Cystatin C Identifies Patients With Stable Chronic Heart Failure at Increased Risk for Adverse Cardiovascular Events

Study Questions:

Is cystatin C (CysC) more prognostic in patients with chronic heart failure (HF) than other measures of renal function?

Methods:

This was a secondary analysis of data collected as part of the GeneBank study, a single-center study of patients with “clinical heart failure” undergoing planning angiography. Serum creatinine, urea levels (blood urea nitrogen [BUN]), CysC, and glomerular filtration rate (GRF) estimated by the MDRD (estimated GFR [eGFR] MDRD) equation were measured. The primary endpoint was major adverse cardiovascular events (MACE), defined as death, myocardial infarction, or stroke. Areas under the receiver operating characteristic (AUC) curves and Cox proportional hazard ratios were calculated for the primary endpoint.

Results:

There were 823 patients in the study with a mean ± standard deviation age of 66 ± 11 years. Ejection fraction (EF) was preserved (EF >50%) in 35% and the median [25th, 75th] creatine was 0.94 [0.80-1.17] mg/dl (25% had an eGFR <60 ml/min/m2) and median CysC was 1.11 [0.92-1.41] mg/dl. Over 3 years of follow-up, there were 201 MACE (24%), of which 39% (n = 80) occurred in those with an eGFR <60 ml/min/m2. AUCs for predicting MACE were modest at best for both CysC (AUC = 0.648) and eGFRMDRD (AUC = 0.615). For those with eGFR <60 ml/min/1.73 m2 versus eGFR >60 ml/min/1.73m2, CysC AUCs for MACE were 0.586 versus 0.600, respectively. CysC increased the risk of MACE by 1.29 [1.15-1.44] when adjusting for B-type natriuretic peptide (BNP) and by 1.20 [1.05-1.36] when adjusting for BNP, age, body mass index, diabetes, coronary disease, hemoglobin, and high-sensitivity C-reactive protein. MACE occurred in 12% in those with both BNP and CysC in the lowest tertile versus 45% in those with both variables in the highest tertile.

Conclusions:

CysC is an independent predictor of adverse events in patients with chronic HF.

Perspective:

CysC is a cysteine protease inhibitor made by nucleated cells that is freely filtered in the kidneys without secretion or reabsorption. It is measured in the plasma with intra- and inter-assay variabilities of 3% and 6%. Studies have shown that CysC is a better predictor of events than serum creatinine. In this large study of patients with HF, CysC was correlated with increased risk of MACE, independent of traditional risk factors. AUCs, however, were not high, and thus, risk discrimination using CysC alone is modest at best. It does appear to improve risk discrimination above that of BNP, but clearly, more studies are needed to better understand CysC’s utility.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Prognosis, Myocardial Infarction, Stroke, Biological Markers, Heart Failure, Cysteine Proteinase Inhibitors, Glomerular Filtration Rate, Cystatin C


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