Renal dysfunction is associated with shorter telomere length in heart failure

This study was a sub-study of the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) of which the main findings have been published [11, 12]. The COACH-study assessed the value of additional support by a specialized heart failure nurse in the treatment of CHF. Eligible patients were aged 18 years or older, had typical signs and symptoms, and evidence for structural heart disease confirmed by cardiovascular imaging. Patients did not necessarily have to have impaired left ventricular ejection fraction (LVEF). At hospital discharge, patients were stable and on oral heart failure medication. In total, 157 (15%) of the 1,023 patients who participated in the COACH were not included in this sub-study, mainly because of no available DNA (n = 133) or missing serum creatinine values (n = 18). This study has been approved by the local Medical Ethics Committee. All patients gave written informed consent.

Baseline characteristics according to quartiles of eGFR are presented in Table 1. The study population consisted of 61% men, median age was 74 years, median LVEF was 30%, with most patients in NYHA class II and III (together 97%). Patients with decreased renal function were less likely to be men, and more likely to be older of age, to have higher NYHA class, hypertension, diabetes, atrial fibrillation or flutter, lower hemoglobin levels, and a previous admission for CHF (Table 1).

Estimated GFR decreased with age at a yearly rate of 0.70 ± 0.058 ml/min/1.73 m² (P < 0.001). Telomere length ratio decreased steadily at a mean rate of 0.0035 ± 0.00064 per year of increase of age (P < 0.001).

Telomere length was 0.719 (interquartile range 0.609–0.881) in the quartile with the highest eGFR, 0.710 (0.604–0.855) in quartile 2, 0.673 (0.582–0.834) in quartile 3, and 0.667 (0.571–0.825) in the quartile with the lowest eGFR (P = 0.031). When leukocyte telomere length was modeled as a continuous predictor, renal function decreased gradually with shorter telomere length. Pearson correlation coefficient for the association between telomere length and eGFR was 0.123 (P < 0.001). The relationship between renal function and telomere length remained significant after adjustment for gender and age (standardized-beta 0.090; Table 2). In the third basic model we also adjusted for the age of CHF onset (Fig. 1). Our findings did not change after additionally adjusting for baseline differences (diabetes, hypertension, history of myocardial infarction, NYHA class, systolic blood pressure, diastolic blood pressure, heart rate, atrial fibrillation, NT-pro-BNP, hemoglobin levels, use of renin-angiotensin system inhibitors, and digoxin; Table 2).

A frequent co-morbidity factor and powerful predictor of mortality in CHF is decreased renal function [7, 10, 13]. The main finding of this study is that reduced leukocyte telomere length, as a marker for advanced intrinsic biological age, is associated with decreased renal function in patients with CHF. This observation remained significant after adjustment for several confounders, including age, age of CHF onset, and severity of CHF.

Telomere length is associated with CHF. We recently demonstrated telomere length to be shorter in 620 patients with CHF compared to healthy controls [21]. This was also observed by others [15]. In addition, levels of TRF2—one of the telomere-stabilizing proteins—in the myocardium of heart failure patients was found to be down-regulated by approximately 50% compared to healthy controls [15]. Interestingly, Werner et al. found that physical exercise in mice up-regulated TRF2, and protected the myocardium from doxorubicin-induced apoptosis [28]. Thus, telomere biology is not only associated with CHF, but seems to be a modifiable factor in heart failure. Possibly, telomeres are a new therapeutic target in heart failure.

A retrospective analysis of the cohort of 620 CHF patients suggested a potential association between telomere length and renal function [23]. Obviously, retrospective analysis is susceptible to type-1 errors. The current prospective study, however, provides important independent confirmation of these preliminary findings. Reduced renal function might be associated with shorter telomere length in patients with CHF for several reasons. First, the processes biological aging and renal senescence associated with renal function decline includes a decreased ability of aged nephrons to cope with diseased states. CHF elicits systemic changes, including decreased cardiac output, inflammation, oxidative stress, and activation of the renin-angiotensin system [4, 22]. Nephrons with shorter telomeres might be less resistant to these challenges and more likely to enter a senescence state, become dysfunctional or even apoptotic. The phenotype of human renal senescence has indeed been described previously as the loss of mass and function, including a loss of GFR [14]. Second, leukocytes telomeres mark replicative history and therefore might mark the cumulative inflammatory burden a patient has been exposed to [1]. Inflammation is a major causal factor of vasculo- and glomerulopathy and consequently might cause a decrease in renal function. Finally, other factors associated with biological aging (e.g., accumulation of advanced glycation endproducts) might cause renal dysfunction and coincide with shorter telomere length [20].

The cross-sectional nature of our study does not allow drawing definite conclusions concerning the nature of the observed association. Although we used multiple statistical adjustments, we cannot exclude possible confounding factors that may have obscured the observed relationship.

In conclusion, decreased renal function was associated with reduced leukocyte telomere length in patients with CHF. This observation support the hypothesis that increased intrinsic biological age affects the kidney in its ability to cope with the systemic changes evoked by CHF and might explain, at least in part, why renal function is closely related to mortality in patients with CHF.