Article

Association of Growth Differentiation Factor-15 with Coronary Atherosclerosis and Mortality in a Young, Multiethnic Population: Observations from the Dallas Heart Study

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9047, USA.
Clinical Chemistry (Impact Factor: 7.91). 11/2011; 58(1):172-82. DOI: 10.1373/clinchem.2011.171926
Source: PubMed

ABSTRACT

Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined.
We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30-65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200-1799; and ≥1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC>10 Agatston units), increased CAC (CAC≥100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths).
Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P<0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15≥1800 ng/L was associated with CAC>10 (odds ratio 2.1; 95% CI 1.2-3.7; P=0.01), CAC≥100 (odds ratio 2.6; 95% CI 1.4-4.9; P=0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1-5.9, P<0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1-5.8, P=0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P=0.025), the integrated discrimination index (0.028; P<0.0001) and the category-less net reclassification index (0.42; P=0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T.
GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.

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Available from: Anand Rohatgi, Dec 01, 2014
    • "It has been shown that an enhanced serum level of GDF15 is an independant risk factor for cardiovascular events (Brown et al., 2002). In recent years, many studies have indicated the role of GDF15 in heart disease and its potential use as a biomarker (Anand et al., 2010; Bonaca et al., 2011; Nickel et al., 2011; Rohatgi et al., 2012; Wallentin et al., 2013; Wang et al., 2012). For example, Arslan et al. reported that measurement of GDF15 levels in combination with Tissue Doppler imaging may be a method to detect asymptomatic anthracycline-mediated cardiomyopathy in young cancer survivors (Arslan et al., 2013). "

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    • "It has been shown that an enhanced serum level of GDF15 is an independant risk factor for cardiovascular events (Brown et al., 2002). In recent years, many studies have indicated the role of GDF15 in heart disease and its potential use as a biomarker (Anand et al., 2010; Bonaca et al., 2011; Nickel et al., 2011; Rohatgi et al., 2012; Wallentin et al., 2013; Wang et al., 2012). For example, Arslan et al. reported that measurement of GDF15 levels in combination with Tissue Doppler imaging may be a method to detect asymptomatic anthracycline-mediated cardiomyopathy in young cancer survivors (Arslan et al., 2013). "
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    ABSTRACT: Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days’ exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular mechanisms behind the late onset apoptosis associated with doxorubicin-induced cardiomyopathy.
    Full-text · Article · Dec 2014 · Toxicology
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    • "In obese non-diabetic individuals, GDF-15 could predict future insulin resistance and impaired glucose control[24], and in patients free of clinically-overt cardiovascular disease, GDF-15 was positively associated with age, diabetes, hypertension, worse kidney function[22] and NT-proBNP levels[23]. Indeed, several studies have also reported higher plasma GDF-15 levels in patients with cardiovascular pathologies such as CAD [25], ACS[7], [8], [26] or chronic heart failure[9], [27]. Furthermore, in patients with CAD, GDF-15 concentrations correlated with other markers of inflammation[28], and elevated GDF-15 levels are now considered a strong biomarker of risk progression and mortality in cardiovascular disease[29]–[31]. "
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    ABSTRACT: Objective Growth differentiation factor-15 (GDF-15) has been identified as a strong marker of cardiovascular disease; however, no data are available concerning the role of GDF-15 in the occurrence of organ dysfunction during coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB). Methods Five arterial blood samples were taken sequentially in 34 patients from anesthesia induction (IND) until 24 h after arrival at the intensive care unit (ICU). Plasma levels of GDF-15, follistatin-like 1 (FLST1), myeloperoxidases (MPO), hydroperoxides and plasma antioxidant status (PAS) were measured at each time-point. Markers of cardiac (cardiac-troponin I, cTnI) and renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL) and other classical biological factors and clinical data were measured. Results Plasma GDF-15 levels increased gradually during and after surgery, reaching nearly three times the IND levels in the ICU (3,075±284 ng/L vs. 1,061±90 ng/L, p<0.001). Plasma MPO levels increased dramatically during surgery, attaining their highest level after unclamping (UNCLAMP) (49±11 ng/mL vs. 1,679±153 ng/mL, p<0.001) while PAS significantly decreased between IND and UNCLAMP (p<0.05), confirming the high oxidative status induced by this surgical procedure. ICU levels of GDF-15 correlated positively with cTnI and NGAL (p = 0.006 and p = 0.036, respectively), and also with hemoglobin and estimated glomerular filtration rate (eGFR). Among all the post-operative biomarkers available, only eGFR, NGAL and GDF-15 measured at ICU arrival were significantly associated with the onset of acute kidney injury (AKI). Patients with a EuroSCORE >3 were shown to have higher GDF-15 levels. Conclusions During cardiac surgery associated with CPB, GDF-15 levels increased substantially and were associated with markers of cardiac injury and renal dysfunction.
    Full-text · Article · Aug 2014 · PLoS ONE
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