Aims. Reperfusion after myocardial ischaemia is associated with a distinct ischaemia/reperfusion injury. Since ACE-inhibition, beyond its influence on cardiac angiotensin II formation and kinin metabolism, has been shown to be cardioprotective by decreasing leucocyte adhesion and endothelin-1 (ET-1) release, we investigated the effects of intracoronary (i.c.) enalaprilat during primary angioplasty in acute myocardial infarction.Methods and results. Twenty-two patients were randomized to receive i.c. enalaprilat (50 mu g) or placebo immediately after reopening of the infarct-related artery (IRA). Plasma concentrations of soluble L-selectin, P-selectin, intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), ET-1 and nitric oxide metabolite concentrations (NO(x)) were measured in pulmonary arterial blood. Coronary blood flow was assessed using corrected thrombolysis in myocardial infarction (TIMI) frame counts (CTFC). During reperfusion, there was a significant increase in sL-selectin, sP-selectin and ET-1 in the placebo group, which was greatly diminished by enalaprilat. Levels of sVCAM-1 and sICAM-1 were not affected in either group. CTFC in the placebo group remained higher than normal in both the IRA and nonculprit vessels, whereas myocardial blood flow improved with enalaprilat.Conclusions. Enalaprilat as adjunct to primary angioplasty might be a protective approach to prevent leucocyte adhesion and the release of ET-1, thereby improving coronary blood flow.

The value of early therapy with beta-blocking agents in acute myocardial infarction (AMI) undergoing reperfusion is not yet well established. Newer beta-blocking agents such as carvedilol offer potential advantages in the setting of ischemia and reperfusion injury.

Background— The utility of N-terminal proBNP (NT-proBNP) to predict the occurrence of death and hospitalization was prospectively evaluated in the COPERNICUS study, which enrolled patients with an ejection fraction <25% and symptoms of chronic congestive heart failure at rest or on minimal exertion. Methods and Results— Baseline plasma concentrations of NT-proBNP were measured in a subgroup of 814 men and 197 women with symptoms at rest or on minimal exertion who were enrolled in the COPERNICUS study and were randomized to placebo (n=506) or carvedilol (n=505). Values of NT-proBNP were markedly increased despite the requirement that patients be euvolemic before the start of treatment (mean±SD, 3235±4392 pg/mL; median, 1767 pg/mL). By univariate Cox regression analysis, NT-proBNP was found to be a powerful predictor of subsequent all-cause mortality (relative risk [RR], 2.7; 95% CI, 1.7 to 4.3; P =0.0001 for above versus below median) and all-cause mortality or hospitalization for heart failure (RR, 2.4; 95% CI, 1.8 to 3.4; P =0.0001 for above versus below median). The predictive value of NT-proBNP was similar when both placebo and carvedilol patients were analyzed separately. No significant interaction was found between NT-proBNP and treatment group ( P =0.93 for above- versus below-median NT-proBNP). Conclusions— NT-proBNP was consistently associated with increased risk for all-cause mortality and for all-cause mortality or hospitalization for heart failure in patients with severe congestive heart failure, even in those who were clinically euvolemic. This marker therefore may be a useful tool in risk stratification of patients with severe congestive heart failure.

Background: Neither profiles nor prognostic value of cardiac N-terminal proBNP (NT-proBNP) have been prospectively evaluated in a sufficient number of patients with severe chronic heart failure (CHF) treated with carvedilol or placebo. Methods: Baseline and follow-up plasma concentrations of NT-proBNP were measured in the European part of the COPERNICUS Trial. This study enrolled patients with an ejection fraction <25% and symptoms of CHF at rest or on minimal exertion, equally randomized to placebo or carvedilol. Results: NT-proBNP concentrations were increased at baseline (mean+/-S.D.=579+/-822 pmol/l, median=322.5 pmol/l) with a marked decrease during follow-up in the carvedilol, but not in the placebo group. One-year mortality rates were 3.9, 12 and 27.9% in the lower, middle and upper tertiles of NT-proBNP, respectively. When mortality was calculated separately in the placebo and carvedilol group, rates were 0.8, 6.3 and 19.1% in the carvedilol treated but 6.7, 17.9 and 36.9% in the placebo treated patients. Conclusions: NT-proBNP was a powerful predictor of subsequent all-cause mortality in patients with severe CHF. This marker should therefore be further evaluated for risk stratification and monitoring of therapy in CHF. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Background - Abnormal heart rate turbulence (HRT) is associated with an increased risk of mortality in the chronic phase of myocardial infarction (MI) in the prethrombolytic and thrombolytic eras. However, the impact of direct percutaneous coronary intervention (PCI) on HRT in the acute phase of MI and its association to the epicardial infarct-related arterial flow has not been examined.Methods and Results - We investigated HRT in 126 patients undergoing direct PCI for a first MI. Turbulence onset and turbulence slope were determined before reperfusion, during the initial 2 hours after reperfusion, and during hours 6 to 24 after reperfusion. HRT significantly improved after PCI. There were no significant differences in baseline clinical characteristics between Thrombolysis in Myocardial Infarction Trial classification (TIMI) 2 (n = 28) and TIMI 3 ( n = 98) flow. After PCI, turbulence slope increased (13.2 +/- 11 to 18.1 +/- 12 ms/beat, P < 0.001) and turbulence onset decreased ( - 0.008 +/- 0.04% to - 0.023 +/- 0.04%, P < 0.01) in patients with TIMI 3 flow after PCI, whereas there were no significant alterations of turbulence slope (12.2 +/- 10 to 12.8 +/- 6.5 ms/beat) and turbulence onset ( - 0.009 +/- 0.05% to - 0.003 +/- 0.03%) in patients with TIMI 2 flow.Conclusions - The improvement of HRT after successful reperfusion is a previously unreported effect of direct PCI for acute MI, reflecting rapid restoration of baroreceptor response. The persistent impairment of HRT after PCI in patients with TIMI 2 flow indicates a sustained blunted baroreflex response and may reflect a more severe microvascular dysfunction.

Background - Complete coronary artery reperfusion in acute myocardial infarction ( AMI) has been shown to significantly improve survival. Electrical stability may be the decisive mechanism for this beneficial effect. Because electrical stability is largely dependent on ventricular repolarization, we sought to determine the impact of a modern reperfusion strategy (ie, direct percutaneous coronary intervention [PCI]) on QT dynamicity in AMI and examined its association with infarct-related artery flow.Methods and Results - We prospectively investigated QT dynamicity in 128 patients undergoing direct PCI for a first AMI. Slopes and correlation coefficients of the linear QT/RR regression were determined in the time interval before reperfusion, within the initial hour after reperfusion, and within the remaining recording period from Holter ECG recordings, which were initiated on admission. Subgroup analysis based on TIMI 3 (n = 100) and TIMI 2 ( n = 28) flow after PCI revealed no significant differences in QT/RR slope before PCI (0.145 +/- 0.12 versus 0.160 +/- 0.19, P = NS). After PCI, QT/RR slopes increased only in the TIMI 2 subgroup ( P < 0.05). In TIMI 2 patients, QT/RR slopes were significantly steeper in the hour after PCI and in the remaining recording period, respectively ( 0.155 +/- 0.12 versus 0.192 +/- 0.15, P < 0.05, and 0.159 +/- 0.10 versus 0.210 +/- 0.17, P < 0.01).Conclusions - Alterations of QT dynamicity in patients with incomplete reperfusion may suggest an altered electrical restitution, potentially providing a substrate for serious ventricular arrhythmias. Thus, our findings offer new insights into mechanisms by which complete reperfusion may affect electrical stability.

BACKGROUND The presence of admission cardiac troponin-T (cTnT) is a means of identifying a high-risk subgroup in patients with acute ST-segment elevation myocardial infarction (AMI). Because a substantial number of these patients has malignant ventricular arrhythmias, we hypothesized that there is a relation between cTnT status on admission and inhomogeneity of ventricular repolarization, and we tested this assumption in the setting of primary percutaneous coronary intervention (PCI). METHODS Temporal fluctuations of ventricular repolarization were studied during and after primary PCI (Thrombolysis In Myocardial Infarction [TIMI] 2 and 3) in 94 consecutive patients with a first AMI by continuous beat-to-beat QT-interval measurement, performed with Holter monitoring initiated on admission. Troponin-T levels on admission were >0.1 ng/mL in 53 patients (cTnT+) and <0.1 ng/mL in 41 patients (cTnT-). There were no significant differences in baseline clinical characteristics between the groups. RESULTS The incidence of severe reperfusion arrhythmias (RAs) was significantly higher in patients in the cTnT+ group within the first 2 hours after recanalization. The course of the QT interval revealed a significant decline (P <.001) after recanalization of the infarcted vessel within 10 hours in both groups; however, hourly values were significantly lower and normalization of the QT parameters was more rapid in patients in the cTnT- group than patients in the cTnT+ in this period (QTc, 438.5 +/- 28.3 ms vs 449.3 +/- 35.3 ms [hour 1, P <.01]; 413.6 +/- 35.8 ms vs 420.1 +/- 39.2 ms [hour 10, P <.05]). QT-interval variability also significantly declined within 4 hours after PCI (P <.001), and likewise, patients in the cTnT- group exhibited lower values in this period (QTSD, 29.7 +/- 6.8 ms vs 33.5 +/- 10.5 ms [hour 1, P <.01]; 23.0 +/- 6.1 ms vs 25.9 +/- 7.5 ms [hour 4, P <.01]). CONCLUSIONS Positivity of cTnT on admission is associated with a significantly higher temporal inhomogeneity of ventricular repolarization and a higher incidence of malignant RAs, which suggests more advanced microvascular injury. Early successful primary PCI ultimately results in a significant recovery of parameters of QT interval and mean RR interval in all patients, although it was significantly delayed in patients in the cTnT+ group.

BACKGROUND:Neither profiles nor prognostic values of neurohormonal markers have been prospectively evaluated in patients with acute myocardial infarction (AMI) undergoing primary angioplasty.METHODS AND RESULTS:In 118 consecutive patients with AMI undergoing successful reperfusion (TIMI 2 and 3) by primary angioplasty, plasma concentrations of norepinephrine, epinephrine and N-terminal proBNP (NT-proBNP) were measured before, 60 min and 10 days after angioplasty. Catecholamine concentrations (mean+/-SEM) rose to a maximum in the first hour after angioplasty (norepinephrine: 602+/-44 ng/L, epinephrine: 213+/-24 ng/L) and returned to normal at day 10. Conversely, NT-proBNP levels maintained a further increase from 799+/-44 pmol/L at baseline to 924+/-54 pmol/L at day 10. A NT-proBNP concentration above median at 60 min post-angioplasty predicted major adverse cardiac events (n=27) during the 18-36 month follow-up with an odds ratio of 5.9 (1.7-20.3) and was superior to catecholamines, to left ventricular ejection fraction and to other established postinfarction risk markers.CONCLUSIONS:In a low-risk cohort of patients with AMI undergoing successful reperfusion therapy, plasma NT-proBNP concentrations are elevated for at least ten days. The prognostic value of early plasma NT-proBNP should be further evaluated concerning its ability to facilitate risk stratification of infarct patients.

During the past 15 years, the pathophysiological concept of heart failure as a neurohormonal disease has influenced heart failure therapy substantially. ACE-inhibitors have become the mainstay of heart failure therapy. In addition, beta blocker evolved to be effective in improving survival in this disease. Recently, the COPERNICUS study established the efficacy of carvedilol in severe heart failure and extended the benefits of this drug first observed in patients with mild and moderate symptoms to those with advanced disease. In this study, carvedilol resulted in a significant reduction of all-cause mortality and combined mortality and hospitalization, the frequency of hospitalizations, the risk of repeated hospitalizations, the number of days in hospital, the average duration of each admission and the utilization of treatments and procedures for heart failure. Carvedilol was well tolerated, improved the sense of well-being, was associated with a lower risk of a serious adverse event, particularly one related to the progression of heart failure and fewer patients requiring withdrawal of treatment for an adverse event. These favourable results were equally seen in all subgroups. Carvedilol treatment was even cost-effective in severe disease. Therefore, this new therapeutic option should be available to all patients with symptomatic systolic heart failure.

BACKGROUND:Cardiac troponin T (cTnT) elevations at admission indicate a high-risk subgroup of patients with acute ST-segment elevation myocardial infarction, possibly due to a higher failure rate of reperfusion therapies. OBJECTIVE:We sought to determine the predictive role of admission cTnT in patients with ST-segment elevation myocardial infarction undergoing successful direct percutaneous coronary intervention. METHODS:A total of 218 consecutive patients with ST-segment elevation myocardial infarction were enrolled. Patients were stratified according to admission cTnT and infarct location. They were followed prospectively for short-term and long-term outcomes. RESULTS A positive cTnT (47.7%) was associated with higher mortality rates at 30 days (14.4% vs. 3.5%, p = .003) and 12 months (17.3% vs. 4.4%, p =.007). cTnT allowed discrimination of patients at high and low risk for cardiac death at 30 days and 12 months among anterior (19.2% vs. 7.9%, p = .19, and 25% vs. 13.2%, p = .22, respectively) and, more impressively, among nonanterior acute myocardial infarction (9.6% vs. 1.3%, p = .04, and 11.5% vs. 1.3%, p = .017, respectively). In multivariate analysis, older age, anterior infarct location, and depressed left ventricular function were the most potent independent predictors of future risk. Among clinical variables available at admission, cTnT indicated independently a higher risk of cardiac death (odds ratio, 3.1 [1.07-9.01], p =.038). This increased risk associated with a positive cTnT was almost independent of time delays from onset of symptoms to admission (3.8 vs. 2.3 hrs in cTnT-positive vs. cTnT-negative patients, p <.001). CONCLUSIONS:Admission cTnT is a strong predictor of future cardiac risk in patients with ST-segment elevation myocardial infarction, despite successful restoration of Thrombolysis in Myocardial Infarction grade 3 coronary flow by direct percutaneous coronary intervention.