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Cystatin C Concentration as a Risk Factor for Heart Failure in Older Adults

Mark J. Sarnak, MD, MS; Ronit Katz, PhD; Catherine O. Stehman-Breen, MD, MS; Linda F. Fried, MD, MPH; Nancy Swords Jenny, PhD; Bruce M. Psaty, MD, PhD; Anne B. Newman, MD, MPH; David Siscovick, MD, MPH; Michael G. Shlipak, MD, MPH, and the Cardiovascular Health Study*
[+] Article and Author Information

From Tufts-New England Medical Center, Boston, Massachusetts; Collaborative Health Studies Coordinating Center and University of Washington, Seattle, Washington; Amgen, Inc., Thousand Oaks, and Veterans Affairs Medical Center and University of California, San Francisco, California; University of Pittsburgh School of Medicine, Veterans Affairs Pittsburgh Healthcare System, and University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania; and University of Vermont, Burlington, Vermont.


Grant Support: Drs. Shlipak, Fried, and Katz are funded by grant R01 HL073208-01 (to Dr. Shlipak) from the National Heart, Lung, and Blood Institute. Dr. Shlipak is also supported by the American Federation for Aging Research and National Institute on Aging (Paul Beeson Scholars Program) and the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program). Dr. Sarnak is supported by grant K23 DK67303 from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Fried is funded by an Advanced Research Career Development award from the Office of Research and Development, Medical Service, of the Department of Veterans Affairs. The Cardiovascular Health Study is supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01 HC-15103 from the National Heart, Lung, and Blood Institute.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Michael G. Shlipak, MD, MPH, Veterans Affairs Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121; e-mail, shlip@itsa.ucsf.edu.

Current Author Addresses: Dr. Sarnak: Division of Nephrology, Tufts-New England Medical Center, 750 Washington Street, NEMC 391, Boston, MA 02111.

Dr. Katz: Collaborative Health Studies Coordinating Center, University of Washington, Box 354922, Building 29, Suite 310, 6200 NE 74th Street, Seattle, WA 98115.

Dr. Stehman-Breen: Amgen, Inc., 1 Amgen Center Drive, Mailstop 38-3-C, Thousand Oaks, CA 91320.

Dr. Fried: Veterans Affairs Pittsburgh Healthcare System, University Drive, 111F-U, Pittsburgh, PA 15240.

Dr. Swords Jenny: Department of Pathology, College of Medicine, University of Vermont, Colchester Research Facility, 208 South Park Drive, Suite 2, Colchester, VT 05446.

Drs. Psaty and Siscovick: Medicine and Epidemiology, University of Washington, Cardiovascular Health Research Unit, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101-1448.

Dr. Newman: Healthy Aging Research Program, Bellefield Professional Building, 130 North Bellefield Avenue, Room 532, Pittsburgh, PA 15213.

Dr. Shlipak: Veterans Affairs Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121.

Author Contributions: Conception and design: M.J. Sarnak, R. Katz, C.O. Stehman-Breen, L.F. Fried, B.M. Psaty, D. Siscovick, M.G. Shlipak.

Analysis and interpretation of the data: M.J. Sarnak, R. Katz, C.O. Stehman-Breen, D. Siscovick, M.G. Shlipak.

Drafting of the article: M.J. Sarnak, R. Katz, C.O. Stehman-Breen, D. Siscovick, M.G. Shlipak.

Critical revision of the article for important intellectual content: M.J. Sarnak, R. Katz, C.O. Stehman-Breen, L.F. Fried, N.S. Jenny, B.M. Psaty, A.B. Newman, D. Siscovick, M.G. Shlipak.

Final approval of the article: M.J. Sarnak, R. Katz, C.O. Stehman-Breen, L.F. Fried, B.M. Psaty, A.B. Newman, D. Siscovick, M.G. Shlipak.

Provision of study materials or patients: B.M. Patsy, A.B. Newman, D. Siscovick.

Statistical expertise: R. Katz, B.M. Psaty.

Obtaining of funding: M.G. Shlipak, B.M. Psaty.

Administrative, technical, or logistic support: C.O. Stehman-Breen, N.S. Jenny, A.B. Newman.

Collection and assembly of data: R. Katz, B.M. Psaty, A.B. Newman.


Ann Intern Med. 2005;142(7):497-505. doi:10.7326/0003-4819-142-7-200504050-00008
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Our results demonstrate that cystatin C concentration is an independent risk factor for heart failure in older adults. In addition, cystatin C concentration was associated with a gradient in risk across all quintiles, in contrast to serum creatinine concentration or estimated GFR. The cystatin C concentration appears to offer novel insights into the importance of kidney function as a cause of heart failure and may have a role in clinical medicine for categorizing kidney function in older adults.

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Figure 1.
Selection of patients.

*Recruited from Forsyth County, North Carolina (1305 patients); Sacramento County, California (1318 patients); Washington County, Maryland (1303 patients); and Allegheny County, Pennsylvania (1275 patients). †Recruited from Forsyth County, North Carolina (238 patients), Sacramento County, California (225 patients); and Allegheny County, Pennsylvania (224 patients).

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Figure 2.
Incidence rates of heart failure, by quintile of cystatin C concentration, creatinine concentration, and estimated glomerular filtration rate (eGFR).

Cutoff values for quintiles 1 to 5 of cystatin C concentration were <67 nmol/L (<0.89 mg/L), 67 to 74 nmol/L (0.89 to 0.99 mg/L), 75 to 81 nmol/L (1.00 to 1.09 mg/L), 82 to 94 nmol/L (1.10 to 1.25 mg/L), and 95 to 506 nmol/L (1.26 to 6.75 mg/L). Cutoff values for quintiles of serum creatinine concentration were ≤57 µmol/L (≤0.65 mg/dL), 58 to 66 µmol/L (0.66 to 0.75 mg/dL), 67 to 75 µmol/L (0.76 to 0.85 mg/dL), 76 to 84 µmol/L (0.86 to 0.95 mg/dL), and 85 to 924 µmol/L (0.96 to 10.45 mg/dL) for women and ≤75 µmol/L (≤0.85 mg/dL), 76 to 93 µmol/L (0.86 to 1.05 mg/dL), 94 to 102 µmol/L (1.06 to 1.15 mg/dL), 103 to 110 µmol/L (1.16 to 1.25 mg/dL), and 111 to 880 µmol/L (1.26 to 9.95 mg/dL) for men. Cutoff values for quintiles of estimated GFR) were ≥82.9 mL/min per 1.73 m2 , 74.0 to 82.8 mL/min per 1.73 m2 , 66.8 to 74.0 mL/min per 1.73 m2 , 58.6 to 66.8 mL/min per 1.73 m2 , and 3.85 to 58.6 mL/min per 1.73 m2 .

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Figure 3.
Association between concentrations of creatinine and cystatin C and the risk for heart failure.

Hazard ratios (solid line) and 95% CIs (dotted lines) were calculated on the basis of Cox proportional hazards models representing cystatin C and creatinine concentrations as natural cubic spline functions and are adjusted for age, sex, ethnicity, body mass index, diabetes, systolic blood pressure, presence of hypertension, high-density lipoprotein cholesterol level, ankle–arm index, common carotid intima–media wall thickness, internal carotid intima–media wall thickness, atrial fibrillation on electrocardiography, C-reactive protein level, albumin level, factor VII level, presence of coronary heart disease, and left ventricular hypertrophy on electrocardiography. A creatinine concentration of 88.4 µmol/L (1 mg/dL) and a cystatin C concentration of 1 mg/L (74.5 nmol/L) were selected as the reference groups for these analyses because they approximated the median values to allow similar precision at both ends of each curve. To convert creatinine concentration to µmol/L, multiply by 88.4. To convert cystatin C concentration to nmol/L, multiply by 74.5.

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Cystatin C not a marker for kidney function
Posted on April 18, 2005
Arie Berghout
mcrz hospital, rotterdam, nl
Conflict of Interest: None Declared

Letter to the editor

Arie Berghout (1), Raymond Wulkan (2), Jan den Hollander(1)

Dear Sir,

With interest we read the article by Sarnak et al (1) on the use of cystatin C as a risk factor for heart failure in older adults. Although we can agree with the conclusion that cystatin C levels are independently associated with the risk to develop heart failure, we have a comment on cystatin C as a measure of kidney function. Recently, we have shown that in patients with thyroid dysfunction cystatin C is unsuitable as such. In hypothyroidism creatinine levels tend to be elevated, and, conversely, in hyperthyroidism creatinine levels are lowered (2). In contrast to our expectations, cystatin C levels turned out to be low in hypothyroid patients and elevated in hyperthyroid patients (3). These findings have now been confirmed by other authors. Our hypothesis is that the production of cystatin C is under the influence of thyroid hormone. Thyroid disorders are prevalent in the elderly population. Furthermore, most patients with heart failure will have low plasma T3 values due to changes in thyroid hormone metabolism during illness. We are not aware of studies that measured cystatin C levels in patients with critical illness.

1. Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Swords Jenny N, Psaty BM, Newman AB, Sisovick D, Shlipak MG. Cystatin C concentration as a risk factor for heart failure in older adults. Ann Intern Med. 2005;142:497-505. 2. Den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Correlation between severity of thyroid dysfunction and renal function. Clin Endocrinol. 2005;62:423-7. 3. Den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Is Cystatin C a marker of glomerular filtration rate in thyroid dysfunction? Clin Chem. 2003;49:1558-9

Author details: Dr.A.Berghout, Consultant Physician Email BerghoutA@mcrz.nl Dr.J.den Hollander, Consultant Physician Dr.R.W.Wulkan, Clinical Biochemist Department of Medicine, Hospital MCRZ, Groene Hilledijk 315, 3075 EA Rotterdam, The Netherlands.

Conflict of Interest:

None declared

The Cystatin C Paradox
Posted on May 23, 2005
Regina Bökenkamp
Dpt. of Pediatric Cardiology, LUMC, Albinusdreef 2, 2300 RC Leiden, The Netherlands
Conflict of Interest: None Declared

Sir, in a recent issue of this journal, Samak et al have shown an elevated serum cystatin C concentration to be an independent predictor of heart failure in adults older than 65 years (1). It can be assumed that heart failure in this age group is mostly due to coronary heart disease. It should therefore not be left unmentioned that a different line of evidence in the literature suggests just a protective role of cystatin C in the pathogenesis of atherosclerosis.

Cystatin C is the most powerful inhibitor of cystein-proteinases such as cathepsin B and as such may play a pivotal role in tissue remodeling by reducing the elastolytic activity of vascular smooth muscle cells (2). Shi et al demonstrated that cystatin C, which is normally expressed in vascular smooth muscle cells, is severely reduced in both atherosclerotic and aneurysmal aortic lesions (2). Interestingly, this group found an inverse relationship between serum cystatin C and aortic diameter in patients with aortic aneurysms but not in healthy controls. In keeping with these results, Eriksson et al (3) found significantly diminished cystatin C concentrations in survivors of a first myocardial infarction before the age of 60 years compared to age- and sex-matched controls. This study excluded only patients with moderate renal failure (serum creatinine concentrations above 200 µmol/l). Analyzing cystatin C gene polymorphisms in the promotor region, they were able to show an association with polymorphisms that impair cystatin C production and the number of stenoses on cardiac angiography. The differences between these studies probably relate to (i) timing of cystatin C measurement (i.e. years prior vs. just after the cardiac event), (ii) baseline demographics and (iii) the endpoints used (i.e. undefined heart failure vs. documented systemic atherosclerosis). Unfortunately, neither Samak (1) nor Eriksson (3) corrected their cystatin C data for kidney function measured by a gold-standard technique.

Until the role of cystatin C in atherosclerosis is better understood, clinical studies on the relationship between cystatin C and cardiovascular disease must include a gold-standard measurement of GFR to assess whether cystatin C in this setting is an independ marker of atherosclerosis or reflects early changes of renal function. It would also be very important to specifically study atherosclerosis in the cystatin C knock-out mouse, which has a normal life-span and no clinical or histological signs of disease at the age of six months (4).

References

(1) Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Swords JN, Psaty BM et al 2005;142:497-505

(2) ShiG-P, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT et al. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest 1999;104:1191-7

(3) Eriksson P, Deguchi H, Samnegard A, Lundman P, Boquist S, Tornvall P et al. Human evidence that the cystatin C gene is implicated in focal progression of coronary atery disease. Arterioscler Thromb Vasc Biol 2004;24:551-7

(4) Huh C-G, Hakansson K, Nathanson C-M, Thorgeirsson UP, Jonsson N, Grubb A et al. Decrease metastatic spread in mice homozygous for a null allele of the cystatin C protease inhibitor gene. J Clin Pathol: Mol Pathol 1999;52:332-40

Conflict of Interest:

None declared

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Summary for Patients

Can a New Blood Test Help Predict Who Is at Risk for Developing Heart Failure?

The summary below is from the full report titled “Cystatin C Concentration as a Risk Factor for Heart Failure in Older Adults.” It is in the 5 April 2005 issue of Annals of Internal Medicine (volume 142, pages 497-505). The authors are M.J. Sarnak, R. Katz, C.O. Stehman-Breen, L.F. Fried, N. Swords Jenny, B.M. Psaty, A.B. Newman, D. Siscovick, M.G. Shlipak, and the Cardiovascular Health Study.

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