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.

Speckle-Tracking-Based Evaluation of Vascular Strain at Different Sites of the Arterial Tree in Healthy Adults.

Purpose: Vascular ultrasound (US) allows the analysis of vascular strain by speckle-tracking. This study sought to assess the extent to which vas cular strain varies between different segments of the arterial tree. Furthermore, this study aimed to investigate the reproducibility of vascular strain determination as well as of the components that contribute to the variance of vascular strain measurements in different vascular beds. Materials and Methods: Speckle-tracking was used to determine the vascular strain of the abdominal aorta (AA), the common carotid artery (CCA), the common femoral (CFA) and the popliteal artery (PA) of healthy adults. Intra- and interday reproducibility and the components of variance of vascular strain of the respective arteries were determined. Results: A total of 589 US clips obtained in 10 healthy adults (7 males, 28.3 ±â€Š3.2 years) were analyzable. Vascular strain was 7.2 ±â€Š3.0 % in the AA, 5.7 ±â€Š2.1 % in the CCA, 2.1 ±â€Š1.1 % in the CFA and 1.9 ±â€Š1.1 % in the PA. The intraday coefficients of variation of vascular strain were 6.2 % (AA), 3.9 % (CCA), 3.3 % (CFA) and 6.1 % (PA), and the interday coefficients of variation were 5.9 % (AA), 8.4 % (CCA), 10 % (CFA) and 4.6 % (PA). The variance of vascular strain mainly depended on the investigated vessel and subject. Individual DUS clips, the day of examination and the (right/left) body side (in paired arteries) had no impact on the variance of vascular strain. Conclusion: Vascular strain substantially varies between different sites of the arterial tree. Speckle-tracking by DUS allows the reliable determination of vascular strain at different arterial sites.

Evolving biomarkers improve prediction of long-term mortality in patients with stable coronary artery disease: the BIO-VILCAD score.

OBJECTIVE: Algorithms to predict the future long-term risk of patients with stable coronary artery disease (CAD) are rare. The VIenna and Ludwigshafen CAD (VILCAD) risk score was one of the first scores specifically tailored for this clinically important patient population. The aim of this study was to refine risk prediction in stable CAD creating a new prediction model encompassing various pathophysiological pathways. Therefore, we assessed the predictive power of 135 novel biomarkers for long-term mortality in patients with stable CAD. DESIGN, SETTING AND SUBJECTS: We included 1275 patients with stable CAD from the LUdwigshafen RIsk and Cardiovascular health study with a median follow-up of 9.8 years to investigate whether the predictive power of the VILCAD score could be improved by the addition of novel biomarkers. Additional biomarkers were selected in a bootstrapping procedure based on Cox regression to determine the most informative predictors of mortality. RESULTS: The final multivariable model encompassed nine clinical and biochemical markers: age, sex, left ventricular ejection fraction (LVEF), heart rate, N-terminal pro-brain natriuretic peptide, cystatin C, renin, 25OH-vitamin D3 and haemoglobin A1c. The extended VILCAD biomarker score achieved a significantly improved C-statistic (0.78 vs. 0.73; P = 0.035) and net reclassification index (14.9%; P < 0.001) compared to the original VILCAD score. Omitting LVEF, which might not be readily measureable in clinical practice, slightly reduced the accuracy of the new BIO-VILCAD score but still significantly improved risk classification (net reclassification improvement 12.5%; P < 0.001). CONCLUSION: The VILCAD biomarker score based on routine parameters complemented by novel biomarkers outperforms previous risk algorithms and allows more accurate classification of patients with stable CAD, enabling physicians to choose more personalized treatment regimens for their patients.

The inflammatory mediator oncostatin M induces stromal derived factor-1 in human adult cardiac cells.

Stromal derived factor 1 (SDF-1) is a CXC chemokine important in the homing process of stem cells to injured tissue. It has been implicated in healing and tissue repair. Growing evidence suggests that the glycoprotein-130 (gp130) ligand family is involved in repair processes in the heart. The aim of our study was to determine whether gp130 ligands could affect SDF-1 expression in cardiac cells. Human adult cardiac myocytes (HACMs) and fibroblasts (HACFs) were treated with gp130 ligands. Protein and mRNA levels of SDF-1 were determined using ELISA and RT-PCR, respectively. mRNA levels of SDF-1 were determined in human and mouse heart samples by RT-PCR. HACMs and HACFs constitutively express SDF-1, which was significantly up-regulated by the gp130 ligand oncostatin M (OSM). This effect was counteracted by a p38 inhibitor and to a lesser extent by a PI3K inhibitor. mRNA expression of SDF-1 in hearts of mice injected with OSM increased significantly. Levels of OSM and SDF-1 mRNA correlated significantly in human failing hearts. Our data, showing that OSM induces SDF-1 protein secretion in human cardiac cells in vitro and murine hearts in vivo, suggest that OSM via the induction of SDF-1 might play a key role in repair and tissue regeneration.

Hemodynamic effects of Vernakalant in cardio-surgical ICU-patients treated for recent-onset postoperative atrial fibrillation.

Postoperative atrial fibrillation (POAF) is one of the most frequent complications after cardiothoracic surgery and a predictor for postoperative mortality and prolonged ICU-stay. Current guidelines suggest the multi-channel inhibitor Vernakalant as a treatment option for rhythm control. However, rare cases of severe hypotension and cardiogenic shock following drug administration have been reported. To elucidate the impact of Vernakalant on hemodynamics, we included ten ICU patients developing POAF after elective cardiac surgery, all of them awake and breathing spontaneously, in this prospective trial. Patients received the recommended dosage of Vernakalant and were clinically observed and monitored (heart rate, invasive blood pressure, pulse oximetry, central venous pressure) in 1-minute-intervals for 20 minutes before- and 120 minutes after the first dose of Vernakalant. The median time from the end of surgery until occurrence of POAF amounted up to 52.8 [45.9-77.4] hours, it took 3.5 [1.2-10.1] hours from occurrence of POAF until the first application of Vernakalant. All patients received catecholamine support with epinephrine that was held steady and not dynamic throughout the observational phase. We noted stable hemodynamic conditions, with a trend towards a reduction in heart rate throughout the 120 minutes after drug administration. In 7 patients (70%), conversion to sustained sinus rhythm (SR) occurred within 8.0 minutes [6.0-9.0]. No serious adverse events (SAEs) were noted during the observation period. In this prospective trial in ICU-patients showing POAF after cardiac surgery, intravenous Vernakalant did not induce clinically relevant negative effects on patients' hemodynamics but resulted in conversion to sustained SR after a median of 8.0 minutes in 7 out of ten patients.

Low high-density lipoprotein cholesterol predicts cardiovascular events after carotid stenting: a long-term survey.

BACKGROUND: Apart from advanced age, little is known about predictors of the long-term outcome after carotid artery stenting (CAS). OBJECTIVE: We sought to determine whether atherosclerotic risk factors predict the long-term outcome after CAS. PATIENTS AND METHODS: We enrolled 532 patients assigned for CAS. The primary composite end-point, including stroke, myocardial infarction and all-cause mortality, was observed in 100 patients (19%) during the long-term follow-up (median 28 months, interquartile range 14-49 months). RESULTS: Cumulative event rates at 1, 3 and 5 years were 4.4%, 17.1% and 33.4%, respectively. High-density lipoprotein (HDL) cholesterol was an independent predictor of event-free survival. The adjusted hazard ratio for the primary end-point was 0.97 per increase of 1 mg dL(-1) HDL cholesterol [95% confidence interval (CI) 0.95-0.99, P = 0.002) and 2.7 (95% CI 1.6-4.4, P < 0.001) for low HDL cholesterol (< 40 mg dL(-1) in men and < 50 mg dL(-1) in women). Inflammatory activation (leukocyte count > 10,000 mL(-1) or fibrinogen > 450 mg dL(-1) or erythrocyte sedimentation rate > 20 mm h(-1)) was the only other independent atherosclerotic risk factor (P = 0.001). Patients with low HDL cholesterol and elevated inflammatory activation were at very high risk, with a 5-year event rate of 59.4% (95% CI 43.6-75.2%) as compared to 15.1% (95% CI 8.2-22.0%) in those without both risk factors (log rank, P < 0.001). Age, occlusion of the contralateral carotid artery and heart failure were further independent risk predictors (P < 0.01 for all). CONCLUSIONS: Low HDL cholesterol is an independent predictor of the long-term outcome after CAS. The combination of low HDL cholesterol and elevated inflammatory markers identified high-risk patients.

Macrophage colony stimulating factor expression in human cardiac cells is upregulated by tumor necrosis factor-alpha via an NF-kappaB dependent mechanism.

INTRODUCTION: Macrophage colony stimulating factor (M-CSF) is a key factor for monocyte and macrophage survival and proliferation. M-CSF has been implicated in cardiac healing and repair after myocardial infarction. METHODS AND RESULTS: We show by immunohistochemistry and Western blotting analysis that M-CSF protein is present in human heart tissue. Cultured human adult cardiac myocytes (HACM) and human adult cardiac fibroblasts (HACF) isolated from human myocardial tissue constitutively express M-CSF. When HACM and HACF were treated with tumor necrosis factor-alpha (TNF-alpha) M-CSF protein production and M-CSF mRNA expression, determined by ELISA or by using RT-PCR, respectively, was significantly increased. To determine a possible role of nuclear factor kappaB (NF-kappaB) and activating protein 1 (AP-1) in M-CSF regulation, blockers to both pathways and an adenovirus overexpressing a dominant negative (dn) form of IkappaB kinase 2 (IKK2) were used. Only the NF-kappaB blocker dimethylfumarate and the dn IKK2, but not januskinase inhibitor-1 (JNK-I), were able to block the TNF-alpha-induced increase in M-CSF production in these cells, suggesting that the induction of M-CSF through TNF-alpha is mainly dependent on the activation of the NF-kappaB pathway. The monocyte activation marker CD11b was significantly increased after incubating U937 cells with conditioned medium from HACM or HACF as determined by FACS analysis. CONCLUSIONS: Our in vitro data taken together with our immunohistochemistry data suggest that human cardiac cells constitutively express M-CSF. This expression of M-CSF in the human heart and its upregulation by TNF-alpha might contribute to monocyte and macrophage survival and differentiation.

Gender differences in the effects of cardiovascular drugs.

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) has a different pathophysiological background compared to heart failure with reduced ejection fraction (HFrEF). Tailored risk prediction in this separate heart failure group with a high mortality rate is of major importance. Inflammation may play an important role in the pathogenesis of HFpEF because of its significant contribution to myocardial fibrosis. We therefore aimed to assess the predictive value of C-reactive protein (CRP) in patients with HFpEF. METHODS AND RESULTS: Plasma levels of CRP were determined in 459 patients with HFpEF in the LUdwigshafen Risk and Cardiovascular Health (LURIC) study using a high-sensitivity assay. During a median follow-up of 9.7 years 40% of these patients died. CRP predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.20 [95% confidence interval (CI) 1.02-1.40, P = 0.018] and cardiovascular mortality with a HR of 1.32 (95% CI 1.08-1.62, P = 0.005) per increase of one standard deviation. CRP was a significantly stronger mortality predictor in HFpEF patients than in a control group of 522 HFrEF patients (for interaction, P = 0.015). Furthermore, CRP added prognostic value to N-terminal pro B-type natriuretic peptide (Nt-proBNP): the lowest 5-year mortality rate of 6.8% was observed for patients in the lowest tertile of Nt-proBNP as well as CRP. The mortality risk peaked in the group combining the highest values of Nt-proBNP and CRP with a 5-year rate of 36.5%. CONCLUSION: It was found that CRP was an independent and strong predictor of mortality in HFpEF. This observation may reflect immunological processes with an adverse impact on the course of HFpEF.

High soluble Fas and soluble Fas Ligand serum levels before stent implantation are protective against restenosis.

Percutaneous coronary intervention (PCI) represents the most important treatment of coronary artery stenosis today. But instent restenosis (ISR) is a limitation for the outcome. Fas and Fas Ligand have been implicated in apoptosis and vessel wall inflammation. Their role in ISR is not known so far. In this prospective study we studied 137 patients with stable coronary artery disease who underwent elective PCI. Blood samples were taken directly before and 24 hours after PCI. Soluble (s)Fas and sFas Ligand serum levels were measured by ELISA. Restenosis was evaluated six to eight months later either by coronary angiography or by exercise testing. During the follow-up period, 18 patients (13%) developed ISR. At baseline, patients with ISR had significantly lower median sFas, as well as sFas Ligand levels compared to patients without ISR (sFAS: ISR 492 pg/ml, no ISR 967 pg/ml, p=0.014; sFAS Ligand: ISR: 26 pg/ml, no ISR: 42 pg/ml, p=0.001). After PCI median sFas levels significantly decreased in patients with ISR compared to patients without ISR [ISR: -152 pg/ml (IQR -36 to -227), no ISR: -38 pg/ml (IQR -173 to +150 pg/ml), p=0.03]. sFas Ligand levels after PCI significantly increased in ISR patients compared to patients without ISR [ISR: 14 pg/ml (IQR -3 to +26 pg/ml), no ISR -6 pg/ml (IQR -22 to +21 pg/ml), p=0.014]. In conclusion, sFas and sFas Ligand seem to be associated with the development of ISR. Determination of serum levels before and after PCI might help identifying patients at higher risk of ISR.

Macrophage-modulating cytokines predict adverse outcome in heart failure.

Cytokines regulating the mobilisation, recruitment and survival of mononuclear cells may play an important role in progression of heart failure. Therefore, we investigated the role of granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and macrophage colony stimulating factor (M-CSF) in patients with advanced heart failure. G-CSF, MCP-1 and M-CSF were determined in plasma of 351 patients with advanced heart failure by specific ELISAs. During a median follow up period of 16 months (95% confidence interval [CI]: 15-17 months) 175 patients (50%) experienced the composite endpoint rehospitalisation and all-cause mortality. M-CSF tertiles were associated with a gradually increasing risk with hazard ratios (HR) of 2.2 (95% CI: 1.5-3.2; for trend, p<0.001) for the composite endpoint and 2.6 (95% CI: 1.5-4.6; for trend, p=0.002) for all-cause mortality comparing third and first tertile. These associations remained significant in a multivariable Cox regression model after adjustment for BNP and other known risk factors (p=0.043 and p=0.024). High MCP-1 concentrations were associated with an increased risk of all-cause mortality with an adjusted HR of 1.9 (third vs. first tertile, 95% CI: 1.1-3.3; for trend, p=0.034). In contrast, G-CSF tertiles were not significantly associated with the composite endpoint or all-cause mortality in multivariable Cox regression. In conclusion, the independent and concentration-dependent association of macrophage-modulating cytokines and in particular of M-CSF with adverse outcome in advanced HF patients suggests that these cytokines may play an important pathophysiological role in progression of cardiomyopathy.

The inflammatory mediator oncostatin M induces angiopoietin 2 expression in endothelial cells in vitro and in vivo.

OBJECTIVES: Members of the glycoprotein 130 (gp130) receptor-gp130 ligand family play a role in angiogenesis in different tissues. We tested the effect of this cytokine family on the angiopoietin (Ang)-Tie system, which is involved in blood vessel maturation, stabilization, and regression. RESULTS: Oncostatin M (OSM) increased Ang2 expression in human umbilical vein endothelial cells via Janus kinase/signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase activation. Furthermore, OSM induced Ang2 expression in macrovascular endothelial cells isolated from the human aorta and in microvascular endothelial cells isolated from human heart. Our in vivo experiments revealed that mRNA expression of Ang2 in hearts of mice injected with OSM increased significantly, and levels of OSM mRNA significantly correlated with mRNA levels of Ang2 in human hearts. In addition, OSM increased the expression of its own receptors, gp130 and OSM receptor, in endothelial cells in vitro and in mice in vivo, and levels of OSM mRNA significantly correlated with mRNA levels of gp130 and OSM receptor in human hearts. CONCLUSION: Our data, showing the effects of OSM on the Ang-Tie system in endothelial cells, in hearts of mice, and in human heart tissue, provide yet another link between inflammation and angiogenesis.

Immune-mediated mechanisms in atherosclerosis: prevention and treatment of clinical manifestations.

Accumulation of inflammatory cells identifies atherosclerotic plaque at risk for rupture. Typically, activated immune cells occupy the rupture-prone areas of the atherosclerotic lesion. These cells are an appealing therapeutic target for novel strategies of plaque stabilization. Biologic consequences of plaque inflammation ultimately depend not only on the cellular players populating the lesion but also on triggers of immune activation originating from within the plaque or arriving from the circulation, and immune effector mechanisms that mediate cellular damage and plaque destabilization. Recent studies have provided insights into particular immune mechanisms in the atherosclerotic plaque that contribute to plaque vulnerability. This knowledge provides the basis for potential immunomodulatory therapies in cardiovascular disease. These therapeutic approaches can be classified as (1) immunomodulatory effects of existing therapies, (2) therapies targeting inflammatory triggers, and (3) agents inhibiting specific immune mechanisms.

[Optimal platelet inhibition therapy in unstable angina pectoris and after coronary interventions]. / Optimierte Plättcheninhibitortherapie bei instabiler Angina pectoris und nach Koronarinterventionen.

ASPIRIN AND HEPARIN: In several studies aspirin has been found to be very effective in unstable angina pectoris reducing fatal and non-fatal myocardial infarction by 50-70%. Unfortunately the optimal dose of aspirin is still an open question. Whereas heparin alone shows only a weak effectiveness the combination of aspirin and heparin is superior to aspirin alone and is still the basis of antithrombotic therapy in unstable angina. TICLOPIDINE AND CLOPIDOGREL: Experience with thienopyridine derivatives in unstable angina is limited. Ticlopidine has been found to be superior to aspirin alone. Data with the combination of clopidogrel and aspirin should be available soon. THERAPEUTIC RECOMMENDATION AFTER CORONARY INTERVENTION: Both, ticlopidine and clopidogrel have been found to be very effective in preventing coronary-stent thrombosis when combined with aspirin. Meanwhile ticlopidine has been widely substituted by clopidogrel due to the better safety profile of the latter one. 75 mg clopidogrel daily combined with aspirin is recommended for at least 4 weeks after coronary stenting.

[Low molecular weight heparins in acute coronary syndrome]. / Niedermolekulare Heparine bei akutem Koronarsyndrom.

BACKGROUND: Low molecular weight heparins (LMWH) have gained an increased role in the treatment of acute coronary syndrome within the last years. Compared to unfractionated heparins LMWH are user-friendly (high bioavailability after subcutaneous application, no needed routine control of plasma efficacy). RESULTS OF STUDIES: International trials have demonstrated a comparable (dalteparin, nadroparin) or even higher (enoxaparin) efficacy of LMWH compared to unfractionated heparin in the treatment of patients with unstable angina or non-Q-wave infarction. The use of LMWH has thereby been accompanied by a low rate of side effects. Enoxaparin appears to have the highest efficacy compared with other LMWH in the acute phase of disease, but confirming "head-to head" studies with different LMWH are lacking. A significant higher efficacy of a prolonged treatment with LMWH compared to placebo has been shown in one study (FRISC-2) in unstable patients who were not treated by coronary intervention in the early phase of disease. This lasted for about 60 days but was associated with a higher risk of bleeding. FUTURE ASPECTS: Currently, prospective clinical trials investigate the efficacy of combined use of LMWH with thrombolytics, GPIIb/IIIa blockers and the optimal dosage of LMWH during coronary interventions.

[Muscle cell proteins are selectively released into the blood stream by marathon running]. / Marathonlaufen lässt intrazelluläre Proteine aus Muskelzellen selektiv in das Plasma austreten.

In 19 marathon runners of both sexes, plasma concentrations of total creatine kinase (CK) activity, CKMB mass, myoglobin and troponin I were determined before and immediately after the race. Total CK activity and myoglobin increased significantly in all runners and showed neither a correlation with the individual age of the runners nor with the time they needed to reach the goal. In 12 of the runners, CKMB mass increased during the race to a level suggesting myocardial necrosis. However, the runners did not show any detectable deterioration of cardiac function after the race. The appearance of considerable amounts of muscle proteins in plasma precipitated by the muscle strain during the race seems explained by damage of skeletal muscle detected by histological studies. These phenomena may also be a consequence of profoundly disturbed cellular permeability, perhaps due to a kind of local stunning of muscle tissue by prolonged muscular strain.