Chagas Cardiomyopathy Bisoprolol Intervention Study: Charity
Chagas Cardiomyopathy Bisoprolol Intervention Study: Charity
Chagas disease (CD) is the major cause of disability secondary to tropical diseases in young
 adults from Latin America. In this region 20 million people are currently infected by T.
 cruzi, the etiologic agent for CD. In Colombia, 18 percent of the population live in CD
 endemic areas, 900,000 people are infected and over three million are at high risk of being
 infected. Heart failure due to Chagas cardiomyopathy (CCM) is the main clinical form of CD in
 Colombia. However, the incidence of CCM among T. cruzi infected people is unknown and the
 mechanisms that lead from infection to CCM are uncertain. 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, but only 20 percent of them will develop symptomatic cardiac involvement. Like CHF
 from other causes, CHF due to CD responds to digital, diuretics and vasodilators therapy.
 Also, some studies have shown that angiotensin-converting enzyme (ACE) inhibitors improve
 survival in patients with moderate to severe CHF due to CD. Increased sympathetic drive
 results in an increased risk of cardiac arrhythmia and sudden death. Beta-adrenoreceptor
 antagonism seems to protect against the deleterious effects of chronic sympathetic
 stimulation. The effects of the selective beta-adrenergic receptor blocker Bisoprolol on
 cardiovascular mortality, hospital readmission due to progressive heart failure and
 functional status in patients with CHF secondary to CCM has not been explored to-date. To
 evaluate the benefit of Bisoprolol in CHF due to CCM, a cohort of T. cruzi seropositive
 patients will be selected from several institutions in Colombia. Patients will be classified
 according to a modified version of the Panamerican Health Organization recommendations for
 patients with CCM. Overall one year mortality in patients with CHF due to Chagas disease has
 been reported as 34 percent. However, one year mortality is only 3 percent in patients in
 NYHA functional class II, 27 percent in those in NYHA functional class III, and 62 percent
 among those in functional class IV (22). The sample size has been calculated assuming an
 event rate of 40 percent in two years in the placebo group, and using a 95 percent confidence
 level and power of 80 percent, we will need to recruit 250 patients per treatment arm to
 detect a reduction of 30 percent in the risk of the primary outcome. The event rate we have
 used to estimate sample size is similar to the expected two-year mortality in patients with
 CHF due to Chagas disease in NYHA functional class II. Therefore, the estimated sample size
 should be enough to measure significant changes in the composite primary outcome (death, HF
 hospitalizations, SMVT, SCD). The recruitment process will follow guidelines set out by the
 FCV Ethics Committee. Most participants will be recruited from the Chagas disease and the
 Heart Failure clinics located in Bucaramanga, Bogotá and Cucuta. During the pretreatment
 period an initial evaluation visit will be scheduled in which participants will sign consent
 forms, baseline measurements and tests will be conducted at the FCV including blood pressure
 measurements obtained with patients in the sitting and standing positions. Laboratory test
 such as twelve-lead ECG will be recorded in each patient. Left ventricular ejection fraction
 at rest will be determined by 2D echocardiography, using a modified Simpsons rule to
 calculate LV volumes. Quality of life questionnaire will be performed two weeks apart during
 baseline examination using the Minnesota living with heart failure questionnaire. Minimum of
 two 6-minutes corridor walk test once a week over a two-week period will be performed to
 measure the functional class. During the treatment period patients will be randomly assigned
 to receive double-blind Bisoprolol or placebo, initially taking a total daily dose of 2.5
 mgrs qd. The dose will be increased every two weeks to 5 up to 7.5 and 10 mgrs qd (maximum
 maintenance dose). Follow-up assessment will include clinical check-up, and blood collection
 for future measurements of inflammatory reactants and markers. Quality of life measurements
 will be obtained at six months. Following the descriptive analysis we will compare the
 patient survival and hospitalization rates using Kaplan-Meier estimates and survival graphs.
 Cox regression will be used for the multivariate analysis of time to death and time to
 hospitalization. This analysis will allow us to explore the pattern of changes in patients
 with chronic heart failure due to Chagas disease such as the effect of beta-blockers in this
 special type of 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.

 Bisoprolol is a beta-1 selective blocker with the highest selectivity for this receptor, in
 doses less than 10 mg it has very little or no effect on beta-2 receptors. Bisoprolol was
 first tested in CHF in the CIBIS I trial which enrolled 641 patients and showed improvement
 in functional class, less hospitalizations for heart failure and a trend to improved
 survival. The much larger randomized CIBIS II assigned 2647 patients with class III or IV HF
 and an LVEF lower than 40 percent to bisoprolol or placebo, the patients also received
 standard therapy with diuretics and ACE inhibitors. After an average follow-up of 1.4 years,
 the trial was prematurely stopped when the benefits were observed in the active treatment
 group: significant reduction in total all-cause mortality (11.8 versus 17.3 percent) that was
 independent of the severity or cause of HF. This benefit was primarily due to a reduction in
 SCD (3.6 versus 6.3 percent, p 0.001), with a non-significant trend toward fewer deaths from
 HF, significant 15 percent reduction in hospital admissions for any cause and a 30 percent
 reduction in admissions for HF (p 0.0001).

 Considering all the beneficial effects beta-blockers in patients with mild to severe CHF due
 to ischemic and non ischemic disease, there is no data regarding its potential effects in
 patients with CHF due to Chagas disease. Based on the aforementioned we propose to develop a
 multi-center placebo controlled clinical trial to evaluate the effect of Bisoprolol in
 patients with CHF due to CD.

 OBJECTIVES

 Primary Objective:

 To investigate the effect of the beta-blocker bisoprolol on survival and HF hospitalization
 rates, and other previously predefined outcomes in patients with Chagas cardiomyopathy and
 heart failure.

 Secondary Objective:

 To investigate the effect of the beta-blocker bisoprolol on quality of life, progression to
 heart block and need for electrical therapy (i.e. pacemaker, ICD, CRT).

 OUTCOMES

 Primary Outcomes:

 The composite of the first occurrence of ANY of the following

 -  Cardiovascular death.

 -  Hospital admission caused by heart failure.

 -  Major adverse cardiovascular events: stroke, systemic embolism, resuscitated sudden
 death.

 -  Bradycardia requiring pacemaker implantation.

 -  Clinically significant sustained monomorphic ventricular tachycardia causing syncope:
 sustained ventricular tachycardia or ventricular fibrillation.

 Secondary Outcomes:

 -  Non-cardiovascular death.

 -  Heart failure worsening or mortality related with CHF.

 -  New AV block.

 -  Need for Implantable cardioverter-defibrillator (ICD), Cardiac resynchronization Therapy
 (CRT) or Pacemaker therapy (PM).

 -  Perceived quality of life worsening.

 HYPOTHESES

 -  Bisoprolol will reduce cardiovascular death in patients with Chagas cardiomyopathy with
 heart failure functional class NYHA II to IV.

 -  Bisoprolol is safe in patients without advanced heart block.

 -  Bisoprolol will significantly reduce hospitalization rates due to heart failure in
 patients with Chagas cardiomyopathy in functional class NYHA II to

 STUDY DESIGN

 CHARITY is a multicenter randomized prospective, double blind, placebo-controlled,
 forced-titration study in subjects with CHF secondary to CCM. Enrolled subjects will receive
 placebo or Bisoprolol in addition to standard therapy for chronic heart failure which
 includes an ACE-inhibitor and may include diuretics or other medication such as digitalis or
 nitrates for heart failure.

 Patients included in CHARITY should be on stable doses of an ACE-inhibitor. Diuretics can be
 added to treatment as needed but patients must be on stable doses of each drug during four
 weeks prior to randomization.

 500 subjects will be randomized in two arms; one will receive oral bisoprolol and the other
 placebo, during the duration of the study. Forced titration will start with the lowest oral
 dose of 2.5 mg qd and will be up-titrated in 2.5 mg increments every two weeks until the
 maximum tolerated dose is achieved or 10 mg qd is reached. In case of intolerance, dose will
 be reduced to the previously tolerated lower dose. Subjects not tolerating the lower dose of
 2.5 qd will have a treatment interruption. The best tolerated dose will be continued for one
 month, then a security visit will re-asses tolerance. Thereafter patients will be controlled
 every three months until they complete the mean follow-up period of two years. Standard heart
 failure therapy with ACE-inhibitors, diuretics, digitalis and nitrates will be strongly
 reinforced in both parallel arms.

 BLINDING

 Patients and investigators will remain blinded during the trial. The treatment codes will
 remain blinded until the database is locked for final analysis.

 PRETREATMENT CONSIDERATIONS

 Baseline vital signs will be obtained with patients in the sitting and after 3 minutes in the
 standing position.

 Twelve-lead ECGs will be recorded in each patient. Left ventricular ejection fraction at rest
 will be determined by echocardiography, using a modified Simpsons rule to calculate LV
 volumes.

 Quality of life questionnaire will be administrated two weeks apart during baseline
 examination using a translated-validated version of the Minnesota living with heart failure
 questionnaire.

 Minimum of two 6-minutes corridor walk test once a week over a 2-week period will be
 performed. The last value will be used if it is within 10 percent of the previous value.

 FOLLOW-UP PERIOD

 ECG tracings will be recorded during the security visit and at 1 and 2 years. Patients will
 be followed for two years after randomization. Repeat echocardiograms will be recorded at 1
 and 2 years of follow-up along with HF Quality of-life questionnaire and six-minute walk
 tests.

 Clinical measurements will be obtained every three months along with an assessment of
 treatment adherence and tolerance. Mortality and hospitalization events will be ascertained
 by telephonic interview and verified with hospital charts review, up to two years after
 randomization.

 MONITORING COMMITTEES

 Steering committee

 The committee has the overall responsibility for producing and conducting a scientifically
 sound design and ensuring accurate reporting of the study. In that capacity, the Steering
 Committee must address and resolve scientific issues encountered during the study. This
 committee will meet at least twice a year. The main role of the Steering Committee is the
 development of the protocol and CRF and to ensure appropriate conduction of the trial. The
 steering committee is composed by the principal investigators and site investigators. The
 chairman of the steering committee is the principal investigator. The primary scientific
 publication reporting the study results is the responsibility of the Steering Committee.

 CHARITY Operations Committee

 The Operations Committee will consist of a select group of Steering Committee members chosen
 for their specific expertise and experience. This group will be responsible for ensuring that
 study execution and management are of the highest quality.

 FCVRI Project Office

 The FCVRI Project Office is located at the Instituto de Investigaciones-FCV in Bucaramanga,
 Santander, Colombia,is independent and its primary function is to facilitate and oversee the
 execution of the study. The FCV Project Office will keep the Operations Committee appraised
 of the progress and conduct of the trial and will provide ongoing administrative and
 methodological support to the Event Adjudication Committee and the DSMB

 Data and Safety Monitoring Board (DSMB)

 The DSMB will include at least 2 prominent cardiologists and a neurologist, as well as a
 statistician. Their mandate will be to provide on-going review of the safety of all the
 investigational treatments.

 Adverse Events and Adjudication Committee

 The Event Adjudication Committee is charged with the responsibility for validating all
 reported primary fatal and nonfatal outcomes and validating the classification of cause of
 death. The Event Adjudication process will be coordinated at the FCVRI Project Office in
 Bucaramanga. This committee, composed of experts in the field will review, in a blinded
 manner; all reported outcome events to provide consistency and validity in the assessment of
 outcomes. Their decisions will be based on blind clinical data provided and they will
 consider the impressions of the clinical investigator. Their decisions will be used in the
 final analysis. The AE Committee (AE-AC) is composed by clinical experts and one principal
 investigator, its responsibilities are to review and verify every AE, SAE and Adverse Drug
 Reactions (ADR) reported, and to supervise all relevant SAE information is complete. The
 AE-EC will validate all SAE in a blinded form and notify investigators, Independent Ethics
 Committees and regulation authorities of all SAE and clinically relevant AE. The AE-EC will
 also validate outcomes providing standard classifications and definitions and reviewing
 supporting information provided by investigators.

 SELECTION AND WITHDRAWAL OF SUBJECTS

 Inclusion Criteria

 -  Males or females aged 18 to 70 years.

 -  Heart failure symptoms NYHA functional class II to IV

 -  Left ventricular ejection fraction lower than 40 percent determined by bi-dimensional
 echocardiography using modified Simpsons rule for ventricular volumes.

 -  Subjects must be on standard and stable outpatient doses of ACEIs or angiotensin II
 receptor antagonist for at least four weeks.

 -  Subjects receiving diuretics must be on a stable dose for at least two weeks.

 -  Clinical Euvolemia:as evidenced by absence of rales, no pleural effusion or ascitis and
 no more than minimal peripheric edema.

 Exclusion Criteria

 -  CHF due to ischemic heart disease, valvular disease or any other etiology different than
 CD.

 -  Severe aortic insufficiency

 -  Baseline advanced AV block defined as Mobitz type 2 or third degree AV block

 -  Serum creatinine greater than 2.5 mg/dl.

 -  Resting Heart rate less than 45 bpm

 -  Known malignancy and other severe disease which shorten life expectancy less than 6
 months.

 -  Subjects with contraindications for beta-blockers: severe obstructive chronic pulmonary
 disease, asthma, severe pulmonary hypertension, type 1 diabetes mellitus or history of
 hypoglycemia.

 -  Suspected or confirmed chronic infectious disease including HIV and hepatitis B.

 -  History of active substance or alcohol abuse within the last year.

 -  Clinically significant psychiatric illness which can negatively affect the subject
 compliance and participation in the trial.

 -  Pregnancy or lactation.

 -  Organic disease or gastrointestinal surgery which can affect the oral absorption and
 pharmacodynamics of the medication under study.

 -  Enrollment and participation in other active treatment trial within the previous month.

 -  Failure to provide written informed consent.

 Interruption of treatment

 Trial treatment should be interrupted under the following conditions.

 -  The patient decides it is in his-her best interest.

 -  The investigator considers it is advisable or in the patients best interest.

 -  Intolerable adverse experience(s).

 -  Presence of life-threatening conditions despite adjustment of therapy.

 If study treatment is interrupted, every effort should be made to reinstate treatment as soon
 as possible and medically acceptable. The re-initiation dose is determined at investigators
 discretion and the dose may be reduced or re-started at the last dose level. Patients with
 treatment interruption should continue on the protocols visit schedule and study procedures
 except drug dispensing.

 TREATMENTS

 The FCV Research Institute will supply ranurated 5 mg bisoprolol tablets and matched placebo
 needed for the whole duration of the trial. Study drug and placebo have been kindly provided
 by Merck Colombia.

 EFFICACY ASSESSMENT

 Efficacy assessments will be made at every visit during the trial following randomization.
 Information will be recorded in the supplied CRF formats dealing with clinical variables,
 Adverse Events (AE), Serious Adverse Events (SAE) and endpoints.

 Each of the primary endpoints will be recorded on the SAE form and in the individual
 corresponding form for each endpoint.

 Endpoint Definitions

 Cardiovascular death: any death attributable to a cardiac or vascular cause occurring within
 two years after randomization.

 Non-cardiovascular death: death from any cause excluding cardiovascular diseases occurring
 within two years after randomization..

 Hospital admission-hospitalization caused by heart failure: admission in a hospital or clinic
 during at least 24 hours caused by heart failure worsening. It excludes procedures and
 hospitalization for procedures which have been scheduled and not due to worsening of the
 current heart failure condition since randomization.

 Heart failure worsening: decline of at least one functional class as defined by the New York
 Heart Association occurring during any inter-visit period of three months needing inotropic
 support, IV diuretics, medication dose adjustments or additional drugs for compensation.

 Perceived quality of life worsening: increase in the Minnesota living with heart failure test
 score of at least 10 points. The tests score ranges from 0 (best) to 100 (worst).

 New AV block: appearance of any AV conduction disturbance including first, second and third
 degree AV block after randomization.

 Bradycardia requiring pacemaker implantation: ventricular rates < 50 per minute due to any
 cause including sick-sinus syndrome and AV block, causing symptoms or disability and
 complying with current indications for permanent pacemaker implantation.

 ICD: Implantable cardioverter-defibrillator indicated for the prevention and treatment of
 sudden death, ventricular tachycardia/ventricular fibrillation.

 CRT: cardiac resynchronization therapy or biventricular pacing or ventricular bifocal pacing
 for the treatment of advanced heart failure.

 PM: permanent pacemaker for the treatment of conduction disturbances. Clinically significant
 ventricular arrhythmias: sustained monomorphic ventricular tachycardia or ventricular
 fibrillation with symptoms caused by hemodynamic or perfusion alterations, circulatory
 collapse or syncope.

 STATISTICAL METHODS

 Descriptive statistical analysis will be composed with simple distribution of frequencies,
 calculation of proportions, means, their respective standard deviations and 95 percent
 confidence intervals. For effects of group comparison, t-test and Mann-Whitney tests will be
 used according to the dependent variable distribution. For categoric variables, the
 Chi-square test or the exact Fisher test will be applied as corresponding.

 Patient survival and hospitalization rates will be described using Kaplan-Meijer estimates
 and survival graphs. Cox regression will be used for the multivariate analysis of time to
 death and time to hospitalization.

 Formal efficacy interim analyses will take place one year after the recruitment phase.

 Expected Results

 Direct Results: Study results will help identify interventions potentially useful to prevent
 the progression from T. cruzi infection to CCM. This may significantly lessen the burden of
 CD in Colombian and other exposed populations. This will have a significant impact on the
 morbidity and mortality of the Colombian population, mainly in areas with high prevalence of
 seropositive subjects for T. cruzi such as Santander. The execution of this project will
 allow us to determine the effect of the b-blocker therapy on the CCM and the behavior of the
 autonomic nervous system on the mortality and morbidity of subjects infected by T. cruzi. The
 results of this study will also arise the need knowledge to suggest new therapeutic
 interventions for patients with CCM.

 Indirect Results: This project will contribute to the consolidate the clinical research group
 of the Easter Cardiovascular Foundation as well the Chagas group that is already working at
 the same institution.

 Strategy to be use for data transferring

 According to recent trends in the field literature we will try to get the results of this
 project in one of the following clinical journals: Circulation, Journal of the American
 College of Cardiology, American Journal of Cardiology and another one in one of the following
 basic journals: Infection and Immunity, Transactions of the Royal Society of Tropical
 Medicine and Hygiene. The obtained results from this study will be presented at the Colombian
 Congress of Cardiology, the Colombian Congress of Intern Medicine and at least in one
 international meeting (Inter American Congress of Cardiology, Meeting of the American College
 of Cardiology or the Annual Meeting of the American Heart Association). This strategy will
 guarantee the communication, discussion and evaluation of the results by the international
 scientific community in this subject.

 Experience of the Research Group and presentation of the research team.

 The members of the research team belong to the Research Institute of the Fundación
 Cardiovascular del Oriente Colombiano (RIFCV) are physician from the medical staff of the FCV
 and from the Instituto Colombiano de Investigacion ICIB, one of the members of the VILANO
 group. The RIFCV is a well recognized research center, that has been promoted by COLCIENCIAS,
 and has received twice economical support. During the last tree years the RIFCV has been
 funded by COLCIENCIAS to make five research projects. Two of them, related to this subject,
 are being carried out right now. Moreover, the RIFCV has also been funded by the Ministry of
 Health for two projects. The RIFCV has also participated in more than ten projects funded by
 pharmaceutical companies.

 The RIFCV is one of the institution that constitute the ICIB. Three of the researcher of this
 project, (CAM, LAC, JPC ) belong to the VILANOs group, which has been qualified by COLCIENCAS
 as a group class A. The research team is a multidisciplinary group constituted by physicians
 of several fields (Basic science, clinic and epidemiology) and includes one masters, tree
 cardiologist, one master student and two general physician. The high academic degree and the
 experience of the group allow to carry out high degree research with good quality. Tree of
 the members of the team has developing research in the autonomic aspects of CCM and one have
 been working in heart failure patients.
Inclusion Criteria:

 -  Males or females aged 18 to 70 years.

 -  Heart failure symptoms NYHA functional class II to IV

 -  Left ventricular ejection fraction <40% determined by bi-dimensional echocardiography
 using modified Simpson's rule for ventricular volumes.

 -  Subjects must be on standard and stable outpatient doses of ACEIs or angiotensin II
 receptor antagonist for at least four weeks.

 -  Subjects receiving diuretics must be on a stable dose for at least two weeks.

 -  Clinical Euvolemia:as evidenced by absence of rales, no pleural effusion or ascitis
 and no more than minimal peripheric edema.

 Exclusion Criteria:

 -  CHF due to ischemic heart disease, valvular disease or any other etiology different
 than CD.

 -  Severe aortic insufficiency

 -  Baseline advanced AV block defined as Mobitz type 2 or third degree AV block

 -  Serum creatinine >2.5 mg/dl.

 -  Resting Heart rate less < 45 bpm

 -  Known malignancy and other severe disease which shorten life expectancy < 6 months.

 -  Subjects with contraindications for beta-blockers: severe obstructive chronic
 pulmonary disease, asthma, severe pulmonary hypertension, type 1 diabetes mellitus or
 history of hypoglicemia.

 -  Suspected or confirmed chronic infectious disease including HIV and hepatitis B.

 -  History of active substance or alcohol abuse within the last year.

 -  Clinically significant psychiatric illness which can negatively affect the subject
 compliance and participation in the trial.

 -  Pregnancy or lactation.

 -  Organic disease or gastrointestinal surgery which can affect the oral absorption and
 pharmacodynamics of the medication under study.

 -  Enrollment and participation in other active treatment trial within the previous
 month.

 -  Failure to provide written informed consent.