Nancy S. Jenny

Cystatin C concentration as a risk factor for heart failure in older adults

Context Is cystatin-C, a novel marker of kidney function, an independent risk factor for heart failure? Contribution This 9-year observational study of 4384 older adults from 4 communities in the United States found that higher cystatin-C levels were independently associated with a stepwise increased risk for heart failure. Higher creatinine levels were not associated with increased risk for heart failure independent of other known risk factors. Implications These pioneering findings merit replication in other studies: Cystatin-C may be a better measure of renal function than serum creatinine and may better predict some cardiovascular diseases. The Editors Several recent studies suggest that chronic kidney disease is an independent risk factor for ischemic heart disease (1-4), particularly among participants with established cardiovascular disease (1, 2) or those who are at increased cardiovascular risk (3, 5-7). Few studies, however, have evaluated the effect of kidney function on risk for heart failure. Gottdiener and colleagues performed a comprehensive evaluation of risk factors for heart failure in the Cardiovascular Health Study and found that a serum creatinine concentration of 123.2 mol/L or greater (1.4 mg/dL) (present in 8% of the cohort) was an independent predictor of heart failure in older adults (8). Similarly, a recent study in women with coronary artery disease noted that a creatinine clearance less than 0.668 mL/s (<40 mL/min) (present in 10% of the cohort) was associated with an increased risk for heart failure (9). Finally, a recent analysis of the Established Populations for Epidemiologic Studies of the Elderly demonstrated that persons with creatinine clearance less than 0.616 mL/s (<36.9 mL/min) (lowest quartile of the sample) had an increased risk for heart failure compared with persons with creatinine clearance greater than 0.952 mL/s (>57 mL/min) (highest quartile of the sample) (10). All 3 studies, however, may underestimate the importance of kidney function as a risk factor for heart failure because creatinine concentration (or estimated glomerular filtration rate [GFR]) is insensitive in detecting reductions in kidney function. Creatinine concentration is a limited measure of kidney function because creatinine is a breakdown product of muscle and its serum levels are influenced not only by kidney function but also by age, sex, ethnicity, and body mass (11). Cystatin C concentration is a novel measure of kidney function that overcomes many of the limitations of the serum creatinine concentration. Cystatin C is a cysteine proteinase inhibitor that is produced by nearly all human cells and released into the bloodstream, from which it is freely filtered by the kidney glomerulus and metabolized by the proximal tubule (12). Several, but not all (13, 14), studies demonstrate that the cystatin C concentration may be a more sensitive indicator of mild kidney dysfunction and may better estimate GFR than serum creatinine concentration (15-17) and that the association of cystatin C concentration with GFR does not differ by age, sex, or muscle mass (15-20). We hypothesized that the cystatin C concentration would be associated with risk for heart failure and would be a better predictor than the serum creatinine concentration. Methods Participants The Cardiovascular Heath Study is a community-based longitudinal study of adults who were 65 years of age or older at baseline. The objective of the study was to evaluate risk factors for development and progression of cardiovascular disease (21). A main cohort of 5201 participants was recruited between 1989 and 1990 from 4 U.S. communities (Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Allegheny County, Pennsylvania) (22). An additional 687 African-American persons were recruited in 1992 and 1993 (Figure 1). Eligible participants were sampled from Medicare eligibility lists in each area. Follow-up interviews for events were done semi-annually at annual examinations and through interim 6-month telephone calls. Figure 1. Selection of patients. Cystatin C was measured from frozen samples that were collected at the 19921993 visit of the Cardiovascular Health Study. Because our goal was to assess the risk for incident heart failure, we excluded participants with prevalent heart failure at baseline and those who developed heart failure before the 19921993 visit (Figure 1). To compare the risk associated with cystatin C concentration with that indicated by serum creatinine concentration, only participants who were alive and had had both measurements at the 19921993 visit (n= 4384) were included in this analysis. The investigational review boards of the 4 clinical sites and the Data Coordinating Center (University of Washington) approved the data collection procedures of the Cardiovascular Health Study. In addition, we obtained investigational review board approval for our study from the University of California, San Francisco. Measurement of Markers All assays were performed on serum that was drawn in the morning and stored at 70 C. Cystatin C was measured by using a BNII nephelometer (Dade Behring, Inc., Deerfield, Illinois) with a particle-enhanced immunonepholometric assay (N Latex Cystatin C, Dade-Behring, Inc.) (23). Polystyrene particles were coated with monoclonal antibodies to cystatin C that agglutinate in the presence of antigen (cystatin C) to increase the intensity of scattered light. The increase in scattered light is proportional to the amount of cystatin C in the sample. The assay range is 14.6 to 549.0 nmol/L (0.195 to 7.330 mg/L); the reference range for young, healthy persons is reported to be 40 to 71 nmol/L (0.53 to 0.95 mg/L). The intra-assay coefficient of variation ranges from 2.0% to 2.8%, and the interassay coefficient of variation ranges from 2.3% to 3.1%. Serum creatinine was measured by using the Kodak Ektachem 700 Analyzer (Eastman Kodak, Rochester, New York), which is a colorimetric method. Clinical Assessments and Measurements Information on baseline risk factors for heart failure that may confound the association of kidney function with heart failure was obtained from the 19921993 visit (8). These included demographic characteristics (age, sex, and race); traditional cardiovascular risk factors, such as body mass index, smoking (current versus past or never), diabetes (defined by use of a hypoglycemic agent or insulin or a fasting glucose level 6.99 mmol/L [126 mg/dL]), systolic blood pressure (as measured by using a Hawksley random-zero sphygmomanometer), and fasting levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol; novel risk factors (C-reactive protein, hemoglobin, albumin, fibrinogen, and factor VII); noninvasive tests of the extent of disease (anklearm index, common carotid intimamedia thickness, internal carotid intimamedia thickness, and left ventricular hypertrophy and atrial fibrillation on electrocardiography); clinical disease (previous coronary heart disease or stroke, which were adjudicated by a combination of self-report of physician diagnosis and review of medical records); and use of blood pressure medications (diuretics, -blockers, angiotensin-converting enzyme inhibitors, or calcium-channel blockers) (24-26). Echocardiography was not done at the 19921993 visit. Adjudication of Heart Failure For the diagnosis of prevalent heart failure, self-reports were confirmed by components of the physical examination or, if necessary, by a validation protocol that included surveys of treating physicians or review of medical records (24). For the diagnosis of incident heart failure, a physicians diagnosis of heart failure was followed by review of the participants medical records. The Cardiovascular Health Study Cardiovascular Events Committee then determined the incidence of heart failure on the basis of diagnosis from a physician and consideration of symptoms, signs, chest radiographic findings, and treatment of heart failure (current prescription for a diuretic agent and either digitalis or a vasodilator) (8, 26). We examine heart failure events through 30 June 2001. Statistical Analysis We compared the distribution of demographic characteristics, traditional cardiovascular risk factors, novel risk factors, clinical disease, and noninvasive assessment of extent of disease across quintiles of cystatin C concentration. P values for linear trend across the quintiles were calculated. Incidence rates were calculated per 100 person-years and are reported as percentage per year. The association of kidney function and risk for heart failure was compared by using 3 measures of kidney function: serum cystatin C concentration, serum creatinine concentration, and GFR, as estimated by using the 4-variable version of the Modification of Diet in Renal Disease formula. This formula is as follows: GFR = 186.3 (serum creatinine concentration1.154) (age0.203) 1.212 (if black) 0.742 (if female) (27, 28). Each measure of kidney function was then divided into quintiles; for serum creatinine concentration, the quintile cut-offs were sex-specific because the distribution of serum creatinine concentration differed substantially between men and women in the Cardiovascular Health Study (29, 30). We used Cox proportional hazards models to examine the relationship of cystatin C and other known risk factors to incident heart failure in multivariable models. To evaluate the contribution of cystatin C as a marker of risk, models were generated in stages: unadjusted; adjusted for demographic characteristics; adjusted for demographic characteristics, traditional cardiovascular risk factors, and use of blood pressure medications; and adjusted for risk factors from the preceding model, other novel risk factors, measurements of clinical cardiovascular disease, and noninvasive measurements of the extent of the disease. We also included a term to adjust for clustering wi

Association of Serum Phosphate with Vascular and Valvular Calcification in Moderate CKD

Within the normal range, higher serum phosphate concentrations are associated with cardiovascular events and mortality in individuals with chronic kidney disease (CKD) and in those with normal kidney function. Experimental models suggest that phosphate has a direct calcifying effect on vascular smooth muscle. We examined associations of serum phosphate concentrations with vascular and valvular calcification in 439 participants from the Multi-Ethnic Study of Atherosclerosis who had moderate CKD and no clinical cardiovascular disease. Serum phosphate concentrations were within the normal range (2.5 to 4.5 mg/dl) in 95% of study participants. The prevalence of calcification in the coronary arteries, descending thoracic aorta, aortic valve, and mitral valve was 67, 49, 25, and 20%, respectively, measured by electron-beam or multi-detector row computed tomography. After adjustment for demographics and estimated GFR, each 1-mg/dl increment in serum phosphate concentration was associated with a 21% (P = 0.002), 33% (P = 0.001), 25% (P = 0.16), and 62% (P = 0.007) greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively. Adjustment for traditional risk factors for atherosclerosis, parathyroid hormone, or 1,25-dihydroxyvitamin D levels did not alter these associations. In conclusion, higher serum phosphate concentrations, although still within the normal range, are associated with a greater prevalence of vascular and valvular calcification in people with moderate CKD. It remains to be determined whether lowering phosphate concentrations will impact calcification risk in the setting of kidney disease.

In the Elderly, Interleukin-6 Plasma Levels and the −174G>C Polymorphism Are Associated With the Development of Cardiovascular Disease

Objective—Interleukin (IL)-6–mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the −174G>C genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study. Methods and Results—Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The −174C allele was associated with higher C-reactive protein (11% higher, P =0.02), fibrinogen (3% higher, P =0.02), and IL-6 (5% higher;P =0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the −174C allele was associated with risk of MRI infarcts (odds ratio 1.5). Conclusions—IL-6 levels differentiated those with subclinical CVD from those without. Although the −174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.

Kidney Function as a Predictor of Noncardiovascular Mortality

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

Variation of C-Reactive Protein Levels in Adolescents Association With Sleep-Disordered Breathing and Sleep Duration

Background—There is increasing evidence that sleep-disordered breathing (SDB) is an independent risk factor for cardiovascular disease (CVD) in adults. C-reactive protein (CRP), a marker of systemic inflammation, is an important predictor of future cardiovascular events. The goal of this study was to quantify the associations of SDB, sleep duration, and CRP in adolescents to better understand the role of SDB in CVD risk. Methods and Results—Adolescents (n=143; age, 13 to 18 years; 36% black; 50% female) with a wide range of SDB severity underwent polysomnography and measurement of high-sensitivity CRP. SDB was quantified with the apnea hypopnea index (AHI) and oxygen desaturation measures. Sleep duration was estimated from 7-day actigraphy. The independent and dose-response associations of SDB with CRP were addressed through linear mixed-effects models. Forty-eight percent were overweight or obese, and 12% had SDB (AHI ≥5). CRP levels varied with increasing body mass index and SDB. After adjustment for body mass index, age, sex, and race, mean CRP levels were 0.50, 0.43, 0.97, and 1.66 mg/L for SDB severity levels of AHI <1, 1 to 4.9, 5 to 14.9, and ≥15, respectively (P=0.0049, AHI ≥15 versus <1). Adjusted mean CRP levels demonstrated a dose response with SDB above a threshold AHI of 5. This association was partially explained by overnight hypoxemia and less so by sleep duration. Conclusions—In adolescents free of known CVD, an AHI ≥5 is associated with increasing levels of CRP, suggesting that pediatric SDB may confer additional CVD risk beyond that of obesity.

Leukocyte Telomere Length and Mortality in the Cardiovascular Health Study

BACKGROUND Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent. METHODS We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992-1993 and survived through 1997-1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews. RESULTS A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22-2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32-5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95-3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant. CONCLUSION These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.

Vitamin D, Parathyroid Hormone, and Cardiovascular Events Among Older Adults

OBJECTIVES The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study). BACKGROUND Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health. METHODS A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality. RESULTS There were 384 participants (17%) with serum 25-OHD concentrations <15 ng/ml and 570 (25%) with serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9% greater (95% confidence interval [CI]: 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI: 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29% greater (95% CI: 5% to 55% greater) risk for mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk for heart failure (95% CI: 6% to 61% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events. CONCLUSIONS Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.

Polymorphisms of the HNF1A Gene Encoding Hepatocyte Nuclear Factor-1α are Associated with C-Reactive Protein

Data from the Pharmacogenomics and Risk of Cardiovascular Disease (PARC) study and the Cardiovascular Health Study (CHS) provide independent and confirmatory evidence for association between common polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha and plasma C-reactive protein (CRP) concentration. Analyses with the use of imputation-based methods to combine genotype data from both studies and to test untyped SNPs from the HapMap database identified several SNPs within a 5 kb region of HNF1A intron 1 with the strongest evidence of association with CRP phenotype.

The association between physical activity and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis.

Prior reports regarding the association between physical activity and subclinical cardiovascular disease have not been consistent. The authors assessed physical activity and walking pace via questionnaire among 6,482 US adults aged 45-84 years without prior clinical cardiovascular disease participating in the Multi-Ethnic Study of Atherosclerosis from 2000 to 2002. Ankle-brachial index (ABI), coronary artery calcification, and internal and common carotid intima-media thickness (IMT) were measured. Metabolic equivalent-hours/week of physical activity were calculated. These data were analyzed by using multivariable linear or relative prevalence regression in gender-specific strata. After adjustment for age, race/ethnicity, clinic site, education, income, and smoking (model 1), increasing total, moderate + vigorous, and intentional-exercise physical activity were not associated with IMT or coronary artery calcification in either gender. These factors were associated with increased ABI (P<0.05) in women only. Walking pace was associated favorably with common carotid IMT, ABI, and coronary artery calcification in men and with common carotid IMT and ABI in women (all P<0.05) after adjustment for model 1 variables. These associations were attenuated and, for common carotid IMT, no longer significant when lipids, hypertension, diabetes, and body mass index were added to the model. These data suggest that walking pace is associated with less subclinical atherosclerosis; these associations may be mediated by cardiovascular disease risk factors.

Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.