Copeptin in cardiovascular disease and dysglycemia

Sammanfattning: Background: The impaired prognosis in patients with cardiovascular disease (CVD) and dysglycemia is not fully explained by traditional risk markers, among them hyperglycemia and hyperlipidemia. Understanding the developmental mechanism of CVD and identifying potential biomarkers are important parts in attempts to reduce cardiovascular mortality and morbidity in people with and without dysglyemia. The overall aim was to study biomarkers, in particular copeptin, in hopes of shedding light on the reasons for this association. Copeptin, a marker of vasopressin release, has been suggested to be involved in both the development of CVD and dysglycaemia. Aims: The general aims were to evaluate copeptin levels in relation to CVD and dysglycemia by studying: 1. the association between copeptin and Insulin-like Growth Factor Binding Protein-1 (IGBFP-1) and the development of levels over time in patients with acute myocardial infarction (MI) and type 2 diabetes mellitus (T2DM) (Study I) 2. the copeptin levels and their prognostic importance in patients with acute MI and newly detected glucose abnormalities (Study II) 3. the copeptin levels beyond the acute phase of MI, whether they differ between known and unknown MI and to explore the prognostic implications of copeptin in relation to markers of stress and heart failure (Study III) 4. whether copeptin is associated with early manifestations of atherosclerosis and the prognostic impact of copeptin in individuals without previous MI (Study IV) Acute MI and T2DM. Copeptin and IGFBP-1 were analyzed in patients with acute MI and known T2DM (median age 70 years; men 68%), measured at hospital admission (n=393) and discharge (n=309) and three months later (n=288). The primary outcome was cardiovascular events (CVE) after 2.5 years of follow up. The copeptin-levels were 21.8 pmol/L (median) at admission, 8.5 pmol/L at discharge and 8.4 pmol/L three months later. IGFBP-1 increased over time. Copeptin and IGFBP-1 correlated with each other at all time points. Copeptin, not IGBFP-1, remained a predictor for CVE at all time points in adjusted Cox-regression analysis. Acute MI and newly discovered glucose abnormalities. Copeptin was analyzed in patients (n=166) with acute MI without previously known glucose abnormalities (median age 64 years; 70% men) and in age and gender matched controls (n=168). Based on an oral glucose tolerance test the participants were classified as having normal (NGT) or abnormal glucose tolerance (AGT). The primary outcome was total mortality. The copeptin levels were higher in patients (median 10.5 pmol/L) than for controls (5.9 pmol/L; p<0.01). Patients with AGT had higher copeptin levels than those with NGT (p<0.01). Copeptin was associated with increased mortality in unadjusted Cox-regression analyses. Elderly individuals with previous MI. Copeptin, cortisol and NT-proBNP were analyzed in 926 participants in the observational ICELAND MI-study (median age 76 years; 49% men). A total of 246 had a previous MI whereof 91 were recognized (RMI) and 155 previously unknown (UMI) but discovered with cardiac magnetic resonance imaging. The primary outcome was CVE during 9.1 years of follow up. The copeptin levels were higher in individuals with previous MI independent of whether it was previously known or not. Copeptin correlated with evening cortisol and NT-proBNP. Copeptin was associated with CVE and total mortality after adjusting for cortisol and NT-proBNP separately. Copeptin continued to associate with total mortality in the final model (including copeptin, copeptin measured in the morning and evening, NT-proBNP, age, sex, serum creatinine and previous heart failure). Copeptin was not associated with heart failure or MI. Elderly individuals and atherosclerosis. Copeptin and coronary artery calcium (CAC) score were analyzed in 677 participants without MI from the ICELAND MI-study. The Agatston method was used to measure CAC score by means of computed tomography. The CAC score was divided into four categories: CAC score 0 (no visible plaque), 1-99 (mild), 100-399 (moderate) and ≥400 (extensive plaque burden). The primary outcome was CVE during a median of 9.1 years follow up. Individuals with CAC score 1-399 had similar copeptin levels as those with a CAC score 0 while participants with CAC ≥400 had significantly higher copeptin levels. Copeptin was not associated with CVE but with total mortality in unadjusted analysis and after adjustments for CAC score but not after adjusting for sex and age. The event rates were significantly higher for participants with high CAC score, irrespective of copeptin level. Conclusion: Copeptin was elevated in patients with acute MI, especially in those with newly detected glucose abnormalities. The levels remain elevated in the post-MI phase independent of dysglycemia. The relationship between copeptin and IGFBP-1 during the acute phase of MI persisted in the post-MI phase in patients with T2DM. Copeptin correlated with stress and heart failure markers, but this did not fully explain the association with total mortality. Individuals with high CAC scores had high copeptin levels, but the prognosis was influenced by other factors. In summary, the results support the theory that copeptin should be seen as an expression of general disease and subsequent poor prognosis, and not as a specific marker for CV disease or dysglycemia.