<figure><img src="image_9.png" /><figcaption>**Figure 10.1** – Algorithm for the pharmacological treatment of patients with heart failure and reduced ejection fraction. EF: ejection fraction; ACEI: angiotensin-converting-enzyme inhibitor; ARB: angiotensin II receptor blocker; SGLT2: sodium-glucose cotransporter-2; HR: heart rate; NSVT: nonsustained ventricular tachycardia; NYHA: New York Heart Association; AF: atrial fibrillation; H-N: hydralazine-nitrate.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>**Figure 10.2** – Algorithm for the pharmacological treatment of patients with heart failure and mildly reduced ejection fraction. EF: ejection fraction; ACEI: angiotensin-converting-enzyme inhibitor; ARB: angiotensin II receptor blocker; NSVT: nonsustained ventricular tachycardia; AF: atrial fibrillation.</figcaption></figure>

The CTX is still considered the best treatment for refractory HF, with evident influence on the patient survival increase and quality of life improvement, especially in CCCD, whose prognosis is poor as compared to HF of other etiologies.⁶³²-⁶³⁴ Thus, CTX in advanced CCCD is considered a strong

recommendation, with level of evidence B, similarly to that occurring in other cardiac diseases with classical indications, as long as there is no contraindication to the procedure and some peculiarities are considered, such as, unfavorable socioeconomic conditions and presence of megacolon and/or megaesophagus,
which can increase the risks of postoperative complications and jeopardize the CTX result.²⁰

### 10.2.1.1. Immunosuppression Strategies

The immunosuppressive regimens for CTX can be classified as of induction and of maintenance and they do not depend on the etiology of the HF leading to CTX indication. Induction regimens cause intense postoperative early immunosuppression, while maintenance regimens are used throughout life to prevent rejection.⁶³⁵,⁶³⁶

### 10.2.1.2. Induction Therapy

The induction therapy for transplanted patients consists in intense immunosuppressive treatment, during transplant or in the immediate postoperative period, used in those at high risk for rejection to reduce this risk or delay the use of higher doses of calcineurin inhibitors, minimizing renal damage, particularly in patients with impaired renal function.⁶³⁵ Patients at high risk for fatal rejection, who could benefit from induction therapy are those with high titers of anti-HLA antibodies in the immune panel (PRA = panel reactive antibody > 10%), who are considered more vulnerable: young women with a previous pregnancy, patients with previous multiple transfusions, and users of mechanical circulatory support. The major inductors are polyclonal antithymocyte immunoglobulin (polyclonal antibody - thymoglobulin) and IL-2 receptor inhibitors, which have low immunogenicity, such as daclizumab and basiliximab.⁶³⁵

Although those agents can reduce the risk of early rejection and/or minimize renal damage, they are associated with an increased risk of infection, and, thus, can reactivate *T. cruzi* infection. Induction therapy is still controversial, and despite being used in 50% of the cardiac recipients, so far large RCTs have not been conducted to demonstrate the benefit of induction therapy versus no induction therapy.⁶³⁶,⁶³⁷ There are no data available on its effects on a recipient with CCCD.

### 10.2.1.3. Maintenance Therapy

The basic maintenance immunosuppressive therapy in heart transplanted patients usually includes a calcineurin inhibitor,

such as cyclosporine A or tacrolimus. These agents should be associated with mycophenolate mofetil (MMF) or mycophenolate sodium or azathioprine or rapamycin or everolimus. Prednisone is also added to this standard regimen, and, in most patients, it can and should be suspended approximately 6 months after transplantation if no rejection occurs.⁶³⁵

In the context of CCCD, the induction and/or maintenance immunosuppressive therapy can reactivate *T. cruzi* infection.²,²⁰ There is no study comparing immunosuppressive regimens in patients with CCCD; however, a higher number of reactivations has been diagnosed with the use of MMF versus azathioprine.⁶³⁸ Thus, strategies to change the immunosuppressive regimen, such as replacement of MMF with azathioprine or MMF dose reduction, have been proposed, but these strategies have not been tested in RCTs.

The early reduction in immunosuppressive agents, mainly corticosteroids, is recommended to prevent RCD, but this can facilitate rejection episodes. So, patients with CCCD should receive the least intense immunosuppressive therapy possible, provided that there is no rejection.²,²⁰

Table 10.2 summarizes the immunosuppression strategies after CTX in the context of CD.

### 10.2.2. Diagnosis and Treatment of Rejection

The incidence of rejection requiring treatment has progressively reduced over the years, currently affecting only 12.6% of the recipients in the first year after CTX.⁶³⁶ Rejection is classified into hyperacute, mediated by antibodies, and acute cellular, which represents the most prevalent form of rejection. Histologically, rejection is defined by an inflammatory infiltrate, in which lymphocytes typically predominate, and myocyte damage. The International Society for Heart & Lung Transplantation (ISHLT) revised the categories of acute cellular rejection (R) as follows: 0R (no rejection), 1R (mild), 2R (moderate), or 3R (severe).⁶³⁹

Hyperacute rejection is an uncommon event, mediated by antibodies previously formed in the recipients, and manifests as severe graft failure within minutes or a few hours after the CTX procedure.⁶³⁹ The frequency of hyperacute rejection after CTX due to CD has not been reported.

Acute cellular rejection occurs in 10% to 14% of the recipients with CCCD and there is no difference in the

<table><caption>**Table 10.2 – Recommendations related to immunosuppressive therapy in CTX recipients with CCCD**</caption><thead><tr><td>Summary of recommendations</td><td>Recommendation grade</td><td>Level of evidence</td></tr></thead><tbody><tr><td>Induction therapy should only be used in patients at high risk for acute rejection or renal function worsening: PRA > 10%; reduced renal function; previous pregnancy; previous multiple transfusions; users of MCS</td><td>Strong</td><td>C</td></tr><tr><td>Use immunosuppressive agents at the lowest possible dose</td><td>Strong</td><td>B</td></tr><tr><td>Prefer azathioprine or mycophenolate at a reduced dose in association with a calcineurin inhibitor (CsA or Tacrolimus)</td><td>Conditional</td><td>B</td></tr><tr><td>In the absence of rejection, suspend corticosteroids gradually 6 months after the CTX</td><td>Conditional</td><td>C</td></tr><tr><td>In the presence of rejection, readjust the regimen and dose of immunosuppressive agents</td><td>Strong</td><td>B</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; CsA: cyclosporin A; PRA: panel reactive antibody; MCS: mechanical circulatory support; CTX: cardiac transplantation.
incidence of acute cellular rejection episodes (2R or 3R) between CTX recipients with or without CD.<sup>636,639-643</sup>

Endomyocardial biopsy remains the standard method for the diagnosis of rejection, and the frequency of the biopsies varies according to the transplant center protocol. Secondary myocarditis to reactivation of the *T. cruzi* infection can occur in the transplanted heart, making the differential diagnosis between rejection and RCD a great challenge.<sup>390,635,643,644</sup>

The definition for one of those two conditions is difficult if parasites are not found in the biopsy fragments. Depending on the routine histopathological staining techniques, if parasites are not seen, the histopathological inflammatory characteristics found in rejection (2R or 3R) and in RCD are very similar. Thus, the mononuclear inflammatory infiltrate detection on the endomyocardial biopsy slides is not sufficient to rule out the diagnosis of RCD and represents a dilemma, because the aggressive immunosuppressive treatment to abort rejection can facilitate and intensify RCD.<sup>390,644</sup> The presence of nests of *T. cruzi* amastigotes with mononuclear inflammatory infiltrate in endomyocardial biopsy fragments does not exclude concomitant graft rejection, because the two conditions can occur simultaneously.<sup>390,644</sup>

Therapy for rejection in transplanted patients with or without CD is similar. Usually, mild rejection (1R), in the absence of clinical or hemodynamic impairment, requires no additional intervention. However, more severe rejection (≥ 2R) requires aggressive supplementary immunosuppressive therapy.<sup>635,636</sup> Rejection is a risk factor for RCD, and more than 85% of the patients have at least one episode of rejection before RCD occurs.<sup>645</sup>

### 10.2.3. Diagnosis and Treatment of *T. cruzi*-Infection
Reactivation

#### 10.2.3.1. Clinical Presentation

Immunosuppressive therapy increases the risk of RCD, whose incidence after CTX ranges from 19.6% to 90%.<sup>2,638,642,643,646-649</sup> Considering its potential morbidity and mortality, the diagnosis and proper management of RCD in the context of organ transplant is extremely important.

The CTX should be performed following a clinical and laboratory structured protocol to monitor the infection reactivation and its subsequent treatment.<sup>2,20,648-651</sup> The diagnosis of RCD is based on clinical signs and symptoms and on the presence of parasites in the blood, cerebrospinal and other fluids, bone marrow, or tissues.<sup>2</sup>

Monitoring is aimed at identifying the firsts signs of reactivation and timely establishing anti-*T. cruzi* treatment. The clinical reactivation has cardiac and extracardiac manifestations that include: myocarditis; ventricular dysfunction; arrhythmias; new atrioventricular/intraventricular blocks on ECG; skin lesions (subcutaneous nodules, panniculitis); fever; bone marrow impairment; and neurological manifestations, such as meningoencephalitis, chagomas, cerebral abscess, and stroke.<sup>2,640,642,643,651-653</sup> The myocarditis of reactivation can be mistakenly diagnosed as graft rejection and treated with intensification of the immunosuppressive treatment,

which will worsen reactivation.<sup>644</sup> The differential diagnosis between myocarditis of rejection and of reactivation is still a great challenge.<sup>390,644,654</sup> In the presence of inflammatory infiltrate, nests of amastigotes and/or positive PCR for *T. cruzi* in the myocardium, we can claim that reactivation is present, but associated graft rejection cannot be safely excluded. Despite this complexity, the survival rate of recipients with CCCD undergoing CTX does not differ from those of cardiomyopathies of other etiologies.<sup>2,636,640,643</sup>

#### 10.2.3.2. Parasitological Diagnosis of Reactivation

The objective of laboratory monitoring is to identify any subclinical sign of RCD before cardiac and extracardiac symptoms appear, as well as graft dysfunction.<sup>2,649-651,655</sup> Serological tests are useful only for potential donors, diagnosis of CCCD in potential recipients, and seronegative recipients who receive organs from seropositive donors.<sup>2</sup> They play no role in the diagnosis of RCD.

Traditionally, laboratory monitoring uses parasitological methods (direct search for *T. cruzi* and blood cultures) and serial histological testing of endomyocardial biopsy, in the search for *T. cruzi* amastigotes, but those are low-sensitivity tests.<sup>2</sup> In recent years, several studies have evidenced the value of PCR in peripheral blood and myocardium to detect early RCD before the appearance of symptoms and/or graft dysfunction.<sup>388,390,391,401,403,656-658</sup>

Regarding the frequency of clinical visits and laboratory monitoring, there is no consensus in the literature. Table 10.3 suggests a protocol for clinical, laboratory, and histological monitoring of patients with CCCD undergoing CTX, in addition to a suggestion of etiological treatment, based on the major guidelines available.<sup>2,20,647,650,651</sup>

#### 10.2.3.3. Etiological Treatment of Reactivation

In the presence of signs/symptoms and/or identification of the parasite in blood, cerebrospinal fluid, or tissue specimens, etiological treatment should be initiated immediately.<sup>2,20</sup> Benznidazole is recommended as first-line treatment.<sup>2,563</sup> Its tablets contain 100mg of active substance. Its absorption is through the gastrointestinal tract, its excretion is predominantly renal, and its half-life is 12 hours. Its recommended dosage is 5mg/kg/day, for 60 days, the daily dose being divided into two or three doses.<sup>2,563</sup> Its most important side effect is urticarial dermatitis, which occurs in approximately 30% to 60% of the patients as early as by the end of the first week of treatment, but with good therapeutic response to antihistamines or small doses of corticosteroids. A few individuals can have fever and adenomegaly, whose presence determines medication suspension. Other adverse effects include polyneuropathy (later), with pain and/or paresthesia in lower limbs, and anorexia. Significant leukopenia and agranulocytosis are rare but, when present, determine treatment interruption.<sup>2,563</sup> Nifurtimox is not routinely available in Brazil. These trypanocidal medications are contraindicated to pregnant women and patients with important renal or hepatic failure.<sup>2</sup> There is no sufficient evidence to support the prophylactic anti-*T. cruzi* treatment for RCD. It is worth considering that those drugs have important side effects, not every recipient
<table><caption>**Table 10.3** – Clinical, histological, and laboratory monitoring of *T. cruzi* infection reactivation after CTX in Chagas disease and etiological treatment</caption><thead><tr><th>Procedure</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td><strong>Before transplantation</strong></td><td></td><td></td></tr><tr><td>Serological tests for Chagas disease in the donor</td><td>Strong</td><td>C</td></tr><tr><td>Serological tests for Chagas disease in the potential recipient with possible CCCD</td><td>Strong</td><td>C</td></tr><tr><td><strong>After transplantation</strong></td><td></td><td></td></tr><tr><td>Periodical clinical consultations with attention to signs/symptoms of reactivation, including ECG and echocardiogram</td><td>Strong</td><td>C</td></tr><tr><td>Routine <em>T. cruzi</em> search in the blood (smear, blood culture) to diagnose infection reactivation</td><td>Strong</td><td>C</td></tr><tr><td>Routine <em>T. cruzi</em> search in the blood by use of PCR</td><td>Strong</td><td>C</td></tr><tr><td>Periodical routine endomyocardial biopsies with <em>T. cruzi</em> search (histology and immunohistochemistry)</td><td>Strong</td><td>C</td></tr><tr><td>Periodical routine endomyocardial biopsies with <em>T. cruzi</em> search by use of PCR, if available</td><td>Strong</td><td>C</td></tr><tr><td><em>T. cruzi</em> search in tissues (skin, bone marrow) in the presence of findings compatible with <em>T. cruzi</em> infection reactivation</td><td>Strong</td><td>C</td></tr><tr><td>Frequency of post-transplantation procedures:<ul><li>1<sup>st</sup> month: weekly</li><li>2<sup>nd</sup> month: every two weeks</li><li>3<sup>rd</sup> to 6<sup>th</sup> month: monthly</li><li>7<sup>th</sup> to 12<sup>th</sup> month: every 3 months</li><li>After 12 months: every 6 months</li></ul></td><td>Conditional</td><td>C</td></tr><tr><td><strong>Etiological treatment of reactivation</strong></td><td></td><td></td></tr><tr><td>Benznidazole 5mg/kg/day for 60 days</td><td>Strong</td><td>C</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; CTX: cardiac transplantation; PCR: polymerase chain reaction.

has RCD, and one patient can have more than one episode of RCD after treatment. Monitoring of reactivation should be maintained even after anti-*T. cruzi* treatment<sup>2,20,650,651</sup> (Table 10.3).

### 10.2.3.4. Post-Heart Transplant Complications and Survival

The clinical outcomes, morbidity and mortality, in CTX recipients with or without CD are similar.<sup>636,640-642</sup> In both categories of patients, the major complications reported after CTX are almost the same: graft dysfunction (20%); rejection 2R or 3R (10%-14%); postoperative bleeding (10%); infection not related to *T. cruzi* (20%-30%); and acute renal failure (up to 70%). However, in recipients with CCDC, graft coronary artery disease appears to be less frequent, while the incidence of neoplasms seems to be higher, although none of these reported differences has been confirmed in all case series.<sup>584,640-642,659</sup>

Despite all the complexity of CD in the context of CTX, the results are good. In Brazil, the survival rates of patients with CCDC undergoing CTX in 6 months, 5 years, and 10 years are 76%, 71%, and 46%, respectively, superior to those of the cohort of patients undergoing CTX due to other etiologies.<sup>641,642</sup> One reason for that better performance would derive from the baseline characteristics, since patients with CCDC are usually younger, have fewer comorbidities, and less often have

undergone previous cardiac surgery.<sup>584,640-642</sup> However, a recent study has reported the evolution of 376 transplanted patients between 1997 and 2019 in a single center in Northeastern Brazil, comparing the following etiologies of HF: CCCD, CMI, and nonischemic cardiomyopathy. A mean 5-year follow-up evidenced stability in survival for individuals with CCCD, while that parameter improved subsequently in the other two groups.<sup>660</sup>

### 10.2.4. Mechanical Circulatory Support

Mechanical circulatory support devices (MCSDs) are used to restore tissue perfusion in patients with advanced HF or cardiogenic shock refractory to optimized clinical therapy, including the use of inotropic drugs. They can provide support to the left or right ventricle, or both.<sup>661</sup>

Mechanical circulatory support can be indicated as bridge to CTX or to recovery, in the perspective of ventricular function improvement after acute injury, or even as a bridge to decision-making in critical patients, when improvement of clinical findings is uncertain. In specific situations, mainly in the presence of contraindication to CTX, MCSDs can be used as permanent therapy.<sup>21</sup>

Evidence on the use of MCSDs for patients with CD is limited to a few reports or case series, mainly as bridge to CTX.<sup>662-666</sup> The indication and contraindication criteria for the
use of MCSDs in patients with CD can be the same applied to other etiologies.⁶⁶¹ Although RV systolic dysfunction is relatively common in patients with CCCD, especially in those who also have LV systolic dysfunction, there is no consensus regarding the choice of the most appropriate type of device in this condition.⁶⁶⁷

The first report of the successful use of MCSDs as bridge to CTX in a patient with CCCD occurred in 1994.⁶⁶² After that, in a noncontrolled phase I clinical trial, including six patients with advanced biventricular HF, Moreira et al. reported the successful use of left MCSD as bridge to CTX in only two cases.⁶⁶³

In developed countries, MCSDs have been implanted in immigrants with HF due to CD. Kransdorf *et al.* have reported the use of biventricular MCSD in two patients with CD from a cohort of patients undergoing CTX in the USA.⁶⁶⁴ Ruzza *et al.* have reported a successful case of total artificial heart as bridge to CTX in a patient with CCCD.⁶⁶⁵ In the Netherlands, a MCSD has been implanted as bridge to CTX in a patient with refractory HF due to CD.⁶⁶⁶ More recently, Atik *et al.* have reported another successful case of axial flow left MCSD used in a patient with CD and biventricular systolic dysfunction.⁶⁶⁷

Mechanical cardiac support is usually considered to have a high potential for success as bridge to CTX, recovery, decision-making, or permanent therapy in patients with CCCD. However, currently, the major limitations to its applicability are high cost, RV dysfunction, and need for a specialized team for device implantation and management. The SBC guideline on mechanical circulatory support recommends careful assessment of the RV function as mandatory before implantation, and, in the presence of moderate to severe dysfunction, one should be prepared for biventricular support implantation.⁶⁶¹

The major indices to assess RV dimensions and function are: RV longitudinal and radial contractility semiquantitative assessment; fractional area change; tricuspid annular plane systolic excursion (TAPSE) on M mode; lateral tricuspid annulus peak systolic velocity estimated by tissue Doppler (s'); and RV myocardial performance index. Left ventricular MCSD implantation should be considered with restrictions to patients with CCCD and significant RV dilation, moderate to severe tricuspid insufficiency, tricuspid annulus > 45 mm, and central venous pressure (CVP) > 15mmHg.⁶⁶¹ The hemodynamic parameters considered optimal regarding RV function and that would reduce the risk of RV dysfunction after implantation are: central venous pressure ≤ 8mmHg, pulmonary capillary pressure (PCP) ≤ 18mmHg, CVP/PCP ≤ 0.66, pulmonary vascular resistance < 2 UW, and RV work index ≥ 400mL/m².⁶⁶¹

# 11. Therapeutic Management of Cardiac Arrhythmias

## 11.1. Pharmacological Resources

### 11.1.1. Introduction

Medical literature related to arrhythmia treatment and sudden death prevention in CCCD is scarce and insufficient for the formulation of strong recommendations supported by evidence directly obtained from randomized studies

and that indisputably proves therapeutic efficacy (level of evidence A).¹,⁶⁶⁸ However, CCCD shares similarities with several extensively studied cardiopathies, particularly those with myocardial fibrosis and systolic dysfunction (global or segmental), such as ICM and DCM,⁶⁶⁹ allowing the therapeutic rationale to follow similar pathophysiological bases. Thus, the treatment and prevention of ventricular and supraventricular arrhythmias in CCCD tend to follow directions similar to those of the other cardiopathies.

However, some specific characteristics that can influence antiarrhythmic treatment are usually more striking in CCCD. Sinus node dysfunction, atrioventricular and intraventricular conduction disorders, and ventricular arrhythmias are frequently found in both asymptomatic and more advanced disease forms.⁶⁶⁹⁻⁶⁷² Despite the classical direct relationship between the degree of ventricular dysfunction and the higher frequency of ventricular arrhythmia, the prevalence of ventricular arrhythmias in CCCD is higher as compared to that in other cardiopathies.⁶⁷²,⁶⁷³

In addition, RV impairment,³⁴³ presence of intracardiac thrombi,⁶⁷⁴ and cardiac dysautonomia due to parasympathetic neuronal lesion²²² are more frequent in CCCD. All those factors could explain the shorter survival of patients with CCCD as compared to that of patients with cardiomyopathies of other etiologies and similar myocardial damage.⁶⁷⁵

Sinus node dysfunction and atrioventricular and intraventricular conduction disorders require more caution with the use of beta-blockers, digitalis, and amiodarone, because of the risk of excessive bradycardias and appearance or worsening of preexisting blockades.

In addition, ventricular tachyarrhythmias demand treatment with drugs frequently associated with severe side effects. Right ventricular impairment, present in 42% of the patients with LV dysfunction,³⁴³ tends to cause more systemic congestion, requiring higher doses of diuretics that can induce severe hypotolassemia, increasing the risk for global, sudden, and cardiovascular death.⁶⁷⁶ In this context, in addition to the routine use of aldosterone inhibitors (spironolactone/ eplerenone),⁶⁶⁰,⁶⁷⁷ oral supplementation with potassium, aimed to maintain its serum levels between 4.0 and 5.0mEq/L, might be necessary.

### 11.1.2. Sudden Death Prevention with Non-Antiarrhythmic Drugs

Sudden death, sometimes unexpected and affecting individuals with good functional capacity during exercise training, clearly predominates in outpatient subpopulations with CCCD.³⁵²,⁴⁰⁸ The RASSI score, developed in that subgroup of CCCD, stratifies the risk of total mortality, which includes the predominant occurrence of sudden death.⁴⁰⁸

However, many of those patients often have varied ventricular dysfunction degrees and clinically manifest HF. The optimized HF treatment in patients with CCCD is likely to result in a potential auxiliary benefit to prevent malignant ventricular arrhythmia and its most feared consequence, sudden death. This has not been specifically proven, and only a few studies on HF have included small samples of patients with HF due to CD.
# Guidelines

Thus, the use of some pharmacological treatments for CCCD complicated with HF, aimed at reducing sudden death, has been extrapolated from results obtained in patients with HF of other etiologies, assuming the existence of clinical and pathophysiological similarities between them.

Optimized dosages of ACEI or ARB, as well as of beta-blockers (carvedilol, bisoprolol, and metoprolol succinate) and spironolactone, should be aimed at for HF due to CD with that auxiliary antiarrhythmic perspective.⁶⁷⁸ For example, the MERIT-HF trial, comparing metoprolol succinate versus placebo for patients with HF and ejection fraction ≤ 40%, was early discontinued (after a mean 12-month follow-up) due to a 40%-60% reduction in overall mortality, in mortality from HF worsening, and in sudden death.⁶⁷⁹ Similar results have been observed with carvedilol and bisoprolol in patients with HFrEF.⁶⁸⁰,⁶⁸¹

It is worth noting that in the REMADHE observational study, beta-blockers were less often used for patients with CCCD than for those with other etiologies.⁶⁰⁵ In a small, but CCCD-specific study, carvedilol has been well tolerated and associated with a trend to increase LVEF.⁶⁸² More recently, in the PARADIGM-HF trial, in patients with HFrEF, sacubitril-valsartan significantly reduced the incidence of sudden death as compared to enalapril at a non-optimal dose in the group receiving ICD (51% reduction) and in that not undergoing ICD implantation (19% reduction).⁶⁸³ Thus, other recommendations from international guidelines might be applied to reduce total and sudden death in CCCD with HF.⁶⁸⁴

## 11.1.3. Ventricular Arrhythmias in Cardiopathies of Other Etiologies

Ventricular arrhythmias can occur in any cardiopathy and manifest as: monomorphic or polymorphic, isolated, bigeminy, trigeminy, and paired VE; NSVT or SVT, which can also be monomorphic or polymorphic. Ventricular arrhythmias can be asymptomatic and, in their most severe forms (SVT and VF), cause syncope, low output, and sudden death.

The prevalence of NSVT episodes on 24-hour Holter has ranged from 21% to 25% in the SCD-HeFT study, which assessed mortality of patients with HF of ischemic and nonischemic etiologies.⁶⁸⁵ The EMIAT study, assessing patients after myocardial infarction with LVEF < 40%, has reported prevalence of ventricular arrhythmia (defined as 10 or more VE/hour or NSVT on Holter) in 39% to 41% of the individuals.⁶⁸⁶ The GESICA study, in patients with severe HF of several etiologies, has reported high occurrence of VE > 10/hour (71%), paired VE (56%), and NSVT (33%) on Holter.⁶⁸⁷

## 11.1.4. Amiodarone for Patients with Cardiopathies of Other Etiologies: Primary Prevention

Amiodarone has the four antiarrhythmic effects of the Vaughan-Williams classification: sodium channel block (class I); noncompetitive alpha- and beta-adrenergic inhibition (class II); interference with potassium channels, leading to prolongation of the action potential, repolarization, and refractoriness (class III); and calcium channel block (class IV).

The use of amiodarone versus placebo, other antiarrhythmic drugs, or control group for the primary prevention of total mortality and sudden death has been assessed in several meta-analyses. In 1997, the ATMA study,⁶⁸⁸ using individual data of patients from eight RCTs after acute myocardial infarction (EMIAT, CAMIAT, GEMICA, PAT, SSSD, BASIS, Hockings et al., and CAMIAT-P) and five studies including patients with congestive HF (CHF-STAT, GESICA, EPAMSA, Nicklas et al., and Hamer et al.), showed a reduction of 13% in the risk of total death (p = 0.03) and of 29% in the risk of arrhythmogenic sudden death (p = 0.0003) with amiodarone. There was no excess of nonarrhythmic deaths with amiodarone, and both groups of patients (after acute myocardial infarction and congestive HF) benefited from the antiarrhythmic treatment.

In that same year, another meta-analysis,⁶⁸⁹ using Bayesian hierarchical modeling and data from the same 13 studies included in the ATMA trial in addition to two other studies (CASCADE and ASSG) involving survivors of cardiac arrest or SVT, concluded that amiodarone reduces all-cause mortality by approximately 19% (p < 0.01) and determines slightly higher reductions in cardiac mortality (23%, p < 0.001) and sudden death (30%, p < 0.001). There was a trend towards a higher reduction in the risk of death in the studies requiring evidence of frequent or complex ventricular ectopia as an inclusion criterion (25%) as compared to other studies (10%).

With the encouraging amiodarone results and the ICD emergence, the next most likely step would be comparison focused on random assignment of patients treated with amiodarone or ICD or placebo in primary prevention of death from any cause. This was the major objective of the SCD-HeFT study, published in 2005, including 2521 patients with ejection fraction ≤ 35%, NYHA functional class II or III, HF of ischemic origin in 52% of the patients and nonischemic in the remaining.⁶⁸⁵ After a median 45.5-month follow-up, total mortality was 29% in the placebo group, 28% in the amiodarone group, and 22% in the ICD group, that is, while amiodarone had no effect on total mortality as compared to placebo, the ICD therapy caused a 23% relative risk reduction (p = 0.007).

Based on pre-specified subgroup analysis, the results did not vary according to HF etiology, but varied according to NYHA functional class. Thus, in class III patients, an increase in mortality was observed with amiodarone (as compared to placebo), while no difference was observed between the ICD and placebo treatments. Despite the extremely significant (p < 0.001) interaction between ICD and functional class, the authors ignored these results and concluded that, in both classes (II and III), therapy with single-chamber ventricular ICD could reduce total mortality.

According to that same paradigm, all guidelines began to recommend ICD, prophylactically, in patients with ejection fraction ≤ 35% and NYHA functional class II and III. Despite the indisputable results of the SCD-HeFT study, two limitations apply. First, the inclusion criterion was ventricular dysfunction and not the recording of complex and frequent ventricular arrhythmia on Holter. Second, of all subgroup analyses, the most important one, from our viewpoint, comparing amiodarone to placebo in patients with recorded NSVT (22% of the study population), for unknown reasons, was not contemplated.
In the CHF-STAT study,⁶⁹⁰ randomizing 674 patients with HF (ejection fraction ≤ 40%) of ischemic and nonischemic etiology and at least 10 VE/hour on 24-hour Holter to receive amiodarone or placebo, after a median 45-month follow-up, amiodarone significantly reduced the ventricular arrhythmia frequency and improved ventricular function but could not increase survival.

In pre-specified subgroup analysis and based on randomization stratified according to HF etiology, there was a trend towards lower mortality with amiodarone in nonischemic patients (p = 0.07). At the time the SCD-HeFT study was published, the results of two small RCTs, EPAMSA (127 patients)⁶⁹¹ and AMIOVIRT (103 patients)⁶⁹² were known. The first compared amiodarone with a control group in patients with ischemic and nonischemic heart disease, ejection fraction < 35%, and Lown's grade 2 or 4 ventricular arrhythmia on Holter. The second compared amiodarone with ICD for exclusively nonischemic HF, ejection fraction ≤ 35%, and NSVT on Holter. In the Argentine pilot study EPAMSA, which included 24 patients with CCCD, after a 1-year follow-up, the reductions in total death and sudden death with amiodarone were 71% (p = 0.02) and 71% (p = 0.04), respectively.⁶⁹¹

In the AMIOVIRT study, early terminated because of the futility criterion, survivals after 1 year (90% versus 96%) and 3 years (88% versus 87%) did not statistically differ between the amiodarone and the ICD groups (p = 0.8), respectively.⁶⁹²

Positive results with amiodarone have also been observed in another Argentine study (GESICA),⁶⁸⁷ which included 516 patients with severe HF of ischemic and nonischemic etiology (48 patients with CCCD), mainly NYHA functional class III or IV, presenting at least two of the following three criteria: ventricular systolic dysfunction indices: CTI > 0.55; ejection fraction ≤ 35%; and LVDD ≥ 32 cm/m². Patients were randomized to an amiodarone or a control group. After a mean 13-month follow-up, total mortality was 41.4% in the control group and 33.5% in the amiodarone group, a relative risk reduction of 28% (p = 0.024). Patients were randomized according to the presence of NSVT on Holter on admission, which was observed in 33.5% of the entire population studied. The reduction in the risk of death with amiodarone occurred regardless of the presence of ventricular arrhythmia but was numerically higher in patients with recorded NSVT (34% versus 24.5%).

More recently, the long-term results of the SCD-HeFT study have been published.⁶⁹³ After a 11-year follow-up, the benefit of ICD as compared to placebo remained statistically significant, but attenuation of effect was observed, with relative reduction in the risk of death decreasing from 23% (after 45.5 months) to 13% (after 11 years, p = 0.028). In addition, there was a significant interaction between follow-up duration (less or more than 6 years) and benefit from ICD (p < 0.0015) and the subgroup analysis according to HF etiology showed heterogeneous long-term results. While the beneficial effect of ICD persisted in patients with ischemic HF (RRR 19%, p = 0.009), in those with nonischemic HF, a reduction in mortality with the use of ICD was no longer observed (RRR 3%, p = 0.802). Considering that, after the publication of the original trial, more than half of the patients assigned to the placebo or amiodarone group received an ICD or resynchronization therapy and that the recommended

statistical analysis was “intention to treat”, this crossover might have interfered with the results. However, these results did not change when the “as treated” analysis was used, comparing the groups according to the treatment received and not according to the initial assignment.

After the SCD-HeFT study publication, more meta-analyses were performed. The first meta-analysis⁶⁹⁴ identified 15 studies (only 1 of secondary prevention, OPTIC), with a total of 8522 patients randomized to amiodarone or placebo/ control. Amiodarone reduced the risk of sudden death by 29% (p < 0.001) and of cardiovascular death by 18% (p = 0.004). The reduction in the risk of all-cause mortality (13%) did not reach statistical significance (p = 0.093). Pre-specified subgroup analysis showed a 19% reduction in the risk of total death (95% CI, 2%-32%) with amiodarone doses > 200mg/day. However, doses ≤ 200mg/day were not effective (1% reduction; 95% CI, -31% to 25%). In addition, the use of amiodarone was associated with a two- and five-fold increase in the risk of pulmonary and thyroid toxicity, respectively. The authors concluded that amiodarone is a feasible alternative to prevent sudden cardiac death in ineligible patients or in those with no access to ICD therapy.⁶⁹⁴

Another systematic review with meta-analysis, following the Cochrane systematic review guidelines, was published in 2015⁶⁹⁵ and included 24 RCTs with a total of 9997 patients. The objective was to compare amiodarone versus placebo/ control or other antiarrhythmic drugs in primary (high-risk patients for sudden death) and secondary (survivors of cardiac arrest or patients with syncopal SVT) preventions.

In the studies of primary prevention (total of 18), amiodarone significantly reduced sudden, cardiovascular, and all-cause mortality, but the quality of the evidence was considered low (compared to placebo) or moderate (compared to other antiarrhythmic drugs). In the studies of secondary prevention (total of 6), no reduction in sudden and all-cause mortality was observed, and the quality of the evidence was considered low or very low.⁶⁹⁵

Based on those results: 1) it is reasonable to conclude that, as compared to placebo or control group or other antiarrhythmic drug, regarding primary prevention, amiodarone modestly reduces all-cause death, having a more expressive reducing effect on sudden death in patients with HF of both ischemic and mainly nonischemic etiology; 2) it is plausible to speculate that the beneficial effect of amiodarone is higher when NSVT and high ventricular arrhythmia density can be recorded on Holter, which seems to be highly relevant in the presence of ventricular dysfunction. Corroborating this assumption, a meta-analysis⁶⁹⁶ including 11 studies with patients with HF (ischemic and nonischemic) or nonischemic DCM associated with LV dysfunction has shown that the presence of NSVT on Holter is an independent predictor of sudden cardiac death (OR 3.03; 95% CI, 2.44-3.77); 3) the only RCT that compared directly amiodarone to ICD in primary prevention (AMIOVIRT)⁶⁹² has shown no superiority of ICD; however, that study was limited by its small sample size.

The SCD-HeFT study,⁶⁸⁵,⁶⁹³ although not comparing amiodarone to ICD, but each of them to placebo instead, did not require the presence of ventricular arrhythmia as an
inclusion criterion, did not perform subgroup analysis based on the presence of NSVT, and showed ICD benefit only for patients in NYHA functional class II (but not class III), a benefit that was maintained in the long run only for those with ischemic HF. All these aspects should be considered when attempting to extrapolate the SCD-HeFT study results to CCCD.

## 11.1.5. Amiodarone for Patients with Cardiopathies of Other Etiologies: Secondary Prevention

Secondary prevention of sudden death relates to patients who recovered from cardiac arrest due to VF or pulseless VT, or who already had at least one documented SVT episode. The other example of this group are patients with syncope of cardiac etiology, whose EPS showed induction of VF or hemodynamically unstable (or even stable according to some authors) SVT.

Sustained ventricular tachyarrhythmias have been typically grouped into a single category and collectively named "life-threatening" or "malignant". Although VF predictably precipitates cardiac arrest, unless if its duration is short and reverts spontaneously (a very rare and poorly documented event), SVT has a wide range of hemodynamic and clinical manifestations.

Thus, indiscriminate grouping of these arrhythmic entities should be avoided because they differ regarding their prognoses and treatments. The ventricular dysfunction degree (expressed by LVEF) and the symptoms associated with the arrhythmia and the type of structural cardiopathy should be considered during the patients' assessment.

The dichotomizing cutoff point for LVEF has usually been 35% or 40%, and a symptom grading has proposed four classes: I - no symptom or only palpitations; II - lipothymia, chest pain or dyspnea; III - syncope, altered mental state or other evidence of important hemodynamic impairment (signs and symptoms of low output, acute pulmonary edema); and IV - cardiac arrest (neither pulse nor breathing).⁶⁹⁷

It is very likely that the prognosis and treatment of a patient with ischemic heart disease, who recovered from cardiac arrest due to VF and with LVEF of 30%, differ from those of a patient with DCM, such as CCCD, hemodynamically stable SVT, relatively preserved LVEF, and palpitations.

Three RCTs (AVID, CIDS, and CASH)⁶⁹⁸⁻⁷⁰⁰ have compared amiodarone (or other antiarrhythmic drug) with ICD for secondary prevention of all cause death.

The AVID study,⁶⁹⁸ the first and largest of them, has assessed 1016 patients (81% with ischemic heart disease) who had been resuscitated from cardiac arrest due to VF (45% of the patients) or who had syncopal SVT (21%) or SVT, with LVEF ≤ 40% and symptoms suggestive of severe hemodynamic impairment (34%). The patients were randomized for therapy with ICD or antiarrhythmic drugs (amiodarone in 96% of the cases), had a mean age of 65 years, mean LVEF of 32% in the ICD group and 31% in the antiarrhythmic group, and 79% were of the male sex. After a mean 18.2-month follow-up, the study was early terminated because of the ICD superiority in reducing total death (15.8% versus 24%), with relative risk reductions of 39%, 27%, and 31%, after 1, 2, and 3 years of follow-up,

respectively (p < 0.02, adjusted to multiple analyses).

The Canadian Implantable Defibrillator Study (CIDS)⁶⁹⁹ has randomized 659 patients (83% with ischemic heart disease) for ICD or amiodarone, 48% of whom had survived cardiac arrest due to VF, 13% had syncopal SVT, 25% had SVT (HR ≥ 150 bpm), LVEF ≤ 35%, causing presyncope or angina, and 14% had syncope and SVT induced by programmed electrical stimulation. Their mean age was 64 years, mean LVEF was 34% in the ICD group and 33% in the amiodarone group, and 85% were of the male sex. After a mean 3-year follow-up, there was a nonsignificant reduction in the annual risk of total death (10.2% versus 8.3%, p = 0.142) and of arrhythmic death (4.5% versus 3.0%, p = 0.094) with ICD.

The smallest of the three studies, the CASH,⁷⁰⁰ was performed in the city of Hamburg, Germany, and compared ICD to different antiarrhythmic drugs (amiodarone, metoprolol, and propafenone). Differently from the previous trials, it included only patients resuscitated from cardiac arrest (due to VF, 84%, and due to VT, 16%). The propafenone arm (58 patients) was discontinued after a mean 11.3-month follow-up because of a mortality rate 61% higher than that observed in the ICD group. The other patients, total of 288 equally assigned to the ICD, amiodarone, and metoprolol groups, remained in the study. The mean age was 58 years, mean LVEF of 46%, 80% were of the male sex, and 73% had ischemic heart disease. In a mean 57-month follow-up, all-cause mortality was lower in the ICD arm as compared to the amiodarone/metoprolol arm (36.4% versus 44.4%), although the difference did not reach statistical significance (1-sided p = 0.08).

The early termination of the AVID study, which could have overestimated the benefit of ICD, in addition to the smaller number of patients enrolled in the CIDS and CASH studies, which could have reduced the power of the statistical tests to detect a real benefit of the ICD treatment, have motivated the conduction of a meta-analysis comparing ICD exclusively with amiodarone.⁷⁰¹ Individual patient data from the three studies were merged into a master database according to a pre-specified protocol and the results were published in 2000. The meta-analysis included 1866 patients (ICD = 934; amiodarone = 932) with mean age of 63.5 years, mean LVEF of 33.5%, most of them of the male sex (81.5%) and diagnosed with ischemic heart disease (82%). The estimates of ICD benefit from the three studies were consistent with each other (p heterogeneity = 0.306). There was a 28% relative risk reduction in death from any cause (HR = 0.72; 95% CI, 0.60-0.87; p = 0.0006) and a 50% reduction in arrhythmic death (HR = 0.50; 95% CI, 0.37-0.67; p < 0.0001) with the ICD, reflecting a mean survival gain of 4.4 months after a mean 6-year follow-up.

However, in the subgroup analysis, the benefit related to survival increase with ICD was observed only in patients with LVEF ≤ 35% (HR = 0.66) and not in those with LVEF > 35% (HR = 1.2; p, interaction = 0.01). Although the use of beta-blockers was higher in the ICD group (42% versus 19%) and the benefit of ICD therapy also higher in those on beta-blockers (HR = 0.58 versus HR = 0.88), this difference was not statistically significant (p, interaction = 0.095).⁷⁰¹
Based on the results from those RCTs,⁶⁹⁸-⁷⁰⁰ their meta-analysis,⁷⁰¹ and some observational studies,⁷⁰² the major international guidelines⁶⁸⁴,⁷⁰³ began to strongly recommend therapy with ICD to all patients resuscitated from cardiac arrest due to VF or VT, as well as to all patients with structural cardiopathy and SVT, regardless of the LVEF and the presence and type of arrhythmia-related symptoms, except, obviously, for the cases of arrhythmias due to probably secondary or reversible causes, such as electrolytic disorders, myocardial ischemia, and proarrhythmia, or individuals with life expectancy shorter than 1 year.

It is worth noting that none of those three RCTs included patients with hemodynamically stable or well-tolerated SVT and the analysis of the subgroups of the previously mentioned meta-analysis showed no benefit of ICD as compared to amiodarone in patients with LVEF > 35%. In addition, according to these guidelines (potentially biased when generalizing, despite the evidence of problems with the analyses of the results), only when ICD therapy is unavailable or contraindicated or refused by the patient, amiodarone could be used in an attempt to reduce sudden death (class IIb).⁶⁸⁴,⁷⁰³

### 11.1.6. Ventricular Arrhythmias in Patients with Chronic Cardiomyopathy of Chagas Disease: Characteristics and Treatment

As already mentioned, although more commonly found in more advanced phases of CCCD, ventricular arrhythmias can occur at the early disease stages and even in the absence of significant global systolic ventricular function impairment.⁶⁷²

#### 11.1.6.1. Ventricular Extrasystoles

Ventricular extrasystoles are present in 86% to 88% of the patients with CCCD without HF (functional classes I and II) and in almost all patients with HF (functional classes III and IV) on 24-hour Holter.⁶⁷²,⁷⁰⁴ The density of VE is also elevated, so that 45% and 89% of the patients without and with HF, respectively, have more than 1000 VE/h on Holter.⁶⁷²

When VEs occur in asymptomatic patients with preserved ventricular function, they require no treatment. However, in asymptomatic patients with high arrhythmia density (> 16-20% of VE on 24-hour Holter), tachycardiomyopathy may develop,⁷⁰⁵ that is, ventricular systolic dysfunction caused or worsened by the arrhythmia, which can be attenuated or reversed with suppression of the VEs, and, thus, survival may be increased.⁷⁰⁶

When the VEs are very symptomatic, even in the absence of ventricular dysfunction or late enhancement (fibrosis) on CMRI, the use of antiarrhythmic drugs is mandatory, but should be individualized, and amiodarone should be avoided at first, because of its adverse effects. In this situation, the use of a beta-blocker (e.g., nadolol or sotalol) or propafenone is suggested. However, in the presence of ventricular dysfunction or arrhythmogenic substrate of fibrosis on CMRI, class I antiarrhythmic drugs should not be used, because of their proarrhythmic effects and occasional negative inotropic effect, which could increase mortality, as described for other

cardiopathies.⁷⁰⁷ Thus, amiodarone can be indicated, at the dosage of 200 to 600 mg/day, because of its high efficacy in significantly reducing the VE density.⁷⁰⁸

#### 11.1.6.2. Nonsustained Ventricular Tachycardia

Nonsustained ventricular tachycardia affects 42% of the patients with CCCD without HF and 89% of those with HF,⁶⁷² a prevalence much higher than that in other cardiopathies. It can be observed even in patients with normal ventricular function and its detection on Holter or during exercise testing is an independent marker of poor prognosis.⁴⁰⁸,⁴³⁶,⁴⁵⁸ When associated with LV dysfunction (global or segmental), a relatively common finding in CCCD, it increases the risk of death by 15 times as compared to that of patients without NSVT and with normal ventricular function.⁴⁵⁸ In the absence of data to assess relevant outcomes, such as mortality and hospitalization, a meta-analysis of old studies with amiodarone in CCCD has shown an important reduction in the ventricular arrhythmia density on serial Holter records (93% of isolated VEs, 79% of paired ones, and 100% of the VT episodes).⁷⁰⁸

As already mentioned, the Argentine RCTs GESICA⁶⁸⁷ and EPAMSA,⁶⁹¹ including patients with CCCD, have shown a reduction in mortality with amiodarone. However, the small number of individuals with CCCD in those two studies (only 72) hinders a definitive conclusion. Thus, how to manage patients with NSVT? In the absence of ventricular dysfunction, the pharmacological treatment should follow, in general, the same recommendation for the treatment of VEs. When ventricular dysfunction is present, three options are available: beta-blocker, amiodarone, and ICD, which is discussed ahead.

The treatment should be aimed at relieving symptoms (when present), improving ventricular function, and preventing sudden death. Because there are no convincing data derived from RCT to support any of those three options, the recommendations for the treatment of those patients are based on extrapolation of the results from the studies performed in other heart diseases and on CCCD-related observational data, which are limited.

After a thorough analysis of the literature, we chose to preferably indicate a selective beta-blocker (metoprolol succinate, carvedilol, or bisoprolol), either associated or not with amiodarone, a decision that should be tailored to the patients' needs and shared with them.

#### 11.1.6.3. Sustained Ventricular Tachycardia and Ventricular Fibrillation

Although the prevalence of sustained ventricular arrhythmias is not widely known, patients with CCCD, regardless of the ventricular function, can have monomorphic SVT, polymorphic SVT (torsades de pointes), and VF, which should be timely reversed in the emergency room. Amiodarone is the best drug option in cases of stable SVT and refractory or recurrent VF.

In the presence of hemodynamic instability, immediate electrical cardioversion is recommended, according to the protocol of Advanced Cardiovascular Life Support (ACLS). In case of immediate relapse (“electrical storm”), administration of antiarrhythmic drugs (preferably amiodarone) should be
# Guidelines

considered, with proper oxygen support, cardiac monitoring, and correction of possible electrolyte disorders.

According to the ACLS protocol, two drugs are indicated for the treatment of sustained ventricular arrhythmias in the emergency room, amiodarone and procainamide, both by the intravenous route. The dosages recommended are shown in Chart 11.1.

It is worth noting that the intravenous administration of amiodarone can cause phlebitis and arterial hypotension, reduce sinus rate, increase the duration of the QRS complex and of the QT interval, increase atrioventricular node refractoriness, reduce the HR (slow down) of the SVT, and improve the ICD defibrillation threshold.

Procainamide can increase the PR interval, the QRS complex duration, and the ICD defibrillation threshold. In addition, it can cause arterial hypotension and LVEF reduction, diarrhea and nausea, and trigger symptoms and signs of the lupus erythematosus syndrome.

Other antiarrhythmic drugs of intravenous administration, such as lidocaine, verapamil, beta-blockers (metoprolol, esmolol, or propranolol), and sotalol have low efficacy in reversing sustained ventricular tachyarrhythmias and should be avoided in CCCD or used only as secondary options in a few contexts.

Once sustained ventricular tachyarrhythmia is controlled or the cardiac arrest is reversed, the subsequent treatment is aimed at preventing relapse and, mainly, sudden death. Despite the high prevalence of CCCD in Latin America and the high fatality rate from those arrhythmias, there is no properly controlled RCT with proper sampling to finally clarify which is the best management to be adopted in each case. Regarding such management, some of the major options are the use of amiodarone, ICD implantation, catheter ablation, or an association of these therapies. The choice for the best option is based either on the results of observational studies or reports on CCCD records, which are very heterogeneous and conflicting, or still on data extrapolated from RCTs or guidelines on other cardiopathies, which have some inconsistencies and might not be applied to CCCD because of its peculiarities.

Thus, the strategy "One-size fits all: what's good for the gander is good for the goose", that is, ICD for all patients as the ideal therapy to prevent sudden death, seems not to be the most appropriate in CCCD. Obviously, when we talk about sudden death prevention, we are actually referring to all-cause

death, because sometimes one cannot distinguish the exact mechanism of death (adjudication error might exist), and there is no use in a treatment that prevents sudden death without reducing total mortality, because it would be only modifying the mode of death.

It is worth noting that, as compared to ischemic and nonischemic heart diseases of other etiologies, patients with CCCD treated with ICD for secondary prevention tend to have higher LVEF, higher spontaneous ventricular arrhythmia density and complexity, higher number of both appropriate (shock and antitachycardia therapy) and inappropriate ICD therapies, shorter time for the first appropriate shock after implantation, most frequent electrical storms, and shorter survival free from ICD therapy, factors that can influence the choice of treatment. Regardless of the type of heart disease, LVEF is the major factor to determine the prognosis and selection of the most suitable therapy.

Because of its high antiarrhythmic efficacy, low incidence of proarrhythmia and of intolerable side effects, mainly when used at lower dosages, in addition to its good safety profile, even when administered to patients with ventricular dysfunction, amiodarone (introduced in Brazil more than four decades ago) is considered the first choice for the treatment of patients with CCCD and high-risk ventricular arrhythmias.

Rassi Jr et al.³⁵² were the first to study the impact of antiarrhythmic drug treatment on the evolution of patients with CCCD. They have analyzed the survival curve of 34 patients with monomorphic SVT empirically treated with amiodarone, isolated or in association with other antiarrhythmic drugs, and compared it with the curve of another cohort of 42 patients not treated or treated with procainamide or quinidine, the only drugs available then. Those authors have reported a significantly higher survival in the group treated with amiodarone. After 1, 4, and 8 years of follow-up, survivals were 87%, 65%, and 59%, respectively, for the group treated with amiodarone, and 57%, 22%, and 7%, respectively, for the group not treated or treated with those class I antiarrhythmics (p < 0.01).

Scanavacca et al.⁷⁰⁹ have also reported long-term results with the empirical use of amiodarone in Brazil in a cohort of 35 patients with CCCD and sustained ventricular tachyarrhythmia (resuscitated from cardiac arrest = 8.5%; SVT with syncope or presyncope = 77%; SVT with well-tolerated tachycardic palpitations = 14.5%). The mean age was 50 years, mean LVEF was 41%, 68.5% of the patients were of the male sex,

<table><caption>Chart 11.1 – Treatment of sustained ventricular arrhythmias in the emergency room.</caption><tr><td><strong>AMIODARONE</strong><br>(1 ampoule = 150mg)</td><td><strong>Stable SVT:</strong><br>1 ampoule IV for 10 minutes, can be repeated in case of no reversion. Intravenous administration of 1mg/min for 6 hours followed by 0.5mg/min IV in the subsequent 18 hours can be performed to stabilize ventricular arrhythmia.<br><br><strong>Cardiac arrest due to refractory VF/pulseless VT:</strong><br>2 ampoules (300mg) IV in bolus after the third shock and 1 more ampoule (150mg) IV in case of no success after the fifth shock.</td></tr><tr><td><strong>PROCAINAMIDE</strong><br>(1 ampoule = 500mg)</td><td><strong>Stable SVT:</strong><br>Attack dose: 10-17mg/kg (20-50mg/min) IV<br>Maintenance dose: 1-4mg/min IV</td></tr></table>
and 86% were in functional class I/II. After 27 months, the probabilities of SVT recurrence were 38%, 44%, and 56% in the 1-year, 2-year, and 3-year follow-up, respectively. The cardiac mortality rates were 4%, 11%, and 18%, and the sudden death rates were 0%, 4%, and 11% in the 1-year, 2-year, and 3-year follow-up, respectively. It is worth noting that all patients in functional class III or IV and with LVEF < 30% had SVT recurrence, and the cardiac mortality in that group was 80%. However, only 30% of the patients in NYHA functional class I/II and with LVEF > 30% had recurrence of SVT (p < 0.05) and none died. The mean dose of amiodarone, by the end of the study, was 356 mg/day and 15 (43%) patients reported side effects.

Leite et al.⁴⁸¹ have assessed the role of programmed ventricular stimulation to predict the long-term efficacy of class III antiarrhythmics. Those authors have studied 115 patients with CCCD and sustained ventricular tachyarrhythmia (recurrent SVT with syncope or presyncope = 54%; NSVT with syncope or presyncope and induction of SVT on EPS = 32%; and hemodynamically stable SVT with tolerable symptoms=14%). Mean age was 52 years, mean LVEF was 49%, 60% of the patients were of the male sex, and 83% were in functional class I/II. Based on the EPS results, after loading with amiodarone (78 patients) or sotalol (37 patients), the patients were divided into three groups: group 1 – no SVT induction (20%); group 2 – hemodynamically stable SVT induction (39%); and group 3 – hemodynamically unstable SVT induction (41%).

After a mean 52-month follow-up, total mortality was 39.1% (9%/year), significantly higher in group 3 than in groups 2 and 1 (69%, 22.2%, and 26%, respectively, p < 0.0001). The SVT recurrence was significantly smaller in group 1 than in groups 2 and 3 (39.1%, 62.2%, and 74.5%, respectively, p = 0.005). Thus, in patients with SVT and relatively preserved LVEF treated with class III antiarrhythmics, EPS apparently identifies those at lower risk of death who could remain on drug treatment. However, for those with worse prognosis, ICD could be an a more appropriate option based on those observations.⁴⁸¹

Sarabanda et al.⁷¹⁰ studying the predictors of mortality in 56 patients with CCCD and VT (SVT in 28 and NSVT in 28), have identified only LVEF as an independent marker of poor prognosis: LVEF < 40% increases the risk of death by 12 times (p = 0.0001). The most accurate cutoff points for sudden death and total death were LVEF of 40% and 38%, respectively. In the 28 patients with SVT, all empirically treated with amiodarone (when ICD implantation was not available), mean age was 54 years, mean LVEF was 42%, 64% were of the male sex, 100% were in functional class I/II, 43% had history of syncope, and the survival rates after 1 and 3 years of follow-up were 85% and 67%, respectively.

### 11.1.7. Care During the Use of Amiodarone

Adverse effects with amiodarone include corneal microdeposits, sinus bradycardia, AVB, QT interval prolongation, dermatologic effects (photosensitivity and blue skin discoloration), thyroid dysfunction (hypothyroidism, most frequent, or hyperthyroidism), pulmonary toxicity, and, less

commonly, hepatotoxicity. Late neurological side effects, such as tremors, paresthesia, and ataxia can occur.⁷¹¹

Pulmonary toxicity is the most severe and potentially fatal complication of amiodarone. Pulmonary impairment secondary to amiodarone manifests as interstitial pneumonia (most frequent) or eosinophilic pneumonia, organized pneumonitis, acute respiratory failure, or diffuse alveolar hemorrhage. The initial symptoms are dyspnea and dry cough, with or without fever. The chest X-ray shows diffuse or localized, reticular or consolidated opacities. Chest tomography shows interstitial impairment and bilateral diffuse opacities.

The first reports on pulmonary toxicity indicated a prevalence ranging from 5% to 15% when maintenance doses ≥ 400mg/day were regularly administered. Currently, with the reduction of the dose to 200mg/day, the incidence ranges from 1% to 5%. The most important risk factors for pulmonary toxicity are, in addition to the high daily doses of amiodarone (≥ 400mg), higher cumulative doses (long periods of administration), previous pulmonary disease, thoracic surgery, and pulmonary angiography.

In a meta-analysis with four studies involving a total of 1465 patients, there was no significant difference in the occurrence of pulmonary toxicity in patients receiving amiodarone at a low dose (defined as 150-330 mg/day) as compared to placebo.⁷¹²

In another meta-analysis with 43 studies and 11 395 patients, the relative risk for adverse pulmonary events secondary to the use of amiodarone was 1.77, at doses ≥ 300 mg/day and clinical follow-up > 12 months. Doses lower than 300 mg/day were not associated with the increased incidence of pulmonary complications as compared to placebo.⁷¹³

In another study, however, even doses lower than 200 mg/day were associated with an increase in pulmonary alterations. Thus, patients on amiodarone should receive the lowest effective dose and undergo clinical and laboratory monitoring periodically and systematically.⁷¹⁴

The initial oral doses of amiodarone for individuals on outpatient care should range from 400 to 600mg/day, until the cumulative attack dose of 6-10 grams is achieved. For in-hospital patients, the attack doses can range from 400 to 1200 mg/day. Maintenance should be individualized, and the lowest effective dose determined.

Table 11.1 summarizes the recommendations for clinical and laboratory monitoring of patients on amiodarone.

### 11.1.8. Prevention of Electrical Shock Recurrence in Patients Treated with Implantable Cardioverter-Defibrillator

In individuals with ICD, multiple shocks, either appropriate or not, and electrical storms are common in CCCD and affect the patient's prognosis and quality of life. An observational study has reported the evolution of 89 patients with CCCD and ICD, most of whom due to secondary prevention, for a mean 12-month period.⁷¹⁵ In that short follow-up, 42% of the patients received appropriate shocks and 15.7% experienced electrical storms, numbers much higher than those of individuals with ICD and other heart diseases (appropriate shocks in 8.4% and 12.1% of the cases of primary
<table><caption>Table 11.1 – Recommendations for clinical and laboratory monitoring of patients on amiodarone.</caption><thead><tr><td>System/Organ</td><td>Test/examination</td><td>Follow-up</td><td>Adverse effects</td><td>Recommendation</td></tr></thead><tbody><tr><td>Cardiovascular</td><td>ECG</td><td>Biannual</td><td>AVB, TdP</td><td>Reduce or stop</td></tr><tr><td>Dermatological</td><td>Ectoscopy</td><td>When necessary</td><td>Photosensitivity</td><td>Avoid sun exposure</td></tr><tr><td>Endocrine</td><td>Free T4 / TSH</td><td>Biannual</td><td>Hypo/Hyperthyroidism</td><td>Endocrine treatment</td></tr><tr><td>Liver</td><td>AST / ALT</td><td>Biannual</td><td>Elevation > 3x</td><td>Reduce or stop</td></tr><tr><td>Neurological</td><td>Physical examination</td><td>When necessary</td><td>Tremors and ataxia</td><td>Reduce or stop</td></tr><tr><td>Ophthalmic</td><td>Ophthalmic examination</td><td>When necessary</td><td>Corneal micro deposits<br>Optical neuropathy</td><td>Ophthalmic guidance</td></tr><tr><td>Pulmonary</td><td>CXR / CT / CMDCT</td><td>In the presence of cough or dyspnea</td><td>Pulmonary toxicity</td><td>Suspend amiodarone<br>Use corticosteroid</td></tr></tbody></table>

AVB: atrioventricular block; CMDCT: carbon monoxide diffusion capacity test; CXR: chest X-ray; CT: computed tomography of the lungs; TdP: torsades de pointes with increased QT interval.

and secondary prevention, respectively). The mean LVEF of patients with CCCD treated with an ICD was 40 ± 11%, indicating that a significant part of that subpopulation did not have severe ventricular systolic dysfunction.⁷¹⁵

The association of amiodarone with beta-blockers (preferably propranolol, nadolol or atenolol, in case of satisfactory ventricular function, and metoprolol or carvedilol, in case of poor ventricular function) is considered to have the highest potential to reduce arrhythmic death and the number of both appropriate and inappropriate electrical shocks delivered by the ICD.⁷¹⁶ The OPTIC study, which has not included patients with CCCD, has shown the superiority of the association of amiodarone and beta-blockers to prevent shocks as compared to sotalol or any other beta-blocker used in isolation.⁷¹⁶ Empirically, that pharmacological association can be indicated to prevent the recurrence of shocks in patients with ICD and CCCD.

The recommendations for the pharmacological management of cardiac arrhythmias and sudden death prevention in CCCD are shown in Table 11.2 and Figure 11.1.

## 11.1.9. Pharmacological Treatment of Atrial Fibrillation in Chronic Cardiomyopathy of Chagas Disease

Atrial fibrillation and HF frequently coexist. According to the Framingham Heart Study, approximately 40% of the patients with AF develop HF and vice-versa.⁷¹⁷ In HFrEF, the prevalence of AF increases with the functional class (NYHA) aggravation, ranging from 4.2% in class I to 49.8% in class IV.⁷¹⁸ The appearance of AF associates with increased all-cause mortality in patients with HF of any etiology, including CCCD.

The prevalence of AF in CCCD is increased as compared to that in the general population. A meta-analysis of 49 studies, including 34 023 patients, has revealed that the prevalence of AF in CCCD was twice that in the general population.⁷¹⁹ However, the prevalence of AF in CCCD does not seem to be higher than that in other structural cardiomyopathies.⁷²⁰

The pharmacological treatment of AF in CCCD is hindered by systolic biventricular dysfunction, as well as by electrical automatism and dromotropism disturbances. Thus,

optimization of the HF therapy is mandatory, and the use of ACEI or ARB in HFrEF can reduce the incidence of AF.⁷²¹

### 11.1.10. Treatment in the Emergency Room

The initial management of patients admitted to the emergency room with AF of high ventricular response is to control HR and anticoagulation with proper medications. Then, indication for arrhythmia reversion should be assessed.

The ventricular rate of AF in patients with CCCD is often low, but, if hemodynamic instability with tachycardia occurs, the most appropriate management can be immediate anticoagulation, followed by electrical cardioversion. Symptomatic, but stable, patients with AF for less than 48 hours, without mural thrombi detectable on transesophageal ECHO, can undergo cardioversion with propafenone or amiodarone. Patients with AF duration ≥ 48 hours or unknown, or refractory AF history, should initially undergo anticoagulation and be medicated for HR control. Asymptomatic patients and/or with low HR and those with intense atrial dilatation usually should be only anticoagulated.⁷²²

### 11.1.11. Outpatient Treatment

#### 11.1.11.1. Reversion to Sinus Rhythm

The strategy of AF reversion is usually more appropriate when AF is of recent onset, occurs in younger patients, is very symptomatic, with little atrial dilatation and high ventricular response. When HF develops or worsens, rhythm reversion with amiodarone or even catheter ablation might be necessary.⁷²³ Amiodarone can be especially indicated when, in addition to AF, patients with CCCD have ventricular arrhythmias, which is usually observed.

#### 11.1.11.2. Heart Rate Control

The chronotropic control strategy, without reversion to sinus rhythm, is usually more indicated in the presence of long-duration AF or large dilatation of the chambers and in very old patients with multiple comorbidities and recurrence
<table><caption>Table 11.2 – Recommendations for pharmacological management of cardiac arrhythmias and prevention of sudden death in CCCD</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>Optimized treatment of HF according to the recommendations of this guideline for prevention of arrhythmias and sudden death in CCCD</td><td>Strong</td><td>B</td></tr><tr><td>Appropriate doses of ACEI, beta-blockers, and mineralocorticoid receptor antagonists for patients with HF and EF ≤ 40% to reduce total and sudden death</td><td>Strong</td><td>B</td></tr><tr><td>Association of beta-blockers, mineralocorticoid receptor antagonists, and sacubitril-valsartan in patients with HF and EF ≤ 40% to reduce total and sudden death</td><td>Conditional</td><td>B</td></tr><tr><td>Correction of hypopotassemia during treatment of ventricular arrhythmias</td><td>Strong</td><td>C</td></tr><tr><td>Beta-blockers (metoprolol succinate, carvedilol, or bisoprolol) either associated or not with amiodarone to treat patients with symptomatic NSVT and EF ≤ 40%</td><td>Strong</td><td>B</td></tr><tr><td>Beta-blockers (metoprolol succinate, carvedilol, or bisoprolol) either associated or not with amiodarone to treat patients with asymptomatic NSVT and EF ≤ 40%</td><td>Conditional</td><td>C</td></tr><tr><td>Beta-blockers, sotalol, propafenone, and amiodarone (refractory cases) in the treatment of very frequent asymptomatic VEs (&gt; 16-20% of beats on 24-h Holter), the first 3 in the absence of AV conduction disorders, ventricular dysfunction, segmental changes, or myocardial fibrosis detected on CMRI</td><td>Conditional</td><td>C</td></tr><tr><td>Beta-blockers, sotalol, propafenone, and amiodarone (refractory cases) in the treatment of symptomatic VEs, the first 3 in the absence of AV conduction disorders, ventricular dysfunction, segmental changes, or myocardial fibrosis detected on CMRI</td><td>Strong</td><td>C</td></tr><tr><td>Amiodarone in the treatment of hemodynamically stable SVT with EF &gt; 40%</td><td>Conditional</td><td>B</td></tr><tr><td>Amiodarone in the treatment of SVT with syncope and EF &gt; 40%</td><td>Conditional</td><td>B</td></tr><tr><td>Amiodarone in the treatment of patients with syncope, monomorphic SVT induced on EPS, and EF &gt; 40%</td><td>Conditional</td><td>B</td></tr><tr><td>Amiodarone in the treatment of spontaneous SVT or symptomatic NSVT with SVT induction on EPS and posterior non-induction of SVT after impregnation with antiarrhythmic drugs (amiodarone or sotalol)</td><td>Conditional</td><td>B</td></tr><tr><td>Amiodarone for patients with strong recommendation for ICD, but with limited life expectancy or no access to the device</td><td>Conditional</td><td>C</td></tr><tr><td>When used empirically, amiodarone should be administered at the lowest effective dose, and the patients should undergo periodical clinical and laboratory control for assessment of adverse effects</td><td>Strong</td><td>B</td></tr><tr><td>Patients with asymptomatic VEs and preserved left ventricular systolic function require no antiarrhythmic treatment</td><td>Strong</td><td>C</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; ACEI: angiotensin-converting-enzyme inhibitor; EF: ejection fraction; HF: heart failure; NSVT: nonsustained ventricular tachycardia; CMRI: cardiac magnetic resonance imaging; AV: atrioventricular; VE: ventricular extrasystole; SVT: sustained ventricular tachycardia; ICD: implantable cardioverter-defibrillator.

<figure><img src="image_11.png" /><figcaption>Figure 11.1 – Algorithm for the management of patients with CCCD and NSVT. CCCD: chronic cardiomyopathy of Chagas disease; NSVT: nonsustained ventricular tachycardia; LV: left ventricular; VE: ventricular extrasystole; BB: beta-blocker.</figcaption></figure>
# Guidelines

of arrhythmia. When beta-blockers are not sufficient to control ventricular response, the addition of digoxin can be considered. It is worth noting that calcium channel blockers are contraindicated in patients with HFrEF. Amiodarone can be occasionally used for chronotropic control when beta-blockers and calcium channel blockers are contraindicated, and catheter ablation is not possible.⁷²²

The recommendations for the pharmacological treatment of AF in CCCD are shown in Table 11.3.

## 11.2. Pacemaker, Cardioverter-Defibrillator, and Cardiac Resynchronization Therapy

### 11.2.1. Artificial Cardiac Pacemaker

The inflammatory processes, necrosis and fibrotic reaction, that follow the severe disorganization of myocardial architecture and structure in CCCD affect not only the contractile fibers, but also the autonomic nervous system and the tissue that generates and conducts the electrical impulse in the heart.⁷²⁴,⁷²⁵

Sinus node dysfunction occurs early in CCCD. The sinus node replacement with fibrotic reaction determines different expressions of the sinus node disease, its most frequent manifestation being sinus bradycardia. In addition, CCCD causes intraventricular blocks, of which isolated or LAFB-associated RBBB predominates.⁷²⁴,⁷²⁶ All degrees of AVB are commonly found and can be asymptomatic or cause lipothymia, syncope, and even HF or sudden death.⁷²⁷ According to the Brazilian Pacemaker Registry, CCCD is the first cause of AVB in Latin America, accounting for approximately 25% of PM indications.⁷²⁸

The prevalence of the PM use in patients with CCCD has been reported in a few cohorts, with rates ranging from 3.5% to 14.1%.³³⁰ Sinus node disease and TAVB are the bradyarrhythmias most commonly treated with PM implantation in patients with CCCD.⁷²⁹,⁷³⁰ The indication of

PM implantation for patients with TAVB due to CD, since its beginning in the 1970s, can be considered as obeying the extreme plausibility principle. In fact, the evidence of the clear benefit of PM implantation consists solely in the observational study historically comparing the survival curves of 147 patients followed up before the PM appearance (survival of only 70%, 37%, and 6% after 1, 5, and 10 years of follow-up, respectively) with those of 74 patients followed up after the PM appearance (significantly higher survival of 86%, 57%, and 44% after 1, 5, and 10 years of follow-up, respectively, p < 0.05).³⁵²

Few studies have reported on the anthropometric and epidemiological characteristics or mortality predictors of patients with CCDC and a PM. A prospective cohort study published in 2018 included 396 patients with a PM followed up for, at least, 24 months. Their mean age was 62.5 ± 12.0 years, and most were of the female sex (64%). Approximately 95% of the patients were in NYHA functional class I or II. Approximately 75% had advanced AVB as the indication for PM implantation, and RV stimulation occurred in 82.2% of the cases. The annual mortality rate was 8.4%.⁷³¹

It is worth noting the potential protective role of avoiding unnecessary ventricular stimulation and of considering the indication for direct stimulation of the conduction system, which is a more physiological modality, but that has not been properly tested in CCCD.⁷³²⁻⁷³⁶

In general, the indications for PM implantation in CCCD do not differ from the classical ones applied to heart diseases of other etiologies.¹³,⁷³⁷ Tables 11.4, 11.5, and 11.6 show the criteria used for PM implantation.

### 11.2.2. Implantable Cardioverter-Defibrillator in CCCD

#### 11.2.2.1. Primary Prevention of Sudden Cardiac Death

The success of primary prevention of sudden cardiac death relates to the identification of individuals at high risk for the event. The risk stratification of total mortality, which is mainly

<table><caption>Table 11.3 – Pharmacological treatment of atrial fibrillation in CCCD</caption><thead><tr><td>Summary of recommendations</td><td>Antiarrhythmic drugs</td><td>Recommendation grade</td><td>Level of evidence</td></tr></thead><tbody><tr><td>Reversion of AF of recent onset in patients without evidence of structural or functional cardiac abnormalities</td><td>Propafenone (or other group I drugs)</td><td>Strong</td><td>B</td></tr><tr><td>Reversion of AF of recent onset but with structural and/or functional cardiac abnormalities</td><td>Amiodarone</td><td>Strong</td><td>B</td></tr><tr><td>Maintenance of sinus rhythm after reversion of persistent AF or in paroxysmal AF in the absence of evidence of cardiac abnormalities</td><td>Propafenone (or other group I drugs)</td><td>Conditional</td><td>B</td></tr><tr><td>Maintenance of sinus rhythm after reversion of persistent AF or in paroxysmal AF with structural and/or functional cardiac abnormalities</td><td>Amiodarone</td><td>Conditional</td><td>B</td></tr><tr><td>Control of HR in AF with or without HF as long as there is no contraindication</td><td>Do not use propafenone (or other group I drugs)</td><td>Strong</td><td>B</td></tr><tr><td>Control of HR in symptomatic patients with high HR, who cannot undergo catheter ablation and to whom beta-blockers and calcium-channel blockers are contraindicated</td><td>Beta-blockers</td><td>Strong</td><td>B</td></tr><tr><td></td><td>Amiodarone</td><td>Conditional</td><td>B</td></tr><tr><td></td><td>Digoxin</td><td>Strong</td><td>B</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; AF: atrial fibrillation, HR: heart rate; HF: heart failure.
<table><caption>**Table 11.4 – Indications for pacemaker implantation in CCCD: sinus node dysfunction**</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>Spontaneous and irreversible SND with syncope, presyncope, dizziness, or HF clearly related to sinus bradycardia (&lt; 40 bpm) or sinus pauses &gt; 3.0s during vigil</td><td>Strong</td><td>C</td></tr><tr><td>SND induced by essential drugs with syncope, presyncope, dizziness, or HF clearly related to bradycardia (&lt; 40 bpm) or sinus pauses &gt; 3.0s during vigil</td><td>Strong</td><td>C</td></tr><tr><td>SND with symptoms of LCF clearly related to chronotropic incompetence</td><td>Strong</td><td>C</td></tr><tr><td>Bradycardia-tachycardia syndrome with no indication for catheter ablation or patient's refusal</td><td>Strong</td><td>C</td></tr><tr><td>Sinus pause &gt; 6.0s in a patient with LCF symptoms</td><td>Strong</td><td>C</td></tr><tr><td>Spontaneous and irreversible SND in patients with syncope, presyncope, or dizziness probably related to bradycardia, but whose association has not been clearly documented</td><td>Conditional</td><td>C</td></tr><tr><td>SND induced by essential drugs in patients with syncope, presyncope, or dizziness probably related to bradycardia, whose association has not been clearly documented</td><td>Conditional</td><td>C</td></tr><tr><td>Sinus bradyarrhythmia that triggers or aggravates HF, angina pectoris, or tachyarrhythmias</td><td>Conditional</td><td>C</td></tr><tr><td>Bradycardia (HR &lt; 40 bpm) during vigil with mild symptoms, not definitely associated with bradyarrhythmia</td><td>Conditional</td><td>C</td></tr><tr><td>Patient with asymptomatic pause &gt; 6.0s</td><td>Conditional</td><td>C</td></tr><tr><td>Asymptomatic SND or SND with symptoms proven not related to bradycardia – PM not indicated</td><td>Strong</td><td>C</td></tr><tr><td>Sinus bradycardia or sinus pauses due to the use of nonessential or replaceable drugs – PM not indicated</td><td>Strong</td><td>C</td></tr><tr><td>Sinus pauses or sinus bradyarrhythmia exclusively during sleep – PM not indicated</td><td>Strong</td><td>C</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; SND: sinus node dysfunction; LCF: low cerebral flow; HR: heart rate; HF: heart failure; PM: pacemaker.

<table><caption>**Table 11.5 – Indications for pacemaker implantation in CCCD: atrioventricular blocks**</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>TAVB, advanced AVB, 2<sup>nd</sup> degree AVB Mobitz II, of irreversible, permanent or intermittent cause, regardless of symptoms and QRS duration</td><td>Strong</td><td>C</td></tr><tr><td>2<sup>nd</sup> degree AVB Mobitz I, of irreversible, permanent or intermittent cause, with defined LCF symptoms consequent to bradycardia</td><td>Strong</td><td>C</td></tr><tr><td>Irreversible AF or atrial flutter with HR &lt; 40 bpm, defined LCF symptoms consequent to bradycardia</td><td>Strong</td><td>C</td></tr><tr><td>TAVB or intra- or infra-his advanced AVB, induced by atrial stimulation or pharmacological test</td><td>Strong</td><td>C</td></tr><tr><td>AF or atrial flutter with mean HR &lt; 40 bpm, during vigil, irreversible or consequent to essential drugs, in asymptomatic patients</td><td>Conditional</td><td>C</td></tr><tr><td>Irreversible 2<sup>nd</sup> degree AVB Mobitz I (up to conduction periods of 2:1) with indication of antiarrhythmics or beta-blocker, in asymptomatic patients</td><td>Conditional</td><td>C</td></tr><tr><td>TAVB, advanced AVB, intermittent and reversible or consequent to nonessential drugs – PM not indicated</td><td>Strong</td><td>C</td></tr><tr><td>1<sup>st</sup> degree AVB, 2<sup>nd</sup> degree AVB Mobitz I, and AVB 2:1, asymptomatic and supposedly AV nodal – PM not indicated</td><td>Strong</td><td>C</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; TAVB: total atrioventricular block; AVB: atrioventricular block; LCF: low cerebral flow; AF: atrial fibrillation; HR: heart rate; PM: pacemaker.

<table><caption>**Table 11.6 – Indications for pacemaker implantation in CCCD: intraventricular blocks**</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>Documented alternating bundle branch block, regardless of the presence of symptoms</td><td>Strong</td><td>C</td></tr><tr><td>IVB with HV interval &gt; 70ms spontaneously on EPS in patients with syncope, presyncope, or dizziness of unknown etiology</td><td>Strong</td><td>C</td></tr><tr><td>IVB with HV interval &gt; 100ms spontaneously on EPS in asymptomatic patients</td><td>Strong</td><td>C</td></tr><tr><td>Bifascicular blocks without documentation of intermittent TAVB in patients with syncope, presyncope, or repetitive dizziness of unknown etiology</td><td>Conditional</td><td>C</td></tr><tr><td>Bundle branch or bifascicular block with or without 1<sup>st</sup> degree AVB in asymptomatic patients – PM not indicated</td><td>Strong</td><td>C</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; IVB: intraventricular block; EPS: electrophysiological study; TAVB: total atrioventricular block; AVB: atrioventricular block; PM: pacemaker
# Guidelines

sudden in patients with CCCD, relies on a tool of simple and rapid use, the RASSI score,⁴⁰⁸ already discussed in another chapter of this guideline.

Recently, relevant additional evidence of the role of myocardial fibrosis in the identification of high-risk individuals with CCCD has been presented. The quantification of myocardial fibrosis > 12.3g has been reported as an independent risk factor for the combined outcome of all-cause mortality, CTX, antitachycardia stimulation or appropriate ICD shock, and aborted sudden cardiac death.⁴²⁴ The impact of this new factor is detailed in that same chapter of this guideline, in the general context of risk stratification and its relationship with the RASSI score.

The study of the correlation between the CCCD stages and the mortality causes has revealed that sudden cardiac death usually affects patients from the stage B on, being onward more relevant in stage C and a little less in stage D, in which refractory HF is the cause of most deaths. In general terms, the major mechanism of sudden death in CCCD is arrhythmogenic, and SVT (subsequent VF) accounts for most lethal events.³⁵² The structural abnormalities of CCCD, characterized by inflammation, cellular death, and reactive or reparative fibrosis, are the anatomic substrate more likely to trigger sudden cardiac death, because they create slow conduction areas and unidirectional blocks prone to the occurrence of electrical reentry. The VEs, frequent in CCCD, act as triggers of those circuits, resulting in VT/VF.⁷³⁸

The scientific evidence regarding primary prevention of sudden cardiac death in CCCD by using antiarrhythmic drugs (basically amiodarone) is scarce and has already been discussed. Regarding ICD, there is only the report of the findings of a series of 13 patients, not allowing conclusions on therapeutic efficacy.⁷³⁹

Although the role of programmed ventricular stimulation in risk stratification of patients with CCCD has not been well established, Silva et al.⁴⁰⁰ have conducted a study with 78 patients with NSVT and syncope or presyncope (mean age of 46 years, mean LVEF of 47%, 58% of the male sex, and 85% in functional class I/II) with a mean follow-up of 56 months. Those authors have shown that the induction of monomorphic SVT in 25 patients (32%), all subsequently treated with amiodarone, was a predictor of spontaneous VT and of cardiac and total mortality.

In addition, as already reported in this guideline, Leite et al.⁴⁸¹ have shown that, in patients with NSVT and induced SVT (n = 37) or with spontaneous SVT (n = 78), the EPS could predict the long-term efficacy of class III antiarrhythmic

drugs (mainly amiodarone). Immediately after oral loading with antiarrhythmic drugs, the induction of hemodynamically unstable SVT was related to higher total, cardiac, and sudden mortality when compared to patients in whom arrhythmia could not be induced or the arrhythmia induced was well-tolerated SVT.

These two studies, although observational, suggest that the EPS could identify patients with ventricular tachyarrhythmias, who, once treated with antiarrhythmic drugs, would evolve to worse prognosis and higher risk of death, and, in such cases, ICD could be a feasible alternative.

Briefly, so far, there is no scientific evidence supporting the use of ICD, with strong recommendation, for primary prevention of sudden cardiac death in CCCD. The ongoing CHAGASICS trial should soon provide relevant information.⁴⁶⁰ It is a multicenter, open RCT designed to compare the effects of ICD with amiodarone for primary prevention of mortality in CCCD, in patients with NSVT on 24-hour Holter and RASSI score ≥ 10 points. The indications for ICD implantation in primary prevention of sudden cardiac death are shown in Table 11.7.

### 11.2.2.2. Secondary Prevention of Sudden Cardiac Death

The ICD is usually considered a resource to be used in some contexts of secondary prevention of sudden cardiac death for patients with CCCD. Its efficacy consists in the interruption of the life-threatening arrhythmic event by use of electric shock or rapid ventricular stimulation (antitachycardia), preventing the occurrence of cardiac arrest and subsequent death, although some arrhythmias aborted by the ICD could revert spontaneously, not necessarily culminating in death. The choice of this therapeutic option involves the thorough analysis of five essential factors: 1. duly documentation of the arrhythmic event causing the cardiac arrest (SVT or VF) and its correlation with irreversibility of the cause; 2. conviction that less invasive clinical therapy and/or procedures, of similar efficacy, have failed; 3. certainty that the underlying heart disease is being fully treated; 4. appreciation of the underlying cardiomyopathy risk stratification; and 5. patient's clinical condition, expressed mainly by the ventricular dysfunction (LVEF) grade and the arrhythmia-related symptom type.

These factors have received little attention in studies of secondary prevention of sudden cardiac death in CCCD. There is no RCT in that population and the scientific evidence is limited to data from records from manufacturers of implantable devices,⁷⁴⁰,⁷⁴¹ single-center observational clinical studies assessing small population samples,³⁵⁵,⁷⁴²⁻⁷⁵⁰ and meta-analyses of those studies.⁷⁵¹,⁷⁵²

<table><caption>**Table 11.7 – Indications for ICD implantation in CCCD: primary prevention of sudden cardiac death**</caption><thead><tr><td>Summary of recommendations</td><td>Recommendation grade</td><td>Level of evidence</td></tr></thead><tbody><tr><td>NSVT with syncope or presyncope of probable cardiac etiology and hemodynamically unstable SVT induction on EPS</td><td>Conditional</td><td>B</td></tr><tr><td>NSVT with SVT induction on EPS, followed by impregnation with amiodarone and EPS repetition, with hemodynamically unstable SVT induction on EPS</td><td>Conditional</td><td>B</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; ICD: implantable cardioverter-defibrillator; NSVT: nonsustained ventricular tachycardia; SVT: sustained ventricular tachycardia; EPS: electrophysiological study.
The largest cohort of patients with CCCD treated with ICD implantation for secondary prevention in a single center has enrolled 116 consecutive patients, 62% of the male sex, and mean age of 54 years. The mean LVEF was 42%, 83% of the patients were in NYHA functional class I/II, and the reason for ICD implantation was resuscitation from cardiac arrest in 18% and symptomatic SVT in 82% of the cases. In a mean 45-month follow-up, the following was reported: annual total mortality rate of 7.1%; appropriate therapies in 50% and inappropriate in 11% of the population. The independent factors of worse prognosis were NYHA functional class III and low LVEF. Patients with RV stimulation rate over 40% also had shorter survival.⁷⁴⁶

On the other hand, in a retrospective cohort of 90 consecutive patients with CCCD (68% of the male sex, mean age of 59 years, and mean LVEF of 47%) treated with ICD implantation, 30% of whom had preserved cardiac function, in a mean 756-day follow-up, the annual mortality rate was high (16.1%). Of the patients who died, 88% were in functional class I at the time of ICD implantation. Although 65% of the patients experienced appropriate shock and antitachycardia therapy, the monthly rate of shocks was the only independent predictor of mortality.⁷⁴³

The mortality rate of another retrospective cohort of 76 patients with CCCD and ICD has been compared to that of a historical series of 28 patients with SVT treated only with amiodarone.⁷⁴⁷ A 72% reduction in total mortality and a 95% reduction in sudden cardiac death were reported in the cohort treated with ICD. However, when subgroup analysis was performed, there was a significant interaction between LVEF and benefit from ICD. While patients with reduced LVEF (< 40%) had a significant and expressive benefit with ICD, those with relatively preserved LVEF (≥ 40%) had little or no benefit.⁷⁴⁷

These data are consistent with the results of a meta-analysis of RCTs of secondary prevention in other heart diseases (AVID, CIDS, and CASH), which showed a reduction in total and sudden mortality with ICD (as compared to amiodarone) only in patients with LVEF < 35%.⁷⁰¹

It is worth emphasizing that a meta-analysis including that study and other five observational studies in CCCD has shown no difference in total mortality between the use of amiodarone (9.6%/year) and ICD (9.7%/year).⁷⁵¹

Recently, a systematic review and meta-analysis has been published including 13 observational studies on CCCD to reassess the global efficacy of ICD to prevent total and sudden death. It included 1041 patients, 92% of them in secondary prevention and only 8% in primary prevention, with mean age of 57 years, 64% of the male sex, mean LVEF of 38%, 79% in functional class I/II, 79% on amiodarone, and 44% on beta-blockers. In a 2.8-year follow-up, total mortality rate was 9.0% per year, and, in a 2.6-year follow-up, sudden cardiac death rate was 2.0% per year. Appropriate ICD therapies (shocks or antitachycardia interventions) occurred in 24.8% of the patients, annually. High rates of inappropriate shocks (4.7%/year) and arrhythmic storms (9.1%/year) have also been observed.⁷⁵²

Regarding the prognosis of the arrhythmia types that usually indicate the need for ICD implantation, Lima et al.⁷⁵³ have compared the clinical evolution of two groups

of patients: group 1, with 318 patients, 36% of whom had CCCD, whose cause of ICD implantation was symptomatic SVT (syncope and/or hemodynamic instability) or SVT induction on EPS in patients with recurrent syncope of unknown etiology; and group 2, with 97 patients, 15% of whom had CCCD, whose cause of ICD implantation was resuscitation from cardiac arrest due to VF or pulseless SVT. While sex (male: 75% versus 73%) and NYHA functional class I/II (77% versus 76%) did not differ between groups 1 and 2, the mean age was higher (57 versus 51 years, p = 0.0004) and the mean LVEF was lower (38% versus 43%, p = 002) in group 1. After a mean follow-up of 24 months for group 1 and of 26 months for group 2, mortality was higher in group 2 (24.7% versus 13.5%, p < 0.005), and both groups experienced appropriate ICD shocks similarly (31% of group 1 patients versus 26% of group 2 patients, p = 0.09), which might indicate higher arrhythmia severity in the subgroup of patients resuscitated from cardiac arrest.

In another study, Leite et al.⁷⁵⁴ have assessed the impact of syncope on total and cardiac mortality of 78 patients with monomorphic SVT (mean age of 53 years, mean LVEF of 50%, 58% were male patients, 88% were in functional class I/II). Syncope during SVT was observed in 45 patients (58%), but not in 33 patients (42%). After a mean 49-month follow-up, neither total (33% versus 39%) and cardiac mortality (27% versus 30%), nor nonfatal SVT recurrence (58% versus 54%) differed between patients with and without syncope, respectively. However, the presence of syncope during recurrences was significantly higher among patients who had that symptom initially (65% versus 18%, p < 0.01). Thus, in CCCD, syncope during monomorphic SVT seems not to be associated with an increase in total and cardiac mortality.

Given the set of results summarized in the previous paragraphs, one can conclude that more scientifically based evidence is still necessary to support the use of ICD for secondary prevention of sudden cardiac death in patients with CCCD. This should ideally be solved with the conduction of an RCT. However, several researchers claim to have ethical concerns about adopting that scientific path, and currently there is no perspective on that.

Others have claimed that there is large positive experience built up over the years with the use of protocols supported by international and national guidelines for patients with ICM or DCM treated with ICD implantation. This created a scenario favorable to the extrapolation of those rules to clinical practice, so that patients with CCCD would be more liberally treated with ICD. However, secondary prevention with ICD implantation in CCCD should be always supported by a thoughtful individualized decision-making with risk/benefit analysis.

That general principle derives from two essential notions. The first is that even in scenarios supported by international guidelines for patients with other cardiopathies, the benefit of ICD is relatively restricted to the existence of severe ventricular systolic dysfunction, being less significant in the absence of that factor. The other one, already mentioned, is that the complex and peculiar pathophysiology of CCCD implies that therapeutic principles only partially validated for other
# Guidelines

cardiopathies can hardly be properly extrapolated to CCCD. Therefore, both LVEF, considering the ideal cutoff point of 40%, and the type of arrhythmia and symptom associated have been used to better support the indications of ICD for secondary prevention of sudden cardiac death.

Of note, by the time this guideline was being finished, a recent publication of the European Society of Cardiology⁷⁵⁵ for the treatment of ventricular arrhythmias explicitly mentioned CCCD and restricted the indications for ICD in that context, very similarly to our recommendations. Table 11.8 and Figure 11.2 show the recommendations of this guideline for ICD implantation in CCCD.

## 11.2.3. Cardiac Resynchronization Therapy

There are no solid data from RCTs to support the use of cardiac resynchronization therapy (CRT) in CCCD. The CRT has been recommended to patients with DCM and ICM, presenting with advanced HF, severe systolic dysfunction, and ventricular dyssynchrony, mainly represented by a widened QRS complex. The CRT has been described as acting positively on LV remodeling, promoting a significant reduction in the functional class of HF, and improving quality of life, based on several other functional parameters.⁷⁵⁶⁻⁷⁶⁰

Some studies have evidenced a benefit of CRT regarding HF mortality reduction,⁷⁵⁶,⁷⁶¹,⁷⁶² especially in the presence

<table><caption>**Table 11.8 – Indications for ICD implantation in CCCD: secondary prevention of sudden cardiac death**</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>Resuscitated cardiac arrest due to VF or documented pulseless SVT (excluding the reversible causes, and life expectancy &lt; 1 year), regardless of EF</td><td>Strong</td><td>B</td></tr><tr><td>Hemodynamically unstable SVT (low output), regardless of EF</td><td>Strong</td><td>B</td></tr><tr><td>SVT with syncope and EF ≤ 40%</td><td>Strong</td><td>B</td></tr><tr><td>Syncope with monomorphic SVT induced on EPS and EF ≤ 40%</td><td>Strong</td><td>B</td></tr><tr><td>Hemodynamically stable SVT and EF ≤ 40%</td><td>Strong</td><td>B</td></tr><tr><td>SVT with syncope and EF &gt; 40%</td><td>Conditional</td><td>B</td></tr><tr><td>Syncope with monomorphic SVT induced on EPS and EF &gt; 40%</td><td>Conditional</td><td>B</td></tr><tr><td>Hemodynamically stable SVT and EF &gt; 40%</td><td>Conditional</td><td>B</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; ICD: implantable cardioverter-defibrillator; VF: ventricular fibrillation; SVT: sustained ventricular tachycardia; EF: ejection fraction; EPS: electrophysiological study.

<figure><img src="image_12.png" /><figcaption>**Figure 11.2 – Algorithm for the management of patients with CCCD and sustained ventricular tachyarrhythmias.** CCCD: chronic cardiomyopathy of Chagas disease; ICD: implantable cardioverter-defibrillator; CA: cardiac arrest; VF: ventricular fibrillation; VT: ventricular tachycardia; SVT: sustained ventricular tachycardia; EPS: electrophysiological study; TTE: transthoracic echocardiography; LVEF: left ventricular ejection fraction; AA: antiarrhythmic.</figcaption></figure>
of LBBB, LVEF ≤ 35%, QRS duration ≥ 130ms, and mitral regurgitation.⁷⁶³,⁷⁶⁴ However, in CCCD the prevalence of LBBB is low, which limits the formal indication of CRT in that scenario. The presence and extension of myocardial fibrosis, which is associated with a worse prognosis regardless of LVEF,⁴²⁴,⁴²⁸,⁷⁶⁵ as well as frequent ventricular arrhythmias, tricuspid regurgitation, and RV dysfunction are examples of other factors that do not favor CRT in CCCD and that can increase the patients' risk of nonresponse.

Importantly, the implantation of the conventional (single-chamber) PM, often used in CCCD, causes LV dyssynchrony ("induced LBBB") mainly when the lead is placed in the RV apical region. This is associated with hemodynamic impairment and worsens the prognosis of patient with HF treated with PM.⁷⁶⁶,⁷⁶⁷

So far, only five single-center, observational studies⁷⁶⁸⁻⁷⁷² have assessed the clinical course of patients with CCCD undergoing CRT, and three of them⁷⁷⁰⁻⁷⁷² have compared the effect of that therapy in CCCD with that in other cardiopathies (Table 11.9). A statistically significant reduction in LVDD and a significant improvement in NYHA functional class and LVEF were observed with CRT in two studies including only patients with CCCD.⁷⁶⁸,⁷⁶⁹ Annual all-cause mortality in those two studies ranged from 9.0% to 9.2%. In other three studies,⁷⁷⁰⁻⁷⁷² the survival of patients with CCCD was significantly lower and the percentage of nonresponders to CRT was significantly higher as compared to that of patients with other cardiomyopathies. In patients undergoing CRT, the presence of CCCD increased the risk of death by approximately two to four times.⁷⁷⁰,⁷⁷²

Although plausible, the use of CRT as a PM upgrade remains controversial. While the COMBAT study, whose sample included 51.6% of patients with CCCD, has reported a significant improvement in the quality of life and an increase in LVEF of patients undergoing CRT as compared to simple RV stimulation,⁷⁷³ the RAFT study, which included no patient with CCCD, has shown no benefit regarding mortality when 54 patients received CRT as compared to other 81 patients treated only with RV stimulation.⁷⁶²

A small RCT including 50 patients has reported a benefit in terms of quality of life when CRT was added to isolated RV simulation in patients mandatorily treated with PM implantation.⁷⁷⁴

Briefly, there is no specific and consistent scientific evidence to support the indication for CRT in CCCD, which will only be possible with the conduction of an RCT comparing CRT associated with optimized clinical treatment versus a control group with only optimized drug treatment. Thus, currently CRT should have its application derived from extrapolation from studies performed in patients with ICM and DCM with careful selection and individualization based on risk/benefit analysis for the patient with CCCD (Table 11.10).

## 11.3. Ablation Methods

### 11.3.1. Sustained Ventricular Tachycardia: Clinical Presentation, Electrophysiological Mechanisms, and Sites of Origin

The clinical manifestations of ventricular arrhythmias in CCCD are heterogeneous, ranging from asymptomatic or slightly symptomatic to disabling tachycardia with syncope,

poorly tolerated ICD shocks, electrical storm, and even sudden death.⁴⁶,³⁵⁴,⁴⁴²,⁷⁴⁷,⁷⁵²,⁷⁷⁵ As already mentioned in other chapters of this guideline, although the coexistence of arrhythmias with HF findings is the most common manifestation, the occurrence of severe arrhythmias as the initial or predominant manifestation without HF is also a hallmark of CCCD.³⁵³

Several pathogenic mechanisms (such as myocardial injury directly caused by the parasite or immune mediated, autonomic denervation, and microcirculation disorders) cause myocardial damage and varied disorders at all levels of cardiac electrical impulse generation and conduction.¹⁷⁶,²⁷⁰,³²⁶

The fundamental electrophysiological mechanism of SVT in CCCD is usually the electrical stimulus reentry in the ventricular scar, constituted by extensive interstitial fibrosis intermingled with viable myocardial fibers. This is more frequent in the LV inferolateral region (70% of the patients), but can also occur in the LV apical region or in the right ventricle.⁷⁷⁶⁻⁷⁷⁹ These areas of fibrosis (scars) can be located in the LV subendocardial, intramyocardial, or subepicardial regions.⁴²⁴,⁴²⁸,⁷⁷⁸⁻⁷⁸¹ In addition, an isthmus of viable myocardium between the mitral annulus and a scar in the LV inferolateral region can form a macroreentrant circuit of SVT.⁷⁸² Finally, a macroreentrant circuit involving the right and left branches (bundle branch reentry) can be the least common cause of SVT.⁷⁸³

In general, the different reentrant mechanisms of SVT have been thoroughly investigated by use of invasive EPS, in which the programmed ventricular stimulation can reproduce that arrhythmia in more than 80% of the patients with clinical history of SVT or syncope and CCCD. In addition, endocardial and/or epicardial mapping has shown abnormal diastolic, presystolic, and mid-diastolic electrograms, predominating in the regions of LV akinesia and dyskinesia.⁴⁸¹,⁷⁷⁶,⁷⁷⁸,⁷⁸⁰,⁷⁸¹

During EPS using ventricular stimulation techniques (concealed entrainment), the critical isthmus of the reentry circuit can be differentiated from the other regions not involved in the VT mechanism, which can be confirmed by the interruption of VT during radiofrequency ablation.⁴⁸¹,⁷⁷⁶,⁷⁷⁸,⁷⁸⁰,⁷⁸¹ In addition to fibrosis in circumscribed ventricular wall regions, the intracardiac autonomic nervous system injury, characterized by ganglionic neuronal depletion and cardiac dysautonomia, and the chronic myocardial inflammation are pathophysiological changes that can contribute to myocardial electrical instability and genesis of ventricular tachyarrhythmias.¹⁹³,²⁰⁸,²²²,⁷⁸⁴⁻⁷⁸⁸

### 11.3.2. Clinical and Laboratory Pre-Ablation Assessment

Patients with CCCD and SVT usually have advanced heart disease⁴³⁰ and HF (which should have its specific treatment optimized), requiring, in order to program ablation, the assessment of kidney function, the presence of infection, and the need for vasoactive drugs in cases of electrical storm. Usually, the presence of comorbidities should not contraindicate ablation, mainly in cases of electrical storm and recurrent shocks, because, without the intervention, mortality is very high.⁷⁴³

The PAINESD (chronic obstructive Pulmonary disease, Age > 60 years, Ischemic cardiomyopathy, NYHA III or IV,
# Guidelines

<table><caption>Table 11.9 – Observational studies of cardiac resynchronization therapy in CCCD.</caption><thead><tr><th>CHARACTERISTICS</th><th>Araujo et al.<br>2014<sup>55</sup></th><th>Menezes et al.<br>2018<sup>56</sup></th><th>Martinelli et al.<br>2018<sup>57</sup></th><th>Scorzini et al.<br>2018<sup>58</sup></th><th>Passos et al.<br>2019<sup>59</sup></th></tr></thead><tbody><tr><td>Population</td><td>CCCD</td><td>CCCD</td><td>CCCD</td><td>ICM</td><td>Others</td></tr><tr><td>N of patients</td><td>72</td><td>50</td><td>115</td><td>134</td><td>43</td></tr><tr><td>Male sex (%)</td><td>NA</td><td>56</td><td>65</td><td>83</td><td>59.5</td></tr><tr><td>Mean age (years)</td><td>NA</td><td>63</td><td>57</td><td>68</td><td>60</td></tr><tr><td>Types of block:</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Induced LBBB (%)</td><td>15</td><td>30</td><td>74</td><td>31</td><td>17</td></tr><tr><td>• Spontaneous LBBB (%)</td><td>47</td><td>30</td><td>11</td><td>63</td><td>78.5</td></tr><tr><td>• Not LBBB (%)</td><td>38</td><td>40</td><td>15</td><td>7</td><td>4.5</td></tr><tr><td>CRT-ICD (%)</td><td>NA</td><td>74</td><td>23.5</td><td>33</td><td>26</td></tr><tr><td>Atrial fibrillation or flutter (%)</td><td>0</td><td>16</td><td>25</td><td>16</td><td>15</td></tr><tr><td>Functional class III/IV (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Pre-implantation</td><td>100</td><td>82</td><td>82</td><td>82</td><td>88</td></tr><tr><td>• Post-implantation</td><td>13</td><td>18</td><td>43.5</td><td>26</td><td>26</td></tr><tr><td>Mean LVEF (%)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Pre-implantation</td><td>27</td><td>29</td><td>26</td><td>26</td><td>24</td></tr><tr><td>• Post-implantation</td><td>44</td><td>39</td><td>27</td><td>28</td><td>29</td></tr><tr><td>Mean QRS length (ms)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Pre-implantation</td><td>148</td><td>150</td><td>163</td><td>164</td><td>162.5</td></tr><tr><td>• Post-implantation</td><td>NA</td><td>116</td><td>NA</td><td>NA</td><td>139</td></tr><tr><td>LVEDD (mm)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>• Pre-implantation</td><td>66</td><td>NA</td><td>66</td><td>69</td><td>74</td></tr><tr><td>• Post-implantation</td><td>65</td><td>NA</td><td>68</td><td>68</td><td>71</td></tr><tr><td>Mean follow-up (months)</td><td>47</td><td>61</td><td>29</td><td>29</td><td>29</td></tr><tr><td>Nonresponders (%)</td><td>33</td><td>34</td><td>43.5</td><td>26</td><td>47</td></tr><tr><td>Annual mortality (%)</td><td>9.0</td><td>9.2</td><td>25.4</td><td>11.3</td><td>10.4</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; ICM: ischemic cardiomyopathy; DCM: dilated cardiomyopathy; LBBB: complete left bundle branch block; CRT-ICD: cardiac resynchronization therapy associated with implantable cardioverter-defibrillator; LVEF: left ventricular ejection fraction; LVEDD: left ventricular end-diastolic diameter; NA: not available.

<table><caption>Table 11.10 – Indication for CRT in CCCD</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>Symptomatic HF, functional class II and III, with LVEF ≤ 35%, sinus rhythm, LBBB morphology, and QRS duration ≥ 130ms, despite optimized therapy to reduce morbidity and mortality</td><td>Conditional</td><td>B</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; CRT: cardiac resynchronization therapy; HF: heart failure; LVEF: left ventricular ejection fraction; LBBB: left bundle branch block.

Ejection fraction < 25%, VT Storm and Diabetes mellitus) risk score has been developed to identify patients that might have hemodynamic decompensation during VT ablation<sup>789</sup> and higher post-procedure early mortality. Because the original cohort included patients with ischemic and nonischemic cardiopathies, except CCCD, it cannot be used to predict 30-day mortality after VT ablation.<sup>790,791</sup>

In addition, patients with CCCD can have megaesophagus and/or megacolon.<sup>792,793</sup> The approach for ablation should

be preferably epicardial;<sup>794</sup> however, in the presence of megacolon, the access to the pericardial space must be obtained through a surgical window or laparoscopy-guided puncture.<sup>795</sup>

Late gadolinium enhancement on CMRI is useful to identify areas of myocardial fibrosis<sup>796</sup> and to assess whether the target substrate is located on the epicardial or endocardial surface.<sup>797</sup> Coronary computed tomography angiography can identify the areas of thinning<sup>798</sup> and hypoperfusion, which
are associated with the arrhythmia substrate. Both CMRI and coronary computed tomography angiography assess the local epicardial fat thickness and location of the coronary arteries, allowing integration with the electroanatomic mapping systems.⁷⁹⁹

Recently, some software for processing 3D images from CMRI have been developed, allowing the definition of potential circuits of arrhythmia.⁸⁰⁰ These images enable integration with electroanatomic mapping systems and contribute to a successful ablation,⁸⁰¹ which becomes faster and more effective, thus eliminating the need for electroanatomic mapping reconstruction.⁸⁰²

Another important point in the ablation planning is the 12-lead ECG assessment during clinical VT, which, whenever possible, should be recorded. This allows comparison with procedure-induced VTs, being important in the search for elimination of clinical VT, given that patients with CCCD usually have multiple morphologies of VT.⁷⁸¹ This is a valid concept although ECG has limitations to define epicardial VT.⁸⁰³

Frequently, patients with CCCD have recurrences after VT ablation, requiring multiple procedures to be performed. Information on the previous procedures is fundamental to plan the new ablation. It is worth noting the following: the maps of previous procedures should be assessed and compared to the current one; the presence of an endo- or epicardial scarring area not approached in the previous procedure should be assessed; and information on bleeding during the previous epicardial access should be obtained, because, if affirmative, epicardial adherence can occur.

### 11.3.3. Mapping Techniques for Ventricular Tachycardias

The recurrence rates of VT episodes in individuals with CCCD are high, even after optimized drug therapy. A recent meta-analysis has reported rates of appropriate therapies and electrical storm of 9% and 25% per year, respectively, in patients with ICD for secondary prophylaxis.⁷⁵² Thus, radiofrequency ablation is indicated in many cases refractory to clinical treatment.⁷⁹⁴

A myocardial scar that propitiates reentry and SVT is usually located in the basal portions of the inferior and lateral LV walls, and mid-myocardial and epicardial impairment is frequent. Thus, the initial results of VT ablation with endocardial approach are frustrating with success rates around 17%.⁷⁷⁷,⁸⁰⁴

Epicardial access by use of percutaneous subxiphoid puncture with fluoroscope-guided Tuohy needle was described in 1996⁸⁰⁴ and has contributed to optimize the results of VT ablations in patients with CCCD. In an RCT, the combined endocardial/epicardial approach, as compared to the exclusively endocardial one, showed a lower rate of recurrence, 40% and 80%, respectively, in a 2-year follow-up.⁷⁸¹

The most feared complication related to percutaneous epicardial access is bleeding, which can occur in approximately 10% of the cases. Most bleedings are small and related to accidental RV puncture. Massive bleeding

requiring surgical approach occurs in 2% of the cases. Hepatic and intestinal lesions can occur during epicardial puncture in the presence of significant hepatomegaly and megacolon. In these cases, pericardial access through either surgery or videolaparoscopy-guided subxiphoid puncture can be chosen.⁷⁹⁵

In recent years, the following variations of the original epicardial puncture technique have appeared: micropuncture;⁸⁰⁵ insufflation of carbon dioxide (CO₂) in the right atrial appendage⁸⁰⁶ or coronary sinus;⁸⁰⁷ needle embedded with a real-time pressure monitor;⁸⁰⁸ computed tomography;⁸⁰⁹ CMRI;⁸¹⁰ and puncture guided by electroanatomic mapping.⁸¹¹ Of these, it is worth noting that, in a multicenter observational study, micropuncture has shown lower rates of massive pericardial effusion and of need for surgical correction of bleeding, as compared to the puncture technique with a high caliber needle.⁸⁰⁵

Some situations can limit the efficacy of ablation on the epicardial surface, such as an ablation target region located under the epicardial fat or close to the trajectory of the phrenic nerve or coronary arteries.⁸¹²

Because of disease severity and procedural complexity, perioperative care is important to reduce the risk of complications. The search for previous intracavitary thrombi is mandatory, while invasive blood pressure monitoring, infusion of vasoactive drugs prior to anesthesia induction, and mechanical circulatory support in selected cases are useful to perioperative hemodynamic optimization.

Catheter ablation can be performed with the patient in VT or sinus rhythm. Each strategy has advantages and disadvantages and there is no study comparing the results in a population with CCCD. Although the procedure performed in a patient in VT favors the identification of tachycardia isthmuses more accurately, most induced VTs are poorly hemodynamically tolerated and warrant immediate electrical cardioversion.

However, even in hemodynamically stable VTs, the mapping time should be maximally shortened due to the risk of low cardiac output post intervention. Catheter ablation in a patient in sinus rhythm is aimed at modifying the substrate, which consists in the identification and elimination of possible tachycardia isthmuses. These areas are related to myocardial scarring, which is identified as a low-voltage region in the electroanatomic mapping system and represented by late, fragmented, and low-amplitude potentials. Although less specific, this technique has the advantage of maintaining the patient hemodynamically stable for a longer period during the procedure, when there is severe ventricular dysfunction.⁸¹³,⁸¹⁴

Of note the technological evolution of the electroanatomic mapping system, mainly the high-definition mapping catheters, significantly increased the accuracy of the anatomical definition of scar regions, in addition to its functional correlation with electrical propagation. However, studies related to VT ablation in patients with CCCD are scarce and practically do not contemplate the currently available technology.
## 11.3.4. Outcomes and Complications During Ventricular Tachycardia Ablation

Historically, programmed ventricular stimulation has been used as the major tool to assess the immediate effectivity of the VT ablation procedure.⁸¹⁵ However, varied definitions of non-inducibility (heterogeneous stimulation protocols and relevance of rapid or “nonclinical” VT induction) associated with the spontaneous daily variation in the results of programmed ventricular stimulation represent relevant limitations and deficiencies in the accuracy of this tool to predict the short- and long-term success of ablation.⁸¹⁶

Despite those limitations, programmed ventricular stimulation at the end of the procedure remains the major tool to assess the immediate ablation success.⁸¹⁵ Patients who remain with slow VT (cycle > 300ms) induced at the end of the procedure more often have recurrence than those without induced VT.⁸¹⁷ Other strategies to assess the procedure's result during ablation include verifying the elimination of excitability,⁸¹⁸ late potentials,⁸¹⁹,⁸²⁰ local abnormal ventricular activities (LAVA),⁸²¹ and scar channels,⁸²² in addition to checking substrate homogenization,⁸²³ central isolation of the scar,⁸²⁴,⁸²⁵ and lesion by use of imaging guidance.⁸²⁶,⁸²⁷

The acute complications include the vascular ones, pericardial effusion, cardiac tamponade, electromechanical dissociation, TAVB, phrenic nerve paralysis, stroke, and death.⁷⁸¹,⁸²⁸

## 11.3.5. Ablation Results and Patients' Follow-up

Recently, a prospective RCT on VT ablation in a small group of patients with CCCD has reported the superiority of the systematic epicardial/endocardial approach over the exclusively endocardial one, with 40% VT recurrence in a mean 19-month follow-up in the first group.⁷⁸¹ This recurrence rate was similar to that of VT ablation in patients with nonischemic cardiopathies in general.⁸²⁸

Post-ablation VT recurrence depends on several factors, the most common being related to the use of antiarrhythmic drugs, programming of implantable cardiac devices, and cardiomyopathy severity.⁸¹⁵,⁸²⁹ All available means for the detection of SVT episodes should be used, including an ICD monitoring zone, capable of detecting slow SVT induced during ablation. In addition to recurrence of any SVT, the follow-up should record the density of arrhythmias, occurrence of electrical storm, hospitalizations, and cardiac and noncardiac death.

Tables 11.11 and 11.12 show the recommendations and levels of evidence for the indication of SVT catheter ablation, as well as the methods used during the procedure in patients with CCCD.

# 12. Managements to Prevent and Treat Thromboembolic Complications

## 12.1. Introduction

Thromboembolic complications represent a heterogeneous group of clinical manifestations associated with CCCD, corresponding to one of its three essential mechanisms of death alongside HF and sudden death.¹ In most cases, mortality due to thromboembolic phenomena is related to cerebral and pulmonary embolisms. Considering that neurologic events are usually the most expressive clinical manifestations, the cerebral thromboembolic complications are most frequently detected in medical practice.⁸³⁰

Cardioembolic stroke can be the first clinical manifestation of CCCD, occur even in early stages of the disease, affect individuals of several age groups, and new episodes can frequently occur when secondary prophylaxis is not established. The clinical manifestations are usually due to embolism of intracardiac thrombi that, because of

<table><caption>**Table 11.11 – Indications for catheter ablation of SVT in CCCD**</caption><thead><tr><td>Summary of recommendations</td><td>Recommendation grade</td><td>Level of evidence</td></tr></thead><tbody><tr><td>Recurrent or incessant monomorphic SVT, refractory to treatment with antiarrhythmic drugs</td><td>Strong</td><td>B</td></tr><tr><td>Patient with ICD and recurrent monomorphic SVT triggering multiple shocks, despite treatment with antiarrhythmic drugs and ICD reprogramming</td><td>Strong</td><td>B</td></tr><tr><td>Patient with ICD and recurrent monomorphic SVT triggering multiple shocks, when treatment with antiarrhythmic drugs is contraindicated or poorly tolerated, despite ICD reprogramming</td><td>Strong</td><td>C</td></tr><tr><td>Monomorphic SVT induced on EPS to elucidate syncope</td><td>Conditional</td><td>C</td></tr><tr><td>Patient with ICD and first episode of spontaneous monomorphic SVT documented on ECG or interrupted by ICD</td><td>Conditional</td><td>C</td></tr><tr><td>Recurrent monomorphic SVT, without previous use of amiodarone</td><td>Conditional</td><td>C</td></tr><tr><td>Poorly tolerated monomorphic SVT induced on EPS to elucidate syncope</td><td>Conditional</td><td>C</td></tr><tr><td>Combined endocardial/epicardial ablation strategy is preferable to isolated endocardial strategy to prevent VT recurrence</td><td>Strong</td><td>B</td></tr><tr><td>Ablation is contraindicated in cases of polymorphic SVT or VF secondary to severe metabolic disorders or to proarrhythmic drugs</td><td>Strong</td><td>C</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; SVT: sustained ventricular tachycardia; ICD: implantable cardioverter-defibrillator; EPS: electrophysiological study; VT: ventricular tachycardia; VF: ventricular fibrillation.
<table><caption>Table 11.12 – Methods used for catheter ablation of SVT in CCCD</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>SVT recording on 12-lead ECG before ablation, whenever the hemodynamic conditions allow</td><td>Strong</td><td>C</td></tr><tr><td>Clinical and laboratory assessment and by use of ECG, chest X-ray, and transthoracic ECHO (transesophageal in patients with AF)</td><td>Strong</td><td>C</td></tr><tr><td>Late gadolinium enhancement on CMRI before ablation</td><td>Conditional</td><td>C</td></tr><tr><td>CT coronary angiography, and chest and upper abdomen CT (identification of megacolon)</td><td>Conditional</td><td>C</td></tr><tr><td>Reserve operation room, blood bank, and intensive care unit recovery when considering epicardial approach</td><td>Strong</td><td>B</td></tr><tr><td>Coronary angiography when CT coronary angiography cannot be perfomed</td><td>Conditional</td><td>C</td></tr><tr><td>Invasive hemodynamic monitoring during SVT ablation</td><td>Strong</td><td>C</td></tr><tr><td>ICD reprogramming before and at the end of the procedure</td><td>Strong</td><td>B</td></tr><tr><td>General anesthesia</td><td>Conditional</td><td>C</td></tr><tr><td>Systemic anticoagulation after access to the left chambers, maintaining ACT > 350s during LV endocardial ablation</td><td>Strong</td><td>B</td></tr><tr><td>Electrophysiological assessment with programmed ventricular stimulation before and after ablation</td><td>Conditional</td><td>B</td></tr><tr><td>Epicardial access and mapping if endocardial ablation fails</td><td>Strong</td><td>B</td></tr><tr><td>Epicardial access and mapping after recurrence of endocardial ablation</td><td>Conditional</td><td>B</td></tr><tr><td>Mapping and endocardial and epicardial ablation in the first procedure</td><td>Conditional</td><td>B</td></tr><tr><td>Exclusive epicardial mapping and ablation in the first procedure or after unsuccessful endocardial ablation</td><td>Conditional</td><td>C</td></tr><tr><td>Limit the procedure to a maximum of 6 hours, except if the patient persists in incessant VT</td><td>Conditional</td><td>B</td></tr><tr><td>Clinical and laboratory assessment and by use of ECG and ECHO 24 hours after the procedure</td><td>Strong</td><td>B</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; SVT: sustained ventricular tachycardia; ECG: electrocardiogram; ECHO: echocardiogram; AF: atrial fibrillation; CMRI: cardiac magnetic resonance imaging; CT: computed tomography; ICD: implantable cardioverter-defibrillator; ACT: activated clotting time; LV: left ventricular; VT: ventricular tachycardia.

their dimensions, have a high potential of obstructing the proximal circulation in the central nervous system, being usually associated with severe and disabling neurological sequelae if not leading directly to death.¹

## 12.2. Epidemiology of Thromboembolic Events

Postmortem studies have shown a variable frequency of cardiac thrombosis in CD, with prevalence ranging from 27% to 79% and a slight predominance of impairment of the right chambers over the left ones (22% to 54% versus 21% to 46%, respectively).⁸³¹⁻⁸³⁴ In those studies, thromboembolic phenomena were more common in the systemic circulation and caused relatively more deaths due to pulmonary embolism.⁸³¹ The incidence of cardiac thrombi was higher in the HF clinical syndrome (36%) than in cases of sudden death (15%), with relationship to neither age nor sex.

Endocardial inflammatory lesions and intracavitary blood stasis are considered important factors in the pathogenesis of parietal thrombosis in the heart, related to the occurrence of multiple thromboembolic phenomena and high risk of death due to embolism.⁸³¹ In addition, apical aneurysm is a relevant factor, being present in 53.2% of 148 autopsies, of which 36.8% would be complicated by localized thrombosis, while only 11.1% of the hearts without apical aneurysm had intracavitary thrombi.⁸³⁵ Another study,

involving 1153 autopsies, identified the presence of apical aneurysm in 52% of the cases,⁸³⁶ predominating in the male sex.

In a prospective observational study of 55 patients with CCCD and apical aneurysm assessed by use of cine ventriculography, Albanesi Filho et al.⁸³⁷ have reported the presence of intraventricular thrombi in only 14.5% of the cases. The low frequency of thrombi described in that study could be attributed to the lower sensitivity of the assessment method as compared to postmortem studies, which, in addition, were probably performed in more advanced phases of the disease.

## 12.3. Risk Factors and Mortality

The presence of severe myocardial dysfunction, LV apical lesion, intracavitary thrombi, previous thromboembolic phenomena, dilatation of the cardiac chambers, and HF has been associated with a higher risk of thromboembolic accidents in anatomopathological and clinical studies.⁸³⁸ Regional ventricular dyskinesias, mainly apical, are a major characteristic of CCCD, in which their prevalence is higher as compared to that in other etiologies, thus predisposing to the formation of mural thrombi and embolic events, especially systemic ones.⁸³⁰ Similarly to other cardiopathies, cardiac dilatation and HF are well-known risk factors for
the occurrence of thromboembolic events. Atrial fibrillation, a relatively late manifestation and usually associated with ventricular dysfunction, is an additional thrombogenic factor in that cardiopathy.⁸³⁰

The mortality associated with thromboembolic events in CCCD is usually related to cerebral and pulmonary embolisms, with more than one arterial territory commonly affected.⁸³⁹ Regarding pulmonary embolism, most events originate in the right cardiac cavities, differently from other cardiopathies, in which the thrombi commonly originate from the lower limbs.⁸³⁹ Pulmonary embolic phenomena are clinically underestimated in CCCD, considering their high prevalence in postmortem examinations,⁸³⁰ the same occurring with noncerebral systemic embolisms. Pulmonary thromboembolism can affect up to 37% of patients with HF, but it is rarely reported in patients without HF. In 85% of the cases, it associates with mural thrombosis of the right cardiac chambers.³⁶³

Systemic thromboembolism affects mainly the brain and can be the initial clinical manifestation of CD, associating with the presence of mural thrombi and LV apical aneurysm. Because of its higher clinical expression, stroke has been in the center of several investigations. Embolic stroke in CCCD was first reported by Nussenzveig et al. in 1953.⁸⁴⁰ In 1955, Rocha & Andrade described systemic thromboembolic phenomena in patients with CCCD.⁸⁴¹

The presence of CCCD is considered an independent risk factor for the occurrence of ischemic stroke. Case-control studies have shown that HF, arrhythmias on ECG, female sex, and LV apical aneurysm are independent risk factors for cerebral thromboembolism in patients with CD.⁸⁴²,⁸⁴³

In a study using transthoracic and transesophageal ECHO and assessing 75 patients, LV mural thrombi were found in 23% of the cases, in a clear association with the history of stroke. Apical aneurysm was identified in 47% of the patients and significantly related to mural thrombosis and stroke. Thrombosis of the left atrial appendage was identified in 4 patients, while thrombosis of the right atrial appendage, in 1 patient. There were 13 deaths in a 24-month follow-up, 7 of which were sudden, 5 due to HF progression, and 1 due to stroke. Differently from other cardiopathies, in CCCD, stroke was more frequent in patients with mild LV systolic dysfunction and NYHA class I.³⁶³

Two hospital case series have reported a low annual incidence (1% to 2%) of thromboembolic phenomena in patients with CCCD and mild to moderate ventricular dysfunction.³⁶³,³⁵⁸ However, that incidence was significantly higher (60% per year) in patients with manifest HF, in whom LV apical aneurysm and LV mural thrombosis were observed in 23% and 37% of the cases, respectively. Overall, lumping all the case series, the prevalence of thrombosis of the right chambers (53%) exceeded that of the left chambers (43%).⁸³¹⁻⁸³⁴

The COVID-19 pandemic, the disease caused by SARS-CoV-2, has evidenced higher predisposition of infected patients to arterial and venous thrombotic complications, because of inflammatory changes, those of the endothelial

microcirculation and blood stasis.⁸⁴⁴ Considering that CCCD also propitiates a proinflammatory and prothrombotic state, the association of those two diseases could act synergistically to potentialize the appearance of thromboembolic events.

However, so far, there has been no clear evidence of more relevant clinical events in the association of both diseases. Nevertheless, interventional settings have reported that acute coronary syndromes in patients with COVID-19 tend to present later after symptom onset and with higher clinical severity.⁸⁴⁵ Therefore, ongoing studies are testing more aggressive antithrombotic therapies in those settings. Patient management when both infections coexist is addressed in a specific topic of this guideline.

## 12.4. Risk Assessment of Stroke

As already discussed, patients with more advanced forms of CCCD are at higher risk for developing thromboembolic episodes because they are more susceptible to thrombus formation, due to the presence of venous stasis and low blood flow, dilatation of cardiac chambers, LV systolic dysfunction, and inflammatory vascular phenomena. Other factors, such as segmental hypocontractility and arrhythmias, especially AF, contribute to increase the risk for thromboembolism.⁸³² Even patients with CCCD without global ventricular dysfunction can have a significant increase in the risk markers of thrombosis, suggesting a prothrombotic state in the earliest stages of disease.⁸⁴⁶

A systematic review of eight observational studies, involving 4158 patients, has evidenced the clear association between CCCD and the risk for stroke. That study has shown that, in chronically *T. cruzi*-infected patients, as compared to noninfected ones, there was an excessive risk for stroke of approximately 70% (RR = 1.70; 95% CI, 1.06-2.71).³⁶¹

A prospective cohort of 1043 patients with CD (with and without cardiopathy), in a mean 5.5-year follow-up, has reported a 3% incidence of cardioembolic stroke, that is, 0.56% per year.³⁶⁴ The authors have proposed a risk score (IPEC-FIOCRUZ) for the stroke occurrence based on points and the indication for prophylaxis of embolic events, considering the presence of LV systolic dysfunction (any grade and location - 2 points), apical aneurysms (1 point), primary alterations of ventricular repolarization on ECG (1 point), and age > 48 years (1 point). Patients with 4-5 points were considered at high risk for cardioembolic stroke. That analysis excluded the classical risk factors associated with cardioembolic complications in other cardiopathies, for which the indication of prophylaxis is already ensured, such as AF, intracavitary thrombi, and previous cardioembolic events. However, the frequency of events was higher than that in other cardiopathies in paired analyses for the same grade of systolic dysfunction, showing that CCCD is in fact a more thrombogenic entity.³⁶⁴

Recent studies have suggested that atrial flutter and AF might be more frequent in CCCD than initially reported, and their prevalence increases in more advanced disease stages, accompanying the ventricular dysfunction worsening and being an additional thrombogenic factor.⁸⁴⁷
However, although cardioembolic complications are very frequent in CCCD and should always be assessed as a potential causal factor for ischemic stroke, other mechanisms, such as atherothrombotic or lacunar strokes, and, more rarely, several etiologies of vasculitis and coagulopathies⁸⁴⁸ can be implicated in the ischemic stroke genesis of patients with CD. The recent increase in life expectancy of that population and changes in lifestyle, with contribution of the classical cardiovascular risk factors for atherosclerosis (SAH, dyslipidemia, and diabetes mellitus), make ischemic stroke one of the major causes of death in historical cohorts of patients with CD,⁸⁴⁹ although not always the cardioembolic mechanism is implicated.

Occasionally, even the cardioembolic risk condition might not mean a manifestation of CCCD but be associated with the progression of cardiopathy in the elderly, also responsible for the increased incidence of AF. The precise causal nexus of stroke in the elderly and patients with multiple clinical comorbidities might not always be established. However, comprehensive care to patients should be considered the most relevant theme, and appropriate treatment and/or prophylaxis should be established in each situation.

## 12.5. Clinical Findings and Diagnostic Investigation of Ischemic Stroke in Chagas Disease

Stroke is defined as a usually focal neurological deficit, of sudden onset, lasting at least for 24 hours, of presumably vascular cause, occasionally followed by death. The presence of focal neurological signs and symptoms that disappear in less than 24 hours characterizes the transient ischemic attack (TIA). The diagnosis of stroke is based on clinical manifestations, with the presence of at least one of the following neurological changes: motor or sensory deficit, aphasia or dysphasia, hemianopsia, conjugate eye deviation, or sudden onset of apraxia, ataxia, or sensory perceptual deficit.⁸⁵⁰

In patients with CD, because of the predominance of cardioembolic stroke, symptoms of cortical manifestation are frequently observed and the anterior circulation syndromes, related to impairment of the territory of the middle and anterior cerebral arteries, are the most common.⁸⁴³ They are characterized by signs of superior cortical dysfunction (alterations of speech, visuospatial functioning, or consciousness level), homonymous hemianopsia (visual deficit affecting both eyes equally), and motor deficit and/or sensory alteration of at least two body areas (face, upper limbs, and lower limbs). Extensive cortical lesions usually cause all those neurological disorders, thus characterizing the total anterior circulation syndrome. Less extensive cortical lesions can lead to partial anterior circulation syndrome, with two of those three sets of neurological manifestations.

The posterior circulation syndromes, related to impairment of the posterior cerebral artery territory, such as the cerebellum and brain stem, are less frequent. These syndromes manifest with at least one of the following alterations: paralysis of the cranial nerves associated with

contralateral sensory/motor deficit; bilateral sensory/motor deficit; conjugate eye deviation; cerebellar dysfunction without ipsilateral long-tract deficit; isolated hemianopsia or cortical blindness.⁸⁵¹

The signs and symptoms of ischemic stroke secondary to atherosclerosis of the great vessels can be similar, and, thus, indistinguishable from those present in cardioembolic events regarding sensory/motor deficit, however without alteration of the cortical functions, such as speech or cognitive functions.

Some patients can experience lacunar syndromes, usually related to the presence of other cardiovascular risk factors concomitant with CD, such as SAH and diabetes mellitus. Lacunar strokes are characterized by the presence of sensory/motor deficits, which can occur in isolation or in combination, or by ataxic hemiparesis.

Silent ischemic stroke can occur in a significant proportion of patients with CCCD, having been reported in 18% of the individuals with CD included in a case-control study.⁸⁵²

Brain computed tomography or MRI is recommended to confirm the diagnosis of structural lesions due to vascular events, to classify the type of event, and to exclude differential diagnoses.⁸⁵³ When assessing acute stroke, computed tomography is the most cost-effective strategy, because it is a fast method largely available in most emergency services. The MRI is particularly useful to assess posterior circulation lesions, small cortical infarctions, lacunar infarctions, and mainly to analyze unusual images when there is doubt about the diagnosis of stroke.⁸⁵⁴

In patients with CD and diagnosis of stroke, the imaging tests show a predominance of cerebral lesions in the territory of the middle cerebral arteries, which is usually the most affected area in individuals with ischemic stroke. A large proportion of patients with CD and ischemic stroke of undetermined etiology have structural impairment of the territory of the cerebral artery lower branches, which can be associated with embolism from the heart, possibly due to anatomic and hemodynamic factors.⁸⁵⁵

The neurological signs and symptoms of stroke can be the first clinical manifestations of patients with CD.⁸⁵⁶ Thus, investigation of *T. cruzi* infection by use of serological tests should be considered in cases of ischemic stroke in patients from CD endemic areas or children of mothers at the same endemic risk, mainly in cases of cerebrovascular events secondary to thromboembolism or of undetermined etiology.⁸⁵⁷

Most patients with CD who develop stroke are known to have cardiomyopathy signs.³⁶¹ Cardiac arrhythmias, mainly atrial flutter and AF, LV systolic dysfunction, left atrial dilatation, apical aneurysm, and intracavitary thrombosis are associated with stroke in patients with CCCD.³⁵⁸,³⁶⁰,³⁶⁴,⁸⁴⁹ Thus, ECG and transthoracic ECHO at rest are recommended to investigate those risk factors. For patients with poor echocardiographic window for proper assessment of the LV apex, microbubble contrast ECHO and CMRI can be useful to identify aneurysms and mural thrombi in the region.⁸⁵⁸
# Guidelines

In cases of embolic ischemic stroke whose thrombogenic source remains undetermined after initial assessment, additional diagnostic investigation can be made with 24-hour Holter monitoring and transesophageal ECHO. If the patient has a PM or ICD, the device's event recording can be assessed aiming to identify arrhythmias with the potential to produce embolization.

The concomitant prevalence of other risk factors for cardiovascular diseases, such as SAH, diabetes mellitus, dyslipidemia, and smoking, in patients with CD can be high, mainly in those with ischemic stroke.⁸⁵⁶ In such cases, noninvasive investigation of atheromatous disease of the carotid and vertebral arteries by use of Doppler ultrasound, computed tomography angiography, or magnetic resonance angiography is recommended, mainly for patients with cerebral infarction related to the anterior cerebral circulation. In addition, transcranial Doppler can be useful in such cases.

Differential diagnosis with other rare clinical conditions, such as vasculitis and thrombophilias, in cases of clinical suspicion or when the diagnosis remains undetermined should be investigated by use of blood coagulation tests,

with assessment of prothrombin time (international normalized ratio - INR) and platelet count or specific search for other rare etiologies.

Table 12.1 summarizes the recommendations for investigation of ischemic stroke in CD.

## 12.6. Treatment of Ischemic Stroke in Chagas Disease

The therapeutic management of ischemic stroke in CD depends on the time from symptom onset, comorbidities, and severity and extension of the ischemic area. The cerebral ischemia can present as TIA, silent cerebral infarctions, or ischemic stroke with mild or severe motor sequelae and hemorrhagic transformation, causing death, chronic cognition impairment or drastic physical limitation.⁸⁵⁹⁻⁸⁶¹

The initial therapeutic approach to stroke in CCCD is similar to that in other etiologies, aiming to stabilize and reduce damages, and prevent complications through admission to the specific intensive care unit for patients with stroke, where the following general measures should be observed:⁸⁶² 1) Control of vital functions and

<table><caption>**Table 12.1 – Investigation of ischemic stroke in CCCD**</caption><thead><tr><th>Indication</th><th>Test</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td rowspan="2">Diagnostic confirmation of acute neurological event, classification of the type of event, and assessment of differential diagnoses or complications</td><td>Brain CT</td><td>Strong</td><td>B</td></tr><tr><td>Brain MRI (particularly to assess small infarctions or posterior circulation impairment)</td><td>Conditional</td><td>B</td></tr><tr><td rowspan="2">Investigation of T. cruzi infection in individuals with ischemic stroke and epidemiological antecedents</td><td>Serology for Chagas disease (two different serological techniques)</td><td>Strong</td><td>C</td></tr><tr><td>ECG and transthoracic ECHO</td><td>Strong</td><td>B</td></tr><tr><td rowspan="4">Investigation of cardiac impairment and source of embolism associated with CCCD</td><td>Cardiac MRI or microbubble contrast ECHO (if inappropriate window for LV apical assessment)</td><td>Conditional</td><td>B</td></tr><tr><td>24-h Holter (undetermined source of embolism after initial assessment)</td><td>Strong</td><td>B</td></tr><tr><td>TEE (undetermined source of embolism after initial assessment)</td><td>Conditional</td><td>C</td></tr><tr><td>Carotid and vertebral artery doppler</td><td>Strong</td><td>B</td></tr><tr><td rowspan="2">Differential diagnosis with atherothrombotic etiology in patients with cardiovascular risk factors</td><td>Brain CT angiography or MRI/angiography</td><td>Conditional</td><td>B</td></tr><tr><td>Transcranial doppler</td><td>Conditional</td><td>C</td></tr><tr><td>Differential diagnosis with other etiologies</td><td>Blood coagulation tests with prothrombin time (INR) and platelet count</td><td>Strong</td><td>B</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; CT: computed tomography; MRI: magnetic resonance imaging; ECG: electrocardiogram; ECHO: echocardiogram; LV: left ventricular; TEE: transesophageal echocardiogram; INR: international normalized ratio.
temperature; 2) Management of SAH, avoiding hypotension and consequent cerebral ischemia worsening; 3) Control of hyper- or hypoglycemia; 4) Careful hydration and serum sodium level control; 5) Protection of the airways and swallowing, preventing infection from bronchoaspiration; 6) Early identification of hypoventilation, preventing CO₂ retention and hypoxemia by use of oxygen supplementation; 7) Prevention of deep venous thrombosis by use of heparin or its oral substitutes or mechanical methods of pneumatic compression when indicated; and 8) Determination of the cerebral damage extension by use of brain computed tomography or MRI to treat cerebral edema and identify the risk for or presence of hemorrhagic transformation, assessing suggestive symptoms, such as intense and persistent headache, sleepiness, decreased level of consciousness, in addition to worsening of the motor/sensory deficits.

For acute and more severe cases presenting in the therapeutic window (time from symptom onset <4.5 hours) and with no contraindication, thrombolysis should be instituted, usually with intravenous rt-PA. If initial brain computed tomography suggests early hypodensity equal to or greater than one third of the middle cerebral artery territory, thrombolysis is contraindicated because of the high risk for hemorrhagic transformation. In specific cases, endovascular thrombectomy enables treatment with a larger therapeutic window, but still shorter than 24 hours.⁸⁶²

After the acute phase of the ischemic event, oral anticoagulation with warfarin is the treatment established for the secondary prophylaxis of thromboembolic complications originated from the heart, in the presence of either arrhythmias or intracavitary thrombosis.¹,²,⁷²²,⁸⁶² Frequent anticoagulation adjustments are necessary to maintain the target therapeutic range (INR between 2 and 3) and treatment should continue throughout life.

As a simpler option, for not requiring recurrent medical visits to adjust anticoagulation, the new oral anticoagulants of direct or indirect action (rivaroxaban, edoxaban and apixabana) can be empirically used for patients with chronic atrial arrhythmias, such as atrial flutter or AF, with potentially beneficial results, even superior to warfarin.⁷²² More recently, meta-analyses comparing the new anticoagulants to warfarin in individuals with LV thrombosis associated with ICM or DCM have suggested that those drugs would have efficacy similar to that of vitamin K antagonists regarding frequency of thrombus resolution, and prevention of stroke or other thromboembolic events and hemorrhagic complications.⁸⁶³ This plausibility might apply to patients with CCCD, but remains to be demonstrated, and the cost of long-term treatment might limit its use in populations of known vulnerability and social marginalization.

The right time to begin chronic oral anticoagulation after ischemic stroke is controversial and has not been studied systematically. For patients with TIA, it is reasonable to begin anticoagulants 24 hours after symptom onset; for patients with mild deficits, after 3 days; for patients with moderate deficits, after 6 to 8 days; and for patients with severe deficits, after 12 to 14 days, as long as, in all these situations, hemorrhagic transformation is ruled out after neuroimaging assessment.⁸⁶²

Risk scores, such as CHADS2 and CHA2DS2-VASc, are used to guide the primary and secondary prophylaxis of cardioembolic stroke in the presence of AF and other cardiovascular risk factors,²,⁷²²,⁸⁶² regardless of the cardiopathy etiology. At first, all patients with 2 or more points (maybe also men with at least 1 point) benefit from prophylaxis with anticoagulants; however, the risk for hemorrhagic complications should be always assessed during the chronic use of those drugs.

The HAS-BLED score (based on uncontrolled hypertension; abnormal renal/hepatic function; previous stroke; history of or predisposition to bleeding, such as anemia; labile INR; age > 65 years; concomitant use of drugs/alcohol) has been validated in different cohorts (but not in individuals with CD) to define the risk for hemorrhagic complications, with high risk of bleeding identified by a score ≥ 3.⁷²²,⁸⁶² In that context, the risk versus benefit assessment should be defined individually and shared with the patients and their families.

## 12.7. Prevention of Cardioembolic Events in Chagas Disease

Prevention of cardioembolic events in patients with CCCD is extremely important because of the high potentially negative impact of those complications on morbidity, mortality, and quality of life.² During clinical follow-up, it is necessary to periodically screen the potential risks for cardioembolic events, such as: systolic ventricular dysfunction and HF, and presence of ventricular aneurysms, mural thrombi, and arrhythmias (especially AF).¹,³⁶⁴

All patients with CCCM should undergo ECG and ECHO periodically during outpatient follow-up and at the clinical assessment of an acute or previous cardioembolic event.¹,² A long ECG tracing of at least 30s should be ideally performed to enable the identification of atrial arrhythmias.¹ The ECHO allows the visualization of the cardiac cavities, identifying different grades of LV systolic dysfunction, regional areas of dyskinesia, aneurysms (mainly apical), spontaneous contrast, and mural thrombi, characterizing them as mobile or sessile, with high potential for embolism, or organized.⁸⁵⁸

Arrhythmias with high potential for embolism, such as atrial flutter or AF, should be actively sought during the clinical follow-up of patients with CD by use of annual ECG, a strategy to identify disease progression from the indeterminate chronic form to cardiopathy.²

In addition, the clinical history and physical examination are essential for the assessment of symptoms, such as palpitation, tachycardia, chest pain, dizziness, lipothymia, malaise, weakness, dyspnea, and functional class worsening, which lead to the clinical suspicion of arrhythmia. Regarding physical examination, the most important is the detection on auscultation of irregular pulse or cardiac rhythm. Because arrhythmic events can occur in paroxysms, arrhythmia might not be identified at the time of clinical assessment. If the clinical suspicion persists, continuous electrocardiographic monitoring by use of 24-hour Holter is required.¹,²,⁷²²

In patients with implanted devices, such as PM, ICD or cardiac resynchronization, the irregular rhythm might not be
# Guidelines

detected on physical examination, and an ECG assessment might be necessary or, even more appropriately, to resort to the event recording of those devices.²,⁷²² These intracardiac devices should be systematically assessed on each visit, aiming at identifying the recording of silent episodes of AF. A proper interface between the clinical follow-up teams (clinical cardiology and arrhythmology) is necessary for the recommendation of appropriate interventions, such as the beginning of anticoagulation for primary prevention.

According to recent guidelines on HF and arrhythmology, considering heart diseases of several etiologies, the identification of mural thrombosis, previous thromboembolic phenomena, and AF with CHA2DS2-VASc ≥ 2 would already indicate anticoagulation for prophylaxis against cardioembolic events.⁷²²,⁸⁶³ It is plausible to admit that the same recommendations would empirically apply, by extrapolation, to patients with CCCD.

As already mentioned, recognizing the CCCD higher potential to produce embolism, a risk score specific for cardioembolic stroke was developed for this etiology, widening the recommendations classically established for other cardiopathies.³⁶⁴ By use of risk-benefit analysis, the researchers proposing that *IPEC-FIOCRUZ* score have also suggested that, for individuals with maximum score (4-5 points), the 4.4% annual incidence of stroke would exceed the estimated 2.0% annual rate of severe bleeding associated with the use of warfarin.³⁶⁴

Although previous guidelines have confirmed the use of that score,¹,² its review is currently mandatory for its specific use in patients with CCCD (that is, not including the IFCD

subgroup, which is practically not at risk for stroke), with occasional correction of the points attributed to the variables (for example, 2 points were attributed to the independent variable systolic dysfunction, with a 2.6 beta coefficient of regression, while the correct would be rounding it up to 3 points), more adequate definition of age groups, and mainly external validation.

The external validation of risk scores is especially relevant for their recommendation in clinical practice, in the context of CCCD, considering the current concepts.⁴⁷³,⁸⁶⁴,⁸⁶⁵ With the implementation of the methodological principles, the score can be invigorated and, in consistency with its undeniable and historical scientific role, recover its coverage and applicability.⁴⁷⁴,⁸⁶⁶ In addition, the empirical therapeutic managements suggested by the time it was formulated³⁶⁴ should be ideally supported by randomized studies of efficacy.⁴⁷⁴,⁸⁶⁶,⁸⁶⁷

Considering the clear trend towards longer survival of patients with CD recently observed with a consequent increase in the frequency of cardiovascular risk factors in that population, there is an increase in the prevalence of AF (not necessarily related to CCCD, but occasionally associated with the cardiopathy of the elderly or other clinical comorbidities), resulting in additional risk for cardioembolic stroke. Thus, recommendations for lifestyle changes with control of SAH, diabetes mellitus, and dyslipidemia, as well as smoking cessation, weight loss, and regular physical activity⁷²² are also important to reduce cardioembolic events in that population. Table 12.2 summarizes the recommendations for treatment and prevention of cardioembolic stroke in CCCD.

<table><caption>Table 12.2 – Treatment and prevention of cardioembolic events in CCCD</caption><thead><tr><th>Indication</th><th>Management</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>Treatment (Δt ≤ 4.5h), excluded the contraindications and potential risk of hemorrhagic transformation</td><td>IV thrombolysis (rt-PA)</td><td>Strong</td><td>B</td></tr><tr><td rowspan="3">Oral anticoagulation (primary or secondary prevention)</td><td>AF with CHADS-VASc ≥ 2 (women) and ≥ 1 (men)</td><td>Strong</td><td>B</td></tr><tr><td>Mural thrombus</td><td>Strong</td><td>C</td></tr><tr><td>Previous ischemic stroke</td><td>Strong</td><td>C</td></tr><tr><td rowspan="3">Investigation of cardiac impairment and source of embolism associated with CCCD</td><td>Transthoracic ECHO</td><td>Strong</td><td>C</td></tr><tr><td>24-h Holter</td><td>Strong</td><td>C</td></tr><tr><td>Interrogate Holter for events (patients with PM/ICD)</td><td>Strong</td><td>C</td></tr><tr><td>Reduction of the risk for AF (regardless of intrinsic predisposition to CCCD)</td><td>Lifestyle change (control SAH, DM, dyslipidemia, weight loss, physical activity, smoking cessation)</td><td>Strong</td><td>C</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; Δt: time from symptom onset; IV: intravenous; rt-PA: recombinant tissue plasminogen activator; AF: atrial fibrillation; ECHO: echocardiogram; PM: pacemaker; ICD: implantable cardioverter-defibrillator; SAH: systemic arterial hypertension; DM: diabetes mellitus.
# 13. Management in Special Subgroups and Handling of Issues Related to *T. cruzi*-HIV Coinfection, Pregnancy, Physical Activity, Surgical Risk, General Anesthesia, and COVID-19

## 13.1. *T. cruzi*-HIV Coinfection

With estimates of 37 million individuals living with HIV/AIDS worldwide, the risk of *T. cruzi*-HIV coinfection<sup>868</sup> is a reality in endemic and nonendemic areas with immigrants infected with the parasite.<sup>869,870</sup>

The *T. cruzi*-HIV coinfection was initially reported in 1990<sup>871</sup> as RCD, and cited in 1988 in Brazil with the identification of the parasite in the cerebrospinal fluid of a patient with AIDS.<sup>83</sup> Described mainly in Brazil and Argentina, but also in other countries (Bolivia, Chile, Spain, USA, Colombia, Venezuela, Jamaica, Germany, and Switzerland), the RCD is characterized by high morbidity and mortality and maternal-fetal transmission,<sup>83,84,580,872,873</sup> interfering in the evolution of both CD and HIV infection. The *T. cruzi*-HIV coinfection usually affects HIV-infected patients with severe immunodeficiency (CD4<sup>+</sup> cells < 200/mm³) and detectable viral load due to failure to respond to effective antiretroviral therapy. In active HIV infection, the marked reduction in CD4<sup>+</sup> cells expresses the deficiency in TH1 response,<sup>874</sup> responsible for the activation of CD4<sup>+</sup> and macrophages capable of secreting IFN-γ and destroying the parasites, thus increasing parasitemia and tissue parasitism.<sup>875</sup>

The RCD presents as meningoencephalitis in approximately 2/3 of the cases, followed by myocarditis, meningoencephalitis plus myocarditis, pericarditis, duodenitis, gastritis, erythema nodosum, and colpitis.<sup>83,580,872,873</sup> In the congenital form of the *T. cruzi*-HIV coinfection,<sup>872,873</sup> abortions, low birth weight, sepsis, and meningoencephalitis occur. More rarely, oligosymptomatic forms manifest as fever, erythema nodosum, myelitis, and as an asymptomatic postpartum woman with a stillborn baby due to congenital CD.<sup>872</sup>

The meningoencephalitis caused by *T. cruzi* should be differentiated from toxoplasmosis, tumors, and infectious and degenerative diseases. Acute myocarditis in RCD should be differentiated from decompensated CCCD. Levels of CD4+ ≤ 200/mm³ are observed in approximately 2/3 of the cases and are even lower in RCD than in patients without RCD. A study has reported a 52.5% mortality in RCD (63 patients out of 120).<sup>83</sup> Retrospective studies have reported RCD in 10%-15% of the coinfection cases, while prospective studies have reported RCD in 10% of patients in previous follow-up.<sup>83,580,873</sup>

The prevalence of coinfection has been estimated at 1.5%-5.0% in Brazil<sup>83,580</sup> and 4.2% in Argentina,<sup>876</sup> being higher among illicit drug users.<sup>877</sup> Approximately 4570-15 360 cases of coinfection have been estimated based on the number of patients infected with *T. cruzi* and HIV in Brazil and Argentina, suggesting a usually underestimated number in the literature.

Of the mortality causes in coinfection,<sup>878</sup> AIDS was the underlying cause of death in 2/3 of the cases and CD in 17.5%. The IFCD predominated in approximately half of

the coinfection cases, the cardiac form occurred in 37%, followed by the digestive and cardiodigestive forms in 5% and 6%, respectively.<sup>873</sup> Reduced levels of CD4<sup>+</sup> (in the diagnosis of coinfection) have been associated with the prognosis of RCD and mortality from RCD. In addition, the presence of parasitemia has been associated with the TH2 response, suggesting imbalance favoring the parasite.

Thus, cases of HIV infection or CD should be actively investigated from the clinical and epidemiological viewpoints with indication for serological screening, aimed at the early diagnosis and control of both infections.

Coinfection is diagnosed by two positive serological tests for both infections and/or parasitological tests for the diagnosis of CD.<sup>580,873</sup> In CD, in case of discordant tests (ELISA, IIF or IHA), a confirmation test (immunoblotting/immunochromatography) or immunoenzymatic test with recombinant antigen or immunofluorescence is indicated. For the HIV infection, a positive ELISA or CLIA for the HIV1 and HIV2 antigens should be confirmed by use of immunoblotting/immunochromatography for the HIV1 and HIV2 antigens.<sup>580,873</sup> Indirect parasitological tests and PCR for *T. cruzi* are specific but have low sensitivity for the diagnosis (approximately 50% in the chronic form), although higher in the coinfection.<sup>879-881</sup>

The diagnosis of RCD should be made by use of the gold-standard methods of direct microscopic detection of the parasite in blood and biological fluids (cerebrospinal and pericardial fluids) and/or in stained tissues.<sup>83,580</sup> Concentration techniques (leukocyte cream, microhematocrit, Strout) are more sensitive than the parasite search in simple peripheral blood smear or fresh peripheral blood. Biopsy can be indicated when other noninvasive methods fail.<sup>83,580</sup> Patients with RCD can have negative CD serological tests,<sup>876</sup> but the investigation should continue by use of direct microscopic methods. Qualitative PCR and indirect parasitological tests with enrichment, such as blood culture and xenodiagnosis, have low positive predictive value for the diagnosis of RCD, because they can be positive in chronic patients without reactivation.<sup>879</sup> However, semiquantitative tests, such as nymph count on the xenodiagnosis<sup>580</sup> and qPCR, are usually useful for RCD monitoring.<sup>880,881</sup>

The antiparasite treatment with benznidazole is mandatory for patients with RCD,<sup>83,580,873</sup> at the dose of 5 mg/kg/day for 60 days. Nifurtimox is indicated as second choice when benznidazole is not available or in the presence of an adverse event contraindicating its use.<sup>83,580</sup> In the first weeks after treatment, the direct search for the parasite in the leukocyte cream helps monitor therapeutic failure in positive cases; negative results do not indicate therapeutic success in the short run. Cure control should be followed up with qualitative PCR or indirect parasitological tests (blood culture) within 3, 6, 9, 12, and 24 months of therapy onset and with serological tests within 6, 12, and 24 months of therapy onset.

Coinfected patients without RCD have shown better antiparasite response in the presence of higher parasitemia levels or higher levels initially.<sup>580</sup>

Follow-up is recommended at reference healthcare services to control both the viral load, with effective antiretroviral therapy control to restore the TH1 response, and CD, with
<table><caption>Table 13.1 – Recommendations for diagnosis and treatment of *T. cruzi* /HIV coinfection</caption><thead><tr><th>Summary of recommendations</th><th>Recommendation grade</th><th>Level of evidence</th></tr></thead><tbody><tr><td>Active search for the coinfection diagnosis, based on clinical-epidemiological suspicion, by use of serological tests</td><td>Strong</td><td>B</td></tr><tr><td>Monitoring of coinfected patients by means of parasitemia and use of molecular and parasitological methods to prevent reactivation, preferably every 3 months</td><td>Strong</td><td>B</td></tr><tr><td>Use of effective antiretroviral therapy to maintain proper immune response</td><td>Strong</td><td>A</td></tr><tr><td>Diagnosis of reactivation by use of concentration methods and direct microscopy in blood and biological fluids or biopsy</td><td>Strong</td><td>B</td></tr><tr><td>Use of quantitative PCR to diagnose reactivation after establishing the boundaries between reactivation and non-reactivation in the endemic region, based on differences between the number of copies in reactivation and in non-reactivation in a large number of patients, by using known initiators and prevalent molecular lineages</td><td>Conditional</td><td>C</td></tr><tr><td>Use neither indirect parasitological methods nor positive qualitative methods for the diagnosis of reactivation in the chronic phase of Chagas disease</td><td>Conditional</td><td>B</td></tr><tr><td>Treat reactivation with benznidazole immediately after the diagnosis, with hospitalization in severe cases with encephalic, myocardial and/or bone marrow impairment</td><td>Strong</td><td>C</td></tr><tr><td>Preemptive treatment of coinfected patients with high parasitemia on xenodiagnosis (&gt;20% of nymphs +) or standardized quantitative PCR with higher values than the median ones in the region</td><td>Conditional</td><td>B</td></tr><tr><td>Maintain effective antiretroviral therapy to ensure proper immune response, CD4+ levels &gt;200 cells/mm³, and undetectable viral load to prevent reactivation</td><td>Conditional</td><td>B</td></tr><tr><td>Secondary prophylaxis 2x/week with benznidazole for patients with CD4+ &lt;200 cells/mm³</td><td>Conditional</td><td>C</td></tr></tbody></table>

parasitemia monitoring to avoid RCD or to enable its early diagnosis and treatment (Table 13.1).

The indication for secondary prophylaxis with benznidazole (5mg/kg/day 3x/week) in patients with CD4+ < 200cells/mm³, similarly to the prevention of other opportunistic infections, is controversial, and there are neither reliable prospective studies nor retrospective series on CD.

## 13.2. Seropositivity in Potential Donors at Blood Banks

In Brazil, serological screening for CD has been mandatory for all blood donors since 1969.⁸⁸² After the appearance of AIDS in the 1980s, several measures and legislations have been developed and adopted to increase the control of blood banks and donors, particularly with the creation of blood centers and the centralization of the control and surveillance activities under the responsibility of the State Health Secretariats.⁸⁸³

The Ministry of Health Ordinance nº 158 from 2016 established as unfit for blood donation individuals with history of household contact with triatomines in endemic areas in addition to those with a clinical or laboratory diagnosis of CD.⁸⁸⁴ The serological screening for CD comprises automated serological tests of high sensitivity and specificity to detect anti-*T. cruzi* IgG antibodies, of which the most often used are ELISA and, more recently, CLIA.⁸⁸⁵,⁸⁸⁶ For the serological screening at blood banks, only one serological test is necessary and it can be repeated if the result is positive.⁸⁸⁷ In such case, the donated blood cannot be used and the donor should be contacted and referred to a CD reference health center for diagnosis elucidation.

With the control of vectorial and blood transfusion transmission, the mean prevalence of CD among blood donors

has been decreasing rapidly. More recent projections have estimated a CD prevalence of 0.18% of the potential blood donors in Brazil.² However, these rates can vary according to the areas where the donations occur and the age of donors, being usually higher in historically endemic regions and at the older groups.⁸⁸⁸

Recent studies conducted with blood donors in the Northeast region have reported prevalence of 0.17% to 0.57% in the state of Ceará and of 0.18% to 2.4% in the state of Piauí.⁸⁸⁹,⁸⁹⁰ A study performed in the city of Uberaba, state of Minas Gerais, with a large number of donors for 15 years has shown a 0.03% annual drop in the prevalence rate, and, in the last year studied, only 0.08% of the donors were ineligible due to seropositivity.⁸⁹¹

With the drop in prevalence among younger donors, an increase in inconclusive or undetermined cases has been observed, most of which resulting from false-positive tests.⁸⁸⁵ All positive cases should be referred to CD reference health centers to undergo new tests to confirm or rule out the diagnosis of CD.

## 13.3. Physical Activity

The practice of physical activity is an important intervention strategy to prevent and treat several chronic diseases, mainly those related to the cardiovascular system.⁸⁹² Recently, the WHO has published recommendations on the practice of physical activity by healthy individuals and those with specific health conditions and diseases. Usually, 150 minutes of moderate physical activity and/or 75 minutes of vigorous physical activity per week are recommended for cardiovascular health benefits.
In addition, moderate strengthening exercises for the major muscle groups should be performed at least twice a week and assessed by use of the perceived exertion scale. Flexibility and balance exercises should also be practiced, mainly by the elderly, to maintain amplitude of movement and autonomy for daily life activities.

Health benefits can be obtained even at lower physical activity levels, and previous inactive individuals should begin training gradually.⁸⁹³ Small amounts of physical activity can be more beneficial to health as compared to being inactive, and, due to the dose-response relationship, higher amounts can be even more beneficial.⁸⁹³,⁸⁹⁴

However, the benefits of physical activity to physical and mental health of individuals with CD have not been completely explored. Some studies have shown promising results regarding improvement of physical functioning and quality of life.⁸⁹⁵⁻⁸⁹⁷ Such studies, however, have included only patients with the cardiac form of CD, and so far there has been no proper assessment of the influence of that strategy on the IFCD.

Thus, the recommendation of physical exercises for individuals with the IFCD should be identical to those of the general population, aiming to control comorbidities, as well as to improve physical fitness and quality of life. Lifestyle interventions that gradually increase physical activity levels should be encouraged, considering each individual's physical capacity and functioning. Some studies have shown that the practice of physical exercises is associated with improvement in bowel transit, but its effects on individuals with the digestive form of CD have not been investigated.⁸⁹⁸

The effects of physical activity on CCCD have been recently assessed, mainly by use of cardiovascular rehabilitation programs.⁸⁹⁵⁻⁸⁹⁷ In a pioneer study on the topic, a RCT has assessed the effects of a cardiovascular rehabilitation program on patients with CCCD followed up for 3 months, and the physical training promoted improvement of physical fitness and quality of life.⁸⁹⁵

Later, an intervention study has reported that a cardiovascular rehabilitation program for patients with HF due to CD was associated with improvement of the cardiac function assessed by use of LVEF, of respiratory muscle strength, and of quality of life after 8 months of follow-up.⁸⁹⁶,⁸⁹⁹

More recently, the PEACH study, a RCT, has reported improvement of physical functioning and microcirculation after 6 months of a cardiovascular rehabilitation program for patients with CCCD with and without HF.⁸⁹⁷,⁹⁰⁰ Thus, physical exercise has been proven to be an effective intervention strategy to improve several clinical and quality of life parameters in CCCD (Table 13.2).

### 13.4. Pregnant Women

The prevalence of *T. cruzi* infection among pregnant women ranges from < 1% to 70.5% depending on the country, geographical area, and location (rural or urban), while the vertical transmission rate in endemic countries ranges from 0% to 18.2%.³⁸,³⁹ The *T. cruzi* vertical transmission rate differs between regions, varying from around 1.0% in Brazil to 4%-12% in other Southern Cone countries, and seems to depend on parasite- and host-related factors.⁴⁰

The congenital transmission of CD can occur at any phase of the maternal disease; however, the highest transmission rate occurs among pregnant women in the acute phase of disease, approximately 30%, while the overall rate is 4.7%.⁸⁸,⁹⁰¹ In Brazil, the congenital transmission rate of CD ranges from 0% to 5.2%; however, there is great heterogeneity depending on the geographical region assessed. The highest regional congenital transmission rate was observed in the Southern-Southeastern region (2.1%), followed by the Northeastern (1.6%) and West-Central (0.9%) regions.⁸⁷

The evidence of increased risk for abortion or prematurity among seropositive pregnant women is inconclusive. However, studies have suggested that the maternal chronic infection influences neither the clinical course of pregnancy nor the newborn health, as long as there is no vertical transmission. However, the fetal infection increases the likelihood of premature delivery, low birth weight, and natimortality.⁹⁰²

The congenital transmission of *T. cruzi* is a complex process, resulting from the interaction of multiple factors related to the parasite, placenta, and fetal and maternal immune response.⁹⁰³ The parasite load of women infected during pregnancy is fundamental to congenital transmission.⁹⁰⁴ Parasitemia can reappear with the RCD usually associated with the transient physiological immunosuppression of pregnancy.⁹⁰⁵ In addition, the role of maternal age and number of gestations in increasing the risk for transmission awaits further investigation. However, there is evidence that the innate immune response activation, by use of pro- and anti-inflammatory mediators, in pregnant women can contribute to reduce the occurrence and severity of the congenital infection.⁹⁰⁶

The impact of CD on the course of pregnancy is controversial. Some studies have pointed to the benignity of the association, while others have reported a high incidence of pregnancy complications and perinatal mortality, as well as of neonatal hypotrophy, considering *T. cruzi*-infected pregnant women a group at high obstetrical risk.⁹⁰⁷

The prognosis of pregnant women with CCCD is closely related to the severity of ventricular dysfunction and functional class at the beginning of pregnancy. Patients in functional class I/II at the beginning of pregnancy usually reach delivery

<table><caption>**Table 13.2 – Recommendations of physical activity practice for individuals with Chagas disease**</caption><thead><tr><td>Summary of recommendations</td><td>Recommendation Grade</td><td>Level Of Evidence</td></tr></thead><tbody><tr><td>Benefits of physical activity for individuals with the indeterminate form of Chagas disease</td><td>Strong</td><td>C</td></tr><tr><td>Benefits of physical activity for individuals with the cardiac form of Chagas disease</td><td>Conditional</td><td>B</td></tr><tr><td>Benefits of physical activity for individuals with the digestive form of Chagas disease</td><td>Conditional</td><td>C</td></tr></tbody></table>
uneventfully; however, those in functional class III/IV have a 25% to 50% probability of death.⁹⁰⁸ Heart disease, as long as assisted and not severe, does not contraindicate pregnancy. Patients with HF and/or severe arrhythmias should be oriented not to get pregnant, but if they do, they require special follow-up and care.

The etiological treatment should not be administered to pregnant women nor women at reproductive age not using contraception. Importantly, there is evidence that etiological treatment reduces the risk for congenital transmission in a subsequent pregnancy.⁵⁶⁹⁻⁵⁷¹

In addition, in the exclusive case of acute CD, the etiological treatment can be instituted for pregnant women, considering maternal morbidity and mortality, higher risk of congenital transmission, and impact on the newborn health. Pregnant women with severe acute CD (myocarditis or meningoencephalitis) should be treated regardless of the gestational age because of the high maternal morbidity and mortality, in addition to the high risk of congenital transmission of CD (22% to 71%), and the potential impact on the newborn health. Pregnant women with non-severe acute CD should be ideally treated after the second trimester of pregnancy, because of the potential risk of congenital malformation related to benznidazole.⁸

The use of cardiovascular drugs by pregnant women with CD should follow selective and individualized medical indication, because of the potential risk of side effects on the fetus. Infected mothers should be treated after the delivery and lactation period to prevent interrupting breastfeeding because of possible adverse reactions. CD should be investigated systematically in the relatives and other children born from infected mothers (serological diagnosis), and the positive cases should be assessed clinically and treated according to the already discussed principles.⁸⁶

## 13.5. Newborns

Currently, in vector-free areas inside and outside Latin America, *T. cruzi* infection is mainly disseminated through congenital or perinatal vertical transmission, which exceeds blood transfusion and organ transplantation. Despite underreporting and underestimation worldwide, over two million women at reproductive age are infected with *T. cruzi* and 1%-10% of the children from infected mothers are born with CD. Based on recent demonstrations that congenital transmission can be avoided, the OMS changed its objective in 2018, from control to elimination of congenital CD.⁸⁶,⁵⁶⁹,⁵⁷¹

The severity of congenital CD varies widely, from asymptomatic cases to fatal infection, which is related to the parasitemia level at birth.⁹⁰⁴ Studies conducted in Brazil, Argentina, Chile, and Paraguay have shown that 60% to 90% of the newborns with congenital infection are asymptomatic. Among the symptomatic ones, the most frequent clinical manifestations were prematurity, low birth weight, fever, and hepatosplenomegaly.⁸⁶

The congenital infection should be investigated in all children born from seropositive mothers, not only in the first month of life, but also at 6 and 12 months of age. Follow-up for 1 year is essential, because a significant proportion of cases is initially negative, the disease being only detected at a later stage.⁸⁶

The most recommended diagnostic methods in the first month after birth are the direct parasitological tests, by using methods of centrifuge concentration, such as microhematocrit.⁹⁰⁸ When positive, those tests provide the undeniable and definitive diagnosis of the infection; however, when the parasite load is low, mainly when transmission occurs in the last trimester of pregnancy or during delivery, the tests can generate false negative results. Thus, more sensitive and automated tests are necessary to the early detection of congenital infection. The positive result determines immediate etiological treatment.⁸⁶ Congenital CD is considered acute, thus requiring mandatory reporting.

In the case of a negative parasitological test, the diagnostic investigation should include serological tests (with two different techniques), after the 7th month of life. A serological study before the 6th month is not useful, because of the passive transfer of maternal antibodies to the baby. After the 10th month, such antibodies disappear and the diagnosis of congenital CD is more precise; however, delay in the diagnosis reduces the efficacy of the treatment and increases the risk of losing to follow-up.⁸⁶ A negative serology after that period allows excluding the diagnosis of *T. cruzi* infection.

The molecular methods represent a promising alternative and have been widely used for the early detection of congenital infections, mainly in Europe. However, they are expensive, and require considerable technical training and careful standardization, which hinder their implementation in laboratory routine. Thus, the molecular methods require wider clinical validations before being considered gold-standard for the diagnosis of congenital infections.⁸⁶

The treatment of the *T. cruzi*-infected newborn is highly effective and can be performed with benznidazole (first option in Brazil) or nifurtimox, for 30 to 60 days, with fewer adverse events as compared to that of adults, and the rate of cure exceeds 90%. The doses recommended for children are 10mg/kg/day of benznidazole in 3 or 2 doses, and 15mg/kg/day of nifurtimox in 3 doses. Benznidazole is available as tablets of 12.5mg, which can be diluted into water and is provided by the State Health Secretariats, while nifurtimox should be requested to the PAHO, through the CD technical group of the Health Surveillance Secretariat of the Brazilian Ministry of Health.

A recently published clinical trial using nifurtimox to treat children (0 to 17 years of age) in Argentina, Colombia, and Bolivia has compared treatments for 30 days versus 60 days. By the end of a 12-month follow-up, both regimens showed significant seroconversion or a reduction in the serum levels as compared to historical controls, and the 60 day regimen was superior to the 30 day regimen in the age group of 2-17 years. Nifurtimox was well tolerated, with mainly mild or moderate adverse effects without sequelae, and only 4% of those events determined interruption of treatment.⁹⁰⁹

The etiological treatment should be followed up by use of parasitological and/or molecular tests in the weeks following treatment onset for neonates with parasitemia. After the end of treatment, the patients should be followed up with quantitative serological tests every 6 months. The patient is considered cured when the serology turns negative in two consecutive tests.⁸⁶
The time necessary for a test to become negative depends on the patient's age and treatment onset. The serology of children diagnosed in the first months of life will become negative between the 2nd and 12th month after treatment onset. The healthcare systems should assess and implement strategies to facilitate the earliest possible diagnosis of the congenital infection, considering the frequent poor adhesion of mothers to follow-up visits in healthcare centers.⁸⁶

Considering the risk of transmission to the newborn through the contact with maternal secretions, breastfeeding should be temporarily suspended only for mothers with RCD or in the acute phase, and more emphatically for those with nipple fissures or bleedings. The individualized assessment of each case is important, considering the great benefit of breastfeeding in the first months of life. In conclusion, mothers on antiparasite treatment for at least 30 days, even in the cases mentioned, can breastfeed freely.²

### 13.6. Surgical and Anesthetic Risk

Patients with CCCD have increased surgical and anesthetic risks due to several reasons, which should be considered in the pre-, intra-, and postoperative periods.

The most important preoperative care is HF control with drug optimization and the correction of occasional electrolyte disorders.

Ventricular function should be assessed by ECHO whenever possible. All candidates to surgery should undergo ECG, and, for those with arrhythmias or compatible symptoms, ambulatory ECG monitoring (Holter) may be necessary. Antiarrhythmic drugs should not be suspended, but oral anticoagulants should be interrupted. The new oral anticoagulants, direct thrombin inhibitors, or direct factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, can simply be suspended 24 to 48 hours prior to surgery. Warfarin, however, should be ideally suspended 5 days prior to surgery, which can be performed when the INR is lower than 1.5. During warfarin suspension, the patients at high risk for thromboembolic events should undergo anticoagulation with heparins, such as subcutaneous full-dose enoxaparin. Finally, preoperative assessment of patients with CD should consider the occasional presence of megaesophagus, which increases the risk of bronchoaspiration in the intra- and postoperative periods.⁹¹⁰

During surgery, patients with CCCD require individualized anesthetic management. The anesthesiologist should consider hemodynamic aspects, such as myocardial dysfunction, sometimes biventricular, which limit the volume infusion and increase the risk for cardiac arrhythmias.⁹¹⁰ Continuous electrocardiographic monitoring is essential to control malignant ventricular arrhythmias and bradyarrhythmias. Invasive arterial and central venous hemodynamic monitoring is useful and should be implemented in more severe cases and major surgeries. Implantation of a temporary transvenous cardiac PM should be considered in patients with advanced AVB, mainly when associated with intraventricular conduction disorders. Intraoperative transesophageal ECHO provides valuable information on the inotropic response to anesthetic medication and the patient's blood volume status, being useful in selected cases.

Anesthetic care is very important. In patients with ventricular dysfunction, the induction of anesthesia can result in rapid hemodynamic deterioration, which occurs mainly by peripheral vasoconstriction and negative inotropic action induced by anesthetic agents.⁹¹⁰ Intraoperative volume infusion should be judicious. In patients on HF treatment with vasodilators and diuretics, blood pressure levels are commonly low and the time needed for the onset of venous anesthetic action is longer because of the slower blood circulation.⁹¹¹ In addition, hepatic failure, consequent to right HF, and renal failure alter the pharmacokinetics of most medications.

The autonomic dysfunction of patients with CCCD reduces the contractile reserve and can attenuate the action of exogenous catecholamines, requiring higher doses than the usual ones for hemodynamic stabilization.⁴²² The best anesthetic regimen should cause the lowest possible grade of myocardial depression and vasodilation. All inhalation anesthetics and most venous anesthetics are myocardial depressant drugs,⁹¹² requiring titration and judicious monitoring by the anesthesiologist. Whenever possible, according to the surgery type, regional anesthesia techniques should be used isolated or associated with general anesthesia due to the lower risk of hemodynamic instability.⁹¹⁰

Patients with CCCD frequently have implantable electronic devices for the treatment of arrhythmias and/or HF. If a thermal cautery is used during surgery, specific attention is needed. The production of electrical noise by the thermal cautery might lead the device to misinterpret cardiac electrical events, resulting in inhibition of necessary electrical stimuli or triggering inappropriate electrical shock. Patients with a PM should have their devices placed in the DOO or VOO mode. ICD patients should have their devices turned off during surgery or a magnet should be placed on the device to prevent occasional inappropriate shocks. Central venous access should be carefully obtained in those patients because the guidewire can generate noise by contacting the shocking electrode, leading to inappropriate electrical discharges.⁹¹³ Regardless of the device type, the thermal cautery should be placed in the bipolar mode at the lowest effective power and be used intermittently with the neutral plate placed as far as possible from the generating unit.

In the postoperative period, patients with CCCD and ventricular dysfunction or cardiac arrhythmias, as well as those undergoing major surgeries, should be at an intensive care unit. The oral anticoagulant used prior to surgery that was temporarily suspended perioperatively, as well as the other medications for HF and arrhythmias, should be reintroduced as soon as possible.

### 13.7. Chagas Disease and Coronavirus Infection

The worldwide spread of COVID-19 made the WHO declare it a pandemic in March 2020. Following the same global epidemiological profile, studies have shown an interrelationship between potential of severity and comorbidities with emphasis on cardiovascular disease and higher fatality rates in patients with those diseases as compared to the general population.⁹¹⁴

Of the patients with COVID-19, more than 80% have mild symptoms, such as fever, sore throat, and cough,⁹¹⁵ but mortality rates can vary from 2.3% to 27%⁹¹⁶,⁹¹⁷ in vulnerable populations,
such as the elderly and patients with comorbidities,⁹¹⁸,⁹¹⁹ due to severe complications, including pneumonia, thromboembolism, sepsis, renal failure, and HF.⁹²⁰,⁹²¹ The SARS-CoV-2 infection can affect the cardiovascular system in several ways, such as inflammatory myocardial injury (myocarditis), intravascular thrombosis, and takotsubo syndrome, causing HF, arrhythmias, and circulatory shock.⁹²² Patients with HF have higher mortality from COVID-19 than those without HF,⁹²³ and that rate can reach 40%.⁹²⁴ Thus, previous HF is an undeniable risk factor for mortality from COVID-19.⁹²³

The consequences of the COVID-19 pandemic on the health of patients with CD have not been totally understood.⁷¹ Because many of those patients have heart disease, they are vulnerable to severe infections and can have severe complications from COVID-19,⁹²⁵ such as higher mortality in the presence of HF.⁹²³ In addition, there is high prevalence of comorbidities in the population with CD, which is aging due to CD transmission control and global improvement of the health system.⁹²⁶ Thus, it is possible, and even likely, that the COVID-19-related morbidity/mortality is higher in patients with CD. However, a recent comprehensive registry in Brazil has shown that the in-hospital mortality from COVID-19 was similar between patients with and without CD, paired for sex, age, hypertension, and diabetes mellitus, even with HF and AF being more prevalent in the group with chronic *T. cruzi* infection.¹⁰⁴

The COVID-19 prevention for patients at any stage of CD follows the same recommendations for the general population presented in the Brazilian Ministry of Health guidelines, although with emphasized recommendations and special attention to vaccine indications according to the age groups, for prophylaxis of pneumococcal infections, influenza virus, and COVID-19.⁹²⁷ Patients with CD have priority indication for anti-COVID-19 vaccination and are important risk groups in vaccination strategies, not only for COVID-19 but also for other immune preventable diseases with risk for the development of severe pneumonias and/or cardiac impairment.

For individuals with CD who get infected with SARS-CoV-2, medical care should be instituted since the PHC level, with emphasis on the risks associated with myocarditis and thromboembolic intravascular phenomena (Figure 13.1).

In moderate or severe COVID-19 cases, corticotherapy can be used, almost always from the 6th day of disease on and for a short period of time. There is no contraindication to the use of corticosteroids for patients with CD coinfected with SARS-CoV-2 because their immunosuppressant effect, which could reactivate *T. cruzi* infection, is not reached at the recommended doses and for short periods of time. However, the management and indications should be shared by an infectiologist and a cardiologist.⁹²⁸

For patients with CCCD and mild COVID-19, the previously established cardiovascular medication and anticoagulation should be maintained, because there is no indication that they are harmful. For moderate or severe cases, oral anticoagulation should be replaced by low-molecular-weight heparin and the cardiovascular medication reassessed according to the patient's hemodynamic state.

## 13.8. Noncardiac Transplantation and Immunosuppressive Therapy

The transmission of CD through organ transplantation was described for the first time in Brazil in 1981 after renal transplantation.⁹²⁹ After that, CD transmission after kidney, liver, heart, or bone marrow donation has been reported worldwide, and the transmission rate has varied according to the transplanted organ: 13%⁹³⁰ to 16%⁹³¹ for kidney, 20%⁹³⁰ to 22%⁹³² for liver, and 75% for heart.⁹³⁰ In addition, RCD has been detected in patients with chronic CD recipients of solid organs.

The largest experience is in renal transplantation, in which RCD occurs mainly in the first year and varies among centers from 8% to 22%.⁹³³,⁹³⁴ Regarding liver transplantation, the experience is limited, and the incidence of RCD varies according to the center similarly to that in renal transplantation.⁹³⁴ For bone marrow transplantation in patients with asymptomatic chronic CD, the RCD has ranged from 17% to 40%.⁵⁸³

In Brazil, the Ordinance nº 2600 from 2009 determines testing for CD: (1) in all donations, with the same algorithms used for blood donor screening; (2) for registration of potential organ recipients in the Unified Technical Register; and (3) in all dead donors of organs, tissues, cells, or body parts prior to graft allocation. That ordinance establishes that the heart from a donor with CD should not be used for transplantation, while the kidneys, pancreas, liver, and lungs of donors with CD can be transplanted as long as authorized by the recipient and transplant team, despite the risk of transmission and implicating in need for post-procedure monitoring.

### 13.8.1. Donor with Chagas Disease and Recipient without Chagas Disease

In this situation, there is risk for CD transmission. Living donors with CD should be ideally treated with benznidazole for 60 days before the procedure. If there is no time for treatment completion, the transplantation can occur after 14 days of treatment,²,⁶⁵¹,⁹³⁴ based on the parasitemia drop in that phase of treatment.⁵⁸⁷

For untreated donors, monitoring the occurrence of CD transmission is recommended, as well as treatment of the diagnosed cases, when good results are observed with a high rate of cure.²,⁵⁸³,⁹³¹,⁹³⁵,⁹³⁶ However, the prophylactic use of benznidazole, which would be routinely applied, is controversial, considering its toxicity and the low transmission rate.

Monitoring is performed with the direct search for *T. cruzi* in peripheral blood weekly for up to 60 days, in addition to indirect parasitological and serological tests at 30 and 60 days after transplantation. Then, clinical, serological, and parasitological (direct/indirect/PCR) tests should be performed every 2 months up to 1 year of follow-up; after that, every 6 months, while immunosuppression, whose duration depends on the transplant modality and type, persists. In addition to the usual monitoring efforts, any suspicious clinical sign of acute CD should be investigated by use of parasitological tests.
<figure><img src="image_13.png" /><figcaption>**Figura 13.1** – Flowchart recommended for the medical care of patients with Chagas disease in two situations: COVID-19 prevention and coinfection. CD: Chagas disease; ACD: acute Chagas disease; CCCD: chronic cardiomyopathy of Chagas disease; SaO2: O2 saturation; ICU: intensive care unit</figcaption></figure>

PCR can be used in the place of indirect parasitological tests.² At any time, if acute infection is detected, conventional antiparasite treatment should be instituted.² In addition, it is worth noting that the serological tests might not turn positive because of the patients' immunosuppression. Monitoring should be more frequent right after transplantation, because, in most cases, transmission and acute infection occur between the 3rd and 29th weeks (mean of 8 weeks).⁹³⁰

A study comparing 13 patients not correctly monitored with 19 who underwent weekly monitoring has shown that 5 patients in the first group were diagnosed with symptomatic CD, 4 of whom died, while, in the other group, 4 transmissions were confirmed, the patients received antiparasite treatment and did not develop symptomatic disease.⁹³⁰ The parasitological tests should be performed weekly during treatment or up to two consecutive negative tests are obtained.⁹³⁴

### 13.8.2. Recipient with Chagas Disease

The prevalence of CD among candidates for solid organ transplantation is higher in the heart group because of the CD specific characteristic of progressing to refractory HF in many cases.

Although the RCD can occur during the immunosuppression period following any solid organ transplantation, severe forms of that complication, such as meningoencephalitis⁹³⁷ and intracerebral tumor-like lesions ("chagomas"),⁹³⁸ are not common. In renal transplantation recipients, RCD occurs mainly in the first year after the procedure or when the immunosuppression

intensifies after rejection episodes. The RCD can be totally asymptomatic but, when clinical manifestations appear, they usually consist of the subcutaneous lesions (erythema nodosum-like, panniculitis) in the limbs. If the treatment is not initiated, the lesions can progress to painful ulcers. Myocarditis and encephalitis are also described but less frequently. The response to treatment is good, with suitable long-term survival of the patient and graft.⁹³³

There are two managements for transplant recipients already diagnosed with CD: treat before transplantation the already infected recipient or remain vigilant to diagnose and treat an eventual RCD. The routine treatment of asymptomatic recipients with CD before undergoing transplantation could theoretically reduce the chance of an RCD after immunosuppression; there is no conclusive evidence, however, favoring that statement and the correspondent prophylactic management. On the contrary, failure of that management has been reported.⁹³⁹

Thus, the preferred management is the routine monitoring of parasitemia and other RCD evidence, so that early specific treatment can be initiated, increasing the treatment success with a smaller number of severe and fatal cases.²,⁹³⁴ In addition, the result of the treatment of RCD is usually favorable, with high rates of cure and low mortality.

All *T. cruzi*-infected recipients should be followed up for the investigation of RCD once a week in the first 2 months, every 2 weeks from the third to the sixth month, and, after that, monthly up to 1 year. After intensification of immunosuppression, the follow-up should be weekly for 2 months, or at any time if acute CD is clinically suspected.⁹³⁴,⁹⁴⁰