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Aims Levosimendan is an inodilator for the treatment of acute decompensated heart failure (HF). Data from clinical studies suggest that levosimendan is particularly effective in HF due to myocardial infarction. After acute revascularization, no reflow-phenomenon is a common complication that may lead to pump failure and cardiogenic shock. Our aim was to examine whether levosimendan interferes with the pro-thrombotic phenotype of activated endothelial cells in vitro. Methods Human heart microvascular endothelial cells (HHMEC) and human umbilical vein endothelial cells (HUVEC) were treated with interleukin-1β (IL-1β) (200 U/mL) or thrombin (5 U/mL) and co-treated with or without levosimendan (0.1–10 μM) for 2–24 h. In addition, flow experiments were performed. Effects on plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) expression and activity were measured by rt-PCR, specific ELISA and flow cytometry. Results Treatment with IL-1β or thrombin significantly increased the expression of PAI-1 and TF in endothelial cells. Co-treatment with levosimendan strongly attenuated the effects of IL-1β and thrombin on PAI-1 and TF mRNA by up to 50% and 45%, in a dose- and time-dependent manner. Similar results were obtained under flow conditions. Furthermore, co-treatment with levosimendan dampened the antigen production of PAI-1 and the surface expression of TF by 35% and 45%, respectively. Additionally, levosimendan diminished both TF and PAI-1 activity. Conclusion Levosimendan down-regulates the expression of the pro-thrombotic and anti-fibrinolytic biomolecules TF and PAI-1 in activated human endothelial cells. Our findings may, at least in part, explain some of the beneficial effects of levosimendan after myocardial reperfusion.

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.

Aging endothelial cells are characterized by increased cell size, reduced telomere length and increased expression of proinflammatory cytokines. In addition, we describe here that aging reduces the migratory distance of endothelial cells. Furthermore, we observe an increase of the quiescence protein Ang1 and a decrease of the endothelial activation protein Ang2 upon aging. Supplementing Ang2 to aged endothelial cells restored their migratory capacity. We conclude that aging shifts the balance of the Ang1/Ang2 network favouring a quiescent state. Activation of endothelial cells in aging might be necessary to enhance wound healing capacities.

The aim of this study was to investigate the distribution of clinical events across the platelet aggregation values in patients treated with prasugrel and ticagrelor. This prospective observational study enrolled 226 patients treated with prasugrel (n=121) or ticagrelor (n=105). Adenosine diphosphate (ADP)-induced platelet aggregation was determined by Multiplate Analyzer in the maintenance phase of treatment with prasugrel or ticagrelor. Clinical outcome was evaluated over 12 months. Platelet aggregation values were divided into quartiles. The first quartile comprised values8 U, the second quartile values between 8 U and15 U, the third one values between 15 U and 23 U, and the forth one values23 U. Myocardial infarction events were observed in patients within the third quartile of aggregation values (15-23 U), and were not associated with high on-treatment platelet reactivity (HTPR46 U). All bleeding events occurred in patients with aggregation values ≤ 23 U, which corresponded to the 75 percentile (p=0.031). There was no difference in the distribution of bleeding events between the 1st-3rd quartiles (p=0.873). In conclusion, patients with ADP-induced aggregation values over 23 U (fourth quartile) were at the lowest risk to develop bleeding during the follow-up.

Mitral regurgitation (MR) is common in ischemic heart disease and contributes to symptoms and mortality. This report compares the results of baseline transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE) imaging of the mechanism and severity of functional MR in patients with ischemic cardiomyopathy in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Independent core laboratories measured both TTE and TEE images on 196 STICH participants. Common measurements to both models included MR grade, mitral valve tenting height and tenting area, and mitral annular diameter. For each parameter, correlations were assessed using Spearman rank correlation coefficients. A modest correlation was present between TEE and TTE for overall MR grade (n = 176, r = 0.52). For mechanism of MR, modest correlations were present for long-axis tenting height (n = 152, r = 0.35), tenting area (n = 128, r = 0.27), and long-axis mitral annulus diameter (n = 123, r = 0.41). For each measurement, there was significant scatter. Potential explanations for the scatter include different orientation of the imaging planes between TEE and TTE, a mean temporal delay of 6 days between TEE and TTE, and statistically significant differences in heart rate and blood pressure and weight between studies. In conclusion, TEE and TTE measurements of MR mechanism and severity correlate only modestly with enough scatter in the data that they are not interchangeable.

The optimal timing of valve surgery remains controversial. Biomarkers can be serially monitored and are objective laboratory measurements. Plasma B-type natriuretic peptide (BNP) and its N-terminal pro-form are well known predictors in heart failure. Diastolic stretch induces cardiomyocyte BNP expression in volume-loaded conditions like aortic or mitral regurgitation (MR) or pressure-loaded conditions like aortic stenosis (AS). Here, we review the value of natriuretic peptide measurements in valve disease. Cardiac decompensation is reflected by increased BNP in AS and in MR. Repeated marked increases in natriuretic peptides are a potential indication for valve replacement in severe asymptomatic AS with normal ejection fraction and exercise test results. High BNP level also predicts postoperative outcome. Increased BNP level is associated with low-flow AS, impaired left ventricular longitudinal strain, and myocardial fibrosis. The BNP ratio to the reference value for age and sex incrementally predicts mortality in AS. Increased BNP reflects the hemodynamic consequences of MR and is associated with exercise-induced pulmonary-arterial hypertension and reduced contractile reserve. In severe primary MR, increased and serially increasing BNP or N-terminal pro-form BNP might be helpful in guiding early mitral replacement. In conclusion, baseline (N-terminal pro-form) BNP should be obtained in all severe valve disease patients and interpreted together with clinical and echocardiography findings. Very high BNP values are associated with increased mortality and should lead to close monitoring peri- and postoperatively. Progressively increasing BNP in asymptomatic patients points to advancing valve disease. BNP adds important incremental prognostic information that is useful for valve patient management and for optimal timing of surgery in particular.

The mechanisms underlying functional mitral regurgitation (MR) and the relation between mechanism and severity of MR have not been evaluated in a large, multicenter, randomized controlled trial. Transesophageal echocardiography (TEE) was performed in 215 patients at 17 centers in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Both 2-dimensional (n = 215) and 3-dimensional (n = 81) TEEs were used to assess multiple quantitative measurements of the mechanism and severity of MR. By 2-dimensional TEE, leaflet tenting area, anterior and posterior leaflet angles, mitral annulus diameter, left ventricular (LV) end-systolic volume index, LV ejection fraction (LVEF), and sphericity index (p0.05 for all) were significantly different across MR grades. By 3-dimensional TEE, mitral annulus area, leaflet tenting area, LV end-systolic volume index, LVEF, and sphericity index (p0.05 for all) were significantly different across MR grades. A multivariate analysis showed a trend for annulus area (p = 0.069) and LV end-systolic volume index (p = 0.071) to predict effective regurgitant orifice area and for annulus area (p = 0.018) and LV end-systolic volume index (p = 0.073) to predict vena contracta area. In the STICH trial, multiple quantitative parameters of the mechanism of functional MR are related to MR severity. The mechanism of functional MR in ischemic cardiomyopathy is heterogeneous, but no single variable stands out as a strong predictor of quantitative severity of MR.

Background Accurate risk prediction is important for an adequate management of heart failure (HF) patients. We assessed the incremental prognostic ability of a multi-biomarker approach in advanced HF. Methods In 349 patients with advanced HF (median 75years, 66% male) we investigated the incremental prognostic value of 12 novel biomarkers involved in different pathophysiological pathways including inflammation, immunological activation, oxidative stress, cell growth, remodeling, angiogenesis and apoptosis. Results During a median follow-up of 4.9years 55.9% of patients died. Using multivariable Cox regression and bootstrap variable-selection age, chronic obstructive pulmonary disease, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the following 5 novel biomarkers were retained in the best mortality prediction model: the chemokine fractalkine, the angiogenic and mitogenic hepatocyte growth factor (HGF), the growth differentiation factor 15 (GDF-15) influencing cardiac remodeling and apoptosis, and the 2 pro-apoptotic molecules soluble apoptosis-stimulating fragment (sFAS) and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). This multi-biomarker score had strong discriminatory power for 5-year mortality (area under the Receiver Operating Characteristic curve [AUC]=0.81) and improved risk prediction beyond the prognostic power of a comprehensive conventional risk score including known clinical predictors and NT-proBNP (AUC=0.77). Net reclassification confirmed a significant improvement of individual risk prediction ( p =0.003). Conclusions Risk prediction by a multi-biomarker score is superior to a conventional risk score including clinical parameters and NT-proBNP. Additional predictive information from different biological pathways reflects the multisystemic character of HF.

Background High platelet reactivity (HPR) under treatment with clopidogrel or aspirin is associated with adverse outcome. We aimed to investigate whether high platelet reactivity (HPR) to both aspirin and clopidogrel is a stronger predictor of adverse events compared to isolated HPR to clopidogrel or aspirin. Methods In this prospective cohort study platelet reactivity to adenosine diphosphate (ADP) and arachidonic acid (AA) was assessed by Multiple Electrode Aggregometry (MEA) in 403 patients undergoing percutaneous coronary intervention. The rates of the composite of cardiac adverse events (acute coronary syndrome, stent thrombosis, stroke, death and revascularization) were recorded during 12-month follow-up. Results The composite endpoint of cardiovascular adverse events occurred more often in patients with high platelet reactivity (HPR) to both agonists ADP and AA (37.5%) than in those with isolated HPR to ADP (33.3%), AA (25.6%) or without any HPR (18.6%; p=0.003). Classification tree analysis indicated that any HPR emerged as an independent predictor influencing outcome, which was associated with a 1.75 higher risk of cardiac adverse events (OR=1.75: 95%CI=1.1–2.9). Interestingly, the predictive value of HPR tended to be greater among patients with diabetes mellitus (OR=2.18; 95%CI=1.20–3.95). C-reactive protein and diabetes mellitus were independent predictors of high platelet reactivity to both agonists. Conclusions Dual low responsiveness to clopidogrel and aspirin is a strong predictor of cardiac adverse events, especially in patients with diabetes mellitus, which underlines the need for personalized antiplatelet treatment.

Objectives This study sought to describe the natural history of combined stenotic and regurgitant aortic valve disease. Background Data on outcome and prognostic factors in combined aortic valve disease are scarce. Methods This study prospectively followed 71 consecutive asymptomatic patients (21 women, age 52 ± 17 years) with at least moderate aortic stenosis in combination with at least moderate aortic regurgitation and preserved left ventricular function (ejection fraction ≥55%). Results During a median potential follow-up of 8.9 years, 50 patients developed an indication for aortic valve replacement and no cardiac deaths were observed. Overall event rates were high with an event-free survival for the entire patient population of 82 ± 5%, 62 ± 6%, 49 ± 6%, 33 ± 6%, and 19 ± 5% at 1, 2, 3, 4, and 6 years, respectively. There was 1 operative and no post-operative deaths. Peak aortic jet velocity (AV-Vel) independently predicted event-free survival. Patients with an AV-Vel between 3 and 3.9 m/s had an event-free survival of 94 ± 4%, 88 ± 6%, 65 ± 9%, and 51 ± 9% after 1, 2, 4, and 6 years, respectively, compared with 92 ± 4%, 67 ± 7%, 38 ± 8%, and 12 ± 6% for patients with an AV-Vel between 4 and 4.9 m/s and 67 ± 8%, 39 ± 10%, 17 ± 9%, and 0% for patients with an AV-Vel ≥5 m/s (p Conclusions Asymptomatic patients with combined aortic valve disease can be safely followed until surgical criteria defined for aortic stenosis, aortic regurgitation, or the aorta are reached. However, high event rates can be expected even in younger patients and those with only moderate disease. AV-Vel, which reflects both stenosis and regurgitant severity, provides an objective and easily assessable predictive parameter.

Background Left-sided heart disease (LHD) is the most common cause of pulmonary hypertension (PH). In patients with LHD, elevated left atrial pressure causes a passive increase in pulmonary vascular pressure by hydrostatic transmission. In some patients, an active component caused by pulmonary arterial vasoconstriction and/or vascular remodeling superimposed on left-sided pressure elevation is observed. This “reactive” or “out-of-proportion” PH, defined as PH due to LHD with a transpulmonary gradient (TPG) > 12 mm Hg, confers a worse prognosis. However, TPG is sensitive to changes in cardiac output and left atrial pressure. Therefore, we tested the prognostic value of diastolic pulmonary vascular pressure gradient (DPG) (ie, the difference between invasive diastolic pulmonary artery pressure and mean pulmonary capillary wedge pressure) to better prognosticate death in “out-of-proportion” PH. Methods A large database of consecutive cases was analyzed. One thousand ninety-four of 2,351 complete data sets were from patients with PH due to LHD. For proof of concept, available lung histologies were reviewed. Results In patients with postcapillary PH and a TPG > 12 mm Hg, a worse median survival (78 months) was associated with a DPG ≥ 7 mm Hg compared with a DPG P = .010). Elevated DPG was associated with more advanced pulmonary vascular remodeling. Conclusions DPG identifies patients with “out-of-proportion” PH who have significant pulmonary vascular disease and increased mortality. We propose a diagnostic algorithm, using pulmonary capillary wedge pressure, TPG, and DPG in sequence to diagnose pulmonary vascular disease superimposed on left-sided pressure elevation.

Anemia is associated with the cardiovascular outcome in healthy subjects but its impact on outcome in patients with cardiovascular disease has not yet been fully understood. Therefore, we assessed the long-term influence of hemoglobin on all-cause and cardiovascular mortality in patients with atherosclerotic disease. We prospectively studied 1,065 of 1,286 consecutive patients with asymptomatic carotid narrowing. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Continuous measures of hemoglobin displayed a significant inverse effect on all-cause mortality and cardiovascular mortality (adjusted hazard ratio [HR] for increase of 1 SD of hemoglobin 0.73, 95% confidence interval [CI] 0.64 to 0.83; p0.001) and adjusted HR 0.76, 95% CI 0.64 to 0.89; p = 0.001, respectively). The cumulative 6-year survival rate was 61%, 79%, 80%, and 81% in the first, second, third, and fourth quartile of hemoglobin (log-rank p0.001). Patients within the first quartile (12.9 g/dl) had a significantly increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.46 to 2.54, p0.001) and cardiovascular mortality (adjusted HR 1.68, 95% CI 1.19 to 2.36, p = 0.003) compared to patients with greater levels. In conclusion, our study has demonstrated a significant association with hemoglobin levels and all-cause and cardiovascular mortality in patients with carotid narrowing. Nevertheless, additional research, in terms of randomized controlled trials, is needed to warrant these findings and to evaluate potential therapeutic interventions.

Objectives This study sought to determine the time dependency of the endothelium-dependent and -independent vascular responses after percutaneous coronary intervention (PCI) with drug-eluting (DEB) or plain balloons, bare-metal (BMS), and drug-eluting (DES) stents, or controls. Background Long-term endothelial dysfunction after DES implantation is associated with delayed healing and late thrombosis. Methods Domestic pigs underwent PCI using DEB or plain balloon, BMS, or DES. The dilated and stented segments, and the proximal reference segments of stents and control arteries were explanted at 5-h, 24-h, 1-week, and 1-month follow-up (FUP). Endothelin-induced vasoconstriction and endothelium-dependent and -independent vasodilation of the arterial segments were determined in vitro and were related to histological results. Results DES- and BMS-treated arteries showed proneness to vasoconstriction 5 h post-PCI. The endothelium-dependent vasodilation was profoundly (p Conclusions Coronary arteries treated with plain balloon, DEB, BMS, and DES showed time-dependent loss of endothelial-dependent and -independent vasomotor function, with imbalanced contraction/dilation capacity.

Besides its effects on glucose and lipid metabolism, the Wnt pathway has been increasingly implicated in the regulation of proliferation, migration and survival of vascular cells. In addition, defective Wnt signaling has been identified in a family with autosomal dominant early coronary artery disease. The aim of this study was to investigate whether premature coronary artery disease is associated with features of decreased Wnt signaling.We prospectively enrolled 100 consecutive young survivors of myocardial infarction (MI≤40 years of age) from two high-volume cardiac catheterization centers and 100 sex and age matched hospital controls. We determined serum levels of Wnt-1 and its antagonist Dkk-1 by ELISA. MI patients showed significantly lower Wnt-1 levels as compared to controls (151 ng/mL, IQR 38-473 ng/mL vs. 233 ng/mL, IQR 62-1756; p0.005) whereas Dkk-1 was not different at baseline. Wnt-1 levels remained stable over time, whereas Dkk-1 significantly increased at one-year follow-up from 3557, IQR 2306-5810 pg/mL to 4973, IQR 3293-7093 pg/mL (p0.001). In the stable phase of the disease, Wnt-1 levels were lower (p0.005) and Dkk-1 levels were significantly higher (p0.001) as compared to controls. Wnt-1 at follow-up was associated with glucose, HbA1c, non-HDL-, HDL-cholesterol and triglyceride levels but no other features of the metabolic syndrome.This study establishes an association between low Wnt-1 and high Dkk-1 serum levels and premature myocardial infarction. Wnt-1 is associated with markers of glucose and lipid metabolism. Further research elucidating the role of Wnt pathways in premature coronary artery disease and metabolic syndrome is warranted.

Objectives This study evaluated the protective effect of nitric oxide–coating of introducer sheath on the local complications in juvenile porcine femoral arteries with similar size to human radial arteries. Background Insertion of an introducer sheath induces vasospasm and transient or permanent vessel occlusion of radial arteries. Methods Nitric oxide–coated or control introducer sheaths with or without spasmolytic cocktail (control + C-sheath) were inserted into porcine femoral arteries, followed by percutaneous coronary intervention (PCI). The diameter of the femoral artery at the puncture site, distally and proximally, was measured by quantitative angiography. Histopathological and histomorphometric parameters of the femoral arteries were analyzed 1 h or 1 week after PCI. Results Insertion of femoral sheath led to mild or severe spasms, with significantly higher vessel diameter at the access site (2.69 ± 0.81 mm vs. 1.77 ± 0.77 mm and 1.85 ± 0.66 mm, p Conclusions Nitric oxide coating on the introducer sheath prevents local complications during PCI and results in less vascular thrombosis and inflammation at the access site, contributing to patency of the access vessel with similar size to the radial artery.

Ischemia/reperfusion (I/R) injury-induced alterations in sarcolemmal and sarcoplasmic reticular ion transport result in typical changes in the electrical activity of myocardial cells that manifest in surface and intracardiac electrocardiograms. Myocardial ischemia results in a progressive loss of the amplitude of the monophasic action potential, as evidenced by decreased endocardial unipolar voltage. To carry out in vivo on-line visualization, quantification, and explorative analysis of I/R injury and ischemic conditioning of the heart (1), we measured endomyocardial unipolar voltage with an endocardial mapping catheter (NOGA STAR Johnson & Johnson, New Brunswick, New Jersey) (2) during 3 cycles of 10 min coronary occlusion/reperfusion in a closed chest I/R model in swine. Our goal was to simulate the ischemic burden of the human myocardium during repetitive episodes of angina pectoris. Here we display on-line regional unipolar voltage maps of the ischemia-affected myocardium (area mapping) and demonstrate immediate changes in unipolar voltage values taken from a single endocardial location within the ischemic area (single location mapping) during I/R. Domestic pigs (n = 5) underwent baseline electroanatomical mapping (Online Video 1) and cardiac catheterization (Figures 1A and 1B) followed by 3 cycles of 10-min I/R via percutaneous intracoronary balloon inflation/deflation of the mid left anterior descending coronary artery (Figure 1C). All animal investigations conformed to the “Position of the American Heart Association on Research Animal Use,” adopted by the American Heart Association on November 11, 1984. After baseline mapping of the left ventricle, ischemic burden was displayed by moving the NOGA STAR catheter within the ischemia-affected mid-distal anteroseptal area between the 5th and 10th min of the ischemia or reperfusion (Figure 1C). The voltage values of the ischemic area immediately decreased during repetitive occlusion without normalizing during reperfusion; the ischemic burden persisted after the final reperfusion (Figure 1D), at 12 h (Figure 1E), and at 24 h (Figure 1F), despite the restoration of normal coronary blood flow. Figure 1 Real-Time in Vivo Visualization of Ischemic Burden During Myocardial I/R and at 12-h and 24-h Follow-Up We recorded the unipolar voltage of a single stable distal anterior left ventricular location within the ischemic area during the I/R cycles without changing the location of the NOGA STAR catheter tip (n = 7), and compared these data to measurements from sham-procedure animals (n = 3) (Figure 2A). Surface and intracardiac electrocardiograms were continuously monitored (Figure 2B and Online Video 2). Due to the developing hypokinesia within the ischemic area, the amplitude of the endocardial catheter movement decreased, and the direction changed (Online Video 2). The unipolar voltage values of the stable myocardial location decreased rapidly during the first occlusion, while the second and third occlusions led to a less rapid decline in unipolar voltage (Figure 2C). By contrast, repetitive ischemia resulted in lower minimum unipolar voltage signals after the third ischemic attack. Interestingly, during permanent occlusion of the artery, unipolar voltage values increased slowly after approximately 5 min of ischemia. Figure 2 Intracardiac Unipolar Voltage of a Single Stable Mapping Location During Repetitive I/R In addition to providing basic scientific information on electrical signals of myocardium during ischemia and reperfusion, this method offers in vivo on-line visualization and immediate assessment of the extent of ischemic injury, as well as the efficacy of protective approaches against it, including pharmacological or ischemic conditioning, therapeutic hypothermia, and cardioplegia. Furthermore, this method allows for investigation of electrophysiologic state of the myocardium during pathological conditions affecting the heart (e.g., sepsis) in an animal model ready for clinical translation.

Objective To assess the prognostic value of the pro-apoptotic, but also cell growth-inducing molecule soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in heart failure (HF). Methods We assayed sTWEAK levels in 351 patients with advanced HF (non-ischemic: 130, ischemic: 221). During a median follow-up of 4.9 years, 195 patients (56%) died. Results sTWEAK concentrations were associated with extended survival in patients with non-ischemic (P = 0.022), but not with ischemic HF (P = 0.82). The inverse association in non-ischemic HF remained significant in a multivariable Cox regression model (P = 0.025) with a hazard ratio of 0.40 (95% confidence interval: 0.21–0.77) comparing the third to the first tertile (P = 0.007). Conclusion Low sTWEAK levels independently predict mortality in advanced non-ischemic HF. sTWEAK-induced proliferation of cardiomyocytes may explain its impact on suvival. The different prognostic value of sTWEAK in ischemic and non-ischemic HF may point towards distinct pathogenic pathways determining the course of disease.

Pulmonary hypertension is defined as an increase in mean pulmonary arterial pressure ≥25 mm Hg at rest and occurs in a majority of patients with heart failure. Diagnostic imaging targets the right ventricle and the pulmonary vasculature. Although echocardiography is cost-effective for screening and follow-up, right heart catheterization is still mandatory to differentiate pre- from post-capillary disease and to directly measure pressure and flow. An important goal is to rule out chronic thromboembolic pulmonary hypertension. This diagnostic step can be achieved by perfusion scintigraphy, whereas computed tomography and cardiac magnetic resonance have become indispensable ancillary methods for the diagnostic allocation to other World Health Organization subtypes of pulmonary hypertension.

Objective Whereas angiogenesis, the formation of new blood vessels from preexisting vessels, may be beneficial in restoring failing myocardium, apoptosis may contribute to the progression of heart failure (HF). We investigated the role of pigment epithelium-derived factor (PEDF), a recently discovered antiangiogenic factor with additional proapoptotic effects, in patients with advanced HF. Methods We assayed PEDF levels in 351 patients with advanced HF at baseline. During the median follow-up time of 16 months, 50% of patients experienced the composite end point of rehospitalization and/or death. Results The risk of a clinical event increased with concentrations of the antiangiogenic marker PEDF, with a 1.94-fold higher risk in the third tertile compared with the first tertile (95% CI, 1.33–2.84). This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model ( P = .015). Experimental data revealed that PEDF may contribute to the progression of HF by inducing apoptosis in human cardiac myocytes and fibroblasts via activation of caspase 3. Conclusions We suggest a role of PEDF in the progression of HF by inducing apoptosis of human cardiac myocytes and fibroblasts. Our clinical data suggest that PEDF concentrations may have the potential to become a valuable marker of the prognosis of HF, in addition to BNP.

Drug eluting stents (DES) reduce recurrent luminal narrowing through anti-migratory and anti-proliferative effects. However, recent concerns arose that DES may also induce significant chronic inflammatory responses that may impair vascular healing and lead to in-stent restenosis (ISR). As the complement components C3a and C5a exert particularly strong chemotactic and proinflammatory effects, we examined the association of serum levels of C3a and C5a and ISR after implantation of DES.We included 82 patients that were treated with 151 DES. Blood samples were taken directly before and 24h after PCI. Serum levels of C3a and C5a were measured by specific ELISA and restenosis was evaluated at 6-8 months by coronary angiography.C5a but not C3a increased after implantation of DES (p0.05). During the follow-up period, two patients (2.4%) died of cardiovascular causes and 12 patients (7.9% of stents, 15% of patients) developed ISR. Serum levels of C3a before and 24h after PCI as well as C5a levels at baseline were significantly higher in patients that developed ISR at follow-up. C3a and C5a at baseline were significantly associated to angiographic late lumen loss independent from clinical and procedural risk factors.Increased complement activation as measured by higher levels of C3a and C5a before PCI is significantly associated with late lumen loss. Inhibition of the complement cascade to prevent ISR warrants further investigation.

BACKGROUND We tested the hypothesis that plasma levels of plasminogen activator inhibitor-1 (PAI-1) are influenced by percutaneous coronary intervention (PCI) with the implantation of drug eluting stents (DES) and are able to predict the occurrence of in-stent restenosis (ISR). METHODS AND RESULTS PAI-1 active antigen plasma levels were determined in 75 patients before and 24 h after PCI with DES implantation. Patients with ISR after six to eight months (16%) showed significantly lower PAI-1 plasma levels before PCI (ISR, 11.7 +/- 8.1 ng mL(-1); non-ISR, 22.8 +/- 18.8 ng mL(-1); P

Plasminogen activator inhibitor-1 (PAI-1) has been shown to increase after percutaneous coronary intervention (PCI). Whether activated platelets, local trauma with activation of resident vascular cells or the acute phase response is the source of this PAI-1 increase is not well defined. Therefore we examined whether intensive platelet inhibition may modulate PAI-1 levels or whether the PAI-1 increase is associated with the acute phase protein C-reactive protein (CRP).We included 51 patients with stable angina who underwent elective PCI with stent implantation. At the time of study, routine pretreatment with clopidogrel before PCI was not standard of care, but left to the discretion of the referring cardiologist. We matched 17 patients with stable angina that were not pretreated with clopidogrel but received a loading dose of 300 mg immediately after stent implantation according age, sex and smoking with 34 patients that received clopidogrel at least 12 to 24 hours before PCI. Blood samples for measurement of PAI-1, t-PA and CRP were taken directly before and 24 hours after the procedure.PAI-1 and t-PA active antigen plasma levels before PCI were not different in patients with and without clopidogrel pretreatment. Whereas PCI induced a significant increase of PAI-1 levels in patients without pretreatment (p0.05), the procedure had no effect on PAI-1 active antigen in patients pretreated with clopidogrel. This resulted in significant lower PAI-1 plasma levels 24 hours after PCI in patients with pretreatment (p0.05). CRP was not associated with pre- or postprocedural PAI-1 levels.Clopidogrel pretreatment completely abolishes the increase of PAI-1 active antigen after coronary stent implantation. This suggests that peri-procedural platelet activation might play a major role for the increase of PAI-1 after PCI thus increasing the risk of acute and subacute thrombus formation based on a reduced endogenous fibrinolytic system.

Background The aim of our prospective multicenter Clopidogrel Registry was to evaluate the efficacy and safety of a 300-mg loading dose of clopidogrel at the time of ad hoc stenting in patients with suspected coronary artery disease who were not pretreated with clopidogrel for any reason, and to compare the 30-day clinical event rates with the outcome of patients pretreated with a loading dose of clopidogrel 6 to 24 hours before stenting. Methods Between March 2002 and February 2004, 4160 consecutively included patients received a 300-mg loading dose of clopidogrel immediately after (group 1, n=2679) or 6 to 24 hours before stenting (group 2, n=1481). Results The primary end point (triple composite end point of acute myocardial infarction, all-cause death, and urgent repeat target vessel revascularization) at 30 days occurred in 4.74% versus 2.77% in groups 1 and 2, respectively ( P = .002). The secondary end point events, the stent thrombosis, occurred significantly more frequently in group 1, with a trend toward increase in incidence of death, target vessel revascularization, or need for glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention. Pretreatment with clopidogrel was associated with more major bleeding (secondary safety end point) (0.41% vs 1.35% in groups 1 and 2, respectively; P = .001). Conclusions The results of our multicenter prospective Clopidogrel Registry demonstrate lower efficacy of a 300-mg loading dose of clopidogrel at the time of stenting compared with pretreatment 6 to 24 hours before percutaneous coronary intervention on the 30-day composite clinical end point in the large unselected patient cohort, which suggests the benefit of clopidogrel pretreatment in all incoming patients with suspected significant coronary artery disease scheduled for coronary angiography.

Elevated homocysteine (Hcy) levels have been associated with increased risk for cardiovascular disease and it has been shown that hyperhomocysteinemia is associated with increased levels of t-PA antigen in individuals without evidence for coronary artery disease (CAD). The aim of this study was to examine if Hcy plasma levels are associated with plasma levels of fibrinolytic factors in patients with CAD and a history of acute myocardial infarction.We measured in 56 patients with CAD, 1 month after their first ST-elevation myocardial infarction, plasma levels of Hcy, the fibrinolytic parameters tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-type-1 (PAI-1), and t-PA-PAI-1 complexes.Hcy plasma levels inversely correlated with t-PA activity (r=-0.303, p0.05). Patients with mild hyperhomocysteinemia (Hcy15 micromol/L, n=8) showed significantly lower plasma levels of t-PA activity (p0.05). Regression analysis revealed that out of cardiovascular risk factors and medical treatment only Hcy was significantly associated with t-PA activity.Patients with CAD after a first myocardial infarction and hyperhomocysteinemia show a reduced t-PA activity independently from cardiovascular risk factors and medical treatment. Homocysteine lowering therapies may increase fibrinolytic activity and thereby may help to avoid atherothrombotic events in patients with CAD after a first myocardial infarction.

We sought to assess outcomes and risk stratification tools in a large population of patients with hypertrophic cardiomyopathy. 178 consecutive patients (71 female, age 48 ± 16 yrs; 109 with outflow tract obstruction) with hypertrophic cardiomyopathy were included and followed. Outcome was assessed

Background In aortic stenosis, natriuretic peptides have recently been shown to correlate with ventricular function and to predict symptom-free survival and outcome. Elevated big endothelin-1 (bigET) is associated with poor prognosis in chronic heart failure, but little is known about its role in severe aortic stenosis. Methods In 61 patients with aortic stenosis (71±10 years, mean gradient 65±20 mm Hg, valve area 0.63±0.15 cm 2 ), plasma bigET was determined by radioimmunoassay and related to echocardiographic parameters, symptoms and survival. Patients were followed for 1 year. Results BigET (mean 2.3±1.5, range 0.1–7.5 fmol/ml) was elevated ≥1.9 fmol/ml in 54% of patients, but was not correlated to the transvalvular gradients or valve area. BigET did not differ significantly between 14 asymptomatic (2.4±1.0 fmol/ml) and 47 symptomatic patients (2.3±1.6 fmol/ml), although the highest levels were observed in 5 patients in NYHA class III–IV (4.2±2.2 fmol/ml, p =0.035). No significant difference in bigET was observed between 51 survivors and 10 patients who died during follow-up (2.2±1.4 vs 2.7±1.6 fmol/ml). BigET did not differ between 7 asymptomatic patients developing symptoms and those remaining asymptomatic during follow-up. BigET was significantly related to the systolic blood pressure and left ventricular systolic pressure ( r =0.389, p =0.0025 and r =0.401, p =0.0018, respectively), but not to the diastolic blood pressure or interventricular septal wall thickness. BigET was inversely related to the left ventricular ejection fraction ( r =0.327, p =0.01) and fractional shortening ( r =0.391, p =0.044). Conclusion Although frequently elevated, bigET-1 is not a useful predictor of symptoms or outcome in patients with severe aortic stenosis. BigET increases inversely with left ventricular function and directly with systolic left ventricular and blood pressure, but is not related to transvalvular gradients or valve area.

Recent findings have implicated hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, an established class of drugs for the treatment of hypercholesterolemia, in tissue remodeling in the heart. Statins induce apoptosis in different cell culture systems including rat neonatal cardiomyocytes. We investigated possible effects of different statins in vitro in human adult cardiac myocytes on the expression of proteins thought to be involved in the regulation of apoptosis such as Mcl-1, an inhibitor of apoptosis, Bax, an inducer of apoptosis, as well as on cytoplasmic histone-associated-DNA-fragments. Human adult cardiac myocytes (HACM) were treated with different statins at concentrations from 0.01 to 5 microM for up to 96 h. Whereas the lipophilic statin simvastatin at a concentration of 5 microM downregulated Mcl-1 mRNA by 49%, the hydrophilic pravastatin had no effect. Bax mRNA levels were not affected by neither of the statins. Simvastatin but not pravastatin reduced Mcl-1 protein expression whereas Bax protein was not detectable in HACM as determined by Western blotting. Simvastatin, atorvastatin and fluvastatin induced an up to seven-fold increase in histone-associated-DNA-fragments whereas pravastatin did not. Simvastatin up regulated histone-associated-DNA-fragments dose-dependently, and mevalonate and geranylgeranyl pyrophosphate reversed this effect to control levels. Our results show that lipophilic statins can induce a pro-apoptotic state in human adult cardiac myocytes in vitro. We speculate that, similar to findings in animal models, statins might be involved in the attenuation of cardiac hypertrophy and remodeling in humans by modulating the balance between cell survival and apoptosis.

Background Noninvasive quantitation of valvular regurgitation remains a difficult problem. Measurements of the vena contracta (VC) by color Doppler echocardiography have been proposed but limited data are available on the actual accuracy of this method. Methods To evaluate how closely the color Doppler VC reflects the true fluid dynamic VC and the anatomic regurgitant orifice and whether this measurement is affected by flow changes, various models of valvular regurgitation were studied in an in vitro flow circuit. The VC diameter was measured with color Doppler using two different ultrasound systems (Agilent Sonos 5500; Agilent Technologies Inc, Palo Alto, Calif and Vingmed CFM 800; GE Healthcare, Chalfront St Giles, UK). Optical planimetry of the anatomic regurgitant orifice was performed, the true VC diameter was determined by laser particle flow visualization. Results Because of flow contraction, the true VC diameter was consistently smaller than the anatomic regurgitant orifice diameter. Anatomic orifice and true VC only marginally changed with flow rate. The diameter of the color Doppler VC, however, not only overestimated the anatomic orifice diameter by 45% to 60% and the true VC diameter by 130% to 160%, but was also highly affected by the flow rate and the ultrasound system. Despite these limitations a color Doppler VC diameter of 0.77 cm or more (Agilent) and 0.89 cm or more (Vingmed) detected severe regurgitation with a sensitivity of 93% and 84% and a specificity of 96% and 79%, respectively. Conclusions Color Doppler estimates of the VC markedly overestimate regurgitant orifice and true VC. In contrast to the true VC, Doppler measurements are significantly affected by flow rate and by the ultrasound system used. Nevertheless, they allow semiquantitative assessment of valvular regurgitation separating severe from nonsevere regurgitation with acceptable accuracy.

ObjectivesThe goal of this study was to determine whether chronic inflammation of the vascular wall may be associated with an impaired activation of the fibrinolytic system.BackgroundInflammation plays an important role in the initiation and progression of atherosclerosis, and the fibrinolytic system may prevent local thrombus formation.MethodsWe included 50 patients six months after their first myocardial infarction. Plasma levels of the inflammatory marker C-reactive protein (CRP) were determined at basal conditions, and the fibrinolytic parameters tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) were measured at basal conditions and after a standardized venous occlusion (VO) of the forearm.ResultsPatients with high CRP levels (≥3 mg/l) showed a significantly higher t-PA activity at baseline compared with patients with medium (1 to 2.9 mg/l) and low (

Aims Immune activation and subsequent release of proinflammatory cytokines plays a central role in the pathophysiology of chronic heart failure (CHF). Cytotoxic CD4 + CD28 null cells are generated under inflammatory conditions and implicated in a variety of pathological processes like atherosclerosis and autoimmune diseases. The study aim was to assess the impact of CD4 + CD28 null cells on survival in CHF patients. Methods and results Circulating lymphocytes from 107 CHF patients were analyzed for the distribution of CD4 subsets by flow cytometry. During a median follow-up of 23 months, 22 (20%) persons died. CD4 + CD28 null cells independently predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.88 per 1-standard deviation increase (95% confidence interval (CI): 1.26–2.79, P = 0.002) and with a HR of 1.83 for cardiovascular mortality (95% CI: 1.18–2.86, P = 0.008), respectively. Further, we found a significant association with NT-proBNP ( r = 0.23). Conclusion Circulating CD4 + CD28 null cells are associated with CHF severity and are a strong and independent predictor of mortality in CHF fostering the implication of the immune system in CHF pathophysiology.

ObjectivesIntermittent coronary sinus occlusion has been described to be effective in salvaging ischemic myocardium. This meta-analysis aims to review the efficacy of intermittent coronary sinus occlusion and intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood as methods of myocardial salvage.MethodsA Medline search was performed to review the published literature on intermittent coronary sinus occlusion. The study inclusion criterion was a randomized, placebo-controlled trial with area of infarction (expressed as a percentage of the area at risk) as the primary end point.ResultsSeven experimental trials comprising 125 test animals were found that analyzed the effects of intermittent coronary sinus occlusion on ischemic damage during coronary occlusion. A further 5 studies comprising 88 animals were designed to evaluate the effect of intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood on the infarct size. A meta-analysis of the 7 studies analyzing the effect of intermittent coronary sinus occlusion revealed a significant reduction in infarct size of 29.3% in the treatment group compared with that in the placebo group (P < .001; 95% confidence interval, −40.9 to −17.7). A meta-analysis of the 5 trials analyzing the effect of intermittent coronary sinus occlusion in combination with retroperfusion revealed a reduction in infarct size of 39.4% in the treatment group compared with that in the placebo group (P < .001; 95% confidence interval, −48.9 to −29.9). Comparison between intermittent coronary sinus occlusion and intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood showed no statistical difference (P = .19). An inverse relationship between achieved coronary sinus pressure increase per minute and infarct size could be found in the intermittent coronary sinus occlusion group (r = −0.92; P < .007), whereas in combination with retroperfusion, there was a negative correlation both between achieved coronary sinus pressure and the amount of the retroperfusate and myocardial salvage (r = −0.97; P < .004).ConclusionsThe use of intermittent coronary sinus occlusion and intermittent coronary sinus occlusion in combination with retroperfusion of arterial blood significantly decreases ischemic damage during coronary occlusions. Intermittent coronary sinus occlusion in combination with retroperfusion exhibits no significant profit in salvaging the ischemic myocardium in comparison with that provided by intermittent coronary sinus occlusion alone.

Prostaglandin E(1) (PGE(1)) has been used to treat pulmonary hypertension and peripheral artery occlusive disease and has been successfully employed for pharmacological bridging to transplantation in patients with chronic end-stage heart failure. In addition to its vasoactive effects PGE(1) was shown to stimulate angiogenesis in animal models. Recently we showed that PGE(1)-induced angiogenesis in hearts of patients with ischemic heart disease. We proposed that the angiogenic action of PGE(1) is mediated by vascular endothelial growth factor (VEGF). In the present paper we studied a possible effect of PGE(1) on the expression of VEGF-1 in cultured human adult cardiac myocytes (HACM) and cultured human adult cardiac fibroblasts (HACFB), respectively, to identify a cellular source of VEGF-1 in patients treated with PGE(1). We also aimed to delineate mechanisms involved in a possible regulation of VEGF-1 by PGE(1) in these cells. When HACM, isolated from human myocardial tissue, were treated with PGE(1), a significant up to 3-fold increase in VEGF-1 production could be observed. These results could be confirmed on the level of specific mRNA expression as determined by real-time polymerase chain reaction. The effect of PGE(1) on VEGF-1 expression could be blocked by H089, an inhibitor of cAMP-dependent protein kinase A. In HACFB, also isolated from human myocardial tissue, no effect of PGE(1) on VEGF-1 production was seen. If this effect of PGE(1) is also operative in the in vivo situation, one could speculate that cardiac myocytes could be a cellular source of PGE(1)-induced VEGF-1 expression in patients treated with this drug.

Burkitt's lymphoma is a highly aggressive type of non-Hodgkin's lymphoma frequently associated with extranodal or abdominal manifestations. We report the case of a young woman with generalized Burkitt's lymphoma, initially presenting with signs and symptoms of central nervous system involvement. Myocardial infiltration mimicking hypertrophic cardiomyopathy was detected with electrocardiogram, echocardiography, magnetic resonance imaging, and positron emission tomographic scintigraphy with F-18 desoxy-glucose. These abnormalities resolved after high-intensity chemotherapy with a modified B-cell acute lymphoblastic leukemia (B-ALL) protocol.

Because hibernation is considered a down-regulation of contractile function in response to reduced regional myocardial perfusion, hibernating myocardium is expected to be supplied by a critically stenosed or even occluded coronary artery. Thus, high-dose dobutamine has been postulated to cause ischemia and reworsening of myocardial function (biphasic response), whereas myocardium that demonstrates sustained improvement with high-dose dobutamine should not be supplied by a significantly stenosed vessel. This study evaluates the type of dobutamine response-biphasic versus sustained improvement-of dyssynergic myocardium in relation to its angiographically documented blood supply.In 38 patients (5 women; mean age 60 +/- 9 years) with chronic coronary artery disease and impaired left ventricular ejection fraction (/=35%), dobutamine echocardiography and quantitative coronary angiography were performed within 4 weeks. Wall-motion response of dyssynergic myocardium to dobutamine, classified as no improvement, biphasic response, or sustained improvement, was compared with the angiographically documented blood supply (presence of coronary stenosis in the corresponding artery, collaterals, and stenoses of the collateral supplying artery) in a segment-by-segment analysis.Of the 465 segments with abnormal wall motion at rest, 201 (47%) showed improvement during dobutamine infusion at low dose. Of these, 145 (72%) were supplied by significantly stenosed epicardial vessels. Only 27 (19%) of these 145 segments showed a biphasic response whereas in the remaining 118 segments wall-motion improvement persisted during high-dose dobutamine infusion. Although mean stenosis severity in the supplying vessel was significantly greater for segments presenting with biphasic response as compared with sustained improvement (95 +/- 7% and 86 +/- 12% luminal diameter reduction, respectively; P.0001), 69% of segments with sustained improvement were supplied by a critically stenosed artery. Only 7 of 27 segments with biphasic response and 22 of 118 segments with sustained improvement had visible collaterals supplied by a vessel without significant stenosis. The percentage of segments viable by thallium-single photon emission computed tomography imaging was similar for those with sustained and biphasic response (96% and 83%, respectively).In this group of patients with coronary artery disease and impaired left ventricular function, the great majority of dyssynergic segments that exhibited a sustained, rather than biphasic, dobutamine response were supplied by a critically stenosed artery. Furthermore, the percentage of segments viable by thallium-single photon emission computed tomography did not appear to be different for segments with sustained improvement and those with biphasic response. These findings challenge the hypothesis that biphasic response is the best criterion to identify viable myocardium.

Background Heart transplantation (HTX) is associated with decreased bone mineral density and changes in bone metabolism. We conducted this study to evaluate the pathophysiology of bone metabolism in HTX candidates and recipients. Methods Thirty-six HTX recipients were compared with 36 HTX candidates concerning biochemical parameters of bone metabolism and bone mineral density. Results Osteocalcin, bone-specific alkaline phosphatase, cross-linked-N-telopeptide of type I collagen, estradiol, serum creatinine, and blood urea nitrogen concentrations were significantly higher, whereas the calcium–creatinine ratio, thyrotropin, thyroxine, and bone mineral density were significantly lower in HTX recipients than in HTX candidates. Compared with a control group, HTX candidates had decreased renal function and increased bone resorption, whereas HTX recipients additionally had increased alkaline phosphatase and osteocalcin levels. In HTX recipients, we found positive correlations between creatinine clearance and bone mineral density; daily and cumulative cortisone doses were not associated with bone mineral density. Conclusion In HTX candidates, disturbances in bone metabolism with increased bone resorption may be caused partly by existing low-grade renal insufficiency, regular intake of loop diuretics, and restriction of mobility. In HTX recipients, immunosuppressive therapy—glucocorticoids and cyclosporine—seem to be responsible for changes in bone metabolism.

Summary Background There is serological and epidemiological evidence of an association between Chlamydia pneumoniae infection and coronary artery disease. Results of previous smaller studies have indicated a reduction of recurrent ischaemic events in patients with acute coronary syndrome when given macrolide antibiotics. We aimed to assess whether short-term treatment with the macrolide antibiotic azithromycin reduces recurrent ischaemic events in patients admitted for unstable angina or myocardial infarction. Methods We assessed the effect of azithromycin in a multi-centre, double-blind randomised trial in 1439 patients with unstable angina or acute myocardial infarction. Patients were randomly allocated to receive 500 mg azithromycin on the first day after randomisation, followed by 250 mg daily for 4 days or placebo. Patients were followed up for 6 months. The primary endpoints were death, recurrent myocardial infarction, or recurrent ischaemia necessitating revascularisation. Analysis was done by intention to treat. Findings Treatment with azithromycin did not result in reduction of either individual endpoints or any of the primary endpoints. Of the 716 patients in the azithromycin group, 23 (3%) died, 17 (2%) developed myocardial infarction, 65 (9%) had recurrent ischaemia needing revascularisation, and 100 (14%) had one or more of these endpoints. In the placebo group (n=723) the corresponding numbers of patients were 24 (4%), 22 (3%), 59 (8%), and 106 (15%), respectively (p=0·664, 95% CI 0·72–1·24). 62 (9%) of patients in the azithromycin group and 59 (8%) in the placebo group reached the secondary endpoint of ischaemia or congestive heart failure necessitating admission (difference 0·5%, 95% CI 0·75–1·53; p=0·707). We recorded few side-effects. Interpretation Short-term treatment with azithromycin does not reduce development of recurrent events in patients with acute coronary syndrome.

K. Macfelda, T. W. Weiss, C. Kaun, J. M. Breuss, B. Kapeller, G. Zorn, U. Oberndorfer, M. Voegele-Kadletz, R. Huber-Beckmann, R. Ullrich, B. R. Binder, U. M. Losert, G. Maurer, R. Pacher, K. Huber and J. Wojta. Plasminogen Activator Inhibitor 1 Expression is Regulated by the Inflammatory Mediators Interleukin-1α, Tumor Necrosis Factor-α, Transforming Growth Factor-β and Oncostatin M in Human Cardiac Myocytes. Journal of Molecular and Cellular Cardiology (2002) 34 , 1681–1691. Accumulating evidence points towards a role for proteases and protease inhibitors in tissue remodelling and repair in a variety of organs. In particular—besides the matrix metalloprotease system—the plasminogen activator (PA)/plasmin system has been implicated in these processes in the heart. Urokinase type PA (u-PA) and PA inhibitor type 1 (PAI-1) seem to modulate cardiac rupture and infarct healing. In this study we aimed to investigate whether inflammatory mediators can regulate the expression of components of the PA/plasmin system in human adult cardiac myocytes (HACM). We could demonstrate that HACM, isolated from pieces of myocardial tissue by mechanical dispersion and characterized by positive immunostaining for the cardiac markers troponin I, tropomyosin, cardiotin and myocardial muscle-actin, in vitro express PAI-1 and tissue type PA (t-PA) whereas u-PA was not detectable in these cells. PAI-1 protein production was increased up to twofold by interleukin-1α (IL-1α) and tumor necrosis factor-α (TNF-α) and up to fivefold by transforming growth factor-β (TGF-β) and oncostatin M (OSM). Similar changes were observed in PAI-1 transcript levels after cytokine treatment. t-PA production in HACM was not affected by these agonists. No effect of these cytokines on PAI-1 production in fibroblasts isolated from human myocardial tissue was seen. In an ex vivo model we could show that incubation of pieces of human myocardial tissue with these cytokines also resulted in an increase in PAI-1 in cardiac myocytes as evidenced by immuno-histochemistry. Furthermore we found increased PAI-1 expression in myocardial tissue from a patient suffering from acute myocarditis. Thus for the first time we provide evidence that inflammatory mediators modulate PAI-1 expression in human adult cardiac myocytes in vitro and ex vivo and could demonstrate that PAI-1 expression is increased in the in vivo setting under inflammatory conditions. If the effect on PAI-1 expression brought about by IL-1α, TNF-α, TGF-β and OSM is not only operative under in vitro and ex vivo conditions but also in the in vivo setting one could speculate that these cytokines contribute to upregulation of PAI-1 in myocardial tissue and that PAI-1, when upregulated in myocardial tissue during inflammatory processes, could serve as a defence mechanism against excessive matrix degradation by proteases. Thus we propose a role for PAI-1 produced in the heart by cardiac myocytes in cardiac remodelling and repair processes.

ObjectivesThe aim of this study was to determine whether nicotine, a constituent of cigarette smoke, contributes to acute endothelial dysfunction after smoking one cigarette.BackgroundAnimal studies suggest that nicotine might cause an impairment of endothelium-dependent vasodilation via an increase in oxidative stress.MethodsSixteen healthy smokers were entered into a randomized, observer-blinded crossover study comparing the effects of nicotine nasal spray (1-mg nicotine) and cigarette smoke (1-mg nicotine, 12 mg tar) on vascular reactivity in the brachial artery. Using high-resolution ultrasound, flow-mediated dilation (FMD) and endothelium-independent, nitroglycerin-induced dilation were assessed at baseline and 20 min after the administration of nicotine (spray or cigarette).ResultsIn response to similar increases in nicotine serum levels, FMD values declined from 10.2 ± 4.4% to 6.7 ± 4.0% after the spray (mean difference: −3.6 ± 2.0%, 95% confidence interval: −4.6; −2.5, p < 0.0001) and from 9.4 ± 3.8% to 4.3 ± 2.8% after the cigarette (−5.1 ± 2.6%, −6.5; −3.7, p < 0.0001). Nitroglycerin-induced dilation remained similar within both periods. Performing a period effect analysis of variance, a significant influence on FMD was found for the mode of administration (p = 0.017) and the baseline value (p = 0.021). The effect on FMD was more pronounced after the cigarette than after the spray (estimated average effect difference: 1.9% FMD). Oxidation parameters did not increase significantly after nicotine spray or tobacco exposure.ConclusionsThese results demonstrate that nicotine alone causes acute endothelial dysfunction, although to a lesser extent than smoking a cigarette of the same nicotine yield. However, the precise mechanisms by which nicotine leads to this altered vascular reactivity remain unclear.

The atherogenic lipoprotein Lp(a) consists of an LDL-like core and apo(a), linked to apoB via a thiol bridge. Apo(a) fragments ranging in size from 60 to 220 kDa are excreted into urine and the excretion rate correlates significantly with the plasma levels of Lp(a). In order to study the interrelationship of apo(a) secretion with that of other plasma proteins, urinary apo(a) and protein secretion of five probands were followed for 24 h at different urinary densities. The excretion rate of apo(a) fragments, despite their high molecular weight, was highest, followed by apoD, orosomucoid, albumin and beta(2)-glycoprotein-I (beta2-GI) and plasminogen (1.58, 0.87, 0.095, 0.027, 0.013 and0.001%/day, respectively). There was a highly significant correlation between apo(a), apoD and beta2-GI concentrations but not with albumin and orosomucoid concentrations in urine. The only protein that was fragmented in urine was apo(a) while the other proteins had molecular weights comparable to those in plasma. We conclude that a previously suggested fragmentation of apo(a) by the kidney is not a rate-limiting step in its excretion. Since plasminogen, another kringle-IV-containing plasma compound, and fragments thereof, are undetectable in urine under identical experimental conditions, it is very unlikely that the characteristic kringle structure is responsible for the high excretion rate of apo(a).

In summary, this study shows that CRP levels do not correlate with the extent and severity of coronary narrowing assessed by angiography. Other mechanisms such as acute inflammation with plaque instability and rupture may explain the higher cardiovascular event rate in patients with elevated CRP levels. 1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340

Study objectives Congenital malformations of the right atrium (RA) and the coronary sinus (CS) are rare, and only sporadic cases have been reported. Little is known about the clinical relevance of this disorder. We report on two patients, one with a giant RA diverticulum, the other with a diverticulum of the CS, and review 103 cases of such malformations that have been reported previously. Design A MEDLINE search was performed to collect all cases of congenital malformations of the RA and the CS reported in the literature between 1955 and 1998. Cases were classified into the following categories: (1) congenital enlargement of the RA; (2) single diverticulum of the RA; (3) multiple diverticula of the RA; and (4) diverticulum of the CS. Clinical presentation and outcome of the different types of malformations were analyzed. Results The patients most frequently presenting with symptoms were those with diverticula of the CS (n = 28) followed by those with single diverticula of the RA (n = 13), multiple diverticula (n = 4), and congenital enlargements of the RA (n = 60). The percentages of symptomatic patients were 93, 84, 75, and 53%, respectively. Symptoms were frequently caused by arrhythmias. Supraventricular tachycardia (SVT) was found in 42 of the patients (40%) and was most common in patients with diverticula of the CS (24 of 28 patients) and multiple atrial diverticula (3 of 4 patients). Sudden cardiac death was reported more frequently in patients with diverticula of the CS (18%) compared to those with congenital enlargement of the RA (5%) or single or multiple diverticula of the RA (6%). All seven patients with diverticula of the CS who were not treated with catheter or surgical ablation eventually died. Conclusion Congenital malformations of the RA and the CS frequently are associated with arrhythmias. SVT and sudden cardiac death have been reported in a significant percentage of patients with diverticula of the CS.

OBJECTIVES This study investigated the feasibility, accuracy and clinical potential of creating polymer hard copies of echocardiographic data using stereolithography. BACKGROUND Three-dimensional (3D) echocardiography has so far been limited by the need to display reconstructed 3D objects on a two-dimensional screen. Thus, tangible stereolithographic polymer models created from echocardiographic data could enhance our spatial perception of cardiac anatomy and pathology. METHODS Hard-copy replicas of water-filled latex balloon phantoms (n = 7) and porcine liver specimens (n = 12) were generated from echocardiographic images using stereolithography (computerized laser polymerization). In addition, we created 24 models of the mitral valve from 12 transesophageal studies (normal = 6, mitral stenosis n = 4, prolapse/flail leaflet n = 8, annular dilation n = 2, leaflet restriction n = 2 and following mitral valve repair n = 2). RESULTS Excellent agreement was found for comparison of volumes (r = 0.98, SEE = 3.46 mm3, mean difference = 0.25 ± 3.33 mm3) and maximal dimensions (r = 0.99, SEE = 0.16 cm, mean difference = 0.03 ± 0.16 cm) between phantoms and their corresponding replicas. Visual and tactile examination of mitral valve models by two blinded observers allowed correct depiction of mitral valve anatomy and pathology in all cases. CONCLUSIONS Stereolithographic modeling of echocardiographic images is feasible and provides tangible polyacrylic models that are true to scale, shape and volume. Such models offer accurate depiction of mitral valve anatomy and pathology in patients studied with transesophageal echocardiography. This technique could have substantial impact on diagnosis, management and preoperative planning in complex cardiovascular disorders.

Extracorporeal elimination of low density lipoprotein (LDL) is frequently used in drug-resistant hypercholesterolemia. LDL-immunoapheresis selectively removes LDL and lipoprotein(a) [Lp(a)] from plasma. Lipid peroxidation is one unwanted side effect, that occurs during extracorporeal plasma treatment. The purpose of this study was to investigate the effect of LDL immunoapheresis on lipid peroxidation. Before and after a single LDL-immunoapheresis treatment, plasma concentrations of lipid hydroperoxides, determined with two different spectophotometric assays, thiobarbituric acid-reacting substances (TBARS), determined spectrophotometrically and malondialdehyde (MDA), determined by an MDA-TBA/HPLC method, were measured in 13 hypercholesterolemic patients. In addition MDA was also determined in the eluate of the apheresis column. Before treatment, plasma cholesterol and LDL cholesterol concentrations were significantly higher in patients than in healthy control subjects, as were the lipid peroxidation products. LDL-immunoapheresis treatment of the patients led to significant decreases in total cholesterol (69+/-8%), LDL-cholesterol (79+/-7%), HDL-cholesterol (35+/-17%), triglycerides (38+/-21%), apolipoprotein-B (77+/-6%), apolipoprotein-A1 (25+/-5%) and Lp(a) concentrations (76+/-10%). Changes in plasma lipid peroxide concentrations (17+/-8 nmol/l before vs. 14+/-5 nmol/l after treatment) were not significant, neither were those in TBARS (3. 0+/-2.6 micromol/l vs. 2.3+/-1.3 micromol/l) or MDA concentrations (1.03+/-0.17 micromol/l vs. 1.0+/-0.20 micromol/l). Patients with high baseline values showed a decrease, whereas others did not. MDA was present (0.57+/-0.13 micromol/l) in the eluate of the apheresis column, suggesting that, along with LDL, lipid peroxidation products are also removed. From these results we conclude that a single LDL-immunoapheresis treatment effectively reduces LDL and Lp(a) in the absence of increases in plasma lipid peroxidation products.

This study investigated the use of artificial neural networks (ANN) for image segmentation and spatial temporal contour linking for the detection of endocardial contours on echocardiographic images. Using a backpropagation network, the system was trained with 279 sample regions obtained from eight training images to segment images into either tissue or blood pool region. The ANN system was then applied to parasternal short axis images of 38 patients. Spatial temporal contour linking was performed on the segmented images to extract endocardial boarders. Left ventricular areas (end-systolic and end-diastolic) determined with the automated system were calculated and compared to results obtained by manual contour tracing performed by two independent investigators. In addition, ejection fractions (EF) were derived using the area-length method and compared with radionuclide ventriculography. Image quality was classified as good in 12 (32%), moderate in 13 (34%) and poor in 13 (34%) patients. The ANN system provided estimates of end-diastolic and end-systolic areas in 36 (89%) of echocardiograms, which correlated well with those obtained by manual tracing (R = 0.99, SEE = 1.44). A good agreement was also found for the comparison of EF between the ANN system and Tc-radionuclide ventriculography (RNV, R = 0.93, SEE = 6.36). The ANN system also performed well in the subset of patients with poor image quality. Endocardial contour detection using artificial neural networks and spatial temporal contour linking allows accurate calculations of ventricular areas from transthoracic echocardiograms and performs well even in images with poor quality. This system could greatly enhance the feasibility, accuracy and reproducibility of calculating cardiac areas to derive left ventricular volumes and ejection fractions.

OBJECTIVES This study sought to evaluate whether pressure recovery can cause significant differences between Doppler and catheter gradients in patients with aortic stenosis, and whether these differences can be predicted by Doppler echocardiography. BACKGROUND Pressure recovery has been shown to be a source of discrepancy between Doppler and catheter gradients across aortic stenoses in vitro. However, the clinical relevance of this phenomenon for the Doppler assessment of aortic stenosis has not been evaluated in patients. METHODS Twenty-three patients with various degrees of aortic stenosis were studied with Doppler echocardiography and catheter technique within 24 h. Using an equation previously validated in vitro, pressure recovery was estimated from peak transvalvular velocity, aortic valve area and cross-sectional area of the ascending aorta and compared with the observed differences between Doppler and catheter gradients. Doppler gradients were also corrected by subtracting the predicted pressure recovery and then were compared with the observed catheter gradients. RESULTS Predicted differences between Doppler and catheter gradients due to pressure recovery ranged from 5 to 82 mm Hg (mean ± SD, 19 ± 16 mm Hg) and 3 to 54 mm Hg (12 ± 11 mm Hg) for peak and mean gradients, respectively. They compared well with the observed Doppler-catheter gradient differences, ranging from −5 to 75 mm Hg (18 ± 18 mm Hg) and −7 to 48 mm Hg (11 ± 13 mm Hg). Good correlation between predicted pressure recovery and observed gradient differences was found (r = 0.90 and 0.85, respectively). Both the noncorrected and the corrected Doppler gradients correlated well with the catheter gradients (r = 0.93–0.97). However, noncorrected Doppler gradients significantly overestimated the catheter gradients (slopes, 1.36 and 1.25 for peak and mean gradients, respectively), while Doppler gradients corrected for pressure recovery showed good agreement with catheter gradients (slopes, 1.03 and 0.96; standard error of estimate [SEE] 8.1 and 6.9 mm Hg; mean difference ± SD 0.4 ± 8.0 mm Hg and 1.1 ± 6.8 mm Hg for peak and mean gradients, respectively). CONCLUSIONS Significant pressure recovery can occur in patients with aortic stenosis and can cause discrepancies between Doppler and catheter gradients. However, pressure recovery and the resulting differences between Doppler and catheter measurements may be predicted from Doppler velocity, aortic valve area and size of the ascending aorta.

High levels of plasma lipoprotein(a) [Lp(a)] represent an independent risk factor for cardiovascular morbidity; however, Lp(a) has not yet been identified as a risk factor for type 1 diabetic patients. Results from the limited number of available studies on plasma Lp(a) levels in relation to renal function in type 1 diabetes mellitus are inconclusive. We hypothesized that only type 1 diabetes mellitus patients with impaired renal function show increased plasma Lp(a) levels, due to decreased urinary apolipoprotein(a) [apo(a)] excretion. We therefore measured urinary apo(a) levels in 52 type 1 diabetes mellitus patients and 52 matched controls, and related the urinary apo(a) concentration to the plasma Lp(a) level, kidney function, and metabolic control. Our findings indicate that patients with incipient diabetic nephropathy as evidenced by microalbuminuria (20 to 200 microg/min) exhibit significantly higher plasma Lp(a) levels (median, 15.6 mg/dL) in comparison to normoalbuminuric patients (median, 10.3 mg/dL) and healthy controls (median, 12.0 mg/dL). Urinary apo(a) normalized to creatinine excretion was significantly elevated in both normoalbuminuric (median, 22.3 microg/dL) and microalbuminuric type 1 diabetic patients (median, 29.1 microg/dL) compared with healthy subjects (median, 16.0 microg/dL) and correlated significantly with Lp(a) plasma levels in both patient and control groups (P.003). No correlation existed between the Lp(a) plasma level or urinary apo(a) concentration and metabolic control in type 1 diabetes mellitus patients. From these studies, we conclude that urinary apo(a) excretion is significantly increased in type 1 diabetic patients and correlates with plasma Lp(a) levels, and only type 1 diabetic patients with microalbuminuria have higher plasma levels of Lp(a) compared with patients with normoalbuminuria and healthy controls.

Objectives. We examined the relationship among viability assessment by dobutamine echocardiography (DE), positron emission tomography (PET) and thallium-201 single-photon emission computed tomography (Tl-SPECT) to the degree of fibrosis. Background. DE, PET and Tl-SPECT have been shown to be sensitive in identifying viability of asynergic myocardium. However, PET and Tl-SPECT indicated viability in a significant percentage of segments without dobutamine response or functional improvement after revascularization. Methods. Twelve patients with coronary artery disease and severely reduced left ventricular function (EF 14.5 ± 5.2%) were studied with DE prior to cardiac transplantation: 5 had additional PET and 7 had Tl-SPECT studies. Results of the three techniques were compared to histologic findings of the explanted hearts. Results. Segments with >75% viable myocytes by histology were determined to be viable in 78%, 89% and 87% by DE, PET and Tl-SPECT; those with 50–75% viable myocytes in 71%, 50% and 87%, respectively. Segments with 25–50% viable myocytes showed response to dobutamine in only 15%, but were viable in 60% by PET and 82% by Tl-SPECT. Segments with

Recent studies suggest prophylactic intraaortic balloon-pulsation (IABP) in patients undergoing coronary reperfusion therapy. However, variable effects of IABP on coronary blood flow are reported. It is suggested that augmentation of coronary flow is more effective in patients with a compromised hemodynamic status, which might have potential relevance in selecting IABP treatment in patients undergoing reperfusion therapy.