Growth Differentiation Factor 15, Its 12-Month Relative Change, and Risk of Cardiovascular Events and Total Mortality in Patients with Stable Coronary Heart Disease: 10-Year Follow-up of the KAROLA Study

BACKGROUND This study considered whether baseline concentrations and 12-month changes of growth differentiation factor 15 (GDF-15) are associated with subsequent cardiovascular events (CVEs) and total mortality in patients with stable coronary heart disease. METHODS Baseline GDF-15 serum concentrations were measured in 1073 participants in a cardiac rehabilitation program (median follow-up 10 years). GDF-15 associations with subsequent CVE and total mortality were evaluated by Cox-proportional hazards models adjusting for well-established cardiovascular risk factors (Model 2), plus N-terminal probrain natriuretic peptide, high-sensitivity (hs) CRP, and hs cardiac troponin T (Model 3). RESULTS In our study population [84.7% men, mean age 59 years, median baseline GDF-15 1232 ng/L (interquartile range, 916, 1674)] we observed 190 CVE and 162 deaths. Compared to participants with GDF-15 <1200 ng/L, increased risk for death was found in participants with GDF-15 ≥1200 and ≤1800 ng/L [hazard ratio (HR) 1.68 (95% CI, 1.08–2.62)] and with GDF-15 >1800 ng/L [HR 1.73 (1.02–2.94)], even in Model 3. The 12-month relative median change was −16.7%. As compared to participants with 12-month relative changes between −20% and 20%, GDF-15 increments >20% were associated with: a) an HR of 1.84 (1.04–3.26) for CVE in Model 2, but found nonsignificant in Model 3; (b) an HR of 2.26 (1.32–3.86) for death even in Model 3. CONCLUSIONS GDF-15 at baseline is independently associated with subsequent CVE and 10-year total mortality. Twelve-month relative changes remained associated with subsequent CVE when adjusting for well-established cardiovascular risk factors, and with total mortality even after further adjustment for established cardiac biomarkers.