Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts.

AIMS Growth differentiation factor 11 and/or its homologue growth differentiation factor 8 (GDF11/8) reverses age-related cardiac hypertrophy and vascular ageing in mice. We investigated whether GDF11/8 associates with cardiovascular outcomes, left ventricular hypertrophy (LVH), or age in humans. METHODS AND RESULTS We measured plasma GDF11/8 levels in 928 participants with stable ischaemic heart disease in the Heart and Soul study. We adjudicated heart failure hospitalization, stroke, myocardial infarction, death, and their composite endpoint. Left ventricular hypertrophy was evaluated by echocardiography. We used multivariable Cox proportional hazards models to compare rates of cardiovascular events and death across GDF11/8 quartiles and logistic regression models to evaluate the association between GDF11/8 and LVH. Four hundred and fifty participants (48.5%) experienced a cardiovascular event or death during 8.9 years of follow-up. The adjusted risk of the composite endpoint was lower in the highest compared with the lowest GDF11/8 quartile [hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.33-0.60; P < 0.001]. We replicated this relationship of GDF11/8 to adverse events in 971 participants in the HUNT3 cohort (adjusted HR, 0.34; 95% CI, 0.23-0.51; P < 0.001). Left ventricular hypertrophy was present in 368 participants (39.7%) at baseline. Participants in the highest quartile of GDF11/8 were less likely to have LVH than those in the lowest quartile (adjusted OR, 0.55; 95% CI, 0.35-0.86; P = 0.009). GDF11/8 levels were lower in older individuals (P < 0.001). CONCLUSION In patients with stable ischaemic heart disease, higher GDF11/8 levels are associated with lower risk of cardiovascular events and death. Our findings suggest that GDF11/8 has similar cardioprotective properties in humans to those demonstrated in mice.

[1]  I. Clay,et al.  GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration. , 2015, Cell metabolism.

[2]  Eric P. Hoffman,et al.  Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy , 2015, Proceedings of the National Academy of Sciences.

[3]  Victor Mor-Avi,et al.  Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. , 2015, European heart journal cardiovascular Imaging.

[4]  Richard T. Lee,et al.  Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors , 2014, Science.

[5]  Richard T. Lee,et al.  Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle , 2014, Science.

[6]  Richard T. Lee,et al.  Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy , 2013, Cell.

[7]  Harold I Feldman,et al.  Estimating glomerular filtration rate from serum creatinine and cystatin C. , 2012, The New England journal of medicine.

[8]  M. Turakhia,et al.  Prognostic significance of increased left ventricular mass index to mortality and sudden death in patients with stable coronary heart disease (from the Heart and Soul Study). , 2008, The American journal of cardiology.

[9]  Shunichi Homma,et al.  Left Ventricular Mass and Geometry and the Risk of Ischemic Stroke , 2003, Stroke.

[10]  J. Rumsfeld,et al.  Depressive symptoms and health-related quality of life: the Heart and Soul Study. , 2003, JAMA.

[11]  Douglas W Mahoney,et al.  Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. , 2003, JAMA.

[12]  A. Joyner,et al.  Expression of growth/differentiation factor 11, a new member of the BMP/TGFβ superfamily during mouse embryogenesis , 1999, Mechanisms of Development.

[13]  D. Levy,et al.  Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. , 1990, The New England journal of medicine.

[14]  D. Levy,et al.  Left ventricular mass and incidence of coronary heart disease in an elderly cohort. The Framingham Heart Study. , 1989, Annals of internal medicine.

[15]  W. Kannel,et al.  The natural history of congestive heart failure: the Framingham study. , 1971, The New England journal of medicine.

[16]  D. Littmann The natural history of congestive heart failure. , 1971, The New England journal of medicine.

[17]  K. Hveem,et al.  COHORT PROFILE Cohort Profile : The HUNT Study , Norway , 2013 .

[18]  M. Whooley,et al.  Development of an echocardiographic risk-stratification index to predict heart failure in patients with stable coronary artery disease: the Heart and Soul study. , 2009, JACC. Cardiovascular imaging.

[19]  H. Tunstall-Pedoe,et al.  Definitions for Acute Coronary Heart Disease in Epidemiology and Clinical Research Studies , 2003 .