Showing papers by "Thomas F. Lüscher published in 2011"

Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Abstract: Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1- and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.

Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6)

Abstract: Aims Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium and calcium channel subunits have been reported. We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit. Methods and results The electrocardiogram of the affected member of a single family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and symmetrical T-waves. Invasive electrophysiological testing showed short ventricular refractory periods and increased vulnerability to induce ventricular fibrillation. DNA screening of the patient identified no mutation in previously known SQTS genes; however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Cavα2δ-1 subunit of the L-type calcium channel. The pathogenic role of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using co-expression of the two other L-type calcium channel subunits, Cav1.2α1 and Cavβ2b, in HEK-293 cells. Barium currents ( I Ba) were recorded in these cells under voltage-clamp conditions using the whole-cell configuration. Co-expression of the p.Ser755Thr Cavα2δ-1 subunit strongly reduced the I Ba by more than 70% when compared with the co-expression of the wild-type (WT) variant. Protein expression of the three subunits was verified by performing western blots of total lysates and cell membrane fractions of HEK-293 cells. The p.Ser755Thr variant of the Cavα2δ-1 subunit was expressed at a similar level compared with the WT subunit in both fractions. Since the mutant Cavα2δ-1 subunit did not modify the expression of the pore-forming subunit of the L-type calcium channel, Cav1.2α1, it suggests that single channel biophysical properties of the L-type channel are altered by this variant. Conclusion In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be determined whether mutations in this gene lead to other manifestations of the J-wave syndrome.

Five-Year Clinical and Angiographic Outcomes of a Randomized Comparison of Sirolimus-Eluting and Paclitaxel-Eluting Stents Results of the Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization LATE Trial

Abstract: Background—Long-term comparative data of first-generation drug-eluting stents are scarce. We investigated clinical and angiographic outcomes of sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) at 5 years as part of the Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) LATE study. Methods and Results—A total of 1012 patients were randomly assigned to SES or PES. Repeat angiography was completed in 444 of 1012 patients (43.8%) at 5 years. Major adverse cardiac events occurred in 19.7% of SES- and 21.4% of PES-treated patients (hazard ratio, 0.89; 95% confidence interval, 0.68 to 1.17; P=0.39) at 5 years. There were no differences between SES and PES in terms of cardiac death (5.8% versus 5.7%; P=0.35), myocardial infarction (6.6% versus 6.9%; P=0.51), and target lesion revascularization (13.1% versus 15.1%; P=0.29). Between 1 and 5 years, the annual rate of target lesion revascularization was 2.0% (95% confidence interval, 1.4% to 2.6%) for SES and 1.4% (9...

SYNTAX score and Clinical SYNTAX score as predictors of very long-term clinical outcomes in patients undergoing percutaneous coronary interventions: a substudy of SIRolimus-eluting stent compared with pacliTAXel-eluting stent for coronary revascularization (SIRTAX) trial

Abstract: Aims To investigate the ability of SYNTAX score and Clinical SYNTAX score (CSS) to predict very long-term outcomes in an all-comers population receiving drug-eluting stents. Methods and results The SYNTAX score was retrospectively calculated in 848 patients enrolled in the SIRolimus-eluting stent compared with pacliTAXel-Eluting Stent for coronary revascularization (SIRTAX) trial. The CSS was calculated using age, and baseline left ventricular ejection fraction and creatinine clearance. A stratified post hoc comparison was performed for all-cause mortality, cardiac death, myocardial infarction (MI), ischaemia-driven target lesion revascularization (TLR), definite stent thrombosis, and major adverse cardiac events (MACE) at 1- and 5-year follow-up. Tertiles for SYNTAX score and CSS were defined as SSLOW ≤7, 7 14 and CSSLOW ≤8.0, 8.0 17.0, respectively. Major adverse cardiac events rates were significantly higher in SSHIGH compared with SSLOW at 1- and 5-year follow-up, which was also seen at 5 years for all-cause mortality, cardiac death, MI, and TLR. Stratifying outcomes across CSS tertiles confirmed and augmented these results. Within CSSHIGH, 5-year MACE increased with use of paclitaxel- compared with sirolimus-eluting stents (34.7 vs. 21.3%, P = 0.008). SYNTAX score and CSS were independent predictors of 5-year MACE; CSS was an independent predictor for 5-year mortality. Areas-under-the-curve for SYNTAX score and CSS for 5-year MACE were 0.61 (0.56–0.65) and 0.62 (0.57–0.67), for 5-year all-cause mortality 0.58 (0.51–0.65) and 0.66 (0.59–0.73) and for 5-year cardiac death 0.63 (0.54–0.72) and 0.72 (0.63–0.81), respectively. Conclusion SYNTAX score and to a greater extent CSS were able to stratify risk for very long-term adverse clinical outcomes in an all-comers population receiving drug-eluting stents. Predictive accuracy for 5-year all-cause mortality was improved using CSS. Trial Registration Number: [NCT00297661][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00297661&atom=%2Fehj%2Fearly%2F2011%2F09%2F27%2Feurheartj.ehr369.atom

Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata.

Abstract: Aims Collagen degradation in atherosclerotic plaques with thin fibrous caps renders them more prone to rupture. Fibroblast activation protein (FAP) plays a role in arthritis and tumour formation through its collagenase activity. However, the significance of FAP in thin-cap human fibroatheromata remains unknown.

Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells.

Abstract: Aims The mammalian silent information regulator-two 1 (Sirt1) blunts the noxious effects of cardiovascular risk factors such as type 2 diabetes mellitus and obesity. Nevertheless, the role of Sirt1 in regulating the expression of tissue factor (TF), the key trigger of coagulation, and arterial thrombus formation remains unknown. Methods and results Human as well as mouse cell lines were used for in vitro experiments, and C57Bl/6 mice for in vivo procedures. Sirt1 inhibition by splitomicin or sirtinol enhanced cytokine-induced endothelial TF protein expression as well as surface activity, while TF pathway inhibitor protein expression did not change. Sirt1 inhibition further enhanced TF mRNA expression, TF promoter activity, and nuclear translocation as well as DNA binding of the p65 subunit of nuclear factor-kappa B (NFκB/p65). Sirt1 siRNA enhanced TF protein and mRNA expression, and this effect was reduced in NFκB/p65−/− mouse embryonic fibroblasts reconstituted with non-acetylatable Lys310-mutant NFκB/p65. Activation of the mitogen-activated protein kinases p38, c-Jun NH2-terminal kinase, and p44/42 (ERK) remained unaffected. In vivo , mice treated with the Sirt1 inhibitor splitomicin exhibited enhanced TF activity in the arterial vessel wall and accelerated carotid artery thrombus formation in a photochemical injury model. Conclusion We provide pharmacological and genetic evidence that Sirt1 inhibition enhances TF expression and activity by increasing NFκB/p65 activation in human endothelial cells. Furthermore, Sirt1 inhibition induces arterial thrombus formation in vivo . Hence, modulation of Sirt1 may offer novel therapeutic options for targeting thrombosis.

Oxidized Low-Density Lipoprotein Activates p66Shc via Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1, Protein Kinase C-β, and c-Jun N-Terminal Kinase Kinase in Human Endothelial Cells

Abstract: Objective— Deletion of the mitochondrial gene p66 Shc protects from endothelial dysfunction and atherosclerotic plaque formation in mice fed a high-fat diet. However, the molecular mechanisms underlying this beneficial effect have not yet been delineated. The present study was designed to elucidate the proatherogenic mechanisms by which p66 Shc mediates oxidized low-density lipoprotein (oxLDL) uptake by the endothelium, a critical step in plaque formation. Methods and Results— Incubation of human aortic endothelial cells with oxLDL led to phosphorylation of p66 Shc at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66 Shc phosphorylation, confirming that this effect is mediated by lectin-like oxLDL receptor-1. OxLDL also increased phosphorylation of protein kinase C β 2 (PKCβ 2 ) at both Thr641 and Ser660, as well as c-Jun N-terminal kinase (JNK). Furthermore, inhibition of PKCβ 2 prevented the activation of JNK, suggesting that PKCβ2 is upstream of JNK. Finally, p66 Shc silencing blunted oxLDL-induced O 2 −. production, underscoring the critical role of p66 Shc in oxLDL-induced oxidative stress in endothelial cells. Conclusion— In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66 Shc . Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66 Shc .

Dietary α-Linolenic Acid Inhibits Arterial Thrombus Formation, Tissue Factor Expression, and Platelet Activation

Abstract: Objective—Plant-derived α-linolenic acid (ALA) may constitute an attractive cardioprotective alternative to fish-derived n-3 fatty acids. However, the effect of dietary ALA on arterial thrombus for...

Acute, Subacute, and Chronic Myocardial Infarction: Quantitative Comparison of 2D and 3D Late Gadolinium Enhancement MR Imaging

Abstract: Single–breath-hold three-dimensional late gadolinium enhancement (LGE) MR imaging enables quantitative evaluation of scar tissue mass and transmurality in patients with acute, subacute, or chronic myocardial infarction at significantly reduced acquisition times compared with two-dimensional LGE MR imaging.

Impact of cardiac hybrid single-photon emission computed tomography/computed tomography imaging on choice of treatment strategy in coronary artery disease

Abstract: Aims Cardiac hybrid imaging by fusing single-photon emission computed tomography (SPECT) myocardial perfusion imaging with coronary computed tomography angiography (CCTA) provides important complementary diagnostic information for coronary artery disease (CAD) assessment. We aimed at assessing the impact of cardiac hybrid imaging on the choice of treatment strategy selection for CAD. Methods and results Three hundred and eighteen consecutive patients underwent a 1 day stress/rest 99mTc-tetrofosmin SPECT and a CCTA on a separate scanner for evaluation of CAD. Patients were divided into one of the following three groups according to findings in the hybrid images obtained by fusing SPECT and CCTA: (i) matched finding of stenosis by CCTA and corresponding reversible SPECT defect; (ii) unmatched CCTA and SPECT finding; (iii) normal finding by both CCTA and SPECT. Follow-up was confined to the first 60 days after hybrid imaging as this allows best to assess treatment strategy decisions including the revascularization procedure triggered by its findings. Hybrid images revealed matched, unmatched, and normal findings in 51, 74, and 193 patients. The revascularization rate within 60 days was 41, 11, and 0% for matched, unmatched, and normal findings, respectively ( P < 0.001 for all inter-group comparisons). Conclusion Cardiac hybrid imaging with SPECT and CCTA provides an added clinical value for decision making with regard to treatment strategy for CAD.

Levels and determinants of inflammatory biomarkers in a Swiss population-based sample (CoLaus study).

Abstract: Objective to assess the levels and determinants of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and C-reactive protein (CRP) in a healthy Caucasian population. Methods population sample of 2884 men and 3201 women aged 35 to 75. IL-1β, IL-6 and TNF-α were assessed by a multiplexed particle-based flow cytometric assay and CRP by an immunometric assay. Results Spearman rank correlations between duplicate cytokine measurements (N = 80) ranged between 0.89 and 0.96; intra-class correlation coefficients ranged between 0.94 and 0.97, indicating good reproducibility. Among the 6085 participants, 2289 (37.6%), 451 (7.4%) and 43 (0.7%) had IL-1β, IL-6 and TNF-α levels below detection limits, respectively. Median (interquartile range) for participants with detectable values were 1.17 (0.48–3.90) pg/ml for IL-1β; 1.47 (0.71–3.53) pg/ml for IL-6; 2.89 (1.82–4.53) pg/ml for TNF-α and 1.3 (0.6–2.7) ng/ml for CRP. On multivariate analysis, greater age was the only factor inversely associated with IL-1β levels. Male sex, increased BMI and smoking were associated with greater IL-6 levels, while no relationship was found for age and leisure-time PA. Male sex, greater age, increased BMI and current smoking were associated with greater TNF-α levels, while no relationship was found with leisure-time PA. CRP levels were positively related to age, BMI and smoking, and inversely to male sex and physical activity. Conclusion Population-based levels of several cytokines were established. Increased age and BMI, and to a lesser degree sex and smoking, significantly and differentially impact cytokine levels, while leisure-time physical activity has little effect.

Electrocardiographic changes in early recognition of Fabry disease

Abstract: Background Fabry disease (FD) is an inherited X-chromosomal lysosomal storage disease resulting in intracellular storage of globotriaosylceramide. Cardiac involvement is most frequently manifested as left ventricular hypertrophy (LVH). However, patients with FD may also have various conduction abnormalities before LVH develops. The present study was designed to analyse early conduction abnormalities on baseline ECG of patients with FD and to investigate their diagnostic value. Methods and results Baseline electrocardiographic (ECG) and echocardiographic measurements of patients with FD (n=30) were compared with those of heart rate and age-matched healthy individuals (n=50). The PQ-interval (131±18 vs 155±20 ms, p peak −T end dispersion: 56±20 vs 37±16 ms, p Conclusions P-wave duration, PQ-interval and QRS width are shorter and repolarisation dispersion more pronounced in patients with FD compared with heart rate and age-matched controls. The significant shortening of the PQ-interval in FD occurs because of a marked shortening of the P-wave duration, which in itself demonstrated a high sensitivity and specificity for early detection and treatment of this disease.

Dietary α-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation.

Abstract: Aims Epidemiological studies report an inverse association between plant-derived dietary α-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. Methods and results Eight-week-old male apolipoprotein E knockout ( ApoE −/−) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-γ, interleukin-4, and tumour necrosis factor α (TNFα) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n −3 long chain fatty acids (LC n −3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFα. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. Conclusion Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n −3 FA.

Cell-based cardiovascular repair and regeneration in acute myocardial infarction and chronic ischemic cardiomyopathy – current status and future developments

Abstract: Ischemic heart disease is the main cause of death and morbidity in most industrialized countries. Stem- and progenitor cell-based treatment approaches for ischemic heart disease are therefore an important frontier in cardiovascular and regenerative medicine. Experimental studies have shown that bone-marrow-derived stem cells and endothelial progenitor cells can improve cardiac function after myocardial infarction, clinical phase I and II studies were rapidly initiated to translate this concept into the clinical setting. However, as of now the effects of stem/progenitor cell administration on cardiac function in the clinical setting have not met expectations. Thus, a better understanding of causes of the current limitations of cell-based therapies is urgently required. Importantly, the number and function of endothelial progenitor cells is reduced in patients with cardiovascular risk factors and/or coronary artery disease. These observations may provide opportunities for an optimization of cell-based treatment approaches. This review provides a summary of current evidence for the role and potential of stem and progenitor cells in the pathophysiology and treatment of ischemic heart disease, including the properties, and repair and regenerative capacities of various stem and progenitor cell populations. In addition, we describe modes of stem/progenitor cell delivery, modulation of their homing as well as potential approaches to “prime” stem/progenitor cells for cardiovascular cell-based therapies.

Transcatheter aortic valve implantation (TAVI) outcome according to standardized endpoint definitions by the Valve Academic Research Consortium (VARC).

Abstract: BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become an accepted treatment option for severe aortic stenosis (AS) in high-risk individuals. Yet, current results are difficult to compare given the lack of standardized definitions. METHODS AND RESULTS: TAVI was performed in 130 high-risk individuals. The Edwards SAPIEN (n = 50) and the Medtronic CoreValve (n = 80) prostheses were implanted by transfemoral (75%) or transapical (25%) access. Outcomes at 30 days and 1 year are reported according to the newly established Valve Academic Research Consortium (VARC) criteria. Median follow-up was 235 days (range, 44-490 days). Thirty-day device success was high (91.5%). Combined safety endpoint at 30 days was 20.8%, with an all-cause mortality of 11.5%. Major vascular complications (11.5%), life-threatening or disabling bleeding (8.5%), and acute kidney injury (6.2%) were further major adverse events. At 1-year follow-up, valve performance was accurate in 94.7% of patients. However, prosthetic-valve associated complications, such as new left bundle branch block (20.0%) or permanent pacemaker implantation (34.7%), were common; cumulative prosthetic-valve associated complications were significantly more frequent in patients treated with a Medtronic CoreValve prosthesis (p = 0.0012). Overall 1-year survival was 80%, with the VARC combined efficacy endpoint (composite of survival, freedom from therapy failure, and accurate valve performance) met in 70.2%. In particular, at 1 year, 68.5% of the patients were living independently at home. CONCLUSION: The newly established VARC standardized definitions are useful for TAVI outcome reporting.

Characteristics and long-term outcome of echocardiographic super-responders to cardiac resynchronisation therapy: ‘real world’ experience from a single tertiary care centre

Abstract: Background The individual benefit from cardiac resynchronisation therapy (CRT) varies largely among patients. Aims To compare different definitions of echocardiographic super-response to CRT regarding their ability to predict the incidence of adverse events. Methods Three definitions of super-response to CRT were evaluated in 110 consecutive patients with CRT implantation: (1) an absolute increase in ejection fraction of ≥10%; (2) a decrease in left ventricular end-systolic volume of ≥30%; and (3) a decrease in left ventricular end-diastolic volume of ≥20%. The primary endpoint was a combination of time to death, heart transplantation, ventricular assist device implantation and hospitalisation for heart failure. Secondary endpoints included time to first appropriate implantable cardioverter defibrillator (ICD) discharge during follow-up. Results All three definitions of super-response were highly predictive of a reduced risk for reaching the primary combined endpoint (3-year estimators: 64%±7% vs 82%±7% for ejection fraction ≥10%; 63%±8% vs 92%±5% for end-systolic volume ≥30%; and 62%±8% vs 94%±4% for end-diastolic volume ≥20%; all p Conclusions All three definitions of super-response are highly predictive for a favourable outcome after CRT. However, even patients with pronounced reverse left ventricular remodelling experience appropriate ICD discharges during follow-up.

Diagnostic accuracy of point-of-care testing for acute coronary syndromes, heart failure and thromboembolic events in primary care: a cluster-randomised controlled trial

Abstract: Evidence of the clinical benefit of 3-in-1 point-of-care testing (POCT) for cardiac troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and D-dimer in cardiovascular risk stratification at primary care level for diagnosing acute coronary syndromes (ACS), heart failure (HF) and thromboembolic events (TE) is very limited. The aim of this study is to analyse the diagnostic accuracy of POCT in primary care. Prospective multicentre controlled trial cluster-randomised to POCT-assisted diagnosis and conventional diagnosis (controls). Men and women presenting in 68 primary care practices in Zurich County (Switzerland) with chest pain or symptoms of dyspnoea or TE were consecutively included after baseline consultation and working diagnosis. A follow-up visit including confirmed diagnosis was performed to determine the accuracy of the working diagnosis, and comparison of working diagnosis accuracy between the two groups. The 218 POCT patients and 151 conventional diagnosis controls were mostly similar in characteristics, symptoms and pre-existing diagnoses, but differed in working diagnosis frequencies. However, the follow-up visit showed no statistical intergroup difference in confirmed diagnosis frequencies. Working diagnoses overall were significantly more correct in the POCT group (75.7% vs 59.6%, p = 0.002), as were the working diagnoses of ACS/HF/TE (69.8% vs 45.2%, p = 0.002). All three biomarker tests showed good sensitivity and specificity. POCT confers substantial benefit in primary care by correctly diagnosing significantly more patients. DRKS: DRKS00000709

Dietary {alpha}-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation

Abstract: Aims Epidemiological studies report an inverse association between plant-derived dietary α-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. Methods and results Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-γ, interleukin-4, and tumour necrosis factor α (TNFα) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n-3 long chain fatty acids (LC n-3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFα. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. Conclusion Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n-3 FA.

Rationale and design of dal-VESSEL: a study to assess the safety and efficacy of dalcetrapib on endothelial function using brachial artery flow-mediated vasodilatation

Abstract: Objective: Dalcetrapib increases high-density lipoprotein cholesterol (HDL-C) levels through effects on cholesteryl ester transfer protein (CETP). As part of the dalcetrapib dal-HEART clinical trial programme, the efficacy and safety of dalcetrapib is assessed in coronary heart disease (CHD) patients in the dal-VESSEL study (ClinicalTrials.gov identifier: NCT00655538), the design and methods of which are presented here.

Anti-aging medicine: Molecular basis for endothelial cell-targeted strategies - A mini-review

Abstract: Due to improvements in lifestyle and healthcare, the proportion of aged people is rising steadily, especially in developed countries. With aging, some physiological functions are altered and resemble those occurring in disease conditions such as hypertension, chronic coronary disease and diabetes. Thus, there is the urge to better understand molecular and cellular mechanisms underlying aging and aging-related diseases. In rodents and possibly primates, calorie restriction is an effective approach to extend lifespan by reducing free radical-induced damage. Increased production of oxygen-derived free radicals plays an important role in the process of aging. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial protein p66(Shc) is considered a longevity assurance gene since its genetic deletion extends the lifespan of rodents and displays protective effects in several models of cardiovascular disease. Silent mating type information regulation 2 homolog 1 Saccharomyces cerevisiae (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that may also be involved in aging and diseases. SIRT1 also deacetylates a number of nonhistone target proteins, including p53, endothelial nitric oxide synthase and forkhead box protein. This review focuses on the latest scientific advances in understanding aging as well as delineates the possible therapeutic implications of p66(Shc) and SIRT1 in this process.

Deletion of L-Selectin Increases Atherosclerosis Development in ApoE−/− Mice

Abstract: Atherosclerosis is an inflammatory disease characterized by accumulation of leukocytes in the arterial intima. Members of the selectin family of adhesion molecules are important mediators of leukocyte extravasation. However, it is unclear whether L-selectin (L-sel) is involved in the pathogenesis of atherosclerosis. In the present study, mice deficient in L-selectin (L-sel(-/-)) animals were crossed with mice lacking Apolipoprotein E (ApoE(-/-)). The development of atherosclerosis was analyzed in double-knockout ApoE/L-sel (ApoE(-/-)L-sel(-/-)) mice and the corresponding ApoE(-/-) controls fed either a normal or a high cholesterol diet (HCD). After 6 weeks of HCD, aortic lesions were increased two-fold in ApoE(-/-)L-sel(-/-) mice as compared to ApoE(-/-) controls (2.46%±0.54% vs 1.28%±0.24% of total aortic area; p<0.05). Formation of atherosclerotic lesions was also enhanced in 6-month-old ApoE(-/-)L-sel(-/-) animals fed a normal diet (10.45%±2.58% vs 1.87%±0.37%; p<0.05). In contrast, after 12 weeks of HCD, there was no difference in atheroma formation between ApoE(-/-)L-sel(-/-) and ApoE(-/-) mice. Serum cholesterol levels remained unchanged by L-sel deletion. Atherosclerotic plaques did not exhibit any differences in cellular composition assessed by immunohistochemistry for CD68, CD3, CD4, and CD8 in ApoE(-/-)L-sel(-/-) as compared to ApoE(-/-) mice. Leukocyte rolling on lesions in the aorta was similar in ApoE(-/-)L-sel(-/-) and ApoE(-/-) animals. ApoE(-/-)L-sel(-/-) mice exhibited reduced size and cellularity of peripheral lymph nodes, increased size of spleen, and increased number of peripheral lymphocytes as compared to ApoE(-/-) controls. These data indicate that L-sel does not promote atherosclerotic lesion formation and suggest that it rather protects from early atherosclerosis.

Arrhythmic Manifestations in Patients With Congenital Left Ventricular Aneurysms and Diverticula

Abstract: Congenital left ventricular aneurysms and diverticula (LVA/Ds) are rare cardiac malformations that can be detected using echocardiography or other imaging techniques. Some of these patients present with ventricular arrhythmias. This study investigated clinical characteristics of patients with congenital LVA/D presenting with arrhythmic manifestations. Over the previous 20 years 250 patients were diagnosed to have congenital LVA/D at our institution. Diagnosis was made using echocardiography after exclusion of coronary artery disease, local cardiac inflammatory processes, traumatic causes, or cardiomyopathies. At initial presentation 32 of the 250 patients (13%, average age 45 years, range 25 to 65, 21 men and 11 women) exhibited arrhythmias. At least 2 LVA/Ds were present in 6 of these patients. LVA/Ds were localized at the posterobasal, apical, anteroseptal, and anterolateral walls in 12, 11, 4, and 5 patients, respectively. The most common complaints at presentation were syncope or presyncope in 18 patients and palpitations in 11 patients. One patient had survived sudden cardiac death. Long-term electrocardiographic recordings showed ventricular tachycardia (VT) or ventricular fibrillation in 17 patients (53%). Twelve patients underwent electrophysiologic testing. Nine patients had inducible ventricular tachyarrhythmia, whereas induced tachycardia was similar to that during spontaneous arrhythmia in 7 patients. In conclusion, patients with congenital LVA/Ds who present with arrhythmic manifestations commonly have VT. Electrophysiologic testing can reproduce clinical VT in most of these patients.

Long-term follow-up of patients with isolated left ventricular noncompaction: role of electrocardiography in predicting poor outcome.

Abstract: Background: Abnormal baseline electrocardiograms (ECGs) are common in patients with isolated left ventricular noncompaction (IVNC). Whether certain electrocardiographic parameters are associated with a poor clinical outcome, however, remains elusive. The present study was therefore designed to comprehensively assess the predictive value of baseline ECG findings in patients newly diagnosed with IVNC. Methods and Results: 74 patients diagnosed with IVNC were included in the analysis. During follow-up, 8 patients (11%) died of a cardiovascular cause or underwent heart transplantation (primary outcome measure). On univariate analysis, several variables, including repolarization abnormalities (ST segment elevation/depression, T-wave inversion) in the inferior leads (5-year estimator: 67.1±10.7% vs. 98±2.2%; P=0.001), an increase in PQ- (hazard ratio (HR) 1.032, P=0.004) and QTc-duration (HR 1.037, P=0.001), were predictive of cardiovascular death or heart transplantation. On multivariate analysis, only PQ- and QTc-duration and the presence of repolarization abnormalities in the inferior leads remained significantly predictive of a poor outcome. Conclusions: PQ duration, QTc duration, and repolarization abnormalities in the inferior leads are independently predictive of a poor prognosis in IVNC. Further prospective studies are required to conclusively investigate the usefulness of baseline ECG parameters for risk stratification in patients with IVNC. (Circ J 2011; 75: 1728-1734)

A novel flow cytometry-based assay to study leukocyte-endothelial cell interactions in vitro.

Abstract: Interactions between peripheral blood mononuclear cells (PBMC) and the endothelium critically determine vascular repair and reparative angiogenesis, but also pathological processes, such as atherosclerosis. Current methodology to study these interactions mostly regards PBMC as a homogenous population or it restricts its focus on individual cell types and therefore does not appreciate the differential behavior of individual PBMC subpopulations, which synergize or antagonize each other to obtain the overall effect. We therefore developed a flow cytometry-based in vitro assay to assess multiple parameters of interaction between several individual populations of PBMC and an endothelial monolayer. Freshly isolated, unlabelled human PBMC were left to adhere to or transmigrate through a monolayer of fluorescence-labeled human aortic endothelial cells grown to confluence on the filter membrane of sterile transwell migration inserts. Monocyte chemoattractant protein-1 (MCP-1) was applied as a chemoattractant to the lower compartment of the migration chamber. After 6 h, transmigrating PBMC were harvested from the lower compartment, while nonadherent and adhering cell populations were harvested from the upper compartment by sequential washing/detachment. All three cell fractions were then individually stained with fluorescence-labeled monoclonal antibodies and analyzed by flow cytometry. Quantification was achieved by the usage of counting beads. Endothelial cells were separated from PBMC during the analysis by a multiparametric gating strategy. Using the newly established assay, we observed distinct migration patterns for inflammatory CD14(hi) CD16(neg) and resident CD16(pos) monocytes. These cell types differed in their basal adhesion and transmigration patterns as well as their responses to the CCR2 ligand MCP-1. This assay allows for the parallel study of interactions between multiple individual leukocyte populations and an endothelial layer. Several readouts can be derived from the same experiment, like the composition of adhering and transmigrating cell fractions or the individual adhesion/migration behavior of several distinct cell types.

Stem cells in cardiovascular regeneration: from preservation of endogenous repair to future cardiovascular therapies.

Abstract: Cardiovascular disease remains the leading cause of morbidity and mortality in the developed countries. This review summarizes current pre-clinical and clinical evidence for the potential role and mechanisms of action of stem and progenitor cells in vascular and cardiac repair and regeneration. Apart from cell transplantation strategies, approaches to maintain stem cell niche function and targeting mobilization/recruitment of specific stem/progenitor cell populations may aid in preserving vascular and cardiac function. Moreover, with the use of patient-derived induced pluripotent stem cells, the field of regenerative medicine is entering a new era. Potential applications of induced pluripotent stem cells and direct reprogrammed cells as well as recent developments in tissue engineering are discussed.

Prognostic value of N-terminal pro-B-type natriuretic peptide in patients with acute coronary syndromes undergoing left main percutaneous coronary intervention.

Abstract: Background: Patients undergoing acute left main (LM) coronary artery revascularization have a high mortality and natriuretic peptides such as N-terminal pro-B-type (NT-proBNP) have been shown to have prognostic value in patients with acute coronary syndromes. The present study looked at the prognostic value of NT-proBNP in these patients. Methods and Results: We studied all consecutive patients undergoing acute LM coronary artery percutaneous coronary intervention between January 2005 and December 2008 in whom NT-proBNP was measured (n=71). We analyzed the clinical characteristics and the short- and long-term outcomes in relation to NT-proBNP level at admission. Median NT-proBNP was 1,364ng/L, ranging from 46 to 70,000ng/L. NT-proBNP was elevated in 63 (89%) patients and was ≥1,000ng/L in 42 (59%). Log NT-proBNP (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.55-7.97, P=0.003) and left ventricular ejection fraction (HR 0.95, 95%CI 0.91-0.99, P=0.007) were predictors for all-cause mortality. Log NT-proBNP was the only independent significant predictor of cardiovascular mortality. In-hospital mortality was 0% for patients with NT-proBNP <1,000, but 17% for those with NT-proBNP ≥1,000 (P=0.036). Conclusions: NT-proBNP is a strong predictor of outcome in patients undergoing acute LM coronary artery stenting. Mortality in such patients is high, but those with NT-proBNP <1,000ng/L may have a favorable short- and long-term prognosis. Further research, including a larger patient population, is needed to determine the optimal cut-off value for NT-proBNP in patients undergoing acute LM coronary artery intervention. (Circ J 2011; 75: 2648-2653)

NT-proBNP Provides Incremental Prognostic Information in Cardiac Outpatients With and Without Echocardiographic Findings

Abstract: Background: Outpatients frequently present with elevated natriuretic peptides in the absence of an obvious cardiac abnormality or with normal natriuretic peptides despite echocardiographic findings. Hypothesis: We aimed to determine the prognostic value of N-terminal pro B-type natriuretic peptide (NTpBNP) in outpatients with normal and abnormal echocardiography. Methods: A total of 433 cardiovascular outpatients were included. The prognostic value of NTpBNP in patients with normal and abnormal echocardiography during a 2-year follow-up was evaluated. Results: Patients with abnormal echocardiography and elevated NTpBNP had a mortality rate of 8.7% and an overall event rate of 20.2% (composite end point of overall mortality, myocardial infarction, and hospitalization for heart failure), which was significantly higher than in patients with abnormal echocardiography and normal NTpBNP, in which no mortality (P = 0.011) and no events were observed (P<0.001). In patients with a normal echocardiography, mortality was 1.5% and 1.8% for patients with normal and elevated NTpBNP, respectively (P = 1.000). Composite event rate was 1.5% and 8.9% (P = 0.093), respectively. Conclusions: Patients with low NTpBNP have an excellent prognosis irrespective of echocardiographic findings. Therefore, determination of NTpBNP appears useful in assessing the clinical relevance of echocardiographic findings. © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. Stefan Toggweiler, MD and Oliver Borst, MD contributed equally to this work.