Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway; Center for Heart Failure Research, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway.
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway; Center for Heart Failure Research, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway.
Exp Gerontol. 2019 May;119:53-60. doi: 10.1016/j.exger.2019.01.020. Epub 2019 Jan 23.
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.
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.
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.
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.
探讨白细胞端粒长度（LTLs）、年龄、性别和冠心病（CAD）合并症之间的关系。进一步评估 LTL 与生长分化因子 11（GDF11）、胰岛素样生长因子 1（IGF1）、沉默调节蛋白 1（SIRT1）和促炎细胞因子之间的变化。
在 300 例稳定 CAD 患者（年龄 36-81 岁，20%为女性）中，从全血中分离 DNA 和 RNA，进行 PCR 分析和 LTL 相对定量以及 GDF11、IGF1、SIRT1、IL-12、IL-18 和 IFNγ基因表达的相对定量。
与无心肌梗死（MI）的患者相比，有 MI 病史的患者的 LTL 短 20%（p=0.019），这表明 LTL 与 CAD 的严重程度有关。然而，这一观察结果仅在男性中观察到（p=0.009，n=115），其中上四分位的 LTL 与前 1-3 四分位相比，MI 的频率降低了 64%（p=0.005，调整）。LTLs 分布不受性别或合并症（如高血压、2 型糖尿病和代谢综合征）的影响。LTLs 与 GDF11 与年龄呈负相关（r=-0.17；p=0.007 和 r=-0.16；p=0.010），然而，这种相关性在性别上是分开的，女性的 LTL 呈负相关（r=-0.37），男性的 GDF11 呈负相关（r=-0.19）（p=0.006，两者）。GDF11 和 SIRT1 之间存在强烈的相关性（r=0.56，p≤0.001），这表明它们可能存在共同的上游调节因子。超重女性（BMI≥25kg/m）中 LTLs 与 GDF11 和 SIRT1 呈中度相关（r=0.41；p=0.027 和 r=0.43；p=0.020），这可能反映了 LTLs 和这些标志物的共同生活方式影响。在所有女性中，我们还观察到，与四分位 1 相比，最高的 LTL 四分位与 GDF11 和 SIRT 表达较高以及循环中 IL-12、IL-18 和 TNFα水平较低有关，这可能表明生活方式对女性 LTLs 有影响。在男性中，最高的 LTL 四分位与 IFNγ表达降低和循环 TNFα水平降低有关。
患有 MI 的 CAD 患者的 LTLs 较短可能表明端粒磨损是其病理生理学的一部分，尤其是在男性中。LTLs 与年龄的负相关仅在女性中存在，这支持了以前报道的男性随年龄增长端粒磨损率下降的现象。由于升高的 GDF11 和 SIRT1 以及减弱的促炎细胞因子似乎对女性的 LTL 有积极影响，我们假设 LTL 调节可能存在性别二态性，这可能暗示了需要进行性别调整的健康预防治疗。
