Digoxin serum levels in patients with Chagas ’ cardiomyopathy and heart failure

Introduction: The purpose of this study was to determine digoxin serum concentrations in patients with Chagas’ cardiomyopathy with chronic heart failure, because little is known concerning this laboratory test in patients with this condition. Methods: This study focuses on 29 (29%) out of 101 patients with chronic heart failure secondary to Chagas’ cardiomyopathy receiving digoxin therapy. Digoxin was measured by the immune-enzymatic method. Results: New York Heart Association Functional Class III/IV was noted in 13 (45%) patients. The mean potassium serum level was 4.3± 0.5mEq/L, mean creatinine serum levels 1.4± 0.3dg/100ml, and left ventricular ejection fraction 34.7± 13.8%. The median digoxin serum level was 1.27 (0.55; 1.79)ng/ml. Sixteen (55%) patients had digoxin serum levels higher than 1.0ng/ml. Abnormal digoxin serum levels were verified in 13 (45%) patients. Digoxin serum levels correlated moderately with creatinine serum levels (r = 0.39; p≤ 0.03) and negatively with sodium serum levels (r= -0.38; p= 0.03). Conclusions: Digoxin serum concentration should be measured in patients with Chagas’ cardiomyopathy with chronic heart failure receiving digoxin therapy due to the potential for digoxin toxicity. Key-words: Chagas’ disease. Trypanosomiasis American. Chronic Heart failure. Digoxin. Cardiomyopathy.

Chagas' disease, a tropical disease caused by the protozoan Trypanosoma cruzi, is a major public health problem in Latin America, since it affects 18 million people and another 100 million are at risk of acquiring the disease 1 .In view of international immigration, Chagas' disease now affects almost 700,000 people outside Latin America 2 .
Chronic heart failure is a protean clinical manifestation of chronic Chagas' disease.In fact, it is the leading cause of chronic heart failure in areas where the disease is endemic 3 , its prognosis is worse than that observed in non-Chagas' disease heart failure 3,4 and affects about 4% to 8% of outpatients living in rural areas and up to 76% of patients followed at a tertiary referral center 5 .Digoxin is an integral component of the pharmacological armamentarium for the treatment of chronic systolic heart failure secondary to Chagas' cardiomyopathy, particularly for patients in New York Heart Association Class III or IV 5 .
In patients with non-Chagas' disease heart failure, chronic digoxin therapy has no impact on all-cause mortality, but decreases the combination of death or hospitalization 6 .However, Rathore et al 7 have shown that all-cause mortality is higher in patients with serum digoxin concentration > 1.2ng/ ml in comparison to patients with serum digoxin concentrations ≤ 1.2ng/ml.More recently, studies have suggested that survival may be improved in patients in whom digoxin serum concentrations are lower (0.5 to 1.0ng/ml) than those previously recommended (0.8 to 2.0ng/ml) [8][9][10] .
In patients with chronic heart failure secondary to Chagas' cardiomyopathy, digoxin serum levels have not routinely been measured thus far, mainly due to economic reasons or lack of proper apparatus to measure it in poor areas.Since the presence of atrioventricular, fascicular and branch block altogether are more common in Chagas' than in non-Chagas' disease heart failure patients, the potential for advanced heart blocks mediated by digoxin toxicity is probably greater in the former group.

RESULTS
In addition, the peculiarities of histological aspects observed in this disease, confluent foci of fibrosis along with mononuclear cell infiltrate throughout the myocardium, similar to that which occurs in catecholamine cardiomyopathy [11][12] , may predispose Chagas' disease patients receiving digoxin therapy to malignant ventricular arrhythmias and ultimately death.In fact, it has been shown that digoxin use may negatively affect survival in Chagas' disease heart failure patients 13 .
Therefore, this study, aimed to determine the prevalence of abnormal and/or high (> 1ng/ml) digoxin serum concentrations in patients with Chagas' cardiomyopathy with chronic heart failure.

Patients
From January 2000 to October 2007, 231 patients with chronic heart failure secondary to Chagas' cardiomyopathy were admitted to the outpatient Cardiomyopathy Service of Hospital de Base.The diagnosis of Chagas' disease was confirmed based on positive serology.Approximately 120 (50%) patients died during the above period.Of the remaining 101 patients, 29 (29%) were receiving digoxin therapy.
Previous patient work-up consisted of anamnesis, physical examination, standard laboratory tests, 12-lead electrocardiogram, chest X-Ray and 2-dimensional trans-thoracic Doppler-echocardiography.
Digoxin was administered as previously described, in the morning, by oral route, according to age (0.125mg/day per patients aged > 65 years, and 0.25mg/day per patient aged < 65 years) 8 .

Digoxin study
All digoxin serum levels measurements were performed in the morning following 12-hour fasting by the patient.The last digoxin ingestion occurred 24 hours before measurement.A blood sample was collected from the antecubital vein from each patient.The blood was centrifuged, stored at -20º and measured by the immuneenzymatic method.

Statistical analysis
Continuous variables with normal distribution are expressed as mean ± standard deviation, whereas those with nonnormal distribution are presented as median (25% percentile, 75% percentile).Categorical variables are shown as proportions (%).One-way ANOVA was used to compare continuous variables when appropriate.Categorical variables were compared by the X 2 test.The Spearman test was used to establish correlations between continuous variables and digoxin serum levels.Correlation between two continuous variables was settled at an r level ≥0.30 and p value < 0.05.Differences for a p level < 0.05 were considered statistically significant.

Ethical
The study was approved by the local ethics in research committee (Protocol 4464/2008).The small risk of complications associated with venous puncture was explained to each patient.After free, informed consent was obtained, digoxin measurement was performed.
Pulmonary venous congestion was verified in 5 (45%) out of 12 patients with digoxin serum concentration < 1ng/ml and in 7 (44%) out of 16 patients with digoxin serum levels ≥ 1ng/ml (p > 0.05).Table 1 presents a comparison of clinical parameters between patients with digoxin serum levels ≥ 1ng/ml and patients with digoxin serum levels < 1ng/ml.The proportion of patients on spironolactone was higher in patients with digoxin serum levels ≥ 1ng/ml.

DISCUSSION
This cross-sectional study shows that roughly half of Chagas' disease patients with chronic heart failure in need of digoxin therapy present higher serum digoxin concentration than that currently recommended.This fact highlights the necessity of measuring digoxin in the serum of such patients to provide the best treatment available for patients with this condition.
Mean age was similar in patients with digoxin serum levels ≥ 1ng/ml and in those with digoxin serum concentrations < 1ng/ ml.In contrast, mean age was higher in patients with serum digoxin concentrations ≥ 1ng/ml in the DIG trial 8 .In this study, however, mean age was slightly lower than that reported for the DIG trial 8 .It is conceivable, therefore, that this difference accounts for the disparity observed between these studies.
The proportion of patients with pulmonary congestion, as shown by the chest radiograph, was similar in patients with serum digoxin concentration ≥ 1ng/ml and in those with serum digoxin concentration < 1ng/ml.This is in contrast with that has been verified in non-Chagas' disease heart failure 8 .Perhaps this discrepancy can be explained by B-Blocker therapy, which is known to increase left ventricular ejection fraction and to decrease pulmonary congestion, but was not used at the time the DIG trial was conducted, but was used in the majority of patients enrolled in this study.
There was no difference in potassium serum levels in patients with digoxin serum concentration ≥ 1ng/ml in comparison to patients with digoxin serum concentration < 1ng/ml in our investigation, despite the fact that 90% of patients were receiving furosemide and 66% spironolactone at the time of digoxin measurement.Moreover, the mean potassium serum level was below the normal range.This fact is in agreement with that reported for the DIG trial 8 .
A key point in this investigation was the fact that about 66% of patients received B-blockers at targeted dose along with digoxin.In non-Chagas' disease patients, B-blocker therapy benefits both patients administered and those not administered digoxin as treatment for chronic heart failure 14 .In the context of Chagas' disease, B-blocker therapy has been shown to provide beneficial effects experimentally 15 , as well as in patients with chronic heart failure 16 .Nonetheless, B-blocker therapy is not devoid of potential complications in Chagas' disease patients.
In fact, carvedilol increases digoxin serum concentration in non-Chagas' disease patients with chronic heart failure, mainly in men 17 .Given the presence of a high frequency of patients with bundle branch and fascicular blocks in Chagas' disease with chronic heart failure, as detected in our study, such an increase in digoxin serum concentration could lead to the appearance of life-threatening arrhythmias 18 due to macroreentry and atrioventricular blocks 19 , cardinal manifestations of digoxin toxicity.Nevertheless, the proportion of patients on B-blockers with digoxin serum concentrations ≥ 1ng/ml was similar to that verified in patients on B-blockers with digoxin serum concentrations < 1ng/ml.Another property of B-blockers, therefore, might have counteracted this potential deleterious effect.
Carvedilol has been shown to decrease proinflammatory cytokine levels in non-Chagas' disease patients with chronic heart failure on digoxin therapy 20 .Proinflammatory cytokines, particularly TNF, are increased in patients with chronic heart failure secondary to Chagas' cardiomyopathy 21 .The interplay of spasm in the small intramyocardial coronary vessels, autoimmunity and parasympathetic impairment is believed to play a role in the pathogenesis of Chagas' cardiomyopathy 22 .In Chagas' disease patients, therefore, TNF could lead to microvascular thrombosis-induced myocardial ischemia, as well as orchestrating chronic myocardial inflammation and ultimately reparative myocardial fibrosis 11 .Thus, B-blocker therapy added to patients with chronic heart failure with Chagas' cardiomyopathy on digoxin therapy does not appear to be detrimental, as observed prior to the current era of heart failure therapy 23 .
Digoxin has not been routinely measured in patients with Chagas' cardiomyopathy with chronic heart failure due to economic reasons, inasmuch as this laboratory test is not paid for by the National Health System.It has not also been determined in distant rural areas, where the disease is endemic, due to the unavailability of proper apparatus to perform the immune-enzymatic method.This study shows the necessity to measure digoxin serum levels in Chagas' disease heart failure patients because of the potential for digoxin toxicity, as observed in non-Chagas' disease heart failure patients.
The main limitation of the present investigation is the small sample size.Thus, a multicentric study analyzing more patients with this condition would be necessary to confirm the results obtained in this work.Nonetheless, it must be emphasized that this investigation was conducted in a tertiary referral center where Chagas' disease patients are routinely followed, thus reflecting the reality of the proper treatment of such patients in daily practice.
In conclusion, the prevalence of abnormal digoxin serum concentration is high in patients with chronic heart failure secondary to Chagas' cardiomyopathy.Further studies are necessary to confirm the results of this investigation.
The authors declare that there is no conflict of interest.

FIgURE 1 -
FIgURE 1 -Digoxin serum levels in patients with Chagas' cardiomyopathy with chronic heart failure.