The Influence of Chronic Kidney Disease, Apoptosis and Inflammatory Biomarkers on the Diagnosis, Prognosis and Management of Acute Coronary Syndromes

Acute coronary syndrome (ACS) results from the occlusion of coronary vessels leading to ischemia in distal cardiac muscle. When ischemia is severe enough to cause myocardial cell death by necrosis, myocardial infarction (MI) is diagnosed, whereas milder cases lead to unstable angina (UA). Challenges in the diagnosis of ACS are important, as the clinical presentation can be atypical and circulating levels of troponin are normal at the time of presentation in 50% of patients with MI. The identification of high-risk patients is also important, in order to select those who will benefit from invasive strategies such as coronary angiography and dilation.;The first objective was to assess whether measuring circulating biomarkers of apoptosis and inflammation (soluble Fas (sFas) and high-sensitivity C-reactive protein (CRP)) at the time of hospital admission could improve diagnostic accuracy and prognostic accuracy following an ACS. We compared circulating levels of these biomarkers in those who had a final non-cardiac chest pain diagnosis, those who had an ACS diagnosis and experienced, or not, recurrent cardiac events during a 1-year follow-up. sFas was associated with a discharge diagnosis of ACS versus non-cardiac chest pain during the index hospitalization, but hs-CRP was not. sFas significantly improved the C-statistic and diagnostic accuracy for ACS. Baseline sFas and CRP did not predict recurrent cardiac events.;The second objective was to assess whether longitudinal trends in sFas and CRP levels were different in ACS patients according to clinical outcomes. In patients with ACS, sFas levels increased faster in time in subjects who experienced recurrent ACS, HF or cardiac related death over a 1-year follow-up. Longitudinal CRP trends were not associated with prognosis in patients with ACS.;The third objective was to explore 2 aspects of the strong link between chronic kidney disease (CKD) and ACS. From a mechanistic viewpoint, we first wished to study whether there was effect modification by CKD in the relationship between sFas and the diagnosis or prognosis of ACS. We could not detect any interaction in this study. From a clinical perspective, we assessed whether the therapy of ACS differed according to renal function. Use of coronary angiography and lipid-lowering drugs at discharge were lower in patients with CKD, while other aspects of care were similar.;In this thesis, we perform a retrospective analysis nested in a prospective cohort of patients admitted to the hospital with a putative diagnosis of ACS, the RISCA study (Recurrence et inflammation dans les syndromes coronariens aigus). The study began in 2000, ended in early 2002, and recruited 1210 patients. Amongst the latter, 100 were eventually discharged with a diagnosis of non-cardiac chest pain. Plasma were collected within 24 hours of the end of ischemic symptoms, at discharge, 1 month after discharge and stored for future analyses. Patients were followed for 1 year after hospital discharge to assess the recurrence of ACS, hospitalization for heart failure (HF) and cardiac death. All the studies summarized below were secondary analyses of the RISCA database.;In conclusion, our results suggest that in suspected ACS cases, sFas measured at baseline helps improving diagnostic accuracy. Increasing sFas levels in ACS patients who have adverse outcomes are consistent with a postulated role for apoptosis in plaque destabilization and heart remodeling. In patients with ACS, the extent of CKD-related undertreatment is less than reported previously, which is partially explained by more complete adjustment for co-treatments/comorbidities in the present study.