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Byline: Annick Haouzi, Hans Berglund, Peter C.D. Pelikan, Gerald Maurer, Robert J. Siegel Abstract: Although prophylactic treatment with [beta]-blockers is used to retard aortic root dilatation in Marfan syndrome, it is not effective in all patients. To assess the effects of [beta]-adrenergic blockade on the aorta's elastic properties, aortic stiffness index and distensibility were calculated in 13 patients with Marfan syndrome and 10 control subjects before and after [beta]-adrenergic blockade. At baseline, patients with Marfan syndrome had a significantly increased stiffness index and decreased distensibility. After [beta]-adrenergic blockade, 8 patients with Marfan syndrome developed stiffness indexes and distensibility values that were closer to normal, whereas these variables deteriorated in 5 patients. Thus the benefit of [beta]-adrenergic blockade in Marfan syndrome may be the reduction in pulse pressure and myocardial contractility and also promotion of the elastic properties of the aorta. Moreover, the differential responses of aortic mechanics (normalizing or worsening) to [beta]-adrenergic blockade may possibly have implications for the prognosis in these patients. (Am Heart J 1997;133:60-3.) Author Affiliation: Vandoeuvre-les-Nancy, France, Los Angeles and Santa Monica, Calif., and Vienna, Austria Article History: Received 13 November 1995; Accepted 11 March 1996 Article Note: (footnote) [star] From the aDepartment of Cardiovascular Surgery, HA[acute accent]pital de Brabois; b Division of Cardiology, Cedars-Sinai Medical Center, and University of California, Los Angeles School of Medicine; the cPacific Heart Institute, St. Johns Hospital and Heart Center; and d Cardiology Department, University of Vienna., [star][star] Supported by grants from the Swedish Society of Medicine, Wenner-Gren Center Foundation, Swedish Institute, Einar Belven Foundation, Herbert Stein MD Research Fund, and Lee E. Siegel MD Memorial Fund, Western Cardiac Foundation., a Reprint requests: Hans Berglund, MD, Division of Cardiology, Room 5335, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048., aa 4/1/75315

Objectives This study sought to assess the natural history and optimal timing of surgery in elderly patients with severe asymptomatic aortic stenosis (AS). Background AS is increasingly diagnosed in an aging population, and large numbers of elderly patients are undergoing aortic valve procedures. However, the average age of patients represented in most natural history studies on AS is between 60 and 70 years. Methods A total of 103 consecutive patients >70 years of age (51 female; mean age 77 ± 5 years) with asymptomatic severe AS (peak aortic jet velocity [AV-Vel] 4.7 ± 0.6 m/s) were prospectively followed. Results During follow-up, 91 events occurred, including an indication for aortic valve replacement in 82 patients and cardiac deaths in 9, respectively. Event-free survival was 73%, 43%, 23%, and 16% at 1, 2, 3, and 4 years, respectively. Physical mobility was impaired in 29% of the patients, and symptom onset was severe (New York Heart Association functional class ≥III) in 43% of those who developed symptoms. Patients with AV-Vel ≥5.0 m/s had event-free survival rates of 21% and 6% at 2 and 4 years, respectively, compared with 57% and 23% for patients with AV-Vel <5.0 m/s (p < 0.001). Seventy-one patients underwent aortic valve replacement, and post-operative survival was 89% and 77% after 1 and 3 years, respectively. Conclusions In elderly patients with severe but asymptomatic AS, mild symptoms may be difficult to detect, particularly when mobility is impaired and severe symptom onset is common, warranting close clinical follow-up. Furthermore, a very high event rate can be expected, and cardiac deaths are not infrequent. Thus, elective aortic valve procedures may be considered in selected elderly patients at low procedural risk. [ABSTRACT FROM AUTHOR]

Background Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. Objective The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100–containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. Methods We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16−), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. Results In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. Conclusions In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Interleukin-6 (IL-6) is a key cytokine in inflammatory diseases. It exerts its biological function via binding to a homodimer of its signal transducer glycoprotein 130 (gp130). Soluble gp130 (sgp130) is the natural inhibitor of IL-6 trans-signalling. The aim of this study was to test a possible influence of the gp130 genotype on sgp130 serum levels. Material and methods: In two separate populations, subjects were genotyped for the gp130 polymorphism G148C. Sgp130, IL-6 and soluble interleukin-6 receptor (sIL-6R) levels were measured. The OSLO population consisted of 546 male subjects at high risk for CAD. The VIENNA population consisted of 299 male subjects with angiographically proven CAD. Results: In the OSLO population, 124 (22.7%) subjects were hetero- or homozygote for the rare C allele. Individuals carrying the polymorphism had significantly higher levels of sgp130. In a multivariate linear regression model this association remained significant (adjusted p=0.001). In the VIENNA population, 48 (16.1%) subjects were hetero- or homozygote for the rare C allele. Consistent with the former study, sgp130 levels were significantly higher in carriers of the polymorphism compared to wildtype carriers (adjusted p=0.038). In the VIENNA population, sgp130 levels were significantly higher in diabetic patients. In the OSLO population, sgp130 was higher in patients with increased body mass index and in smokers (p<0.05). Conclusions: Sgp130 serum levels are significantly higher in subjects carrying the gp130 polymorphism G148C compared to wildtype carriers. This finding proposes a possible genetical influence on sgp130 levels which may alter individual coping mechanisms in inflammatory diseases. [Copyright &y& Elsevier]

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 < 0.05) impaired early after PCI (9.8 ± 3.7%, 13.4 ± 9.2%, 5.7 ± 5.3%, and 7.6 ± 4.7% using plain balloon, DEB, BMS, and DES, respectively), as compared with controls (49.6 ± 9.5%), with slow recovery. In contrast to DES, the endothelium-related vasodilation of vessels treated with plain balloon, DEB, and BMS was increased at 1 month, suggesting enhanced endogenous nitric oxide production of the neointima. The endothelium-independent (vascular smooth muscle–related) vasodilation decreased significantly at 1 day, with slow normalization during FUP. All PCI-treated vessels exhibited imbalance between vasoconstriction–vasodilation, which was more pronounced in DES- and BMS-treated vessels. No correlation between histological parameters and vasomotor function was found, indicating complex interactions between the healing neoendothelium and smooth muscle post-PCI. 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. [Copyright &y& Elsevier]

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 < 0.001), and proximal and distal to it, during PCI in the nitric oxide–sheath group versus the control-sheath and control + C-sheath groups, respectively. Immediately following PCI, significantly less luminal thrombosis (12% vs. 33% and 31% of all analyzed segments, p < 0.001) was observed in the nitric oxide–sheath arteries. At 1 week, lower intimal inflammation score (0.43 ± 11 vs. 1.03 ± 0.35 and 1.04 ± 0.32, p < 0.05), less luminal thrombosis (8% vs. 21% and 30% p < 0.05), and smaller intimal hyperplasia (0.31 ± 0.31 mm2 vs. 0.47 ± 1.00 mm2 and 0.86 ± 0.82 mm2, p < 0.05) were observed in NO-sheath arteries at the injury site. 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to test whether serum levels of matrix metalloproteinase (MMP)-2 and -9 are associated with the development of in-stent restenosis (ISR) after implantation of drug-eluting stents (DES). Background: With the introduction of DES coronary ISR could be reduced dramatically. However, it still plays a significant role, particularly after treatment of multiple, complex lesions. Methods: We studied 85 patients who were treated with 159 DES. Blood samples for measurement of MMP-2 and -9 antigen and activity were taken directly before and 24 h after percutaneous coronary intervention (PCI). Restenosis was evaluated at 6 to 8 months by coronary angiography. Results: During the follow-up period, 2 patients (2.4%) died of cardiovascular causes, and 12 patients developed angiographic ISR. Patients with ISR showed significantly higher serum activity of MMP-9 at baseline (p = 0.017) and of MMP-2 (p < 0.0001) and MMP-9 (p < 0.0001) after the procedure. The PCI increased serum activity of MMP-2 (p = 0.005) and MMP-9 (p = 0.008) only in patients with ISR. The restenosis rates of patients in the highest quartile of MMP-2 after and MMP-9 before and after PCI were 40.0%, 38.9%, and 42.9% compared with 6.3%, 7.7%, and 4.0% in the lower quartiles, respectively. This was independent of clinical and procedural characteristics. Conclusions: Elevated serum activities of MMP-2 and -9 are associated with dramatically increased restenosis rates after PCI with implantation of DES. Determination of MMP levels might be useful for identification of patients who are at high risk for ISR despite implantation of DES. [Copyright &y& Elsevier]

Background: The aim of this study was to test the hypothesis that diastolic dysfunction associated with increased filling pressures is unlikely in a structurally normal heart and to assess whether 2-dimensional echocardiography can facilitate diastolic function grading in a clinical setting. Methods: Consecutive patients referred for transthoracic echocardiography received a comprehensive Doppler echocardiographic evaluation of diastolic function and measurements of left ventricular ejection fraction (EF) by biplane Simpson's method, left atrial volume index (LAVI) by area-length method, and interventricular septal thickness (IVS) from 2-dimensional images. Patients with atrial fibrillation, cardiac pacemaker, severe mitral regurgitation, or mitral prosthesis were excluded. Results: Of 187 patients, 38 had normal diastolic function and 77 had grade I; 54, grade II; and 18, grade III diastolic dysfunction. The presence of any 2-dimensional abnormality (EF < 55%, IVS > or = 14 mm, LAVI > or = 40 mL/m2) identified any diastolic dysfunction (grade I-III) with 92.6% sensitivity and 92.1% specificity. In a receiver operating characteristic analysis to predict any diastolic dysfunction, the areas under the receiver operating characteristic curve for EF, IVS, and LAVI and the sum of all 3 abnormalities were 0.69, 0.81, 0.87, and 0.95 (all P < .0001), respectively. Among all patients with at least one abnormality, the probability of diastolic dysfunction was 97.9% (138/141). Interpretation of 2-dimensional abnormalities together with the mitral inflow pattern resulted in correct diastolic function grading in 98.4% (184/187). Conclusions: Structural abnormalities on 2-dimensional echocardiography are not only statistically associated with diastolic dysfunction, but the combination of LAVI, EF, and IVS is of practical value for diastolic function grading. The presence of any such 2-dimensional abnormality should be considered indicative of diastolic dysfunction. [ABSTRACT FROM AUTHOR]

Background Remnant cholesterol has been defined as the cholesterol present in triglyceride-rich remnant lipoproteins. Elevated levels of remnant cholesterol have been associated with increased cardiovascular risk. Acute myocardial infarction (AMI) in very young individuals (≤40 years) represents a rare disease with a typical risk factor profile and a lipid phenotype that is characterized by a predominance of elevated triglyceride-rich lipoproteins. Objective The aim of this study was to investigate the role of remnant cholesterol in premature AMI. Methods We prospectively enrolled 302 patients into our multicenter case-control study comprising 102 consecutive myocardial infarction survivors (≤40 years) and 200 hospital controls. Myocardial infarction patients were frequency matched for age, gender, and center. Remnant cholesterol was calculated from standard lipid parameters. Results Remnant cholesterol was 1.7-fold higher in premature AMI patients compared with controls (61.1 ± 36.8 vs 35.8 ± 16.8 mg/dL; P < .001). Remnant cholesterol was the lipid fraction most strongly associated with premature myocardial infarction (odds ratio 3.87; 95% confidence interval 2.26–6.64; P < .001) for an increase of 1-standard deviation. This observation was independent from clinical risk factors and plasma lipid levels. Conclusions Remnant cholesterol is strongly associated with premature myocardial infarction, can be easily calculated, and might serve as a new potent risk marker in this young patient population. [ABSTRACT FROM AUTHOR]

An abstract of the article "Epicardial fat volume is inversely correlated with the degree of diastolic dysfunction and outcome in patients with heart failure with preserved ejection fraction," by Beatrice A. Marzhuf, Diana Bonderman, Jamil Babayev,, and Stefan Pfaffenberger is presented.

An abstract of the article "Diffuse myocardial fibrosis by post-contrast T1- time predicts outcome in heart failure with preserved ejection fraction," by Beatrice A Marzluf and colleagues is presented.

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. [ABSTRACT FROM AUTHOR]

Background: Veno-arterial extracorporeal membrane oxygenation (ECMO) is rapidly evolving as bailout option in patients with refractory cardiogenic shock after cardiovascular surgery (CV). Cardiac arrest represents a common and severe complication in the immediate post-operative phase. We therefore evaluated the impact of cardiac arrest at time of ECMO implantation on short- and long-term mortality in patients following CV surgery.Methods and Results: We included 385 patients undergoing veno-arterial extracorporeal membrane oxygenation therapy following CV surgery at a university-affiliated tertiary-care center into our single-center registry. Thirty patients underwent cardiopulmonary resuscitation (CPR) followed by immediate initiation of ECMO support. During a median follow-up time of 44 months (IQR 21-76 months), 68% of patients (n=262) died. We did not detect a significant impact of CPR during ECMO initiation on 30-day mortality (HR 1.04, 95%CI 0.89-1.83, P=0.86) as well as for long-term mortality (HR 1.01, 95%CI 0.63-1.61, P=0.97). Results were virtually unchanged for 30-day (HR 0.88, 95%CI 0.44-1.73, P=0.70) and long-term mortality (HR 0.93, 95%CI 0.54-1.60, P=0.79) after adjustment for age, sex, left ventricular ejection fraction, SAPS2 score, type of CV surgery, and year of study inclusion in order to unveil a potential negative confounding.Conclusion: Cardiac arrest did not affect short-tem and long-term mortality in a large cohort of patients with therapy refractory cardiogenic shock undergoing ECMO support following CV surgery. Our results suggest that the decision to initiate ECMO support in this specific patient population should not be influenced by the occurrence of cardiac arrest. [ABSTRACT FROM AUTHOR]

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 values < 8 U, the second quartile values between 8 U and < 15 U, the third one values between 15 U and 23 U, and the forth one values > 23 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 (HTPR > 46 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: The quantity of cells with paracrine effects for use in myocardial regeneration therapy is limited. This study investigated the effects of catheter-based endomyocardial delivery of secretome of 2.5 × 109 apoptotic peripheral blood mononuclear cells (APOSEC) on porcine chronic post-myocardial infarction (MI) left ventricular (LV) dysfunction and on gene expression. Closed-chest reperfused MI was induced in pigs by 90-min occlusion followed by reperfusion of the mid-LAD (day 0). At day 30, animals were randomized to receive porcine APOSEC (n = 8) or medium solution (control; n = 8) injected intramyocardially into the MI border zone using 3D NOGA guidance. At day 60, cardiac MRI with late enhancement and diagnostic NOGA (myocardial viability) were performed. Gene expression profiling of the infarct core, border zone, and normal myocardium was performed using microarray analysis and confirmed by quantitative real-time PCR. Injection of APOSEC significantly decreased infarct size (p < 0.05) and improved cardiac index and myocardial viability compared to controls. A trend towards higher LV ejection fraction was observed in APOSEC vs. controls (45.4 ± 5.9% vs. 37.4 ± 8.9%, p = 0.052). Transcriptome analysis revealed significant downregulation of caspase-1, tumor necrosis factor and other inflammatory genes in APOSEC-affected areas. rtPCR showed higher expression of myogenic factor Mefc2 (p < 0.05) and downregulated caspase genes (p < 0.05) in APOSEC-treated pigs. In conclusion, overexpression of MEF2c and repression of caspase was related to decreased infarct size and improved cardiac function in secretome-treated animals. Altered gene expression 1-month post-APOSEC treatment proved the long-acting effects of cell-free therapy with paracrine factors. [Copyright &y& Elsevier]

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 (p <0.05 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 (p <0.05 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 heterogenous, but no single variable stands out as a strong predictor of quantitative severity of MR. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Background and objectives: Clopidogrel non-responsiveness is associated with adverse clinical outcome. We aimed to investigate whether individualized antiplatelet treatment in clopidogrel non-responders is an effective and safe strategy. Methods: This was a prospective non-randomized non-blinded study comparing two cohorts (guided and non-guided treatment) with a follow-up of 1-month. Responsiveness to clopidogrel was assessed by multiple electrode aggregometry (MEA) in 798 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). In the guided group (n=403) clopidogrel non-responders received repeated loading doses of clopidogrel or prasugrel, in the non-guided group (n=395) clopidogrel non-responders did not undergo any change in treatment. Results: Stent thrombosis occurred significantly less often in the guided group than in the non-guided group (0.2% vs. 1.9%; p=0.027). The multivariate Cox regression analysis showed that patients in the non-guided group were at a 7.9-fold higher risk to develop stent thrombosis compared to the guided group (OR: 7.9; 95% CI: 1.08–69.2; p=0.048). In line with this, acute coronary syndrome occurred significantly less often in the guided group than in the non-guided group (0% vs. 2.5%; p=0.001) whereas there was no difference in the event rates of cardiac death (2% vs. 1.3%; p=0.422) or major bleedings (1% vs. 0.3%; p=0.186). Conclusion: Personalized antiplatelet treatment according to the platelet function testing with MEA resulted in an improved efficacy with an equal safety compared to the standard treatment. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Background: Data on the risk stratification of patients undergoing mitral valve (MV) surgery for non-ischemic mitral disease are sparse. The present study seeks to define them in a contemporary cohort. Methods: 193 consecutive patients referred to non-ischemic MV surgery were prospectively studied. Baseline characteristics and the type of surgery were analyzed with regard to operative and late mortality as well as functional outcome. Results: 129 patients underwent MV replacement and 64 MV repair. MV replacement patients presented with more symptoms (p=0.010), higher EuroSCORE (6.1 versus 5.6; p=0.009), more frequently underwent additional valve surgery (7.8 versus 0%; p=0.003) and were more frequently female (p=0.048). Operative mortality was 3.1%, two thirds of operative deaths had additional surgery of the tricuspid valve (p=0.019). Patients were followed for 5.2±2.7years. 1-, 3-, 5- and 7-year survival rates were 93-, 91-, 82-, and 79% in MV replacement patients versus 100-, 98-, 96-, and 89% in patients with MV repair (p=0.015). However, by multivariate logistic regression, overall mortality was determined by additional surgery of the tricuspid valve (p=0.0103), multivessel coronary disease (p=0.026), and age (p<0.0001), but not by the type of surgery (p=0.066). Furthermore, the type of surgery did not influence functional outcome (p=0.515). Conclusions: Apart from age and coronary artery disease the need for additional tricuspid valve surgery significantly determines the outcome of non-ischemic MV surgery. The type of operation appears less important when the need for additional valve surgery and co-morbidities like coronary artery disease are taken into consideration. [Copyright &y& Elsevier]

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 < 0.0001). 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. [ABSTRACT FROM AUTHOR]

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; p <0.001) 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 p <0.001). 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, p <0.001) 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. [Copyright &y& Elsevier]

Abstract: Objective: 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. Methods and results: We prospectively enrolled 100 consecutive young survivors of myocardial infarction (MI≤40years 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 (151ng/mL, IQR 38–473ng/mL vs. 233ng/mL, IQR 62–1756; p <0.005) 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 2306–5810pg/mL to 4973, IQR 3293–7093pg/mL (p <0.001). In the stable phase of the disease, Wnt-1 levels were lower (p <0.005) and Dkk-1 levels were significantly higher (p <0.001) 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. Conclusion: 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. [Copyright &y& Elsevier]

Abstract: Introduction: Acute myocardial infarction (AMI) at young age is a rare disease with a poor prognosis. Bone metabolism parameters such as 1,25 (OH)2 vitamin D3, 25 (OH) vitamin D3 and osteocalcin have been recently implicated in the development of coronary heart disease (CHD). We evaluated the role of these serum markers in a study population of very young AMI survivors (≤40years). Methods and results: We prospectively enrolled 302 subjects into our multi-center case control study, including 102 young myocardial infarction patients (≤40years) and 200 control subjects who were frequency-matched on gender and age in an approximate 2:1 ratio per case patient. In the adjusted logistic regression analysis, we used baseline laboratory measurements for the first analysis (acute phase analysis) and measurements from one-year follow-up visits (stable phase analysis). In both, elevated levels of 25 (OH) vitamin D3 (acute phase: OR per IQR 2.02, 95% CI 1.13–3.58, p=0.017; stable phase: OR 4.07, 95% CI 1.8–9.21, p=0.001) and 1,25 (OH)2 vitamin D3 (acute phase: OR 2.82, 95% CI 1.7–4.7, p<0.001; stable phase: OR 4.57, 95% CI 2.31–9.05, p<0.001) were associated with premature AMI. Conversely, osteocalcin was inversely associated with premature myocardial infarction (acute phase: OR 0.53, 95% CI 0.28–1.03, p=0.059; stable phase: OR 0.26, 95% CI 0.12–0.6, p<0.001). The observed associations were independent of the acute phase of myocardial infarction. Conclusion: In our study, elevated levels of 25 (OH) vitamin D3 and 1,25 (OH)2 vitamin D3, as well as decreased levels of osteocalcin were associated with myocardial infarction in very young patients. The precise mechanism and implications of these findings will have to be elucidated in future studies. [Copyright &y& Elsevier]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: 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. Methods: 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. Results: C5a but not C3a increased after implantation of DES (p <0.05). 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. Conclusion: 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. [Copyright &y& Elsevier]

Abstract: Background: 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). Methods: 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. Results: 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 (p<0.05), 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 (p<0.05). CRP was not associated with pre- or postprocedural PAI-1 levels. Conclusion: 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. [Copyright &y& Elsevier]

Abstract: Background: 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. Methods: We measured in 56patients with CAD, 1month 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. Results: Hcy plasma levels inversely correlated with t-PA activity (r =−0.303, p <0.05). Patients with mild hyperhomocysteinemia (Hcy>15μmol/L, n =8) showed significantly lower plasma levels of t-PA activity (p <0.05). Regression analysis revealed that out of cardiovascular risk factors and medical treatment only Hcy was significantly associated with t-PA activity. Conclusions: 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. [Copyright &y& Elsevier]

Abstract: In addition to lipid lowering effects, statins appear to have pleiotropic immunomodulatory properties. As they particularly affect monocyte functions, we tested the influence of statin treatment on the monocyte activating toll-like receptors (TLR) 4 and 2 in response to lipopolysaccharides (LPS) in vivo. In this double-blind, placebo-controlled study, 20 healthy, male subjects were randomized to receive either simvastatin (80mg/day) or placebo for 4 days before intravenous LPS administration (20IU/kg). Simvastatin did not influence the increase in TLR transcripts after LPS administration measured in mRNA isolated from whole blood by quantitative RT-PCR. In contrast, the parallel upregulation of TLR4 and TLR2 on the surface of monocytes determined by flow cytometry was attenuated by more than half after LPS challenge (P <0.02). Suppressed TLR4 and TLR2 expression was associated with diminished circulating concentrations of tumor necrosis factor-α and monocyte chemoattractant protein-1. In conclusion, high-dose simvastatin pretreatment blunted TLR4 and TLR2 expression on monocytes in a human endotoxemia model on a posttranscriptional level. This suppressive effect of statins on key receptors of the innate immunity which was associated with a reduction of effector cytokines reveals a potential mechanism for their beneficial effects in sepsis and cardiovascular disease. [Copyright &y& Elsevier]

Abstract: 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 cm2), 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. [Copyright &y& Elsevier]