Activated protein C levels and outcome in patients with cardiogenic shock complicating acute myocardial infarction.

INTRODUCTION: In patients with severe sepsis, low levels of activated protein C are associated with high morbidity and mortality. In an observational study we investigated whether patients with cardiogenic shock have decreased circulatory levels of activated protein C, and if these are associated with increased mortality. METHODS: We measured serum activated protein C and interleukin-6 levels in 43 patients with cardiogenic shock following acute myocardial infarction and in 15 control patients with uncomplicated myocardial infarction at days 0-5 and 7 after the onset of shock/myocardial infarction. RESULTS: Activated protein C levels were significantly lower in patients with cardiogenic shock compared to controls. In cardiogenic shock patients, there was no difference in activated protein C levels at baseline, whereas activated protein C levels significantly declined in 28-day non-survivors at day 2, compared with 28-day survivors. Lower levels of activated protein C were associated with a higher degree of vasopressor need, whereas there was no significant association with multiple organ failure in the first days. Regarding the inflammatory response, a strong inverse correlation was observed between interleukin-6 and activated protein C levels. CONCLUSION: Patients with cardiogenic shock who did not survive up to 28 days showed a decline in activated protein C levels during the course of the disease, which was inversely correlated with interleukin-6. This study underlines sustained inflammatory mechanisms in the development and persistence of cardiogenic shock, highlighting a potential effect of anti-inflammatory interventions early during cardiogenic shock.

Electrocardiogram changes and wall motion abnormalities in the acute phase of Tako-Tsubo syndrome.

BACKGROUND: The Tako-Tsubo syndrome is still rarely diagnosed in patients presenting with symptoms of acute myocardial ischaemia. It is accompanied by wall motion abnormalities of the left ventricle but significant narrowings or occlusions of epicardial coronary arteries are absent. We investigated a potential relationship between electrocardiogram (ECG) changes, wall motion abnormalities and gender influence of Tako-Tsubo syndrome in an Austrian cohort of Tako-Tsubo syndrome patients. METHODS AND RESULTS: We were recently able to describe four different anatomical types of Tako-Tsubo syndrome in 153 patients of the Austrian Tako-Tsubo syndrome registry. In the present retrospective analysis we investigated ischaemia-related changes in the first diagnostic ECG for the different types of Tako-Tsubo syndrome: the apical and the combined apical-midventricular type showed most frequently a ST elevation (41.1% and 35.3%), whereas the midventricular type of Tako-Tsubo syndrome was more often accompanied by T wave inversion (60%). ECG changes in relation to the Tako-Tsubo syndrome type were similar in women and men. There was no difference in the prevalence of clinical complications among patients presenting with ST elevation or left bundle branch block (14.5%) compared with patients without ST elevation (10.4%) (p=0.476). CONCLUSION: Patients with Tako-Tsubo syndrome show characteristic ECG changes in the first diagnostic ECG which are associated to some extent with the anatomical type of Tako-Tsubo syndrome, but these ECG changes were not related to clinical outcome.

Stress-induced cardiomyopathy (Tako-Tsubo syndrome) in Austria.

BACKGROUND: Tako-Tsubo syndrome (TS) is a still rarely diagnosed clinical syndrome, which is characterized by acute onset of chest pain, transient cardiac dysfunction with (frequently) reversible wall motion abnormalities (WMAs), but with no relevant obstructive coronary artery disease. METHODS AND RESULTS: Among 179 consecutive patients with proven diagnosis of TS that were retrospectively analysed in this multicentre registry, women represented the majority of patients (94%) while only 11 men (6%) developed TS. Mean age was 69.1±11.5 years (range 35-88 years). Cardinal symptoms of TS, which led to admission, were acute chest pain (82%) and dyspnoea (32%), respectively. All patients demonstrated typical WMAs, whereby four different types of WMAs could be defined: (1) a more common apical type of TS (n=89; 50%); (2) a combined apical and midventricular form of TS (n=23; 13%); (3) the midventricular TS (n=6; 3%); and (4) an unusual type of basal WMAs of the left ventricle (n=3). Only in 101 patients (57%), a clear causative trigger for onset of symptoms could be identified. In-hospital cardiovascular complications occurred in 25 patients (14%) and consisted of cardiac arrhythmias in 10 patients (40%), cardiogenic shock in six patients (24%), cardiac decompensation in eight patients (32%) and cardiovascular death in one patient, respectively. Echocardiographic control of left ventricular function after the initial measurement was available in almost 70% of the patients: complete recovery of WMAs was found in 73 patients (58.87%); 49 patients (39.52%) showed persistent WMAs. Recurrences of TS were only seen in four patients. During the follow-up period, 13 patients died: three of cardiovascular causes and 10 of non-cardiac causes. In-hospital mortality was 0.6%, 30-day mortality was 1.3% and 2-year mortality was 6.7%. CONCLUSIONS: This study represents to date the largest series of patients suffering from TS in Austria and worldwide. Similar to others, in our series the prevalence of TS was significantly higher in women than in men, while in contrast to other studies, the apical type of TS was detected most frequently. The similar clinical presentation of TS patients to the clinical picture of acute myocardial infarction demonstrates the importance of immediate coronary angiography for adequate differential diagnosis of TS. TS is not necessarily a benign disease due to cardiovascular complications as well as persistent WMAs with delayed recovery.

The role of ST-segment elevation in lead aVR in the risk assessment of patients with acute pulmonary embolism.

UNLABELLED: BACKGROUD AND AIM: Patients with acute pulmonary embolism (APE) present with highly variable symptoms and ECG abnormalities. As ST-elevation in lead aVR has recently been described to predict right ventricular dysfunction (RVD), we aimed to correlate this sign to the severity of APE. METHODS: Three-hundred ninety-six consecutive patients (in centers a and b) with proven APE were retrospectively analysed with respect to 12-lead-ECG, symptoms, thrombus location, echocardiograpy, troponin T, initial therapy and outcome. Data were then compared between patients with and without aVR-ST-elevation. RESULTS: On admission aVR-ST-elevation was present in 34.3% (n = 136). Presence of aVR-ST-elevation was assossiated with more severe clinical presentation (dyspnoea at rest 44.9 vs. 29.2%; p = 0.002, hypotension 17.0 vs. 6.5%; p = 0.001, syncope 16.2 vs. 6.5%; p = 0.002), higher median troponin T levels (0.035 [0.01-0.2] versus 0.01 [0.01-0.02]; p < 0.001), more frequent RVD (74.5 vs. 46.6%; p < 0.001) and central located thrombi (50.8 vs. 29.2; p < 0.001). Thrombolysis was used more frequently (29.1 vs. 7.5%; p < 0.001) and in-hospital-mortality was increased (10.3 vs. 5.4%; p = 0.07) when compared to patients without that sign. Mortality in intermediate-risk APE patients with aVR-ST-elevation was 8.9% compared to 0% in those without (p = 0.04). In contrast, the presence of other classical ECG pattern of APE did not further increase mortality in intermediate-risk patients. CONCLUSIONS: ST-elevation in lead aVR is associated with a more severe course of APE, especially in patients with intermediate-risk. Therefore, aVR-ST-elevation might be useful in risk stratification of APE.

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.

Inflammation and postinfarct remodeling: overexpression of IkappaB prevents ventricular dilation via increasing TIMP levels.

OBJECTIVE: Nuclear factor-kappa B (NF-kappaB) orchestrates genes involved in inflammation and extracellular matrix (ECM) remodeling following myocardial infarction (MI). The objective of the present study was to investigate the effect of overexpression and mode of function of IkappaB, the natural inhibitor of NF-kappaB, on ECM remodeling in a rat model of MI. METHODS: MI was induced in male Sprague-Dawley rats by ligation of the left anterior descending coronary artery (LAD) and was followed by adenovirus-mediated intramyocardial transfection of IkappaB (n = 26) or LacZ reporter genes (n = 26). Sham-operated animals (n = 14) served as controls. RESULTS: In transthoracic echocardiography 49 days after MI, systolic and diastolic left ventricular dimensions were reduced while fractional shortening was preserved in the treatment group. Additionally, evaluation on the isolated heart showed an attenuated downward shift of pressure-volume relationships in the IkappaB group compared to LacZ. NF-kappaB p65 DNA binding activity was diminished both at 5 and 49 days post-MI in the treatment group. Five days post-MI in the treatment group, protein levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were significantly reduced by 72.6% and 73.2%, respectively, compared to LacZ (p<0.05). In parallel, matrix metalloproteinase (MMP)-2 and MMP-9 levels were reduced 5 days post-MI, with MMP-9 still being decreased 49 days post-MI (p<0.01). In contrast, tissue inhibitors of metalloproteinases (TIMP)-1, -2, and -3 were increased compared to LacZ (p<0.01 and p<0.05, respectively) 5 days post-MI. After 49 days, TIMP-2, -3, and -4 expressions were significantly elevated (p<0.05). CONCLUSION: Reducing NF-kappaB activity via IkappaB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IkappaB overexpression prevents ventricular dilation and consequently preserves cardiac function.

S-nitroso human serum albumin attenuates ischemia/reperfusion injury after cardioplegic arrest in isolated rabbit hearts.

BACKGROUND: Depletion of nitric oxide (NO) is associated with ischemia/reperfusion injury. The novel NO donor, S-nitroso human serum albumin (S-NO-HSA), could bridge NO depletion during reperfusion in cardiac transplantation and minimize ischemia/reperfusion injury. METHODS: In an isolated erythrocyte-perfused working heart model, rabbit hearts were randomly assigned after assessment of hemodynamic baseline values to receive S-NO-HSA (0.2 micromol/100 ml, n = 8), L-arginine (10 mmol/100 ml, n = 8) or albumin (control) (0.2 micromol/100 ml, n = 8). After 20 minutes of infusion, the hearts were arrested and stored in Celsior (4 degrees C) enriched with respective drugs for 6 hours, followed by 75 minutes of reperfusion. Hemodynamic values were assessed and biopsy specimens were taken to determine calcium-ionophore stimulated release of NO and superoxide. RESULTS: During early reperfusion, recovery of cardiac output (75% +/- 6% vs 49% +/- 5%, p < 0.05) and coronary flow (99% +/- 8% vs 70% +/- 5%, p < 0.05) were higher, and myocardial oxygen consumption was reduced in the S-NO-HSA Group compared with Control (4.08 +/- 0.46 ml/min/0.1 kg vs 6.78 +/- 0.38 ml/min/0.1 kg, p < 0.01). At the end of the experiment cardiac output (53% +/- 5% vs 27% +/- 5%, p < 0.01) was higher and left atrial pressure (115% +/- 9% vs 150% +/- 8%, p < 0.05) was lower in the S-NO-HSA Group compared with Control. NO release was increased (1,040 +/- 50 nmol/liter and 1,070 +/- 60 nmol/liter vs 860 +/- 10 nmol/liter, p < 0.01) and superoxide release diminished (31 +/- 5 nmol/liter and 38 +/- 5 nmol/liter vs 64 +/- 5 nmol/liter, p < .01) in the S-NO-HSA and L-arginine Groups compared with Control. CONCLUSION: S-NO-HSA improved hemodynamic functions after prolonged hypothermic cardiac arrest by supplementing NO and thereby decreasing ischemia/reperfusion injury.

Adenovirus-mediated overexpression of inhibitor kappa B-alpha attenuates postinfarct remodeling in the rat heart.

OBJECTIVE: The transcription factor nuclear factor kappa B (NF-kB) plays an important role in the inflammatory response following myocardial infarction. We hypothesized that NF-kB-blockade in an animal model of acute ischemia reduces the inflammatory response and therefore attenuates ventricular remodeling. METHODS: Myocardial infarcts (MI) were produced in male Sprague-Dawley rats by ligation of the LAD and followed by adenovirus-mediated intramyocardial delivery of inhibitor kappa Balpha-gene (n=10), the physiological inhibitor of the transcription factor nuclear factor kappa B, respectively, of a beta-gal reporter-gene (n=11). Sham-operated animals (n=10) received neither ligation nor gene transfer. Five days after MI IkB-expression levels were determined by western blotting. Seven weeks after MI in vivo cardiac function was evaluated by transthoracic echocardiography. Based on left ventricular endsystolic and enddiastolic diameters ejection fraction and fractional shortening were calculated. Only animals with MI involving more than 30% of the left ventricle were included. Data are given as mean+/-SD. RESULTS: In IkBalpha-transfected hearts IkBalpha-levels were six-fold higher (P<0.05) than in beta-gal transfected hearts. Concerning in vivo hemodynamics IkBalpha-treated hearts showed reduced systolic and diastolic left ventricular dimensions compared to the beta-gal MI-group (systolic 48+/-4 vs. 66+/-3 mm; diastolic 67+/-5 vs. 84+/-6 mm; P<0.01). Consequently fractional shortening (27.8+/-1.5 vs. 20.4+/-4.0%; P<0.01) and ejection fraction (63.4+/-3.6 vs. 49.1+/-8.3%; P<0.05) were preserved in IkBalpha hearts compared to beta-gal MI-hearts. CONCLUSION: It can be concluded that overexpression of IkBalpha leads to an improved cardiac function thereby attenuating postinfarct remodeling.

Optimizing ischemia/reperfusion in the failing rat heart--improved myocardial protection with acute ACE inhibition.

BACKGROUND: Whereas the number of patients with reduced left ventricular function after myocardial infarction who need revascularization is increasing, the operative outcome is still inadequate. Consequently, drugs that increase myocardial perfusion and decrease oxygen consumption of the remodeled myocardium are of particular interest to cardiac surgeons. Angiotensin-converting enzyme inhibitors (ACE-I) provide this pharmacologic profile. This study tests the hypothesis whether acute ACE inhibition during cardioplegic arrest improves outcome in failing rat hearts. METHODS AND RESULTS: Male Wistar rats (260+/-15 g) underwent coronary ligation. Ten weeks later the rats had developed heart failure (HF). Hearts were harvested and studied on a red cell-perfused working heart: 60 minutes of ischemia, protected by cold blood cardioplegia (CP) every 20 minutes, and 45 minutes of reperfusion. Rats were randomly assigned to 2 groups, 1 group receiving the ACE-I quinaprilat with CP (QuinaMI, n=11), and 1 group receiving CP only (MI, n=8). Hemodynamic recovery, high-energy phosphates (HEP), and morphometry were analyzed. Groups showed similar degrees of myocardial infarction (44+/-5 versus 39+/-4% of LVmass), LVEDP (5.0+/-1 versus 4+/-1 mm Hg) and no differences in baseline values such as external heart work (EHW) and coronary flow (CF). At the end of reperfusion, EHW and CF were significantly higher in QuinaMI than MI (P<0.05 and 0.01), LVEDP had returned to baseline in QuinaMI (P<0.01). HEP were significantly higher preserved in QuinaMI than MI (P<0.05). CONCLUSIONS: Acute ACE inhibition during CP improves postischemic systolic and diastolic function, coronary perfusion as well as HEP-levels in a rat model of HF. These results may have clinical impact on patients with HF undergoing cardiac surgery.