Impact of concomitant atrial fibrillation on the prognosis of Takotsubo cardiomyopathy.

AIMS: Previous studies revealed that patients with Takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. Supraventricular tachycardia is a well-known complication of TTC. This study was performed to determine the short- and long-term prognostic impact of atrial fibrillation associated with TTC patients. METHODS AND RESULTS: Our institutional database constituted a collective of 114 patients diagnosed with TTC from 2003 to 2015. The patients were divided into two groups according to the presence (n = 21, 18.4%) or absence (n = 93, 81.5%) of atrial fibrillation. The endpoint was a composite of in-hospital events (thromboembolic events and life-threatening arrhythmias), all-cause mortality, rehospitalization due to heart failure, stroke, and the recurrence of TTC. The in-hospital mortality, 30-day mortality, and long-term mortality were significantly higher in the atrial fibrillation group. Kaplan-Meier analysis indicated a significantly lower event-free survival rate over a mean follow-up of 3 years in the atrial fibrillation group than that in the non-atrial fibrillation group (log-rank, P < 0.01). In a multivariate cox regression analysis, atrial fibrillation (hazard ratio, HR 2.3, 95% confidence interval, CI: 1.1-4.9, P < 0.05) and EF ≤ 35% (HR 2.0, 95% CI: 1.1-3.8, P < 0.05) were the only independent predictors of a primary endpoint. CONCLUSION: Rates of in-hospital events and short- as well as long-term mortality were significantly higher in TTC patients suffering from atrial fibrillation compared with patients without atrial fibrillation.

Health-promoting lifestyle behaviours in pregnant women in Turkey.

This study aims to describe the health-promoting lifestyle behaviours of pregnant women. The study was carried out with pregnant women who applied to the polyclinics in different maternity and children hospitals located in Adana, Turkey, between 1 March and 30 May 2009. The data collection tools used in the study were (i) a questionnaire that was used to collect sociodemographic data from the participants and (ii) the Health Promoting Lifestyle Profile II (HPLP II). The results obtained from the study showed that total HPLP II scores were moderate; the highest scores were obtained on the spiritual growth dimension and the lowest scores on the physical activity dimension. Pregnant women with older age, those with a higher educational level, those with a better socioeconomic status and those living in a nuclear family were found to be more likely to have health-promoting lifestyles. Health promotion and healthy lifestyle need to be an integral part of health services provided for pregnant women. Midwives and nurses have prominent roles in encouraging pregnant women to engage in health-promoting behaviours.

Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model.

Disseminated intravascular coagulation in sepsis is associated with microvascular thrombosis and organ dysfunction. It was expected that prothrombotic disposition such as factor V Leiden (FVL) mutation would worsen clinical outcome. Astonishingly, clinical trial and animal experimental data indicate that FVL can be associated with improved survival. This study investigated the effect of FVL on the response to endotoxin of the coagulation and fibrinolytic system in humans. Fourteen healthy male subjects without FVL and 15 healthy males with heterozygous FVL received an intravenous bolus dose of endotoxin, 2 ng/kg of body weight. Blood samples were drawn before and 1, 2, 4, 6, and 24 hours after administration of the endotoxin. Injection of endotoxin led to a more pronounced increase in soluble fibrin in patients with FVL than in controls. Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activator-induced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogen- and fibrin-degradation products.

Platelet and monocyte activity markers and mediators of inflammation in Takotsubo cardiomyopathy.

Patients with Takotsubo cardiomyopathy (TC) often present with symptoms similar to those of myocardial infarction (MI). We analyzed blood concentrations of mediators of inflammation and platelet- and monocyte-activity markers in patients with TC and MI for significant differences. Clinical data of patients with TC (n = 16) and acute MI (n = 16) were obtained. Serial blood samples were taken at the time of hospital admission (t(0)), after 2-4 days (t(1)) and after 4-7 weeks (t(2)), respectively. Plasma concentrations of interleukin (IL)-6, IL-7, soluble CD40 ligand (sCD40L), and monocyte chemotactic protein 1 (MCP-1) were determined with an ELISA. Tissue factor binding on monocytes, platelet-activation marker CD62P, platelet CD40-ligand (CD40L), and platelet-monocyte aggregates were measured using flow cytometry. Expression of CD62P on platelets and IL-6 plasma levels were significantly lower in patients with TC compared to MI at the time of hospital admission. IL-7 plasma levels were significantly elevated in patients with TC compared to patients with MI at 2-4 days after hospital admission. No significant differences were observed concerning sCD40L and MCP-1 plasma levels, tissue factor binding on monocytes, CD40L expression on platelets, and platelet-monocyte aggregates at any point in time. Our results indicate that inflammatory mediators and platelet-activity markers contribute to the differences in the pathogenesis of MI and TC.

No evidence for an association between the rs2824292 variant at chromosome 21q21 and ventricular fibrillation during acute myocardial infarction in a German population.

BACKGROUND: In a recently published genome-wide association study (GWAS), three single nucleotide polymorphisms (SNPs) (rs2824292, rs1353342, rs12090554) were significantly associated with increased susceptibility for ventricular fibrillation (VF) during acute myocardial infarction (AMI). The association of rs2824292 could be confirmed in a second cohort. Both cohorts were from the Netherlands. We aimed to replicate this association in a German cohort of AMI patients with or without VF. METHODS: We included a German cohort of 90 individuals with AMI and VF (cases) and 167 AMI individuals without VF and used Taqman assays for SNP typing. RESULTS: None of the loci showed evidence for a statistically significant association with VF. The observed genotype frequencies of the three loci were in Hardy-Weinberg equilibrium, which essentially excludes genotyping errors. CONCLUSIONS: In contrast to the data from the Netherlands, we could not detect a significant association of the rs2824292 locus and risk of VF during AMI in our German cohort. Differences in recruitment and clinical phenotypes between the Dutch and German cohorts may underlie different genotype associations.

1α,25-dihydroxyvitamin D3 attenuates platelet activation and the expression of VCAM-1 and MT1-MMP in human endothelial cells.

OBJECTIVE: Inflammatory conditions contribute to increased expression of various activity markers in platelets and endothelial cells, leading to atherosclerotic changes in the vascular wall. The objective of this study was to investigate possible protective effects of 1α,25-dihydroxyvitamin D3 in an endothelial cell model. METHODS: After a 24-hour incubation with 1α,25-dihydroxyvitamin D3, human umbilical vein endothelial cells were stimulated with lipopolysaccharide (LPS) and incubated in direct contact with platelets. The expression of CD40L and CD62P in platelets, the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), the urokinase receptor uPAR and membrane type 1 matrix metalloproteinase (MT1-MMP) in endothelial cells and endothelial cell reactive oxygen species generation were measured by flow cytometry. Endothelial nitric oxide synthase was analyzed by Western blot. RESULTS: The increased expression of VCAM-1 and MT1-MMP in endothelial cells by proinflammatory stimulation with LPS and by direct contact with activated platelets was significantly reduced through preincubation with 1α,25-dihydroxyvitamin D3. Platelets in direct contact with preincubated endothelial cells showed significantly reduced CD62P expression when compared to platelets incubated with untreated endothelial cells. CONCLUSIONS: 1α,25-Dihydroxyvitamin D3 attenuates platelet activation and the expression of VCAM-1 and MT1-MMP in human endothelial cells and could have early therapeutic relevance in atherosclerotic diseases.

Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism.

INTRODUCTION: There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin. METHODS: In this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, 12, 18, or 24 µg/kg/hour of DAA or a placebo. Blood samples were drawn before starting DAA infusion, after 4, 8 and 12 hours (at the end of the infusion period), and on treatment days 2, 3, 4, 5 and 6. RESULTS: Initial endogenous plasma activated protein C (APC) levels were 0.36 ± 0.48 ng/ml (<0.10 to 1.72 ng/ml) and remained in the same range in the placebo group. APC levels in patients treated with DAA were 13.67 ± 3.57 ng/ml, 32.71 ± 8.76 ng/ml, 36.13 ± 7.60 ng/ml, and 51.79 ± 15.84 ng/ml in patients treated with 6, 12, 18, and 24 µg/kg/hour DAA, respectively. In patients with a D-dimer level >4 mg/L indicating a high level of acute fibrin formation and dissolution, DAA infusion resulted in a more rapid drop in soluble fibrin, D-dimer, and fibrinogen/fibrin degradation products (FDP) levels, compared to enoxaparin alone. There was a parallel decline of soluble fibrin, D-dimer, FDP, and plasmin-plasmin inhibitor complex (PPIC) in response to treatment with enoxaparin ± DAA, with no evidence of a systemic profibrinolytic effect of the treatment. CONCLUSIONS: In patients with acute submassive PE endogenous APC levels are low. DAA infusion enhances the inhibition of fibrin formation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00191724.

The P-selectin gene polymorphism Val168Met: a novel risk marker for the occurrence of primary ventricular fibrillation during acute myocardial infarction.

UNLABELLED: The P-Selectin Gene Polymorphism Val168Met. AIMS: Ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI) is the leading cause of sudden cardiac death (SCD). Family history of SCD is described as risk factor for primary VF during acute AMI. Genetic factors may be associated with primary VF. We examined polymorphisms in genes related to the activation and adhesion of blood platelets in patients with and without VF in the setting of AMI and among healthy controls. METHODS: Two hundred and forty patients with a history of AMI and 475 healthy controls were studied. Seventy-three patients (30%) had primary VF during AMI. By using PCR techniques with sequence-specific primers (PCR-SSP), we genotyped 5 single nucleotide polymorphisms (SNPs) in P-selectin (SELP) (V168M, S290N, N592D, V599L, T715P), 2 SNPs (M62I, S273F) in P-selectin glycoprotein ligand-1 (SELPLG), 5 SNPs in CD40LG (-3459A>G, -122A>C, -123A>C, 148T>C, intr4-13T>C), the H558R SNP in SCN5A, and rs2106261 in ZFHX3. In addition, length polymorphisms in SELPLG (36bp-tandem repeat) and CD40LG (CA-repeat) were genotyped by PCR methods. Results were evaluated by 2-sided t-tests, chi-square tests, and logistic regression analysis. RESULTS: None of the gene polymorphisms showed significant differences between AMI patients and healthy controls. Among patients with a history of VF, however, the SELP 168M variant showed a significantly higher prevalence (14/73 patients; 19.2%) as compared with patients without VF (13/167 patients; 7.8%; P < 0.01). This association remained significant in a logistic regression analysis after adjustment for age and gender (P = 0.013; odds ratio 2.8; 95% confidence interval 1.2-6.3). CONCLUSIONS: This is the first description of an association of the SELP gene variant 168M with primary VF during acute MI. This variant may be a candidate polymorphism for evaluating the susceptibility for VF in the setting of acute MI.

Comparison of long-term prognostic value of N-terminal-proBNP and midregional-pro-adrenomedullin in patients with acute myocardial infarction.

BACKGROUND: N-terminal-proBNP (NT-proBNP) and Midregional-pro-Adrenomedullin (MR-proADM) predict mortality of patients with acute myocardial infarction (AMI). Comparison of the prognostic values of NT-proBNP and MR-proADM to predict long-term adverse clinical events (AE) after AMI has not been evaluated yet. METHODS: 30 patients with AMI were enrolled into this prospective study. Measurements of NT-proBNP and MR-proADM were performed at initial presentation, two or three days and four months after AMI. Long-term AE defined as recurrent AMI, need for repeated percutaneous transluminal angioplasty or coronary bypass graft surgery, congestive heart failure, cardiopulmonary resuscitation, cardiogenic shock, syncope, and death were documented during a follow-up period of ten months. RESULTS: At initial presentation, NT-proBNP values were significantly higher in patients with AE compared to patients without AE (p < 0.05). The area under the ROC curve (AUC) indicated good predictive performance of NT-proBNP (AUC 0.78, 95% CI 0.59-0.91, p = 0.003) and MR-proADM (AUC 0.71, 95% CI 0.51-0.86, p = 0.046) regarding AE. Comparing both AUC revealed no differences between NT-proBNP and MR-proADM as predictors of AE (p = 0.59). Patients with NT-proBNP levels > or = 370 pg/mL were more likely to suffer from AE than patients with lower levels (relative risk 6.7, 95% CI 1.0-46, p = 0.018). With this cutoff, NT-proBNP could exclude AE with a negative predictive value of 92% being similar to MR-proADM (negative predictive value 76%, relative risk 2.8, 95% CI 1.2-6.9, p = 0.042). CONCLUSIONS: Early measurements of NT-proBNP or MR-proADM during the acute phase of AMI may allow the risk of a long-term AE to be excluded, based on the comparable test characteristics,.

Enhanced proinflammatory response of mononuclear cells to in vitro LPS-challenge in patients with ventricular fibrillation in the setting of acute myocardial infarction.

AIMS: Ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI) is the leading cause of sudden cardiac death. A potential role of intrinsic, subclinical inflammatory states in patients suffering from ischemia-related VF has not been investigated yet. The aim of the present study was (i) to examine serum levels of proinflammatory markers in VF survivors and (ii) to evaluate basal and lipopolysaccharide (LPS)-stimulated interleukin-8-mRNA (IL-8-mRNA) levels in patients with and without VF complicating AMI. METHODS: Twenty-five patients with a history of VF during AMI and a control group of 25 AMI patients without VF were included. Blood samples were taken remote from AMI with a mean of 590 days. Circulating serum levels of IL-8, IL-6, soluble E-selectin (sE-selectin), tissue factor activity (TFA), tissue inhibitor of matrix-metalloproteinase-1 (TIMP-1) and matrix-metalloproteinase-9 (MMP-9) were measured. Mononuclear cells were isolated by density gradient centrifugation. The cells were stimulated with lipopolysaccharide (LPS) from Escherichia coli (700 ng/mL). IL-8-mRNA levels in mononuclear cells were determined by a colorimetric mRNA quantification assay. RESULTS: Serum levels (median; range) of IL-8 (VF: 2.24 pg/mL; <0.10-19.3 pg/mL versus controls: 0.10 pg/mL; <0.10-7.7 pg/mL; p=0.014), IL-6 (VF: 0.68 pg/mL; <0.05-2.9 pg/mL versus controls: 0.23 pg/mL; <0.05-1.8 pg/mL; p=0.042) and TIMP-1 (VF: 229 ng/mL; 144-348 ng/mL versus controls: 186 ng/mL; 126-263 ng/mL; p=0.014) were significantly higher among patients with VF as compared to controls. Baseline IL-8-mRNA concentrations of blood mononuclear cells were significantly higher among patients with VF (257 amol/mL; 52-2672 amol/mL) as compared to patients without VF (37 amol/mL, 3.2-770 amol/mL; p<0.01). IL-8-mRNA levels after LPS-challenge were significantly higher among patients with VF (3503 amol/mL; 215-13,573 amol/mL) than in patients without VF (1003 amol/mL; 208-3386 amol/mL; p<0.01). CONCLUSIONS: Circulating IL-8, IL-6, and TIMP-1 concentrations as well as IL-8-mRNA expression in mononuclear cells at baseline and after LPS-challenge are increased among patients with a history of VF in the setting of AMI as compared to patients without VF. These findings indicate an enhanced inflammatory response to a proinflammatory stimulus in VF survivors. The magnitude of this increased acute phase reactants may indicate a novel pathway of arrhythmogenesis in patients with AMI.

Association of NT-proBNP with severity of heart valve disease in a medical patient population presenting with acute dyspnea or peripheral edema.

BACKGROUND AND AIM OF THE STUDY: The study aim was to perform a comprehensive evaluation of the association between N-terminal pro B-type natriuretic peptide (NT-proBNP) and the severity of heart valve diseases in a typical clinical population presenting with acute dyspnea or peripheral edema. METHODS: Among 401 eligible patients, 210 demonstrated evaluable complete echocardiographic examinations. Plasma levels of NT-proBNP were measured after the initial clinical evaluation. RESULTS: Patients with a prior valve replacement had higher plasma levels of NT-proBNP (median 3,366 pg/ml; n = 10) compared to all other patients (median 931 pg/ml; n = 200) (p < 0.05). In univariable analyses, NT-proBNP levels correlated with multiple valve diseases (r = 0.5; p < 0.001) and the severities of specific heart valve diseases, including aortic valve stenosis (AS) and regurgitation (AR), tricuspid (TR) and mitral valve regurgitation (MR) (p < 0.001). Within multivariable linear regression models, multiple heart valve diseases (Beta = 0.21; T = 3.56; p = 0.0001) and specifically valve regurgitations (AR (Beta = 0.16; T = 2.54; p = 0.012), MR (Beta = 0.36; T = 5.55; p = 0.0001), TR (Beta = 0.17; T = 2.55; p = 0.012)) were associated with increasing plasma levels of NT-proBNP. Patients with NT-proBNP plasma levels > 1,100 pg/ml showed the highest risk for future clinical events (odds ratio (OR) 4.86; p = 0.02), followed by patients with TR (OR 3.17; p = 0.03) and AS (OR 3.49; p = 0.06). CONCLUSION: In addition to clinical assessment and echocardiographic evaluation, the measurement of plasma NT-proBNP levels may serve as a valuable additional indicator of the severity of heart valve disease in individual patients.

Performance evaluation of a new rapid quantitative assay system for measurement of D-dimer in plasma and whole blood: PATHFAST D-dimer.

D-dimer is an indicator for in vivo fibrin formation, reflecting the formation of fibrin crosslinked by factor XIIIa. D-dimer assays are frequently used in emergency situations, such as diagnosis of venous thrombosis and pulmonary embolism, or disseminated intravascular coagulation. In these conditions, short sample turnaround times are essential. The PATHFAST D-dimer assay allows rapid quantitative measurement of D-dimer in plasma and whole blood. The study shows an excellent correlation between whole blood and plasma measurement of D-dimer both in the high range, as well as in the normal range. Intra-assay and inter-assay coefficients of variation (CV) were below 10%. The upper limit of normal (ULN = mean value measured in 100 samples from healthy blood donors + 2 x S.D.) was approximately 1 microg/ml FEU, using the assay-specific calibration. The maximal value measured in 20 replicates of calibrator 1 containing no D-dimer antigen was 0.00052 microg/ml FEU, and this 10-fold lower than the declared detection limit of 0.005 microg/ml FEU. In conclusion, the PATHFAST D-dimer assay is the first automated fully quantitative D-dimer assay, which can use plasma and whole blood as sample materials in parallel.

Effects of alimentary lipemia and inflammation on platelet CD40-ligand.

INTRODUCTION: In patients with chronic hypercholesterolemia, the CD40-CD40L dyad is upregulated, contributing to the initiation and progression of atherosclerosis. Our aim was to describe the role of postprandial lipemia and inflammatory stimulation on platelet and monocyte activation and CD40-ligand (CD40L) levels. METHODS AND RESULTS: Before and 2 h after consumption of a defined fatty meal, whole blood samples of 31 healthy subjects were incubated with endotoxin (LPS). CD40-ligand and CD62P expression on platelets, tissue-factor expression on monocytes and platelet-monocyte aggregates were measured with flow cytometry. Soluble CD40-ligand plasma levels were measured with an ELISA. After the meal, serum triglyceride levels increased from 137.6+/-60.5 mg/dl to 201.5+/-75.0 mg/dl. Expression of CD40L and CD62P on platelets and plasma levels of soluble CD40L were significantly decreased. No significant changes after the meal were observed concerning tissue factor expression on monocytes and platelet-monocyte aggregates. Addition of LPS showed no significant effect concerning CD40L or CD62P expression on platelets, whereas the amount of platelet-monocyte aggregates significantly increased under LPS stimulation after the fatty meal. CONCLUSIONS: Acute alimenatry lipemia leads to a decreased expression of CD40L on platelets and a reduced plasma level of sCD40L, suggesting an increased turnover in the CD40L system. CONDENSED ABSTRACT: Before and after a fatty meal, blood samples of 31 healthy subjects were incubated with LPS. After the meal, expression of CD40L and CD62P on platelets and plasma levels of soluble CD40L were significantly decreased. Addition of LPS showed no effect concerning CD40L or CD62P expression, whereas the amount of platelet-monocyte aggregates significantly increased under LPS stimulation after the fatty meal.

Coagulation activation and expression of CD40 ligand on platelets upon in vitro lipopolysaccharide-challenge in patients with unstable angina.

BACKGROUND: Elevated markers of inflammation and coagulation are found in patients with coronary heart disease. A role of inflammatory stimulation on coagulation time and expression of CD40 ligand on platelets in acute coronary syndromes has not been described yet. METHODS AND RESULTS: Whole blood samples of 9 patients with coronary heart disease and stable angina, 10 patients with unstable angina, 7 patients with acute myocardial infarction and 7 patients without coronary heart disease were incubated with lipopolysaccharide (LPS). Coagulation time was measured in arterial and coronary blood with the ReoRox(R), a viscometric whole blood coagulometer. CD40L and CD62P expression on platelets and platelet-monocyte aggregates were measured by flow cytometry. Without LPS, patients with unstable angina showed a significantly decreased coagulation time in arterial and coronary blood compared to patients without coronary heart disease. After incubation with LPS, in patients with unstable angina, a significantly decreased coagulation time in coronary blood was observed compared to patients with stable angina or patients without coronary heart disease. CD40L expression on platelets in patients with unstable angina was significantly higher in arterial and coronary blood compared to patients with stable angina. No significant differences between the patient groups were observed concerning CD62P expression on platelets, tissue factor binding on monocytes, platelet-monocyte aggregates and plasma levels of platelet factor 4. CONCLUSIONS: Patients with unstable angina show an enhanced coagulation activation and an upregulation of CD40L on platelets. This may be of importance in the understanding of coronary plaque rupture and formation of coronary thrombosis.

Enhanced expression of platelet CD40-ligand by in vitro lipopolysaccharide-challenge in patients with ventricular fibrillation complicating acute myocardial infarction.

BACKGROUND: Acute myocardial infarction can be complicated by ventricular arrhythmias due to electrophysiological changes in the ischemic myocardium, but the exact predisposing factors causing ventricular fibrillation during myocardial infarction still remain unclear. A role of inflammatory stimulation on platelets as a potential risk factor for ventricular fibrillation during acute myocardial infarction has not been described yet. METHODS AND RESULTS: Whole blood samples of 21 patients with a history of acute myocardial infarction (AMI) and ventricular fibrillation (VF) were incubated with lipopolysaccharide (LPS). As a control group, we studied 19 patients without VF during AMI. CD40-ligand and CD62P expression on platelets and tissue factor binding on monocytes were measured by flow cytometry. Platelet-monocyte aggregates were measured by CD41 expression on platelets adherent to monocytes. Soluble CD40-ligand plasma levels were measured with an ELISA. Without LPS, no significant difference between the patient groups concerning CD40L expression on platelets was observed, but plasma levels of soluble CD40L were significantly higher in patients with a history of AMI with VF. After LPS stimulation, patients with a history of VF showed a significantly increased expression of CD40L in comparison to the patients without ventricular fibrillation, based on a significantly higher increase of CD40L expression. CD62P expression on platelets was significantly increased in patients with a history of VF. CONCLUSIONS: Patients with a history of VF complicating AMI show an enhanced expression of CD40L on platelets after in vitro lipopolysaccharide-challenge with an enhanced platelet activation.

Assessment of markers of thrombin generation in patients with acute myocardial infarction complicated by ventricular fibrillation.

BACKGROUND: In most cases, sudden cardiac death is triggered by ischemia-related ventricular tachyarrhythmias and accounts for 50% of deaths from cardiovascular disease in developed countries. Chronic elevation of indicators of coagulation activation has been found in patients with coronary heart disease, but a role of coagulation activation as a potential risk factor for ventricular fibrillation (VF) during acute myocardial infarction (MI) has not been investigated. METHODS: We enrolled 50 patients with a history of MI, of whom 26 presented with VF in the acute phase of myocardial ischemia; 24 patients had an acute MI without ventricular tachyarrhythmias. Levels of thrombin-antithrombin complexes (TAT), prothrombin fragment F1 + 2 (F1 + 2), fibrinopeptide A (FPA), plasmin-antiplasmin complexes (PAP), protein C, antithrombin, activated partial thromboplastin time (aPTT), thromboplastin time, D-Dimer, fibrinogen, and high-sensitivity C-reactive protein (hs-CRP) were measured in plasma samples of all patients. Blood collection was obtained sequentially in two separate settings. Patients were studied at a median of 351 days after the acute coronary event. RESULTS: Higher levels of TAT complexes (13.4 +/- 22.2 vs. 3.03 +/- 4.3 microg/l; p = 0.02), FPA (79.7 +/- 132.3 vs. 24.04 +/- 41.3 ng/ml; p = 0.04), and F1+2 (1.89 +/- 1.3 vs. 1.16 +/- 0.5 nmol/l; p = 0.01) were observed in patients with VF compared with patients without ventricular tachyarrhythmias during the acute phase of MI. D-Dimer levels displayed a trend without reaching statistical significance (0.69 +/- 0.48 vs. 0.48 +/- 0.24 mg/l; p = 0.06). No differences were found in hs-CRP (3.25 +/- 4.5 vs. 4.4 +/- 8.8 mg/l; p = 0.5) and fibrinogen (2.8 +/- 0.9 vs. 2.7 +/- 0.9 g/l; p = 0.6) measurements. Repeat assessment of markers of coagulation activation at a median of 847 days revealed a highly significant decrease in patients with VF. CONCLUSIONS: Markers of thrombin generation are transiently increased in patients with VF during the acute phase of MI. These findings have implications for risk assessment and genetic screening of patients prone to VF during acute myocardial ischemia.

Expression of Inflammation-related Intercellular Adhesion Molecules in Cardiomyocytes In Vitro and Modulation by Pro-inflammatory Agents.

BACKGROUND: Cell-surface adhesion molecules regulate multiple intercellular and intracellular processes and play important roles in inflammation by facilitating leukocyte endothelial transmigration. Whether cardiomyocytes express surface-adhesion molecules related to inflammation and the effect of pro-inflammatory mediators remain unknown. MATERIALS AND METHODS: In the present study, the expression of different cell-adhesion molecules (CD11a, CD11b, CD31, CD62P, CD162, F11 receptor and mucosal vascular addressin cell adhesion molecule 1 (MADCAM1)) and the effect of pro-inflammatory mediators were investigated in an in vitro model of human cardiomyocytes. Cells were supplied as a primary culture of cardiac alpha actin-positive cells from human heart tissue. The cells were incubated for 24 h with 1 U/ml thrombin or 700 ng/ml lipopolysaccharide (LPS) or with a combination of both. The expression of the cell adhesion molecules was measured by flow cytometry. RESULTS: In cultured human cardiomyocytes, 22.8% of cells expressed CD31, 7.1% MADCAM1 and 2.6% F11R. CD11a, CD11b, CD62P and CD162 were expressed by fewer than 2% of the cells at baseline. CD31 expression increased on incubation of cardiomyocytes with thrombin by 26% (p<0.05) and with LPS by 26% (p=0.06). The combination of thrombin and LPS did not result in increased levels of CD31 (p>0.10). The pro-inflammatory agents LPS and thrombin had no effect on the expression of MADCAM1 and F11R. CONCLUSION: Inflammation-related cell-adhesion molecules CD31, MADCAM1 and F11R were shown to be expressed on the surface of human cardiomyocytes in an in vitro model. Incubation with LPS or thrombin resulted in increased expression of CD31, however, it did not modify the expression of the cell adhesion molecules MADCAM1 and F11R.

Clinical and echocardiographic analysis of patients suffering from recurrent takotsubo cardiomyopathy.

BACKGROUND: Recurrence of takotsubo cardiomyopathy (TTC) is a well-known complication. However, current literature lists only a few isolated cases. We aimed to determine the incidence and clinical significance of recurrent TTC. METHODS & RESULTS: Our institutional database constituted a collective of 114 patients diagnosed with TTC since 2003. Close follow-up of these patients revealed a recurrence of TTC in seven of these (6.1%). The time interval between the index event and its recurrence varied between six months and six years. Arterial hypertension was more revealed in the recurrence group of TTC compared to non-recurrence group, (P = 0.02). Chronic obstructive pulmonary disease and/or asthma was more diagnosed in the recurrence group, (P = 0.04). Clinical events like right ventricular involvement, TTC related complications such as life-threatening arrhythmias, pulmonary congestion and in hospital death were observed more frequently in the recurrent episode. Over a mean follow-up of one year the mortality rate was similar in both groups. CONCLUSIONS: Recurrence of TTC within six years after index event is not an uncommon phenomenon. In the event of right ventricular involvement in the relapse phase, it might be associated with a higher complication rate. TTC recurrence should be the first differential diagnosis in patients with a past history of TTC.

Characteristics and long-term outcome of right ventricular involvement in Takotsubo cardiomyopathy.

OBJECTIVE: Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy (SCM) resembles a reversible cardiomyopathy that is characterized by localized wall motion abnormalities in the absence of stenotic coronary vascular disease. Patients typically present with apical ballooning of the left ventricle (LV), however the right ventricle (RV) is also affected in up to 50.0% of patients. Long-term prognosis of classical SCM resembles that of patients after ST elevation myocardial infarction. Data on long-term prognosis of biventricular compared to classical SCM is controversial. The aim of this study was therefore to analyze patients with biventricular SCM regarding in-hospital outcome and long-term prognosis. MATERIALS AND METHODS: 114 consecutive patients with SCM were retrospectively analyzed. 88 patients presented with classical SCM, 26 patients (22.8%) were diagnosed with biventricular SCM. Follow-up was conducted for a total of 4.4years. Mean age was 67.1years with 83.3% of patients being female. The primary endpoint was a composite of all-cause mortality, recurrence of SCM and re-hospitalization due to heart failure. RESULTS: Although patients with biventricular SCM presented with a tendency towards an increased rate of cardiogenic shock (30.8% vs. 15.9%; p=0.09) and significantly more usage of inotropic support upon hospital admission (34.6% vs. 13.6%; p=0.01), there was no difference concerning the primary endpoint in both groups (50.0% vs. 44.3%; p=0.31). Furthermore, there was no difference in mortality both in-hospital (7.7% vs. 7.9%; p=0.66) and during long-term follow-up (27.3% vs. 23.1%; p=0.46). CONCLUSION: Patients with biventricular SCM have the same in-hospital and long-term outcome compared to classical SCM.

SCN5A mutations and polymorphisms in patients with ventricular fibrillation during acute myocardial infarction.

Mutations in the SCN5A gene encoding the Nav1.5 channel α-subunit are known to be risk factors of arrhythmia, including Brugada Syndrome and Long QT syndrome subtype 3. The present study focused on the role of SCN5A variants in the development of ventricular fibrillation (VF) during acute myocardial infarction (AMI). Since VF during AMI is the major cause of sudden death in the Western world, SCN5A mutations represent genetic risk factors for sudden death. By exon re-sequencing, the entire coding region and flanking intron regions were sequenced in 46 AMI/VF+ patients. In total, nine single nucleotide variants were identified of which four represented common single nucleotide polymorphisms (SNPs; 87G>A, 1673A>G, IVS16­6C>T and 5457T>A). Only five rare variants were identified, each in only one patient. Only two of the rare variants represented missense mutations (3578G>A and 4786T>A). The common SNPs and the missense mutations were also genotyped using polymerase chain reaction methods in 79 AMI/VF­ patients and 480 healthy controls. The SNPs did not demonstrate significant differences in allele and genotype frequencies between the study groups. The 3578G>A mutation was identified in one out of the 480 controls, whereas the 4786T>A mutation was not present in AMI/VF- patients and controls. In conclusion, the majority of AMI/VF+ patients demonstrated a wild type sequence or common SNPs in SCN5A. Only two out of 46 (4.3%) AMI/VF+ patients revealed mutations that may be involved in Nav1.5 dysfunction and VF. However, this requires further functional validation.