Published online before print February 10, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.807271
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original Articles |
Association of Cystatin C With Left Ventricular Structure and Function
The Dallas Heart Study
From the Division of Cardiology (P.C.P., R.P., A.K., J.A.L., J.A.B., S.G., P.P.A.M., M.H.D., D.W.M.), Donald W. Reynolds Cardiovascular Clinical Research Center (C.R.A., R.P., A.K., J.A.L., M.H.D. D.W.M.), University of Texas Southwestern Medical Center, Dallas, Tex; and Brigham and Women’s Hospital (S.A.M.), Boston, Mass.
Correspondence to David W. Markham, MD, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, HA9.133, Dallas, TX 75390-9047. E-mail David.Markham{at}utsouthwestern.edu
Received July 16, 2008; accepted December 3, 2008.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussion and ConclusionsConclusionsReferences |
|---|
Background— Cystatin C, a novel marker of renal function, has been associated with heart failure and cardiovascular mortality in older individuals. We tested the hypothesis that cystatin C is associated with preclinical cardiac structural and functional abnormalities in a younger population-based sample.
Methods and Results— The study included participants in the Dallas Heart Study (ages 30 to 65 years) who had measurements of cystatin C and cardiac MRI. The associations of cystatin C with left ventricular (LV) mass, LV end-systolic and -diastolic volumes, concentricity (LV mass/LV end-diastolic volume), LV wall thickness, and LV ejection fraction were evaluated. Cystatin C levels ranged from 0.46 to 6.55 mg/L. In univariable analyses, increasing levels of cystatin C correlated with higher LV mass, concentricity, and wall thickness (P<0.001), but not with LV end-systolic volume, LV end-diastolic volume, or LV ejection fraction. After adjustment with traditional covariates and estimated glomerular filtration rate by the modification of diet in renal disease formula, log-transformed cystatin C remained independently associated with LV mass (P<0.001), concentricity (P=0.027), and wall thickness (P<0.001). These associations persisted when creatinine or estimated glomerular filtration rate by the Cockcroft-Gault formula were included in the models.
Conclusions— Higher levels of cystatin C were associated with increased LV mass and a concentric LV hypertrophy phenotype. These findings were independent of potential confounding variables including standard measurements of renal function, supporting the hypothesis that cystatin C may be useful to identify individuals with preclinical structural heart abnormalities.
Key Words: cystatin C • concentricity • left ventricular hypertrophy • hypertension • renal function • Dallas Heart Study
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussion and ConclusionsConclusionsReferences |
|---|
Abnormal renal function is known to be an independent risk factor for atherosclerotic cardiovascular disease, heart failure, and increased overall cardiovascular mortality.1–4 Traditionally, glomerular filtration rate (GFR) has been estimated from serum creatinine or creatinine-based equations. However, this approach has numerous limitations including a nonlinear relationship between creatinine and GFR, inability of creatinine to detect small changes in GFR, and difficulty in accounting for the confounding influences of nonrenal factors (ie, age, body weight, ethnicity, and sex).5
Editorial see p 86
Clinical Perspective see p 98
Recently, cystatin C has been shown to be a biomarker of renal function that overcomes many of the above limitations.6 Concentrations of cystatin C are independent of age, sex, and muscle mass.6–9 In many studies, serum cystatin C has performed better than creatinine and is at least comparable with creatinine-based equations to estimate GFR, primarily when assessing mild to moderate renal impairment.9–11 These qualities make cystatin C measurement attractive for the detection of subtle changes in renal function.
Furthermore, cystatin C has been shown to be a risk factor for heart failure and cardiovascular disease mortality.12–17 We hypothesized that cystatin C could be a marker for subclinical cardiac structural and functional abnormalities. We tested this hypothesis in 2548 participants in the Dallas Heart Study (DHS), a multiethnic, population-based sample of Dallas county residents between 30 and 65 years old.18
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussion and ConclusionsConclusionsReferences |
|---|
The Dallas Heart Study
Details of the design and methods of the DHS have been previously reported.18 In summary, we conducted a multistage probability sampling of the estimated 1.43 million civilian, noninstitutionalized English- or Spanish-speaking Dallas County residents based on the US Postal Service 2000 Delivery Sequence File. Oversampling was performed in the black population so that they represented 50% of the final cohort. The study was conducted in 3 sequential visits: (1) an initial home visit, including a household survey (ages 18 to 65, n=6101), (2) a second home visit (ages 30 to 65, n=3399) to obtain blood and urine specimens, and (3) a clinic visit at the University of Texas Southwestern Medical Center to perform a cardiac MRI and DEXA scan (ages 30 to 67, n=3072). The survey was completed by trained field interviewers at the first home visit. They obtained detailed information on patient demographics, medical history, and medications. Demographic variables and blood pressures were similar between subjects completing all 3 visits. Sampling weights reflecting the different probabilities of selection and sample attrition were created at each step so that the findings could be extrapolated back to the target population.18 In the present study, patients were included in this analysis if they completed cardiac MRI and cystatin C measurements (n=2548).
Measures of Renal Function
Cystatin C
Venous blood was collected in standard blood collection tubes and samples were maintained at 4°C for 
4 hours and then centrifuged (1430 g for 15 minutes) at 4°C. Plasma was then removed and frozen at –70°C until assays were performed. Measurements of serum cystatin C were completed with a BNII nephelometer (Dade Behring, Inc, Deerfield, Ill; now Siemens Healthcare Diagnostics, Inc) with a particle enhanced immunonephelometric assay (N Latex Cystatin C, Dade Behring, Inc). The nephelometer used monoclonal antibodies coated on polystyrene particles which agglutinate to increase the intensity of scattered light based on cystatin C concentrations.19 The inter- and intra-assay coefficient of variations (CV) were less than 3.5%. The range of detection of the assay was 0.195 to 7.330 mg/L.
Creatinine and Estimated Glomerular Filtration Rate
A Beckman Coulter analyzer (Beckman Coulter, Fullerton, Calif) was used for measuring serum creatinine concentrations through the alkaline picrate method. The interand intra-assay CVs for serum creatinine were less than 5.0%.20 GFR, mL/min per 1.73 m2 body surface area, was estimated with the modified modification of diet in renal disease study formula: GFR=186x(serum creatinine–1.154)x (age–0.203)x0.742 (if female)x1.21 (if black); and the Cockcroft-Gault formula: GFR=[(140–age)xweight (kg)]/[72xcreatinine (mg/dL)]x0.85 (if female).
Cardiac MRI
The MRI protocol has been previously described.21,22 Briefly, 2 comparable 1.5 T MRI systems (Philips Medical Systems) were used for all of the cardiac MRIs. Short-axis breath-hold, electrocardiographic-gated cine MR images were obtained from the apex to the base of the left ventricle using the following parameters: 6-mm slice, 4-mm gap, field of view of 36 to 40, acquired pixel size at 36 cm field of view 1.29x2.58, and temporal resolution of 40 ms. MASS software (Medis medical imaging systems, Leiden, The Netherlands) was used to analyze the data. Endocardial and epicardial borders were traced manually allowing calculation of ventricular volumes. Left ventricular ejection fraction (LVEF) was calculated in the standard fashion from the endocardial volumes: ejection fraction=100x(end-diastolic volume (LVEDV)–end-systolic volume)/end-diastolic volume. Interobserver difference for LVEDV was –3.0±9.4 mL, intraobserver difference was –2.7±3.2 mL, and interscan variability was –2.3±8.9 mL. Interobserver difference for LVEF was –4±4%, intraobserver difference was 1±1%, and interscan variability was –1.3±2.5%. Interobserver difference for LV mass was 9.2±5 g (n=1), intraobserver difference was 10.5±8.6 g (n=8), and interscan variability was 4.9±10.9 g (n=8).21
Covariates
All DHS participants completed a computerized questionnaire during the initial home visit. The questionnaire consisted of 27 modules that were administered in either Spanish or English and queried medical history, use of medications, and use of tobacco. Race and ethnicity were self-reported. BP was measured as previously described.21 C-reactive protein measurements (Roche Diagnostics, Indianapolis, Ind) and brain natriuretic peptide (Biosite, San Diego, CA) were measured as described.23 Body composition was measured by DEXA scans (Delphi W Unit, Hologic, Inc, Bedford, Mass) as described.23,24
Variable Definitions
Hypertension was defined as a self-reported diagnosis, utilization of antihypertensive medications, or an average systolic blood pressure from the 3 separate measurements 
140 mm Hg or an average diastolic blood pressure 90 mm Hg. Diabetes was defined as previously.25 Concentricity was defined as left ventricular mass (LV Mass) divided by LVEDV. The criteria for left ventricular hypertrophy (LVH) were as follows: LV mass/body surface area 89 g/m2 (women) and 112 g/m2 (men), LV mass/height2.7 39 g/m2.7 (women) and 48 g/m2.7 (men), and LV mass/fat-free mass 3.8 g/kg (men and women) as before.21
Statistics
Smoothed histograms of cystatin C concentrations were constructed for each sex. Differences in cystatin C concentrations between men and women were compared using Wilcoxon Rank Sum Tests because of non-normally distributed data. Cystatin C levels were categorized into gender specific quartiles and baseline characteristics were compared across quartiles using analysis of variance or the Kruskal-Wallis test for continuous variables and 
2 for categorical variables. Multivariable linear regression analysis was used to evaluate the association of the predictor variable, log-transformed cystatin C (logcystatin C), with the following outcome variables: LVEDV, LV mass, concentricity (LV mass/LVEDV), LV wall thickness, and LVEF. Multivariable logistic regression analysis was used to evaluate the association of the predictor variable, logcystatin C, with the outcome variable LVH. Cystatin C concentrations were logarithmically transformed because their distribution did not follow a Gaussian distribution. The following covariates were considered potential confounders that influence the development of LV structural abnormalities: age, sex, race, diabetes, history of hypertension, systolic blood pressure, history of coronary artery disease, height2.7, lean mass, fat mass, C-reactive protein, and log transformed brain natriuretic peptide (model 1). In additional models, traditional markers of renal function were added to model 1 as covariates: creatinine (model 2), estimated GFR by the modification of diet in renal disease (model 3), and estimated GFR by Cockcroft-Gault (model 4). For statistical analysis, SAS 9.13 (SAS Institute, Inc, Cary, NC) was used. The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed on the manuscript as written.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussion and ConclusionsConclusionsReferences |
|---|
Cystatin C Baseline Characteristics in DHS
Cystatin C levels ranged from 0.46 to 6.55 mg/L with a median of 0.82 mg/L (interquartile range: 0.74 to 0.92 mg/L; Table 1 and Figure 1A). The range of cystatin C concentrations for all patients by quartiles is as follows: quartile I,
0.73 mg/L; quartile II, 0.74 to 0.82 mg/L; quartile III, 0.83 to 0.92 mg/L; and quartile IV, 0.93 mg/L. Median and interquartile ranges of cystatin C by gender are shown in the footnotes of Table 1. Women had significantly lower levels of cystatin C compared with men (P<0.001; Figure 1B). Baseline characteristics of the study sample, stratified by gender-specific quartiles of cystatin C, are shown in the Table 1. Participants with higher concentrations of cystatin C were more likely to be older, hypertensive, and on antihypertensive medications. Those with higher cystatin C levels were less commonly black and were more likely to have diabetes and higher body mass indices. As anticipated, increasing quartiles of cystatin C were associated with higher levels of creatinine and lower estimated glomerular filtration rates.
|
|
Cystatin C and LV Structure
The association of LV structural characteristics with gender-specific quartiles of cystatin C are shown (Table 2). Higher measurements of cystatin C were associated with increased LV mass, indexed LV mass (LV mass/height2.7 and LV mass/body surface area), concentricity, and wall thickness. Similar associations were present when cystatin C was modeled as a log transformed continuous variable. In contrast, cystatin C was not associated with LVEF, LV end-systolic volume, or LVEDV.
|
In multivariable linear regression analysis adjusting for age, sex, race, diabetes, history of hypertension, systolic blood pressure, history of coronary artery disease, fat mass, lean mass, height2.7, C-reactive protein, and log transformed brain natriuretic peptide (model 1), cystatin C remained independently associated with LV mass, concentricity, and LV wall thickness (Table 3). This association persisted after further adjustment for traditional measures of renal function including creatinine (model 2), estimated GFR by modification of diet in renal disease (model 3), and estimated GFR by Cockcroft-Gault (model 4).
|
In subgroup multivariable analyses, there were significant associations of cystatin C with LV mass and wall thickness in hypertensives and in blacks (Table 4). There was a strong trend for the association of cystatin C with LV concentricity in these 2 groups. These associations were not present in normotensives or whites. The interaction probability values for both of these subgroups with logcystatin C are described in the footnotes of Table 4.
|
Cystatin C was also significantly associated with LVH when defined by indexation to body surface area in models 2 to 4 (model 3: OR, 3.8; 95% CI, 1.7 to 8.5; P=0.001). As with LV mass, this association remained present in patients with a history of hypertension (model 3: OR, 3.9; 95% CI, 1.4 to 10.5; P=0.007) but not in patients without a history of hypertension (model 3: OR, 2.5; 95% CI, 0.5 to 12.5; P=0.28) and was more robust in blacks (model 3: OR, 4.0; 95% CI, 1.6 to 9.9; P=0.003) than whites (model 3: OR, 5.5; 95% CI, 0.4 to 81; P=0.22).
|
Discussion and Conclusions |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussion and ConclusionsConclusionsReferences |
|---|
The DHS is the first study evaluating the association of cystatin C with LV structure and function in the general population. The major finding of this study is that cystatin C was independently associated with a specific cardiac phenotype of concentric hypertrophy, including increased LV mass, concentricity, and wall thickness even after adjustment for various traditional measures of renal function. This association was particularly robust in hypertensives and blacks. Cystatin C was not associated with LV systolic function or volume. Our findings suggest that cystatin C may be a potential predictor of the presence or development of cardiac structural abnormalities.
The only prior study to our knowledge evaluating the association of cardiac structural abnormalities with cystatin C was the Heart and Soul Study (HS).15 This study evaluated echocardiograms in 818 participants with known coronary artery disease but without a history of clinical heart failure. Although this study did not adjust for traditional measures of renal function, after multivariable analysis higher levels of cystatin C were significantly associated with LVH and diastolic dysfunction. LVEF was not significantly associated with cystatin C after multivariable adjustment. Compared with the Heart and Soul Study, the DHS participants were younger and healthier with less comorbidities. As expected, the DHS cohort had lower levels of cystatin C (DHS: median, 0.82 mg/L; interquartile range, 0.74 to 0.92 mg/L; Heart and Soul: median, 1.05 mg/L; interquartile range, 0.91 to 1.28 mg/L). Because cystatin C maintained similar associations with measures of concentricity in this study, we postulate that the DHS participants may represent a preclinical population compared with the Heart and Soul study. Thus, the association of cystatin C with subclinical measures of concentricity may precede the clinical development of diastolic dysfunction.
Cystatin C: Clinical and Research Considerations
Three hypotheses potentially explain the association of cystatin C with a concentric phenotype: (1) cystatin C may be a stronger predictor of preclinical changes in cardiovascular structure because it is a better estimate of renal function when compared to traditional measures of GFR; (2) cystatin C may be primarily associated with a hypertensive phenotype and, as a result, be indirectly associated with subclinical concentricity; and (3) cystatin C may be directly associated with the development of concentricity. We will discuss each of these separately.
As a more sensitive marker of renal function (hypothesis 1), cystatin C may better predict changes in LV structure compared to other biomarkers. Previous studies implicate cystatin C as a sensitive marker for early renal damage and as a predictor of renovascular disease in patients with essential hypertension,26 preeclampsia,27 and atherosclerotic hypertensive disease.28 Severity of renal disease has been linked to diastolic dysfunction, concentricity, and changes in LV geometry in different subsets of patients.29–31 Because cystatin C may more accurately estimate glomerular function in people with normal and mildly decreased renal function as compared to serum creatinine,6–11 cystatin C may be a better marker of subclinical cardiorenal disease.
Cystatin C may be directly associated with a hypertensive phenotype and indirectly associated with LV concentricity (hypothesis 2). Prior studies have suggested an association of cystatin C with hypertension. In the Physician’s Health Study, the association of heart failure with cystatin C was limited to hypertensive individuals during subgroup analysis.32 In patients with coronary artery disease, cystatin C was linearly associated with systolic blood pressure even in people with normal renal function.15 In the DHS, blacks had 2 to 3 times increased prevalence of hypertension and left ventricular hypertrophy when compared to the whites.21 The robust association of cystatin C with LV mass in the black subgroup may be explained by the significantly increased prevalence of hypertension in this population. Thus, cystatin C could be a surrogate of a hypertensive phenotype that influences chronic changes in LV structure.
Cystatin C may directly be associated with the development of concentricity (hypothesis 3). Because the association of cystatin C with measures of LV concentricity is independent of traditional markers of renal function in our study, one could hypothesize that cystatin C is more than simply a measure of renal function and may directly influence changes in LV structure. The balance between cysteine proteases, such as cathepsin B, S, and K, with cysteine protease inhibitors, such as cystatin C, has been implicated in the pathogenesis of cardiac remodeling in hypertrophied and failing hearts.33–35 Cathepsins are responsible for the physiological digestive turnover of cellular molecules, and abnormal levels may adversely influence cardiac remodeling.35 Even though the mechanistic link between cystatin C and LV concentricity is unknown, it is possible that the alteration of the balance between these 2 families of proteins may lead to the development of concentricity and hypertrophy.
To elucidate which of these 3 hypotheses truly define the mechanism of the association of cystatin C with LV structure, additional studies are needed. Additional insights could be garnered from cystatin C knockout or overexpressing animal models, or in other animal models of cardiac hypertrophy. Furthermore, given the association of cystatin C with diastolic dysfunction, incident heart failure, cardiac events, and all-cause mortality in ambulatory patients with coronary disease,15,16 longitudinal studies that assess the utility of cystatin C as a predictor for the development of cardiac structural abnormalities or future adverse outcomes are warranted.
Study Limitations
Strengths of this study include the large sample size and the detailed phenotyping of subjects, including MRI measurements of cardiac structure and function and DEXA assessments of lean and fat mass. This allowed for a more precise determination of the associations of cystatin C with cardiac parameters. Several limitations should be considered when interpreting our results. The DHS is a cross-sectional study; therefore, causality between cystatin C and LV mass should not be inferred. The assessment of coronary artery disease, hypertension, and diabetes was based on self-report and may be subject to recall or response bias. Furthermore, a participant’s willingness to participate may have introduced selection bias; however, multiple efforts were made to minimize this possibility. As such, we previously have demonstrated that inferences from the DHS can be extrapolated back to its reference population (Dallas County).18 In addition, single measurements of cystatin C were taken for each patient. Whether daily variations exist with this biomarker is unknown. Some studies also suggest that corticosteroids, inflammation and abnormalities of thyroid function influence cystatin C concentrations.36–38 Because of the limited data that was available, adjustment for these potential confounders was not possible. Because most of the patients in the DHS had normal renal function, measures of estimated GFR (modification of diet in renal disease and Cockcroft-Gault) might not be as accurate as cystatin C for predicting subclinical changes in cardiovascular structure in this cohort. Also, because the study participants were a random sample of the general population, our conclusions may not apply to patients with cardiovascular disease who are typically older and with some degree of renal dysfunction.
|
Conclusions |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussion and ConclusionsConclusionsReferences |
|---|
Higher levels of serum cystatin C were independently associated with LV mass, concentricity, and LV wall thickness even after adjustment with traditional markers of renal function. This association was particularly strong in hypertensive and black subjects, suggesting that the association of cystatin C with concentric LVH may be mediated via elevated blood pressure. Further study of cystatin C may provide insights into the mechanisms linking renal function and cardiac structural abnormalities.
|
Acknowledgments |
|---|
Sources of Funding
The Dallas Heart Study is funded by a center grant from the Donald W. Reynolds Foundation (Las Vegas, Nev). D.M. is supported by the University of Texas Southwestern Clinical Scholars Program (North and Central Texas Clinical and Translational Science Initiative KL2). This work was supported by an unrestricted grant from Dade Behring, Inc (now Siemens Healthcare Diagnostics, Inc).
Disclosures
J.D. has served as a consultant for Roche and has consulting and grant funding from Biosite. The other authors do not have any pertinent disclosures.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussion and ConclusionsConclusionsReferences |
|---|
1. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DN, Levey AS, Sarnak MJ. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001; 38: 955–962.
2. Verma A, Anavekar NS, Meris A, Thune JJ, Arnold JM, Ghali JK, Velazquez EJ, McMurray JJ, Pfeffer MA, Solomon SD. The relationship between renal function and cardiac structure, function, and prognosis after myocardial infarction: the VALIANT Echo Study. J Am Coll Cardiol. 2007; 50: 1238–1245.
3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004; 351: 1296–1305.
4. Shlipak MG, Smith GL, Rathore SS, Massie BM, Krumholz HM. Renal function, digoxin therapy, and heart failure outcomes: evidence from the digoxin intervention group trial. J Am Soc Nephrol. 2004; 15: 2195–2203.
5. Levey AS. Measurement of renal function in chronic renal disease. Kidney Int. 1990; 38: 167–184.[Medline]
6. Fliser D, Ritz E. Serum cystatin C concentration as a marker of renal dysfunction in the elderly. Am J Kidney Dis. 2001; 37: 79–83.[Medline]
7. Bokenkamp A, Domanetzki M, Zinck R, Schumann G, Byrd D, Brodehl J. Cystatin C–a new marker of glomerular filtration rate in children independent of age and height. Pediatrics. 1998; 101: 875–881.
8. Keevil BG, Kilpatrick ES, Nichols SP, Maylor PW. Biological variation of cystatin C: implications for the assessment of glomerular filtration rate. Clin Chem. 1998; 44: 1535–1539.
9. Bokenkamp A, Herget-Rosenthal S, Bokenkamp R. Cystatin C, kidney function and cardiovascular disease. Pediatr Nephrol. 2006; 21: 1223–1230.[CrossRef][Medline]
10. Newman DJ, Thakkar H, Edwards RG, Wilkie M, White T, Grubb AO, Price CP. Serum cystatin C measured by automated immunoassay: a more sensitive marker of changes in GFR than serum creatinine. Kidney Int. 1995; 47: 312–318.[Medline]
11. Coll E, Botey A, Alvarez L, Poch E, Quinto L, Saurina A, Vera M, Piera C, Darnell A. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis. 2000; 36: 29–34.[Medline]
12. Luc G, Bard JM, Lesueur C, Arveiler D, Evans A, Amouyel P, Ferrieres J, Juhan-Vague I, Fruchart JC, Ducimetiere P. Plasma cystatin-C and development of coronary heart disease: the PRIME Study. Atherosclerosis. 2006; 185: 375–380.[CrossRef][Medline]
13. Lassus J, Harjola VP, Sund R, Siirila-Waris K, Melin J, Peuhkurinen K, Pulkki K, Nieminen MS. Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP. Eur Heart J. 2007; 28: 1841–1847.
14. Koenig W, Twardella D, Brenner H, Rothenbacher D. Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate. Clin Chem. 2005; 51: 321–327.
15. Ix JH, Shlipak MG, Chertow GM, Ali S, Schiller NB, Whooley MA. Cystatin C, left ventricular hypertrophy, and diastolic dysfunction: data from the Heart and Soul Study. J Cardiac Fail. 2006; 12: 601–607.[CrossRef][Medline]
16. Ix JH, Shlipak MG, Chertow GM, Whooley MA. Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study. Circulation. 2007; 115: 173–179.
17. Shlipak MG, Katz R, Fried LF, Jenny NS, Stehman-Breen CO, Newman AB, Siscovick D, Psaty BM, Sarnak MJ. Cystatin-C and mortality in elderly persons with heart failure. J Am Coll Cardiol. 2005; 45: 268–271.
18. Victor RG, Haley RW, Willett DL, Peshock RM, Vaeth PC, Leonard D, Basit M, Cooper RS, Iannacchione VG, Visscher WA, Staab JM, Hobbs HH. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am J Cardiol. 2004; 93: 1473–1480.[CrossRef][Medline]
19. Erlandsen EJ, Randers E, Kristensen JH. Evaluation of the Dade Behring N Latex Cystatin C assay on the Dade Behring Nephelometer II System. Scand J Clin Lab Invest. 1999; 59: 1–8.[CrossRef][Medline]
20. Kramer H, Toto R, Peshock R, Cooper R, Victor R. Association between chronic kidney disease and coronary artery calcification: the Dallas Heart Study. J Am Soc Nephrol. 2005; 16: 507–513.
21. Drazner MH, Dries DL, Peshock RM, Cooper RS, Klassen C, Kazi F, Willett D, Victor RG. Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: the Dallas Heart Study. Hypertension. 2005; 46: 124–129.
22. Chung AK, Das SR, Leonard D, Peshock RM, Kazi F, Abdullah SM, Canham RM, Levine BD, Drazner MH. Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: the Dallas Heart Study. Circulation. 2006; 113: 1597–1604.
23. Das SR, Drazner MH, Dries DL, Vega GL, Stanek HG, Abdullah SM, Canham RM, Chung AK, Leonard D, Wians FH, de Lemos JA. Impact of body mass and body composition on circulating levels of natriuretic peptides: results from the Dallas Heart Study. Circulation. 2005; 112: 2163–2168.
24. Kelly TL, Berger N, Richardson TL. DXA body composition: theory and practice. Appl Radiat Isot. 1998; 49: 511–513.[CrossRef][Medline]
25. Khera A, de Lemos JA, Peshock RM, Lo HS, Stanek HG, Murphy SA, Wians FH, Grundy SM, McGuire DK. Relationship between C-reactive protein and subclinical atherosclerosis: the Dallas Heart Study. Circulation. 2006; 113: 38–43.
26. Watanabe S, Okura T, Liu J, Miyoshi K, Fukuoka T, Hiwada K, Higaki J. Serum cystatin C level is a marker of end-organ damage in patients with essential hypertension. Hypertens Res. 2003; 26: 895–899.[CrossRef][Medline]
27. Strevens H, Wide-Swensson D, Grubb A, Hansen A, Horn T, Ingemarsson I, Larsen S, Nyengaard JR, Torffvit O, Willner J, Olsen S. Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies. BJOG. 2003; 110: 825–830.[CrossRef][Medline]
28. Olivieri O, Bassi A, Pizzolo F, Tinazzi E, Corrocher R. Cystatin C versus creatinine in renovascular disease. Clin Chem. 2002; 48: 2256–2259.
29. Melenovsky V, Borlaug BA, Rosen B, Hay I, Ferruci L, Morell CH, Lakatta EG, Najjar SS, Kass DA. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol. 2007; 49: 198–207.
30. Mitsnefes M, Kimbal T, Kartal J, Kathman T, Mishra J, Devarajan P. Serum cystatin C and left ventricular diastolic dysfunction in children with chronic kidney disease. Pediatr Nephrol. 2006; 21: 1293–1298.[CrossRef][Medline]
31. Afshinnia F, Spitalewitz S, Chou SY, Gunsburg DZ, Chadow HL. Left ventricular geometry and renal function in hypertensive patients with diastolic heart failure. Am J Kidney Dis. 2007; 49: 227–236.[CrossRef][Medline]
32. Djousse L, Kurth T, Gaziano JM. Cystatin C and risk of heart failure in the Physicians’ Health Study (PHS). Am Heart J. 2008; 155: 82–86.[CrossRef][Medline]
33. Cheng XW, Obata K, Kuzuya M, Izawa H, Nakamura K, Asai E, Nagasaka T, Saka M, Kimata T, Noda A, Nagata K, Jin H, Shi GP, Iguchi A, Murohara T, Yokota M. Elastolytic cathepsin induction/activation system exists in myocardium and is upregulated in hypertensive heart failure. Hypertension. 2006; 48: 979–987.
34. Stypmann J, Glaser K, Roth W, Tobin DJ, Petermann I, Matthias R, Monnig G, Haverkamp W, Breithardt G, Schmahl W, Peters C, Reinheckel T. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc Natl Acad Sci USA. 2002; 99: 6234–6239.
35. Sam F, Siwik DA. Digesting the remodeled heart: role of lysosomal cysteine proteases in heart failure. Hypertension. 2006; 48: 830–831.
36. Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, de Jong PE. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int. 2004; 65: 1416–1421.[CrossRef][Medline]
37. Singh D, Whooley MA, Ix JH, Ali S, Shlipak MG. Association of cystatin C and estimated GFR with inflammatory biomarkers: the Heart and Soul Study. Nephrol Dial Transplant. 2007; 22: 1087–1092.
38. Shlipak MG, Katz R, Cushman M, Sarnak MJ, Stehman-Breen C, Psaty BM, Siscovick D, Tracy RP, Newman A, Fried L. Cystatin-C and inflammatory markers in the ambulatory elderly. Am J Med. 2005; 118: 1416.[Medline]
Related Articles
This article has been cited by other articles:
CLINICAL PERSPECTIVE
Cystatin C, a novel marker of renal function, has been shown to be a risk factor for heart failure and cardiovascular disease mortality. Whether cystatin C is associated with preclinical cardiac structural abnormalities is unknown. In this study, we evaluated the association of cystatin C with various measures of LV structure and function within the Dallas Heart Study, a young population-based sample. We observed that cystatin C was associated with measures of LV structure including LV mass, wall thickness, and concentricity independent of various markers of renal function. This association was particularly robust in hypertensives and in blacks. Additional evaluation of the mechanistic link between cystatin C and these measures of ventricular structure may provide insight into the pathophysiology of cardiorenal disease. Prospective studies are also warranted to assess if cystatin C is a predictor for the development of cardiac structural abnormalities and adverse outcomes.
Circ Heart Fail 2009 2: 86-89.
Circ Heart Fail 2009 2: 98-104.
 |
|
 |
|
  M. D. McMurray, J. E. Trivax, and P. A. McCullough Serum Cystatin C, Renal Filtration Function, and Left Ventricular Remodeling Circ Heart Fail, March 1, 2009; 2(2): 86 - 89. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||