Higher cystatin C level predicts long-term mortality in patients with peripheral arterial disease

Abstract

Aims

Cystatin C and cathepsins could play a role in different processes and stages of the atherosclerotic disease. We aimed to investigate the relationship of cystatin C, and cathepsins L, and S, to lethal outcome in patients with peripheral arterial disease (PAD).

Methods and results

We studied 378 patients with established PAD. Cox regression was used to assess relationships between serum cystatin C or cathepsins L and S, and time to lethal outcome. The role of cystatin for prognosis of cardiovascular death was assessed with c-statistic, and net reclassification improvement (NRI). Patients with cystatin C levels above 1 mg/l (fifth quintile) had a significantly increased adjusted risk for all-cause and cardiovascular mortality compared to patients with cystatin C levels below or equal to 1 mg/l (hazard ratios (HR) 2.2, 95% CI 1.22–4.12, and HR 3.2, 95% CI 1.39–7.59, respectively). Furthermore, high cystatin C levels were related with higher all-cause (adjusted HR 2.99, 95% CI 1.31–6.85) and cardiovascular mortality (adjusted HR 4.36, 95% CI 1.07–18.8) among PAD patients without renal impairment. Although the addition of cystatin C to conventional risk factors improved the accuracy of risk prediction model for cardiovascular mortality (0.72–0.79; p = 0.03), it did not reclassify a substantial proportion of patients to risk categories (NRI = 0.12, p = 0.128).

Conclusions

Higher cystatin C levels independently predicted 5 years all-cause, and cardiovascular death in PAD patients. However, a small improvement in discrimination with the addition of cystatin C to conventional risk factors, and no improvement in reclassification of risk categories suggest that clinical usefulness of cystatin C for predicting cardiovascular mortality in PAD population might be modest.

Introduction

Peripheral arterial disease (PAD) is common in the elderly population affecting about 27 million people in Europe and North America. PAD patients have significantly increased all-cause mortality, and a high incidence of cardiovascular morbidity and mortality compared with patients without PAD [1]. Identifying high-risk patients, especially those undergoing non-cardiovascular surgery, remains a priority task. Since traditional atherosclerotic risk factors have been shown as poor predictors of outcomes for PAD patients [2] measurement of markers involved in the development and progression of atherosclerosis has been proposed to improve the prediction of adverse outcome in the population of these patients [3].

Recently, an imbalance between the expression of cysteine cathepsins and their endogenous inhibitor cystatin C has been shown in human's atherosclerotic lesions [4]. This imbalance may play an important role in pathological vascular remodeling [5]. Experimental studies showed cathepsin S expression in human atherosclerotic plaques [6], and cathepsin L involvement in the development of atherosclerotic plaque instability [7]. The findings of clinical studies demonstrated significantly higher serum cathepsin L [8], [9] and cathepsin S [10] in patients with coronary artery stenosis suggesting that these proteins might assist in predicting cardiovascular diseases. At the same time, decreased expression of cystatin C was found in atherosclerotic lesions, and a lower plasma concentration of cystatin C in postinfarction patients [4], [5]. However, recently increased cystatin C expression was observed due to regional myocardial ischemia [11], and elevated levels of cystatin C were independently associated with inducible ischemia among outpatients with stable CAD [12]. These findings raise a hypothesis that increased concentration of cystatin C may reflect an attempt to counterbalance a potentially damaging increased elastolytic activity [13].

In addition, cystatin C is becoming an increasingly known endogenous marker of renal function that may identify a “preclinical” stage of kidney dysfunction [14], [15]. Current clinical research have demonstrated that cystatin C was not simply a marker of glomerular filtration rate (GFR) because it predicted future cardiovascular events in healthy elderly populations [14] and patients with documented atherosclerotic diseases [16], [17], [18], [19], [20], [21], [22]. However, a prognostic role of serum cystatin C has not been evaluated among patients with PAD.

On the basis of the current research we hypothesized that cysteine cathepsins and their major inhibitor could associate with lethal outcome, and therefore, we investigated the impact of cathepsin L, cathepsin S, and cystatin C on the prognosis of lethal outcome based on 5-year follow-up in patients with symptomatic PAD.