Telomere shortening and telomerase activity in ischaemic cardiomyopathy patients - Potential markers of ventricular arrhythmia.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) reduce mortality in patients with ischaemic cardiomyopathy at high risk of ventricular arrhythmias (VA). However, the current indication for ICD prescription needs improvement. Telomere and telomerase in leucocytes have been shown to associate with biological ageing and pathogenesis of cardiovascular diseases. We hypothesised that leucocyte telomere length, load-of-short telomeres and/or telomerase activity are associated with VA occurrence in ischaemic cardiomyopathy patients. METHODS AND RESULTS: 90 ischaemic cardiomyopathy patients with primary prevention ICDs were recruited. 35 had received appropriate therapy from the ICD for potentially-fatal VA while the remaining 55 patients had not. No significant differences in baseline demographic data relevant to telomere biology were seen between the two groups. There was no significant difference in the age and sex adjusted mean telomere length analysed by qPCR between the groups (p=0.88). In contrast, the load-of-short telomeres assessed by Universal-STELA method and telomerase activity by TRAP assay were both higher in patients who had appropriate ICD therapy and were significantly associated with incidence of ICD therapy (p=0.02, p=0.02). ROC analyses demonstrated that the sensitivity and specificity of these telomere dynamics in predicting potentially-fatal VA was higher than the current gold-standard - left ventricular ejection fraction (AUC 0.82 versus 0.47). CONCLUSION: The load-of-short telomeres and telomerase activity had a significant association with ICD therapy (for VA) in ischaemic cardiomyopathy patients. These biomarkers should be tested in prospective studies to assess their clinical utility in predicting VA after myocardial infarction and guiding primary prevention ICD prescription.

Socioeconomic status and telomere length: the West of Scotland Coronary Prevention Study.

BACKGROUND: It has been hypothesised that socioeconomically deprived people age more rapidly than their more advantaged counterparts and this is biologically manifest in shorter telomeres. However, in the very few studies conducted, substantial uncertainty exists regarding this relationship. METHODS: In the present investigation, 1542 men in the West of Scotland Coronary Prevention Study responded to a series of enquiries about their socioeconomic position (educational attainment, employment status, area-based deprivation), had their physical stature measured (a proxy for early life social circumstances) and provided a blood specimen from which leucocyte DNA was extracted and telomere length derived. RESULTS: There was no strong evidence that any of these four indices of socioeconomic position was robustly related to telomere length. The only exception was employment status: men who reported being out of work had significantly shorter telomeres than those who were employed (p = 0.007). CONCLUSION: In this cross-sectional study-the largest to date to examine the relationship-we found little evidence of an association between socioeconomic status and telomere length.

Association of increased telomere lengths in limited scleroderma, with a lack of age-related telomere erosion.

OBJECTIVES: Telomere erosion, a feature of biological ageing, is implicated in a wide range of diseases. Its impact on autoimmune diseases remains unclear although autoantibodies against many telomere nucleoprotein components are prevalent in these diseases. We aimed to assess if telomere biology was abnormal in a cohort of patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: Telomere lengths in peripheral blood leucocytes (PBL) were determined using Southern blotting methods in a cohort of lcSSc subjects (n=43; age range 37-80 years) and a control population (n=107; age range 21-65 years). RESULTS: Telomere lengths in lcSSc subjects were longer than controls (p<0.001), did not show age-related telomere erosion and differed significantly from age-matched controls only after 50 years of age (p<0.001). CONCLUSIONS: This is the first report of maintenance of telomere lengths in an autoimmune disease state. These data indicate aberrant telomere biology and irregular biological ageing from the fifth decade of life. These findings provide insight into compromised DNA damage repair in lcSSc. Whether these observations indicate a causal or consequential relationship requires further investigation. This in turn, may provide potential novel targets for therapeutic intervention.

Telomere length is shorter in healthy offspring of subjects with coronary artery disease: support for the telomere hypothesis.

BACKGROUND: Telomeres are shorter in subjects with coronary artery disease (CAD) and may indicate premature biological ageing. However, whether shorter telomeres are a primary abnormality or secondary to the disease is unclear. OBJECTIVE: To investigate whether shorter telomeres are a primary abnormality or secondary to CAD, telomere lengths in healthy young adults with contrasting familial risk of CAD were compared. DESIGN: Case-control study. METHODS: Mean telomere restriction fragment (TRF) length in DNA from circulating leucocytes was determined by Southern blotting in 45 healthy offspring of subjects with premature CAD (case offspring) and 59 offspring from families without such a history (control offspring). Correlation in mean TRF length was also assessed in 67 offspring-parent pairs. RESULTS: On average, a decrease of 27.5 (10.7) bp in mean TRF per year of age was found. The unadjusted mean TRF length was 6.34 kb (95% CI 6.13 to 6.55) for case offspring and 6.75 kb (95% CI 6.57 to 6.94) for offspring of controls (p = 0.004). The adjusted difference in mean TRF between case and control offspring was 472 bp (95% CI 253 to 691, p<0.001), equivalent to about 17 years of age-related attrition in telomere length. Furthermore, there was a significant positive correlation in mean TRF length between offspring and their parents (r = 0.37, p = 0.002). CONCLUSION: These findings suggest that inheritance of shorter telomeres is associated with increased familial risk of CAD. They support the hypothesis that telomere length is a primary abnormality involved in the pathogenesis of CAD.