cause mortality was 5.2% (71/1371) and 7.7% (105/1371), respectively. There was an observed increase in the incidence of AKI from the first to the third tertile of sNGALpre-op (30.5%, 41.5% and 45.9%, respectively, p<0.001). There was also an increase in both cardiovascular and all-cause mortality from the first to the third tertile of sNGALpre-op, linear trend test with adjusted p=0.018 and p=0.013, respectively. The adjusted HRs for those in the second and third tertiles of sNGALpre-op compared with the first tertile were 1.60 (95% CI 0.78 to 3.25) and 2.22 (95% CI 1.13 to 4.35) for cardiovascular mortality, and 1.25 (95% CI 0.71 to 2.22) and 1.91 (95% CI 1.13 to 3.25) for all-cause mortality at 1 year. Conclusion In a cohort of high-risk adult patients undergoing cardiac surgery, there was an increase in postoperative AKI and 1-year mortality from the first to the third tertile of preoperative serum NGAL. Those in the last tertile (>220 ng/L) had an estimated twofold increase risk of cardiovascular and all-cause mortality at 1 year. Clinical trial registration NCT101247545; Post-results.

Coronary artery fistula draining into pulmonary artery and optimal management: a review

Coronary artery fistula is a rare congenital malformation of high variability. The disease is illustrated with a description of a case example. The management of patients with coronary artery fistulas remains controversial. Both spontaneous regression and life threatening complications have been described. The fistula can be ligated or embolised; however, there are no long term outcome data regarding management. Intraoperative risk of myocardial infarction is less than 5% and death rate varies between 0% and 6%. Due to a small number of cases being described in the literature and a lack of evidence on optimal management, further research is needed in order to determine the best treatment options.