AUTOANTIBODIES TO C-TERMINAL APOA-1 AS A BIOMARKER OF CARDIOVASCULAR DISEASE

Ce travail de thèse s’intéresse aux anticorps dirigés contre l’apolipoprotéine A-1 (anti-apoA-1 IgG), la principale fraction protéique des particules de HDL cholestérol. Jusqu’à présent, des travaux scientifiques fondamentaux ont établi le rôle des anti-apoA-1 IgG en tant que molécules pro-inflammatoires et pro-athérogènes, associées à une mortalité accrue dans des modèles murins. Par ailleurs, des travaux cliniques préliminaires ont démontré la valeur pronostique indépendante des anti-apoA-1 IgG dans la maladie cardiovasculaire (CV) dans des populations des patients atteints de maladies auto-immunes, des patients à risque CV élevé ou post infarctus du myocarde. En utilisant des données de la “Cohorte Lausannoise” (étude CoLaus), une cohorte populationnelle de plus de 6500 habitants de la ville de Lausanne, ce travail de recherche s’est décliné en 3 objectifs : 1) mieux comprendre la prévalence des anti-apoA-1 IgG dans la population générale, 2) examiner l’association entre anti-apoA-1 IgG et la prévalence et facteurs de risque de la maladie CV 3) examiner les déterminants génétiques des anti-apoA-1 IgG et établir leur valeur pronostique pour la mortalité globale et les évènement coronariens dans la population générale. Concernant les deux premiers objectifs, nos résultats publiés dans la revue « Thrombosis and Haemostasis » révèlent, pour la première fois, que des taux élevés d’anti-apoA-1 IgG sont présents dans environ 20% des individus dans la population générale. Ils sont, par ailleurs, associés à une prévalence accrue de maladies CV dans la population générale, indépendamment des facteurs de risque CV traditionnels. Par ailleurs, dans le sous-groupe des sujets atteints de maladie CV dans le passé (prévention secondaire), nous mettons en évidence une association des anti-apoA-1 IgG avec un profil pro-inflammatoire, témoigné par un taux de HDL cholestérol diminué, mais aussi par des valeurs de protéine C-réactive de haute sensibilité et d’acide urique élevées. En partant de ces observations, nous avons, par la suite, investigué une prédisposition génétique à la présence des anti-apoA-1 IgG. Nos résultats publiés dans le journal « Frontiers in Immunology » démontrent que des taux élevés d’ anti-apoA-1 IgG sont associés à des polymorphismes du gène FCRL3, gène impliqué dans la susceptibilité aux maladies auto-immunes chez l’être humain. Dans le même manuscrit, nous montrons que la présence des anti-apoA-1 IgG est associée de manière significative et indépendante à la mortalité toutes causes confondues dans la population générale. Finalement, concernant le lien entre anti-apoA-1 IgG et maladie coronarienne, nous avons récemment démontré que les anti-apoA-1 IgG seraient davantage des prédicteurs indépendants de nouveaux événements coronariens et que cette association serait modulée par un polymorphisme fonctionnel du gène du récepteur CD14. Ses observations sont publiés dans le journal « Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) » sous le titre « Impact of CD14 polymorphisms on anti-apolipoprotein A1 IgG related coronary artery disease prediction in the general population ». D’un point de vue de santé publique, ces résultats innovants, obtenus dans une étude populationnelle à grande echelle, sont prometteurs concernant le rôle des anti-apoA-1 IgG non seulement comme un nouveau facteur de risque CV indépendant, mais également en tant que cible spécifique potentielle de thérapies immuno-modulatrices avec des implications cliniques futures. -- We aimed to determine the association between autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG) and prevalent cardiovas- cular (CV) disease (CVD) as well as markers of CV risk in the general population. Cross-sectional data were obtained from 6649 subjects (age 52.6 ± 10.7 years, 47.4 % male) of the population-based CoLaus study. CVD was defined as myocardial infarction, angina pectoris, per- cutaneous revascularisation or bypass grafting for ischaemic heart dis- ease stroke or transient ischaemic attack, and was assessed according to standardised medical records. Anti-apoA-1 IgG and biological markers were measured by ELISA and conventional automated tech- niques, respectively. Prevalence of high anti-apoA-1 IgG in the general population was 19.9 %. Presence of anti-apoA-1 IgG was significantly associated with CVD [odds ratio 1.34, 95 % confidence interval (1.05–1.70), p=0.018], independently of established CV risk factors (CVRFs) including age, sex, hypertension, smoking, diabetes, low and high-density lipoprotein cholesterol levels. The n=455 (6.8 %) study participants with a history of CVD (secondary prevention subgroup) presented higher median anti-ApoA-1 IgG values compared with sub- jects without CVD (p=0.029). Among patients in the secondary pre- vention subgroup, those with positive anti-apoA-1 IgG levels had lower HDL (p=0.002) and magnesium (p=0.001) levels, but increased uric acid and high-sensitivity C-reactive protein levels (p=0.022, and p<0.001, respectively) compared to patients with negative anti- apoA-1 IgG levels. In conclusion, anti-apoA-1 IgG levels are indepen- dently associated with CVD in the general population and also related to CV biomarkers in secondary prevention. These findings indicate that anti-apoA-1 IgG may represent a novel CVRF and need further study in prospective cohorts

Cardiogenic shock due to reverse takotsubo syndrome triggered by multiple sclerosis brainstem lesions: a case report and mini review

BackgroundTakotsubo syndrome (TTS) is mainly characterized by chest pain, left ventricular dysfunction, ST-segment deviation on electrocardiogram (ECG) and elevated troponins in the absence of obstructive coronary artery disease. Diagnostic features include left ventricular systolic dysfunction shown on transthoracic echocardiography (TTE) with wall motion abnormalities, generally with the typical “apical ballooning” pattern. In very rare cases, it involves a reverse form which is characterized by basal and mid-ventricular severe hypokinesia or akinesia, and sparing of the apex. TTS is known to be triggered by emotional or physical stressors. Recently, multiple sclerosis (MS) has been described as a potential trigger of TTS, especially when lesions are located in the brainstem.Case summaryWe herein report the case of a 26-year-old woman who developed cardiogenic shock due to reverse TTS in the setting of MS. After being admitted for suspected MS, the patient presented with rapidly deteriorating clinical condition, with acute pulmonary oedema and hemodynamic collapse, requiring mechanical ventilation and aminergic support. TTE found a severely reduced left ventricular ejection fraction (LVEF) of 20%, consistent with reverse TTS (basal and mid ventricular akinesia, apical hyperkinesia). Cardiac magnetic resonance imaging (MRI) performed 4 days later showed myocardial oedema in the mid and basal segments on T2-weighted imaging, with partial recovery of LVEF (46%), confirmed the diagnosis of TTS. In the meantime, the suspicion of MS was also confirmed, based on cerebral MRI and cerebral spinal fluid analyses, with a final diagnosis of reverse TTS induced by MS. High-dose intravenous corticotherapy was initiated. Subsequent evolution was marked by rapid clinical improvement, as well as normalization of LVEF and segmental wall-motion abnormalities.ConclusionOur case is an example of the brain-heart relationship: it shows how neurologic inflammatory diseases can trigger a cardiogenic shock due to TTS, with potentially serious outcomes. It sheds light on the reverse form, which, although rare, has already been described in the setting of acute neurologic disorders. Only a handful of case reports have highlighted MS as a trigger of reverse TTS. Finally, through an updated systematic review, we highlight the unique features of patients with reversed TTS triggered by MS

Atypical Electrocardiographic Presentations in Need of Primary Percutaneous Coronary Intervention.

Early initiation of reperfusion therapy remains the cornerstone of successful management for ST-elevation myocardial infarction (STEMI). Rapid restoration of coronary blood flow relies on prompt recognition of the typical ST-segment elevation on a 12-lead electrocardiogram (ECG)-a surrogate for coronary occlusion or critical stenosis-allowing timely activation of the STEMI protocol cascade, with a major positive impact in mortality and clinical outcomes. However, atypical, very high risk ECG patterns-known as "STEMI equivalents"-are present in 10% to 25% of patients with ongoing myocardial ischemia in need of urgent primary percutaneous coronary intervention. Though briefly mentioned in the current recommendations, structured clinical data on those specific ECG presentations are lacking. By thoroughly searching MEDLINE and EMBASE we conducted a structured review of non-STEMI, albeit very high risk, ECG patterns of acute coronary syndrome, often associated with coronary occlusion or critical stenosis. After screening 997 studies, we identified the following distinct "STEMI equivalent" ECG patterns: Wellens' syndrome, de Winter sign, hyperacute T waves, left bundle branch block-including paced rhythm-and right bundle branch block. For each pattern, a brief summary of the existing evidence, together with the sensitivity, specificity, and positive predictive value-whenever available-are presented. In conclusion, prompt recognition of "STEMI equivalent" ECG patterns is crucial for every physician or paramedic dealing with acute coronary syndrome patients in the emergency department or the prehospital setting, as misinterpretation of those high risk presentations can lead to reperfusion delays and worse outcomes