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Cystatin C As a Predictor of Mortality and Cardiovascular Morbidity After Circulation Journal ORIGINAL ARTICLE Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Heart Failure Cystatin C as a Predictor of Mortality and Cardiovascular Morbidity After Cardiac Resynchronization Therapy Toshihiko Yamamoto, MD; Masayuki Shimano, MD, PhD; Yasuya Inden, MD, PhD; Shinjiro Miyata, MD; Yoko Inoue, BSc; Naoki Yoshida, MD, PhD; Yukiomi Tsuji, MD, PhD; Makoto Hirai, MD, PhD; Toyoaki Murohara, MD, PhD Background: Cardiac resynchronization therapy (CRT) has been reported to improve symptoms and cardiac per- formance in patients with severe heart failure (HF), but CRT recipients with advanced HF do not always experience improved mortality rates. Cystatin C has recently been involved in HF, but the association of serum cystatin C level with adverse events and long-term prognosis after CRT is unknown. This study investigated whether cystatin C level can predict mortality and cardiovascular events after CRT. Methods and Results: A total of 117 consecutive patients receiving a CRT device for the treatment of advanced HF were assessed according to cystatin C level and long-term outcome after implantation of the device. Over a median follow-up of 3.2 years, 34 patients (29.1%) died and 59 patients (50.4%) developed cardiovascular events. Kaplan-Meier survival analysis indicated that elevated cystatin C level was significantly associated with higher all- cause mortality and prevalence of cardiovascular events, including hospitalization for progressive HF. After multi- variate Cox regression analysis, serum cystatin C level and QRS duration, but not conventional echocardiographic parameters, were found to independently predict all-cause death or cardiovascular events. Of importance, only cystatin C level was an independent predictor of all-cause mortality after CRT. Conclusions: Cystatin C level independently predicts cardiac mortality or morbidity in patients receiving CRT. The assessment of cystatin C level could provide valuable information about long-term prognosis after CRT. (Circ J 2013; 77: 2751 – 2756) Key Words: Biomarker; Cardiac resynchronization therapy; Cystatin C ardiac resynchronization therapy (CRT) has been es- Approximate two-thirds of patients hospitalized with HF have tablished as a therapeutic option in patients with ad- renal failure.18,19 The presence of renal insufficiency in patients C vanced heart failure (HF).1–4 Accumulating evidence receiving CRT has been associated with an increased risk of has shown that CRT decreases mortality and hospital admis- mortality and cardiovascular events.20–23 Serum creatinine, how- sion rates,5,6 but approximately one-third of patients do not re- ever, which is the usual clinical tool for measuring renal func- spond to CRT.7–11 Based on current knowledge of the involved tion, is not useful for the detection of moderate renal dysfunc- mechanisms, patients with beneficial CRT outcomes have con- tion because it is affected by various factors unrelated to renal sisted of those suffering impairment of electromechanical ven- function, such as age, sex, race, and lean muscle mass.24 In tricular dyssynchrony leading to reverse remodeling.12–16 It is contrast, severe HF is associated with age, gender and muscle difficult, however, to identify which patients will have the best atrophy by cardiac cachexia.25 Consequently, in patients re- outcome after CRT from pre-implant assessments because echo- ceiving CRT, the evaluation of renal function using creatinine cardiographic measurements of dyssynchrony have completely is likely problematic. failed in patient selection for CRT,8,17 whereas restoring dys- Cystatin C, a cysteine protease inhibitor produced at a con- synchrony is one of the important factors for the prognosis of stant rate by nearly all human cells, is freely filtered by the renal CRT.12–16 Therefore, it is clinically valuable to identify pre- glomerulus and excreted into the bloodstream. This protein implant characteristics that predict good outcome after CRT. has a low molecular weight and does not form a complex with Received February 5, 2013; revised manuscript received June 2, 2013; accepted June 30, 2013; released online August 2, 2013 Time for primary review: 40 days Department of Cardiology, Nagoya University Graduate School of Medicine (T.Y., M.S., Y. Inden, S.M., Y. Inoue, T.M.); Nagoya University Graduate School of Health Science (M.H.), Nagoya; Department of Molecular Pathophysiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Y.T.), Japan; and Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL (N.Y.), USA Mailing address: Masayuki Shimano, MD, PhD, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-13-0179 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.77, November 2013 2752 YAMAMOTO T et al. Table 1. Baseline CRT Recipient Characteristics vs. Cystatin C Tertile Cystatin C (mg/l) All (n=117) (n=40) (n=39) (n=38) P-value ≤1.14 1.14–1.54 >1.54< Age (years) 67.1±11.0 61.4±12.7 68.2±10.1 71.9±6.6 <0.005 Gender (male) 65.8 62.5 69.2 65.8 n.s. NYHA class 3.3±0.5 3.2±0.4 3.3±0.5 3.4±0.5 n.s. Ischemic heart disease 22.2 2.5 20.5 44.7 <0.001 Valvular heart disease 6.8 10.0 5.1 5.3 n.s. Upgrading of existing device 9.4 10.0 7.7 10.5 n.s. Creatinine (mg/dl) 1.18±0.62 0.76±0.18 1.05±0.26 1.76±0.71 <0.001 eGFR (ml · min–1 · 1.73 m–2) 54.8±24.3 77.5±20.2 54.1±13.4 31.6±11.1 <0.001 BNP (pg/ml) 500±722 305±227 530±838 674±887 <0.005 ANP (pg/ml) 200±269 152±101 181±197 271±418 <0.05 LDL-C (mg/dl) 100±31 101±33 103±29 97±32 n.s. HDL-C (mg/dl) 47.5±14.4 52.1±13.8 49.0±15.2 40.6±11.5 n.s. TG (mg/dl) 125±84 130±106 132±86 112±51 n.s. QRS width (ms) 165±29 164±30 167±26 163±30 n.s. Echocardiography LVEDD (mm) 69.0±9.7 69.0±10.6 69.9±9.9 68.1±8.6 n.s. LVEDV (ml) 228±91 226±94 236±94 222±85 n.s. LVEF (%) 27.0±7.6 26.9±8.6 27.4±6.8 26.6±8.3 n.s. SPWMD (ms) 172±94 169±89 161±99 185±96 n.s. LV-PEP (ms) 143±31 144±31 142±29 143±25 n.s. Death 29.1 15 30.8 42.1 <0.05 Data given as % or mean ± SD. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CRT, cardiac resynchro- nization therapy; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low- density lipoprotein cholesterol; LV, left ventricular; LVEDD, left ventricular end diastolic diameter; LVEDV, left ventric- ular end diastolic volume; LVEF, left ventricular ejection fraction; LV-PEP, LV pre-ejection period; NYHA, New York Heart Association; SPWMD, septal-to-posterior wall motion delay; TG, triglyceride. other secreted proteins in the blood.26,27 Therefore the serum each patient rested for 10 min in the supine position, their vital level of cystatin C does not depend on patient size, has a strong signs were recorded and a 35-ml blood sample was collected negative correlation with glomerular filtration rate (GFR) and from the antecubital vein. Serum cystatin C level was measured is clearly superior to serum creatinine as a marker of GFR.26,28 by SRL (Tokyo, Japan), a commercial clinical testing laboratory. Given its reported superiority over creatinine as a proxy for GFR, we hypothesized that cystatin C could predict the risk of Echocardiography illness and death after CRT. In the present study, we investi- Two-dimensional echocardiography was performed by 2 ex- gated whether this secreted protein could predict long-term perienced sonographers using a Vivid 7 Dimension/Pro System outcome after CRT. (GE Healthcare, UK) before the CRT device was implanted. The images were recorded, using a 3.5-MHz transducer, in cineloop format and were digitally stored for offline analysis. LV Methods end-diastolic diameter (LVEDD) and LV end-diastolic volume Subjects (LVEDV) were measured as recommended by the American We assessed 119 consecutive patients with HF who underwent Society of Echocardiography. LVEF was calculated using a CRT at Nagoya University Hospital between September 2003 modified Simpson’s rule. Septal-to-posterior wall motion delay and December 2011. The patients were selected according to the (SPWMD) and LV pre-ejection period (LV-PEP) were assessed following established selection criteria for CRT of the Cardiac as dyssynchrony parameters. REsynchronization in HF (CARE-HF):3 (1) severe HF despite optimized medical therapy; (2) left ventricular (LV) systolic Follow-up and Assessment of Cardiac Events dysfunction with an LV ejection fraction (LVEF) <35%; and All patients underwent regular follow-up (typically every 2 (3) QRS duration >120 ms. Additionally, patients with a QRS months) via outpatient clinical visits or telephone interview. interval 120–149 ms were required to meet 2 of 3 additional Cardiovascular events including hospitalizations for exacerba- criteria for dyssynchrony (aortic pre-ejection delay >140 ms, tion of HF were adjudicated by cardiologists from Nagoya interventricular mechanical delay >40 ms, delayed activation University Hospital. Causes of death were ascertained by re- of the posterolateral LV wall). Two patients with hemodialysis viewing the clinical records. were excluded from the study.
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