AHA hyperuricemia and heart failure 2009

Hyperuricemia and Incident Heart Failure Eswar Krishnan Circ Heart Fail 2009;2:556-562; originally published online August 6, 2009; doi: 10.1161/CIRCHEARTFAILURE.108.797662 Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2009 American Heart Association, Inc All rights reserved Print ISSN: 1941-3289 Online ISSN: 1941-3297 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circheartfailure.ahajournals.org/content/2/6/556 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Heart Failure can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services Further information about this process is available in the Permissions and Rights Question and Answer document Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Heart Failure is online at: http://circheartfailure.ahajournals.org//subscriptions/ Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 13, 2013 Hyperuricemia and Incident Heart Failure Eswar Krishnan, MD, MPhil Background—Hyperuricemia, a known correlate of oxidative stress, is a marker for adverse prognosis among individuals with heart failure However, the relationship between hyperuricemia and the risk for incidence of heart failure in a community-based population has not been studied Methods and Results—We prospectively analyzed the relationship between serum uric acid concentration at baseline and subsequent heart failure among the participants of the Framingham Offspring cohort (nϭ4912; mean baseline age, 36 years; 52% women) By using Cox regressions, we calculated the risk of heart failure with increasing serum uric acid after adjusting for sex, age, smoking, body mass index, renal dysfunction, diuretics, systolic blood pressure, valvular heart disease, diabetes, alcohol, and use of antihypertensive medications The incidence rates of heart failure were Ϸ6-fold higher among those at the highest quartile of serum uric acid (Ͼ6.3 mg/dL) compared with those at the lowest quartile (Ͻ3.4 mg/dL) The adjusted hazard ratio for the highest quartile of serum uric acid compared with the lowest was 2.1 (1.04 to 4.22) The relationship between hyperuricemia and heart failure was found in participants without metabolic syndrome and other subgroups as well Conclusions—Hyperuricemia is a novel, independent risk factor for heart failure in a group of young general community dwellers This has implications for development of preventive strategies for heart failure (Circ Heart Fail 2009;2:556-562.) Key Words: heart failure Ⅲ risk Ⅲ uric acid Ⅲ incidence Ⅲ hyperuricemia Ⅲ prospective studies Ⅲ biological markers N early million Americans currently suffer from heart failure, and Ϸ550 000 new cases of heart failure are now diagnosed each year.1 Heart failure is associated with high risk of morbidity, mortality, and hospital utilization in the United States.2 The established risk factors for heart failure include male sex, hypertension, valvular heart disease, coronary artery disease, and obesity.3 Despite the progress made in its management, the mortality from heart failure remains high, underlining the need for identification of novel risk factors that may be amenable to intervention Clinical Perspective on p 562 Earlier studies have shown that heart failure is often associated with hyperuricemia.4,5 Hyperuricemia is associated with worse hemodynamic measures such as increased left atrial pressure and decreased cardiac index among patients with primary pulmonary hypertension, cor pulmonale, and dilated cardiomyopathy in a small case series.6 Among those with established heart failure, hyperuricemia is a risk factor for adverse outcomes, including mortality.5,7–15 Serum uric acid may be useful for prognostication among those with preexisting heart failure.5,10 –15 Hyperuricemia can predict heart failure among those with preexisting hypertension.16 There have not been any studies that examined hyperuricemia as an independent risk factor for heart failure risk among the general population The single available study from Austria did not account for confounders such as valvular heart disease and diuretics, and renal disease suggested that highest quantiles of serum uric acid was associated with increased risk for death from heart failure.17 Hyperuricemia can be easily detected in routine medical care If indeed presence of hyperuricemia provides additional information on future heart failure risk (over and above other risk factors), it has the potential to be a screening tool Accordingly, we hypothesized that hyperuricemia is a risk factor for heart failure independent of other known risk factors Methods Study Cohort and Data Source We used data from the Framingham Offspring Study, a longitudinal observational study of children of the original Framingham Heart Study cohort and their spouses.18 All participants of the Framingham Offspring cohort that began in 1971 were eligible to be included in this study The data for our analyses were obtained from the National Heart, Lung, and Blood Institute limited access dataset program This analysis protocol was approved by the Stanford University institutional review board We excluded all the subjects who did not have uric acid measurement Follow-Up and Observation Period Participants were under surveillance for cardiovascular events and were followed up approximately every years by study visits that included medical review, physical examination, and laboratory testing In the current analyses, we used data collected from the first through seventh study visit The exact number of days from baseline to each study visit or outcome event was used in our analyses The Received June 9, 2008; accepted July 22, 2009 From the Department of Medicine, Stanford University School of Medicine, Stanford, Calif Correspondence to Eswar Krishnan, MD, 1000 Welch Rd, Suite 203, Stanford, CA 94304 E-mail e.krishnan@stanford.edu © 2009 American Heart Association, Inc Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.108.797662 556 Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 13, 2013 Krishnan median follow-up of this cohort was 29 years, and the cumulative observation time was 135 991 person-years For analyses of the effects of serum uric acid, each observation started in the first (baseline) visit and ended at the day of outcome event, death, or last contact with the study In using such a definition, we acknowledge that the duration of hyperuricemia for each individual in the observation period is an underestimation of the true duration of hyperuricemia In all analyses, the observation ended at the time of death, last contact, or the outcome event Hyperuricemia and Heart Failure Table Framingham Criteria for Heart Failure Used for Case Definition in this Study A definite diagnosis of congestive heart failure requires that a minimum of major or major and minor criteria be present concurrently The presence of other conditions capable of producing the symptoms and signs were considered in evaluating the findings Major criteria Paroxysmal nocturnal dyspnea or orthopnea Measurement of Covariates Distended neck veins (in other than the supine position) Exercise, diet, drugs, and state of hydration may result in transient fluctuations of uric acid levels, and one measurement of uric acid may not be an accurate metric of the hyperuricemic “trait.” We examined this possibility in our data by calculating the probability of an individual participant changing the quartile of uric acid during the time interval between the first and second visit (ie, transition probability) for each of the uric acid stratum Because this estimate was Ϸ20%, we deemed the variability to be too high, and serum uric acid was measured at the first and the second visits and averaged to arrive at a mean value that replaced the single baseline measurement Serum uric acid was assayed using the uricase method Information on renal dysfunction, obesity measures, blood pressure, serum lipids, serum glucose, smoking, alcohol, aspirin, antihypertensive, and antidiabetic medication use was available at all visits Detailed information on individuals’ diabetes and hypertension medications such as name, dosage, and duration of treatment were not available For the purpose of this study, participants with a cardiac murmur at the time of the first study visit was assessed to have valvular heart disease, a risk factor for heart failure Participants were evaluated for coronary artery disease at baseline and at subsequent visits by medical history, clinician assessment, and ECG The determination of renal dysfunction at baseline was made by the study physician Serum creatinine or other laboratory measures of renal function was not available for this analysis Gout was defined as a diagnosis of definite gouty arthritis by the study physician.19 Rales Outcome Assessment Heart Failure Heart failure events (both hospitalized and nonhospitalized) were adjudicated by a study physician panel according to the predetermined Framingham criteria shown in Table 1.20,21 Heart failure was considered to be present if major or major and minor criteria were present in the absence of alternative explanation for the clinical picture (please see Table for further details) There were no participants with heart failure at baseline Statistical Analysis Risk Factors for Heart Failure Our primary analyses addressed the following question: Does elevated serum uric acid independently predict the risk for incident heart failure? We used Cox proportional hazards regression model to study the relationship between baseline serum uric acid level and heart failure In these regressions, the time variable was defined as the period (number of days) from the baseline date to the date of incidence of heart failure or the date of last study visit Observations of patients who did not die or develop heart failure were censored at the time of last observation In the primary analyses, the baseline values of the covariates were used to adjust for confounding However, the relationship between hyperuricemia and other cardiovascular risk factors is complex (Figure 1) because hyperuricemia is a risk factor for kidney disease, hypertension, and atherosclerotic cardiovascular diseases.22–27 Changes in health conditions over time, such as increased blood pressure and worse renal function, can potentially be a cause and a consequence of hyperuricemia Thus, using time varying measures of these covariates may be problematic Therefore, in addition to Cox regressions with time-varying values of covariates, we preformed extensive stratified analyses for those who 557 Increasing heart size by chest radiograph Acute pulmonary edema on chest radiograph Ventricular S(3) gallop Increased venous pressure Ͼ16 cm water Hepatojugular reflux Pulmonary edema, visceral congestion, or cardiomegaly shown on autopsy Weight loss of Ն10 lb over d on CHF treatment Minor criteria Bilateral ankle edema Night cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion by chest radiograph Decrease in vital capacity by one third from maximum record Tachycardia (120 bpm or more) Pulmonary vascular engorgement on chest radiograph CHF indicates congestive heart failure did not meet the adult treatment panel criteria for metabolic syndrome baseline,28 who died of any cause during the follow-up, and those who survived until the cutoff date for observation (visit 7) Results Overall, of the 4989 participants in the Offspring study, there were 4912 eligible participants with 196 incident cases of heart failure Participants who developed heart failure were more likely to be older, men, and with a worse traditional risk factor profile, have gout and currently used allopurinol, a uric acid-reducing medication These individuals had a greater prevalence of gout and higher serum uric acid concentration Increasing serum concentrations of serum uric acid was associated with worse cardiovascular risk (Table 2) During the follow-up period, the cumulative incidence of gout was 12.6% (nϭ171) and 4.5% (nϭ192) among heart failure and no heart failure groups, respectively (PϽ0.001) Overall, 155 participants with gout reported using allopurinol during the follow-up Only participants without gout reported using allopurinol Figure shows the heart failure-free survival curve Those in the higher quartiles of serum uric acid had greater incidence of heart failure (Table 3) Proportional hazards assumptions were met in all the Cox regression models In these models, increasing level of serum uric acid was associated with increased risk for heart failure in unadjusted and age-sex–adjusted models (Table 3) In multivariable regres- Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 13, 2013 558 Circ Heart Fail November 2009 Figure Potential epidemiological pathways linking hyperuricemia and heart failure can be direct, mediated through risk factors such as hypertension, confounded by medication use, or a combination of these sions, the increased risk relationship between uric acid level and heart failure was most evident in the highest quartile In this cohort of relatively young adults (median baseline age 36 years, interquartile range 28 to 44), the prevalence of documented coronary artery disease at baseline was infrequent (nϭ6), and exclusion of these individuals did not change our overall risk estimate There were no participants with renal dysfunction at the baseline Multivariable Cox regressions were performed for each of the following subgroups: participants who did not use diuretics, any blood pressure medications, nondiabetics; those who did not develop renal dysfunction anytime during follow-up; and those who did not develop the metabolic syndrome (Table 4) The link between hyperuricemia and heart failure was consistent across all these analyses Analyses for Survivor Effect When the multivariable analyses were repeated separately among the 892 participants who died during follow-up from any cause and those who survived until the seventh visit, each Table Baseline Characteristics of Framingham Offspring Study Participants According to Serum Uric Acid Concentrations (n‫؍‬4912) Quartile (1.2 to 4.34 mg/dL) No of participants 1164 Age, y 34Ϯ10 Proportion of men Quartile (4.35 to 5.2 mg/dL) 1194 36Ϯ10 Quartile (5.3 to 6.2 mg/dL) 1227 36Ϯ11 Quartile (6.3 to 13.7 mg/dL) P (for Trend) 1329 38Ϯ11 Ͻ0.001 Ͻ0.001 30 65 88 Body mass index, kg/m2 23Ϯ3 25Ϯ4 26Ϯ4 28Ϯ4 Ͻ0.001 Alcohol use 81 84 85 90 Ͻ0.001 Proportion of current smokers 60 65 62 68 Ͻ0.001 Ͻ0.001 Systolic blood pressure, mm Hg 114Ϯ13 119Ϯ15 123Ϯ15 129Ϯ17 Ͻ0.001 Diastolic blood pressure, mm Hg 73Ϯ9 77Ϯ10 79Ϯ10 84Ϯ11 Ͻ0.001 Fasting glucose, mg/dL 93Ϯ17 99Ϯ23 104Ϯ33 108Ϯ32 Ͻ0.001 Total cholesterol, mg/dL 187Ϯ37 191Ϯ38 199Ϯ41 205Ϯ40 Ͻ0.001 LDL cholesterol, mg/dL 115Ϯ33 121Ϯ35 130Ϯ36 131Ϯ35 Ͻ0.001 HDL cholesterol, mg/dL 57Ϯ14 53Ϯ15 48Ϯ13 45Ϯ13 Ͻ0.001 Triglycerides, mg/dL 101Ϯ69 112Ϯ73 131Ϯ107 163Ϯ162 Ͻ0.001 Serum uric acid, mg/dL 7.2Ϯ0.8 Diuretic users 3.7Ϯ0.5 4.8Ϯ0.3 5.7Ϯ0.3 Valvular heart disease 8.3 7.7 6.0 7.0 0.16 History of gout at baseline 0.1 0.6 0.3 6.9 Ͻ0.001 History of diabetes at baseline 0.9 1.8 2.7 2.3 0.008 Data are presented as meanϮSD or % Valvular heart disease was defined for this study as presence of cardiac murmur at baseline Gout was determined based on physician diagnosis Diabetes was defined using the American Diabetes Association criteria or use of antidiabetes medications LDL indicates low-density lipoprotein; HDL, high-density lipoprotein Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 13, 2013 Krishnan Hyperuricemia and Heart Failure 559 Proportion without heart failure 1.00 0.98 Figure Kaplan-Meier estimates for heart failure-free follow-up among the 4912 participants of the Framingham Offspring Study by quartiles of serum uric acid For this survival model, the observation started at the first study visit and ended at the time of incident heart failure (nϭ196) Note that the y axis scale is adjusted for the sake of clarity 0.96 0.94 0.92 Baseline serum uric acid (mg/dl) 0.90 1.2-4.4 4.5-5.3 5.3-6.2 6.3-13.7 10 15 20 25 30 Follow-up in years unit increase in serum uric acid increased the risk for incident heart failure for the deceased (nϭ125; hazard ratio, 1.2 [0.9 to 1.5]) and survivors (nϭ76; hazard ratio, 1.1 [0.9 to 1.5]), although neither reached statistical significance Gender Effects In multivariable regressions, the impact of such statistical interaction was tested for but was found to be statistically insignificant (Pϭ0.21) Furthermore, when data were analyzed for men and women separately, the risk estimates were greater than unity but not statistically significant in both groups because of small number of events in each Discussion We report for the first time that hyperuricemia is a risk factor for heart failure in a large prospective study of a communitydwelling population Similar to the Vorarlberg study, this risk Table was most evident at serum uric acid levels greater than Ϸ6 mg/dL—a cutoff point close to the solubility of urate in the normal human body.17 Our observation is not unexpected given the knowledge about the significance of hyperuricemia as a marker of abnormal oxidative metabolism.29 Serum uric acid level is an index of oxidative stress in the human body.30 Serum uric acid is known to contribute to endothelial dysfunction by impairing nitric oxide production.31 Serum uric acid has also been shown to be inversely correlated with the measures of functional capacity and maximal oxygen intake.5 Among patients with chronic heart failure, serum uric acid concentrations are associated with greater activity of superoxide dismutase and endothelium-dependent vasodilatation.32 Another potential pathophysiological link between hyperuricemia and heart failure might be through inflammation Asymptomatic hyperuricemia is a proinflammatory state Incident Heart Failure According to Baseline Uric Acid Quartiles in Framingham Offspring Cohort (n‫؍‬4912) 1.2 to 4.34 mg/dL (nϭ1164) Characteristic No of incident heart failure 13 4.35 to 5.2 mg/dL (nϭ1193) 5.3 to 6.2 mg/dL (nϭ1227) 6.3 to 13.7 mg/dL (nϭ1328) P (for Trend) 36 57 90 3.9 (2.3 to 6.8) 10.8 (1.8 to 15.0) 17.3 (13.4 to 22.4) 25.8 (21.0 to 31.7) Ͻ0.001* Unadjusted hazard ratio 1.00 2.8 (1.5 to 5.3) 4.5 (2.5 to 8.3) 7.0 (3.9 to 12.4) Ͻ0.001 Age-sex–adjusted hazard ratio 1.00 1.9 (1.0 to 3.7) 2.6 (1.3 to 4.9) 3.3 (1.7 to 6.3) Ͻ0.001 Model 1: multivariable-adjusted hazard ratio with baseline values of covariates 1.00 1.6 (0.8 to 3.2) 1.7 (0.9 to 3.3) 2.1 (1.0 to 4.2) 0.007 Model 2: multivariable-adjusted hazard ratio with time-varying values of covariates 1.00 1.6 (0.7 to 3.5) 2.1 (0.9 to 4.0) 2.3 (1.0 to 5.1)† Ͻ0.01 Model 3: multivariable-adjusted hazard ratio with time-varying values of covariates among the subgroup without metabolic syndrome 1.00 1.5 (0.6 to 3.5) 2.0 (0.8 to 4.8) 2.5 (1.0 to 6.2)‡ Ͻ0.01 Rate per 10 000 person-years (95% CI) Multivariable models were adjusted for sex, baseline values of age, smoking, systolic blood pressure, serum total cholesterol:high-density lipoprotein ratio, alcohol use, renal dysfunction, coronary artery disease, valvular heart disease, diuretic use, and nondiuretic blood pressure medications CI indicates confidence interval *Age-sex–adjusted trend †95% CI, 1.01 to 5.10 ‡95% CI, 1.04 to 6.18 Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 13, 2013 560 Circ Heart Fail November 2009 Table Multivariable Adjusted Risk of Heart Failure Among Various Subgroups of the Framingham Offspring Cohort No of Participants in Model Hazard Ratio for Each 1-mg/dL Increase in Serum Uric Acid 95% CI No of renal dysfunction anytime during the observation 3587 1.3 1.10 to 1.50 Nonusers of any nondiuretic blood pressure medications 3677 1.20 1.01 to 1.44 Nonusers of diuretics 3639 1.20 1.00 to 1.41* Nondiabetics 3517 1.28 1.01 to 1.52 No metabolic syndrome at study end date 3765 1.26 1.07 to 1.47 Unless specified otherwise, multivariable models were adjusted for sex, time-varying measures of age, smoking, systolic blood pressure, serum total cholesterol, high-density lipoprotein ratio, alcohol use, renal dysfunction, coronary artery disease, valvular heart disease, diuretic use, and nondiuretic blood pressure medications *Pϭ0.048 associated with higher levels of serum markers of inflammation, such as C-reactive protein, interleukin-6, and neutrophil count.31,33,34 Among patients with heart failure, hyperuricemia is associated with higher levels of markers of endothelial activation, such as the soluble intercellular adhesion molecule-1, and inflammatory markers such as interleukin-6, tumor necrosis factor-␣, and its receptors.12 Similar observations have been made in other population-based studies35 and hospital-based studies.11,12 The risk of heart failure was proportionate to the degree of elevation of serum uric acid among patients with gout.36 Locally, even when there is no active arthritis, the synovial fluid of patients with gout shows low-grade inflammatory activity.37 Increased levels of serum uric acid among normal individuals predict hypertension,27,38 renal dysfunction,25 and coronary artery disease22 and portend reduced life expectancy.39 Lowering of serum uric acid with allopurinol can reduce blood pressure among hypertensives.40,41 This raises the possibility of the hyperuricemia-heart failure link being mediated by hypertension, a hypothesis that cannot be directly tested in observational studies such as ours Nevertheless, other studies have shown that hyperuricemia is an independent risk factor for heart failure among those who already have hypertension.16 In our study, this link was consistently observed (a) in time-varying Cox models in which incident hypertension was adjusted for and (b) in stratified analyses of participants who did not develop hypertension The significance of our observation lies in its use for developing a risk prediction rule for heart failure Although observations we have made raise the possibility of primary prevention of heart failure, the literature is conflicting on whether a reduction in serum uric acid will result in measurable clinical benefit among those with established heart failure.42,43 Some even argue that increased serum uric acid caused by diuretic use might have a beneficial role in itself.43 On the other hand, the uricosuric property of Losartan, an antihypertensive, has been thought to have a beneficial effect among patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study.44 The putative mechanisms by which uric acid reduction treatments have shown benefit are also unclear Specifically, it is unclear whether the observed benefit from the use of xanthine oxidase inhibitors is medi- ated through reduction in serum uric acid levels or some other mechanism Inhibition of xanthine oxidase enzyme by allopurinol has beneficial effects in terms of improved peripheral vasodilator capacity, systemic blood flow, and clinical outcomes.45,46 Randomized controlled studies have also been unclear about the putative benefit of allopurinol or its metabolite oxypurinol on established heart failure Although La Plata study showed improvement in left ventricular ejection fraction with the use of allopurinol,47 the Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) study did not show an overall benefit.48 In our study, the majority of patients with gout were treated with allopurinol; the number of participants with gout but not on allopurinol was too few for a meaningful comparison If indeed allopurinol is protective from heart failure, the excess risk for serum uric acid we have found is likely to be an underestimate Limitations apply to our analysis Our observational data on serum uric acid are essentially left truncated In other words, we know the severity of hyperuricemia but not the duration of hyperuricemia In addition, the long interval between follow-up visits (Ϸ4 years) may be too long to capture heart failure that results in death in shorter time The distribution of serum uric acid concentrations among men and women was different, the former having higher concentrations Thus, the lowest quartile of the pooled data was constituted mainly by women and the highest quartile by men The sex-uric acid statistical interaction was insignificant, but limitations in statistical power precluded a more detailed analysis In summary, this large prospective study found that hyperuricemia is associated with greater incidence of heart failure Future studies of various urate reduction strategies with adequate power to detect small improvement in clinical outcomes would be needed to determine whether, if at all, heart failure is preventable Given the increasing prevalence and serious health impact of heart failure, even such small clinical benefit can translate into substantial public health benefit Sources of Funding The Framingham Offspring Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the Framingham Offspring Study Investigators This research was supported in part by grant KL2 RR024154-01 from the National Center for Research Resources, a component of the National Institutes of Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 13, 2013 Krishnan Health, and National Institutes of Health Roadmap for Medical Research Its contents are solely the responsibility of the authors and not necessarily represent the official view of the National Center for Research Resources, the National Heart, Lung, and Blood Institute, or the National Institutes of Health Information on the National Center for Research Resources is available at http:// www.ncrr.nih.gov Information on Reengineering the Clinical Research Enterprise is available at http://nihroadmap.nih.gov/ clinicalresearch/overview-translational.asp No commercial products are discussed in this manuscript 15 16 17 Disclosures Dr Krishnan has received grant support from Takeda Pharmaceuticals of North America, Inc, Deerfield, Ill (formerly TAP Pharmaceutical Products, Inc) and has held stock in Savient Pharmaceuticals He has served as an advisor/consultant for both these companies Proprietary products manufactured by these companies are not named or discussed in this manuscript This manuscript was prepared using a limited access dataset that Dr Krishnan obtained from the National Heart, Lung, and Blood Institute and does not necessarily reflect the opinions or views of the Framingham Offspring Study or the National Heart, Lung, and Blood Institute He conceived the manuscript idea, designed the analysis plan, performed statistical analysis, interpreted the results, drafted the manuscript, and will serve as the guarantor References Heart Disease and Stroke Statistics—2006 update Dallas, Tex.: American Heart Association; 2006 Gwadry-Sridhar FH, Flintoft V, Lee DS, Lee H, Guyatt GH A systematic review and meta-analysis of studies comparing readmission rates and mortality rates in patients with heart failure Arch Intern Med 2004;164: 2315–2320 Kenchaiah S, Narula J, Vasan RS Risk factors for heart failure Med Clin North Am 2004;88:1145–1172 Thomas RD, Newill A, Morgan DB The cause of the raised plasma urea of acute heart failure 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