Jens J. Kaden

Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis

Background—Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. Methods and Results—Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (P<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (r=0.68, P<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (P<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). Conclusions—NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis

Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1 beta on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1 beta and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1 beta and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1 beta were present. Double-label immunostaining localized IL-1 beta expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1 beta lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1 beta as determined by bromodesoxyuridine incorporation. Thus, IL-1 beta may regulate remodeling of the extracellular matrix in calcific AS.

ESC Working Group on Valvular Heart Disease Position Paper: assessing the risk of interventions in patients with valvular heart disease

AIMS Risk scores provide an important contribution to clinical decision-making, but their validity has been questioned in patients with valvular heart disease (VHD), since current scores have been mainly derived and validated in adults undergoing coronary bypass surgery. The Working Group on Valvular Heart Disease of the European Society of Cardiology reviewed the performance of currently available scores when applied to VHD, in order to guide clinical practice and future development of new scores. METHODS AND RESULTS The most widely used risk scores (EuroSCORE, STS, and Ambler score) were reviewed, analysing variables included and their predictive ability when applied to patients with VHD. These scores provide relatively good discrimination, i.e. a gross estimation of risk category, but cannot be used to estimate the exact operative mortality in an individual patient because of unsatisfactory calibration. CONCLUSION Current risk scores do not provide a reliable estimate of exact operative mortality in an individual patient with VHD. They should therefore be interpreted with caution and only used as part of an integrated approach, which incorporates other patient characteristics, the clinical context, and local outcome data. Future risk scores should include additional variables, such as cognitive and functional capacity and be prospectively validated in high-risk patients. Specific risk models should also be developed for newer interventions, such as transcatheter aortic valve implantation.

Variant form of the acute apical ballooning syndrome (takotsubo cardiomyopathy): observations on a novel entity

Takotsubo cardiomyopathy (TTC) consists of an acute onset of transient akinesia of the apical and mid portions of the left ventricle, without significant coronary artery stenosis. TTC is often accompanied by chest pain, dynamic reversible ST-T segment abnormalities, and increased cardiac enzymes disproportionate to the extent of akinesia.1 Until now, it was believed that wall motion abnormalities (WMA) in this syndrome invariably affect the left ventricular (LV) apex. However, we present a syndrome mimicking classic TTC without involvement of the LV apex. We retrospectively evaluated consecutive patients admitted with an acute coronary syndrome between January 2004 and December 2004. Patients who met the following criteria were selected: firstly, reversible akinesia/dyskinesia beyond a single major coronary artery vascular distribution on left ventriculography sparing the LV apex; secondly, no coronary artery diameter stenosis > 50% on angiography; thirdly, increased cardiac enzymes; and lastly, available results of a gadolinium enhanced cardiovascular magnetic resonance (CMR) scan. Laboratory tests, serial ECGs, and echocardiography were performed according to standard protocol for management of acute coronary syndromes at our …

Aortic valve calcification: basic science to clinical practice

Calcific aortic valve stenosis is the result of regulated cell processes. The histological hallmarks are inflammation and a remodelling of the extracellular matrix leading to bone formation. In the last 15 years the view has changed from it being an unmodifiable degenerative disease to an active biological process regulated by highly conserved ubiquitous cellular pathways. Many mechanisms and risk factors are the same as in atherosclerosis. Thus, statins and angiotensin II antagonists seemed promising treatment options. However, clinical trials failed to support this. This review describes the current understanding of major molecular mechanisms and discusses their role in clinical practice and possible therapy.

Comparison of Impedance Cardiography and Thermodilution-Derived Measurements of Stroke Volume and Cardiac Output at Rest and During Exercise Testing

Background: Non-invasive evaluation of haemodynamic variables remains a preferable and attractive option in both pharmacologic research and clinical cardiology.Objectives: The objective of this study was to evaluate the correlation, feasibility and diagnostic value of haemodynamic measurements by ICG with the thermodilution (TD) method at rest and during exercise testing.Methods: We measured stroke volume (SV) and cardiac output (CO) with both methods in 20 patients with suspected coronary artery disease (CAD). All measurements were performed simultaneously at rest and during bicycle exercise.Results: There was a highly significant correlation (p < 0.001) for measurements of SV between both methods at rest (r = 0.83) and during exercise (r = 0.85–0.87) with 50–100 watts. For measurements of CO, the respective correlations were r = 0.85 at rest and r = 0.92–0.94 during exercise. The mean difference for measurements of SV were 3.8 ± 12.6 ml at rest and 6.5± 11.4 ml during exercise. For measurements of CO, the mean difference between both methods was 0.9 ± 1.0 l/min at rest and 1.0± 0.8 l/min during exercise. Compared to TD measurements, ICG had a bias to overestimate SV and CO of approximately by 5–10%. One patient had to be excluded because of inappropriate quality of the ICG signals during exercise.Conclusions: ICG is a feasible and accurate method for non-invasive measurements of SV and CO. Haemodynamic measurements by ICG were correlated highly significant to simultaneous measurements by the TD method.

Time-dependent changes in the plasma concentration of matrix metalloproteinase 9 after acute myocardial infarction

Matrix metalloproteinase (MMP)-2 and MMP-9 are believed to play a pathophysiologic role in acute myocardial infarction (MI). The time course of their plasma concentrations in correlation with the extent of myocardial damage is unclear. In a prospective study, 20 patients with proven acute MI underwent successful reperfusion within 6 h after the onset of symptoms. The patients were divided into two groups according to the size of their MI, i.e. large or moderate MI. Plasma concentrations of MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 were determined on admission, and after 24 h, 48 h, 1 week, 4 weeks, 3 months and 6 months. MMP-2 levels remained unchanged over time in both groups. The plasma concentration of MMP-9 was elevated on admission in patients with large MI versus moderate MI (195 ± 190 versus 78 ± 63 ng/ml, p < 0.01) as determined by left ventriculography, and returned to baseline (18 ± 16 ng/ml) by 1 week after MI. TIMP-1 levels rose slowly in patients with large MI and returned to baseline at 6 months. The ratio of MMP-9 to TIMP-1 was significantly increased on admission in both groups and returned to baseline at 48 h. These data suggest that MMP-9 might play a pathophysiologic role during the early phase of acute MI.

Expression and activity of matrix metalloproteinase-2 in calcific aortic stenosis.

Die degenerativ- kalzifizierende Aortenstenose ist die häufigste Herzklappenerkrankung und Hauptursache eines Herzklappenersatzes im fortgeschrittenen Alter. Sie führt zu massiver Verkalkung sowie zu einem extensivem Umbau der extrazellulären Matrix; es wird vermutet, dass Matrix-Metalloproteinasen (MMPs) hierbei eine pathogenetische Rolle spielen. Wir untersuchten daher die Expression der Gelatinase MMP-2 und MMP-9 sowie ihres endogenen Inhibitors „Tissue Inhibitor of Metalloproteinase-2“ (TIMP-2) sowie die gelatinolytische Aktivität in 24 stenotischen und 8 normalen Aortenklappen. In der immunhistochemischen Färbung zeigten die stenotischen Klappen eine signifikant höhere Färbeintensität für MMP-2 und TIMP-2 im Vergleich zu den Kontrollklappen. Eine geringe Färbung von MMP-9 war ausschließlich bei stenotischen Klappen nachweisbar. In der in situ Zymographie wiesen normale Klappen eine minimale basale gelatinolytische Aktivität auf, die durch Zugabe des MMP-Aktivators p-Aminophenymercuroazetat (APMA) signifikant gesteigert werden konnte. In stenotischen Klappen war hingegen eine deutlich vermehrte Enzymaktivität nachweisbar, die durch Zugabe von APMA nicht mehr signifikant gesteigert werden konnte. MMP-2 und TIMP-2 zeigen somit eine differentielle Expression bei kalzifizierender Aortenstenose. MMP-2 liegt in normalen Klappen vorwiegend als inaktives Proenzym vor, in stenotischen Klappen hingegen in der aktivierten Form. Diese Ergebnisse sprechen für einen durch MMP-2 vermittelten Umbau der extrazellulären Matrix bei kalzifizierender Aortenstenose. Calcific aortic stenosis is the main heart valve disease in the elderly, leading to massive focal calcification and thickening of the valve cusps. Matrix metalloproteinases (MMPs) are thought to contribute to this process. Therefore, the study assessed the expression of the gelatinases MMP-2 and MMP-9 and the endogenous tissue inhibitor of metalloproteinase (TIMP)-2 as well as the gelatinolytic activity in normal and stenotic valves. Human tricuspid aortic valves with and without calcific aortic stenosis were studied by immunohistochemistry for MMP-2, MMP-9 and TIMP-2. The gelatinolytic activity in native valve sections was assessed by gelatin in situ zymography with or without addition of the MMP activator p-aminophenymercuric acetate (APMA). Staining intensities for MMP-2 and TIMP-2 were elevated in stenotic valves as compared to controls. Minor staining of MMP-9 was present exclusively in stenotic valves. The morphologic distribution of gelatinolytic activity was comparable to the staining pattern of MMP-2, and since MMP-9 immunostaining demonstrated only a low number of positive cells, the observed gelatinolytic activity is likely due to MMP-2. Gelatinolytic activity was low in normal valves but significantly increased by the MMP activator APMA. In contrast, stenotic valves showed a strong basal gelatinolytic activity that could not be significantly enhanced by APMA suggesting that MMP-2 is present as a latent pro-enzyme in normal valves and activated in stenotic valves. Thus, MMP-2 might be involved in the matrix remodeling during calcific aortic stenosis.

Recombinant human activated protein C upregulates cyclooxygenase- 2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1

Prostacyclin (PGI(2)) has beneficial cytoprotective properties, is a potent inhibitor of platelet aggregation and has been reported to improve microcirculatory blood flow during sepsis. The formation of PGI(2) in response to proinflammatory cytokines is catalysed by the inducible cyclooxygenase (COX) isoform COX-2. Recombinant human activated protein C (rhAPC, drotrecogin alfa (activated)) was shown to have multiple biological activities in vitro and to promote resolution of organ dysfunction in septic patients. Whether rhAPC exerts its beneficial effects by modulating prostanoid generation is unknown up to now. It was therefore the aim of the study to examine the in vitro effect of rhAPC on COX-2-mRNA-expression and PGI(2) release from human umbilical vein endothelial cells (HUVEC). We found that rhAPC, at supra-therapeutical concentrations (500 ng/ml-20 microg/ml), upregulated the amount of COX-2-mRNA in HUVEC at t=3-9 h and caused a time- and dose-dependent release of 6-keto PGF(1 alpha), the stable hydrolysis product of prostacyclin. RhAPC further increased the stimulating effect of tumor necrosis factor-alpha (TNF-alpha) and thrombin on COX-2-mRNA-levels. Transcript levels of cyclooxygenase-1 (COX-1) and prostaglandin 12 synthase, however, were unaffected by the stimulation with rhAPC or thrombin. The upregulatory effect on COX2-mRNA levels was specific for rhAPC since the zymogen protein C in equimolar concentrations had no effect on COX-2-mRNA-levels or 6-keto PGF(1 alpha)-release. Western Blot analysis revealed an increase of COX-2-protein content in HUVEC after treatment with rhAPC. As shown by experiments using monoclonal antibodies against the thrombin receptor PAR-1 (mAb=ATAP2) and against the endothelial protein C receptor (EPCR; mAb=RCR-252), the effect of rhAPC on COX-2-mRNA upregulation was mediated by binding to the EPCR-receptor and signaling via PAR-1. These results demonstrate that induction of COX-2-expression is an important response of HUVEC to stimulation with rhAPC and may represent a new molecular mechanism, by which rhAPC promotes upregulation of prostanoid production in human endothelium.

Global and regional myocardial function quantification by two-dimensional strain in Takotsubo cardiomyopathy

AIMS This study sought to characterize global and regional systolic function in Takotsubo cardiomyopathy (TC) using two-dimensional (2D) strain imaging. METHODS AND RESULTS Twelve consecutive patients (11 women, 1 man) underwent 2D echocardiography on admission and on early follow-up (34 +/- 16 days). Two-dimensional images were analysed to measure longitudinal and radial strain and to calculate post-systolic shortening (PSS) and the post-systolic index (PSI). Mean age was 64 +/- 14 years. Upon presentation ejection fraction, average longitudinal and radial strains were 42 +/- 9%, -10.6 +/- 5.5%, and 20.1 +/- 17.3%, respectively. Values improved to 59 +/- 8%, -17.6 +/- 3.0%, and 50.2 +/- 17.0%, respectively (all P < 0.001). PSS was present in 69% of segments upon presentation and in 53% of segments upon follow-up. PSI was -0.16 at baseline and improved to -0.06 upon follow-up (P < 0.001). CONCLUSION Patients with TC show abnormal global and regional strain patterns during the acute phase of the disease which improve over time. However, subtle abnormalities of regional LV function seem to persist into the early follow-up period as suggested by the presence of PSS in more than half of LV segments. Long-term follow-up studies are needed to clarify whether these subtle abnormalities will further improve.