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Activation of mitochondrial telomerase reverses relative lymphopenia post myocardial infarction: results from the randomised, double-blinded TACTIC phase IIa pilot trial

Lookup NU author(s): Professor Ioakim SpyridopoulosORCiD, Dr Bilal Bawamia, Dr Luke Spray, Vincent Wangsaputra, Professor Konstantinos StellosORCiD, Dr Karim Bennaceur, Dr Ehsan Kharatikoopaei, Dr Emmanuel Ogundimu, Rebecca Maier, Professor Helen Hancock, Dr Gavin RichardsonORCiD, Dr David Austin


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Background: Immune ageing is a phenomenon which includes lymphopenia, expansion of pro-inflammatory T-lymphocyte subsets and telomere shortening. While lymphopenia predicts mortality after myocardial infarction (MI), MI itself leads to both an increase in terminally differentiated memory CD8+ T-lymphocytes (CD8+ TEMRAs) and a decrease in telomere length. Activation of telomerase has been shown to ameliorate lymphopenia, and improve heart function after MI in mouse models. TA-65 is an oral telomerase activator, which may ameliorate immune ageing and improve outcome after MI.Methods.This double-blinded, randomized placebo-controlled pilot study evaluated the use of TA-65 in 90 MI patients over 65 years, the average onset age for immune ageing. Patients were randomised to either TA-65 (16 mg daily, n=45) or placebo (n=45) for 12 months. The majority of patients underwent percutaneous coronary intervention (87%) or coronary artery bypass surgery (2%) as treatment for their index MI. The pre-defined primary endpoint was the proportion of CD8+ TEMRA T-lymphocytes at 12 months, a marker of immune ageing. A linear mixed effects model was used for the analysis.Results.The proportion of CD8+ TEMRAs after 12 months did not differ between the 2 treatment groups, although only increased significantly in the placebo group (+2.2%, 95% CI: 0.14–4.24). TA-65 was well tolerated, with total adverse events lower in the treatment group (TA-65 vs. placebo group: n=130 vs. n=185). We observed at 12 months a 62% reduction in mean high-sensitivity CRP (hsCRP: TA-65 vs. placebo group: 1.1±0.9 vs. 2.9±6.4 mg/L) and a 15%-increase in mean peripheral blood lymphocytes in TA-65 after 12 months. In the whole sample, among those who were treated with TA-65 compared to Placebo, after 12 months peripheral blood lymphocytes increased (+285 cells /μl, 95% CI: 117–452). The latter was due to significant increases in the TA-65 group from baseline to 12 months across all major lymphocyte populations: CD3+ (+15%), CD4+ (+14%),CD8+ T-lymphocytes (+19%), B-lymphocytes (+17%) and natural killer cells (+12%), while no changes occurred in major lymphocyte populations in the placebo group over the course of the study.Conclusion.In this randomised clinical trial, we found that while CD8+ TEMRAs were not significantly altered after 12 months, the telomerase activator TA-65 significantly increased all major lymphocyte subsets and substantially reduced hsCRP at 12 months in patients with MI. These findings suggest TA-65 holds great promise in potentially reducing inflammation while improving an age-related decline in major lymphocyte populations, thereby enhancing immunity. A larger, multicentre, powered phase IIb efficacy trial to examine the potential effect of TA-65 in prognosis and heart function after MI is therefore warranted.

Publication metadata

Author(s): Spyridopoulos I, Bawamia B, Spray L, Wangsaputra V, Stellos K, Bennaceur K, Kharatikoopaei E, Ogundimu E, Gale CP, Keavney B, Maier R, Hancock H, Richardson G, Austin D

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: ESC Congress 2022

Year of Conference: 2022

Pages: ehac544.1225

Print publication date: 03/10/2022

Online publication date: 03/10/2022

Acceptance date: 29/08/2022

ISSN: 0195-668X

Publisher: Oxford University Press


DOI: 10.1093/eurheartj/ehac544.1225

Series Title: European Heart Journal