Publications by authors named "Stephan Winnik"

35 Publications

Differential effect of cardiac resynchronization therapy in patients with diabetes mellitus: a long-term retrospective cohort study.

ESC Heart Fail 2020 10 11;7(5):2773-2783. Epub 2020 Jul 11.

Department of Cardiology, University Heart Center Zurich, Raemistr. 100, Zurich, 8091, Switzerland.

Aims: Cardiac resynchronization therapy (CRT) has become an important therapy in patients with heart failure with reduced left ventricular ejection fraction (LVEF). The effect of diabetes on long-term outcome in these patients is controversial. We assessed the effect of diabetes on long-term outcome in CRT patients and investigated the role of diabetes in ischaemic and non-ischaemic cardiomyopathy.

Methods And Results: All patients undergoing CRT implantation at our institution between November 2000 and January 2015 were enrolled. The study endpoints were (i) a composite of ventricular assist device (VAD) implantation, heart transplantation, or all-cause mortality; and (ii) reverse remodelling (improvement of LVEF ≥ 10% or reduction of left ventricular end-systolic volume ≥ 15%). Median follow-up of the 418 patients (age 64.6 ± 11.6 years, 22.5% female, 25.1% diabetes) was 4.8 years [inter-quartile range: 2.8;7.4]. Diabetic patients had an increased risk to reach the composite endpoint [adjusted hazard ratio (aHR) 1.48 [95% CI 1.12-2.16], P = 0.041]. Other factors associated with an increased risk to reach the composite endpoint were a lower body mass index or baseline LVEF (aHR 0.95 [0.91; 0.98] and 0.97 [0.95; 0.99], P < 0.01 each), and a higher New York Heart Association functional class or creatinine level (aHR 2.14 [1.38; 3.30] and 1.04 [1.01; 1.05], P < 0.05 each). Early response to CRT, defined as LVEF improvement ≥ 10%, was associated with a lower risk to reach the composite endpoint (aHR 0.60 [0.40; 0.89], P = 0.011). Reverse remodelling did not differ between diabetic and non-diabetic patients with respect to LVEF improvement ≥ 10% (aHR 0.60 [0.32; 1.14], P = 0.118). However, diabetes was associated with decreased reverse remodelling with respect to a reduction of left ventricular end-systolic volume ≥ 15% (aHR 0.45 [0.21; 0.97], P = 0.043). In patients with ischaemic cardiomyopathy, survival rates were not significantly different between diabetic and non-diabetic patients (HR 1.28 [0.83-1.97], P = 0.101), whereas in patients with non-ischaemic cardiomyopathy, diabetic patients had a higher risk of reaching the composite endpoint (HR 1.65 [1.06-2.58], P = 0.027). The latter effect was dependent on other risk factors (aHR 1.47 [0.83-2.61], P = 0.451). The risk of insulin-dependent patients was not significantly higher than in patients under oral antidiabetic drugs (HR 1.55 [95% CI 0.92-2.61], P = 0.102).

Conclusions: Long-term follow-up revealed diabetes mellitus as independent risk factor for all-cause mortality, heart transplantation, or VAD in heart failure patients undergoing CRT. The detrimental effect of diabetes appeared to weigh heavier in patients with non-ischaemic compared with ischaemic cardiomyopathy.
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http://dx.doi.org/10.1002/ehf2.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524059PMC
October 2020

Long-term follow-up after cardiac resynchronization therapy-optimization in a real-world setting: A single-center cohort study.

Cardiol J 2020 Jan 21. Epub 2020 Jan 21.

University Heart Center Zurich, Raemistr. 100, 8091 Zurich, Switzerland.

Background: Suboptimal device programming is among the reasons for reduced response to cardiac resynchronization therapy (CRT). However, whether systematic optimization is beneficial remains unclear, particularly late after CRT implantation. The aim of this single-center cohort study was to assess the effect of systematic atrioventricular delay (AVD) optimization on echocardiographic and device parameters.

Methods: Patients undergoing CRT optimization at the University Hospital Zurich between March 2011 and January 2013, for whom a follow-up was available, were included. AVD optimization was based on 12-lead electrocardiography (ECG) and echocardiographic left ventricular inflow characteristics. Parameters were assessed at the time of CRT optimization and follow-up, and were compared between patients with AVD optimization (intervention group) and those for whom no AVD optimization was deemed necessary (control group).

Results: Eighty-one patients with a mean age of 64 ± 11 years were included in the analysis. In 73% of patients, AVD was deemed suboptimal and was changed accordingly. After a median follow-up time of 10.4 (IQR 6.2 to 13.2) months, the proportion of patients with sufficient biventricular pacing (> 97% pacing) was greater in the intervention group (78%) compared to controls (50%). Furthermore, AVD adaptation was associated with an improvement in interventricular mechanical delay (decrease of 6.6 ± 26.2 ms vs. increase of 4.3 ± 17.7 ms, p = 0.034) and intraventricular septal-to-lateral delay (decrease of 0.9 ± 48.1 ms vs. increase of 15.9 ± 15.7 ms, p = 0.038), as assessed by tissue Doppler imaging. Accordingly, a reduction was observed in mitral regurgitation along with a trend towards reduced left ventricular volumes.

Conclusions: In this "real-world" setting systematic AVD optimization was associated with beneficial effects regarding biventricular pacing and left ventricular remodeling. These data show that AVD optimization may be advantageous in selected CRT patients.
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http://dx.doi.org/10.5603/CJ.a2020.0004DOI Listing
January 2020

Pulsatile arterial blood pressure mimicking aortic valve opening during continuous-flow LVAD support: a case report.

J Cardiothorac Surg 2019 Dec 18;14(1):219. Epub 2019 Dec 18.

University Heart Center Zurich, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

Background: Left ventricular assist devices (LVAD) have become a common treatment option in advanced heart failure. Lack of aortic valve opening during left ventricular unloading is a common complication and associated with a worse outcome. Maintaining a minimum pulse pressure is an important goal during the early postoperative period after LVAD implantation since it is commonly seen as secure sign of aortic valve opening.

Aims/objective: We report a case of an LVAD-supported patient with early permanent closure of the aortic valve despite a pulse pressure > 15 mmHg at all times following LVAD implantation. We demonstrate how careful assessment of the invasive arterial blood pressure curve can indicate aortic valve closure irrespective of pulsatile blood flow.

Method: A 69-year old male patient with terminal ischemic cardiomyopathy was referred for long-term mechanical circulatory support. Due to mild aortic regurgitation both an aortic bioprosthesis and a continuous-flow left ventricular assist device were implanted. Postoperative echocardiography documented a patent aortic bioprosthesis and an acceptable residual systolic left ventricular contractility. During invasive arterial blood pressure monitoring repetitive transient slight blood pressure decreases followed by slight blood pressure increases coincided with programmed LVAD flushing cycles. Permanent pulsatile flow with a pulse pressure of ≥15 mmHg conveyed systolic opening of the aortic valve. Echocardiography, however, proved early permanent aortic valve closure. In retrospect, transformation of the automated LVAD flushing cycles into visible changes of the arterial blood pressure curve during invasive blood pressure monitoring is indicative of ejection of the complete cardiac output through LVAD itself, and therefore an early clinical sign of aortic valve closure.

Discussion/conclusion: We present this interesting didactic case to highlight caveats during the early postoperative period after LVAD implantation. Moreover, this case demonstrates that careful and differentiated observation of the arterial blood pressure waveform provides crucial information in this unique and growing patient population of continuous-flow LVAD support.
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http://dx.doi.org/10.1186/s13019-019-1039-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921524PMC
December 2019

Right Ventricular Failure: Pathophysiology, Diagnosis and Treatment.

Card Fail Rev 2019 Nov 4;5(3):140-146. Epub 2019 Nov 4.

Department of Cardiology, University Hospital Zurich Zurich, Switzerland.

The prognostic significance of the right ventricle (RV) has recently been recognised in several conditions, primarily those involving the left ventricle, the lungs and their vascular bed, or the right-sided chambers. Recent advances in imaging techniques have created new opportunities to study RV anatomy, physiology and pathophysiology, and contemporary research efforts have opened the doors to new treatment possibilities. Nevertheless, the treatment of RV failure remains challenging. Optimal management should consider the anatomical and physiological particularities of the RV and include appropriate imaging techniques to understand the underlying pathophysiological mechanisms. Treatment should include rapid optimisation of volume status, restoration of perfusion pressure and improvement of myocardial contractility and rhythm, and, in case of refractory RV failure, mechanical circulatory support.
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http://dx.doi.org/10.15420/cfr.2019.15.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848943PMC
November 2019

The effect of oxygen in Sirt3-mediated myocardial protection: a proof-of-concept study in cultured cardiomyoblasts.

J Thromb Thrombolysis 2018 Jul;46(1):102-112

Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Ramistr. 100, 8098, Zurich, Switzerland.

Sirtuin 3 is a nicotinamide adenine dinucleotide dependent mitochondrial deacetylase that governs mitochondrial metabolism and oxidative defense. The demise in myocardial function following myocardial ischemia has been associated with mitochondrial dysfunction. Sirt3 maintains myocardial contractile function and protects from cardiac hypertrophy. The role of Sirt3 in ischemia is controversial. Our objective was to understand, under what circumstances Sirt3 is protective in different facets of ischemia, using an in vitro proof-of-concept approach based on simulated ischemia in cultured cardiomyoblasts. Cultured H9c2 cardiomyoblasts were subjected to hypoxia and/or serum deprivation, the combination of which we refer to as simulated ischemia. Apoptosis, as assessed by Annexin V staining in life-cell imaging and propidium-iodide inclusion in flow cytometry, was enhanced following simulated ischemia. Interestingly, serum deprivation was a stronger trigger of apoptosis than hypoxia. Knockdown of Sirt3 further increased apoptosis upon serum deprivation, whereas no such effect occurred upon additional hypoxia. Similarly, only upon serum deprivation but not upon simulated ischemia, silencing of Sirt3 led to a deterioration of mitochondrial function in extracellular flux analysis. In the absence of oxygen these Sirt3-dependent effects were abolished. These data indicate, that Sirt3-mediated myocardial protection is oxygen-dependent. Thus, mitochondrial respiration takes center-stage in Sirt3-dependent prevention of stress-induced myocardial damage.
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http://dx.doi.org/10.1007/s11239-018-1677-3DOI Listing
July 2018

Usefulness of a clinical risk score to predict the response to cardiac resynchronization therapy.

Int J Cardiol 2018 06;260:82-87

Clinique Pasteur, Toulouse, France.

Background: Almost 1/3 of heart failure patients fail to respond to cardiac resynchronization therapy (CRT). A simple clinical score to predict who these patients are at the moment of referral or at time of implant may be of importance for early optimization of their management.

Methods: Observational study. A risk score was derived from factors associated to CRT response. The derivation cohort was composed of 1301 patients implanted with a CRT defibrillator in a multi-center French cohort-study. External validation of this score and assessment of its association with CRT response and all-cause mortality and/or heart transplant was performed in 1959 CRT patients implanted in 4 high-volume European centers.

Results: Independent predictors of CRT response in the derivation cohort were: female gender (OR = 2.08, 95% CI 1.26-3.45), NYHA class ≤ III (OR = 2.71, 95% CI 1.63-4.52), left ventricular ejection fraction ≥ 25% (OR = 1.75, 95% CI 1.27-2.41), QRS duration ≥ 150 ms (OR = 1.70, 95% CI 1.25-2.30) and estimated glomerular filtration rate ≥ 60 mL/min (OR = 2.01, 95% CI 1.48-2.72). Each was assigned 1 point. External validation showed good calibration (Hosmer-Lemeshow test-P = 0.95), accuracy (Brier score = 0.19) and discrimination (c-statistic = 0.67), with CRT response increasing progressively from 37.5% in patients with a score of 0 to 91.9% among those with score of 5 (Gamma for trend = 0.44, P < 0.001). Similar results were observed regarding all-cause mortality or heart transplant.

Conclusion: The ScREEN score (Sex category, Renal function, ECG/QRS width, Ejection fraction and NYHA class) is composed of widely validated, easy to obtain predictors of CRT response, and predicts CRT response and overall mortality. It should be helpful in facilitating early consideration of alternative therapies for predicted non-responders to CRT therapy.
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http://dx.doi.org/10.1016/j.ijcard.2018.02.012DOI Listing
June 2018

Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity.

Cardiovasc Res 2018 07;114(8):1178-1188

Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.

Aims: Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI).

Methods And Results: Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3-/- mice (n = 6) was reduced by half compared to Sirt3+/+ wild-type (n = 8, P < 0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry revealed accelerated clot formation and increased clot stability in Sirt3-/- compared to wild-type blood. rotational thromboelastometry of cell-depleted plasma showed accelerated clotting initiation in Sirt3-/- mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap formation was increased in Sirt3-/- bone marrow-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3-/- mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in bone marrow -derived Sirt3-/- neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, P < 0.01).

Conclusions: Sirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of neutrophil extracellular traps and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.
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http://dx.doi.org/10.1093/cvr/cvy036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014146PMC
July 2018

SAVE-AMD: Safety of VEGF Inhibitors in Age-Related Macular Degeneration.

Ophthalmologica 2017 2;238(4):205-216. Epub 2017 Sep 2.

Department of Ophthalmology, City Hospital Triemli Zurich, Zurich, Switzerland.

Objective: To determine whether intraocular treatment with vascular endothelial growth factor (VEGF) inhibitors change systemic endothelial function (EF) in patients with neovascular age-related macular degeneration (AMD).

Methods: In this prospective, randomized, 2-center, double-masked controlled interventional trial, patients with neovascular and dry AMD were enrolled. Eligible neovascular AMD patients received 2 intravitreal loading doses of either ranibizumab 0.5 mg or bevacizumab 1.25 mg at 4-week intervals and were subsequently followed every 4 weeks and treated according to a pro re nata regime for up to 1 year. Patients with dry AMD served as controls. The primary endpoint was the change in EF assessed by flow-mediated dilatation (FMD) after 2 months of treatment with VEGF inhibitors in patients with AMD compared to patients with dry AMD. FMD was assessed with B-mode high-resolution ultrasonography of the left brachial artery.

Results: 24 patients with neovascular AMD and 26 patients with dry ADM were included in the trial. Treatment with VEGF inhibitors did not significantly change FMD (from 4.7 ± 2.4 to 3.9 ± 1.9% after 8 weeks, p = 0.07, and to 5.1 ± 2.0% after 1 year; p = 0.93 vs. baseline, respectively).

Conclusions: EF did not significantly differ between patients with neovascular AMD treated with intravitreal VEGF inhibition and patients with dry AMD.
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http://dx.doi.org/10.1159/000478665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804860PMC
November 2017

"Real world" experience in Cardiac Resynchronization Therapy at a Swiss Tertiary Care Center.

Swiss Med Wkly 2017 18;147:w14425. Epub 2017 Apr 18.

University Heart Center Zurich.

Background: Based on a reduction in morbidity and mortality, cardiac resynchronisation therapy (CRT) has evolved as a standard therapy for patients with advanced heart failure.

Objective: To provide insight into patient demographics, safety, echocardiographic remodelling and long-term follow-up of patients treated with CRT in a "real-world" setting at a Swiss tertiary care centre.

Methods: Patients implanted with a CRT device at the University Heart Centre Zurich between 2000 and 2015 were consecutively enrolled. Initial clinical and echocardiographic therapy response as well as long-term follow-up for mortality (defined as all-cause death, heart transplantation or ventricular assist device implantation) and hospitalisation for heart failure were assessed.

Results: A total of 418 patients with a median age of 66 years at the time of CRT implantation (78% male) were enrolled. Serious peri-interventional complications (from the time of implantation up to 14 days thereafter) were rare and included systemic infections in 2.4%, pneumothorax in 3.3% and haematoma requiring revision in 2.2% of cases. Overall, the Kaplan-Meier estimate for 5-year freedom from the composite endpoint (hospitalisation for heart failure or mortality) was 55.8%; the Kaplan-Meier estimate for 5-year freedom from mortality was 64.1%. CRT was associated with a significant symptomatic improvement and left ventricular reverse remodelling. Overall, 3.9% of patients did not respond to cardiac resynchronisation therapy (decline in left ventricular ejection fraction [LVEF] >5%), whereas 35.1% experienced neither a continued decline nor a relevant improvement of LVEF (±5%). In the remaining 61% of patients we observed an improvement in LVEF of more than 5%. Forty percent and 31% of patients were super responders, defined as an absolute LVEF improvement of 10% and by a relative reduction of left ventricular end-diastolic volume index by 20% or more. Super-response to CRT was associated with a significant benefit in terms of survival and rehospitalisation rates.

Conclusion: Our data are consistent with large multicentre trials and indicate that CRT is similarly effective in a real-world setting in Switzerland.
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http://dx.doi.org/10.4414/smw.2017.14425DOI Listing
October 2017

Successful Cryoablation of an Anteroseptal Accessory Pathway Guided by Electroanatomical Activation Mapping.

J Invasive Cardiol 2016 Dec;28(12):E227

Arrhythmia and Electrophysiology Division, University Heart Center, 8091, Zurich, Switzerland.

The use of electroanatomical mapping can facilitate the identification of the ideal cryoablation site by providing a three-dimensional map of the earliest activation site. Combined use of the cryoablation technology with electroanatomical mapping can further increase the precision and safety of the procedure by applying test applications at a lower energy level.
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December 2016

Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2.

Basic Res Cardiol 2016 May 12;111(3):33. Epub 2016 Apr 12.

Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Raemistr. 100, 8091, Zurich, Switzerland.

Sirtuin 3 (Sirt3) is an NAD(+)-dependent mitochondrial deacetylase associated with superoxide dismutase 2 (SOD2)-mediated protection from oxidative stress. We have reported accelerated weight gain and impaired metabolic flexibility in atherosclerotic Sirt3 (-/-) mice. Oxidative stress is a hallmark of endothelial dysfunction. Yet, the role of Sirt3 in this context remains unknown. Thus, we aimed to unravel the effects of endogenous Sirt3 on endothelial function and oxidative stress. Knockdown of Sirt3 in human aortic endothelial cells (HAEC) increased intracellular mitochondrial superoxide accumulation, as assessed by electron spin resonance spectroscopy and fluorescence imaging. Endothelium-dependent relaxation of aortic rings from Sirt3 (-/-) mice exposed to a normal diet did not differ from wild-type controls. However, following 12 weeks of high-cholesterol diet and increasing oxidative stress, endothelial function of Sirt3 (-/-) mice was mildly impaired compared with wild-type controls. Relaxation was restored upon enhanced superoxide scavenging using pegylated superoxide dismutase. Knockdown of Sirt3 in cultured HAEC diminished SOD2 specific activity, which was compensated for by a CCAAT/enhancer binding protein beta (C/EBP-β)-dependent transcriptional induction of SOD2. Abrogation of this feedback regulation by simultaneous knockdown of C/EBP-β and Sirt3 exacerbated mitochondrial superoxide accumulation and culminated into endothelial cell death upon prolonged culture. Taken together, Sirt3 deficiency induces a mild, superoxide-dependent endothelial dysfunction in mice fed a high-cholesterol diet. In cultured endothelial cells, a novel C/EBP-β-dependent rescue mechanism maintains net SOD2 activity upon transient knockdown of Sirt3.
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http://dx.doi.org/10.1007/s00395-016-0552-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829622PMC
May 2016

Brain-derived neurotrophic factor Val66Met polymorphism in depression and thrombosis: SIRT1 as a possible mediator.

Eur Heart J 2017 05;38(18):1436-1438

Center for Molecular Cardiology, University of Zurich and University Heart Center Zurich, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehv692DOI Listing
May 2017

AV Block on Exertion: Pulmonary Sarcoidosis with Involvement of the His-Purkinje System.

Am J Med 2015 Dec 17;128(12):e31-3. Epub 2015 Aug 17.

Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1016/j.amjmed.2015.07.026DOI Listing
December 2015

Protective effects of sirtuins in cardiovascular diseases: from bench to bedside.

Eur Heart J 2015 Dec 25;36(48):3404-12. Epub 2015 Jun 25.

Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

Sirtuins (Sirt1-Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD(+))-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation-all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7. Most is known about Sirt1. This deacetylase protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction. Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia. Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy. Sirt7 plays a role in lipid metabolism and cardiomyopathies. Most of these data were derived from experimental findings in genetically modified mice, where NFκB, Pcsk9, low-density lipoprotein-receptor, PPARγ, superoxide dismutase 2, poly[adenosine diphosphate-ribose] polymerase 1, and endothelial nitric oxide synthase were identified among others as crucial molecular targets and/or partners of sirtuins. Of note, there is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity. Given the availability of specific Sirt1 activators or pan-sirtuin activators that boost levels of the sirtuin cofactor NAD⁺, we anticipate that this field will move quickly from bench to bedside.
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http://dx.doi.org/10.1093/eurheartj/ehv290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685177PMC
December 2015

The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.

Eur Heart J 2015 Jan 6;36(1):51-9. Epub 2014 Mar 6.

Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

Aims: The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture.

Methods And Results: Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis.

Conclusion: We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis.
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http://dx.doi.org/10.1093/eurheartj/ehu095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286317PMC
January 2015

Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development.

Basic Res Cardiol 2014 Jan 27;109(1):399. Epub 2013 Dec 27.

Division of Cardiology, Department of Medicine, University Hospital Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland,

Sirt3 is a mitochondrial NAD(+)-dependent deacetylase that governs mitochondrial metabolism and reactive oxygen species homeostasis. Sirt3 deficiency has been reported to accelerate the development of the metabolic syndrome. However, the role of Sirt3 in atherosclerosis remains enigmatic. We aimed to investigate whether Sirt3 deficiency affects atherosclerosis, plaque vulnerability, and metabolic homeostasis. Low-density lipoprotein receptor knockout (LDLR(-/-)) and LDLR/Sirt3 double-knockout (Sirt3(-/-)LDLR(-/-)) mice were fed a high-cholesterol diet (1.25 % w/w) for 12 weeks. Atherosclerosis was assessed en face in thoraco-abdominal aortae and in cross sections of aortic roots. Sirt3 deletion led to hepatic mitochondrial protein hyperacetylation. Unexpectedly, though plasma malondialdehyde levels were elevated in Sirt3-deficient mice, Sirt3 deletion affected neither plaque burden nor features of plaque vulnerability (i.e., fibrous cap thickness and necrotic core diameter). Likewise, plaque macrophage and T cell infiltration as well as endothelial activation remained unaltered. Electron microscopy of aortic walls revealed no difference in mitochondrial microarchitecture between both groups. Interestingly, loss of Sirt3 was associated with accelerated weight gain and an impaired capacity to cope with rapid changes in nutrient supply as assessed by indirect calorimetry. Serum lipid levels and glucose tolerance were unaffected by Sirt3 deletion in LDLR(-/-) mice. Sirt3 deficiency does not affect atherosclerosis in LDLR(-/-) mice. However, Sirt3 controls systemic levels of oxidative stress, limits expedited weight gain, and allows rapid metabolic adaptation. Thus, Sirt3 may contribute to postponing cardiovascular risk factor development.
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http://dx.doi.org/10.1007/s00395-013-0399-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898152PMC
January 2014

The wealth of nations and the dissemination of cardiovascular research.

Int J Cardiol 2013 Nov 10;169(3):190-5. Epub 2013 Sep 10.

University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland; Department of Medicine, GZO Spital Wetzikon, Switzerland. Electronic address:

Background: This study aimed at understanding whether investigators from less wealthy countries were at a disadvantage in disseminating their research, after accounting for potential differences in research quality and infrastructure.

Methods And Results: In this bibliometric analysis a representative random selection of 10% (n=1002 studies) of all abstracts submitted to the European Society of Cardiology (ESC) congress 2006 was followed for publication and citation from September 2006 to December 2011. The main variable of interest was the per-capita gross domestic product (GDP) of the country of the principal investigator. Using multivariable models that adjusted for socioeconomic indicators and previously identified markers of research quality, we examined the relationship between per-capita GDP and three study endpoints: Acceptance at the ESC congress, full-text publication, and number of two-year citations. Among 1002 abstracts from 63 countries, per-capita GDP was positively correlated with all three study endpoints. After adjusting for markers of research quality and infrastructure, per-capita GDP remained a strong predictor for acceptance at the ESC congress (adjusted OR for every 10,000 USD increase in per-capita GDP, 1.44; 95% CI, 1.15 to 1.80), full-text publication within 5years (adjusted OR, 1.49; 95% CI, 1.17 to 1.90), and high citation frequency (adjusted OR, 2.30; 95% CI, 1.31 to 4.04). These findings were largely consistent in a subgroup of abstracts of high-quality, prospective clinical trials.

Conclusion: Investigators in less wealthy countries face challenges to disseminate their research, even after accounting for potential differences in the quality of their work and research infrastructure.
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http://dx.doi.org/10.1016/j.ijcard.2013.08.101DOI Listing
November 2013

Multimodal imaging in rats reveals impaired neurovascular coupling in sustained hypertension.

Stroke 2013 Jul 4;44(7):1957-64. Epub 2013 Jun 4.

Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.

Background And Purpose: Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown.

Methods: Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertension-induced impairments.

Results: Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20- and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo- and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension.

Conclusions: Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension.
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http://dx.doi.org/10.1161/STROKEAHA.111.000185DOI Listing
July 2013

[Exacerbation of chronic lower back pain with an unexpected twist].

Praxis (Bern 1994) 2013 Jun;102(12):747-50

Medizinische Klinik, GZO Spital Wetzikon.

We report a case of an 88-year old male patient with known chronic lower back pain who presented in late August with progressive pain in his right knee and lower leg as well as paraesthesias. Diagnostic work-up revealed an acute Lyme-Borreliosis.
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http://dx.doi.org/10.1024/1661-8157/a001311DOI Listing
June 2013

Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.

Eur Heart J 2013 Dec 17;34(45):3515-24. Epub 2013 Apr 17.

Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

Aims: Aldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis.

Methods And Results: C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR.

Conclusion: Obesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.
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http://dx.doi.org/10.1093/eurheartj/eht095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844149PMC
December 2013

Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis--implications for cardiovascular safety.

Int J Cardiol 2013 Oct 2;168(3):2453-61. Epub 2013 Apr 2.

Division of Cardiology, University Hospital Zurich, Zurich, Switzerland; Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.

Objectives: This study sought to examine the effects and underlying mechanisms of systemic VEGF inhibition in experimental atherosclerosis and aortic endothelial cells.

Background: Pharmacological inhibition of vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, has become a widely applied treatment of certain cancers and multiple ocular diseases including age-related macular degeneration. However, recent clinical trials raise concern for systemic vascular adverse effects, prompting the Food and Drug Administration to revoke the approval of bevacizumab for metastatic breast cancer.

Methods: Eight-week old apolipoprotein E knockout mice received a high-cholesterol diet (1.25% cholesterol) for 24 weeks and were exposed to a systemic pan-VEGF receptor inhibitor (PTK787/ZK222584, 50mg/kg/d) or placebo (gavage) for the last 10 weeks. Atherosclerotic lesions were characterized in thoraco-abdominal aortae and aortic arches. Mechanistic analyses were performed in cultured human aortic endothelial cells.

Results: Systemic VEGF inhibition increased atherosclerotic lesions by 33% whereas features of plaque vulnerability (i.e. necrotic core size, fibrous cap thickness) remained unchanged compared with controls. Aortic eNOS expression was decreased (trend). In human endothelial cells VEGF inhibition induced a dose-dependent increase in mitochondrial superoxide generation with an uncoupling of eNOS, resulting in reduced NO availability and decreased proliferation.

Conclusion: Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. Cardiovascular safety profiles of currently applied anti-angiogenic regimens should be determined to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk.
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http://dx.doi.org/10.1016/j.ijcard.2013.03.010DOI Listing
October 2013

Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2.

Immunity 2013 Apr 7;38(4):754-68. Epub 2013 Mar 7.

Cardiovascular Center, Cardiology, University Hospital Zurich and Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.

Endothelial injury and dysfunction (ED) represent a link between cardiovascular risk factors promoting hypertension and atherosclerosis, the leading cause of death in Western populations. High-density lipoprotein (HDL) is considered antiatherogenic and known to prevent ED. Using HDL from children and adults with chronic kidney dysfunction (HDL(CKD)), a population with high cardiovascular risk, we have demonstrated that HDL(CKD) in contrast to HDL(Healthy) promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDL(CKD) that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDL(CKD) reduced endothelial NO availability via toll-like receptor-2 (TLR-2), leading to impaired endothelial repair, increased proinflammatory activation, and ABP. These data demonstrate how SDMA can modify the HDL particle to mimic a damage-associated molecular pattern that activates TLR-2 via a TLR-1- or TLR-6-coreceptor-independent pathway, linking abnormal HDL to innate immunity, ED, and hypertension.
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http://dx.doi.org/10.1016/j.immuni.2013.02.009DOI Listing
April 2013

SIRT1 - an anti-inflammatory pathway at the crossroads between metabolic disease and atherosclerosis.

Curr Vasc Pharmacol 2012 Nov;10(6):693-6

Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

Atherosclerosis is a chronic inflammatory disease that is based on the interaction between inflammatory cell subsets and specific cells in the arterial wall. SIRT1 deacetylates histone and non-histone proteins and has been implicated in protective effects of caloric restriction on lifespan and metabolic pathways in yeast, nematodes, and mice. In the vasculature of rodents, SIRT1 mediates vasodilatation through the release of endothelial nitric oxide synthase-derived nitric oxide and scavenges reactive oxygen species. Using a genetic loss-of-function approach, SIRT1 has been shown to interfere with crucial steps of endothelial activation and atherogenesis by suppressing NFκB signaling: Partial SIRT1 deletion in ApoE-/- mice prevented expression of endothelial adhesion molecules thereby hampering the extravasation of circulating monocytes. In monocyte-derived macrophages SIRT1 deletion reduced the expression of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1) resulting in reduced foam cell formation and atherosclerosis. Moreover, it was reported that SIRT1 regulates the activity of liver X-receptor, thereby promoting ABCA1-driven reverse cholesterol transport in plaque-resident macrophages slowing foam cell formation. Finally, SIRT1 suppressed the expression of endothelial tissue factor, and thus exerted anti-thrombotic properties during induced carotid thrombosis in mice. These findings indicate protective effects of SIRT1 in atherogenesis and thrombosis at an experimental level and highlight the opportunity to translate this concept from bench to bedside. Indeed, SIRT1 activators are available and have been shown to exert beneficial effects at the preclinical level in obesity and type 2 diabetes mellitus (T2DM). SIRT1 activators are currently being evaluated in phase II clinical trials in patients with T2DM. The concept of SIRT1 activation appears a promising strategy for novel therapeutic approaches in patients with atherothrombosis.
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http://dx.doi.org/10.2174/157016112803520756DOI Listing
November 2012

From abstract to impact in cardiovascular research: factors predicting publication and citation.

Eur Heart J 2012 Dec 5;33(24):3034-45. Epub 2012 Jun 5.

Division of Cardiology, Department of Medicine, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.

Aims: Through a 4-year follow-up of the abstracts submitted to the European Society of Cardiology Congress in 2006, we aimed at identifying factors predicting high-quality research, appraising the quality of the peer review and editorial processes, and thereby revealing potential ways to improve future research, peer review, and editorial work. METHODS AND RESULTS All abstracts submitted in 2006 were assessed for acceptance, presentation format, and average reviewer rating. Accepted and rejected studies were followed for 4 years. Multivariate regression analyses of a representative selection of 10% of all abstracts (n= 1002) were performed to identify factors predicting acceptance, subsequent publication, and citation. A total of 10 020 abstracts were submitted, 3104 (31%) were accepted for poster, and 701 (7%) for oral presentation. At Congress level, basic research, a patient number ≥ 100, and prospective study design were identified as independent predictors of acceptance. These factors differed from those predicting full-text publication, which included academic affiliation. The single parameter predicting frequent citation was study design with randomized controlled trials reaching the highest citation rates. The publication rate of accepted studies was 38%, whereas only 24% of rejected studies were published. Among published studies, those accepted at the Congress received higher citation rates than rejected ones.

Conclusions: Research of high quality was determined by study design and largely identified at Congress level through blinded peer review. The scientometric follow-up revealed a marked disparity between predictors of full-text publication and those predicting citation or acceptance at the Congress.
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http://dx.doi.org/10.1093/eurheartj/ehs113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530902PMC
December 2012

Lack of association between connexin40 polymorphisms and coronary artery disease.

Atherosclerosis 2012 May 8;222(1):148-53. Epub 2012 Feb 8.

Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland.

Objective: Cx40 is a gap junction protein important for cell-cell communication in the endothelium. Polymorphisms in the promoter region of the human Cx40 gene, -44G>A and +71A>G, were shown to reduce Cx40 transcription by half. As mice with an endothelial-specific deletion of Cx40 are more susceptible to atherosclerosis, this study was designed to discover a correlation between these polymorphisms and atherosclerosis in European populations.

Methods And Results: 803 patients referred to the Geneva University Hospitals for elective coronary angiography were divided according to the number of significantly stenosed vessels (from 0 to 3) and were genotyped for the Cx40 polymorphisms. Genotype distribution in the control group was -44GG/+71AA=59.8%, -44AG/+71AG=35.1% and -44AA/+71GG=5.2%. Surprisingly, this distribution was similar in the CAD group, with -44GG/+71AA=58.5%, -44AG/+71AG=37.6% and -44AA/+71GG=3.8% (p=0.67). Moreover, no significant association between histological carotid plaque composition of culprit lesions and Cx40 polymorphisms could be detected in 583 Dutch patients of the Athero-Express study.

Conclusions: Despite a clear antiatherogenic role of Cx40 in mice, our study could not detect an association of Cx40 promoter polymorphisms and CAD in human. Moreover, a correlation with atherosclerotic plaque stability or hypertension could not be demonstrated either. Connexin polymorphisms affecting channel function may be of greater importance for cardiovascular disease than polymorphisms affecting the expression level of the protein.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.01.050DOI Listing
May 2012

Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study.

Eur Heart J 2012 Jul 11;33(13):1589-97. Epub 2012 Jan 11.

Cardiovascular Center Cardiology, University Hospital Zürich, Rämistrasse 100, Zürich, Switzerland.

Aims: Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive.

Methods And Results: Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 (P < 0.0001), while no change was observed with placebo (5.4 ± 2.4 to 4.7 ± 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F(2t)-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo.

Conclusion: This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.
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http://dx.doi.org/10.1093/eurheartj/ehr482DOI Listing
July 2012

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

Eur Heart J 2011 Nov 2;32(21):2713-22. Epub 2011 Feb 2.

Cardiovascular Research, Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

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.

Methods And Results: We detected enhanced FAP expression in type IV-V human aortic atheromata (n = 12), compared with type II-III lesions (n = 9; P < 0.01) and healthy aortae (n = 8; P < 0.01) by immunostaining and western blot analyses. Fibroblast activation protein was also increased in thin-cap (<65 µm) vs. thick-cap (≥ 65 µm) human coronary fibroatheromata (n = 12; P < 0.01). Fibroblast activation protein was expressed by human aortic smooth muscle cells (HASMC) as shown by colocalization on immunofluorescent aortic plaque stainings (n = 10; P < 0.01) and by flow cytometry in cell culture. Although macrophages did not express FAP, macrophage burden in human aortic plaques correlated with FAP expression (n = 12; R(2)= 0.763; P < 0.05). Enzyme-linked immunosorbent assays showed a time- and dose-dependent up-regulation of FAP in response to human tumour necrosis factor α (TNFα) in HASMC (n = 6; P < 0.01). Moreover, supernatants from peripheral blood-derived macrophages induced FAP expression in cultured HASMC (n = 6; P < 0.01), an effect abolished by blocking TNFα (n = 6; P < 0.01). Fibroblast activation protein associated with collagen-poor regions in human coronary fibrous caps and digested type I collagen and gelatin in vitro (n = 6; P < 0.01). Zymography revealed that FAP-mediated collagenase activity was neutralized by an antibody directed against the FAP catalytic domain both in HASMC (n = 6; P < 0.01) and in fibrous caps of atherosclerotic plaques (n = 10; P < 0.01).

Conclusion: Fibroblast activation protein expression in HASMC is induced by macrophage-derived TNFα. Fibroblast activation protein associates with thin-cap human coronary fibroatheromata and contributes to type I collagen breakdown in fibrous caps.
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http://dx.doi.org/10.1093/eurheartj/ehq519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205479PMC
November 2011

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

Eur Heart J 2011 Oct 31;32(20):2573-84. Epub 2011 Jan 31.

Cardiovascular Research, Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

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.
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http://dx.doi.org/10.1093/eurheartj/ehq501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195262PMC
October 2011