JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2005; 45:1802-1806, doi:10.1016/j.jacc.2005.02.066
© 2005 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ingelsson, E.
Right arrow Articles by Lind, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ingelsson, E.
Right arrow Articles by Lind, L.

CLINICAL RESEARCH: HEART FAILURE

Inflammation, as Measured by the Erythrocyte Sedimentation Rate, Is an Independent Predictor for the Development of Heart Failure

Erik Ingelsson, MD*,*, Johan Ärnlöv, MD, PhD*, Johan Sundström, MD, PhD* and Lars Lind, MD, PhD{dagger},{ddagger}

* Public Health and Caring Sciences, Uppsala, Sweden
{dagger} Medical Sciences, Uppsala University, Uppsala, Sweden
{ddagger} Astra Zeneca R & D, Mölndal, Sweden

Manuscript received December 14, 2004; revised manuscript received February 16, 2005, accepted February 22, 2005.

* Reprint requests and correspondence: Dr. Erik Ingelsson, Department of Public Health and Caring Sciences, Section of Geriatrics, Uppsala University, Box 609, SE-75125 Uppsala, Sweden. (Email: erik.ingelsson{at}pubcare.uu.se).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: Our objective was to explore inflammation, measured as erythrocyte sedimentation rate (ESR), as a predictor for the development of heart failure (HF).

BACKGROUND: In recent years, evidence of the importance of inflammation in the pathophysiology of HF has emerged, and various inflammatory markers have been found to predict future HF. Erythrocyte sedimentation rate is an inexpensive and easily accessible marker of systemic inflammation, but to this date it is unknown whether ESR predicts subsequent HF.

METHODS: In a community-based prospective study of 2,314 middle-aged men free from HF, myocardial infarction, and valvular disease at baseline, ESR was analyzed in multivariable models together with established risk factors for HF (hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, obesity, and serum cholesterol) and hematocrit.

RESULTS: A total of 282 men developed HF during a median follow-up time of 30 years. In Cox proportional hazards analyses, ESR was an independent predictor of HF (hazard ratio 1.46 for highest quartile vs. the lowest, 95% confidence interval 1.04 to 2.06). This observation remained significant when also adjusting for interim myocardial infarction during follow-up.

CONCLUSIONS: Erythrocyte sedimentation rate was a significant predictor of HF, independent of established risk factors for HF, and interim myocardial infarction after three decades of follow-up in a population-based sample of middle-aged men. Our findings indicate that inflammation occurs early in the process leading to HF and that ESR could be used to evaluate this process.

Abbreviations and Acronyms
  BMI = body mass index
  CI = confidence interval
  ESR = erythrocyte sedimentation rate
  HF = heart failure
  HR = hazard ratio
  ICD = International Classification of Diseases
  IL = interleukin
  TNF = tumor necrosis factor
  ULSAM = Uppsala Longitudinal Study of Adult Men

In recent years, the association between inflammation and cardiovascular diseases has gained considerable interest (1). Several systemic markers of inflammation, including erythrocyte sedimentation rate (ESR), have been found to be predictors of coronary heart disease (2–4). C-reactive protein, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6, all markers of cytokine-mediated inflammation, have all been shown to predict incident heart failure (HF) (5,6), but to this date, there are no studies of the possible association between ESR and future HF. The ESR is a well-validated and inexpensive tool for evaluating inflammation (including aspects of inflammation other than cytokine-mediated reactions) and is available at every outpatient clinic.

Thus, our aim was to analyze ESR as a possible predictor of heart failure during a median follow-up time of 30 years in a community-based sample of middle-aged men free from HF, previous acute myocardial infarction, and valvular disease at baseline. Because ESR is a known predictor of coronary heart disease, a secondary aim was to analyze whether it predicted HF independently of an interim myocardial infarction during the follow-up period.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study sample.   The study used the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, to which all 50-year-old men living in Uppsala county in 1970 to 1974 were invited. Of the 2,841 invited men, 82% (2,322 men) participated in the investigation (7). The ULSAM study is described in detail on the Internet (8). None of the subjects had been diagnosed with HF in the hospital discharge register before baseline. Seven subjects were excluded because of previous myocardial infarction and one subject because of valvular disease at baseline; thus, 2,314 men were eligible for the investigation. In a secondary analysis, we excluded all subjects receiving treatment with corticosteroids (n = 7) or potentially anti-inflammatory analgesics (n = 16). All subjects gave written consent, and the Ethics Committee of Uppsala University approved the study.

Examinations at baseline.   Examinations performed when the subjects were 50 years of age (7) included a structured interview; a questionnaire; blood sampling (after an overnight fast) for glucose, lipid, and ESR determinations; an electrocardiogram; and a physical examination with determinations of supine blood pressure and anthropometric measurements.

The ESR was determined by Westergren’s method. Body mass index (BMI) was calculated as weight (in kg) divided by height (in m) squared (kg/m2). The presence of hypertension at baseline was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, and/or the use of antihypertensive medication. The presence of diabetes at baseline was defined as fasting blood glucose ≥6.1 mmol/l and/or the use of oral hypoglycemic agents or insulin. Electrocardiographic left ventricular hypertrophy was defined as high amplitude R-waves according to the revised Minnesota code (9) together with a left ventricular strain pattern (10). The presence of valvular disease (International Classification of Diseases [ICD]-8 codes 394–396 and 424, ICD-9 codes 394–397 and 424, or ICD-10 codes I05-I08 and I34-I37) and previous myocardial infarction (ICD-8 code 410, ICD-9 code 410, or ICD-10 code I21) were assessed from the hospital discharge register.

Follow-up and outcome parameter.   The subjects had a median follow-up time of 29.6 years (range, 0.04 to 32.7 years), contributing to 59,122 person-years at risk. The possible HF cases were selected by linking the ULSAM participants to the hospital discharge register using the Swedish unique personal identification numbers. As a possible diagnosis of heart failure, we considered ICD heart failure codes 427.00, 427.10, 428.99 (ICD-8), 428 (ICD-9), and I50 (ICD-10) and hypertensive heart disease with heart failure, I11.0 (ICD-10), which were allowed in any of the six possible diagnosis positions. Three hundred forty-six men had a hospital discharge register diagnosis of HF between the entry to the ULSAM study and the end of 2002. The medical records from the relevant hospitalization were reviewed by two physicians (E.I. and L.L.), blinded to the baseline data, who classified the cases as definite, questionable, or miscoded. The classification relied on the definition proposed by the European Society of Cardiology (11). After this validation, 282 cases of definite HF were included in the present study. None of the subjects was lost to follow-up.

Statistical methods.   Data are given as means ± SD and percent. Proportional hazards assumptions were confirmed both graphically and by Schoenfeld’s tests. Cumulative hazard curves according to ESR levels were established by the Nelson-Aalen estimation method (12). Inspecting HF incidence rates in quartiles of ESR, an apparent threshold level at the median was observed (Fig. 1). On the basis of this, we assessed ESR as a nominal variable, both as four groups (quartiles) and as two groups (above vs. below or at the median). In the quartiles models, the lowest HF incidence was observed in the second quartile of ESR (Fig. 1), which was used as a reference level. The prognostic value of ESR for HF incidence was investigated using Cox proportional hazards analyses. We investigated three sets of models in a hierarchical fashion: 1) unadjusted analyses; 2) multivariable-adjusted analyses using the following baseline covariates: hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, BMI, serum cholesterol, and hematocrit; and 3) covariates as in model 2, with the addition of interim myocardial infarction during follow-up.



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1 Incidence rates of congestive heart failure (CHF) by quartiles (quartile 1, erythrocyte sedimentation rate [ESR] = 1 to 3 mm/h; quartile 2, 4 to 6 mm/h; quartile 3, 7 to 10 mm/h; quartile 4, 11 to 83 mm/h) of ESR. Lines indicate 95% confidence intervals.

 
Hematocrit was included as a covariate in models 2 and 3, together with the established risk factors for HF, to adjust for the red blood cell characteristics, leaving ESR to reflect mainly systemic inflammation. Two-tailed 95% confidence intervals (CIs) and p values are given, with p < 0.05 regarded as significant. All analyses were specified a priori. Statistical software package STATA 8.2 (Stata Corp., College Station, Texas) was used.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The incidence rate for HF during the follow-up period was 4.8/1,000 person-years at risk. Table 1 shows the participant characteristics at baseline. In unadjusted Cox proportional hazards analyses, ESR was significantly associated with HF incidence, with the highest hazard ratio observed in the highest quartile of ESR compared with the reference level (Fig. 1, Table 2 middle column). In addition, an ESR greater than the median was a predictor of future HF compared with an ESR less than or equal to the median (Table 2, middle column). A cumulative HF incidence plot for ESR split by the median is presented in Figure 2. When evaluating ESR as a diagnostic test for future HF (ESR greater than the median [>6 mm/h] considered to be a positive test), the sensitivity was 48%, specificity 57%, positive predictive value 13%, and the negative predictive value was 89%. As a comparison, we calculated the corresponding values for hypertension (sensitivity 57%, specificity 59%, positive predictive value 16%, and negative predictive value 91%). Adjusting for established risk factors for HF (hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, BMI, serum cholesterol) and hematocrit, ESR remained a significant predictor of HF in both the dichotomous and the quartile Cox proportional hazards models (Table 2, right column).


View this table:
[in this window]
[in a new window]
  		Table 1. Baseline Characteristics of the Cohort
 

View this table:
[in this window]
[in a new window]
  		Table 2. Incidence of Heart Failure in Relation to Erythrocyte Sedimentation Rate (ESR) in the Total Sample (n = 2,314) Free From Heart Failure (HF), Myocardial Infarction, and Valvular Disease at Baseline, Unadjusted and Adjusted for Established Risk Factors
 


View larger version (17K):
[in this window]
[in a new window]
  		Figure 2 Nelson-Aalen plot of cumulative incidence of heart failure in the cohort free from heart failure, myocardial infarction, and valvular disease at baseline by two groups (greater than vs. less than or equal to the median [erythrocyte sedimentation rate (ESR) ≤6 mm/h]) of ESR.

 
Evidence of myocardial infarction during the follow-up was present in 411 of the subjects in the total cohort and in 107 of the 282 HF cases (38%). When adjusting for interim myocardial infarction in addition to the established baseline risk factors for HF, an ESR in the highest quartile (compared with quartile 2; hazard ratio [HR] 1.46, 95% CI 1.04 to 2.05, p = 0.03) and greater than the median (compared with less than or equal to the median; HR 1.35, 95% CI 1.06 to 1.72, p = 0.01) remained significant predictors of future HF. In the subsample free from corticosteroids and anti-inflammatory analgesics, the results were essentially the same in all models (data not shown).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
In this community-based cohort study of middle-aged men free from heart failure, myocardial infarction and valvular disease at baseline, erythrocyte sedimentation was a significant predictor of HF, taking established risk factors for HF and hematocrit at baseline and interim myocardial infarction during follow-up into account. Our observations indicate that inflammation might be an important factor that occurs early in the process leading to HF. This fact is further supported by the lag time of one decade before development of HF observed in this cohort (Fig. 2). The diagnostic capacity of ESR as a test for incident HF, in terms of sensitivity and specificity, was comparable with that of hypertension.

Previous studies.   In the last decade, evidence of inflammation as a crucial part of the atherosclerosis process has emerged (1). Inflammation can be initiated in the vessels as a response to retained and modified low-density-lipoprotein cholesterol, injury, and infections. Other major risk factors for cardiovascular diseases, such as hypertension, diabetes, obesity, and smoking, also have been associated with a low-grade chronic inflammation (1,13). In recent years, the role of inflammation in the pathogenesis of HF has been investigated. Elevated levels of various inflammatory markers have been observed in patients with HF (14,15) and, in recent prospective studies, increased levels of C-reactive protein, TNF-alpha, and IL-6, markers of cytokine-mediated inflammation, predicted subsequent HF (5,6). Cesari et al. (5) used a study sample about as large as ours, whereas Vasan et al. (6) used a smaller sample with slightly more than 700 subjects. Both studies had much shorter follow-up (3.6 years and 5.2 years, respectively), and fewer HF cases (92 and 56 cases, respectively) than our study. The subjects in these studies were older (mean age, 74 and 78 years, respectively). The hazard ratios observed for high versus low levels of the studied cytokines in these studies were somewhat higher than for high versus low ESR in our study, but it is difficult to draw any firm conclusions about possible differences in the strengths of associations between the various inflammatory markers and HF because of the large differences in study design.

C-reactive protein, TNF-alpha, and IL-6 are specific markers of cytokine-mediated inflammation but provide no information about other (potentially equally or more important) aspects of inflammation. The ESR is a less-specific marker of systemic inflammation that is known to be elevated in many acute and chronic diseases characterized by tissue necrosis and inflammation. It is a simple and inexpensive laboratory test that is in widespread use and is easily accessible. In his classic report, Wood observed a low ESR in a small sample of patients with HF of different origins (16), but more recent studies have reported that in patients with manifest HF a high ESR is associated with a more severe stage of HF and a worse prognosis (14,15). The aforementioned studies have examined the association between ESR and already diagnosed HF (14–16), whereas the present study is the first to examine ESR as a predictor of subsequent incident HF.

Possible mechanisms.   The ESR has repeatedly been found to be a predictor of subsequent coronary heart disease in longitudinal studies (2–4). Nonetheless, in the present study the association between ESR and HF remained significant, even after adjusting for interim myocardial infarction, which may indicate that inflammation could directly impair myocardial function. Previous studies have shown that proinflammatory cytokines, such as TNF-alpha, can depress myocardial contractility (17) and affect left ventricular remodeling through local induction of matrix metalloproteinases (18,19). Inflammation also can induce endothelial dysfunction in small vessels (20), resulting in an impaired coronary flow reserve and impaired left ventricular function.

Strengths and limitations.   The strengths of this study include the large population, the long follow-up period, and the detailed characterization of the cohort. Furthermore, all HF cases were validated, limiting the inclusion of false-positive cases. Some limitations to this study exist. Because we only examined men of the same age with a similar ethnic background, this study has an unknown generalizability to women and other age and ethnic groups. Furthermore, because this study was initiated in the 1970s and the HF diagnosis was based on a review of medical records, it was not possible to differentiate between systolic and diastolic heart failure as echocardiography was not available at the time of diagnosis for many of the cases. At that time, ESR was the only measured inflammatory marker; thus, it was not possible to directly compare ESR and other inflammatory markers as predictors of HF in this study.

Conclusions.   Inflammation measured as ESR was a significant predictor of HF, independent of established risk factors for HF, including an interim myocardial infarction, after almost three decades of follow-up in a population-based sample of middle-aged men. Further research is warranted to determine potential gender and ethnic variations of the relation between inflammation and HF incidence and to compare ESR with other markers of inflammation as predictors of incident congestive heart failure.


   Footnotes
 
Sources of support: Primary Health Care in Uppsala County, Swedish Heart Lung Foundation (Hjärt-Lungfonden), and Thuréus Foundation. The funding source had no involvement in the work reported in this paper.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor Circulation 2004;109:II2-II10.
  2. Gillum RF, Mussolino ME, Makuc DM. Erythrocyte sedimentation rate and coronary heart diseasethe NHANES I Epidemiologic Follow-up Study. J Clin Epidemiol 1995;48:353-361.[CrossRef][ISI][Medline]
  3. Andresdottir MB, Sigfusson N, Sigvaldason H, Gudnason V. Erythrocyte sedimentation rate, an independent predictor of coronary heart disease in men and womenthe Reykjavik Study. Am J Epidemiol 2003;158:844-851.[Abstract/Free Full Text]
  4. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease N Engl J Med 2004;350:1387-1397.[Abstract/Free Full Text]
  5. Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular eventsresults from the Health ABC study. Circulation 2003;108:2317-2322.[Abstract/Free Full Text]
  6. Vasan RS, Sullivan LM, Roubenoff R, et al. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarctionthe Framingham Heart Study. Circulation 2003;107:1486-1491.[Abstract/Free Full Text]
  7. Hedstrand H. A study of middle-aged men with particular reference to risk factors for cardiovascular disease Ups J Med Sci Suppl 1975;19:1-61.[Medline]
  8. ULSAM. Uppsala Longitudinal Study of Adult Men. Available at: http://www.pubcare.uu.se/ULSAM/. Accessed April 14, 2005..
  9. Prineas RJ, Crow RS, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings, Standards and Procedures for Measurement and Classification. London: John Wright; 1982. pp. 239.
  10. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure JAMA 1996;275:1557-1562.[Abstract]
  11. The Task Force on Heart Failure of the European Society of Cardiology Guidelines for the diagnosis of heart failure Eur Heart J 1995;16:741-751.[Free Full Text]
  12. Nelson W. Theory and applications of hazard plotting for censored failure data Technometrics 1972;14:945-965.[CrossRef][ISI]
  13. Saito M, Ishimitsu T, Minami J, Ono H, Ohrui M, Matsuoka H. Relations of plasma high-sensitivity C-reactive protein to traditional cardiovascular risk factors Atherosclerosis 2003;167:73-79.[CrossRef][ISI][Medline]
  14. Sharma R, Rauchhaus M, Ponikowski PP, et al. The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors J Am Coll Cardiol 2000;36:523-528.[Abstract/Free Full Text]
  15. Schulze PC, Kratzsch J, Linke A, et al. Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure Eur J Heart Fail 2003;5:33-40.[CrossRef][ISI][Medline]
  16. Wood P. The erythrocyte sedimentation rate in diseases of the heart Quart J Med 1936;5:1.
  17. Kelly RA, Smith TW. Cytokines and cardiac contractile function Circulation 1997;95:778-781.[Free Full Text]
  18. Bradham WS, Moe G, Wendt KA, et al. TNF-alpha and myocardial matrix metalloproteinases in heart failurerelationship to LV remodeling. Am J Physiol Heart Circ Physiol 2002;282:H1288-H1295.[Abstract/Free Full Text]
  19. Diwan A, Dibbs Z, Nemoto S, et al. Targeted overexpression of noncleavable and secreted forms of tumor necrosis factor provokes disparate cardiac phenotypes Circulation 2004;109:262-268.[Abstract/Free Full Text]
  20. Landmesser U, Hornig B, Drexler H. Endothelial functiona critical determinant in atherosclerosis?. Circulation 2004;109:II27-II33.



This article has been cited by other articles:


Home page
 Physiol. Rev.Home page
E. D. Abel, S. E. Litwin, and G. Sweeney
Cardiac Remodeling in Obesity
Physiol Rev, April 1, 2008; 88(2): 389 - 419.
[Abstract] [Full Text] [PDF]

Home page
 Annals of Clinical & Laboratory ScienceHome page
T.-J. Wu, H.-Y. Ou, C.-W. Chou, S.-H. Hsiao, C.-Y. Lin, and P. C. Kao
Decrease in Inflammatory Cardiovascular Risk Markers in Hyperlipidemic Diabetic Patients Treated with Fenofibrate
Ann. Clin. Lab. Sci., January 1, 2007; 37(2): 158 - 166.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
E Ingelsson, J Arnlov, L Lind, and J Sundstrom
Metabolic syndrome and risk for heart failure in middle-aged men
Heart, October 1, 2006; 92(10): 1409 - 1413.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
E. Ingelsson, J. Arnlov, J. Sundstrom, B. Zethelius, B. Vessby, and L. Lind
Novel Metabolic Risk Factors for Heart Failure
J. Am. Coll. Cardiol., December 6, 2005; 46(11): 2054 - 2060.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ingelsson, E.
Right arrow Articles by Lind, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ingelsson, E.
Right arrow Articles by Lind, L.

HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK