A Randomized Double-blind Placebo Force-titration Controlled Study With Bisoprolol in Patients With Chronic Heart Failure Secondary to Chagas´ Cardiomyopathy.

BACKGROUND

Chagas disease (CD) is a permanent threat for almost a quarter of the population of Latin America. Although the disease has been described in almost all Central and South America, clinical presentation and epidemiological characteristics are highly variable among the different endemic zones (1,2). A wide range of prevalence rates has also been reported suggesting local differences in transmission of the disease as well as differences in vectors and reservoirs (3). Chagas cardiomyopathy (CCM) represents a serious public health problem in most Latin American countries, and the most recent statistics provided by the World Health Organization indicate that 100 million persons are exposed to the disease and approximately 20 million are currently infected (4). Interestingly, in addition to the natural infection foci, an increase in the transmission associated with blood transfusions has also been noticed. These statistics are considered an underestimation of the real rates of infection, most likely due to lack of reports from highly endemic retired rural communities. In countries in which the disease is endemic such as Colombia, Venezuela and Brazil, the overall prevalence of infection averages 10 percent. However, in highly endemic rural areas rates have ranged from 25 to 75 percent (5). Prevalence of infection varies widely even between cities and provinces within the same country because of variations in climate, housing condition, public health measures, and urbanization. The actual prevalence of clinical Chagas disease and the number of case fatalities are largely unknown, mainly because case reporting is virtually nonexistent in many areas in which CD is highly endemic. Congestive heart failure (CHF) is a late manifestation of CD that results from structural abnormalities and extensive and irreversible damage to the myocardium. Heart failure in T. cruzi infected patients usually occurs after age 40 and follows AV block or ventricular aneurysm. However, when CHF develops in patients less than 30 years old it is frequently associated with a more aggressive myocarditis and an extremely poor prognosis (1). The mortality attributable to CD is related to the severity of the underlying heart disease. Very high mortality is often found in patients with congestive heart failure (2), however, mortality in asymptomatic seropositive patients varies greatly between geographic regions, suggesting that other factors may influence the severity and progression rate of cardiac disease. It is believed that cardiac damage in CD progresses slowly but steadily over decades, from subclinical myocarditis to mild segmental abnormalities with conduction defects, to severe ventricular structural abnormalities, and finally to overt congestive heart failure and sudden cardiac death.

Besides the poor prognosis of CHF due to Chagas disease, it is important to estimate the risk of complications and death in patient infected with T. cruzi. Unfortunately, few clinical studies have addressed this issue. Most T. cruzi infected patients have mild or no clinical disease, however, the percentage of infected people that will develop detectable cardiac abnormalities is approximately 30 to 40 percent (3), but only 20 percent of them will develop symptomatic cardiac involvement (6). Like CHF from other causes, CHF due to CD responds to digital, diuretics and vasodilators therapy (7). Additionally, some studies have shown that angiotensin converting enzyme (ACE) inhibitors improve survival in patients with moderate to severe CHF due to CD (8). In spite of its benefits on patients with non Chagas disease CHF, there is considerable uncertainty about the potential role of ACE inhibitors in patients with CHF due to Chagas disease. Captopril, and ACE inhibitors, has been shown to reduce neurohormonal activation and non lethal arrhythmias in a small number of patients with Chagas heart failure (8,9). Another intervention currently included in the management of CHF patients is the use of b blockers. Observational studies (10) as well as clinical trials (11,12) have shown that b-blockers reduce morbidity and mortality in CHF patients. The effects of b-blockers on CHF patients are being studied in large scale clinical trials (13-19). Apparently, the cardiac sympathetic hyperstimulation that initially helps to preserve ventricular function in CHF patients, later on, results in an increased risk of cardiac arrhythmia and sudden death (20) b-adrenoreceptor antagonism seems to protect against the deleterious effects of chronic sympathetic stimulation (21). Moreover, b-blockers reduce heart rate, improve myocardial energetic balance and lead to a less negative force-frequency relationship. These effects contribute to the benefits of b-blocker therapy in CHF patients. Clinical studies with Carvedilol, a a1 and non selective b-blocker, further support the beneficial effects of b-adrenoceptor antagonism (18,19,23,24). Results from the US CARVEDILOL and COPERNICUS trial, suggest that prognosis in CHF may partly depend on left ventricular dysfunction improvement as well as sympathetic activity reduction (18,23). However, additional data are needed to define more precisely the relationships between heart rate reduction, left ventricular function improvement and survival in CHF patients. In some studies like CIBIS II and MERIT HF, the beneficial effects of the selective b- blockers on morbidity and mortality were observed specially in patients functional class II and III. In COPERNICUS a multicentric placebo controlled clinical trial with Carvedilol, these effect was ascertained even in patients functional class IV (23), demonstrating that patients with CHF, independently of their functional class, should receive b-blocker therapy. Current guidelines for the management of CHF strongly recommend the use of beta-blockade in management of CHF. However, these benefits have not been proven in Chagas´ cardiomyopathy (25,26). Nevertheless, there are reasons to believe that beta-blockade will be beneficial for these patients.

First, patients with CHF due to CD have a raised end-diastolic pressure associated with a low systemic blood pressure, which lead to low transmyocardial pressure gradient and subendocardial ischemia. Therefore, reduction in myocardial oxygen demand due to beta-blockade could be expected to be beneficial in this situation, even in non ischemic CHF patients. Second the reduction in sudden cardiac deaths and serious ventricular arrhythmias suggest that an anti arrhythmic effect is an important component of beta-blockade. This anti-arrhythmic effect is explicable not only on an anti-ischemic basis but also by blockade of sympathetic activity, which is indeed increased in patients with Chagas cardiomyopathy. Third, prolonged activation of the sympathetic nervous system can accelerate the progression of heart failure, and the rate of progression can be substantially decreased using pharmacological agents that interfere with sympathetic activity in the heart and peripheral blood vessels. There is clear evidence of increased circulating beta-adrenergic antibodies in Chagas disease providing further theoretical support for the use of beta-adrenergic blockade in this group of patients.

Beta-blockers already proven to be beneficial in CHF patients are metoprolol, bisoprolol and carvedilol, drugs which have been tested in over 10.000 patients in more than 20 placebo-controlled clinical trials enrolling men and women with systolic dysfunction due to ischemia, hypertension and dilated idiopathic cardiomyopathy.