C-reactive protein: an inflammatory marker with prognostic value in patients with decompensated heart failure

Abstracts

BACKGROUND: Inflammation has been implicated in the pathophysiology of a series of cardiovascular diseases. C-reactive protein (CRP) is a marker of inflammation easily obtained in the emergency room. OBJECTIVE: To study the prognostic value of CRP in patients admitted for acute decompensated heart failure (ADHF). METHODS: A prospective cohort of 119 patients with ADHF treated in the emergency room. Mean age was 74±11 years and 76 (64%) of patients were male. All were New York Heart Association Functional Class III or IV. CRP was measured by nephelometry at admission. Patients were followed after hospital discharge for an average of 12±9.7 months and cardiovascular mortality was the outcome analyzed. RESULTS: There were 44 (36.9%) deaths, all from cardiovascular causes. Individuals with CRP > 3 mg/dl had higher mortality than those below this level (p=0.018). In the multivariate analysis using Cox proportional model, CRP proved to be the most important independent prognostic factor (odds ratio 0.0916 [95% CI = 0.0341 - 0.1490] for each one-unit increment in CRP). CONCLUSION: CRP is an independent cardiovascular mortality predictor in patients with ADHF, indicating that inflammation represents an important component in the pathophysiology of the disease.

C-reactive protein; inflammation; cytokines; heart failure; cardiac output; low

FUNDAMENTO: A inflamação vem sendo implicada na fisiopatologia de uma série de doenças cardiovasculares. A proteína C-reativa (PCR) titulada é um marcador de inflamação de fácil obtenção na sala de emergência. OBJETIVO: Estudar o valor prognóstico da PCR em pacientes admitidos por insuficiência cardíaca (IC) descompensada. MÉTODOS: Coorte prospectiva de 119 pacientes com IC descompensada, atendidos na sala de emergência, com média de idade de 74 ± 11 anos, dos quais 76 (64%) eram do sexo masculino. Todos estavam em classe funcional III ou IV da New York Heart Association. A dosagem da PCR foi realizada por ocasião da admissão na sala de emergência, pelo método de nefelometria. Os pacientes foram acompanhados, após a alta hospitalar, por um tempo médio de 12 ± 9,7 meses e o desfecho analisado foi a mortalidade cardiovascular. RESULTADOS: Houve 44 (36,9%) óbitos, todos por causa cardiovascular. Indivíduos com PCR > 3 mg/dl apresentaram maior mortalidade que indivíduos com valores inferiores a esse (p=0,018). A análise multivariada pelo modelo proporcional de Cox destacou como fator independente para prognóstico mais importante a PCR (razão de chances de 0,0916 [intervalo de confiança de 95% = 0,0341 a 0,1490] para aumentos de uma unidade na PCR). CONCLUSÃO: A PCR é um preditor independente de mortalidade cardiovascular em pacientes com IC descompensada, indicando que a inflamação representa componente importante na fisiopatologia da doença.

Proteína C-reativa; inflamação; citocinas; insuficiência cardíaca; baixo débito cardíaco

ORIGINAL ARTICLE

C-reactive protein: an inflammatory marker with prognostic value in patients with decompensated heart failure

Humberto Villacorta; Antonio Claudio Masetto; Evandro Tinoco Mesquita

Universidade Federal Fluminense, Faculdade de Ciências Médicas – Niterói, RJ – Emergency Department - Pró-Cardíaco Hospital – Rio de Janeiro, RJ, Brazil

^{Mailing address}

SUMMARY

BACKGROUND: Inflammation has been implicated in the pathophysiology of a series of cardiovascular diseases. C-reactive protein (CRP) is a marker of inflammation easily obtained in the emergency room.

OBJECTIVES: To study the prognostic value of CRP in patients admitted for acute decompensated heart failure (ADHF).

METHODS: A prospective cohort of 119 patients with ADHF treated in the emergency room. Mean age was 74±11 years and 76 (64%) of patients were male. All were New York Heart Association Functional Class III or IV. CRP was measured by nephelometry at admission. Patients were followed after hospital discharge for an average of 12±9.7 months and cardiovascular mortality was the outcome analyzed.

RESULTS: There were 44 (36.9%) deaths, all from cardiovascular causes. Individuals with CRP > 3 mg/dl had higher mortality than those below this level (p=0.018). In the multivariate analysis using Cox proportional model, CRP proved to be the most important independent prognostic factor (odds ratio 0.0916 [95% CI = 0.0341 - 0.1490] for each one-unit increment in CRP).

CONCLUSION: CRP is an independent cardiovascular mortality predictor in patients with ADHF, indicating that inflammation represents an important component in the pathophysiology of the disease.

Key words: C-reactive protein; inflammation; cytokines; heart failure; cardiac output, low.

Introduction

Acute heart failure (HF) can appear as a decompensation in patients who are already in heart failure or occur in patients with no prior heart failure history. Besides the underlying disease, some factors can influence a decompensation episode and are identified as precipitating factors. Among these we underscore non-compliance with diet or medication, uncontrolled arterial hypertension, acute coronary syndromes, cardiac arrhythmias, and infections¹.

It has been known for some time that inflammation plays a vital role in the pathophysiology of some cardiovascular diseases, such as acute coronary syndromes, where it has prognostic value². More recently, its participation in acute HF has been evident since it may be a precipitating factor in a decompensation^3-5. Its role in the long-term progression of a disease after hospitalization, however, is poorly understood.

Initially described in 1930, C-reactive protein (CRP) is an acute phase protein and an unspecific marker of systemic inflammation⁶. Its prognostic value is well established in patients with coronary artery disease^7-9. The objective of this article was to analyze the long-term prognostic value of CRP measured in patients admitted to an emergency unit with acute decompensated heart failure (ADHF).

Methods

From March 1997 to December 1999, 170 consecutive patients were seen with ADHF at the emergency unit of a tertiary hospital in Rio de Janeiro (108 were male, age range of 17 to 99 years). Patients were excluded from the study if they showed signs of infection, acute coronary syndrome, acute myocardial infarct, neoplastic diseases, and other inflammatory illnesses such as pericarditis and rheumatoid arthritis. After exclusions, 119 patients were included, 76 (64%) men and 43 (36%) women, with a mean age of 74±11 years. Etiologies for HF were ischemic in 73 (61.5%) cases, hypertensive in 21 (18%), valvar in 9 (7.7%), and 'other' in 16 patients (12.8%). All were NYHA functional class III or IV. All patients had a troponin I levels lower than 1.0 ng/l and CK-MB lower than 10 UI/l. Patients with LV shortening fractions < 25% were considered as having systolic dysfunction and 82 (68.9%) of them were in this group.

The diagnosis of HF was based on Boston criteria, and only patients with more than 8 points were included¹⁰. Variables studied were age, sex, etiology, New York Heart Association (NYHA) functional class, mean blood pressure, left ventricle shortening fraction, creatinine, and serum sodium levels. CRP plasma levels were determined upon admission by nephalometry (Array 360 System Beckman, Abbott Laboratories, North Chicago, IL). Values under 0.8 mg/dl are considered normal (variation coefficient under 5%)¹¹.

Follow-up - Clinical progression and events from 119 patients were obtained by telephone contact with the patients or their relatives and referring physicians every six months for three years (mean 12.4±9.7 months). Deaths were classified according to the criterion established by Narang et al¹², considering activity, cause, mode, and event related to the death. The primary outcome analyzed was cardiovascular mortality.

Statistical analysis - The data collected were analyzed using SPSS statistical package, version 6.0. The univariate comparisons with categorical variables were performed using the chi-square test - c², and continuous variables were analyzed by Student’s t test or the Mann-Whitney test for non-normal distributions. Survival probability was estimated using the Kaplan-Meier method and comparisons were made by the log-rank test. Multivariate comparisons of the factors that influenced survival were done using the Cox poportional method. Values for p<0.05 were considered significant.

The study was approved by the institutional ethics committee, and is compliant with Helsinki criteria. Informed consent was obtained from all patients.

Results

There were no differences among the baseline characteristics of patients stratified according to CRP terciles, with the exception of a greater number of coronary patients in the group with CRP>4.3 mg/dl when compared to the group with CRP<1.3 mg/dl (p=0.04), as shown in Table 1. Of the 119 patients, 44 (36%) died during follow-up, 26 of them men (21.8%) and 18 women (15.2%). Thirty patients (68.2%) died from circulatory failure due to HF progression, 9 patients (20.5%) from sudden death, 2 patients (4.5%) from stroke, 2 patients (4.5%) during cardiac surgery, and 1 patient (2.3%) from pulmonary thromboembolism. The accumulated probability of survival for all patients was 73.6% in six months (87 alive), 66% in 12 months (78 alive), and 52% in 24 months (61 alive). CRP levels among systolic dysfunction patients and those with preserved systolic function were, respectively, 3.8±4.3 and 3.5±3.6 mg/dl (p=0.79). There was a tendency toward a higher CRP value in coronary patients than in non-coronary patients (4.4±4.9 vs 3.03±3 mg/dl, p=0.08).

CRP concentrations and mortality - In 87 patients (73.2%), CRP concentrations were above normal values. The group mean was 3.8±4.2 mg/dl. The mean CRP of patients who died at hospital was 5.4±4.8 mg/dl, and 3.9±4.7 in the survivors (p=0.21).

During follow-up, the mean CRP for patients who died was 5.1±5.0 mg/dl, while among survivors it was 3.02±3.4 mg/dl (p=0.02), as shown in Figure 1.

Patients were subdivided by serum CRP levels above and below or equal to 3 mg/dl, the median of CRP values. Twelve-month survival probability among those with levels over 3 mg/dl was 52%, and 77% for patients with levels below this value (p=0.018). The survival curve is illustrated in Figure 2.

Variables related to survival - The log-rank test analysis demonstrated that CRP (p=0.02), age (p=0.037), and mean blood pressure (inverse relation, p=0.041) were the variables related to 12-month survival. The mean blood pressure in patients who died and survivors was, respectively, 96±28 and 106±22 (p=0.041). The shortening fraction (p=0.152), serum creatinine (p=0.156), ischemic etiology (p=0.200), and serum sodium (p=0.788) did not correlate with survival.

Cox proportional hazards analysis - The variables independently associated with survival were CRP (odds ratio [OR] = 0.0916, 95% confidence interval [95% CI]: 0.0341 - 0.1490, for each one-unit increment in CRP), and age (OR = 0.0304, 95% CI: 0.0274 - 0.0333, for each one-unit increase in age). Mean blood pressure (OR= -0.0128, 95% CI: -0.0263 - 0.0007) was not an independent predictor for survival (Table 2). CRP was the independent factor with the greatest prognostic value.

Discussion

This study adds new information on the role of inflammation in ADHF. We demonstrated that CRP measurement, a test easily carried out in the emergency room, is capable of predicting long-term events after a hospital stay.

In the 1990s, it was shown that CRP is elevated in patients with chronic HF^13,14. Shortly after that, its elevation in patients with ADHF was observed^3-5. More recently, its prognostic value was established in patients with chronic HF^15,16. A retrospective analysis of the Val-HeFT study showed that, regarding the lowest CRP quartile, patients in the highest quartile had a higher risk of death or of a morbid event¹⁶. CRP values have not changed over time for patients in the placebo group, but they did change in the group receiving valsartan without angiotensin conversion enzyme inhibitors, suggesting a modulation of inflammation with the medication.

The prognostic role of CRP in patients with ADHF was recently demonstrated in a study similar to ours. Mueller et al¹⁷ retrospectively studied 214 ADHF patients treated at the emergency unit who were followed up for 24 months. Mortality rates from the first to the third tercile in CRP values were, respectively, 33.5%, 42.2%, and 53.6%. After multivariate adjustment, CRP remained as an independent predictor of death or death combined with hospitalizations. Our study confirms these findings and presents some particularities relative to the study done by Mueller et al. First of all, ours is the only study that we are aware of in which this issue was prospectively evaluated. Second, we excluded patients who had infections or inflammatory diseases. Therefore, data from our study suggest that inflammation was related to HF and not to external factors. On the other hand, Müeller suggests that, even when inflammation is associated to an infection, there is an impact on the short-term and long-term prognosis in the ADHF patient.

The mechanisms by which inflammation is set off are not yet well defined. Different theories besides that of infection include an autoimmune mechanism, hemodynamic overload, tissue hypoxia, and LDL oxidation¹⁸. Another increasingly accepted theory is that of endotoxins^4,19. According to this assumption, intestinal edema and hypoperfusion would cause an increased capillary permeability, allowing the translocation of bacteria and endotoxins to circulation and leading to the activation of the inflammatory processes seen in heart failure. Peschel et al⁴ demonstrated the presence of high concentrations of endotoxins in hepatic veins compared to the left ventricle in patients with ADHF, supporting this premise. It has also been shown that with treatment for the edema using diuretics, serum levels of endotoxins are reduced²⁰. Reinforcing this hypothesis even further, Conraads demonstrated that selective intestinal decontamination with antibiotics in patients with serious chronic HF reduces plasma inflammatory endotoxins and cytokines with an improvement in endothelial function²¹.

Some clinical implications merit emphasis. This study suggests that immune modifications are not an epiphenomenon in decompensated HF patients, but play an important role in the pathophysiology of the illness. This affords a therapeutic opportunity, since procedures that reduce inflammation could lead to an improved prognosis. This could explain the good response with statins in acute HF patients^22,23. Our group is in an initial phase of a project of intestinal decontamination with neomycin in patients with serious and decompensated HF, which will evaluate clinical outcomes, cardiac remodeling, and inflammatory cytokine quantification.

Some limitations need to be mentioned. Serum CRP concentration may be influenced by other factors, such as hormone replacement and smoking. Our data were not adjusted for these factors. Another limitation refers to infectious causes. Despite our great care in excluding patients with pneumonia, this diagnosis is not always easy to make in elderly patients with associated ADHF, and some cases may have not been caught at admission. Lastly, we measured CRP at admission. Although the value of this measurement is evident, successive measurements would be even more important, since peak levels of CRP usually take place 48 hours after admission⁵.

Concluding, we demonstrated that CRP quantification at admission in patients with ADHF has an important long-term prognostic value.

Supported by: Pró-Cardíaco Hospital.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

References

Manuscript received July 15, 2006; revised manuscript received September 7, 2006; accepted November 27, 2006.

• 1. Ghali JK, Kadakia S, Cooper R, Ferlinz J. Precipitating factors leading to decompensation of heart failure. Traits among urban blacks. Arch Intern Med. 1988; 148: 2013-8.
• 2. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease: FRISC Study Group: Fragmin During Instability in Coronary Artery Disease. N Engl J Med. 2000; 343: 1139-47.
• 3. Sato Y, Takatsu Y, Kataoka K, Yamada T, Taniguchi R, Sasayama S, et al. Serial circulating concentrations of C-reactive protein, interleukin IL-4, and IL-6 in patients with acute left heart decompensation. Clin Cardiol. 1999; 22: 811-3.
• 4. Peschel T, Schonauer M, Thiele H, Anker SD, Schuler G, Niebauer J. Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. Eur J Heart Fail. 2003; 5: 609-14.
• 5. Milo O, Cotter G, Kaluski E, Brill A, Blatt A, Krakover R, et al. Comparison of inflammatory and neurohormonal activation in cardiogenic pulmonary edema secondary to ischemic versus nonischemic causes. Am J Cardiol. 2003; 92: 222-7.
• 6. Tillet WS, Francis T Jr. Serological reactions in pneumonia with non-protein somatic fraction of pneumococcus. J Exp Med. 1930; 52: 561-71.
• 7. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med. 1994; 331: 417-24.
• 8. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997; 349 (9050): 462-6.
• 9. Morrow DA, Rifai N, Antman EM, Weiner DL, McCabe CH, Cannon CP, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1998;31(7): 1460-5.
• 10. Carlson KJ, Lee DC, Goroll AH, Leahy M, Johnson RA. An analysis of physicians reasons for prescribing long-term digitalis therapy in outpatients. J Chronic Dis. 1985; 38 (9): 733-9.
• 11. Shine B, de Beer FC, Pepys MB. Solid phase radioimmunoassays for CRP. Clin Chim Acta. 1981; 117: 13-23.
• 12. Narang R, Cleland JG, Erhardt L, Ball SG, Coats AJ, Cowley AJ, et al. Mode of death in chronic heart failure. A request and proposition for more accurate classification. Eur Heart J. 1996; 17: 1390-403.
• 13. Pye M, Era AP, Cobbe SM. Study of serum C-reactive protein concentration in cardiac failure. Br Heart J. 1990; 63: 228-30.
• 14. Steele IC, Nugent AM, Maguire S, Hoper M, Campbell G, Halliday MI, et al. Cytokine profile in chronic cardiac failure. Eur J Invest. 1996; 26: 1018-22.
• 15. Chirinos JA, Zambrano JP, Chakko S, Schob A, Veerani A, Perez GO, et al. Usefulness of C-reactive protein as an independent predictor of death in patients with ischemic cardiomyopathy. Am J Cardiol. 2005; 95: 88-90.
• 16. Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005; 112: 1428-34.
• 17. Müeller C, Laule-Kilian K, Christ A, Brunner-La Roca HP, Perruchoud AP. Inflammation and long-term mortality in acute congestive heart failure. Am Heart J. 2006; 151: 845-50.
• 18. Adamopoulos S, Parissis JT, Kremastinos DT. A glossary of circulating cytokines in chronic heart failure. Eur J Heart Fail. 2001; 3: 517-26.
• 19. Krack A, Sharma R, Figulla HR, Anker SD. The importance of the gastrointestinal system on the pathogenesis of heart failure. Eur Heart J. 2005; 26: 2368-74.
• 20. Niebauer J, Volk HD, Kemp M, Dominguez M, Schummann RR, Rauchhaus M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999; 353: 1838-42.
• 21. Conraads VM, Jorens PG, De Clerck LS, Van Saene HK, Ieven MM, Bosmans JM, et al. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur J Heart Fail. 2004; 6: 483-91.
• 22. Folkeringa RJ, Van Kraaij DJ, Tieleman RJ, Nieman FH, Pinto YM, Crijns HJ. Statins associated with reduced mortality in patients admitted for heart failure. J Card Fail. 2006; 12: 134-8.
• 23. Foody JM, Shah R, Galusha D, Masoudi FA, Havranek EP, Krumhlz HM. Statins and mortality among elderly patients hospitalized with heart failure. Circulation. 2006; 113: 1086-92.

Publication Dates

• Publication in this collection
  15 June 2007
• Date of issue
  May 2007

History

• Accepted
  27 Nov 2006
• Reviewed
  07 Sept 2006
• Received
  15 July 2006