Circulating Fibroblast Growth Factor 21 is Associated with Diastolic Dysfunction in Heart Failure Patients with Preserved Ejection Fraction.

Fibroblast growth factor 21 (FGF21), a polypeptide ligand promoted glucose homeostasis and lipids metabolism, was recently reported to attenuate cardiac hypertrophy. The aim of this study was to investigate the impact of FGF21 in diastolic heart failure. Subjects admitted for coronary angiogram were screened for heart failure, and those with left ventricular (LV) ejection fraction < 45% were excluded. Diastolic dysfunction was defined as functional abnormalities that exist during LV relaxation and filling by echocardiographic criteria. Plasma levels of FGF21 and N-terminal Pro-Brain Natriuretic Peptide (NT-pro-BNP) were determined. All patients were followed up for 1 year, or till the occurrence of heart failure readmission or death. Totally 95 patients with diastolic dysfunction and 143 controls were enrolled. Circulating FGF21 level was correlated with echocardiographic parameters of diastolic function and LV end-diastolic pressure (LVEDP). In multivariate logistic analysis, FGF21 was significantly associated with diastolic dysfunction, either identified by echocardiographic criteria (odds ratio: 2.97, p = 0.012) or confirmed with LVEDP level (odds ratio: 3.73, p = 0.030). Both plasma FGF21 (log rank p < 0.0001) and NT-pro-BNP levels (log rank p = 0.0057) showed good predictive power to the 1-year adverse cardiac events. This finding suggested FGF21 could be involved in the pathophysiology of diastolic heart failure.

Novel Biomarkers of Cardiac Stress, Cardiovascular Dysfunction, and Outcomes in HIV-Infected Individuals.

OBJECTIVES: This study sought to determine whether biomarkers ST2, growth differentiation factor (GDF)-15, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin I are elevated in patients infected with human immunodeficiency virus (HIV) and are associated with cardiovascular dysfunction and all-cause mortality. BACKGROUND: HIV-infected patients have high rates of cardiovascular disease. Markers of myocardial stress may identify at-risk patients and provide additional prognostic information. METHODS: Biomarkers and echocardiograms were assessed in 332 HIV-infected patients and 50 age- and sex-matched control subjects. Left ventricular systolic dysfunction was defined as ejection fraction <50%, diastolic dysfunction (DD) as stage 1 or higher, and pulmonary hypertension as pulmonary artery systolic pressure ≥35 mm Hg. Mortality data were obtained from the National Death Index. RESULTS: Patients with HIV had a median age of 49 years, and 80% were male. Compared with control subjects, HIV-infected patients had higher adjusted percent estimates of all biomarkers except ST2 and interleukin-6. Among HIV-infected patients, 45% had DD; only ST2 was associated with DD (relative risk [RR]: 1.36; p = 0.047). Left ventricular systolic dysfunction was rare in this cohort (5%). Pulmonary hypertension was present in 27% of HIV-infected patients and was associated with GDF-15 (RR: 1.18; p = 0.04), NT-proBNP (RR: 1.18; p = 0.007), and cystatin C (RR: 1.54; p = 0.03). Thirty-eight deaths occurred among HIV-infected patients over a median of 6.1 years. In adjusted analysis, all-cause mortality was independently predicted by ST2 (hazard ratio [HR]: 2.04; p = 0.010), GDF-15 (HR: 1.42; p = 0.0054), high-sensitivity C-reactive protein (HR: 1.25; p = 0.023), and D-dimer (HR: 1.49; p = 0.029). Relationships were unchanged when analyses were restricted to virally suppressed HIV-infected patients receiving antiretroviral therapy. CONCLUSIONS: Among HIV-infected patients, ST2 and GDF-15 were associated with both cardiovascular dysfunction and all-cause mortality, and these variables may be useful at identifying those at risk for developing cardiovascular events and death.

Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure).

OBJECTIVES: This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains. BACKGROUND: Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. METHODS: Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. RESULTS: Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). CONCLUSIONS: In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF.

Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: evidence of M2 macrophage activation in disease pathogenesis.

BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is a major health problem associated with myocardial leukocyte infiltration, inflammation, and fibrosis. Monocyte and macrophage subsets play a role in HFPEF but have not been studied. We analyzed peripheral blood monocyte phenotype and plasma markers of monocyte activation in patients with HFPEF, asymptomatic LV diastolic dysfunction (aLVDD), and asymptomatic hypertension (aHTN). METHODS AND RESULTS: Peripheral blood was collected from 23 aHTN, 30 aLVDD, and 30 HFPEF patients. Peripheral cytokines of classic/pro-inflammatory (tumor necrosis factor alpha, interleukin (IL) 12, IL-6, monocyte chemoattractant protein 1, C-X-C motif chemokine 10) and alternative/anti-inflammatory monocytes (chemokine-C-C motif ligand (CCL) 17, CCL-18, soluble CD163) were increased in aLVDD and HFPEF. Peripheral blood mononuclear cells and monocytes were purified and surface-stained for CD14, CD16, CD163, and CD206. Peripheral monocyte percentage was increased in aLVDD and HFPEF and correlated with echocardiographic LVDD indices. Classic/pro-inflammatory monocyte numbers were increased in aLVDD and HFPEF, and alternative/anti-inflammatory monocyte numbers were increased in HFPEF. CD163 M2-macrophage receptor was reduced in HFPEF. Culture of healthy donor monocytes (n = 3) with HFPEF patient-derived sera (n = 6) promoted M2 macrophage features as evidenced by altered morphology and genes (CD206, IL-10). CONCLUSIONS: Increased peripheral inflammation, monocytosis, and monocyte differentiation to anti-inflammatory/profibrotic M2 macrophages likely associate with HFPEF and its precedent asymptomatic LVDD phase.

Association of serum total bilirubin levels with diastolic dysfunction in heart failure with preserved ejection fraction.

BACKGROUND: Left ventricular diastolic dysfunction is one of the main characteristics of heart failure patients with a preserved left ventricular ejection fraction. As bilirubin is regarded as an important endogenous antioxidant molecule, serum total bilirubin levels were compared between heart failure patients with a preserved left ventricular ejection fraction and normal controls in this study. We recruited 327 heart failure patients with a preserved left ventricular ejection fraction and 200 healthy controls. Patients were divided into 4 subgroups by their comprehensive echocardiographic manifestations, 1-mild, 2-moderate, 3-severe (reversible restrictive), 4-severe (fixed restrictive). Total bilirubin levels were compared using stepwise multiple regressions adjusted for selected factors. RESULTS: After adjusting for gender, age, smoking, systolic blood pressure, diastolic blood pressure, total cholesterol and triglyceride, serum total bilirubin levels were significantly lower in the heart failure group compared with the control group (P < 0.01). Patients in the subgroup (4-severe) showed significantly (P < 0.05) lower levels of total bilirubin when compared with the subgroup (1-mild). CONCLUSIONS: TB level was negatively correlated with left ventricular diastolic dysfunction in heart failure patients with a preserved left ventricular ejection fraction, which might provide a new insight into the complicated mechanisms of heart failure with a preserved left ventricular ejection fraction.

Association of serum total bilirubin levels with diastolic dysfunction in heart failure with preserved ejection fraction

BACKGROUND: Left ventricular diastolic dysfunction is one of the main characteristics of heart failure patients with a preserved left ventricular ejection fraction. As bilirubin is regarded as an important endogenous antioxidant molecule, serum total bilirubin levels were compared between heart failure patients with a preserved left ventricular ejection fraction and normal controls in this study. We recruited 327 heart failure patients with a preserved left ventricular ejection fraction and 200 healthy controls. Patients were divided into 4 subgroups by their comprehensive echocardiographic manifestations, 1-mild, 2-moderate, 3-severe (reversible restrictive), 4-severe (fixed restrictive). Total bilirubin levels were compared using stepwise multiple regressions adjusted for selected factors. RESULTS: After adjusting for gender, age, smoking, systolic blood pressure, diastolic blood pressure, total cholesterol and triglyceride, serum total bilirubin levels were significantly lower in the heart failure group compared with the control group (P < 0.01). Patients in the subgroup (4-severe) showed significantly (P < 0.05) lower levels of total bilirubin when compared with the subgroup (1-mild). CONCLUSIONS: TB level was negatively correlated with left ventricular diastolic dysfunction in heart failure patients with a preserved left ventricular ejection fraction, which might provide a new insight into the complicated mechanisms of heart failure with a preserved left ventricular ejection fraction.

[Left ventricular mass, diastolic function and collagen metabolism biomarkers in essential hypertension]. / Masa ventricular izquierda, función diastólica y marcadores de metabolismo del colágeno en la hipertensión arterial refractaria.

BACKGROUND AND OBJECTIVE: To evaluate the association between circulating biomarkers of collagen metabolism in serum, left ventricular mass index (LVMI) and diastolic dysfunction in patients with resistant hypertension. PATIENTS AND METHODS: Fifty-two patients with resistant hypertension and 24 healthy individuals were included. The following biomarkers of collagen metabolism were analyzed by ELISA: carboxy-terminal propeptide of procollagen type I (PICP) and transforming growth factor beta1 (TGFß1). The biomarker C-terminal telopeptide of collagen type-I (ICTP) was assayed by electrochemiluminescence immunoassay. In the patient's group a record of 24-h blood pressure monitoring was obtained and an echocardiography was performed. Left ventricular mass was measured according to the formula of Devereux and the diastolic function according to the relation of E and A waves and mitral propagation velocity. RESULTS: Hypertensive patients showed higher levels of PICP and lower levels of ICTP than controls: 83.7 (24.7) vs. 55.0 (8.7), P<.0001; and 175.0 (136.4) vs. 323.3 (121.3), P<.0001). Hypertensive patients showed a significant relationship between PICP and LVMI (r=0.631, P<.0001) and between PICP and diastolic dysfunction (r=-0.519, P<.0001). The groups with and without hypertrophy, and with or without diastolic dysfunction, differed in the mentioned peptides but not in BP values. CONCLUSIONS: Our findings suggest that the analyzed markers of synthesis and degradation of collagen may be related to myocardial hypertrophy and diastolic dysfunction independent of blood pressure values.

Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase.

OBJECTIVE: The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism. DESIGN: Prospective case-controlled cohort and molecular studies. SETTING: University hospital and research laboratory. SUBJECTS: Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. INTERVENTIONS: Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. MEASUREMENTS AND MAIN RESULTS: Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p < .01 for each) were found for tumor necrosis factor-α and E/Em (r = .87) and E/A (r = -0.69), and for interleukin-6 and E/Em (r = .80) and E/A (r = -0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. CONCLUSIONS: Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.

Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders.

BACKGROUND: Diabetes mellitus (DM) has reached epidemic proportions and is an important risk factor for heart failure (HF). Left ventricular diastolic dysfunction (LVDD) is recognized as the earliest manifestation of DM-induced LV dysfunction, but its pathophysiology remains incompletely understood. We sought to evaluate the relationship between proinflammatory cytokine levels (TNF-alpha, IL-6) and tissue Doppler derived indices of LVDD in patients with stable coronary artery disease. METHODS: We enrolled 41 consecutive patients (mean age 65+/-10 years) submitted for coronary angiography. Echocardiographic assessment was performed in all patients. Pulsed tissue Doppler imaging was performed at the mitral annulus and was characterized by the diastolic early relaxation velocity Em. Conventional transmitral flow was measured with pw-doppler. Early (E) transmitral flow velocity was measured. LVDD was defined as E/Em ratio >or= 15, E/Em 8-14 was classified as borderline. Plasma levels of TNF-alpha and IL-6 were determined in all patients. A standardized oral glucose tolerance test was performed in subjects without diabetes. RESULTS: Patients with E/Em ratio >or= 15, classified as LVDD and those with E/Em ratio 8-14 (classified as borderline) had significantly higher IL-6 (P = 0,001), TNF-alpha (P < 0,001) and NT-pro- BNP (P = 0,001) plasma levels compared to those with normal diastolic function. TNF-alpha and IL-6 levels remains significantly elevated after adjustment for sex, age, left ventricular ejection function, body mass index, coronary heart disease, smoking, hypertension and diabetes mellitus with linear regression analysis. Furthermore, in subjects LVDD or borderline LV diastolic function, 75% had diabetes or IGT, respectively. When subjects without diabetes were excluded, both IL-6 (P = 0,006) and TNF-alpha (P = 0,002) remained significantly elevated in subjects with E/Em ratio >or= 15. CONCLUSION: This study reveals that increased plasma levels of IL-6 and TNF-alpha were associated with LVDD. These findings suggest a link between low-grade inflammation and the presence of LVDD. An active proinflammatory process may be of importance in the pathogenesis of diastolic dysfunction.

Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone.

OBJECTIVES: This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF). BACKGROUND: Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown. METHODS: We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained. RESULTS: The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide. CONCLUSIONS: This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

Utility of B-natriuretic peptide in the evaluation of left ventricular diastolic function and diastolic heart failure.

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction or diastolic heart failure is an increasingly prevalent disease process today. Natriuretic peptides have been shown to provide diagnostic and prognostic utility in patients with systolic heart failure. Here we review current publications exploring the relationship between B-natriuretic peptide (BNP) and diastolic dysfunction. RECENT FINDINGS: Investigators have found significant correlations between echocardiographic parameters for diastolic dysfunction and serum BNP levels in diagnosing diastolic heart failure. This relationship is linear with respect to severity of left ventricular dysfunction. Newer echocardiographic modalities like tissue Doppler imaging provide measures of elevated left ventricular filling pressures, which are associated with higher plasma BNP levels. Admission and predischarge BNP levels in patients with decompensated diastolic heart failure have been prognostic with respect to in-hospital mortality, short-term mortality, and hospital readmission. SUMMARY: Review of current literature shows that BNP can be useful in providing diagnostic and prognostic data in patients with symptomatic and asymptomatic diastolic dysfunction. These data, combined with other values such as echocardiographic indices and cardiovascular risk factors, can augment the sensitivity and specificity of BNP.

Association of hepatitis C virus seropositivity with inflammatory markers and heart failure in persons with coronary heart disease: data from the Heart and Soul study.

BACKGROUND: How hepatitis C virus (HCV) affects coronary heart disease (CHD) risk factors and outcomes is largely unknown. METHODS AND RESULTS: Among a cohort of patients with stable CHD, we examined the association between HCV seropositivity and levels of inflammatory markers (C-reactive protein [CRP], fibrinogen, interleukin-6, and tumor necrosis factor [TNF]-alpha) and risk for the following outcomes: death, cardiovascular (CV) events, and heart failure events. A total of 84 (8.6%) participants were found to be seropositive for HCV. HCV-seropositive patients were found to have significantly lower adjusted mean levels of CRP (2.6 vs. 4.4; P < .01) and fibrinogen (340 vs. 398; P < .01), but higher levels of TNF-alpha (7.1 vs. 4.8; P < .01). Age-adjusted rates for HCV seropositive vs. seronegative were as follows: death 93 vs. 42/1,000p-y (P < .01), CV events 62 vs. 40 (P=.13), and heart failure 76 vs. 29 (P < .01). After adjustment for demographic and clinical factors, HCV remained significantly associated with an increased risk for heart failure events (HR=2.13; 95% CI: 1.19-3.80). CONCLUSIONS: In this cohort with CHD, HCV seropositive participants had higher rates of death, CV events, and heart failure hospitalizations during follow-up. After adjustment for CV risk factors, HCV seropositivity remained independently associated with risk for heart failure events.

N-terminal prohormone brain natriuretic peptide (NT-proBNP) as a noninvasive marker for restrictive syndromes

Constrictive pericarditis (CP) and restrictive cardiomyopathy share many similarities in both their clinical and hemodynamic characteristics and N-terminal prohormone brain natriuretic peptide (NT-proBNP) is a sensitive marker of cardiac diastolic dysfunction. The objectives of the present study were to determine whether serum NT-proBNP was high in patients with endomyocardial fibrosis (EMF) and CP, and to investigate how this relates to diastolic dysfunction. Thirty-three patients were divided into two groups: CP (16 patients) and EMF (17 patients). The control group consisted of 30 healthy individuals. Patients were evaluated by bidimensional echocardiography, with restriction syndrome evaluated by pulsed Doppler of the mitral flow and serum NT-proBNP measured by immunoassay and detected by electrochemiluminescence. Spearman correlation coefficient was used to analyze the association between log NT-proBNP and echocardiographic parameters. Log NT-proBNP was significantly higher (P < 0.05) in CP patients (log mean: 2.67 pg/mL; 95 percentCI: 2.43-2.92 log pg/mL) and in EMF patients (log mean: 2.91 pg/mL; 95 percentCI: 2.70-3.12 log pg/mL) compared with the control group (log mean: 1.45; 95 percentCI: 1.32-1.60 log pg/mL). There were no statistical differences between EMF and CP patients (P = 0.689) in terms of NT-proBNP. The NT-proBNP log tended to correlate with peak velocity of the E wave (r = 0.439; P = 0.060, but not with A wave (r = -0.399; P = 0.112). Serum NT-proBNP concentration can be used as a marker to detect the presence of diastolic dysfunction in patients with restrictive syndrome; however, serum NT-proBNP levels cannot be used to differentiate restrictive cardiomyopathy from CP.

Recognition of diastolic heart failure in the postoperative heart.

Diastolic dysfunction is assuming more importance as it is increasingly evident that it can be solely responsible for heart failure. Although many comprehensive studies pertinent to diastolic dysfunction and diastolic heart failure have been recently published, there is a paucity of information on diastolic dysfunction appearing in the postoperative cardiac surgical patient. We sought to look into current literature searching for criteria that could be applied to help diagnose it in this group of patients in the intensive care setting where cardiac surgical patients are usually managed in the immediate postoperative period. Because of the almost similar clinical features it is important to make the distinction between diastolic or systolic heart failure.

Cystatin C concentration as a predictor of systolic and diastolic heart failure.

BACKGROUND: Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study. METHODS AND RESULTS: Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50%) or SHF (EF < 50%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]). CONCLUSIONS: Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.