Imbalance between plasma double-stranded DNA and deoxyribonuclease activity predicts mortality after out-of-hospital cardiac arrest.

AIM: Despite an increased rate of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA) patients, almost half of patients do not survive up to hospital discharge. Understanding pathophysiological mechanisms of post-cardiac arrest syndrome is essential for developing novel therapeutic strategies. During systemic inflammatory responses and concomitant cell death, double-stranded (ds) DNA is released into circulation, exerting pro-inflammatory effects. Deoxyribonuclease (DNase) degrades dsDNA. The role of DNase activity in OHCA survivors and impact on clinical outcome has not been analyzed yet. METHODS: In a prospective, single-center study, dsDNA and DNase activity were determined at hospital admission (acute phase) and 24 h (subacute phase) after ROSC. The ratio between dsDNA levels and DNase activity was calculated to determine the extent of dsDNA release in relation to the patients' capacity of degradation. Thirty-day mortality was defined as study end point. RESULTS: We enrolled 64 OHCA survivors, of whom 26.6% (n = 17) died within 30 days. A peak of circulating dsDNA was observed at admission which decreased within 24 h. DNase activity did not differ between acute and subacute phase, while dsDNA load per DNase activity significantly decreased. The ratio between dsDNA levels and DNase activity in the subacute phase was the strongest predictor of 30-day mortality with an adjusted HR per 1 SD of 3.59 (95% CI, 1.80-7.18, p < 0.001). CONCLUSION: Disproportionally increased dsDNA levels uncompensated by DNase activity are a strong predictor of mortality in OHCA survivors. This pilot study points to a potentially protective effect of DNase activity in patients undergoing cardiac arrest.

Chronic complications of venous thromboembolism.

Venous thromboembolism (VTE) is a common disease (~700 per 100 000) that is associated with significant risk of recurrence, chronic complications, and substantial mortality, with reported death rates of up to 40% at 10 years. The development of novel anticoagulants has revolutionized the treatment of acute VTE, while strategies for prevention and treatment of chronic complications still seek for such a landmark change. Impaired thrombus resolution is the common denominator behind VTE complications, which are postthrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH). PTS and CTEPH are associated with substantial morbidity and high healthcare expenses. While PTS occurs in up to 50% of patients after symptomatic deep vein thrombosis, only a small and poorly defined number of patients are diagnosed with CTEPH after pulmonary embolism. This review is a comprehensive summary of VTE-related chronic complications, their epidemiology, diagnosis, and treatment.

Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension.

Alterations in the nitric oxide (NO) pathway play a major role in pulmonary arterial hypertension (PAH). L-arginine (LA) and tetrahydrobiopterin (BH4) are main substrates in the production of NO, which mediates pulmonary vasodilation. Administration of either LA or BH4 decrease pulmonary artery pressure (PAP). A combined administration of both may have synergistic effects in the therapy of PAH. In a telemetrically monitored model of unilateral pneumonectomy and monocrotaline-induced PAH, male Sprague-Dawley rats received either LA (300 mg/kg; n = 15), BH4 (20 mg/kg; n = 15), the combination of LA and BH4 (300 mg/kg, 20 mg/kg; n = 15), or vehicle (control group; n = 10) from day 28 after monocrotaline induction. Therapy was orally administered once daily over consecutive 14 days. LA, BH4, or both equally lowered PAP, increased pulmonary vascular elasticity, restored spontaneous locomotoric activity, prevented body weight loss and palliated small vessel disease of severely pulmonary hypertensive rats. BH4 substitution lowered asymmetric dimethylarginine levels sustainably at 60 min after administration and downregulated endothelial NO synthase mRNA expression. No significant survival, macro- and histomorphologic or hemodynamic differences were found between therapy groups at the end of the study period. Administration of LA and BH4 both mediated a decrease of mean PAP, attenuated right ventricular hypertrophy and small vessel disease in monocrotaline-induced pulmonary hypertensive rats, though a combined administration of both substances did not reveal any synergistic therapy effects in our animal model.

[Pulmonary hypertension associated with left heart disease: recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Linksherzerkrankungen: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. While the guidelines contain detailed recommendations regarding pulmonary arterial hypertension (PAH), they contain only a relatively short paragraph on other, much more common forms of PH such as PH due to left heart disease. Despite the lack of data, targeted PAH treatments are increasingly being used for PH associated with left heart disease. This development is of concern because of limited ressources and the need to base treatments on scientific evidence. On the other hand, PH is a frequent problem that is highly relevant for morbidity and mortality in patients with left heart disease, representing an unmet need of targeted PH therapies. It that sense, the practical implementation of the European Guidelines in Germany requires the consideration of several specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, several working groups were initiated, one of which was specifically dedicated to PH associated with left heart disease. This article summarizes the results and recommendations of this working group.

Gender-related impact on outcomes of high density lipoprotein in acute ST-elevation myocardial infarction.

BACKGROUND AND AIMS: There is rising evidence that cardioprotective functions of high-density lipoprotein (HDL) have significant impact on clinical outcomes. ST-elevation myocardial infarction (STEMI) represents a high-risk vascular condition. Whether higher HDL-cholesterol concentrations in women correspond to protective anti-oxidant properties in the setting of STEMI is unknown. METHODS: We prospectively assessed gender related differences in the anti-oxidant function of HDL, and the impact of HDL properties on mortality in 242 women and men with STEMI. Blood samples to determine HDL function and sex hormone levels were collected during primary percutaneous coronary intervention. RESULTS: Patients were stratified according to preserved anti-oxidant HDL function (HDL oxidant index (HOI) < 1) and pro-oxidant HDL (HOI≥1). Despite higher serum levels of HDL-cholesterol in postmenopausal women (48 mg/dl, IQR 42-54, versus 39 mg/dl, IQR33-47, p < 0.001 in men), the proportion of patients with pro-oxidant HDL was not different between women (35%) and men (46%, p = 0.132). Kaplan-Meier analysis revealed higher cardiovascular mortality in both women (p = 0.021) and men (p = 0.045) with pro-oxidant HDL. We identified pro-oxidant HDL as strong and independent predictor of cardiovascular mortality with an adjusted HR of 8.33 (95% CI, 1.55-44.63; p = 0.013) in women and with an adjusted HR of 5.14 (95% CI, 1.61-16.42; p = 0.006) in men. Higher levels of free sex hormones (estradiol and testosterone) were associated with pro-oxidant HDL. HDL-cholesterol levels showed no association with mortality (HR in women 1.03, 95% CI 0.96-1.11, p = 0.45 and HR in men 0.99, 95% CI 0.94-1.05, p = 0.72). CONCLUSIONS: Total HDL-cholesterol serum levels were not associated with mortality in STEMI patients. Pro-oxidant HDL was a strong and independent predictor of mortality in women and men with STEMI. The present study provides a link between sex hormones, HDL function and clinical events in STEMI patients. In clinical practice and future clinical trials, anti-oxidant properties of HDL rather than total HDL serum levels should be used for risk stratification.

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.

Peri-interventional endothelin--a receptor blockade improves long-term outcome in patients with ST-elevation acute myocardial infarction.

Endothelin (ET)-1 is a pro-fibrotic vasoconstrictive peptide causing microvascular dysfunction and cardiac remodelling after acute ST-elevation myocardial infarction (STEMI). It acts via two distinct receptors, ET-A and ET-B, and is involved in inflammation and atherogenesis. Patients with posterior-wall STEMI were randomly assigned to intravenous BQ-123 at 400 nmol/minute (min) or placebo over 60 min, starting immediately prior to primary percutaneous coronary intervention (n=54). Peripheral blood samples were drawn at baseline as well as after 24 hours and 30 days. Myeloperoxidase (MPO), as a marker of neutrophil activation and matrix metalloproteinase 9 (MMP-9), a marker of extracellular matrix degradation were measured in plasma. Clinical follow-up was conducted by an investigator blinded to treatment allocation over three years. During the median follow-up period of 3.6 years (interquartile range [IQR] 3.3-4.1) we observed a longer event-free survival in patients randomised to receive BQ-123 compared with patients randomised to placebo (mean 4.5 years (95% confidence interval: 3.9-5) versus mean 3 years (2.2-3.7), p=0.031). Patients randomised to ET-A receptor blockade demonstrated a greater reduction of MPO levels from baseline to 24 hours compared to placebo-treated patients (-177 ng/ml (IQR 103-274) vs -108 ng/ml (74-147), p=0.006). In addition, a pronounced drop in MMP-9 levels (-568 ng/ml (44-1157) vs -117 ng/ml (57-561), p=0.018) was observed. There was no significant difference in amino-terminal propetide of pro-collagen type III levels. In conclusion, short-term administration of BQ-123 leads to a reduction in MPO, as well as MMP-9 plasma levels and to a longer event-free survival in patients with STEMI.

AMPA receptor subunits expression and phosphorylation in cingulate cortex in rats following esophageal acid exposure.

BACKGROUND: We recently reported an increase in N-methyl-d-aspartate (NMDA) receptor subunit expression and CaMKII-dependent phosphorylation of NR2B in the rostral cingulate cortical (rCC) neurons following esophageal acid exposure in rats. As α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors mediate the fast excitatory transmission and play a critical role in synaptic plasticity, in this study, we investigated the effect of esophageal acid exposure in rats on the expression of AMPA receptor subunits and the involvement of these molecular alterations in acid-induced sensitization of neurons in the anterior cingulate (ACC) and midcingulate (MCC) cortices. METHODS: In molecular study, we examined GluA1 and GluA2 expression and phosphorylation in membrane preparations and in the isolated postsynaptic densities (PSDs) from rats receiving acute esophageal exposure of either saline (control group) or 0.1 N HCl (experimental group). In electrophysiological study, the effect of selective AMPA receptor (Ca(2+) permeable) antagonist IEM-1460 and CaMKII inhibitor KN-93 was tested on responses of cortical neurons during acid infusion to address the underlying molecular mechanism of acid-induced sensitization. KEY RESULTS: The acid exposure significantly increased expression of GluA1, pGluA1Ser(831) , and phosphorylated CaMKIIThr(286) , in the cortical membrane preparations. In isolated PSDs, a significant increase in pGluA1Ser(831) was observed in acid-treated rats compared with controls. Microinjection of IEM-1460 or KN-93 near the recording site significantly attenuated acid-induced sensitization of cortical neurons. CONCLUSIONS & INFERENCES: The underlying mechanism of acid-induced cortical sensitization involves upregulation and CaMKII-mediated phosphorylation of GluA1. These molecular changes of AMPA receptors subunit GluA1 in the cortical neurons might play an important role in acid-induced esophageal hypersensitivity.

The role of the superior laryngeal nerve in esophageal reflexes.

The aim of this study was to determine the role of the superior laryngeal nerve (SLN) in the following esophageal reflexes: esophago-upper esophageal sphincter (UES) contractile reflex (EUCR), esophago-lower esophageal sphincter (LES) relaxation reflex (ELIR), secondary peristalsis, pharyngeal swallowing, and belch. Cats (N = 43) were decerebrated and instrumented to record EMG of the cricopharyngeus, thyrohyoideus, geniohyoideus, and cricothyroideus; esophageal pressure; and motility of LES. Reflexes were activated by stimulation of the esophagus via slow balloon or rapid air distension at 1 to 16 cm distal to the UES. Slow balloon distension consistently activated EUCR and ELIR from all areas of the esophagus, but the distal esophagus was more sensitive than the proximal esophagus. Transection of SLN or proximal recurrent laryngeal nerves (RLN) blocked EUCR and ELIR generated from the cervical esophagus. Distal RLN transection blocked EUCR from the distal cervical esophagus. Slow distension of all areas of the esophagus except the most proximal few centimeters activated secondary peristalsis, and SLN transection had no effect on secondary peristalsis. Slow distension of all areas of the esophagus inconsistently activated pharyngeal swallows, and SLN transection blocked generation of pharyngeal swallows from all levels of the esophagus. Slow distension of the esophagus inconsistently activated belching, but rapid air distension consistently activated belching from all areas of the esophagus. SLN transection did not block initiation of belch but blocked one aspect of belch, i.e., inhibition of cricopharyngeus EMG. Vagotomy blocked all aspects of belch generated from all areas of esophagus and blocked all responses of all reflexes not blocked by SLN or RLN transection. In conclusion, the SLN mediates all aspects of the pharyngeal swallow, no portion of the secondary peristalsis, and the EUCR and ELIR generated from the proximal esophagus. Considering that SLN is not a motor nerve for any of these reflexes, the role of the SLN in control of these reflexes is sensory in nature only.

Risk factors for chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by obstruction and vascular remodelling of pulmonary arteries following pulmonary embolism. Risk factors that predispose patients to CTEPH include the size of the initial thrombus and numerous associated host or medical conditions. Haemostatic risk factors include elevated levels of factor VIII and phospholipid antibodies or intrinsic abnormalities in fibrinogen. Medical conditions that are associated with an increased risk of CTEPH include a history of splenectomy, cancer, ventriculoatrial shunt, chronic inflammatory disease, antiphospholipid antibodies and hypothyroidism. Although CTEPH is potentially curable by pulmonary endarterectomy (PEA), up to 40% of patients evaluated for PEA may be denied surgery depending on the level of surgical experience and disease accessibility after pre-operative assessment. Furthermore, an estimated 10-15% of patients are at risk for residual pulmonary hypertension following PEA surgery, due to significant concomitant small-vessel disease. However, pre-operative identification of small-vessel involvement remains a challenge. The current medications effective in the treatment of pulmonary arterial hypertension have not demonstrated efficacy in CTEPH. Accordingly, identification of CTEPH, followed by early referral for evaluation and treatment by an experienced PEA centre, is recommended.

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study.

BACKGROUND: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. OBJECTIVES: To compare different assays for prediction of events during long-term follow-up. METHODS: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA-100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. RESULTS: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. CONCLUSIONS: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.

A noninvasive algorithm to exclude pre-capillary pulmonary hypertension.

Current guidelines recommend right heart catheterisation (RHC) in symptomatic patients at risk of pre-capillary pulmonary hypertension (PH) with echocardiographic systolic pulmonary artery pressures ≥ 36 mmHg. Growing awareness for PH, a high prevalence of post-capillary PH and the inability to distinguish between pre- and post-capillary PH by echocardiography have led to unnecessary RHCs. The aim of our study was to assess whether standard noninvasive diagnostic procedures are able to safely exclude pre-capillary PH. Data from 251 patients referred for suspicion of pre-capillary PH were used to develop a noninvasive diagnostic decision tree. A prospectively collected data set of 121 consecutive patients was utilised for temporal validation. According to the decision tree, patients were stratified by the presence or absence of an electrocardiographic right ventricular strain pattern (RVS) and serum N-terminal brain natriuretic peptide (NT-proBNP) levels below and above 80 pg·mL⁻¹. In the absence of RVS and elevated NT-proBNP, none of the patients in the prospective validation cohort were diagnosed with pre-capillary PH by RHC. Combining echocardiography with the diagnostic algorithm increased specificity to 19.3% (p = 0.0009), while sensitivity remained at 100%. Employing ECG and NT-proBNP on top of echocardiography helps recognise one false positive case per five patients referred with dyspnoea and echocardiographic suspicion of PH, while not missing true pre-capillary PH.

Long-term outcome after thrombectomy in acute myocardial infarction.

BACKGROUND: Current data appear in favour of thrombectomy for ST-elevation myocardial infarction (STEMI). However, information on long-term outcome after thrombectomy is limited. We performed a retrospective long-term study to assess the risk of cardiac re-hospitalizations and survival after discharge from the index hospitalization for STEMI. METHODS: Patients originally randomized to percutaneous coronary intervention (PCI) with thrombectomy vs. standard PCI were included in a retrospective long-term observational study. The primary study endpoint was the combined risk for all-cause death or cardiac re-hospitalization after index discharge under optimal medical therapy. The cumulative number of cardiac hospitalization days and ventricular remodelling assessed by echocardiography and plasma biomarkers were secondary endpoints. RESULTS: Of 94 STEMI patients who had been randomized between 11/2000 and 03/2003, 89 patients consented to long-term follow-up. A total of 43 patients had been allocated to thrombectomy and 46 to standard primary PCI. The minimum follow-up time was 1115 days. There was a significantly lower risk for death or cardiac re-hospitalization for patients of the thrombectomy group (hazard ratio = 0.69, 95% CI: 0.49-0.98, P = 0.036). The incidence of recurrent myocardial infarction was not different (P = 0.343). No differences in cardiac remodelling were detected by echocardiography, with the exception that heart-type fatty acid binding protein at 53.2 +/- 17 months was lower in the thrombectomy group (P = 0.045). CONCLUSION: Thrombectomy in STEMI may decrease the long-term risk for death or cardiac re-hospitalization.

Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay.

BACKGROUND AND AIM: The prognostic value of the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) for thrombotic adverse events has been shown in independent studies. As no direct comparison between the two methods has been made so far, we investigated which laboratory approach has a better predictive value for stent thrombosis. METHODS: The VASP phosphorylation assay and MEA were performed in 416 patients with coronary artery disease undergoing percutaneous coronary intervention. The rate of stent thrombosis was recorded during a 6-month follow-up. RESULTS: Definite stent thrombosis occurred in three patients (0.7%) and probable stent thrombosis in four (1%). Receiver operating characteristic (ROC) analysis demonstrated that MEA distinguishes between patients with or without subsequent stent thrombosis better than the VASP phosphorylation assay: the area under the ROC curve was higher for MEA (0.92; P=0.012) than for the VASP phosphorylation assay (0.60; P=0.55). At equal levels of sensitivity (100%), the specificity was greater for MEA than for the VASP phosphorylation assay (86% vs. 37%). Stent thrombosis occurred in 9% of patients with platelet hyperreactivity in MEA, who were simultaneously clopidogrel non-responders in the VASP phosphorylation assay. Interestingly, clopidogrel non-responders in the VASP phosphorylation assay without platelet hyperreactivity in MEA did not suffer from stent thrombosis. CONCLUSIONS: Platelet hyperreactivity in MEA might be a better risk predictor for stent thrombosis than the assessment of the specific clopidogrel effect with the VASP phosphorylation assay.

Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation in patients with aortic stenosis.

Severe aortic stenosis is associated with a haemostatic abnormality that resembles acquired von Willebrand syndrome type 2. It is assumed that high shear conditions render large von Willebrand factor (VWF) multimers accessible to cleavage by ADAMTS-13. However, whether loss of these large multimers affects platelet function by impairing adhesion, aggregate formation, or both has not been evaluated in clinical studies. We prospectively enrolled 47 patients with severe aortic stenosis, and studied them prior to aortic valve surgery and at a median of six months after valve replacement. We investigated levels of large VWF multimers, platelet function under high shear conditions, and residual response to suboptimal concentrations of ADP to express P-selectin. As expected, there was a significant reduction of VWF large multimers before surgery that resolved thereafter in most patients (p<0.0001). The closure time of the ADP cartridge of the PFA-100 was also corrected in most patients after the operation (p<0.0001). We used the cone and plate(let) analyser Impact-R to differentiate between adhesion and aggregation. Both adhesion (p=0.03) and ADP-inducible platelet aggregation (p=0.002) improved considerably after valve replacement. Consequently, ADP-inducible expression of P-selectin was higher after valve replacement (p=0.001). We conclude that reduced levels of large VWF multimers associated with aortic stenosis lead to impairment of both adhesion and, especially, ADP-inducible platelet aggregation.

Outcome after device implantation in chronic heart failure is dependent on concomitant medical treatment.

BACKGROUND: Device implantation in chronic heart failure (CHF) for cardiac resynchronization therapy (CRT) with or without implantable cardioverter/defibrillator (ICD) is an established treatment option for symptomatic patients under medical baseline therapy. Although recommended, the need for optimization of medical therapy was never proven. As in 'the real world', medical therapy is not always up-titrated to the desirable dosages; this provides the opportunity to evaluate the impact of optimizing medical therapy in patients who had received a device therapy with proven effectiveness. MATERIALS AND METHODS: This observational cohort study retrospectively assessed the 'real life'-effect of CRT compared with that of CRT/ICD therapy and the impact of concomitant pharmacotherapy on outcome. Outcome of patients with guideline recommended renin-angiotensin system inhibitor and ss-blocker dosages was compared with that of patients who failed to reach the desired dosages. Mean follow-up for the 205 CHF (95 CRT and 110 CRT/ICD) patients was 16.8 + or - 12.4 months. RESULTS: In the total study cohort, 83 (41%) reached the combined primary endpoint of all-cause death or cardiac hospitalization [CRT group: 25 (26%), CRT/ICD group: 58 (52.7%), P < 0.001]. Multiple cox regression analysis revealed non-optimized medical therapy at follow-up [HR = 2.080 (1.166-3.710), P = 0.013] and CRT/ICD vs. CRT [HR = 2.504 (1.550-4.045), P < 0.001] as significant predictors of the primary endpoint. CONCLUSION: Our data stress the importance of professional monitoring and titration of pharmacotherapy not only in medically treated CHF patients but also in patients under device therapy by a heart failure unit or a specialized cardiologist.

Inhomogeneous vasomotor effects of moderate selective and non-selective endothelin-receptor blockade in stable coronary artery disease.

OBJECTIVE: To explore the morphological and functional effect of selective and non-selective endothelin (ET)-receptor blockade in coronary artery disease (CAD). DESIGN: Prospective randomised controlled trial. SETTING: University hospital. PATIENTS: 26 patients with stable CAD. INTERVENTIONS: Intracoronary infusion (30 minutes) of the ET-A receptor blocker BQ-123 (40 nmol/min, group A, n = 13) alone or with the ET-B receptor blocker BQ-788 (10 nmol/min, group AB, n = 13) as well. MAIN OUTCOME MEASURES: Fractional flow reserve (FFR), coronary flow reserve (CFR) and intramyocardial resistance (IMR) by PressureWire, mean arterial blood pressure (MAP), minimal lumen diameter (MLD) and average angiographic lumen diameter (mean LD) of the target vessel before and after intracoronary infusion of ET antagonists. Concentrations of C-terminal pro-endothelin-1 (CT-proET1) in arterial blood were determined before and after infusion. RESULTS: Mean MLD, mean LD, FFR, CFR, IMR and MAP remained unaffected by ET-receptor blockade in both groups; their changes were comparable. Concentrations of CT-proET-1 increased by 6.2 (SD 5.9) pmol/l (95% CI 1.2 to 11.1 pmol/l; p = 0.022) in group A and by 4.1 (SD 4.3) pmol/l (95% CI 1.1 to 7.2 pmol/l; p = 0.014) in group AB. CONCLUSIONS: We found a broad variety of individual haemodynamic responses to ET-receptor antagonists with an overall neutral effect after an infusion period of 30 minutes despite an overall effective blockade of ET-receptors. Prolonged infusion time may be needed to cause a more distinct vasomotor response. TRIAL REGISTRATION NUMBER: NCT00427232.

Pulmonary hypertension in chronic heart failure.

The presence of PH in patients who suffer from CHF is common and predicts a poor outcome. However, precise definitions for PH associated with left heart disease, or 'out-of-proportion' PH as well as standardised vasodilator testing protocols are lacking. Moreover, apart from single-centre observations no large-scale trial to date has demonstrated a long-term benefit from pulmonary vasoactive drugs. As a result, there are currently no consensus recommendations for the treatment of PH in the presence of CHF. Off-label use of specific vasodilators in this patient population is discouraged. In a majority of cases, treatment of the underlying left heart disease leads to a decrease in pulmonary pressures. In light of novel agents to treat PH, trials that specifically address 'out-of-proportion' PH in CHF patients are warranted.