Christian H. Møller

Acute myocardial hypoxia increases BNP gene expression

It is well established that cardiac failure increases cardiac B‐type natriuretic peptide (BNP) expression due to myocardial stretching. However, patients with ischemic heart disease also display increased plasma BNP and proBNP concentrations despite preserved cardiac function. In this study, we examined whether acute myocardial hypoxia increases cardiac BNP expression. Surgical reduction of the blood flow to an area of the anterior ventricular wall in pigs reduced the myocardial oxygen tension from 46 ± 4 to 13 ± 5 mmHg. The tissue contents of VEGF and BNP mRNA increased 1.8‐fold and 3.5‐fold, respectively (n=10, P<0.005) in hypoxic compared with normoxic ventricular myocardium after 2.2 ± 0.2 h; the magnitude of the increase in BNP mRNA expression was positively correlated with that of VEGF in hypoxic myocardium (r=0.66, P<0.05). In support of a hypoxia‐induced increase of BNP gene transcription, the content of a premature BNP mRNA was increased in hypoxic myocardium (4.8‐fold, P<0.005) and in freshly harvested ventricular myocytes when kept in culture flasks and oxygen‐deprived for 3 h (2.2‐ fold, P=0.002). ProBNP peptide accumulated in the medium of freshly harvested ventricular myocyte cultures but was undetectable in ventricular myocardium, indicating rapid release of the newly synthesized proBNP peptide. Accordingly, the plasma proBNP concentration increased after 2 h of myocardial hypoxia (P=0.028). Cumulatively, the data suggest that acute hypoxia stimulates cardiac BNP expression.

Clinical outcomes in randomized trials of off- vs. on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses

AIMS To assess the clinical outcomes of off- vs. on-pump coronary artery bypass surgery in randomized trials. METHODS AND RESULTS We searched electronic databases and bibliographies until June 2007. Trials were assessed for risk of bias. Outcome measures were all-cause mortality, myocardial infarction, stroke, atrial fibrillation, and renewed coronary revascularization at maximum follow-up. We applied trial sequential analysis to estimate the strength of evidence. We found 66 randomized trials. There was no statistically significant differences regarding mortality [relative risk (RR) 0.98; 95% confidence interval (CI) 0.66-1.44], myocardial infarction (RR 0.95; 95% CI 0.65-1.37), or renewed coronary revascularization (RR 1.34; 95% CI 0.83-2.18). We found a significant reduced risk of atrial fibrillation (RR 0.69; 95% CI 0.57-0.83) and stroke (RR 0.53; 95% CI 0.31-0.91) in off-pump patients. However, when continuity correction for zero-event trials was included, the reduction in stroke became insignificant (RR 0.62; 95% CI 0.32-1.19). Trial sequential analysis demonstrated overwhelming evidence supporting that off-pump bypass surgery reduces atrial fibrillation. CONCLUSION Off-pump surgery reduces the risks of postoperative atrial fibrillation compared with on-pump surgery. For death, myocardial infarction, stroke, and renewed coronary revascularization, the evidence is still weak and more low-bias risk trials are needed.

Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials

PurposeWe conducted a systematic review of randomized trials to compare the benefits and harms of tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation.Methods and resultsWe searched electronic databases and bibliographies up to April 2010. Our review followed the Cochrane and PRISMA guidelines. The meta-analysis included 10 randomized trials with 952 patients. Tacrolimus was significantly superior to cyclosporine (both formula-combined) with regard to hypertension (relative risk [RR] 0.8; 95% confidence interval [CI] 0.69–0.93, p = 0.003), hyperlipidaemia (RR 0.57; 95% CI 0.44–0.74, p < 0.0001), hirsutism (RR 0.17 95% CI 0.04–0.62, p = 0.008), and gingival hyperplasia (RR 0.07 95% CI 0.01–0.37, p = 0.002). No significant differences between the two calcineurin inhibitors were found with regard to acute rejections causing haemodynamic instability, diabetes, renal dysfunction, infection, malignancy, or neurotoxicity. Tacrolimus was significantly superior to microemulsion cyclosporine with regard to mortality (RR 0.64; 95% CI 0.42–0.96, p = 0.03), acute severe biopsy-proven rejection (RR 0.71; 95% CI 0.56–0.90, p = 0.004), hyperlipidaemia (RR 0.57; 95% CI 0.41–0.79, p = 0.0009), hirsutism (RR 0.17 95% CI 0.04–0.62, p = 0.008), and gingival hyperplasia (RR 0.07; 95% CI 0.01–0.37, p = 0.002). Tacrolimus was significantly superior to oil-based cyclosporine with regard to hypertension (RR 0.66; 95% CI 0.54–0.80, p < 0.0001), and hyperlipidaemia (RR 0.57; 95% CI 0.38–0.87, p = 0.009).ConclusionTacrolimus seems to be superior to cyclosporine in heart transplant patients with regard to hypertension, hyperlipidaemia, gingival hyperplasia and hirsutism. In addition, tacrolimus seems to be superior to microemulsion cyclosporine in heart transplant patients with regard to a number of outcomes, including death. More trials with a low risk of bias are needed to determine if the results of the present meta-analysis can be confirmed.

Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial

SummaryBackground. Erythropoietin (EPO) is neuroprotective in experimental models of stroke and subarachnoid haemorrhage (SAH) and possibly in patients with thromboembolic stroke. We studied the efficacy and safety of EPO in patients with SAH. Methods. A larger scale clinical trial was planned but preliminarily terminated because of a lower than expected inclusion rate. However, 73 patients were randomised to treatment with EPO (500 IU/kg/day for three days) or placebo. The primary endpoint was Glasgow Outcome Score at six months. We further studied surrogate measures of secondary ischaemia, i.e. transcranial Doppler (TCD) flow velocity, symptomatic vasospasm, cerebral metabolism (microdialysis) and jugular venous oximetry, biochemical markers of brain damage (S-100β and neuron specific enolase) and blood–brain barrier integrity. Findings. The limited sample size precluded our primary hypotheses being verified and refuted. However, data from this study are important for any other study of SAH and as much raw data as possible are presented and can be included in future meta analyses. On admission the proportion of patients in a poor condition was higher in the EPO group compared with the placebo group but the difference was statistically insignificant. In the EPO-treated patients the CSF concentration of EPO increased 600-fold. Except for a higher extracelullar concentration of glycerol in the EPO group probably caused by the poorer clinical condition of these patients, there were no statistically significant group differences in the primary or secondary outcome measures. EPO was well tolerated. Conclusions. Beneficial effects of EPO in patients with SAH cannot be excluded or concluded on the basis of this study and larger scale trials are warranted.

Three-year follow-up in a subset of high-risk patients randomly assigned to off-pump versus on-pump coronary artery bypass surgery: the Best Bypass Surgery Trial

Objective To evaluate off-pump versus on-pump coronary artery bypass grafting (CABG) in patients with three-vessel disease and a high-risk operative profile. Design A randomised clinical trial. Setting Rigshospitalet, University Hospital, Copenhagen, Denmark. Participants 341 patients with three-vessel disease and a EuroSCORE of 5 or greater. Main exclusion criteria were previous heart surgery, poor left ventricular function (ejection fraction <30%), or unstable preoperative condition. Intervention CABG performed with versus without cardiopulmonary bypass. Main outcome measure The primary outcome was a composite of major adverse cardiac and cerebrovascular events (MACCE) including all-cause mortality, acute myocardial infarction, cardiac arrest with successful resuscitation, low cardiac output syndrome/cardiogenic shock, stroke and coronary reintervention. Results MACCE occurred in 69 (40%) patients allocated to off-pump versus 54 (33%) patients allocated to on-pump CABG during the median 3.7 years of follow-up (HR 1.22; 95% CI 0.86 to 1.75; p=0.26). All-cause mortality was significantly increased in the off-pump group (24% vs 15%; HR 1.66, 95% CI 1.02 to 2.73; p=0.04), but cardiac-related death was not significantly different (10% vs 7%; HR 1.30, 95% CI 0.64 to 2.66; p=0.47). An insignificant trend towards a reduction in myocardial infarction after off-pump CABG was observed (7% vs 14%; HR 0.53, 95% CI: 0.27 to 1.04; p=0.06). Conclusions No significant difference in the primary outcome of MACCE was found between off-pump and on-pump CABG. However, mortality seemed higher after off-pump CABG. Trial registration http://clinicaltrials.gov/ number, NCT00120991.

Transit‐Time Flow Measurement as a Predictor of Coronary Bypass Graft Failure at One Year Angiographic Follow‐Up

Transit‐time flow measurement (TTFM) is a commonly used intraoperative method for evaluation of coronary artery bypass graft (CABG) anastomoses. This study was undertaken to determine whether TTFM can also be used to predict graft patency at one year postsurgery.

Interleukin-2 receptor antagonists as induction therapy after heart transplantation: systematic review with meta-analysis of randomized trials

BACKGROUND About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras. METHODS We searched CENTRAL, PubMed, EMBASE and Web of Science up to November 2007 for randomized trials comparing IL-2Ra vs placebo/no treatment or another antibody induction therapy. Data were extracted and quality was assessed independently by two investigators. Outcome measures were mortality, biopsy-proven acute rejection (Grade > or =3A), infections and malignancy. Data were presented as the relative risk (RR) with 95% confidence interval (CI). RESULTS We found 9 randomized trials evaluating IL-2Ra as induction therapy after heart transplantation. All were high-bias risk trials. Four trials compared IL-2Ra with placebo/no treatment, 3 trials compared IL-2Ra with polyclonal antibody and 2 trials compared IL-2Ra with monoclonal antibody. Follow-up ranged from 6 to 12 months, except for 2 trials with up to 10 years of follow-up. When IL-2Ra vs placebo/no treatment was meta-analyzed with a fixed-effect model, IL-2Ra significantly reduced the risk of acute rejection (RR 0.73, 95% CI 0.59 to 0.90), but not according to a random-effects model (RR 0.73, 95% CI 0.46 to 1.17). IL-2Ra significantly increased acute rejection when compared with polyclonal antibody (RR 2.99, 95% CI 1.42 to 6.28), but not when compared with monoclonal antibody (RR 0.94, 95% CI 0.74 to 1.20). No significant differences were found regarding mortality, infections or malignancy. CONCLUSIONS Evidence for the use of induction therapy after heart transplantation is sparse. This systematic review found no convincing evidence of a survival benefit or reduction in cardiac allograft rejection. Thus, the routine use of IL-2Ra in cardiac transplantation remains unsupported.

Acute Kidney Injury Is Independently Associated With Higher Mortality After Cardiac Surgery

OBJECTIVES To investigate the incidence of acute kidney injury after cardiac surgery and its association with mortality in a patient population receiving ibuprofen and gentamicin perioperatively. DESIGN Retrospective study with Cox regression analysis to control for possible preoperative, intraoperative and postoperative confounders. SETTING University hospital-based single-center study. PARTICIPANTS All patients who underwent coronary artery bypass grafting ± valve surgery during 2012. INTERVENTIONS None. MEASUREMENT AND MAIN RESULTS Acute surgery within 24 hours of coronary angiography, previous nephrectomy, preoperative sCr >2.26 mg/dL and selective cerebral perfusion during cardiopulmonary bypass were used as exclusion criteria. Acute kidney injury was defined, using the Acute Kidney Injury Network (AKIN) criteria. Six hundred eight patients were included in the study. Mean age was 68.2 ± 9.7 years, and 81% were males. Acute kidney injury was seen in 28.1% of the patients. Overall mortality at one year was 7% and 3% in the no-AKI group. At one year, mortality was 15% in patients with AKIN stage 1 and AKIN stage 2 compared to 70% in AKIN stage 3. A hazard ratio of 2.34 (95% CI: 1.21-4.51, p = 0.011) and 5.62 (95% CI: 2.42-13.06), p<0.0001) were found for AKIN stage 1 and 2/3 combined, respectively. CONCLUSIONS More than 28% of the patients undergoing elective or subacute cardiac surgery developed AKI in this contemporary cohort. Furthermore, acute kidney injury was an independent predictor of increased mortality irrespective of the perioperative risk factors.

Patient-Prosthesis Mismatch and Reduction in Left Ventricular Mass After Aortic Valve Replacement

BACKGROUND The presence of patient-prosthesis mismatch (PPM) after aortic valve replacement may influence patient survival. We examined the relationship between PPM and changes in left ventricular mass index at 3 months follow-up and also overall survival. METHODS From patients included in the Mosaic trial, we studied data from 266 patients who underwent aortic valve replacement with the Medtronic Mosaic porcine bioprosthesis and had an echocardiography performed 3 months postoperatively. Complete echocardiographic data, to calculate left ventricular mass index, was available in 78% of the patients. The primary outcome for this substudy was prevalence and severity of PPM. Secondary outcomes were reduction in left ventricular mass index at 3 months follow-up and medium-term survival. Patients without PPM were defined as having an indexed effective orifice area greater than 0.85 cm(2)/m(2), and those with moderate and severe PPM as having an indexed effective orifice area between 0.65 cm(2)/m(2) and 0.85 cm(2)/m(2) or below 0.65 cm(2)/m(2), respectively. RESULTS PPM was found in 217 (82%) patients. No difference in overall survival was found between patients with PPM and those without PPM. The change in left ventricular mass index was significantly different between groups (no PPM -31.4 ± 28.0 g/m(2), moderate PPM 1.1 ± 34.4 g/m(2), and severe PPM -5.9 ± 29.7 g/m(2), respectively (p = 0.01). CONCLUSIONS The presence of PPM did not influence medium-term survival. However, patients without PPM showed a marked reduction in left ventricular mass index as soon as 3 months postoperatively.

Graft patency after off-pump versus on-pump coronary artery surgery in high-risk patients

Abstract Objective. To compare angiographic graft patency in high-risk patients randomly allocated to off-pump vs. on-pump coronary artery bypass grafting (CABG). Design. From a randomised, single-centre clinical trial including patients undergoing isolated first-time coronary bypass surgery a subgroup of patients were scheduled to 1-year coronary angiographic follow-up. Patients had 3-vessel disease and a EuroSCORE ≥5. We evaluated graft patency using a patency index (percentage of patent grafts out of the total number of grafts in each patient). Results. One-year angiography was performed in 34 patients undergoing off-pump surgery and 35 patients undergoing on-pump surgery. The mean number of distal anastomoses was 3.38±0.65 in the off-pump group versus 3.46±0.61 in the on-pump group (NS). The number of patients without graft failure was 22 in the off-pump group and 24 in the on-pump group (NS). The overall patency index was 85% in the off-pump group versus 87% in the on-pump group with a mean difference of –2.1%, 95% confidence interval –12.9 to 8.7 (NS). Conclusions. In patients with 3-vessel disease and a high-risk profile we found no statistically significant difference in graft patency between off-pump and on-pump CABG at 1-year coronary angiographic follow-up. Trial registration: ClinicalTrials.gov identifier: NCT00120991.