Rudolf Jarai

Complementary role of copeptin and high‐sensitivity troponin in predicting outcome in patients with stable chronic heart failure

Copeptin, the C‐terminal part of the vasopressin pro‐hormone, is elevated after myocardial infarction and predicts adverse outcome. In the present study we investigated whether the complementary role of copeptin and cardiac troponin T (cTnT) could be used for identification of high‐risk patients with chronic stable heart failure.

Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation

The aim of the study was to evaluate the effect of the concomitant treatment with proton-pump inhibitors (PPIs) and clopidogrel on the incidence of stent thrombosis, acute coronary syndrome (ACS) and death in patients who underwent percutaneous coronary intervention (PCI) and stent implantation. In total, 1,210 patients under dual antiplatelet therapy, who underwent PCI and stent implantation, were included in a prospective registry from January 2003 until December 2006. The patients were divided retrospectively into those with or without long-term PPI treatment (for the duration of dual antiplatelet therapy). All-cause mortality, cardiovascular death, re-hospitalisation for re-ACS, stent thrombosis, as well as the combined endpoint all-cause death, re-ACS or stent thrombosis were evaluated over a mean follow-up period of 7.8 (± 3.63) months (range 1-12 months). Propensity score analysis was performed to reduce potential selection bias and exhibited no significant difference between the two study groups with respect to all-cause mortality, cardiovascular death, re-ACS, stent thrombosis and the combined endpoint. In pre-specified subgroup analyses performed in patients presenting with ACS and referred for acute PCI or for stable patients referred for elective PCI, receiving drug-eluting stents or bare metal stents, in diabetics or non-diabetics, in males or females, and in patients older than 75 years or ≤75 years of age use of PPIs had no significant impact on clinical outcome. Our data suggest that a combined use of clopidogrel as part of dual antiplatelet therapy (DAPT) after coronary stenting and PPIs does not significantly influence the clinical outcome.

Platelet function variability and non-genetic causes

Dual antiplatelet therapy (DAPT) has been established for the treatment of coronary artery disease, especially in and after acute coronary syndromes, and after coronary interventions. Data suggest that a significant percentage of individuals treated with clopidogrel do not receive the expected therapeutic benefit because of a decreased responsiveness of their platelets, which is caused by several extrinsic and intrinsic mechanisms. The clinical consequence of clopidogrel non-responsiveness is severe cardiovascular complications. Besides genetic variability in response to antiplatelet therapy, non-genetic causes such as drug interactions (proton-pump inhibitors, statins, calcium-channel blockers, coumarin derivates, antibiotics, antimycotics) and co-morbidities (diabetes mellitus, renal failure, obesity) are responsible for this phenomenon. Large clinical trials with standardised laboratory methods and hard clinical endpoints are needed to identify these interactions with clopidogrel and predictors for its non-responsiveness.

Soluble ST2 and Interleukin-33 Levels in Coronary Artery Disease: Relation to Disease Activity and Adverse Outcome

Objectives ST2 is a receptor for interleukin (IL)-33. We investigated an association of soluble ST2 (sST2) and IL-33 serum levels with different clinical stages of coronary artery disease. We assessed the predictive value of sST2 and IL-33 in patients with stable angina, non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI). Methods We included 373 patients of whom 178 had stable angina, 97 had NSTEMI, and 98 had STEMI. Patients were followed for a mean of 43 months. The control group consisted of 65 individuals without significant stenosis on coronary angiography. Serum levels of sST2 and IL-33 were measured by ELISAs. Results sST2 levels were significantly increased in patients with STEMI as compared to patients with NSTEMI and stable angina as well as with controls. IL-33 levels did not differ between the four groups. During follow-up, 37 (10%) patients died and the combined endpoint (all cause death, MI and rehospitalisation for cardiac causes) occurred in 66 (17.6%) patients. sST2 serum levels significantly predicted mortality in the total cohort. When patients were stratified according to their clinical presentation, the highest quintile of sST2 significantly predicted mortality in patients with STEMI, but not with NSTEMI or stable coronary artery disease. sST2 was a significant predictor for the combined endpoint in STEMI patients and in patients with stable angina. Serum levels of IL-33 were not associated with clinical outcome in the total cohort, but the highest quintile of IL-33 predicted mortality in patients with STEMI. Conclusions Serum levels of sST2 are increased in patients with acute coronary syndromes as compared to levels in patients with stable coronary artery disease and in individuals without coronary artery disease. sST2 and IL-33 were associated with mortality in patients with STEMI but not in patients with NSTEMI or stable angina.

Early assessment of outcome in cardiogenic shock: relevance of plasma N-terminal pro-B-type natriuretic peptide and interleukin-6 levels.

Objective:Plasma N-terminal pro-B-type natriuretic peptide (Nt-pro-BNP) levels are frequently elevated in critically ill patients and are associated with an increased mortality. In this study, we determined Nt-pro-BNP levels in patients with cardiogenic shock (CS) and evaluated its association with clinical and hemodynamic parameters and 30-day mortality. Design:Retrospective study. Setting:Two, eight-bed intensive care units at a university and a community hospital. Patients:Retrospective study on stored plasma samples of 58 patients with CS, obtained at admission to the intensive care unit. Interventions:None. Measurements and Main Results:Massively elevated Nt-pro-BNP concentrations showed no significant association with duration of shock, total Sequential Organ Failure Assessment score, or invasive hemodynamic parameters at the time of blood sampling but a significant association with estimated glomerular filtration rate (p < 0.001), C-reactive protein (p = 0.03), age (p = 0.005), and body weight (p = 0.03). Both in univariate and multivariate survival analyses, Nt-pro-BNP levels above the median (>12,782 pg/mL) were significant predictors of 30-day mortality (p < 0.001) and showed a complementary role with interleukin (IL)-6 in predicting outcome. Patients with IL-6 >195 pg/mL and Nt-pro-BNP above the median value had the highest 30-day mortality (93.7%), whereas patients with lower IL-6 levels together with lower Nt-pro-BNP levels had significantly better survival (mortality rate 26.3%). Among patients who had acute myocardial infarction, those with Nt-pro-BNP concentrations above the median level showed a highly impaired clinical course even if coronary revascularization was successful (30-day mortality 90.9% vs. 29.4%, p = 0.001), whereas survival of patients with unsuccessful revascularization did not differ significantly with respect to the median of Nt-pro-BNP (30-day survival rate 81.8% vs. 75.0%, p = 0.71). Conclusion:The massive elevations of Nt-pro-BNP observed in the early phase of CS seem to be independent of ventricular performance. Nt-pro-BNP levels are nevertheless predictive of 30-day survival in patients with CS especially in those with successful revascularization and might be used in combination with IL-6 for estimation of outcome early on.

B-type Natriuretic Peptide and Risk of Contrast-Induced Acute Kidney Injury in Acute ST-Segment–Elevation Myocardial Infarction A Substudy from the HORIZONS-AMI Trial

Background—Contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention is associated with adverse short- and long-term outcomes. However, identification of patients at risk for CI-AKI is challenging. Using a large contemporary randomized trial database of patients with ST-segment–elevation myocardial infarction, we therefore sought to examine whether admission B-type natriuretic peptide (BNP) levels predict the development of CI-AKI. Methods and Results—A total of 979 ST-segment–elevation myocardial infarction patients enrolled in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial had BNP levels measured in the emergency room prior to primary percutaneous coronary intervention as part of the study protocol. CI-AKI was defined as a relative increase in serum creatinine of ≥25%, or an absolute increase of ≥0.5 mg/dL, occurring within 48 hours after contrast administration. Logistic regression analysis was used to estimate the association of admission BNP with development of CI-AKI. CI-AKI occurred in 131 patients (13.3%). Baseline BNP was a significant univariable correlate of CI-AKI (odds ratio 1.31, 95% confidence interval, 1.14–1.51; P=0.0001). After multivariable adjustment for clinical, laboratory, and angiographic variables, BNP remained a significant independent predictor of CI-AKI (1.29 [1.10, 1.51]; P<0.001). Significant net reclassification improvement was achieved by addition of BNP to the current clinical risk prediction model (net reclassification improvement=0.177; P<0.001) and to the Mehran Risk Score (net reclassification improvement=0.100; P=0.015). Conclusions—Measurement of serum BNP at hospital admission may help identify patients who are at risk for developing CI-AKI after primary percutaneous coronary intervention in ST-segment–elevation myocardial infarction. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Circulating B-type natriuretic peptides in patients with acute coronary syndromes Pathophysiological, prognostical and therapeutical considerations

Fifty percent of patients who experience death or develop heart failure after acute coronary syndromes (ACS) have extremely elevated concentrations of plasma B-type natriuretic peptides. These elevations, however, seem not to reflect permanent ventricular dysfunction or heart failure and are assumed to exist already at the onset of ischemic symptoms. The underlying mechanisms of BNP/Nt-proBNP elevations in patients with ACS are still not known at present. Furthermore, the relationship of elevated BNP/Nt-proBNP with mortality but not with atherothrombotic complications of underlying disease makes it difficult to choose optimal therapeutic strategies based on plasma levels of these peptides. The remarkably high short- and long-term mortality rate associated with increases of BNP/Nt-proBNP elevations clearly show the need of further investigation to focus on this high-risk group of patients in order to clarify underlying pathomechanisms and to find optimal therapeutic approaches.

Human cardiac fibroblasts express B-type natriuretic peptide: fluvastatin ameliorates its up-regulation by interleukin-1α, tumour necrosis factor-α and transforming growth factor-β

B‐type natriuretic peptide (BNP) is a cardiac hormone, which plays a major role in body fluid and cardiovascular homeostasis. Produced by cardiac ventricles, its expression is highly regulated by various mediators. Canine cardiac fibroblasts have been identified as a source of BNP. Cardiac fibroblasts are key regulators of myocardial structure and function. We treated cultured human adult cardiac fibroblasts (HACF) with 2000 U/ml tumour necrosis factor‐α (TNF‐α), 200 U/ml interleukin‐1α (IL‐1α) or 50 ng/ml transforming growth factor‐β (TGF‐β) in the presence or absence of 500 nM fluvastatin. N‐terminal pro‐BNP (Nt‐proBNP) concentration was determined by a competitive enzyme immunoassay. RealTime polymerase chain reaction (real‐time PCR) was performed to investigate changes in BNP mRNA expression. Nt‐proBNP peptide was present in the conditioned media of HACF and incubation with fluvastatin significantly reduced Nt‐proBNP peptide levels. Treatment of HACF with TNF‐α, IL‐1α or TGF‐β significantly increased Nt‐proBNP levels compared with untreated cells. This effect was completely abolished in the presence of fluvastatin. Real‐time PCR analysis confirmed these changes at the level of mRNA expression. Our data suggest that cardiac fibroblasts are a potential source of BNP in the human heart. Pro‐inflammatory cytokines, associated with ventricular dysfunction and cardiac fibrosis, seem to be major inducers of BNP production in cardiac fibroblasts. This effect can be reverted by a statin. Based on our data, we speculate that elevated plasma BNP levels might not only reflect increased myocardial stretch but also inflammatory and remodelling processes. A possible benefit of statin‐induced reduction in BNP production requires further studies.

Usefulness of Pre-Operative Copeptin Concentrations to Predict Post-Operative Outcome After Major Vascular Surgery

The aim of this study was to investigate whether preoperative determination of plasma copeptin levels in addition to plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) could help improve risk stratification in patients who undergo major vascular surgery. One hundred ninety-eight consecutive patients who underwent major vascular surgery (58.6% infrainguinal aortic reconstruction, 23.7% abdominal aortic aneurysm surgery, 17.7% carotid endarterectomy) were included in this study. Patients were monitored for in-hospital and long-term (2-years) major adverse cardiac events, consisting of cardiac death, nonfatal myocardial infarction, and emergent coronary revascularization. Overall, 40 patients (20.2%) reached the primary end point, and most of these events occurred during the index hospital stay (n = 18 [45%]). In univariate Cox regression analysis, increasing concentrations of copeptin were significant determinants of outcome as a continuous variable (hazard ratio [HR] 1.012, p = 0.005) and as a dichotomized variable according to the recommended cutoff of 14.0 pmol/L (HR 4.116, p <0.001). Subgroup analyses revealed that especially patients at low estimated risk according to plasma NT-pro-BNP levels were at significantly higher risk for worse outcomes with higher copeptin levels (HR 5.983, p = 0.002). In multivariate Cox regression analysis, copeptin concentrations >14 pmol/L were significant independent predictors of outcome (HR 2.842, p = 0.002) in addition to type of surgery, history of myocardial infarction, elevated levels of cardiac troponin T, and NT-pro-BNP levels. In conclusion, the results of this study suggest that preoperative determination of this new biomarker could substantially improve prediction of perioperative and postoperative outcomes in vascular surgery patients.

Influence of updated guidelines on short- and long-term mortality in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS)

AIM In 2002 the ACC/AHA guidelines for the management of patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) were updated. We aimed to answer whether the implementation of updated guidelines was capable of influencing short- and long-term mortality in these patients. METHODS We analyzed data on 812 consecutive patients who were admitted with either UA or NSTEMI between 2001 and 2004. Patients admitted in the two years before the implementation of updated guidelines (UA(01/02) group and NSTEMI(01/02) group) were compared to patients admitted in the two years thereafter (UA(03/04) group and NSTEMI(03/04) group). Yearly follow-up concerning all-cause mortality was obtained up to four years. RESULTS The rate of revascularizations, the percentage of procedures performed within 48 h of admission, and the administration of clopidogrel increased significantly. However, still many - especially high-risk - patients did not receive revascularization. Patients of both UA groups had an identical in-hospital mortality rate. Differences in mortality between groups gained statistical significance over time (four-year mortality; 15.1% for the UA(03/04) group vs. 26.5% for the UA(01/02) group, p=0.014; HR 0.49 95% CI 0.28-0.87). In patients with NSTEMI in-hospital mortality decreased from 18.4% in the NSTEMI(01/02) group to 9.6% in the NSTEMI(03/04) group (p=0.011; HR 0.47 95% CI 0.26-0.84), and 1-year mortality from 34.7% to 25.1% (p=0.038; HR 0.63 95% CI 0.41-0.98), respectively. Mortality rates beyond one year were still lower in the NSTEMI(03/04) group as compared to the NSTEMI(01/02) group but it did not reach statistical significance. Multivariate Cox-regression analysis revealed furthermore that also patients with higher age and/or renal dysfunction benefit from an early invasive strategy. CONCLUSION The implementation of updated guidelines for NSTE-ACS had significant impact on short- and long-term mortality. However, an early invasive strategy is still withheld to a significant number of high-risk patients, who would benefit from an invasive treatment.