Ulf Landmesser

2014 ESC/EACTS Guidelines on myocardial revascularization The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI)

Authors/Task Force members: Stephan Windecker* (ESC Chairperson) (Switzerland), Philippe Kolh* (EACTS Chairperson) (Belgium), Fernando Alfonso (Spain), Jean-Philippe Collet (France), Jochen Cremer (Germany), Volkmar Falk (Switzerland), Gerasimos Filippatos (Greece), Christian Hamm (Germany), Stuart J. Head (The Netherlands), Peter Jüni (Switzerland), A. Pieter Kappetein (The Netherlands), Adnan Kastrati (Germany), Juhani Knuuti (Finland), Ulf Landmesser (Switzerland), Günther Laufer (Austria), Franz-Josef Neumann (Germany), Dimitrios J. Richter (Greece), Patrick Schauerte (Germany), Miguel Sousa Uva (Portugal), Giulio G. Stefanini (Switzerland), David Paul Taggart (UK), Lucia Torracca (Italy), Marco Valgimigli (Italy), William Wijns (Belgium), and Adam Witkowski (Poland).

2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

ACC : American College of Cardiology ACCOAST : Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction ACE : angiotensin-converting enzyme ACS : acute coronary syndromes ACT

ROLE OF OXIDATIVE STRESS IN ATHEROSCLEROSIS

The common risk factors for atherosclerosis increase production of reactive oxygen species (ROS) by endothelial, vascular smooth muscle, and adventitial cells. These ROS initiate processes involved in atherogenesis through several important enzyme systems, including xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and nitric oxide synthase. Physical forces also regulate vascular production of ROS. Oscillatory shear, which is present at sites where atherosclerosis develops, seems a particularly potent stimulus of superoxide production. The signaling cascade for activation of the NAD(P)H oxidase by angiotensin II has recently been elucidated and seems to involve a feed-forward mechanism that permits ongoing production of ROS for prolonged periods. Oxidative stress in humans with coronary artery disease is also exacerbated by a reduction of vascular extracellular superoxide dismutase, normally an important protective enzyme against the superoxide anion.

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias

The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)  Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR)  ABI : ankle-brachial index

Role of p47 phox in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II

Abstract—Hypertension caused by angiotensin II is dependent on vascular superoxide (O2·−) production. The nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase is a major source of vascular O2·− and is activated by angiotensin II in vitro. However, its role in angiotensin II-induced hypertension in vivo is less clear. In the present studies, we used mice deficient in p47phox, a cytosolic subunit of the NADPH oxidase, to study the role of this enzyme system in vivo. In vivo, angiotensin II infusion (0.7 mg/kg per day for 7 days) increased systolic blood pressure from 105±2 to 151±6 mm Hg and increased vascular O2·− formation 2- to 3-fold in wild-type (WT) mice. In contrast, in p47phox-/- mice the hypertensive response to angiotensin II infusion (122±4 mm Hg;P <0.05) was markedly blunted, and there was no increase of vascular O2·− production. In situ staining for O2·− using dihydroethidium revealed a marked increase of O2·−production in both endothelial and vascular smooth muscle cells of angiotensin II-treated WT mice, but not in those of p47phox-/- mice. To directly examine the role of the NAD(P)H oxidase in endothelial production of O2·−, endothelial cells from WT and p47phox-/- mice were cultured. Western blotting confirmed the absence of p47phox in p47phox-/- mice. Angiotensin II increased O2·− production in endothelial cells from WT mice, but not in those from p47phox-/- mice, as determined by electron spin resonance spectroscopy. These results suggest a pivotal role of the NAD(P)H oxidase and its subunit p47phox in the vascular oxidant stress and the blood pressure response to angiotensin II in vivo.

A Cathepsin D-Cleaved 16 kDa Form of Prolactin Mediates Postpartum Cardiomyopathy

Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology and exposes women to high risk of mortality after delivery. Here, we show that female mice with a cardiomyocyte-specific deletion of stat3 develop PPCM. In these mice, cardiac cathepsin D (CD) expression and activity is enhanced and associated with the generation of a cleaved antiangiogenic and proapoptotic 16 kDa form of the nursing hormone prolactin. Treatment with bromocriptine, an inhibitor of prolactin secretion, prevents the development of PPCM, whereas forced myocardial generation of 16 kDa prolactin impairs the cardiac capillary network and function, thereby recapitulating the cardiac phenotype of PPCM. Myocardial STAT3 protein levels are reduced and serum levels of activated CD and 16 kDa prolactin are elevated in PPCM patients. Thus, a biologically active derivative of the pregnancy hormone prolactin mediates PPCM, implying that inhibition of prolactin release may represent a novel therapeutic strategy for PPCM.

2014 ESC/EACTS Guidelines on myocardial revascularization

Acute coronary syndromes Bare-metal stents Coronary artery bypass grafting Coronary artery disease Drug-eluting stents EuroSCORE Guidelines Heart Team Myocardial infarction Myocardial ischaemia Myocardial revascularization Medical therapy Percutaneous coronary intervention Recommendation Revascularisation Risk stratification Stents Stable angina Stable coronary artery disease ST-segment elevation myocardial infarction SYNTAX score

Vascular Oxidative Stress and Endothelial Dysfunction in Patients With Chronic Heart Failure Role of Xanthine-Oxidase and Extracellular Superoxide Dismutase

Background—Impaired flow-dependent, endothelium-mediated vasodilation (FDD) in patients with chronic heart failure (CHF) results, at least in part, from accelerated degradation of nitric oxide by oxygen radicals. The mechanisms leading to increased vascular radical formation, however, remain unclear. Therefore, we determined endothelium-bound activities of extracellular superoxide dismutase (ecSOD), a major vascular antioxidant enzyme, and xanthine-oxidase, a potent radical producing enzyme, and their relation to FDD in patients with CHF. Methods and Results—ecSOD and xanthine-oxidase activities, released from endothelium into plasma by heparin bolus injection, were determined in 14 patients with CHF and 10 control subjects. FDD of the radial artery was measured using high-resolution ultrasound and was assessed before and after administration of the antioxidant vitamin C (25 mg/min; IA). In patients with CHF, endothelium-bound ecSOD activity was substantially reduced (5.0±0.7 versus 14.4±2.6 U · mL−1 · min−1;P <0.01) and closely related to FDD (r =0.61). Endothelium-bound xanthine-oxidase activity was increased by >200% (38±10 versus 12±4 nmol O2·− · &mgr;L−1;P <0.05) and inversely related to FDD (r =−0.35) in patients with CHF. In patients with low ecSOD and high xanthine-oxidase activity, a greater benefit of vitamin C on FDD was observed, ie, the portion of FDD inhibited by radicals correlated negatively with ecSOD (r =−0.71) but positively with xanthine-oxidase (r =0.75). Conclusions—These results demonstrate that both increased xanthine-oxidase and reduced ecSOD activity are closely associated with increased vascular oxidative stress in patients with CHF. This loss of vascular oxidative balance likely represents a novel mechanism contributing to endothelial dysfunction in CHF.

Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase

Background—Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI. Methods and Results—Wild-type (WT) and eNO synthase (eNOS)−/− mice with extensive anterior MI were randomized to treatment with vehicle (V) or atorvastatin (Ator, 50 mg/kg QD by gavage) for 4 weeks starting on day 1 after MI. Ator markedly improved endothelium-dependent, NO-mediated vasorelaxation; mobilization of endothelial progenitor cells; and myocardial neovascularization of the infarct border in WT mice after MI while having no effect in eNOS−/− mice. LV dysfunction and interstitial fibrosis were markedly attenuated by Ator in WT mice, whereas no effect was observed in eNOS−/− mice after MI. Importantly, Ator significantly increased the survival rate during 4 weeks after MI in WT mice (Ator versus V, 80% versus 46%; P<0.01, n=75) but not in eNOS−/− mice (43% versus 48%; NS, n=42). Conclusions—These findings suggest that increased eNO availability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after MI. eNO bioavailability after MI likely represents an important therapeutic target in heart failure after MI and mediates beneficial effects of statin treatment after MI.

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

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.