Primary objective: Platelet-derived growth factor-BB (PDGF-BB) has been shown to promote the structural integrity of the vessel wall and to increase wound healing capacity. Aim of the present study was to determine the role of PDGF-BB in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C (rhAPC) on plasma levels of PDGF-BB in severe sepsis was evaluated as well as the in vitro effect of rhAPC on PDGF-BB-release from human endothelial cells (HUVEC).
Background/Aim: The association between ejection fraction (EF) and mortality in TTS patients as compared to ACS is limited. This study aims to investigate the association between EF and clinical outcomes in patients with TTS as compared to ACS. Patients and Methods: This study compared in-hospital, and long-term incidence of clinical outcomes for 5 years in patients with TTS and ACS. The study was composed of two groups EF≥35% and EF<35%. Results: The long-term mortality of the EF≥35% for 5 years was significantly higher in TTS patients as compared to ACS (18.1% vs. 7.7%, log-Rank; p<0.01). Irrespective of EF, a non-cardiovascular death was significantly higher in TTS as compared to ACS patients with EF≥35 (6.4% vs. 2.1%; p=0.02) and with EF<35% (21.4% vs. 7.5%; p=0.03). Conclusion: The long-term mortality is significantly higher in TTS as compared to ACS dominated by a non-cardiovascular cause of death at 5-years-follow-up.
Background Left atrial function (LAF) plays an interactive role between pulmonary and systemic circulation. Cardiac biomarkers, such as amino-terminal pro-brain natriuretic peptide (NT-proBNP) and troponins, might reflect cardiac function. This study aims to evaluate the association between high sensitivity troponins (hsTn) and left atrial function in patients undergoing cardiac magnetic resonance imaging (cMRI). Methods Patients undergoing cardiac magnetic resonance imaging (cMRI) were enrolled prospectively. Patients with right ventricular dysfunction (<50%) were excluded. Blood samples for measurements of hsTn and NT-proBNP were collected at the time of cMRI. Results Eighty-four patients were included. Median LVEF was 59% (IQR 51-64%). HsTn correlated inversely with LAF within multivariable linear regression models (hsTnI: Beta -0.46; T -4.44; P = 0.0001; hsTnT: Beta -0.29; T -3.06; P = 0.003). High sensitivity troponins increased significantly according to decreasing stages of impaired LAF ( P = 0.0001). High sensitivity troponins discriminated patients with impaired LAF < 55% (hsTnT: AUC = 0.80; P = 0.0001; hsTnI: AUC = 0.74; P = 0.0001) and <45% (hsTnT: AUC = 0.75; P = 0.0001; hsTnI: AUC = 0.73; P = 0.001) and were still significantly associated in multivariable logistic regression models (LAF < 55%: hsTnT: OR = 21.78; P = 0.0001; hsTnI: OR = 5.96; P = 0.009; LAF < 45%: hsTnT: OR = 10.27; P = 0.0001; hsTnI: OR = 12.56; P = 0.001). Conclusions This study demonstrates that hsTn are able to reflect LAF being assessed by cardiac magnetic resonance imaging.
Background: Sepsis is well known to lead to the activation of multiple pro-inflammatory markers, like MCP-1 (Monocyte chemotactic protein 1), TNF-alpha (Tumor necrosis factor alpha), while the underlying genetic changes still remain poorly studied. Methods: We used human umbilical vein endothelial cells to test the reactions to nicotine or acetylcholine/pyridostigmine administration in regards to MCP-1 levels, gene regulation and RNR expression. Results: Pyridostigmine and Acetylcholine (Ach) lead to a significant decrease of MCP-1 levels in TNF-alpha stimulated human umbilical vein endothelial cells, while nicotine had no effect. Interestingly nicotine and acetylcholine lead to different gene expression (nicotine up-regulates epidermal growth factor and down-regulates matrix metalloproteinase-8, while Ach/pyridostigmine up-regulates thioredoxin interacting protein and down-regulates insulin like growth factor 1). Furthermore RNA levels and gene activation were similar after nicotine administration, while changes in RNA levels after Ach/pyridostigmine differed significantly. Conclusions: Our results suggest that the effects of Ach/pyridostigmine and nicotine are modulated by different underlying pathways, despite their common activation of nicotinergic receptors.
Aims: Gene variants the calcium channels have been associated with Brugada syndrome (BrS). The investigation of the human cellular phenotype and the use of drugs for BrS is still lacking. Methods and results: This study recruited cells from a BrS patient carrying a missense variant (c.425C>T/p.S142F) in CACNB2 with uncertain significance as well as from three healthy persons. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from skin biopsies of healthy persons and the BrS patient (BrS-hiPSC-CMs) as well as CRISPR/Cas9 corrected cells (isogenic control, site-variant corrected) were used. HiPSC-CMs from the BrS patient showed a significantly reduced L-type calcium channel current (ICa-L). The inactivation curve was shifted to a more positive potential and the recovery from inactivation was accelerated. The protein expression of CACNB2 from the BrS-patient was significantly decreased. Moreover, the correction of the CACNB2 site-variant rescued the changes. In addition, the peak sodium current was significantly reduced as compared with the controls consistent with the reduction of the amplitude and upstroke velocity of action potentials in BrS-hiPSC-CMs. Arrhythmia events were more frequently detected in BrS-hiPSC-CMs. In cells without arrhythmic events, carbachol induced the occurrence of arrhythmias with a higher chance in BrS-hiPSC-CMs than in healthy cells. Whereas ajmaline (sodium channel blocker) did not increase arrhythmic events, bisoprolol (beta-blocker) at low concentration and quinidine decreased arrhythmic events. Conclusions: The CACNB2 variant (c.425C>T/p.S142F) causes a loss-of-function of L-type calcium channels and is pathogenic for this type of BrS. Bisoprolol and quinidine may be effective for treating BrS with this variant.
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.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.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).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,.
PURPOSE: Gremlin-1 is an inhibitor of bone morphogenetic proteins regulating cardiomyocyte formation. Gremlin-1 is involved in fibrotic and inflammatory processes and correlates with the degree of cardiac fibrosis. Congestive heart failure is characterized by an adverse structural remodelling of the myocardium. This study evaluates serum levels of Gremlin-1 in patients being suspected of acute congestive heart failure (aCHF) in the emergency department. PATIENTS AND METHODS: 401 patients presenting with symptoms of acute dyspnea and/or peripheral edema in the emergency department were evaluated. Patients were followed up to five years after presentation in the emergency department. Blood samples for measurement of Gremlin-1 (Human Grem1 ELISA®, USCN Life Science Inc.), Osteopontin (OPN) (R&D Systems, Inc.) and NT-proBNP (Dimension System, Siemens AG) were collected at the initial clinical presentation. RESULTS: Median Gremlin-1 levels were significantly higher in patients with aCHF (291 ng/ml, n=122) as compared to patients without aCHF (205 ng/ml, n=279) (p=0.0001). Median Gremlin-1 correlated significantly with OPN (r=0.16, p=0.002) and NT-proBNP (r=0.24, p=0.001). Median Gremlin-1 levels were higher in patients with a left ventricular (LV) dysfunction (258 ng/ml, n=91) compared to patients with a normal LV function (221 ng/ml, n=135) (p=0.05). Median Gremlin-1 levels were higher in ACC/AHA class C/D patients (246 ng/ml, n=215) compared to class A/B patients (208 ng/ml, n=133) (p=0.02). Median Gremlin-1 levels were significantly higher in patients being rehospitalized because of aCHF (1 year: 477 ng/ml (n=34) vs. 215 ng/ml (n=367), p=0.0001; 5 years: 301 ng/ml (n=73) vs. 212 ng/ml (n=328); p=0.001) and in patients who died during follow-up (1 year: 255 ng/ml (n=57) vs. 218 ng/ml (n=344), p=0.04; 5 years: 229 ng/ml (n=129) vs. 210 ng/ml (n=272); p=0.08). CONCLUSIONS: Gremlin-1 serum levels were increased in patients suffering from aCHF. Gremlin-1 correlated with OPN, NT-proBNP, functional NYHA and structural AHA/ACC classification. Increased Gremlin-1 levels were associated with long-term aCHF related rehospitalization and all-cause mortality after 5 years.
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