Growth Differentiation Factor 15 for Risk Stratification and Selection of an Invasive Treatment Strategy in Non–ST-Elevation Acute Coronary Syndrome

Abstract

Background-An invasive treatment strategy improves outcome in patients with non-ST-elevation acute coronary syndrome at moderate to high risk. We hypothesized that the circulating level of growth differentiation factor 15 (GDF-15) may improve risk stratification. Methods and Results-The Fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial randomized patients with non-ST-elevation acute coronary syndrome to an invasive or conservative strategy with a follow-up for 2 years. GDF-15 and other biomarkers were determined on admission in 2079 patients. GDF-15 was moderately elevated (between 1200 and 1800 ng/L) in 770 patients (37.0%), and highly elevated (Ͼ1800 ng/L) in 493 patients (23.7%). Elevated levels of GDF-15 independently predicted the risk of the composite end point of death or recurrent myocardial infarction in the conservative group (Pϭ0.016) but not in the invasive group. A significant interaction existed between the GDF-15 level on admission and the effect of treatment strategy on the composite end point. The occurrence of the composite end point was reduced by the invasive strategy at GDF-15 levels Ͼ1800 ng/L (hazard ratio, 0.49; 95% confidence interval, 0.33 to 0.73; Pϭ0.001), between 1200 and 1800 ng/L (hazard ratio, 0.68; 95% confidence interval, 0.46 to 1.00; Pϭ0.048), but not Ͻ1200 ng/L (hazard ratio, 1.06; 95% confidence interval, 0.68 to 1.65; Pϭ0.81). Patients with ST-segment depression or a troponin T level Ͼ0.01 g/L with a GDF-15 level Ͻ1200 ng/L did not benefit from the invasive strategy. Conclusions-GDF-15 is a potential tool for risk stratification and therapeutic decision making in patients with non-ST-elevation acute coronary syndrome as initially diagnosed by ECG and troponin levels. A prospective randomized trial is needed to validate these findings.

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

“…However, the magnitude and time course of RGC death after axonal injury was not different in mice that are genetically deficient in GDF15 compared with littermate controls, which suggests that it did not influence the temporal progression of RGC death (25). Of interest, it has also been reported that GDF15 provides independent prognostic information on cardiovascular events beyond previously identified cardiovascular risk factors and other markers of chronic and acute coronary disease (26,27).…”

Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

“…Circulating osteoprotegerin has been reported to be associated with cardiovascular outcomes, including mortality, MI, and incident heart failure, in several ACS cohorts 16, 17, 18, 19. However, although most of these studies include natriuretic peptides,16, 17, 19 troponins,16, 17, 18 and CRP16, 17, 18 in their adjustment strategy, none include GDF‐15, which increases in response to myocardial stress associated with inflammation and tissue damage30 and is becoming a recognized biomarker in ACS 9, 10, 14. In this large study population, the association between high osteoprotegerin levels at admission and risk of the primary end point or cardiovascular death was markedly attenuated and no longer significant after addition of NT‐proBNP, hs‐TnT, and GDF‐15 to the model that included clinical variables and inflammatory biomarkers.…”

“…In addition to the established natriuretic peptides and cardiac troponins, which have been extensively evaluated and shown to be suitable biomarkers for prognosis and/or risk stratification of ACS,12, 13 the recently characterized inflammatory marker, growth differentiation factor‐15 (GDF‐15), may also provide additional clinically useful prognostic information in ACS 14. Also, cystatin C, a marker of kidney function, has recently gained increasing relevance as an independent marker of mortality in ACS 15.…”

Czynnik różnicowania wzrostu 15 jako biomarker w niewydolności serca

“…Czynniki wpływające na stężenie czynnika różnicowania wzrostu 15 (GDF-15, growth differentiation factor 15) i potencjalny wpływ tego biomarkera na mięsień sercowy (na podstawie [14,15] umożliwiła zautomatyzowanie oznaczania GDF-15, a tym samym jego szersze wykorzystanie [17]. Przeważająca liczba dotychczasowych badań wskazuje na trzy przedziały ryzyka sercowo-naczyniowego: stężenia poniżej 1200 ng/l odpowiadają niskiemu ryzyku (górna granica wartości referencyjnych dla osób zdrowych), 1200-1800 ng/lumiarkowanemu (przeciętnemu) ryzyku, a przekraczające 1800 ng/l -wysokiemu ryzyku [18].…”

“…Stało się to możliwe po dodatkowym uwzględnieniu innych biomarkerów, w tym rozpuszczalnej izoformy receptora ST2 (sST2, soluble ST2). Dopiero określenie stosunku stężeń (białko C-reaktywne [CRP, C-reactive protein] + + GDF-15 + sST2)/NT-proBNP pozwoliło na efektywne róż-nicowanie typu HF (iloraz szans [OR, odds ratio] 3,7; 95% CI 1,9-8,5; p < 0,001) [18]. Stężenie GDF-15 okazało się również skorelowane z echokardiograficznymi markerami dysfunkcji rozkurczowej oraz zmniejszeniem pojemności wyrzutowej serca [23].…”