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Observational Study
. 2015 Dec 21;36(48):3426-34.
doi: 10.1093/eurheartj/ehv385. Epub 2015 Aug 20.

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

Kristoff A Olson  1 , Alexis L Beatty  2 , Bettina Heidecker  1 , Mathilda C Regan  3 , Edward N Brody  4 , Trudi Foreman  4 , Shintaro Kato  5 , Robert E Mehler  4 , Britta S Singer  4 , Kristian Hveem  6 , Havard Dalen  7 , David G Sterling  4 , Richard M Lawn  4 , Nelson B Schiller  1 , Stephen A Williams  4 , Mary A Whooley  8 , Peter Ganz  9
Affiliations
Observational Study

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

Kristoff A Olson et al. Eur Heart J. .

Abstract

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.

Keywords: Ageing; Cardiovascular outcomes; Epidemiology; Growth differentiation factor 11 and 8; Hypertrophy.

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Figures

Figure 1
Figure 1
Incidence of heart failure hospitalization, stroke, myocardial infarction, death, and composite endpoint in Heart and Soul cohort, unadjusted, stratified by quartile of GDF11/8. P-Values for trend are <0.001 for heart failure, death, and composite endpoint, 0.18 for stroke, and 0.004 for myocardial infarction.
Figure 2
Figure 2
Incidence of heart failure, stroke or transient ischaemic attack (TIA), myocardial infarction, death, and composite endpoint in HUNT3 cohort, unadjusted, stratified by quartile of GDF11/8. P-Values for trend are <0.001 for heart failure, death, and composite endpoint, 0.004 for stroke, and 0.02 for myocardial infarction.
Figure 3
Figure 3
Prevalence of left ventricular hypertrophy by quartile of GDF11/8. Unadjusted. Left ventricular hypertrophy defined as left ventricular mass index >88 g/m2 in females, >102 g/m2 in males. P-Value is 0.02.
Figure 4
Figure 4
GDF11/8 levels by age, unadjusted. Inner line = median, box 25th–75th percentile, outer whiskers denote adjacent value 1.5 times height of box. Units = relative fluorescence units. (A) Heart and Soul cohort and (B) HUNT3 cohort. P-Value is <0.001 for both Heart and Soul and HUNT3 cohorts.
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