Chagas cardiomyopathy

Introduction

Chagas disease (CD) (American trypanosomiasis) is generated by the protozoan parasite Trypanosoma cruzi (T. cruzi) and transmitted by the reduviid bug in Latin America: it was discovered and described by the Brazilian physician Carlos Chagas in 1909. CD has been considered a neglected disease and a public health concern, with no vaccines available so far and only a few antiparasitic drugs; it primarily affects low-income populations and is a major cause of chronic morbidity and mortality.

Epidemiology

Approximately 8-12 million people are infected with T. cruzi in Central and South America. At least 120 million are at risk from CD and 300,000 new cases are reported each year. Estimates of the number of annual deaths are around 50,000. Of these, 60% are related to sudden cardiac death (SCD), 25% to heart failure and 15% to stroke [1]. CD is a major cause of heart disease and cardiovascular-related deaths in areas where it is endemic.

Europe is currently hosting large populations of migrants that were estimated to account for 8.7% of the total European population in 2010. A systematic review indicates that, overall, 4.2% of Latin American individuals living in European countries are chronically infected with CD. Bolivian migrants had the highest prevalence (18%); similarly, migrants from Paraguay also present a high prevalence (12.7%) [2]. Thirteen million persons have migrated from countries where the disease is endemic to countries such as the United States, and it is estimated that 0.3-1 million of them have chronic T. cruzi infection [3]. However, these numbers may even be understating the extent of the CD burden outside of Latin America where there is a lack of universal screening systems and where physicians are often poorly trained in recognising the disease. On the other hand, patients with CD cardiomyopathy require long-term treatment, including medications and costly interventional procedures such as pacemakers, implantable cardioverter-defibrillators (ICD), ablations, and heart transplantation, imposing a large economic burden.

Transmission

Transmission to humans occurs not directly through the blood meal, but through infected faeces, of the Triatominae insect vectors, that are deposited during the blood meal, most commonly when the bitten person rubs the infective faeces into the bite wound while scratching the area [1]. Once within host cells they reproduce, which leads to cell lysis and haematogenous dissemination, at which point parasites are apparent on peripheral blood smear.

One cause of newly acquired T. cruzi infections is congenital transmission. Although the precise number in non-endemic countries is unknown, it is estimated that 40,000 pregnant women and 2,000 newborns are infected with T. cruzi in North America [3]. Other non-vectorial mechanisms include blood transfusion, organ transplantation, accidental contamination and direct oral transmission.

Pathogenesis

Inoculation is followed by a short incubation period of one to two weeks, after which the acute phase of the disease begins. Acute infection is typically asymptomatic, with only 5% of cases experiencing symptoms including malaise and fever that may last four to eight weeks. Death during the acute phase is rare (<1/2,500 infections). After that, people enter the indeterminate phase that is characterised by chronic asymptomatic infection; that phase involves host-parasite equilibrium and is without progressive host damage. At least 50% of infected people will remain in the indeterminate phase for life and experience no long-term problems. After the indeterminate phase, 20-30% of those infected will experience cardiac damage and develop cardiovascular alterations. Finally, 15-20% of cases experience digestive damage including megaoesophagus and megacolon [1,4]. The indeterminate phase is diagnosed when there are positive serologic test results, but no specific organic injury.

The pathogenesis of cardiac damage is not completely understood. At least four possible mechanisms have been proposed: immune-mediated myocardial injury, parasite persistence in cardiac tissue with secondary antigenic stimulation, cardiac parasympathetic neuronal depopulation and coronary microvascular abnormalities causing myocardial ischaemia.

Several authors have shown that myocarditis with myocytolysis and reparative fibrosis, the hallmark of chronic CD, has the characteristics of a delayed hypersensitivity reaction, with the inflammatory infiltrates composed mainly of mononuclear cells. In addition, cross-reactive antibodies between human cardiac myosin heavy chain and the T. cruzi protein B13 are more frequently found in sera from chagasic patients with manifestations of cardiomyopathy than in patients with the indeterminate form. These findings, together with the demonstration of immunoglobulin and complement deposition in myocardial tissue, constitute first-line evidence for the involvement of immune-mediated myocardial injury [5].

The appearance of studies using immunohistochemistry, polymerase chain reaction, and in situ hybridisation methods to identify tissue T. cruzi antigens or its genomic material has renewed the focus on a pathogenetic role for myocardial aggression directly dependent on parasite persistence in host tissues. The exact mechanism whereby parasitism causes tissue damage is unclear, although stimulation of immune responses that are targeted at the parasite and self tissues is the most likely cause of inflammation and myocytolysis [5].

Cardiac parasympathetic neuronal depopulation has been correlated with abnormal cardiac autonomic heart rate regulation, suggesting that patients with CD are deprived of normal inhibitory parasympathetic tone in the sinus node. This autonomic imbalance in chagasic patients could, over time, lead to catecholamine-induced cardiomyopathy [5]. In a study of 52 patients with CD with pacemaker or ICD, we found more positive serological response against 2e-m2MAChR (the antibody that recognises the muscarinic acetylcholine receptor type II) than in 52 patients with pacemaker or ICD without CD (32.7% vs. 3.8%, p<0.01) [6].

Experimental and clinical studies strongly support that structural and functional microvascular abnormalities occur in CD, possibly as a consequence of the underlying inflammatory process [5].

Clinical manifestations

The most common cardiac complications of chronic CD are left ventricular dilation and dysfunction, aneurysm, congestive heart failure, thromboembolism, ventricular arrhythmias, and sudden cardiac death (SCD). Additionally, cardiac conduction system abnormalities are common in CD.

Chronic heart failure (CHF) usually appears at least 20 years after the original infection.  The most frequent clinical presentation is biventricular heart failure, with predominance of symptoms related to serious higher impairment of the right ventricular function (jugular venous stasis, hepatomegaly, ascites and lower limb oedema). Patients usually complain of weakness rather than of dyspnoea. Some patients complain of chest pain, usually resembling atypical angina. In CD, arrhythmia-related symptoms are common, including palpitations, dizziness, lipothymia and syncope. Syncope can be due to either tachyarrhythmias or bradyarrhythmias [7].

Diagnosis

The diagnosis of chronic CD is based on serology to detect immunoglobulin G antibodies to T. cruzi, using at least two serological tests of different principles. The most commonly used are an enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) and indirect haemagglutination (IHA) [7].

Electrocardiographic abnormalities are common in CD vs. non-Chagas cardiomyopathy (87.6% vs. 77.7%). They are frequently the first indicator of CD. Right bundle branch block (RBBB) associated with left anterior hemiblock (LAHB) is the most frequently found abnormality change (>50% of patients). RBBB is more common than other non-Chagas heart disease (23.2% vs. 3.3%). Atrial fibrillation (AF) is 3.4 times more frequent in chagasic patients. Variable grades of AV block are commonly described as signs of dysfunction of the sinus node [1,7]. Left bundle branch block (LBBB) or left posterior fascicle hemiblock is present in a minority of cases.

Polymorphic ventricular extrasystoles are common in the presence of ventricular dysfunction. Non-sustained ventricular tachycardia (VT) or sustained VT usually occurs in more advanced cases [7]. Excellent prognosis for almost a decade has been reported for patients with a normal electrocardiogram [4].

Echocardiography allows the assessment of regional and global contractility. The myocardial damage in CD can manifest as segmental contraction defects (commonly inferolateral hypokinesis), left ventricular (LV) dilation with systolic dysfunction and LV aneurysms. The presence of LV aneurysms is a predictor of mural thrombus and stroke and can also be the origin of VT. Similarly, segmental myocardial damage has been correlated with sustained VT. The classic echocardiogram of advanced Chagas cardiomyopathy is large dilatation, both atrial and ventricular, with diffuse biventricular hypokinesia and ventricular aneurysms (detected in 47-67% of cases) [7].

The first Latin American guidelines for the diagnosis and treatment of Chagas cardiomyopathy [7] have proposed a clinical classification of chronic chagasic cardiomyopathy (Table 1).

Table 1. Clinical stages of chronic chagasic cardiomyopathy (modified from ref. 7).

CHF: chronic heart failure; LV: left ventricular

Prognosis

Chronic chagasic cardiomyopathy is almost always progressive. Several observational case series have shown a worse outcome for patients with CD as compared to those with other cardiomyopathies. Rassi et al [8] developed and validated a risk score for predicting death in 424 patients followed for a mean of 7.9 years; 130 patients died. They identified six independent prognostic factors: NYHA Class III or IV (5 points), cardiomegaly on chest radiography (5 points), segmental or global wall motion on echocardiography (3 points), non-sustained VT on Holter monitoring (3 points), low QRS voltage (2 points), and male sex (2 points). They defined three risk groups: low risk (0-6 points), intermediate risk (7 to 11 points), and high risk (12 to 20 points). The 10-year mortality rates for these three groups were 10%, 44% and 84%, respectively.

Treatment

Aetiological treatment

The two antiparasitic drugs available for the treatment of CD are benznidazole and nifurtimox. In the acute phase, these agents are most effective, with rates of parasitological cure of 60-80%. Treatment is recommended for all cases of acute reactivated, congenitally transmitted infection or accidental contamination, and also for children up to 18 years old with chronic infection [4,7]. Nowadays, these conditions are considered class I indications for aetiological treatment. The use of aetiological treatment in chagasic patients with an advanced cardiac form of the disease is a class III indication [7].

In the indeterminate form, the aetiological treatment has non-consensual indications.  However, despite the lack of proof that antiparasitic Chagas changes the natural history, it is commonly recommended [7]. Recently, the BENEFIT trial was published; 2,854 patients with Chagas cardiomyopathy, with no severe myocardial damage (mean LVEF 54%, NYHA Class I-II 97%) were randomised to benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. Trypanocidal therapy did not significantly reduce cardiac clinical deterioration [9].

Treatment of ventricular dysfunction and heart failure

Patients with CHF must receive angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) and adrenergic beta-blockers (BB) to reduce mortality and diuretics and/or digoxin to reduce morbidity.

Renin-angiotensin-aldosterone system blockade

Several studies have shown the benefit of the administration of ACEI or ARB to the treatment of patients with CHF; however, almost none of these studies has enrolled chagasic patients. Small studies have used ACEI in Chagas cardiomyopathy with fewer subrogated results, but none has demonstrated changes in mortality. On the other hand, many physicians believe that patients with Chagas cardiomyopathy do not tolerate high doses of ACEI. Nowadays, ACEI/ARB are considered treatment class I in chagasic patients with an LVEF <45% [7]. In the same way, spironolactone or eplerenone is indicated in chagasic patients with an LVEF <35% and NYHA Class III/IV.

Beta-adrenergic blockade

Beta-blockers (BBs) are indicated in ischaemic cardiopathy and dilated cardiomyopathy with systolic dysfunction. This treatment is effective, increasing survival, reducing hospitalisations and symptoms, and improving quality of life. However, the effectiveness of BBs in chagasic patients has not been demonstrated. BBs have been avoided in patients with CD because of bradyarrhythmias and AV block. A small randomised placebo-controlled trial in chagasic patients found that the addition of BBs to treatment with ACEI and spironolactone is safe, haemodynamically well tolerated, and not associated with symptomatic bradycardia [10]. However, a systematic review of Cochrane found very low-quality evidence for the effects of carvedilol compared with placebo for treating heart failure in people with CD [11]. Despite this, BBs are a class I indication in chagasic patients.

Other medications

The combination of hydralazine and nitrate is recommended to treat chagasic patients with a contraindication to ACEI or ARB [7]. There are no studies supporting this indication. Digoxin can be justified in chagasic patients with symptomatic LVEF 45%, especially when the ventricular frequency is elevated in the presence of atrial fibrillation (class II A) [7]. Diuretics have the same indication as in other causes of CHF, basically in patients with signs and symptoms of congestion.

Oral anticoagulation is indicated in chagasic patients with atrial fibrillation, mural thrombus or previous embolic events. The cardioembolic ischaemic stroke is an important clinical manifestation of CD. A study with 1,043 patients with CD developed a score for predicting these events assigning a certain number of points to each of these clinical manifestations such as systolic dysfunction (2 points), apical aneurysm (1 point), primary alteration of the ventricular repolarisation (1 point) and age >48 years (1 point). Cox regression was performed to create a risk score that was related to the annual incidence of embolic events: 4-5 points >4%; 3 points 2-4%; 2 points 1-2%, 0-1 points <1%. Based on the risk/benefit, in patients with 4-5 points oral anticoagulation is useful [12].

Cardiac resynchronisation therapy

Cardiac resynchronisation therapy (CRT) is an established therapeutic modality for patients with non-Chagas heart disease with an LVEF <35%, with appropriate medical management and LBBB with a QRS 150 mseg (class I). Evidence of the usefulness of CRT in CD is limited. A study analysed 72 chagasic patients in NYHA Class III or IV. At the end of the evaluation, 87.4% of patients were in NYHA Class I or II [14]. However, the most frequently found interventricular conduction dysfunction is RBBB alone or with LAHB, and there is insufficient evidence to support the use of CRT in patients without LBBB. Despite the lack of high-quality evidence, the indications for CRT in CD are extrapolated from those used for ischaemia and idiopathic dilated cardiomyopathy [7].

Treatment of arrhythmias

Bradyarrhythmias

In some Latin American regions where CD is endemic, bradyarrythmias are a frequent reason for pacemaker implantation, associated with sick sinus syndrome or AV block. In a cross-sectional study of 332 patients with a pacemaker, 17.1% had anti-T. cruzi antibodies, and the chagasic patients were younger (55 vs. 60 years) [13]. Nowadays, the pacemaker implant indications of other aetiologies apply to chagasic patients [7].

Supraventricular tachyarrhythmias

The management of chagasic patients with supraventricular tachyarrhythmias is not different from non-chagasic patients [7]. In left ventricular dysfunction amiodarone is frequently used when catheter ablation is not available or has not been effective [7].

Ventricular tachyarrhythmias

 In symptomatic non-sustained ventricular tachyarrhythmias (ventricular ectopy or non-sustained VT), BBs or amiodarone in refractory cases with left ventricular dysfunction are useful. In sustained VT, endo-epicardial catheter ablation is the first choice with or without amiodarone and the use of ICD [7].

Sudden cardiac death

So far, no large randomised clinical trial has been published demonstrating the efficacy of ICD in CD. Nonetheless, in secondary prevention most groups recommend ICD therapy as an initial approach, possibly associated with the use of amiodarone [7].

In primary prevention the information is poorer, and, as expected, no randomised controlled study has been carried out. In the only study available, 19 chagasic patients were compared with 13 non-chagasic patients with an LVEF <35%; the median follow-up was 292 days. In eight chagasic patients (42%), sustained ventricular arrhythmias (VT or VF) were detected. In non-chagasic patients, the incidence was 30% [15]. Actually, European guidelines recommend using ICD in chagasic patients with an LVEF <40% [16]. However, a significant number of SCDs occur in patients with an LVEF >40% and in these subjects there is no adequate way to establish their risk.

Heart transplantation

There are uncertainties regarding indications for the procedure; however, a systematic review found that heart transplantation was safe and efficacious. Indications for the procedure are similar, and short-term results are comparable to non-Chagas. T. cruzi infection reactivation varies from 27% to 90%, but can nonetheless be easily treated. Mortality is lower than that found in non-Chagas heart transplant recipients [17].

Conclusions

Chagas cardiomyopathy is a common aetiology of CHF in endemic countries and it is increasing in other countries as a result of migration. Chagasic patients have a poorer prognosis than non-chagasic patients. The diagnosis is based on serology to detect immunoglobulin G antibodies to T. cruzi. Treatment of CHF in Chagas cardiomyopathy is similar to that in non-Chagas aetiology, despite the lack of strong evidence. New, better quality research is needed in this population to provide appropriate treatment strategies.