Imbalance between plasma double-stranded DNA and deoxyribonuclease activity predicts mortality after out-of-hospital cardiac arrest.

AIM: Despite an increased rate of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA) patients, almost half of patients do not survive up to hospital discharge. Understanding pathophysiological mechanisms of post-cardiac arrest syndrome is essential for developing novel therapeutic strategies. During systemic inflammatory responses and concomitant cell death, double-stranded (ds) DNA is released into circulation, exerting pro-inflammatory effects. Deoxyribonuclease (DNase) degrades dsDNA. The role of DNase activity in OHCA survivors and impact on clinical outcome has not been analyzed yet. METHODS: In a prospective, single-center study, dsDNA and DNase activity were determined at hospital admission (acute phase) and 24 h (subacute phase) after ROSC. The ratio between dsDNA levels and DNase activity was calculated to determine the extent of dsDNA release in relation to the patients' capacity of degradation. Thirty-day mortality was defined as study end point. RESULTS: We enrolled 64 OHCA survivors, of whom 26.6% (n = 17) died within 30 days. A peak of circulating dsDNA was observed at admission which decreased within 24 h. DNase activity did not differ between acute and subacute phase, while dsDNA load per DNase activity significantly decreased. The ratio between dsDNA levels and DNase activity in the subacute phase was the strongest predictor of 30-day mortality with an adjusted HR per 1 SD of 3.59 (95% CI, 1.80-7.18, p < 0.001). CONCLUSION: Disproportionally increased dsDNA levels uncompensated by DNase activity are a strong predictor of mortality in OHCA survivors. This pilot study points to a potentially protective effect of DNase activity in patients undergoing cardiac arrest.

Gender-related impact on outcomes of high density lipoprotein in acute ST-elevation myocardial infarction.

BACKGROUND AND AIMS: There is rising evidence that cardioprotective functions of high-density lipoprotein (HDL) have significant impact on clinical outcomes. ST-elevation myocardial infarction (STEMI) represents a high-risk vascular condition. Whether higher HDL-cholesterol concentrations in women correspond to protective anti-oxidant properties in the setting of STEMI is unknown. METHODS: We prospectively assessed gender related differences in the anti-oxidant function of HDL, and the impact of HDL properties on mortality in 242 women and men with STEMI. Blood samples to determine HDL function and sex hormone levels were collected during primary percutaneous coronary intervention. RESULTS: Patients were stratified according to preserved anti-oxidant HDL function (HDL oxidant index (HOI) < 1) and pro-oxidant HDL (HOI≥1). Despite higher serum levels of HDL-cholesterol in postmenopausal women (48 mg/dl, IQR 42-54, versus 39 mg/dl, IQR33-47, p < 0.001 in men), the proportion of patients with pro-oxidant HDL was not different between women (35%) and men (46%, p = 0.132). Kaplan-Meier analysis revealed higher cardiovascular mortality in both women (p = 0.021) and men (p = 0.045) with pro-oxidant HDL. We identified pro-oxidant HDL as strong and independent predictor of cardiovascular mortality with an adjusted HR of 8.33 (95% CI, 1.55-44.63; p = 0.013) in women and with an adjusted HR of 5.14 (95% CI, 1.61-16.42; p = 0.006) in men. Higher levels of free sex hormones (estradiol and testosterone) were associated with pro-oxidant HDL. HDL-cholesterol levels showed no association with mortality (HR in women 1.03, 95% CI 0.96-1.11, p = 0.45 and HR in men 0.99, 95% CI 0.94-1.05, p = 0.72). CONCLUSIONS: Total HDL-cholesterol serum levels were not associated with mortality in STEMI patients. Pro-oxidant HDL was a strong and independent predictor of mortality in women and men with STEMI. The present study provides a link between sex hormones, HDL function and clinical events in STEMI patients. In clinical practice and future clinical trials, anti-oxidant properties of HDL rather than total HDL serum levels should be used for risk stratification.

Beneficial effects of levosimendan on survival in patients undergoing extracorporeal membrane oxygenation after cardiovascular surgery.

BACKGROUND: The impact of levosimendan treatment on clinical outcome in patients undergoing extracorporeal membrane oxygenation (ECMO) support after cardiovascular surgery is unknown. We hypothesized that the beneficial effects of levosimendan might improve survival when adequate end-organ perfusion is ensured by concomitant ECMO therapy. We therefore studied the impact of levosimendan treatment on survival and failure of ECMO weaning in patients after cardiovascular surgery. METHODS: We enrolled a total of 240 patients undergoing veno-arterial ECMO therapy after cardiovascular surgery at a university-affiliated tertiary care centre into our observational single-centre registry. RESULTS: During a median follow-up period of 37 months (interquartile range 19-67 months), 65% of patients died. Seventy-five per cent of patients received levosimendan treatment within the first 24 h after initiation of ECMO therapy. Cox regression analysis showed an association between levosimendan treatment and successful ECMO weaning [adjusted hazard ratio (HR) 0.41; 95% confience interval (CI) 0.22-0.80; P=0.008], 30 day mortality (adjusted HR 0.52; 95% CI 0.30-0.89; P=0.016), and long-term mortality (adjusted HR 0.64; 95% CI 0.42-0.98; P=0.04). CONCLUSIONS: These data suggest an association between levosimendan treatment and improved short- and long-term survival in patients undergoing ECMO support after cardiovascular surgery.

Peri-interventional endothelin--a receptor blockade improves long-term outcome in patients with ST-elevation acute myocardial infarction.

Endothelin (ET)-1 is a pro-fibrotic vasoconstrictive peptide causing microvascular dysfunction and cardiac remodelling after acute ST-elevation myocardial infarction (STEMI). It acts via two distinct receptors, ET-A and ET-B, and is involved in inflammation and atherogenesis. Patients with posterior-wall STEMI were randomly assigned to intravenous BQ-123 at 400 nmol/minute (min) or placebo over 60 min, starting immediately prior to primary percutaneous coronary intervention (n=54). Peripheral blood samples were drawn at baseline as well as after 24 hours and 30 days. Myeloperoxidase (MPO), as a marker of neutrophil activation and matrix metalloproteinase 9 (MMP-9), a marker of extracellular matrix degradation were measured in plasma. Clinical follow-up was conducted by an investigator blinded to treatment allocation over three years. During the median follow-up period of 3.6 years (interquartile range [IQR] 3.3-4.1) we observed a longer event-free survival in patients randomised to receive BQ-123 compared with patients randomised to placebo (mean 4.5 years (95% confidence interval: 3.9-5) versus mean 3 years (2.2-3.7), p=0.031). Patients randomised to ET-A receptor blockade demonstrated a greater reduction of MPO levels from baseline to 24 hours compared to placebo-treated patients (-177 ng/ml (IQR 103-274) vs -108 ng/ml (74-147), p=0.006). In addition, a pronounced drop in MMP-9 levels (-568 ng/ml (44-1157) vs -117 ng/ml (57-561), p=0.018) was observed. There was no significant difference in amino-terminal propetide of pro-collagen type III levels. In conclusion, short-term administration of BQ-123 leads to a reduction in MPO, as well as MMP-9 plasma levels and to a longer event-free survival in patients with STEMI.

Long-term outcome after thrombectomy in acute myocardial infarction.

BACKGROUND: Current data appear in favour of thrombectomy for ST-elevation myocardial infarction (STEMI). However, information on long-term outcome after thrombectomy is limited. We performed a retrospective long-term study to assess the risk of cardiac re-hospitalizations and survival after discharge from the index hospitalization for STEMI. METHODS: Patients originally randomized to percutaneous coronary intervention (PCI) with thrombectomy vs. standard PCI were included in a retrospective long-term observational study. The primary study endpoint was the combined risk for all-cause death or cardiac re-hospitalization after index discharge under optimal medical therapy. The cumulative number of cardiac hospitalization days and ventricular remodelling assessed by echocardiography and plasma biomarkers were secondary endpoints. RESULTS: Of 94 STEMI patients who had been randomized between 11/2000 and 03/2003, 89 patients consented to long-term follow-up. A total of 43 patients had been allocated to thrombectomy and 46 to standard primary PCI. The minimum follow-up time was 1115 days. There was a significantly lower risk for death or cardiac re-hospitalization for patients of the thrombectomy group (hazard ratio = 0.69, 95% CI: 0.49-0.98, P = 0.036). The incidence of recurrent myocardial infarction was not different (P = 0.343). No differences in cardiac remodelling were detected by echocardiography, with the exception that heart-type fatty acid binding protein at 53.2 +/- 17 months was lower in the thrombectomy group (P = 0.045). CONCLUSION: Thrombectomy in STEMI may decrease the long-term risk for death or cardiac re-hospitalization.