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Chronic renal impairment in patients with Chagas cardiomyopathy with chronic systolic heart failure: Prevalence and prognostic significance
Letters to the Editor
133
Chronic renal impairment in patients with Chagas cardiomyopathy with chronic systolic heart failure: Prevalence and prognostic significance Sabrina Q. Ardito, Reinaldo B. Bestetti ⁎, Augusto Cardinalli-Neto, Ana P. Otaviano, Paulo R. Nogueira Department of Cardiology and Cardiovascular Surgery, Hospital de Base, São José do Rio Preto City, Brazil
a r t i c l e
i n f o
Article history: Received 18 July 2011 Accepted 25 July 2011 Available online 17 August 2011 Keywords: Chagas disease Chagas cardiomyopathy Heart failure Cardiac failure Chronic kidney disease Outcome
Chronic systolic heart failure (CHF) is a cardinal clinical manifestation of Chagas cardiomyopathy. It affects 2–4% of a general, unselected community-based population, up to 76% of patients referred to a tertiary referral center [1], and is the leading cause of CHF in areas where the disease is endemic [2]. The underlying myocardial lesions in patients with Chagas cardiomyopathy with CHF is the association of confluent foci of fibrosis and disseminated mononuclear cell infiltrate [3], which accelerates the remodeling process and makes the prognosis worse than that observed in patients with non-Chagas disease CHF [4,5]. In non-Chagas disease CHF, chronic renal failure (CRF) affects about half of patients, is an independent predictor of mortality, and is associated with a worse prognosis [6,7]. This study was performed to determine the prevalence of CRF and its impact on prognosis of patients with Chagas cardiomyopathy with CHF, inasmuch as such a study is still lacking. All patients followed at our ambulatory with a positive serology for Chagas disease and decreased left ventricular ejection fraction (LVEF) in the absence of any other disease that could induce heart disease by itself were studied. Renal function was evaluated according to creatinine serum levels or the estimated glomerular filtration rate (e-GFR) according to the Modification of Diet in Renal Disease. Patients with either a creatinine serum level N 1.5 mg/dl or e-GFRb 60 ml/kg/m2 were diagnosed as having CRF. A Cox proportional hazards model was used to examine the association of CRF with all-cause mortality. Variables known to be associated with mortality were entered the univariate analysis. Creatinine and e-GFR were entered the model either as a continuous variable or a variable dichotomized as normal or abnormal. All variables univariately associated with all-cause mortality were entered the Multivariable analysis. Survival analysis was performed by the Kaplan–Meir method, whereas survival curves were compared by the log-rank test. In all circumstances, a p value b 0.05 denotes statistical significance. CRF was diagnosed in 42 (17%) patients. Table 1 shows the baseline clinical characteristics of patients with CHF secondary to Chagas cardiomyopathy with and without CRF. No difference was observed between both groups. Abbreviations: AF, atrial fibrillation; LA, left atrium; LAD, left atrial dimension; BMI, body mass index. ⁎ Corresponding author at: Setor de eletrocardiografia, Avenida Brigadeiro Faria Lima, 5564, São José do Rio Preto City, 15000, Brazil. Tel.: +55 16 32015746; fax: + 55 16 32015065. E-mail address: [email protected] (R.B. Bestetti).
In the multivariate model, inotropic support [(Hazard Ratio (HR) = 1.8; 95% Confidence Interval (CI) 1.21 to 2.64, p = 0.03)], LVEF (HR = 0,97: 95% CI 0.95 to 0.99; p = 0.005), serum sodium (HR = 0.94; 95% CI 0.90 to 0.98; p = 0.004), digoxin use (HR = 2.35; 95% CI 1.15 to 4.81; p = 0.02), and Beta-Blocker therapy (HR = 0.42; 95% CI 0.27 to 0.63; p b 0.005) were retained as independent predictors of mortality. Fig. 1 shows survival probability for patients with Chagas disease CHF with and without CRF. Survival probability at 12, 24, 36, and 60 months was 74%, 60%, 52%, and 37%, respectively, in patients with CRF, and 84%, 70%, 70%, and 35%,respectively, in patients without (p N 0.05). This investigation clearly shows that patients with CHF secondary to Chagas cardiomyopathy have a low prevalence (17%) of moderate CRF. Furthermore, our work also shows that CRF was neither a marker (association with mortality in the univariable analysis) nor a risk factor (association with mortality in the multivariable analysis) for all-cause mortality in patients with this condition. The prevalence of CRF in patients with CHF has been determined in non-Chagas disease patients enrolled in randomized clinical trials as well as in those studied in prospective longitudinal cohort studies. In these studies, the prevalence of CRF varies from 42 to 56%[6–8]. Therefore, our findings concerning the prevalence of CRF in patients with Chagas cardiomyopathy with CHF are lower than those observed in non-Chagas disease CHF. Abnormalities in the renal function – decreased plasma renal flow and increased urinary sodium excretion – have been detected in patients with Chagas cardiomyopathy with CHF [9]. We suggest that the low prevalence of CRF in patients with Chagas cardiomyopathy with CHF is lower than that seen in non-Chagas disease patients with CHF because the lack of co-morbidities in the former group[10]. The negative impact of CRF on outcome of non-Chagas disease patients with CHF has been demonstrated in clinical trials [8,11,12] as well as in longitudinal studies [6,7]. Compared with such studies, our investigation had a higher proportion of patients receiving evidencebased treatment for CHF (principally Beta-Blocker therapy and
Table 1 Baseline clinical characteristics of patients with Chagas cardiomyopathy with and without chronic renal impairment. Variable
Chronic renal impairment (n = 42)
No chronic renal impairment (n = 203)
Age (years) Male Heart rate (beats per minute) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Follow up (months) NYHA III/IV Hospitalization Inotropic support ACEI/BRA Betablockers Digoxin Diuretics Spironolactone Amiodarone
57 ± 14 34 (80%) 68 ± 11
54 ± 14 126 (61%) 71 ± 15.5
104.4 ± 14.9
108.4 ± 16.4
69.5 ± 8.8
70.9 ± 11.5
14 (6–50) 18 (43%) 34 (80%) 19 (45%) 40 (95%) 17 (40) 34 (81%) 40 (95%) 33 (79%) 15 (36%)
17 (6–38) 59 (29%) 120 (59%) 48 (24%) 188 (93%) 111 (55%) 141 (69%) 162 (80%) 131 (64%) 82 (40%)
NYHA = New York Heart Association Class; ACEI/ARB = Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Block; Median (25th, 75th) percentile.
134
Letters to the Editor
intervals of variables retained as independent predictors in the multivariable model. Furthermore, despite the non-randomization of the study, the variables evaluated regarding outcome were wellbalanced at study entry. Finally, patients were followed at a specialized heart failure clinic, receiving evidence-based treatment for CHF under the supervision of the same physician (RBB) throughout the follow up, what might avoiding treatment bias. In conclusion, CRF seems to be not associated with mortality in patients with CHF secondary to Chagas cardiomyopathy, and its prevalence is lower than that observed in patients with non-Chagas disease CHF. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1-2).
References
Fig. 1. Survival probability of patients with chronic systolic heart failure secondary to Chagas cardiomyopathy according to the presence or absence of chronic renal insufficiency: RI = Renal Insufficiency.
spironolactone use) [7,11], dealt with patients with chronic systolic left ventricular dysfunction only [6,7,12], included patients with no comorbidities (systemic arterial hypertension, overt coronary artery disease, peripheral or cerebrovascular disease) [6,7,11,12], and were managed in a specialized heart failure outpatient clinic. Particularly, it should be emphasized the small number of patients on Beta-blocker therapy in such studies [7,11], which has been demonstrated to improve survival in patients with non-Chagas disease CHF with CRF [8] and also has a beneficial effect in Chagas disease CHF [13–16]. One limitation of our study is that we did not determine the incidence of worsening CRF in patients with Chagas disease CHF. Detecting worsening renal failure over time would be important because of its association with mortality. Therefore, although CRF at baseline failed to predict all-cause mortality in our study, it might be possible that the worsening renal function over 6 months would have had a positive association with all-cause mortality. The strength of this investigation, on the other hand, is that it was a prospective longitudinal cohort study carried out in a relative large sample size with a follow-up duration long enough to detect the adequate number of events to perform the multivariable analysis without overfitting. This is supported by the narrowed 95% confidence
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.07.060
[1] Bestetti RB, Theodoropoulos TAD, Cardinalli-Neto A, Cury PM. Treatment of chronic systolic heart failure secondary to Chagas' heart disease in the current era of heart failure therapy. Am Heart J 2008;156:422–30. [2] Bocchi EA, Braga FG, Ferreira SM, et al. III Brazilian guidelines on chronic heart failure. Arq Bras Cardiol 2009;93(Suppl 1):3–70. [3] Rossi MA, Ramos SG, Bestetti RB. Chagas' heart disease: clinical–pathological correlation. Front Biosci 2003;8:e94–e109. [4] Bertolino ND, Villafanha DF, Cardinalli-Neto A, et al. Prognostic impact of Chagas' disease in patients awaiting heart transplantation. J Heart Lung Transplant 2010;29:449–53. [5] Freitas HFG, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas' heart disease. Int J Cardiol 2005;102:239–47. [6] Waldum B, Westheim AS, Sandvik L, et al. Renal function in outpatients with chronic heart failure. J Card Fail 2010;16:374–80. [7] McAlister FA, Ezekowicz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure. Prognostic and therapeutic implications from a prospective cohort study. Circulation 2004;109:1004–9. [8] Castagno D, Jhund PS, McMurray JJV, et al. Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial. Eur J Heart Fail 2010;12:607–16. [9] Acquatella H. Renal hemodynamics of Chagas disease. Rev Venez Sanid Asist Soc 1969;34:237–80. [10] Ferreira SMA, Guimarães GV, Cruz FD, et al. Anemia and renal failure as predictors in a mainly non-ischemic heart failure population. Int J Cardiol 2010;141:198–200. [11] Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000;102:203–10. [12] Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006;113:671–8. [13] Bestetti RB, Sales-Neto VN, Pinto LZ, Soares EG, Muccillo G, Oliveira JS. Effects of long term metoprolol administration on the electrocardiogram of rats infected with T cruzi. Cardiovasc Res 1990;24:521–7. [14] Issa VS, Amaral AF, Cruz FD, et al. Beta-blocker therapy and mortality of patients with Chagas' cardiomyopathy—a subanalysis of the REMADHE prospective trial. Circ Heart Fail 2010;3:82–8. [15] Theodoropoulos TAD, Bestetti RB, Otaviano AP, Cordeiro JÁ, Rodrigues VC, Silva AC. Predictors of all-cause mortality in chronic Chagas' heart disease in the current era of heart failure therapy. Int J Cardiol 2008;128:22–9. [16] Bestetti RB, Otaviano AP, Cardinalli-Neto A, da Rocha BF, Theodoropoulos TA, Cordeiro JA. Effects of b-blockers on outcome of patients with Chagas' cardiomyopathy with chronic heart failure. 2011, doi:10.1016/j.ijcard.2010.05.033.
133
Chronic renal impairment in patients with Chagas cardiomyopathy with chronic systolic heart failure: Prevalence and prognostic significance Sabrina Q. Ardito, Reinaldo B. Bestetti ⁎, Augusto Cardinalli-Neto, Ana P. Otaviano, Paulo R. Nogueira Department of Cardiology and Cardiovascular Surgery, Hospital de Base, São José do Rio Preto City, Brazil
a r t i c l e
i n f o
Article history: Received 18 July 2011 Accepted 25 July 2011 Available online 17 August 2011 Keywords: Chagas disease Chagas cardiomyopathy Heart failure Cardiac failure Chronic kidney disease Outcome
Chronic systolic heart failure (CHF) is a cardinal clinical manifestation of Chagas cardiomyopathy. It affects 2–4% of a general, unselected community-based population, up to 76% of patients referred to a tertiary referral center [1], and is the leading cause of CHF in areas where the disease is endemic [2]. The underlying myocardial lesions in patients with Chagas cardiomyopathy with CHF is the association of confluent foci of fibrosis and disseminated mononuclear cell infiltrate [3], which accelerates the remodeling process and makes the prognosis worse than that observed in patients with non-Chagas disease CHF [4,5]. In non-Chagas disease CHF, chronic renal failure (CRF) affects about half of patients, is an independent predictor of mortality, and is associated with a worse prognosis [6,7]. This study was performed to determine the prevalence of CRF and its impact on prognosis of patients with Chagas cardiomyopathy with CHF, inasmuch as such a study is still lacking. All patients followed at our ambulatory with a positive serology for Chagas disease and decreased left ventricular ejection fraction (LVEF) in the absence of any other disease that could induce heart disease by itself were studied. Renal function was evaluated according to creatinine serum levels or the estimated glomerular filtration rate (e-GFR) according to the Modification of Diet in Renal Disease. Patients with either a creatinine serum level N 1.5 mg/dl or e-GFRb 60 ml/kg/m2 were diagnosed as having CRF. A Cox proportional hazards model was used to examine the association of CRF with all-cause mortality. Variables known to be associated with mortality were entered the univariate analysis. Creatinine and e-GFR were entered the model either as a continuous variable or a variable dichotomized as normal or abnormal. All variables univariately associated with all-cause mortality were entered the Multivariable analysis. Survival analysis was performed by the Kaplan–Meir method, whereas survival curves were compared by the log-rank test. In all circumstances, a p value b 0.05 denotes statistical significance. CRF was diagnosed in 42 (17%) patients. Table 1 shows the baseline clinical characteristics of patients with CHF secondary to Chagas cardiomyopathy with and without CRF. No difference was observed between both groups. Abbreviations: AF, atrial fibrillation; LA, left atrium; LAD, left atrial dimension; BMI, body mass index. ⁎ Corresponding author at: Setor de eletrocardiografia, Avenida Brigadeiro Faria Lima, 5564, São José do Rio Preto City, 15000, Brazil. Tel.: +55 16 32015746; fax: + 55 16 32015065. E-mail address: [email protected] (R.B. Bestetti).
In the multivariate model, inotropic support [(Hazard Ratio (HR) = 1.8; 95% Confidence Interval (CI) 1.21 to 2.64, p = 0.03)], LVEF (HR = 0,97: 95% CI 0.95 to 0.99; p = 0.005), serum sodium (HR = 0.94; 95% CI 0.90 to 0.98; p = 0.004), digoxin use (HR = 2.35; 95% CI 1.15 to 4.81; p = 0.02), and Beta-Blocker therapy (HR = 0.42; 95% CI 0.27 to 0.63; p b 0.005) were retained as independent predictors of mortality. Fig. 1 shows survival probability for patients with Chagas disease CHF with and without CRF. Survival probability at 12, 24, 36, and 60 months was 74%, 60%, 52%, and 37%, respectively, in patients with CRF, and 84%, 70%, 70%, and 35%,respectively, in patients without (p N 0.05). This investigation clearly shows that patients with CHF secondary to Chagas cardiomyopathy have a low prevalence (17%) of moderate CRF. Furthermore, our work also shows that CRF was neither a marker (association with mortality in the univariable analysis) nor a risk factor (association with mortality in the multivariable analysis) for all-cause mortality in patients with this condition. The prevalence of CRF in patients with CHF has been determined in non-Chagas disease patients enrolled in randomized clinical trials as well as in those studied in prospective longitudinal cohort studies. In these studies, the prevalence of CRF varies from 42 to 56%[6–8]. Therefore, our findings concerning the prevalence of CRF in patients with Chagas cardiomyopathy with CHF are lower than those observed in non-Chagas disease CHF. Abnormalities in the renal function – decreased plasma renal flow and increased urinary sodium excretion – have been detected in patients with Chagas cardiomyopathy with CHF [9]. We suggest that the low prevalence of CRF in patients with Chagas cardiomyopathy with CHF is lower than that seen in non-Chagas disease patients with CHF because the lack of co-morbidities in the former group[10]. The negative impact of CRF on outcome of non-Chagas disease patients with CHF has been demonstrated in clinical trials [8,11,12] as well as in longitudinal studies [6,7]. Compared with such studies, our investigation had a higher proportion of patients receiving evidencebased treatment for CHF (principally Beta-Blocker therapy and
Table 1 Baseline clinical characteristics of patients with Chagas cardiomyopathy with and without chronic renal impairment. Variable
Chronic renal impairment (n = 42)
No chronic renal impairment (n = 203)
Age (years) Male Heart rate (beats per minute) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Follow up (months) NYHA III/IV Hospitalization Inotropic support ACEI/BRA Betablockers Digoxin Diuretics Spironolactone Amiodarone
57 ± 14 34 (80%) 68 ± 11
54 ± 14 126 (61%) 71 ± 15.5
104.4 ± 14.9
108.4 ± 16.4
69.5 ± 8.8
70.9 ± 11.5
14 (6–50) 18 (43%) 34 (80%) 19 (45%) 40 (95%) 17 (40) 34 (81%) 40 (95%) 33 (79%) 15 (36%)
17 (6–38) 59 (29%) 120 (59%) 48 (24%) 188 (93%) 111 (55%) 141 (69%) 162 (80%) 131 (64%) 82 (40%)
NYHA = New York Heart Association Class; ACEI/ARB = Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Block; Median (25th, 75th) percentile.
134
Letters to the Editor
intervals of variables retained as independent predictors in the multivariable model. Furthermore, despite the non-randomization of the study, the variables evaluated regarding outcome were wellbalanced at study entry. Finally, patients were followed at a specialized heart failure clinic, receiving evidence-based treatment for CHF under the supervision of the same physician (RBB) throughout the follow up, what might avoiding treatment bias. In conclusion, CRF seems to be not associated with mortality in patients with CHF secondary to Chagas cardiomyopathy, and its prevalence is lower than that observed in patients with non-Chagas disease CHF. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1-2).
References
Fig. 1. Survival probability of patients with chronic systolic heart failure secondary to Chagas cardiomyopathy according to the presence or absence of chronic renal insufficiency: RI = Renal Insufficiency.
spironolactone use) [7,11], dealt with patients with chronic systolic left ventricular dysfunction only [6,7,12], included patients with no comorbidities (systemic arterial hypertension, overt coronary artery disease, peripheral or cerebrovascular disease) [6,7,11,12], and were managed in a specialized heart failure outpatient clinic. Particularly, it should be emphasized the small number of patients on Beta-blocker therapy in such studies [7,11], which has been demonstrated to improve survival in patients with non-Chagas disease CHF with CRF [8] and also has a beneficial effect in Chagas disease CHF [13–16]. One limitation of our study is that we did not determine the incidence of worsening CRF in patients with Chagas disease CHF. Detecting worsening renal failure over time would be important because of its association with mortality. Therefore, although CRF at baseline failed to predict all-cause mortality in our study, it might be possible that the worsening renal function over 6 months would have had a positive association with all-cause mortality. The strength of this investigation, on the other hand, is that it was a prospective longitudinal cohort study carried out in a relative large sample size with a follow-up duration long enough to detect the adequate number of events to perform the multivariable analysis without overfitting. This is supported by the narrowed 95% confidence
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.07.060
[1] Bestetti RB, Theodoropoulos TAD, Cardinalli-Neto A, Cury PM. Treatment of chronic systolic heart failure secondary to Chagas' heart disease in the current era of heart failure therapy. Am Heart J 2008;156:422–30. [2] Bocchi EA, Braga FG, Ferreira SM, et al. III Brazilian guidelines on chronic heart failure. Arq Bras Cardiol 2009;93(Suppl 1):3–70. [3] Rossi MA, Ramos SG, Bestetti RB. Chagas' heart disease: clinical–pathological correlation. Front Biosci 2003;8:e94–e109. [4] Bertolino ND, Villafanha DF, Cardinalli-Neto A, et al. Prognostic impact of Chagas' disease in patients awaiting heart transplantation. J Heart Lung Transplant 2010;29:449–53. [5] Freitas HFG, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas' heart disease. Int J Cardiol 2005;102:239–47. [6] Waldum B, Westheim AS, Sandvik L, et al. Renal function in outpatients with chronic heart failure. J Card Fail 2010;16:374–80. [7] McAlister FA, Ezekowicz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure. Prognostic and therapeutic implications from a prospective cohort study. Circulation 2004;109:1004–9. [8] Castagno D, Jhund PS, McMurray JJV, et al. Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial. Eur J Heart Fail 2010;12:607–16. [9] Acquatella H. Renal hemodynamics of Chagas disease. Rev Venez Sanid Asist Soc 1969;34:237–80. [10] Ferreira SMA, Guimarães GV, Cruz FD, et al. Anemia and renal failure as predictors in a mainly non-ischemic heart failure population. Int J Cardiol 2010;141:198–200. [11] Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000;102:203–10. [12] Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006;113:671–8. [13] Bestetti RB, Sales-Neto VN, Pinto LZ, Soares EG, Muccillo G, Oliveira JS. Effects of long term metoprolol administration on the electrocardiogram of rats infected with T cruzi. Cardiovasc Res 1990;24:521–7. [14] Issa VS, Amaral AF, Cruz FD, et al. Beta-blocker therapy and mortality of patients with Chagas' cardiomyopathy—a subanalysis of the REMADHE prospective trial. Circ Heart Fail 2010;3:82–8. [15] Theodoropoulos TAD, Bestetti RB, Otaviano AP, Cordeiro JÁ, Rodrigues VC, Silva AC. Predictors of all-cause mortality in chronic Chagas' heart disease in the current era of heart failure therapy. Int J Cardiol 2008;128:22–9. [16] Bestetti RB, Otaviano AP, Cardinalli-Neto A, da Rocha BF, Theodoropoulos TA, Cordeiro JA. Effects of b-blockers on outcome of patients with Chagas' cardiomyopathy with chronic heart failure. 2011, doi:10.1016/j.ijcard.2010.05.033.