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European Journal of Heart Failure 2005 7(5):869-873; doi:10.1016/j.ejheart.2004.10.014
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© 2005 European Society of Cardiology

The influence of aetiology on inflammatory and neurohumoral activation in patients with severe heart failure: A prospective study comparing Chagas' heart disease and idiopathic dilated cardiomyopathy

Amilcar O. Mocelin, Victor S. Issa, Fernando Bacal, Guilherme V. Guimarães, Edecio Cunha and Edimar A. Bocchi*

Heart Institute (InCor), University of São Paulo Medical School, Avenida Dr. Eneas de Carvalho Aguiar 455 São Paulo-SP, CEP: 050403-000, Brazil

* Corresponding author. Tel.: +55 11 3069 5307; fax: +55 11 3069 5502. dcledimar{at}incor.usp.br


   Abstract
Top
 Abstract
1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 
Patients with Chagas' cardiomyopathy have the worst prognosis when compared to other aetiologies. It has been suggested that a more intense inflammatory activation could be responsible for this excessive mortality. We studied 35 patients with idiopathic dilated cardiomyopathy (IDC group) and 28 patients with Chagas' heart disease (Chagas' group) and 12 control subjects. We compared plasma tumor necrosis factor {alpha} (TNF-{alpha}), soluble TNF-{alpha} receptor type 1 (sTNF-R1), soluble Fas (sFas), interleukin 6 (IL-6), and brain natriuretic peptide type B (BNP) concentrations between the groups. TNF-{alpha} and IL-6 concentrations were higher in the IDC and Chagas groups as compared to controls (p<0.001 and p=0.001, respectively). sTNF-R1 concentration was higher in IDC after stratification for functional class (p=0.039), and there was a trend toward higher plasma TNF-{alpha} concentration in the Chagas' group (p=0.092). IL-6 concentration was higher in Chagas than in IDC (p=0.005). Higher IL-6 levels were associated with worse outcome (p=0.03 for Chagas; p=0.003 for IDC). sFas concentration was similar among groups. BNP concentrations were higher in IDC (350 pg/ml) and in Chagas (444.6 pg/ml) as compared to the controls (20.3 pg/ml; p<0.01). Higher BNP levels were associated with death and heart transplantation in both aetiologies. Inflammatory activation in Chagas heart disease differs from IDC and is associated with heart failure severity.

Key Words: Chagas' heart disease • Cytokines • Brain natriuretic peptide

Received March 23, 2004; Revised August 26, 2004; Accepted October 14, 2004


   1. Background
Top
 Abstract
 1. Background
2. Methods
 3. Results
 4. Discussion
 References
 
Cytokines are elevated in patients with heart failure [1,2], are associated with the development of ventricular remodeling [3,4], and have prognostic significance [5–9]. Chagas' disease affects approximately 18 million people worldwide [10], and patients with Chagas' heart disease have the worst prognosis when compared to patients with other aetiologies [11,12]. The chronic myocardial and systemic inflammatory activation found in patients with Chagas' disease could be responsible for the excessive morbidity and mortality. To evaluate this issue, we prospectively studied the plasma concentrations of different cytokines and brain natriuretic peptide in patients with Chagas' cardiomyopathy (Chagas) as compared to idiopathic dilated cardiomyopathy (IDC).


   2. Methods
Top
 Abstract
 1. Background
 2. Methods
3. Results
 4. Discussion
 References
 
From March 2000 through May 2001, we prospectively studied patients aged over 18 years who had dilated cardiomyopathy, and either heart failure symptoms or left ventricular systolic dysfunction during the previous 6 months. The study was approved by our institutional review board and, before enrolment, patients gave written informed consent.

Exclusion criteria were: patient refusal, alcohol abuse, immunossuppressive therapy, arterial hypertension, chronic obstructive pulmonary disease, pulmonary or systemic embolism, auto-immune disease, malignant tumors, renal failure, coronary artery disease, hypertrophic or restrictive cardiomyopathy, left-ventricle ejection fraction greater than 0.4, or moderate/severe valvular dysfunction (patients with valvar regurgitation secondary to chamber dilation were not excluded). Although only patients with chronic heart failure were enrolled in the study, three patients in each group had been admitted due to an acute deterioration of their previous status, and were receiving intravenous inotropes.

Patients with epidemiological (indirect immunofluorescence, passive haemaglutination, immunoenzymatic assay) information indicating infection with Trypanosoma cruzi received a diagnosis of Chagas' cardiomyopathy (Chagas group, n=28). The IDC group (n=35) consisted of patients with dilated cardiomyopathy whose investigation for Chagas disease was negative. The control group (n=12) consisted of healthy volunteers with a similar distribution of age and gender.

All individuals underwent clinical evaluation; blood was centrifuged and stored under –80 °C for measurement of plasma tumor necrosis factor {alpha} (TNF-{alpha}), soluble TNF-{alpha} receptor type 1 (sTNF-R1), soluble Fas (sFas), soluble Fas ligand (sFasL), interleukin 6 (IL-6), and brain natriuretic peptide type B (BNP) [13]. Patients in the IDC and Chagas' groups underwent radionuclide angiocardiogram and coronary angiography (Table 1).


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  		Table 1 Baseline characteristics of patients

 
Variables without normal distribution were submitted to logarithmic transformation. Statistical tests used were linear model algorithm, {chi}2 test, Fisher's Exact Test, and Kaplan–Meier method. Survival curves were compared by log-rank test and Cox regression model; p value was considered significant when less than 0.05.


   3. Results
Top
 Abstract
 1. Background
 2. Methods
 3. Results
4. Discussion
 References
 
Plasma TNF-{alpha} and IL-6 concentrations were higher in the IDC and Chagas' groups as compared to the controls (p<0.001 and p=0.001, respectively). Plasma IL-6 concentration was higher in the Chagas as compared to the IDC group (p=0.005). There was no difference in plasma sFas and sTNFR-1 concentrations between groups. Although standard curves showed the expected pattern, sFasL concentrations were under the detection limit in all samples.

Once categorised according to NYHA functional class, a trend toward higher plasma TNF-{alpha} concentration was observed in patients in the Chagas' group compared to the IDC group (p=0.092), and higher levels of sTNF-R1 in the IDC group compared with the Chagas group (p=0.039; Table 2 and Fig. 1).


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  		Table 2 Plasma cytokines and BNP concentrations according to aetiology and NYHA functional class

 


Figure 1
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  		Fig. 1 Distribution of plasma cytokines concentrations according to aetiology and functional status. TNF: tumor necrosis factor; sTNFR-1: soluble form of tumor necrosis factor receptor type 1; IL-6: interleukine 6; sFAs: soluble Fas; NYHA: New York Heart Association. P value refers to comparisons between Chagas' and IDC groups.

 
Patients were grouped into quartiles according to plasma IL-6 concentrations, and event-free survival (death or heart transplantation) was plotted. Patients in the last quartile had the worst prognosis (p=0.03 in IDC group; p=0.003 in Chagas group; Fig. 2). Once IL-6 concentration was considered in a Cox regression model, the only variable independently associated with survival was functional class. No significant association was detected between plasma TNF-{alpha}, sTNF-R1, and sFas concentrations and clinical events.


Figure 2
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  		Fig. 2 Survival free from death or heart transplantation in patients with idiopathic dilated cardiomyopathy and Chagas' heart disease, according to plasma IL-6 and BNP concentrations. For interleukine-6 (IL-6) in patients with idiopathic dilated cardiomyopathy (IDC): first quartile: 0.61–1.42 pg/ml; second quartile: 1.67–2.33 pg/ml; third quartile: 2.46–3.44 pg/ml; fourth quartile: 3.68–20 pg/ml. For IL-6 in patients with Chagas' heart disease: first quartile: 0.76–2.02 pg/ml; second quartile: 2.07–5.12 pg/ml; third quartile: 5.27–9.84 pg/ml; fourth quartile: 17.8–20 pg/ml. For brain natriuretic peptide (BNP): first quartile: 10–162 pg/ml; second quartile: 167–305 pg/ml; third quartile: 310–505 pg/ml; fourth quartile: 512–13000 pg/ml.

 
Plasma BNP concentrations were higher in the IDC and Chagas' groups as compared to the controls (350.6, 44.6, and 20.3 pg/ml, respectively; p<0.001 for both comparisons). BNP concentration was similar in the Chagas and IDC groups. Patients in NYHA class IV had higher BNP levels (Table 2).

When assembled into quartiles, we observed a statistical association between BNP concentration and clinical events (p=0.002; Fig. 2). However, BNP was not independently associated to clinical events in a Cox regression model.


   4. Discussion
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
References
 
In the present study, the plasma TNF-{alpha} and IL-6 concentrations were elevated in IDC and Chagas groups as compared to the controls. Plasma IL-6 concentration was higher in Chagas than in IDC; higher levels of IL-6 were associated with a worse outcome. These findings suggest that specific inflammatory pathways are particularly active (locally or systemically) in patients with Chagas' cardiomyopathy, and may be responsible for differences in the clinical course of the disease, when compared to other aetiologies. Baseline differences between the groups regarding left-ventricle diastolic diameter and left-ventricle ejection fraction and a trend towards a higher frequency of women in the Chagas group may have influenced the findings.

Despite not being a study end-point, our findings regarding BNP levels are significant, as they represent not only an independent validation criterion for the distribution of patients according to functional status but also suggest that BNP can be used for clinical risk stratification of patients with Chagas' cardiomyopathy.

The small number of patients and the limited period of follow-up are the main shortcomings of our study. They limit the statistical power of the analysis and prevent us from establishing causality associations. It is possible that new information will arise from larger studies with longer follow-up periods.


   References
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Torre-Amione G., Kapadia S., Benedict C., et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left ventricular Dysfunction (SOLVD). J. Am. Coll. Cardiol. (1996) 27:1201–1206.[Abstract]
  2. Wollert K.C., Heineke J., Westermann J., et al. The cardiac Fas (APO-1/CD95) receptor/Fas ligand system: relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes. Circulation (2000) 101:1172–1178.[Abstract/Free Full Text]
  3. Kelly R.A., Smith T.W. Cytokines and cardiac contractile function. Circulation (1997) 95:778–781.[Free Full Text]
  4. Li Y.Y., Feng Y.Q., Kadokami T., et al. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy. Proc. Natl. Acad. Sci. U. S. A. (2000) 97:12746–12751.[Abstract/Free Full Text]
  5. Pulkki K.J. Cytokines and cardiomyocyte death. Ann. Med. (1997) 29:339–343.[Web of Science][Medline]
  6. Rauchhaus M., Doehner W., Francis D.P., et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation (2000) 102:3060–3067.[Abstract/Free Full Text]
  7. Anker S.D., Ponikowski P.P., Clark A.L., et al. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure. Eur. Heart J. (1999) 20:683–693.[Abstract/Free Full Text]
  8. Orús J., Roig E., Perez-Villa F., et al. Prognostic value of serum cytokines in patients with congestive heart failure. J. Heart Lung Transplant. (2000) 19:419–425.[CrossRef][Web of Science][Medline]
  9. Deswal A., Petersen N.J., Feldman A.M., et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone Trial (VEST). Circulation (2001) 103:2055–2059.[Abstract/Free Full Text]
  10. World Health Organization. Control of Chagas' disease. W.H.O. Tech. Rep. Ser. (1991) 811:1–95.
  11. Bahia-Oliveira L.M.G., Gomes J.A.S., Rocha M.O.C., et al. IFN-{gamma} in human Chagas' disease: protection or pathology? Braz. J. Med. Biol. Res. (1998) 31:127–131.[Web of Science][Medline]
  12. Bestetti R.B., Muccillo G. Clinical course of Chagas' heart disease: a comparison with dilated cardiomyopathy. Int. J. Cardiol. (1997) 60:187–193.[CrossRef][Web of Science][Medline]
  13. R&D Systems, Human-High Sensitivity, Quantikine HS. Minneapolis, US.

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