Anti-apoA-1 auto-antibodies increase mouse atherosclerotic plaque vulnerability, myocardial necrosis and mortality triggering TLR2 and TLR4.

Auto-antibodies to apolipoprotein A-1 (anti-apoA-1 IgG) were shown to promote inflammation and atherogenesis, possibly through innate immune receptors signalling. Here, we aimed at investigating the role of Toll-like receptors (TLR) 2 and 4 on anti-apoA-1 IgG-induced atherosclerotic plaque vulnerability, myocardial necrosis and mortality in mice. Adult male apolipoprotein E knockout (ApoE)-/- (n=72), TLR2-/-ApoE-/- (n=36) and TLR4-/-Apo-/- (n=28) mice were intravenously injected with 50 µg/mouse of endotoxin-free polyclonal anti-apoA-1 IgG or control isotype IgG (CTL IgG) every two weeks for 16 weeks. Atherosclerotic plaque size and vulnerability were assessed by histology. Myocardial ischaemia and necrosis, respectively, were determined by electrocardiographic (ECG) changes assessed by telemetry and serum troponin I (cTnI) measurements. Impact on survival was assessed by Kaplan-Meier analyses. In ApoE-/- mice, anti-apoA-1 IgG passive immunisation enhanced histological features of atherosclerotic plaque vulnerability (increase in neutrophil and MMP-9 and reduction in collagen content), induced a substantial cTnI elevation (p=0.001), and increased mortality rate by 23 % (LogRank, p=0.04) when compared to CTL IgG. On a subgroup of ApoE-/- mice equipped with telemetry (n=4), a significant ST-segment depression was noted in anti-apoA-1 IgG-treated mice when compared to CTL IgG recipients (p< 0.001), and an acute ST-segment elevation myocardial infarction preceding mouse death was observed in one case. The deleterious effects of anti-apoA-1 IgG on atherosclerotic plaque vulnerability, myocardial necrosis and death were partially reversed in TLR2-/-ApoE-/- and TLR4-/-ApoE-/- backgrounds. In conclusion, anti-apoA-1 auto-antibodies seem to be active mediators of atherosclerotic plaque vulnerability, myocardial necrosis, and mortality in mice through TLR2- and TLR4-mediated pathways.

[My patient is too old for a lipid-lowering therapy: myths and reality]. / Mon patient est trop âgé pour une statine: mythes et réalités.

Lipid-lowering treatment in the elderly patient is conditioned by a high incidence and prevalence of cardiovascular disease in the setting of a limited remaining life span. The clinical benefit of statin therapy can be seen after a few months, thus supporting use in secondary prevention even when the lifespan is restricted to a few years. Recent guidelines propose the use of moderate doses in the elderly > 75 years. The evidence for treatment in primary prevention is weaker and the evaluation of the total cardiovascular risk is complicated by the high baseline risk of many elderly. Rational treatment decisions should be based on biologic rather than chronologic age. Statins are generally well tolerated in the elderly, requiring clinical monitoring only, with particular attention to pharmacokinetic interactions and renal failure.

[Testosterone: a treatment for the prevention of cardiovascular disease]. / La testostérone: un traitement pour la prévention des maladies cardiovascutaires?

Testosterone treatment was largely prescribed and marketed as a potential therapy to treat symptoms of aging. Testosterone levels decrease progressively with aging and low testosterone levels were associated with an increase risk of cardiovascular events and death. Controversies persist whether this association is causal or mediated by confounders of the general health. Systematic screening of testosterone is not recommended in a check-up visit, but only in case of suggestive symptoms. Furthermore a recent meta-analysis and large prospective cohort studies have reported a concern regarding the safety of testosterone therapy and the associated risk of major cardiovascular events. The decision to prescribe testosterone should be made with the patient after evaluating the risks and benefits.

[PCSK9 inhibitors: emerging treatment to lower cholesterol?]. / Inhibiteurs de PCSK9: futur traitement pour baisser le cholestérol?

The achievement rate of recommended low-density lipoprotein cholesterol (LDL-C) targets of < 1.8 mmol/l for secondary prevention in very high risk patients is difficult. Observational studies reported that loss of function mutation of the PCS9 was associated with LDL-C decrease level and reduction of cardiovascular events. Monoclonal antibodies to PCSK9 (REGN727 and AMG 145, PSCK9 inhibitors) have been tested in clinical studies of phase I and II and showed LDL-C level reduction of 60-70% compared to placebo. This approach appears safe and well-tolerated. The PCSK9 inhibitors are now tested in large phase III clinical studies to assess the long-term safety and efficacy of this new promising approach.

Analysis of the expression of nine secreted matrix metalloproteinases and their endogenous inhibitors in the brain of mice subjected to ischaemic stroke.

Matrix metalloproteinases (MMPs) are a family of more than twenty secreted and cell-surface endopeptidases. Among them, MMP2, MMP3 and MMP9 are involved in blood-brain barrier injury and neuronal death after cerebral ischaemia. On the other hand, very little is known about the expression of the other secreted MMPs. Herein, we compared the global changes in MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12 and MMP13, and their endogenous inhibitors TIMP1 and TIMP2, both at the mRNA and protein levels, during the hyperacute (6 h), acute (24 h) and subacute (72 h) stages following transient focal cerebral ischaemia and treatment with recombinant tissue plasminogen activator (rtPA). We observed a significant increase in MMP1, MMP2, MMP9, MMP10, MMP13 and TIMP1 levels during the acute stage of reperfusion, which was further amplified during the subacute stage for MMP1, MMP2, MMP10 and TIMP1. In general, no change of MMP3, MMP7, MMP8, MMP12 and TIMP2 was observed. However, rtPA treatment induced a rapid increase in MMP1/TIMP2, MMP2/TIMP2, MMP8/TIMP2 and MMP9/TIMP2 ratios during the hyperacute stage of reperfusion compared to saline treatment, which may have potential implications in the early disruption of the blood-brain barrier after rtPA treatment.

The liver and the kidney: two critical organs influencing the atherothrombotic risk in metabolic syndrome.

The increased atherothrombotic risk in patients with metabolic syndrome (MetS) has been classically explained by the multiplicative effect of systemic concomitant pro-atherosclerotic factors. In particular, centripetal obesity, dyslipidaemia, glucose intolerance, hypertension (differently combined in the diagnosis of the disease) would be expected to act as classical cardiovascular risk conditions underlying accelerated atherogenesis. In order to better understand specific atherosclerotic pathophysiology in MetS, emerging evidence focused on the alterations in different organs that could serve as both pathophysiological targets and active players in the disease. Abnormalities in adipose tissue, heart and arteries have been widely investigated in a variety of basic research and clinical studies in MetS. In this narrative review, we focus on pathophysiological activities of the liver and kidney. Considering its key role in metabolism and production of soluble inflammatory mediators (such as C-reactive protein [CRP]), the liver in MetS has been shown to be altered both in its structure and function. In particular, a relevant amount of the fat accumulated within this organ has been shown to be associated with different degrees of inflammation and potential insulin resistance. In humans, non-alcoholic fatty liver disease (NAFLD) has been described as the hepatic manifestation of MetS. In an analogous manner, epidemiological evidence strongly suggested a "guilty" association between MetS and chronic kidney disease (CKD). Some biomarkers of hepatic (such as C-reactive protein, TNF-alpha or other cytokines) and renal diseases (such as uric acid) associated with MetS might be particularly useful to better manage and prevent the atherothrombotic risk.

[Role of percutaneous coronary intervention in diabetic patients]. / Rôle de la revascularisation coronarienne chez le patient diabétique avec maladie coronarienne stable.

Clinical outcomes after revascularization, both for surgery and percutaneous coronary intervention (PCI), is significantly worse in diabetic patients compared with non-diabetic patients. While in acute coronary syndrome, PCI is favored because of the increased risk of surgery performed during ongoing infarction, in stable patients assessment of clinical factors, such as coronary anatomy and comorbidities should guide decision of the revascularization modality (e.g., surgical, PCI, or conservative). Surgery should be favored in patients with multivessel coronary disease and acceptable surgical risk. Overall, the threshold for surgery compared to PCI should be lower in diabetic patients compared with non-diabetic ones.

[Adults with congenital heart diseases: a growing population, a multidisciplinary approach]. / Cardiopathies congénitates de l'âge adulte: nouvelle population de patients, prise en charge multidisciplinaire.

Untill recently, congenital heart disease was considered as a childhood's disease. With improvement in pediatric survival, adults with a congenital heart disease (ACHD) represent an emerging group of patients who need specialized medical care. In 2010, the ESC published newguidelines on global and specific management of adults with congenital heart disease. ACHD centers organize appropriate medical care for these patients, promote specialist training and national scientific research in collaboration with other national ACHD centers.

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.

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.

Anti-apolipoprotein A-1 autoantibodies as biomarker for atherosclerosis burden in patients with periodontitis.

BACKGROUND AND OBJECTIVE: Anti-apolipoprotein A-1 (anti-apoA-1) IgG is a potential marker of atherosclerotic plaque vulnerability and cardiovascular complications. In patients with periodontitis the presence of anti-apoA-1 IgGs in serum and their association with atherosclerosis is unknown. MATERIAL AND METHODS: One-hundred and thirty subjects with periodontal disease and 46 healthy subjects, matched for age and gender, participated in this study. Anti-apoA-1 IgG, high-sensitivity C-reactive protein (hsCRP) and matrix metalloproteinase (MMP) -2, -3, -8 and -9 were measured in serum samples. An ankle-brachial index (ABI) value below 1.11 served as a surrogate marker of atherosclerosis. Predictive accuracies of biomarkers for abnormal ABI were determined using receiver-operating characteristics curves and logistic regression analyses. RESULTS: Compared with healthy controls, periodontitis patients showed lower median ABI values (1.10 vs. 1.15; p < 0.0001), a higher prevalence of anti-apoA-1 IgG positivity (23.8% vs. 6.5%; p = 0.009) and higher concentrations of hsCRP (1.62 mg/L vs. 0.85 mg/L; p = 0.02) and MMP-9 (435 µg/mL vs. 283 µg/mL; p < 0.0001). In patients younger than 50 years of age (n = 66), anti-apoA-1 IgG was found to be the best predictor for an abnormal ABI (area under the curve = 0.63; p = 0.03). Anti-apoA-1 IgG positivity increased the risk of having an abnormal ABI (odds ratio = 4.20; p = 0.04), independently of diabetes, smoking and body mass index. CONCLUSIONS: Anti-apoA-1 IgG positivity and atherosclerosis, as reflected by abnormal ABI, were more prevalent in periodontitis patients than in age- and gender-matched controls. In younger periodontitis patients, anti-apoA-1 IgG was found to be the best predictor of atherosclerosis burden.

Autoantibodies against apolipoprotein A-1 and phosphorylcholine for diagnosis of non-ST-segment elevation myocardial infarction.

OBJECTIVES: To explore the diagnostic accuracies of anti-apolipoproteinA-1 (anti-ApoA-1) IgG and anti-phosphorylcholine (anti-PC) IgM alone, expressed as a ratio (anti-ApoA-1 IgG/anti-PC IgM), and combined with the Thrombolysis In Myocardial Infarction (TIMI) score for non-ST-segment elevation myocardial infarction (NSTEMI) (NSTEMI-TIMI score) to create a new diagnostic algorithm - the Clinical Autoantibody Ratio (CABR) score - for the diagnosis of NSTEMI and subsequent cardiac troponin I (cTnI) elevation in patients with acute chest pain (ACP). METHODS: In this single-centre prospective study, 138 patients presented at the emergency department with ACP without ST-segment elevation myocardial infarction. Anti-ApoA-1 IgG and anti-PC IgM were assessed by enzyme-linked immunosorbent assay on admission. Post hoc determination of the CABR score cut-off was performed by receiver operating characteristics analyses. RESULTS: The adjudicated final diagnosis was NSTEMI in 17% (24/138) of patients. Both autoantibodies alone were found to be significant predictors of NSTEMI diagnosis, but the CABR score had the best diagnostic accuracy [area under the curve (AUC): 0.88; 95% confidence interval (CI): 0.82-0.95]. At the optimal cut-off of 3.3, the CABR score negative predictive value (NPV) was 97% (95% CI: 90-99). Logistic regression analysis showed that a CABR score >3.3 increased the risk of subsequent NSTEMI diagnosis 19-fold (odds ratio: 18.7; 95% CI: 5.2-67.3). For subsequent cTnI positivity, only anti-ApoA-1 IgG and CABR score displayed adequate predictive accuracies with AUCs of 0.80 (95% CI: 0.68-0.91) and 0.82 (95% CI: 0.70-0.94), respectively; the NPVs were 95% (95% CI: 90-98) and 99% (95% CI: 94-100), respectively. CONCLUSION: The CABR score, derived from adding the anti-ApoA-1 IgG/anti-PC IgM ratio to the NSTEMI-TIMI score, could be a useful measure to rule out NSTEMI in patients presenting with ACP at the emergency department without electrocardiographic changes.

[Selection and preoperative follow-up of heart transplantation candidates in the French part of Switzerland]. / Sélection et suivi prétransplantation des patients candidats à la greffe cardiaque en Suisse romande.

Heart transplantation (HTx) started in 1987 at two university hospitals (CHUV, HUG) in the western part of Switzerland, with 223 HTx performed at the CHUV until December 2010. Between 1987 and 2003, 106 HTx were realized at the HUG resulting in a total of 329 HTx in the western part of Switzerland. After the relocation of organ transplantation activity in the western part of Switzerland in 2003, the surgical part and the early postoperative care of HTx remained limited to the CHUV. However, every other HTx activity are pursued at the two university hospitals (CHUV, HUG). This article summarizes the actual protocols for selection and pre-transplant follow-up of HTx candidates in the western part of Switzerland, permitting a uniform structure of pretransplant follow-up in the western part of Switzerland.

[Reducing heart rate to treat angina pectoris]. / Traiter l'angine de poitrine en ciblant la fréquence cardiaque: validation par des données récentes.

Elevated heart rate induces an increase in myocardial oxygen consumption as well as a decrease in oxygen delivery. Myocardial ischemia is double in patients with resting heart rate above 80 bpm, compared to those with heart rate below 60 bpm. In addition, angina during effort increases the risk of mortality, directly depending on the degree of angina. Thus, in patients with myocardial angina, reducing heart rate could decrease symptoms and improve cardiovascular prognosis. A recent retrospective analysis of the results from the BEAUTIFUL study provides new evidence on this topic and is discussed in this article.

Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study.

BACKGROUND: Poor response to both aspirin and clopidogrel (dual poor responsiveness [DPR]) is a major risk factor for recurrent ischemic events. OBJECTIVES: The aim of this study was to identify factors associated with DPR, defined with specific tests, and derive a predictive clinical score. METHODS: We studied 771 consecutive stable cardiovascular patients treated with aspirin (n = 223), clopidogrel (n = 111), or both drugs (n = 37). Aspirin responsiveness was evaluated by serum thromboxane (Tx)B2 assay, and clopidogrel responsiveness by calculating the platelet reactivity index (PRI) on the basis of the phosphorylation status of the vasodilator phosphoprotein. The analysis was focused on patients treated with both drugs, and on independent predictors of DPR. RESULTS: Among patients on dual therapy, there was no relevant correlation between TxB2 levels and PRI values (r = 0.11). Sixty-seven patients (15.4%) had DPR. Diabetes [odds ratio (OR) 1.89, 95% confidence interval (CI) 1.06-3.39], high body weight (> 86 kg vs. < 77 kg, OR 4.74, 95% CI 2.49-9.73), low aspirin dose (75-81 mg vs. ≥ 160 mg, OR 0.12, 95% CI 0.09-0.93) and high C-reactive protein (CRP) level (> 1.6 mg L⁻¹ vs. < 0.6 mg L⁻¹, OR 3.66, 95% CI 1.74-8.72) were independently associated with DPR, via increased TxB(2) levels, increased PRI, or both. These associations with TxB2 and PRI were reproduced across the whole population. With use of a factor-weighed score (c-index = 0.74), the predicted prevalence of DPR was 57% in the highest strata of the score as compared with < 4% for the lowest strata. CONCLUSIONS: Diabetes, body weight, the aspirin dose and CRP levels are readily available independent predictors of DPR, and some are potential targets for reducing its prevalence.