François Mach

2016 European Guidelines on cardiovascular disease prevention in clinical practice the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR)

The VI European Guidelines for Cardiovascular Prevention recommend combining population and high-risk strategies with lifestyle changes as a cornerstone of prevention, and propose the SCORE function to quantify cardiovascular risk. The guidelines highlight disease specific interventions, and conditions as women, young people and ethnic minorities. Screening for subclinical atherosclerosis with noninvasive imaging techniques is not recommended. The guidelines distinguish four risk levels (very high, high, moderate and low) with therapeutic objectives for lipid control according to risk. Diabetes mellitus confers a high risk, except for subjects with type 2 diabetes with less than 10 years of evolution, without other risk factors or complications, or type 1 diabetes of short evolution without complications. The decision to start pharmacological treatment of arterial hypertension will depend on the blood pressure level and the cardiovascular risk, taking into account the lesion of target organs. The guidelines dont recommend antiplatelet drugs in primary prevention because of the increased bleeding risk. The low adherence to the medication requires simplified therapeutic regimes and to identify and combat its causes. The guidelines highlight the responsibility of health professionals to take an active role in advocating evidence-based interventions at the population level, and propose effective interventions, at individual and population level, to promote a healthy diet, the practice of physical activity, the cessation of smoking and the protection against alcohol abuse.

CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke.

The definition of ischaemic stroke has been recently updated as an acute episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischaemia in the presence of a cerebral infarction. This tissular definition has highlighted the importance of pathophysiological processes underlying cerebral damage. In particular, post- ischaemic inflammation in the brain and in the blood stream could influence crucial steps of the tissue injury/repair cascade. CC and CXC chemokines orchestrate the inflammatory response in atherosclerotic plaque vulnerability and cerebral infarction. These molecules exert their activities through the binding to selective transmembrane receptors. CC and CXC chemokines modulate crucial processes (such as inflammatory cell recruitment and activation, neuronal survival, neoangiogenesis). On the other hand, CXC chemokines could also modulate stem cell homing, thus favouring tissue repair. Given this evidence, both CC and CXC chemokines could represent promising therapeutic targets in primary and secondary prevention of ischaemic stroke. Only preliminary studies have been performed investigating treatments with selective chemokine agonists/antagonists. In this review, we will update evidence on the role and the potential therapeutic strategies targeting CC and CXC chemokines in the pathophysiology of ischaemic stroke.

Pathophysiological role of neutrophils in acute myocardial infarction

The pathogenesis of acute myocardial infarction is known to be mediated by systemic, intraplaque and myocardial inflammatory processes. Among different immune cell subsets, compelling evidence now indicates a pivotal role for neutrophils in acute coronary syndromes. Neutrophils infiltrate coronary plaques and the infarcted myocardium and mediate tissue damage by releasing matrix-degrading enzymes and reactive oxygen species. In addition, neutrophils are also involved in post-infarction adverse cardiac remodelling and neointima formation after angioplasty. The promising results obtained in preclinical modelswith pharmacological approaches interfering with neutrophil recruitment or function have confirmed the pathophysiological relevance of these immune cells in acute coronary syndromes and prompted further studies of these therapeutic interventions. This narrative review will provide an update on the role of neutrophils in acute myocardial infarction and on the pharmacological means that were devised to prevent neutrophil-mediated tissue damage and to reduce post-ischaemic outcomes.

Stairs instead of elevators at workplace: cardioprotective effects of a pragmatic intervention

Background Population strategies to increase physical activity are an essential part of cardiovascular disease prevention. However, little data exist on lifestyle interventions that are easy to integrate into everyday life such as using stairs instead of elevators at the workplace. Design Pre and postintervention study. Methods A 12-week promotional campaign for stair use consisting in posters and floor stickers at the point of choice between stairs and elevators at each hospital floor was organized in a university hospital building. In 77 selected employees with an inactive lifestyle, physical activity, aerobic fitness, anthropometrics, blood pressure, lipids, insulin sensitivity, and C-reactive protein were assessed at baseline, 12 weeks, and 6 months. Results During the intervention median daily number of ascended and descended one-story staircase units was 20.6/day (14.2–28.1) compared with 4.5/day (1.8–7.2) at baseline (P<0.001). At 12 weeks, estimated maximal aerobic capacity had increased by 9.2±15.1% (P<0.001) corresponding with approximately 1 MET. There were significant declines in waist circumference (–1.7 ± 2.9%), weight (– 0.7 ± 2.6%), fat mass (–1.5 ± 8.4%), diastolic blood pressure (–1.8 ± 8.9%), and low-density lipoprotein cholesterol (– 3.0 ± 13.5%). At 6 months, the median daily number of ascended and descended one-story staircase units had decreased to 7.2 (3.5–14.0). Benefits on estimated maximal aerobic capacity (+ 5.9 ±12.2%, P= 0.001) and fat mass (–1.4 ± 8.4%, P = 0.038) persisted. Conclusion Encouraging stair use at work is effective for improving fitness, body composition, blood pressure, and lipid profile in asymptomatic individuals with an inactive lifestyle and thus may be a simple way to significantly reduce cardiovascular disease risk at the population level.

Inhibition of Nicotinamide Phosphoribosyltransferase Reduces Neutrophil-Mediated Injury in Myocardial Infarction

AIMSnNicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed.nnnRESULTSnTreatment with FK866 reduced myocardial infarct size, neutrophil infiltration, and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes), suggesting a direct involvement of these cells in cardiac injury. Sera from FK866-treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866, as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing, implying a pivotal role for this NAD(+)-dependent deacetylase in the production of this chemokine.nnnINNOVATIONnThe pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation- and oxidative stress-mediated tissue damage in early phases of reperfusion after a myocardial infarction.nnnCONCLUSIONSnNampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice.

Osteoprotegerin Predicts Progression of Chronic Heart Failure: Results From CORONA

Background—Osteoprotegerin (OPG) may be implicated in the pathogenesis of heart failure (HF), and circulating levels predict survival in patients with postinfarction HF. Our primary goal was to determine whether OPG provided independent prognostic information in patients with chronic HF, and to examine its potential interactions with statin therapy. Methods and Results—OPG as a risk factor for the primary end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke; n=318), all-cause mortality (n=329), and all-cause mortality/hospitalization for worsening of heart failure (WHF; n=475) was investigated in 1464 patients (≥60 years, New York Heart Association class II to IV, ischemic systolic HF, optimal pharmacological therapy) in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. In multivariate analyses, OPG (continuous variable) added no significant predictive information for risk estimation of the primary end point (adjusting for left ventricular ejection fraction, New York Heart Association class, age, body mass index, diabetes, sex, intermittent claudication, heart rate, serum creatinine, apoA1, and N-terminal pro-B-type natriuretic peptide). However, OPG added independent predictive information for WHF hospitalization (hazard ratio [HR] 1.10 [1.04 to 1.16], P<0.001) and all-cause mortality/WHF hospitalization (HR 1.06 [1.01 to 1.11]). The HR indicated a reduced risk for all-cause mortality in the rosuvastatin group in those with lowest OPG values (tertile 1, HR=0.66 unadjusted [P=0.025]; HR=0.71 Cox adjusted [P=0.025]; interaction by treatment effect for the tertiles P=0.086). Conclusions—OPG added no predictive information for the primary end point, but independently predicted WHF hospitalization in older patients with advanced chronic systolic HF of ischemic etiology. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Shear stress modulates the expression of the atheroprotective protein Cx37 in endothelial cells.

High laminar shear stress (HLSS) is vasculoprotective partly through induction of Kruppel-like factor 2 (KLF2). Connexin37 (Cx37) is highly expressed in endothelial cells (ECs) of healthy arteries, but not in ECs overlying atherosclerotic lesions. Moreover, Cx37 deletion in apolipoprotein E-deficient (ApoE(-/-)) mice increases susceptibility to atherosclerosis. We hypothesized that shear stress, through KLF2 modulation, may affect Cx37 expression in ECs. Cx37 expression and gap-junctional intercellular (GJIC) dye transfer are prominent in the straight portion of carotid arteries of ApoE(-/-) mice, but are reduced at the carotid bifurcation, a region subjected to oscillatory flow. Shear stress-modifying vascular casts were placed around the common carotid artery of ApoE(-/-) mice. Whereas Cx37 expression was conserved in HLSS regions, it was downregulated to ~50% in low laminar or oscillatory flow regions. To study the mechanisms involved, HUVECs or bEnd.3 cells were exposed to flow in vitro. Cx37 and KLF2 expression were increased after 24h of HLSS. Interestingly, shear-dependent Cx37 expression was significantly reduced after silencing of KLF2. Moreover after exposure to simvastatin, a well-known KLF2 inducer, KLF2 binds to the Cx37 promoter region as shown by ChIP. Finally, GJIC dye transfer was highly reduced after KLF2 silencing and was increased after exposure to simvastatin. HLSS upregulates the expression of Cx37 in ECs by inducing its transcription factor KLF2, which increases intercellular communication. Therefore, this effect of shear stress on Cx37 expression may contribute to the synchronization of ECs and participate in the protective effect of HLSS.

Treatment with Evasin-3 reduces atherosclerotic vulnerability for ischemic stroke, but not brain injury in mice

Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a cast’ carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes.

Evidence on the pathogenic role of auto-antibodies in acute cardiovascular diseases

Atherothrombosis is the major determinant of acute ischaemic cardiovascular events, such as myocardial infarction and stroke. Inflammatory processes have been linked to all phases of atherogenesis In particular, the identification of autoimmunity mediators in the complex microenvironment of chronic inflammation has become the focus of attention in both early and advanced atherogenic processes. Auto-antibodies against self-molecules or new epitopes generated by oxidative processes infiltrate atherosclerotic plaques and were shown to modulate the activity of immune cells by binding various types of receptors. However, despite mounting evidence for a pathophysiological role of autoantibodies in atherothrombosis, the clinical relevance for circulating autoantibodies in cardiovascular outcomes is still debated. This review aims at illustrating the mechanisms by which different types of autoantibodies might either promote or repress atherothrombosis and to discuss the clinical studies assessing the role of auto-antibodies as prognostic biomarkers of plaque vulnerability.

Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice

Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.