Novel biomolecules of ageing, sex differences and potential underlying mechanisms of telomere shortening in coronary artery disease.

UNLABELLED

Telomere length (TL), growth differentiate factor (GDF)11, insulin growth factor (IGF)1, sirtuin (SIRT)1 and inflammatory processes have been related to ageing and age-related diseases, like coronary artery disease (CAD). We aimed to investigate the associations between leukocyte TLs (LTLs), chronological age, sex and comorbidities in CAD patients. Any covariations between LTL, GDF11, IGF1, SIRT-1 and pro-inflammatory cytokines were further assessed.

METHODS

In 300 patients with stable CAD (age 36-81 years, 20% females), DNA and RNA were isolated from whole blood for PCR analysis and relative quantification of LTLs and gene-expression of GDF11, IGF1,SIRT1, IL-12, IL-18 and IFNƴ, respectively. Serum was prepared for the analyses of circulating IL-18, IL-12, IL-6 and TNFα.

RESULTS

Patients with previous myocardial infarction (MI) presented with 20% shorter LTLs vs. patients without (p = 0.019) indicating LTLs to be of importance for CAD severity. The observation however, was only observed in men (p = 0.009, n = 115), in which the upper LTL quartile associated with 64% lower frequency of previous MI compared to quartile 1-3 (p = 0.005, adjusted). LTLs were not differently distributed according to sex or comorbidities such as hypertension, diabetes type 2 and metabolic syndrome. LTLs and GDF11 were inversely correlated to age (r = -0.17; p = 0.007 and r = -0.16; p = 0.010, respectively), however, separated in gender, LTL only in women (r = -0.37) and GDF11 only in men (r = -0.19) (p = 0.006, both). GDF11 and SIRT1 were strongly inter-correlated (r = 0.56, p ≤ 0.001), suggesting common upstream regulators. LTLs were moderately correlated to GDF11 and SIRT1 in overweight women (BMI ≥ 25 kg/m) (r = 0.41; p = 0.027 and 0.43; p = 0.020, respectively), which may reflect common life-style influences on LTLs and these markers. In all women, we observed further that the highest LTL quartile associated with higher GDF11 and SIRT expression and lower circulating levels of IL-12, IL-18 and TNFα, as compared to quartile 1, which may indicate lifestyle influences on female LTLs. In men, the highest LTL quartile associated with lower IFNƴ expression and lower circulating TNFα. Overall, the results indicate an association between chronic low-grade inflammation and LTLs.

CONCLUSIONS

Shorter LTLs in CAD patients with previously suffered MI may indicate telomere attrition as part of its pathophysiology in men. The inverse association between LTLs and age exclusively in women underpins the previously reported decline in attrition rate in men with increasing age. As elevated GDF11 and SIRT1 along with attenuated pro-inflammatory cytokines seem to positively affect LTL in women, we hypothesize a potential sex-dimorphism in LTL regulation, which may implicate sex- adjusted health-preventive therapies.