# SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease – 2023

José Antonio Marin-Neto, Anis Rassi, Gláucia Maria Moraes Oliveira, Luís

Claudio Lemos Correia, Alberto Novaes Ramos, Alejandro Ostermayer

Luquetti, Alejandro Marcel Hasslocher-Moreno, Andréa Silvestre De Sousa, Angelo Amato Vincenzo De Paola, Antônio Carlos Sobral Sousa, et al.

► To cite this version:

José Antonio Marin-Neto, Anis Rassi, Gláucia Maria Moraes Oliveira, Luís Claudio Lemos Correia, Alberto Novaes Ramos, et al. SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease – 2023. Arquivos Brasileiros de Cardiologia, 2023, 120, 10.36660/abc.20230269. hal-04289028

HAL Id: hal-04289028

https://amu.hal.science/hal-04289028v1

Submitted on 17 Nov 2023

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# SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease – 2023

**Development:** Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia – SBC)

**Coordinators:** José Antonio Marin-Neto, Anis Rassi Júnior, Gláucia Maria Moraes Oliveira

**Writing Committee:** José Antonio Marin-Neto, Anis Rassi Júnior, Gláucia Maria Moraes Oliveira, Luís Claudio Lemos Correia

**Guideline Authors:** José Antonio Marin-Neto,\*1 Anis Rassi Jr.,\*2 Gláucia Maria Moraes Oliveira,\*3 Luís Claudio Lemos Correia,\*4 Alberto Novaes Ramos Júnior,\*5 Alejandro Ostermayer Luquetti,\*6 Alejandro Marcel Hasslocher-Moreno,\*7 Andréa Silvestre de Sousa,\*7 Angelo Amato Vincenzo de Paola,\*8 Antônio Carlos Sobral Sousa,\*9,10 Antonio Luiz Pinho Ribeiro,\*11 Dalmo Correia Filho,\*9 Dilma do Socorro Moraes de Souza,\*12 Edecio Cunha-Neto,\*13 Felix José Alvarez Ramires,\*14 Fernando Bacal,\*14 Maria do Carmo Pereira Nunes,\*11 Martino Martinelli Filho,\*14 Maurício Ibrahim Scanavacca,\*14 Roberto Magalhães Saraiva,\*7 Wilson Alves de Oliveira Júnior,\*15 Adalberto Menezes Lorga-Filho,\*16,17 Adriana de Jesus Benevides de Almeida Guimarães,\*18,19 Adriana Lopes Latado Braga,\*20 Adriana Sarmento de Oliveira,\*14 Alvaro Valentim Lima Sarabanda,\*21 Ana Yecê das Neves Pinto,\*7 Andre Assis Lopes do Carmo,\*22 Andre Schmidt,\*1 Andréa Rodrigues da Costa,\*7 Barbara Maria Ianni,\*14 Brivaldo Markman Filho,\*23 Carlos Eduardo Rochitte\*14,24 Carolina Thé Macêdo,\*25 Charles Mady,\*14 Christophe Chevillard,\*26 Cláudio Marcelo Bittencourt das Virgens,\*20 Claudson Nery de Castro,\*27 Constança Felicia De Paoli de Carvalho Britto,\*28 Cristiano Pisani,\*14 Daniela do Carmo Rassi,\*29 Dário Celestino Sobral Filho,\*15 Dirceu Rodrigues de Almeida,\*8 Edimar Alcides Bocchi,\*14 Evandro Tinoco Mesquita,\*30 Fernanda de Souza Nogueira Sardinha Mendes,\*7 Francisca Tatiana Pereira Gondim,\*31 Gilberto Marcelo Sperandio da Silva,\*7 Giselle de Lima Peixoto,\*32 Gustavo Glotz de Lima,\*33 Henrique Horta Veloso,\*7 Henrique Turin Moreira,\*34 Hugo Bellotti Lopes,\*35 Ibraim Masciarelli Francisco Pinto,\*35,36 João Marcos Bemfica Barbosa Ferreira,\*37 João Paulo Silva Nunes,\*14,38 José Augusto Soares Barreto-Filho,\*9 José Francisco Kerr Saraiva,\*39 Joseli Lannes-Vieira,\*28 Joselina Luzia Menezes Oliveira,\*9 Luciana Vidal Armaganijan,\*35 Luiz Cláudio Martins,\*40 Luiz Henrique Conde Sangenis,\*7 Marco Paulo Tomaz Barbosa,\*11 Marcos Antonio Almeida-Santos,\*41 Marcos Vinicius Simões,\*1 Maria Aparecida Shikanai Yasuda,\*13 Maria da Consolação Vieira Moreira,\*11 Maria de Lourdes Higuchi,\*14 Maria Rita de Cassia Costa Monteiro,\*42 Mauro Felippe Felix Mediano,\*7,43 Mayara Maia Lima,\*44 Maykon Tavares de Oliveira,\*1 Minna Moreira Dias Romano,\*1 Nadjar Nitz Silva Lociks de Araujo,\*27 Paulo de Tarso Jorge Medeiros,\*35 Renato Vieira Alves,\*45 Ricardo Alkmim Teixeira,\*14 Roberto Coury Pedrosa,\*46 Roque Aras Junior,\*47 Rosalia Morais Torres,\*11 Rui Manoel dos Santos Povoa,\*8 Sergio Gabriel Rassi,\*2 Silvia Marinho Martins Alves,\*48 Suelene Brito do Nascimento Tavares,\*29,49 Swamy Lima Palmeira,\*44 Telêmaco Luiz da Silva Júnior,\*50 Thiago da Rocha Rodrigues,\*51 Vagner Madrini Junior,\*14 Veruska Maia da Costa Brant,\*44 Walderez Ornelas Dutra,\*11 João Carlos Pinto Dias\*7

\* Contributed equally to the manuscript.

Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto,¹ Ribeirão Preto, SP – Brazil

Hospital do Coração Anis Rassi,² Goiânia, GO – Brazil

Universidade Federal do Rio de Janeiro,³ Rio de Janeiro, RJ – Brazil

Escola Bahiana de Medicina e Saúde Pública (EBMSP),⁴ Salvador, BA – Brazil

Universidade Federal do Ceará, Faculdade de Medicina,⁵ Fortaleza, CE – Brazil

Centro de Estudos da Doença de Chagas, Hospital das Clínicas da Universidade Federal de Goiás,⁶ Goiânia, GO – Brazil

Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz,⁷ Rio de Janeiro, RJ – Brazil

Universidade Federal de São Paulo,⁸ São Paulo, SP – Brazil

Universidade Federal de Sergipe,⁹ São Cristóvão, SE – Brazil

Hospital São Lucas, Rede D'Or São Luiz,¹⁰ Aracaju, SE – Brazil

Universidade Federal de Minas Gerais,¹¹ Belo Horizonte, MG – Brazil

Universidade Federal do Pará,¹² Belém, PA – Brazil

Universidade de São Paulo, Faculdade de Medicina da Universidade,¹³ São Paulo, SP – Brazil

Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo,¹⁴ São Paulo, SP – Brazil

Universidade de Pernambuco, Faculdade de Ciências Médicas,¹⁵ Recife, PE – Brazil

Instituto de Moléstias Cardiovasculares,¹⁶ São José do Rio Preto, SP – Brazil
Hospital de Base de Rio Preto,¹⁷ São José do Rio Preto, SP – Brazil

Secretaria de Saúde do Distrito Federal,¹⁸ Brasília, DF – Brazil

Escola Superior de Ciências da Saúde,¹⁹ Brasília, DF – Brazil

Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia,²⁰ Salvador, BA – Brazil

Instituto de Cardiologia do Distrito Federal,²¹ Brasília, DF – Brazil

Hospital das Clínicas da Universidade Federal de Minas Gerais,²² Belo Horizonte, MG – Brazil

Hospital das Clínicas da Universidade Federal de Pernambuco,²³ Recife, PE – Brazil

Hcor, Associação Beneficente Síria,²⁴ São Paulo, SP – Brazil

Hospital São Rafael, Fundação Monte Tabor,²⁵ Salvador, BA – Brazil

Institut National de la Santé Et de la Recherche Médicale (INSERM),²⁶ Marseille – France

Universidade de Brasília,²⁷ Brasília, Distrito Federal – Brazil

Instituto Oswaldo Cruz, Fundação Oswaldo Cruz,²⁸ Rio de Janeiro, RJ – Brazil

Universidade Federal de Goiás, Faculdade de Medicina,²⁹ Goiânia, GO – Brazil

Hospital Universitário Antônio Pedro da Faculdade Federal Fluminense,³⁰ Niterói, RJ – Brazil

Hospital Universitário Walter Cantídio da Universidade Federal do Ceará,³¹ Fortaleza, CE – Brazil

DentCor Clínica Médica e Odontológica,³² Santo André, SP – Brazil

Instituto de Cardiologia do Rio Grande do Sul,³³ Porto Alegre, RS – Brazil

Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo,³⁴ Ribeirão Preto, SP – Brazil

Instituto Dante Pazzanese de Cardiologia,³⁵ São Paulo, SP – Brazil

Grupo Fleury,³⁶ São Paulo, SP – Brazil

Universidade do Estado do Amazonas,³⁷ Boca do Acre, AM – Brazil

Fundação Zerbini, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo,³⁸ São Paulo, SP – Brazil

Sociedade Campineira de Educação e Instrução,³⁹ Campinas, SP – Brazil

Universidade Estadual de Campinas, Faculdade de Ciências Médicas,⁴⁰ Campinas, SP – Brazil

Universidade Tiradentes,⁴¹ Aracaju, SE – Brazil

Organização Social de Saúde VivaRio,⁴² Rio de Janeiro, RJ – Brazil

Instituto Nacional de Cardiologia (INC),⁴³ Rio de Janeiro, RJ – Brazil

Secretaria de Vigilância em Saúde, Ministério da Saúde,⁴⁴ Brasília, DF – Brazil

Instituto René Rachou, Fundação Oswaldo Cruz,⁴⁵ Belo Horizonte, MG – Brazil

Hospital Universitário Clementino Fraga Filho, Instituto do Coração Edson Saad – Universidade Federal do Rio de Janeiro,⁴⁶ RJ – Brazil

Universidade Federal da Bahia (UFBA),⁴⁷ Salvador, BA – Brazil

Ambulatório de Doença de Chagas e Insuficiência Cardíaca do Pronto Socorro Cardiológico Universitário da Universidade de Pernambuco

(PROCAPE/UPE),⁴⁸ Recife, PE – Brazil

Prefeitura Municipal de Goiânia,⁴⁹ Goiânia, GO – Brazil

Cardion - Cardiologia Preventiva e Avançada,⁵⁰ Uberlândia, MG – Brazil

Hospital Felicio Rocho,⁵¹ Belo Horizonte, MG – Brazil

**SBC Clinical Practice Guidelines Committee:** Carisi Anne Polanczyk (Coordinator), Humberto Graner Moreira, Mário de Seixas Rocha, Jose Airton de Arruda, Pedro Gabriel Melo de Barros e Silva – Period 2022-2024

**How to cite this Guideline:** Marin-Neto JA, Rassi Jr. A, Oliveira GMM, Correia LCL, Ramos Jr. AN, Luquetti AO, et al. SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease – 2023. Arq Bras Cardiol. 2023;120(6):e20230269

**Note:** These guidelines are for information purposes and should not replace the clinical judgment of a physician, who must ultimately determine the appropriate treatment for each patient.

**Correspondence:** Sociedade Brasileira de Cardiologia – Av. Marechal Câmara, 360/330 – Centro – Rio de Janeiro, Brazil – Posta Code 20020-907. E-mail: diretrizes@cardiol.br
# Guidelines

## SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease - 2023

The report below lists declarations of interest as reported to the SBC by the experts during the period of the development of these statements, 2021-2023.

<table><thead><tr><th>Expert</th><th>Type of relationship with industry</th></tr></thead><tbody><tr><td>Adalberto Menezes Lorga Filho</td><td>Nothing to be declared</td></tr><tr><td>Adriana de Jesus Benevides de Almeida Guimarães</td><td>Nothing to be declared</td></tr><tr><td>Adriana Lopes Latado Braga</td><td>Nothing to be declared</td></tr><tr><td>Adriana Sarmento de Oliveira</td><td>Nothing to be declared</td></tr><tr><td>Alberto Novaes Ramos Júnior</td><td>Nothing to be declared</td></tr><tr><td>Alejandro Marcel Hasslocher-Moreno</td><td>Nothing to be declared</td></tr><tr><td>Alejandro Ostermayer Luquetti</td><td>Nothing to be declared</td></tr><tr><td>Alvaro Valentim Lima Sarabanda</td><td>Nothing to be declared</td></tr><tr><td>Ana Yecê das Neves Pinto</td><td>Nothing to be declared</td></tr><tr><td>Andre Assis Lopes do Carmo</td><td>Financial declaration<br>A - Economically relevant payments of any kind made to (i) you, (ii) your spouse/partner or any other person living with you, (iii) any legal person in which any of these is either a direct or indirect controlling owner, business partner, shareholder or participant; any payments received for lectures, lessons, training instruction, compensation, fees paid for participation in advisory boards, investigative boards or other committees, etc. From the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br>- Biosense Webster; Abbott.<br>Other relationships<br>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br>- Biosense Webster; Abbott.</td></tr><tr><td>Andre Schmidt</td><td>Nothing to be declared</td></tr><tr><td>Andréa Rodrigues da Costa</td><td>Nothing to be declared</td></tr><tr><td>Andréa Silvestre de Sousa</td><td>Nothing to be declared</td></tr><tr><td>Angelo Amato Vincenzo de Paola</td><td>Nothing to be declared</td></tr><tr><td>Anis Rassi Junior</td><td>Nothing to be declared</td></tr><tr><td>Antônio Carlos Sobral Sousa</td><td>Nothing to be declared</td></tr><tr><td>Antônio Luiz Pinho Ribeiro</td><td>Nothing to be declared</td></tr><tr><td>Barbara Maria Ianni</td><td>Nothing to be declared</td></tr><tr><td>Brivaldo Markman Filho</td><td>Nothing to be declared</td></tr><tr><td>Carlos Eduardo Rochitte</td><td>Nothing to be declared</td></tr><tr><td>Carolina Thé Macêdo</td><td>Nothing to be declared</td></tr><tr><td>Charles Mady</td><td>Nothing to be declared</td></tr><tr><td>Christophe Chevillard</td><td>Nothing to be declared</td></tr></tbody></table>
<table><tr><td>Cláudio Marcelo Bittencourt das Virgens</td><td>Financial declaration<br/>A - Economically relevant payments of any kind made to (i) you, (ii) your spouse/partner or any other person living with you, (iii) any legal person in which any of these is either a direct or indirect controlling owner, business partner, shareholder or participant; any payments received for lectures, lessons, training instruction, compensation, fees paid for participation in advisory boards, investigative boards or other committees, etc. From the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Daiichi-Sankyo: Lixiana e Benicar Triplo; Pfizer: Eliquis; AstraZeneca: Forxiga; Novo Nordisk: Ozempic.<br/>Other relationships<br/>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Novo Nordisk: Ozempic; Daiichi-Sankyo: Lixiana e Benicar Triplo.</td></tr><tr><td>Cleudson Nery de Castro</td><td>Nothing to be declared</td></tr><tr><td>Constança Felicia De Paoli de Carvalho Britto</td><td>Nothing to be declared</td></tr><tr><td>Cristiano Faria Pisani</td><td>Financial declaration<br/>A - Economically relevant payments of any kind made to (i) you, (ii) your spouse/partner or any other person living with you, (iii) any legal person in which any of these is either a direct or indirect controlling owner, business partner, shareholder or participant; any payments received for lectures, lessons, training instruction, compensation, fees paid for participation in advisory boards, investigative boards or other committees, etc. From the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Johnson &amp; Johnson; Biosense Webster.</td></tr><tr><td>Dalmo Correia Filho</td><td>Nothing to be declared</td></tr><tr><td>Daniela do Carmo Rassi</td><td>Nothing to be declared</td></tr><tr><td>Dário Celestino Sobral Filho</td><td>Nothing to be declared</td></tr><tr><td>Dilma do Socorro Moraes de Souza</td><td>Financial declaration<br/>B - Research funding under your direct/personal responsibility (directed to the department or institution) from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Novartis: bioscience.</td></tr><tr><td>Dirceu Rodrigues de Almeida</td><td>Nothing to be declared</td></tr><tr><td>Edecio Cunha Neto</td><td>Nothing to be declared</td></tr><tr><td>Edimar Alcides Bocchi</td><td>Nothing to be declared</td></tr><tr><td>Evandro Tinoco Mesquita</td><td>Financial declaration<br/>A - Economically relevant payments of any kind made to (i) you, (ii) your spouse/partner or any other person living with you, (iii) any legal person in which any of these is either a direct or indirect controlling owner, business partner, shareholder or participant; any payments received for lectures, lessons, training instruction, compensation, fees paid for participation in advisory boards, investigative boards or other committees, etc. From the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- AVE; AstraZeneca; Pfizer; Bayer; Anylan; Boeringer; Novo Nordisk; Norvartis.<br/>Other relationships<br/>Any economically relevant equity interest in companies in the healthcare or education industry or in any companies competing with or supplying to SBC:<br/>- Partner at EC Tinoco.<br/>Employment relationship with the Brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry, as well as any employment relationship with health insurance companies or medical audit companies (including part-time jobs) in the year to which your declaration refers:<br/>- UnitedHealth Group (UHG).<br/>Performance, in the previous year, as a medical auditor for health insurance companies or the like:<br/>- Vice President of the Sociedad Interamericana de Cardiologia (SIAC).</td></tr><tr><td>Felix Jose Alvarez Ramires</td><td>Financial declaration<br/>A - Economically relevant payments of any kind made to (i) you, (ii) your spouse/partner or any other person living with you, (iii) any legal person in which any of these is either a direct or indirect controlling owner, business partner, shareholder or participant; any payments received for lectures, lessons, training instruction, compensation, fees paid for participation in advisory boards, investigative boards or other committees, etc. From the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Novartis; Pfizer; AstraZeneca; Amgen.</td></tr><tr><td>Fernanda de Souza Nogueira Sardinha Mendes</td><td>Nothing to be declared</td></tr></table>
# Guidelines

<table><tr><td>Fernando Bacal</td><td>Other relationships<br/>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Novartis: heart failure; Pfizer: amyloidosis.</td></tr><tr><td>Francisca Tatiana Pereira Gondim</td><td>Nothing to be declared</td></tr><tr><td>Gilberto Marcelo Sperandio da Silva</td><td>Nothing to be declared</td></tr><tr><td>Giselle de Lima Peixoto</td><td>Nothing to be declared</td></tr><tr><td>Gláucia Maria Moraes de Oliveira</td><td>Nothing to be declared</td></tr><tr><td>Gustavo Glotz de Lima</td><td>Financial declaration<br/>A - Economically relevant payments of any kind made to (i) you, (ii) your spouse/partner or any other person living with you, (iii) any legal person in which any of these is either a direct or indirect controlling owner, business partner, shareholder or participant; any payments received for lectures, lessons, training instruction, compensation, fees paid for participation in advisory boards, investigative boards or other committees, etc. From the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Abbott: atrial fibrillation; Bayer: atrial fibrillation; Sankyo: anticoagulation.</td></tr><tr><td>Henrique Horta Veloso</td><td>Nothing to be declared</td></tr><tr><td>Henrique Turin Moreira</td><td>Nothing to be declared</td></tr><tr><td>Hugo Bellotti Lopes</td><td>Other relationships<br/>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Abbott.<br/>Participation in procurement committees for supplies or drugs in health institutions or any similar roles taken:<br/>- Bidding of OPME materials by SUS.</td></tr><tr><td>Ibraim Masciarelli Francisco Pinto</td><td>Other relationships<br/>Participation in government-related regulatory authorities or advocacy authorities in cardiology:<br/>- Delegate CFM.</td></tr><tr><td>João Carlos Pinto Dias</td><td>Nothing to be declared</td></tr><tr><td>João Marcos Bemfica Barbosa Ferreira</td><td>Nothing to be declared</td></tr><tr><td>João Paulo Silva-Nunes</td><td>Nothing to be declared</td></tr><tr><td>Jose Antonio Marin Neto</td><td>Nothing to be declared</td></tr><tr><td>José Augusto Soares Barreto-Filho</td><td>Nothing to be declared</td></tr><tr><td>José Francisco Kerr Saraiva</td><td>Nothing to be declared</td></tr><tr><td>Joseli Lannes Vieira</td><td>Nothing to be declared</td></tr><tr><td>Joselina Luzia Menezes Oliveira</td><td>Nothing to be declared</td></tr><tr><td>Luciana Vidal Armaganijan</td><td>Nothing to be declared</td></tr><tr><td>Luis Cláudio Lemos Correia</td><td>Other relationships<br/>Participation in government-related regulatory authorities or advocacy authorities in cardiology:<br/>- CONASS representative at CONITEC.</td></tr><tr><td>Luiz Cláudio Martins</td><td>Nothing to be declared</td></tr><tr><td>Luiz Henrique Conde Sangenis</td><td>Nothing to be declared</td></tr><tr><td>Marco Paulo Tomaz Barbosa</td><td>Nothing to be declared</td></tr><tr><td>Marcos Antonio Almeida-Santos</td><td>Nothing to be declared</td></tr></table>
<table><tr><td>Marcus Vinicius Simões</td><td>Financial declaration<br/>B - Research funding under your direct/personal responsibility (directed to the department or institution) from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- MSD: heart failure; Novartis: hypercholesterolemia; Alnylam: amyloidosis; IONIS: amyloidosis; Behringer: heart failure.<br/>Other relationships<br/>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- BMS: cardiomyopathies.</td></tr><tr><td>Maria Aparecida Shikanai Yasuda</td><td>Nothing to be declared</td></tr><tr><td>Maria Carmo Pereira Nunes</td><td>Nothing to be declared</td></tr><tr><td>Maria da Consolação Vieira Moreira</td><td>Nothing to be declared</td></tr><tr><td>Maria de Lourdes Higuchi</td><td>Nothing to be declared</td></tr><tr><td>Maria Rita de Cassia Costa Monteiro</td><td>Nothing to be declared</td></tr><tr><td>Martino Martinelli Filho</td><td>Financial declaration<br/>B - Research funding under your direct/personal responsibility (directed to the department or institution) from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Impulse Dynamics Inc.</td></tr><tr><td>Mauricio Ibrahim Scanavacca</td><td>Financial declaration<br/>B - Research funding under your direct/personal responsibility (directed to the department or institution) from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- J&amp;J: Catheter ablation of patients with ventricular tachycardia and Chagas disease; ABBOTT: autonomic denervation of patients with vasovagal syncope; Medtronic: cryoablation of patients with heart failure and reduced LV ejection fraction with atrial fibrillation.</td></tr><tr><td>Mauro Felippe Felix Mediano</td><td>Nothing to be declared</td></tr><tr><td>Mayara Maia Lima</td><td>Nothing to be declared</td></tr><tr><td>Maykon Tavares de Oliveira</td><td>Nothing to be declared</td></tr><tr><td>Minna Moreira Dias Romano</td><td>Nothing to be declared</td></tr><tr><td>Nadjar Nitz Silva Lociks de Araujo</td><td>Nothing to be declared</td></tr><tr><td>Paulo de Tarso Jorge Medeiros</td><td>Nothing to be declared</td></tr><tr><td>Renato Vieira Alves</td><td>Nothing to be declared</td></tr><tr><td>Ricardo Alkmim Teixeira</td><td>Financial declaration<br/>A - Economically relevant payments of any kind made to (i) you, (ii) your spouse/partner or any other person living with you, (iii) any legal person in which any of these is either a direct or indirect controlling owner, business partner, shareholder or participant; any payments received for lectures, lessons, training instruction, compensation, fees paid for participation in advisory boards, investigative boards or other committees, etc. From the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Boehringer-Ingelheim: Pradaxa, Jardiance; Daiichi-Sankyo: Lixiana; Abbott: Implantable Electronic Heart Devices; Biotronik: Implantable Electronic Heart Devices; Medtronic: Implantable Electronic Heart Devices; Biomedical: Lead Extraction from Implantable Electronic Cardiac Devices.<br/>Other relationships<br/>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Biomedical: Biomedical: Lead Extraction from Implantable Electronic Cardiac Devices.</td></tr><tr><td>Roberto Coury Pedrosa</td><td>Nothing to be declared</td></tr><tr><td>Roberto Magalhães Saraiva</td><td>Nothing to be declared</td></tr><tr><td>Roque Aras Junior</td><td>Financial declaration<br/>B - Research funding under your direct/personal responsibility (directed to the department or institution) from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br/>- Novartis: Sacubitril.</td></tr></table>
Guidelines

<table><tr><td>Rosalia Morais Torres</td><td>Nothing to be declared</td></tr><tr><td>Rui Manuel dos Santos Povoa</td><td>Other relationships<br>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br>- Servier: Perindopril.</td></tr><tr><td>Sergio Gabriel Rassi</td><td>Nothing to be declared</td></tr><tr><td>Silvia Marinho Martins Alves</td><td>Other relationships<br>Funding of continuing medical education activities, including travel, accommodation and registration in conferences and courses, from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br>- Novartis: Entresto.</td></tr><tr><td>Suelene Brito do Nascimento Tavares</td><td>Nothing to be declared</td></tr><tr><td>Swamy Lima Palmeira</td><td>Nothing to be declared</td></tr><tr><td>Telêmaco Luiz da Silva Júnior</td><td>Nothing to be declared</td></tr><tr><td>Thiago da Rocha Rodrigues</td><td>Nothing to be declared</td></tr><tr><td>Vagner Madrini Junior</td><td>Nothing to be declared</td></tr><tr><td>Veruska Maia da Costa Brant</td><td>Nothing to be declared</td></tr><tr><td>Walderez Ornelas Dutra</td><td>Nothing to be declared</td></tr><tr><td>Wilson Alves de Oliveira Junior</td><td>Financial declaration<br>B - Research funding under your direct/personal responsibility (directed to the department or institution) from the brazilian or international pharmaceutical, orthosis, prosthesis, equipment and implants industry:<br>- Entresto/Novartis: heart failure in Chronic Chagas Disease.</td></tr></table>
List of Abbreviations

¹²³I-MIBG – iodine-123-metaiodobenzylguanidine

¹⁸F-FDG – 18F-fluorodeoxyglucose+

ACEI – angiotensin-converting-enzyme inhibitor

ACLS – Advanced Cardiovascular Life Support

AF – atrial fibrillation

AIDS – acquired immunodeficiency syndrome

ANVISA – Brazilian Health Surveillance Agency

ARB – angiotensin II receptor blocker

ATP – adenosine triphosphate

AVB – atrioventricular block

BNP – brain natriuretic peptide

CCCD – chronic cardiomyopathy of Chagas disease

CCD – cardiomyopathy of Chagas disease

CD – Chagas disease

CI – confidence interval

CLIA – chemiluminescence immunoassay

CMIA – chemiluminescent microparticle immunoassay

CMRI – cardiac magnetic resonance imaging

CONITEC – National Commission of Technology Incorporation in the SUS

COVID-19 – disease caused by the new coronavirus

CRT – cardiac resynchronization therapy

CTI – cardiothoracic index

CTX – cardiac transplantation

CVP – central venous pressure

DCM – dilated cardiomyopathy

DTU – discrete typing units

EBM – Evidence-Based Medicine

ECG – electrocardiogram

ECHO – echocardiography

ECLIA – electrochemiluminescence immunoassay

ELISA – enzyme-linked immunosorbent assay

EPS – electrophysiological study

FDA – Food and Drug Administration

FINDECHAGAS – International Federation of Associations of Individuals With Chagas Disease

FIOCRUZ – Fundação Oswaldo Cruz

G-CFS – granulocyte-colony stimulating factor

GLS – global longitudinal strain

GRADE – Grading of Recommendations, Assessment, Development, and Evaluations

GWAS – Genome Wide Association Study

HF – heart failure

HFmrEF – heart failure with mildly reduced ejection fraction

HFrEF – heart failure with reduced ejection fraction

HIV – human immunodeficiency virus

HR – heart rate

HRV – heart rate variability

ICD – implantable cardioverter-defibrillator

ICM – ischemic cardiomyopathy

IDI – integrated discrimination index

IFCD – indeterminate form of Chagas disease

IFN-γ – interferon-gamma

IHA – indirect hemagglutination

IIF – indirect immunofluorescence

IL – interleukin

INR – international normalized ratio

INSS – National Institute of Social Security (in Portuguese, Instituto Nacional do Seguro Social)

IPEC-FIOCRUZ – Instituto de Pesquisa Evandro Chagas-Fundação Oswaldo Cruz

ISHLT – International Society for Heart & Lung Transplantation

LACEN – Public Health Central Laboratories

LAFB – left anterior fascicular block

LAVA – local abnormal ventricular activities

LBBB – left bundle branch block

LV – left ventricular

LVDD – left ventricular diastolic diameter

LVEF – left ventricular ejection fraction

MCSD – mechanical circulatory support device

MESH – Medical Subject Headings

miRNA – microRNA

MMF – mycophenolate mofetil

MRI – magnetic resonance imaging

mTOR – mechanistic target of rapamycin

NK – natural killers

NNT – number needed to treat

NRI – net reclassification index

NSVT – nonsustained ventricular tachycardia

NTD – neglected tropical diseases

NT-proBNP – N-terminal pro-brain natriuretic peptide

NYHA – New York Heart Association

PAHO – Panamerican Health Organization

PCDT – Clinical Protocol and Therapeutic Guidelines

PCP – pulmonary capillary pressure

PCR – polymerase chain reaction

PET/CT – positron emission tomography computed tomography

PHC – primary health care

PM – pacemaker

PRA – panel reactive antibody

qPCR – real time or quantitative PCR

RBBB – right bundle branch block

RCD – reactivation of Chagas disease

RCT – randomized clinical trial
# Guidelines

RV – right ventricular

SAH – systemic arterial hypertension

SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2

SBC – Brazilian Society of Cardiology (in Portuguese, Sociedade Brasileira de Cardiologia)

SDG – Sustainable Development Goals

SGLT2 – sodium-glucose cotransporter-2

SINAN – Notifiable Diseases Information System (in Portuguese, Sistema de Informação de Agravos de Notificação)

SNP – single nucleotide polymorphism

SPECT-CT – single photon emission computed tomography and computed tomography

SSFP – steady-state free precession

STE – speckle tracking echocardiography

SUS – Brazilian Unified Health System (in Portuguese, Sistema Único de Saúde)

SVT – sustained ventricular tachycardia

T. cruzi – Trypanosoma cruzi

TAPSE – tricuspid annular plane systolic excursion

TAVB – total atrioventricular block

TIA – transient ischemic attack

TNF-α – tumor necrosis factor alpha

Tregs – regulatory T cells

UBS – Basic Healthcare Units

UPAE – specialized emergency care units

USA – United States of America

VE – ventricular extrasystole

VF – ventricular fibrillation

VT – ventricular tachycardia

WHO – World Health Organization
Table of Contents

1. Initial Considerations 12

1.1. Methodology Used to Elaborate this Guideline 14

1.2. Scientific Rationale for Recommendations of Diagnostic Methods 15

2. Epidemiology – 21st Century Update 16

2.1. Introduction 16

2.2. World Distribution of Chagas Disease 18

2.3. Overview of Chagas Disease in Brazil 19

2.4. Epidemiological Surveillance in Brazil 21

2.5. Association of Chagas Disease with COVID-19 21

2.6. Final Reflection on the Current Chagas Disease Epidemiological Scenario 23

3. Pathogenesis of Cardiomyopathy of Chagas Disease 23

3.1. Introduction 23

3.2. Immune Dynamics and Differential Progression to Chronic Cardiomyopathy of Chagas Disease 24

3.3. Myocardial Mitochondrial Dysfunction and Chronic Cardiomyopathy of Chagas Disease 25

3.4. Genetics in Chronic Cardiomyopathy of Chagas Disease 26

3.5. Coronary Microvascular Disorder 26

3.6. Cardiac Denervation 27

3.7. Final Considerations 28

4. Cardiomyopathy Pathophysiology – Acute and Chronic Phases 28

4.1. Introduction 28

4.2. Myocardial Parasitism and Immune Response 29

4.2.1. Immune response in the acute phase 29

4.2.2. Immune response in the chronic phase 29

4.3. Autonomic Nervous System Alterations in Chagas Disease: Evidence from Histopathological Studies 29

4.4. Chagas Disease Pathophysiology Dependent on the Parasite and Human Host Genetic Characteristics 30

4.5. Peculiar Histopathology of Chagas Disease 31

4.6. Coronary Microcirculation Injury 32

4.7. Potential Therapeutic Applications of Pathophysiological Targets in Chronic Cardiomyopathy of Chagas Disease 32

5. Natural History 33

5.1. Acute Myocarditis of Chagas Disease 33

5.2. The Indeterminate Form and Clinical Syndromes of Chronic Cardiomyopathy of Chagas Disease 34

5.2.1. Natural History of the Chronic Phase of Chagas Disease 34

5.2.2. Indeterminate Form of Chagas Disease: Importance of the Concept and Abnormalities on More Sophisticated Additional Tests 34

5.2.3. Progression to Chronic Cardiomyopathy 35

5.2.4. Clinical Forms of Chronic Cardiomyopathy of Chagas Disease 36

5.2.4.1. Abnormalities on Complementary Tests 36

5.2.4.2. Cardiac Arrhythmias 36

5.2.4.3. Heart Failure Syndrome 37

5.2.4.4. Systemic and Pulmonary Thromboembolic Syndrome 37

6. Diagnosis of Cardiomyopathy of Chagas Disease 38

6.1. Methods to Determine the *T. cruzi* Infection 38

6.1.1. Introduction 38

6.1.2. Serological Tests Available and Which to Request 38

6.1.3. Interpretation of the Results 38

6.1.4. Special Situations 39

6.1.4.1. Inconclusive Serological Results 39

6.1.4.2. Test Result Not Corresponding to Clinical Expectation 39

6.1.4.3. Parasitemia 39

6.1.4.4. Negative Serology in Patients in the Chronic Phase 39

6.1.4.5. Spontaneous Cure 39

6.1.4.6. Acute Phase Diagnosis 39

6.1.4.7. Blood Services 40

6.1.4.8. Congenital transmission 41

6.1.4.9. Serology of Infected Individuals Treated with Chemotherapy Drugs 41

6.1.4.10. Rapid Serological Tests 41

6.1.4.11. Parasitological Tests 41

6.1.4.11.1. Indications for Parasitological Tests, particularly Polymerase Chain Reaction 41

6.1.4.11.2. Interpretation of the Results of Parasitological Tests 42

6.1.4.12. Polymerase Chain Reaction 42

6.1.4.13. Operational Procedures for PCR Use 42

6.2. Diagnostic Methods for Structural and Functional Cardiac Abnormalities 43

6.2.1. Electrocardiogram in Chagas Disease 43

6.2.2. Chest Radiography 43

6.2.3. Echocardiography 45

6.2.3.1. Left Ventricular Systolic Function 45

6.2.3.2. Segmental Changes in Ventricular Contractility 46

6.2.3.3. Left Ventricular Diastolic Function 46

6.2.3.4. Right Ventricular Assessment 46

6.2.3.5. Stress Echocardiography 46

6.2.4. Cardiac Magnetic Resonance Imaging 46

6.2.5. Nuclear Medicine 47

6.2.5.1. Radionuclide Ventriculography 47

6.2.5.2. Myocardial Perfusion 47

6.2.5.3. Sympathetic Innervation Assessment 47

6.2.6. Computed Tomography of Coronary Arteries 48

6.2.7. Ambulatory Electrocardiography (Holter) 48

6.2.8. Intracardiac Electrophysiological Study 48

6.2.9. Exercise and Cardiopulmonary Tests 48

6.2.10. Cardiac Catheterization 49

7. Risk Stratification and Prognosis 49

8. Therapeutic Management in the Indeterminate Form of Chagas Disease 54

9. Etiological Treatment of Chagas Disease 56

9.1. Introduction 56

9.2. Drugs and Administration 57

9.3. Etiological Treatment of Individuals with Chagas Disease 60

9.4. Acute Infection 60

9.5. Congenital Infection 61

9.6. Children and Adolescents with Chronic Infection 61

9.7. Women of Reproductive Age with Chronic Infection 61

9.8. Adults with Chronic Infection 62

9.9. Reactivation of Chagas Disease 63

9.10. Accidental Infection 64

9.11. Assessment of Chagas Disease Cure after Etiological Treatment 64

9.11.1. Where to Treat an Individual with Chagas Disease 65
# Guidelines

## 10. Therapeutic Management of Ventricular Dysfunction and Heart Failure

<table><tr><td>10.1. Pharmacological Resources</td><td>66</td></tr><tr><td>10.1.1. Heart Failure Classification</td><td>66</td></tr><tr><td>10.1.2. Maximum Dosage of Medications</td><td>66</td></tr><tr><td>10.1.3. The Contemporary Patient</td><td>66</td></tr><tr><td>10.1.4. Literature Review</td><td>66</td></tr><tr><td>10.1.5. Pharmacological Therapy</td><td>66</td></tr><tr><td>10.1.5.1. Diuretics</td><td>66</td></tr><tr><td>10.1.5.2. Renin-Angiotensin-Aldosterone System Inhibitors</td><td>67</td></tr><tr><td>10.1.5.3. Beta-blockers</td><td>67</td></tr><tr><td>10.1.5.4. Spironolactone</td><td>68</td></tr><tr><td>10.1.5.5. Ivabradine</td><td>68</td></tr><tr><td>10.1.5.6. Digoxin</td><td>68</td></tr><tr><td>10.1.5.7. Sacubitril-valsartan</td><td>68</td></tr><tr><td>10.1.5.8. Sodium-Glucose Cotransporter-2 Inhibitors</td><td>69</td></tr><tr><td>10.2. Non-Pharmacological Resources</td><td>71</td></tr><tr><td>10.2.1. Cardiac Transplantation</td><td>71</td></tr><tr><td>10.2.1.1. Immunosuppression Strategies</td><td>73</td></tr><tr><td>10.2.1.2. Induction Therapy</td><td>73</td></tr><tr><td>10.2.1.3. Maintenance Therapy</td><td>73</td></tr><tr><td>10.2.2. Diagnosis and Treatment of Rejection</td><td>73</td></tr><tr><td>10.2.3. Diagnosis and Treatment of T. cruzi-Infection Reactivation</td><td>74</td></tr><tr><td>10.2.3.1. Clinical Presentation</td><td>74</td></tr><tr><td>10.2.3.2. Parasitological Diagnosis of Reactivation</td><td>74</td></tr><tr><td>10.2.3.3. Etiological Treatment of Reactivation</td><td>74</td></tr><tr><td>10.2.3.4. Post-Heart Transplant Complications and Survival</td><td>75</td></tr><tr><td>10.2.4. Mechanical Circulatory Support</td><td>75</td></tr></table>

## 11. Therapeutic Management of Cardiac Arrhythmias

<table><tr><td>11.1. Pharmacological Resources</td><td>76</td></tr><tr><td>11.1.1. Introduction</td><td>76</td></tr><tr><td>11.1.2. Sudden Death Prevention with Non-Antiarrhythmic Drugs</td><td>76</td></tr><tr><td>11.1.3. Ventricular Arrhythmias in Cardiopathies of Other Etiologies</td><td>77</td></tr><tr><td>11.1.4. Amiodarone for Patients with Cardiopathies of Other Etiologies: Primary Prevention</td><td>77</td></tr><tr><td>11.1.5. Amiodarone for Patients with Cardiopathies of Other Etiologies: Secondary Prevention</td><td>79</td></tr><tr><td>11.1.6. Ventricular Arrhythmias in Patients with Chronic Cardiomyopathy of Chagas Disease: Characteristics and Treatment</td><td>80</td></tr><tr><td>11.1.6.1. Ventricular Extrastoles</td><td>80</td></tr><tr><td>11.1.6.2. Nonsustained Ventricular Tachycardia</td><td>80</td></tr><tr><td>11.1.6.3. Sustained Ventricular Tachycardia and Ventricular Fibrillation</td><td>80</td></tr><tr><td>11.1.7. Care During the Use of Amiodarone</td><td>82</td></tr><tr><td>11.1.8. Prevention of Electrical Shock Recurrence in Patients Treated with Implantable Cardioverter-Defibrillator</td><td>82</td></tr><tr><td>11.1.9. Pharmacological Treatment of Atrial Fibrillation in Chronic Cardiomyopathy of Chagas Disease</td><td>83</td></tr><tr><td>11.1.10. Treatment in the Emergency Room</td><td>83</td></tr><tr><td>11.1.11. Outpatient Treatment</td><td>83</td></tr><tr><td>11.1.11.1. Reversion to Sinus Rhythm</td><td>83</td></tr><tr><td>11.1.11.2. Heart Rate Control</td><td>83</td></tr><tr><td>11.2. Pacemaker, Cardioverter-Defibrillator, and Cardiac Resynchronization Therapy</td><td>85</td></tr><tr><td>11.2.1. Artificial Cardiac Pacemaker</td><td>85</td></tr></table>

<table><tr><td>11.2.2. Implantable Cardioverter-Defibrillator in CCCD</td><td>85</td></tr><tr><td>11.2.2.1. Primary Prevention of Sudden Cardiac Death</td><td>85</td></tr><tr><td>11.2.2.2. Secondary Prevention of Sudden Cardiac Death</td><td>87</td></tr><tr><td>11.2.3. Cardiac Resynchronization Therapy</td><td>89</td></tr><tr><td>11.3. Ablation Methods</td><td>90</td></tr><tr><td>11.3.1. Sustained Ventricular Tachycardia: Clinical Presentation, Electrophysiological Mechanisms, and Sites of Origin</td><td>90</td></tr><tr><td>11.3.2. Clinical and Laboratory Pre-Ablation Assessment</td><td>90</td></tr><tr><td>11.3.3. Mapping Techniques for Ventricular Tachycardias</td><td>92</td></tr><tr><td>11.3.4. Outcomes and Complications During Ventricular Tachycardia Ablation</td><td>93</td></tr><tr><td>11.3.5. Ablation Results and Patients' Follow-up</td><td>93</td></tr></table>

## 12. Managements to Prevent and Treat Thromboembolic Complications

<table><tr><td>12.1. Introduction</td><td>93</td></tr><tr><td>12.2. Epidemiology of Thromboembolic Events</td><td>94</td></tr><tr><td>12.3. Risk Factors and Mortality</td><td>94</td></tr><tr><td>12.4. Risk Assessment of Stroke</td><td>95</td></tr><tr><td>12.5. Clinical Findings and Diagnostic Investigation of Ischemic Stroke in Chagas Disease</td><td>96</td></tr><tr><td>12.6. Treatment of Ischemic Stroke in Chagas Disease</td><td>97</td></tr><tr><td>12.7. Prevention of Cardioembolic Events in Chagas Disease</td><td>98</td></tr></table>

## 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

<table><tr><td>13.1. T. cruzi-HIV Coinfection</td><td>100</td></tr><tr><td>13.2. Seropositivity in Potential Donors at Blood Banks</td><td>101</td></tr><tr><td>13.3. Physical Activity</td><td>101</td></tr><tr><td>13.4. Pregnant Women</td><td>102</td></tr><tr><td>13.5. Newborns</td><td>103</td></tr><tr><td>13.6. Surgical and Anesthetic Risk</td><td>104</td></tr><tr><td>13.7. Chagas Disease and Coronavirus Infection</td><td>104</td></tr><tr><td>13.8. Noncardiac Transplantation and Immunosuppressive Therapy</td><td>105</td></tr><tr><td>13.8.1. Donor with Chagas Disease and Recipient without Chagas Disease</td><td>105</td></tr><tr><td>13.8.2. Recipient with Chagas Disease</td><td>106</td></tr><tr><td>13.8.3. Autoimmune Diseases</td><td>107</td></tr><tr><td>13.9. Chagas Disease and Aging</td><td>107</td></tr></table>

## 14. Recommendations for Implantation of Structured Health Services for the Follow-Up of Individuals with Chronic Cardiomyopathy of Chagas Disease

<table><tr><td>14.1. Assignments of Structured Health Services for the Follow-up of Individuals with Chronic Cardiomyopathy of Chagas Disease</td><td>108</td></tr><tr><td>14.2. Expected Benefits of Structured Health Services for the Follow-up of Individuals with Chronic Cardiomyopathy of Chagas Disease</td><td>109</td></tr></table>

## 15. Definition of Severe Cardiopathy and Medico-Legal Assessment

<table><tr><td>15.1. Introduction</td><td>110</td></tr><tr><td>15.2. Concept and Scope</td><td>110</td></tr><tr><td>15.3. Score to Predict the Risk of Death in Patients with Chronic Cardiomyopathy of Chagas Disease</td><td>110</td></tr><tr><td>15.4. Clinical Aspects</td><td>111</td></tr><tr><td>15.5. Medico-Legal Expert Assessment</td><td>111</td></tr><tr><td>15.6. Conclusion</td><td>111</td></tr><tr><td>Acknowledgements</td><td>111</td></tr><tr><td>References</td><td>112</td></tr></table>
# 1. Initial Considerations

In 2021, the then president of the Brazilian Society of Cardiology (SBC), Dr. Marcelo Queiroga Cartaxo Lopes, commissioned us to coordinate the elaboration of the new guideline on Chagas disease (CD). The undertaking was justified because since 2011 the SBC had not directly been responsible for a guideline on that subject. Differently from the guideline published more than one decade ago in the *Arquivos Brasileiros de Cardiologia*,¹ the current one would no longer be “Latin American” but would count essentially on an expressive number of Brazilian collaborators. The summoned group of notorious active researchers in the field would represent a comprehensive team of professionals from different parts of Brazil, involved in and directly contributing to the advance of the fight against CD. These researchers are responsible for this guideline authorship, as explained below.

In addition, considering that in 2015 we collaborated extensively with the Brazilian Society of Tropical Medicine guideline on the general context of CD,² the scope of the current one was limited only to aspects related to the diagnosis and treatment of the most frequent and severe manifestation of CD, the cardiomyopathy of Chagas disease (CCD).

Despite the large number of documents on the theme in its varied aspects (Chart 1.1),¹⁻²² discrepancies exist mainly regarding the strength of the recommendations and levels of evidence related to the different types of treatment, as well as the appearance of new scientific evidence, corroborating the understanding that guidelines need to be periodically reviewed and updated.

This guideline, particularly its usual framework naturally directed to the formulation of rules of conduct and scientific evidence that support the countless aspects of CCD diagnosis and treatment, has some characteristics conferred by the temporal context of its elaboration. In fact, we lived the distressful circumstance of adding to CCD, a markedly inflammatory illness, the problems from the disease caused by the new coronavirus (COVID-19) pandemic, with its own inflammation component. Thus, the scientific community, both worldwide and specially in Brazil, had to face at least three big obstacles to control the pandemic: first, it is a special virus, with peculiar behavior regarding the injury to the host's organs; second, there were inherent and unpredictable difficulties regarding the epidemiological behavior of that virus; third, our national indigence, when we verify that, to overcome the pandemic, the appropriate measures bump into basic facts, such as the very precarious sanitary conditions of 30-40% of our population, lacking sewage, piped water, and minimally appropriate housing.

Denialist attitudes and dissemination of fake concepts, including by part of the medical community, represent an incremental obstacle to the performance of Science and Medicine in the fight against the pandemic.²³ To that set of challenges and obstacles, the Brazilian scientific community responded with notable readiness and efficiency, as exemplified by the large-scale development and application of vaccines against COVID-19. It is worth noting that the difficulties faced to widen the protection against contamination

and to implement population vaccination were remains from the wars fought during the 20th century against the deleterious influence of the tobacco industry, which for a long time tried to hide the tobacco's harms.²⁴ It is worth noting that some aspects of the concomitance of the infections by *Trypanosoma cruzi* (T. cruzi) and by coronavirus in the same individual are properly addressed in specific topics of this guideline.

Thus, the sanitary conquests in fighting the pandemic in the 21st century achieved by the scientific community, well represented by FIOCRUZ, a historical heir of its first and unsurpassed epigone, Oswaldo Cruz, are reminders of his success with the vaccination campaigns against yellow fever in the beginning of the 20th century. In addition, a parallel can be drawn between the current scientific and medical community situation in the fight against the COVID-19 pandemic and the difficult context experienced by Carlos Chagas and his mentor Oswaldo Cruz during the first decades of the 20th century.

Similarly to today's denialism, that great Brazilian, despite his scientifically epic discovery, had to confront the nihilism and misunderstanding of a considerable part of the medical community regarding his deeds in the history of Medicine, according to professor João Carlos Pinto Dias, and son of his direct collaborator, Emmanuel Dias, and also participating in this guideline. In addition, the early sudden death of Carlos Chagas might have been triggered emotionally, consequent to the obscurantist attack.

As it has been reported, "It is plausible that his great humanistic perspicacity had provided him with the vision of the tragically real social meaning of the disease he had just discovered, affecting literally millions of vulnerable individuals in large areas of Brazil. In contrast to the denial by part of the academic community to accept the existence of the new disease, Carlos Chagas might have envisioned the national tragedy of his discovery, which still unfolds in multiple socially deplorable acts and chapters".²⁵

It will never be too much to glorify Carlos Chagas' memory. According to Alejandro Hasslocher-Moreno, another collaborator of this guideline, "Carlos Chagas was the right physician and scientist, at the right time, in the right place. The circumstances involving the disease's discovery had as protagonist an individual prepared to face a known challenge and, at the same time, to discover the unknown. In the biomedical context, the Brazilian science was boosted after the discovery of CD, gaining international recognition, one of the major legacies of Carlos Chagas to the Brazilian Science and Medicine".²⁶

When revisiting and elaborating guidelines, it is justifiable to pay tribute to the emeritus physicians and scientists who either had left us right before the publication of the 2011 guideline or now, when we are finishing the 2022 guideline. We want to honor all of them for their legacy in CD research, and especially professors Joaquim Romeu Cançado 1913-2011 (Belo Horizonte), Alúzio Rosa Prata 1920-2011 (Uberaba), Zilton Araújo Andrade 1924-2020 (Salvador), José Rodrigues Coura 1927-2021 (Rio de Janeiro), and Anis Rassi 1929-2021 (Goiânia). To them we devote our gratitude and recognition. Their influence on this guideline kept us in the luminous scientific pathway trod by Carlos Chagas.
# Guidelines

<table><caption>Chart 1.1 – Consensus, guidelines, and relevant documents approaching patients with Chagas disease.</caption><thead><tr><td>TITLE OF THE DOCUMENT</td><td>THEME</td><td>PUBLICATION YEAR</td><td>RESPONSIBLE</td></tr></thead><tbody><tr><td>"Consenso Brasileiro em Doença de Chagas"<sup>3</sup></td><td>general</td><td>2005</td><td>Brazilian Ministry of Health</td></tr><tr><td>"Diagnosis, Management and Treatment of Chronic Chagas' Heart Disease in Areas Where Trypanosoma cruzi infection is not Endemic"<sup>4</sup></td><td>general</td><td>2007</td><td>SEMTSI</td></tr><tr><td>"Evaluation and Treatment of Chagas Disease in the United States: A Systematic Review"<sup>5</sup></td><td>general</td><td>2007</td><td>CDC and panel of experts on Chagas disease</td></tr><tr><td>"I Diretriz Latino Americana para o Diagnóstico e Tratamento da Cardiopatia Chagásica"<sup>1</sup></td><td>general</td><td>2011</td><td>SBC</td></tr><tr><td>"Consenso de Enfermedad de Chagas-Mazza"<sup>6</sup></td><td>general</td><td>2011</td><td>SAC</td></tr><tr><td>"II Consenso Brasileiro em Chagas disease"<sup>2</sup></td><td>general</td><td>2015</td><td>Brazilian Ministry of Health</td></tr><tr><td>"Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association"<sup>7</sup></td><td>general</td><td>2018</td><td>AHA</td></tr><tr><td>"Protocolo Clínico e Diretrizes Terapêuticas (PCDT) da Doença de Chagas"<sup>8</sup></td><td>general</td><td>2018</td><td>CONITEC</td></tr><tr><td>"Acuerdo Regional de los Expertos en Chagas de las Sociedades de Cardiología Sudamericanas"<sup>9</sup></td><td>general</td><td>2018</td><td>SSC</td></tr><tr><td>"Guía para el diagnóstis y el Tratamiento de la Enfermedad de Chagas"<sup>10</sup></td><td>general</td><td>2018</td><td>PAHO</td></tr><tr><td>"Consenso Enfermedad de Chagas 2019"<sup>11</sup></td><td>general</td><td>2020</td><td>SAC</td></tr><tr><td>"Consenso do Comitê de Eletrofisiologia da USCAS sobre o Tratamento das Arritmias Ventriculares na Doença de Chagas"<sup>12</sup></td><td>arrhythmia</td><td>2002</td><td>SBC</td></tr><tr><td>"Diretrizes Brasileiras de Dispositivos Cardíacos Eletrônicos Implantáveis (DCEI)"<sup>13</sup></td><td>arrhythmia</td><td>2007</td><td>SBC</td></tr><tr><td>"Consenso de Prevención Primaria y Secundaria de Muerte Súbita"<sup>14</sup></td><td>arrhythmia</td><td>2012</td><td>SAC/SUC</td></tr><tr><td>"Diretrizes Brasileiras de Dispositivos Cardíacos Eletrônicos Implantáveis"<sup>15</sup></td><td>arrhythmia</td><td>2015</td><td>DECA/SBCCV</td></tr><tr><td>"II Diretrizes da Sociedade Brasileira de Cardiologia para o Diagnóstico e Tratamento da Insuficiência Cardíaca"<sup>16</sup></td><td>HF</td><td>1998</td><td>SBC</td></tr><tr><td>"Revisão das II Diretrizes da Sociedade Brasileira de Cardiologia para o Diagnóstico e Tratamento da Insuficiência Cardíaca"<sup>17</sup></td><td>HF</td><td>2002</td><td>SBC</td></tr><tr><td>"III Diretriz Brasileira de Insuficiência Cardíaca Crônica"<sup>18</sup></td><td>HF</td><td>2009</td><td>SBC</td></tr><tr><td>"Atualização da Diretriz Brasileira de Insuficiência Cardíaca"<sup>19</sup></td><td>HF</td><td>2012</td><td>SBC</td></tr><tr><td>"3ª Diretriz Brasileira de Transplante Cardíaco"<sup>20</sup></td><td>HF</td><td>2018</td><td>SBC</td></tr><tr><td>"Diretriz Brasileira de Insuficiência Cardíaca Crônica e Aguda"<sup>21</sup></td><td>HF</td><td>2018</td><td>SBC</td></tr><tr><td>"Consenso de Enfermedad de Chagas. Insuficiência cardiaca em miocardiopatia chagásica crónica"<sup>22</sup></td><td>HF</td><td>2019</td><td>FAC</td></tr></tbody></table>

AHA: American Heart Association; CDC: US Centers for Disease Control and Prevention; CONITEC: Brazilian National Commission of Technology Incorporation in the SUS; DECA/SBCCV: Department of Artificial Cardiac Stimulation of the Brazilian Society of Cardiovascular Surgery; FAC: Federación Argentina de Cardiologia; HF: heart failure; PAHO: Pan American Health Organization; SAC: Argentinian Society of Cardiology; SBC: Brazilian Society of Cardiology; SEMTSI: Sociedad Española de Medicina Tropical y Salud Internacional; SSC: Sociedad Sudamericana de Cardiologia; SUC: Sociedad Uruguaya de Cardiologia.

The authors, collaborators and coordinators of this document are aware that, in this phase of intensified perception of CD as a neglected disease, it is mandatory to rescue the affected individuals from their miserable conditions and their deplorable medical-social implications. Thus, we should strive to minimize the stigma of CD, beginning by banning the term "Chagasic" from this guideline. This is based on the recent understanding that instead of being an eponym to honor the historical trajectory of Carlos Chagas, that term, for some patients, would sound as if they had a true and painful incurable wound in their hearts.

Involved in the elaboration of this guideline, we are clearly aware that our responsibility has greatly increased recently.

In addition to being mainly directed to physicians and paramedics, the principles herein contained should be useful to guide managers and agencies in charge of providing proper public health conditions nationally. And last but not least, the individuals currently affected by the disease are much more in need for safe guidance by health professionals than in the past. The number of individuals with CD increased in parallel with the democratization of the information provided in the web. Health professionals must provide better instructions on how to manage and decrease the problems deriving from CD.

We will use the introduction of this new guideline to describe the process that culminated in this document.
Right from the beginning we realized that the timeline initially planned to be concluded in a few months did not correspond to our ambition to build a reflexive, scientifically deep document, with consistent clinical and population implications.

The starting point was the meeting where the coordinators discussed the scientific principles to guide the elaboration of the topics, introducing the idea that the knowledge of experts would be essential to interpret and judge the applicability of the evidence, but not to foster opinions based on individual preferences. Disagreements would be solved by deep analysis of evidence, not by majority vote. At that time, we planted the seed of a guideline to challenge our own intuitions and recognized that often the truth antagonizes our expectations, requiring the cultivation of doubt, which usually contrasts with the eloquence of a group of opinion makers in their respective areas. This was the seed of a guideline built based on intense debates, creative attrition, and learning for all, totaling seven virtual meetings and 28 hours of debates.

From conception to the last subject presented in this guideline, we tried to follow the most legit principles of the classic paradigm of Evidence-Based Medicine (EBM). Even though a comprehensive systematic review of the literature could not be performed, in some more polemic points we analyzed the evidence that should answer the so-called PICO question, which comprises the characteristics of the population ("P"), intervention ("I"), comparing control ("C"), and outcome ("O").²⁷ We hope we were able to 'rescue' at least most of the recommendations and the analyses of evidence that support them from the bias and other management deviations identified in previous contexts. We are sure that, unfortunately, the paradigm of EBM itself is currently abused and distorted, paradoxically amid the exponential multiplication of research and knowledge generated and disclosed without proportional control by entities that should supervise the entire process of advances in such a noble area of human activity. One example of such distortions, fortunately not observed in the context of CD, but very clear in some areas of Medicine, is the profusion of inappropriate, inconsistent, routine, or redundant meta-analyses, resulting in "fake news", as already suggested.²⁸

Thus, we retrieve and emphasize the essential principle of the last section of the SBC 2011 guideline,¹ which briefly is "Cardiologists should improve their patients' clinical management, wisely administering medications and interventions that respect as much as possible the peculiar pathophysiology of the disease, neither appealing to measures without proof of benefit nor wasting plausible therapeutic opportunities".

## 1.1. Methodology Used to Elaborate this Guideline

The construction of a guideline for medical management is an underappreciated opportunity of reflection on the rationale that enables the translation from the scientific paradigm to clinical decision. This type of reflection can develop strategies to reduce the gap between evidence and recommendation.

Scientific evidence has two major functions: the epistemological function (counterfactual), relative to the construction of knowledge of causality, and the pragmatic function, which influences the decision-making process (consequentialist). In the first function, evidence of an exploratory character, whose quality is satisfactory, is valued by suggesting the scientific pathway. In the second function, the use of evidence with a high risk for bias or statistical imprecision servs more to justify the desire to act rather than to increase the likelihood that the action represents the best choice for the patient or population. It is the intuitive desire searching for scientific justification.

Guidelines usually make clinical recommendations based on the quality of the evidence found after careful search. Several systems have been proposed to classify evidence and to categorize the "strength" of the clinical recommendation, such as GRADE, CEBM, SIGN, NZGG, SORT, USPSTF, ACCF/AHA/ESC, ACCP, IDSA, and NICE.²⁹ The strength of the recommendation is usually related to the level of evidence. For this guideline, we adopted a simple classification based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach,²⁷ but with some modifications, grouping the studies into only 3 levels of quality of evidence (A = high level; B = moderate level; and C = low level), from which 2 grades of recommendation derive (1 = strong; and 2 = conditional). The starting point in assessing the quality of the evidence should be the delineation of the research. Evidence originating from analytical experimental studies, such as randomized clinical trials (RCTs), and systematic reviews with meta-analyses of those studies are less prone to biases, being, consequently, considered of better quality or high level (A). In contrast, evidence originating from analytical observational studies (case-control, cross-sectional, and cohort) are considered of moderate level (B), and those originating from descriptive observational studies (without a comparing group), such as case series, are considered of low quality or low level (C).

In the specific case of CCD, because we do not usually have high quality evidence deriving from RCTs and, in some situations, not even from observational studies with convincing results to generate endorsed recommendations, there is a natural tendency to resort to free "expert opinion" or "consensus", abstract words of uncertain significance and consequences, which should not be formally characterized as evidence.³⁰ One solution for this question is the recognition of the value of indirect evidence, originating from results of RCTs performed on other cardiopathies, and the understanding of the difference between representative sample and generalizable sample.²⁷

In observational descriptive studies, the sample representativeness is essential. For example, regarding the prognosis of a patient with heart failure (HF), what is observed in ischemic cardiomyopathy (ICM) might not apply to CCD. However, in analytical, observational, or experimental (of causality) studies, a nonrepresentative sample can become generalizable. For generalization to be justified, lack of interaction (effect modification) between the populations' differences and the effect of a risk factor or a medical management is required.
# Guidelines

Because biological interaction is a rare phenomenon, nonrepresentative samples generate generalizable concepts for different types of patients. This justifies a large part of the recommendations for elderly and children, subgroups usually not properly represented in RCTs. The prescription, for example, of an angiotensin-converting-enzyme inhibitor (ACEI) for a patient with CCD and reduced left ventricular ejection fraction (LVEF) is not based on preference or use of evidence of low quality in that type of population. It is based on evidence of high quality in patients with HF of other etiologies, in accordance with the perception that “effect modification” by the cardiomyopathy etiology (interaction) is unlikely. This is how scientific knowledge is built. For example, the theory supporting the knowledge that the speed of light is constant did not derive from its measure in all environments and circumstances. Only a few measures, in accordance with the notion of low probability of interaction between the environment and speed of light, enable us to generalize that the speed of light is, in fact, constant.

When making generalization, we should question if there is a characteristic in the population of interest that would change the study's result. For example, is there any characteristic of the patient with CCD that can modify the beneficial effect (interaction) of the vasodilating therapy, which was confirmed in ICM or dilated cardiomyopathy (CDM)? Probably not.

In the absence of direct experimental evidence, which is obtained from the results of RCTs performed on CCD (level A), and of indirect evidence, which is obtained from extrapolation of the results of RCTs performed on other cardiopathies (level B), we chose to value the results obtained from observational analytical studies (level B) or from observational descriptive studies (level C), both performed on CCD, in addition to adopting the principle of extreme plausibility and the principle of asymmetry as level C of evidence.

It is worth noting that decision-making that dispense empirical evidence is common in Medicine. In the essential absence of *équipoise*, decisions are not made based on experimental data, but on natural data. There are situations that do not require “judgement” (mental measurement of the likelihoods) and it would be unethical to perform an experiment with a control group. One example is the use of diuretic in HF with marked congestion, whose benefit has never been specifically measured in a placebo-controlled clinical trial, because of its almost deterministic character. If it were, we would have a number needed to treat (NNT) of 1 for symptom improvement and a possibly very relevant NNT for reduction of mortality.

By failing to understand that statement, the medical community places diuretics at a lower level of benefit because of the lack of experimental proof of mortality reduction. Therefore, in the presence of HF with systemic and/or pulmonary congestion, the careful prescription of a diuretic should be considered based on essential evidence, leading to its strong recommendation. For situations like that, the parachute analogy can be used as a strategy to reduce mortality of individuals in free fall.³¹ This is another circumstance in which the level C of evidence should be applied: absence of experimental evidence, but strong natural evidence. This should be emphatically differentiated

from the paradigm of preference, contained in “consensus”, because the evidence regarding the use of parachute requires no consensus. It is indisputable.

Another principle that will be used as level C of evidence is that of asymmetry of effect, which can be applied to situations in which, despite the lack of proof of the efficacy of a certain intervention, there is great asymmetry between the magnitude of a potential benefit and the magnitude of an occasional harm, such as the use of masks to control COVID-19 and the etiological treatment in middle-aged adults with the indeterminate form of CD (IFCD).

Once the situations of extreme plausibility and asymmetry (level C) are resolved, we should solve the indications based on level B of evidence. This level should not be represented by evidence of dubious quality. The quality of the evidence should be of low risk for bias and high precision, here represented as indirect evidence of high level and direct evidence of satisfactory quality.

While the classification of the level of evidence is part of the scientific dimension, the strength of the recommendation involves and translates the dimension of clinical thinking: of the individual probability of benefit (magnitude of the effect) versus risk (harm/loss), of the doubt regarding feasibility (effectiveness), or even of cost-effectiveness questions (impact on the health system).

Thus, in analogy to the classification system adopted by ACC/AHA, we will name the grade of recommendation I and most of the time the grade of recommendation IIa as “strong”, which should be applied to those situations with little or no doubt regarding the ‘prescription’ process, which becomes almost a rule, except if specific contraindications apply. For example, the prescription of etiological treatment in cases of reactivation of CD (RCD). In contrast, the term “conditional” recommendation will apply to grade IIb (and occasionally to grade IIa), whose decision-making depends on a clinical analysis individualized in its magnitude of benefit and risk, patient’s values and preferences (shared decision-making), and aspects regarding the health system (Chart 1.2).

## 1.2. Scientific Rationale for Recommendations of Diagnostic Methods

In parallel with the organization of the scientific thinking applied to recommendation on therapeutic management, a predominant theme in any guideline, we should widen the discussion for recommendation of diagnostic tests, because we also have chapters on such dimensions of medical decision.

In the context of diagnosis and differently from that of treatment, the grounding scientific concept of the level of evidence is not efficacy. Diagnosis involves the concept of accuracy, the ability to discriminate between sickness (sensitivity) and healthiness (specificity). Thus, the question is neither the conceptual proof of causality, nor the need for randomized experimental studies to minimize confounding factors. The need is to demonstrate enough accuracy so that the new information added by the test increases significantly the pretest diagnostic probability, within a structure of Bayesian thinking.
<table><caption>Chart 1.2 – Grades of recommendation and levels of evidence.</caption><thead><tr><th>TARGET AUDIENCE</th><th colspan="2">GRADES OF RECOMMENDATION</th></tr></thead><tbody><tr><td>Policy makers</td><td>(1) STRONG<br>The intervention should be adopted as a public health policy.</td><td>(2) CONDITIONAL<br>The intervention can be adopted as a health policy in some specific contexts, considering the risk-benefit analysis of this and other alternative interventions and health priorities.</td></tr><tr><td>Health professionals</td><td>Physicians are sure and confident to recommend the intervention.</td><td>Different choices can be adopted by physicians and the shared and informed decision-making process should consider the patients' values and preferences.</td></tr><tr><td>Patients</td><td>Most patients, when well informed, would want the intervention; only a few would not.</td><td>Most patients, when well informed, would want the intervention, but many would not.</td></tr></tbody></table>

CCCD: chronic cardiomyopathy of Chagas disease; RCT: randomized clinical trial.

<table><thead><tr><th colspan="2">LEVELS OF EVIDENCE</th></tr></thead><tbody><tr><td>A</td><td>Direct evidence of good/high quality (RCTs with no important limitation or observational studies with indisputable expressive results conducted on CCCD).</td></tr><tr><td>B</td><td>Indirect evidence of good/high quality (extrapolation of results from RCTs without important limitation or observational studies with indisputable expressive results conducted on other cardiopathies) or Direct evidence of moderate quality (RCTs with limitations, subanalyses of RCTs including patients with CCCD, observational studies with satisfactory results conducted on CCCD).</td></tr><tr><td>C</td><td>Absence of empirical evidence (case series, extreme plausibility, and principle of asymmetry).</td></tr></tbody></table>

In that case, the best level of evidence for diagnostic accuracy derives from cross-sectional studies with proper methodology for patients' selection, execution and reading of the predefined tests, performed to reduce systematic errors. It is worth noting that the studies of diagnostic accuracy are very sensitive to biases caused by retrospective observations from data banks (selection bias, spectrum bias, nonblind and non-standardized observation bias).

Thus, the quality of the evidence is essential, and recommendation based on preliminary information should be avoided. Similarly to what is used for treatment, the current guideline classifies as level of diagnostic evidence A and B those with satisfactory precision and low risk for bias, with level B refering to indirect evidence with high potential of generalization or to direct evidence of satisfactory quality. Level of evidence C is reserved for situations that do not require empirical evidence, incontrovertible situations. For example, the accuracy of the electrocardiogram (ECG) to define baseline cardiac rhythm.

Regarding the strength of the recommendation, the accuracy observed is a necessary, but not sufficient, condition. An accurate test has not necessarily strong indication. For that, three essential conditions apply: first, the diagnosis should be clinically useful, that is, should benefit the patient; second, the test's additional information should be necessary and sufficient to increase the pretest diagnostic probability, which was previously undefined; and third, less complex, less invasive, of lower risk, or less expensive options should be absent. For example, although cardiac magnetic resonance imaging (CMRI) has better accuracy to assess systolic function, it is not strongly recommended because

echocardiography (ECHO) is usually sufficiently accurate and widely available, unlike CMRI.

This analysis of the need for a certain diagnostic test and of its impact determines its strength of recommendation, which is usually defined based on clinical rationale. For example, in the case of a symptomatic patient, finding a defined problem is obviously useful, if a specific solution applies. However, the diagnostic usefulness becomes dubious in the case of screening tests, when there is strong equipoise between the intentional consequences of early diagnosis and the probability of harm. In such dubious circumstances, performing diagnostic tests by use of RCTs is suggested to substantiate the diagnostic effort.

Finally, it is worth emphasizing that the rationale described for diagnosis also applies to the definition of the level of evidence and strength of recommendation for risk factors and prognostic models.

## 2. Epidemiology – 21st Century Update

### 2.1. Introduction

Chagas disease, also known as American trypanosomiasis, is a transmissible, potentially life-threatening illness caused by the protozoan parasite *T. cruzi* and belongs to the group of neglected tropical diseases (NTD) from the World Health Organization (WHO).32-36 Discovered by Carlos Ribeiro Justiniano Chagas in 1909,37 in the 21st century it continues to affect mainly socially vulnerable individuals and can generate severe physical (especially death and permanent disability), psychological (fear and stigma), and
socioeconomic impacts, which reflect directly and indirectly on the quality of life.¹,²,³,⁶,³⁸⁻⁴³

Political-institutional, economic, environmental (environmental degradation, climate changes – particularly temperature increase) and social (national and international human migrations, as well as precarious socioeconomic conditions, housing, education, sanitation, income, etc) factors are equally important central determinants of the global impact of *T. cruzi* transmission to the human species.²,³⁴,³⁶,⁴²,⁴⁴

For a deeper analysis of CD, it is essential to identify the different epidemiological scenarios and their transmission dynamics, involving not only individuals at risk for infection or already infected but also different *T. cruzi* strains, vector species, and reservoirs of the etiological agent, from the One Health perspective.⁴⁵

*T. cruzi* is a hemoflagellate parasite, transmitted mainly through the contact of feces of different species of bugs of the *Hemiptera* order, *Reduviidae* family, *Triatominae* subfamily, whose habitat extends from Argentina and Chile to the southern half of the United States of America (USA), contaminated when sucking blood from infected individuals or animals.²,³⁶,³⁸,³⁹

In addition, transmission can occur through: 1. ingestion of contaminated foods and beverages with triatomine bugs or their feces; 2. congenitally, from an infected mother to her fetus or newborn during pregnancy or delivery; 3. transfusion of blood or blood products from *T. cruzi*-infected individuals; 4. solid organ transplant from an infected person; and 5. accidents with biological materials, particularly in laboratories, in addition to sharing contaminated needles/syringes by individuals on illegal drugs.²,³²,³⁴,³⁶,³⁸,³⁹ From that perspective, the CD prevention and control actions are directly related to the *T. cruzi* transmission modes.³⁴,⁴⁴

Chagas disease is multisystemic and its natural history is characterized by an acute phase, which can last some weeks or months, usually asymptomatic or mildly symptomatic, and a chronic phase.¹,³⁸,⁴⁴,⁴⁶⁻⁴⁸ When not properly treated, the *T. cruzi* infection can last a whole life.⁴⁶ It is estimated that 30-40% of untreated infected individuals develop relevant clinical syndromes in the chronic phase, which can be life-threatening. In that phase, target-organs can be impaired, leading to cardiac, digestive, neurological, or mixed manifestations, which might require etiological treatment.²,³²,⁴⁴ This aspect emphasizes the importance of the timely diagnosis, in initial phases of disease, particularly in individuals originating from poor or socially vulnerable communities.²,⁴²,⁴⁴,⁴⁹

The economic burden generated by CD in the national health systems and society is significant, matching or even exceeding that of other diseases, such as rotavirus infection or cervical cancer, even in nonendemic areas.³⁶,⁵⁰,⁵¹ A substantial proportion of the economic burden is consequent to loss of productivity due to early morbidity and mortality induced, particularly, by chronic cardiomyopathy.³⁴,⁵⁰,⁵¹ Globally, the annual burden is US$ 627.46 million in health costs, with a current global net value of US$ 24.73 billion (annual costs per individual of US$ 4660 and, throughout life, per individual, of US$ 27 684). The global costs reached US$ 7.19 billion per year and US$ 188 billion throughout life. It is worth noting that

approximately 10% of those costs are associated with areas where CD is not endemic, such as USA and Canada.⁵⁰ Thus, overcoming barriers to diagnosis and treatment access with the proper implementation of whole attention to individuals with CD would reduce the occurrence of chronic complication and the costs associated with the national health systems (for example, pacemaker (PM) implantation and repair surgeries), with a beneficial impact on the entire society.¹⁴,⁴⁴,⁵⁰,⁵¹

From that perspective, a comprehensive economic assessment regarding measures to expand access to CD diagnosis and treatment revealed the importance of the serological screening of candidates for blood donation and pregnant women, as the best cost-effective public health strategies.⁵²,⁵³ Broader policies that recognize the different dimensions of social determination are fundamental to reduce that burden, requiring the involvement of other areas beyond the health sector.²,³³,⁴⁵,⁵⁴ Chagas disease is included in the 2030 Sustainable Development Goals (SDG) agenda, in its third objective, "ensure healthy lives and promote well-being for all at all ages", aimed at "ending the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases, and fighting hepatitis, waterborne diseases and other communicable disease" by 2030.³³,³⁴,⁵⁵

Despite the high morbidity and mortality burden of CD and the elevated costs for the national health systems and mainly for society, 70-90% of the individuals with CD are reported to ignore their diagnosis, and only 1% effectively receives proper etiological treatment in the 21st century.⁴⁹,⁵⁴,⁵⁶ There is strong evidence that the diagnosis and proper etiological treatment of CD have several benefits, such as prevention of the congenital transmission in treated mothers, serological cure in babies and children, and a reduction in the progression to advanced clinical forms of CD in acutely and chronically infected individuals.¹,²,⁷,⁸,⁴¹,⁴⁴,⁵⁶⁻⁶⁰ However, once the disease has progressed to a more advanced clinical phase, with severe heart impairment, the etiological treatment seems not to have any clinical benefit.¹,²,⁷,⁸,⁴⁴,⁴⁶,⁶⁰ This strengthens the need to develop enhanced diagnostic methods in the local health services to guarantee access to early, safe, and effective treatment.⁸,⁵³,⁵⁴,⁵⁶,⁵⁷,⁶⁰

In addition to the complex political, geographical, socioeconomic, cultural, technological, and legal challenges of the territories with higher endemicity for CD, barriers are known to persist regarding access to diagnosis, treatment, and longitudinal care.⁴⁴,⁵⁴ Those barriers include: lack and inconsistency of data on the disease; limitation of integrated actions of surveillance, control, and care in the Primary Health Care (PHC) network; distance to health services; complicated diagnostic flowcharts and slow and costly processes (referral and counter-referral systems); limited integration of policies and actions for reproductive, maternal, neonatal, and child health; disproportional impact of CD on more vulnerable populations; limited knowledge of both the population and healthcare professionals about the disease; limited interest of the media and pharmaceutical industry; reduced health education initiatives; limited availability of tools and materials in healthcare centers; fear; stigma and discrimination against affected individuals; low capacity for social mobilization and limited political leadership of individuals at higher risk.²,⁴⁰,⁴¹,⁴⁴,⁴⁵,⁴⁹,⁶¹
It is worth noting that the limited knowledge of healthcare professionals about CD is one of the critical factors to ensure wide access to proper diagnosis and treatment in the national health systems.²,⁶¹ In addition, there is clear need to overcome the access barriers related to the etiological treatment, currently limited to only two effective drugs - benznidazole and nifurtimox – which require relatively long periods of administration and may be associated with adverse reactions that can complicate treatment, requiring clinical and laboratory monitoring.¹,⁴¹,⁴⁹,⁵⁴,⁵⁶,⁵⁸,⁶⁰ Furthermore, the antiparasitic drugs have limitations regarding their use by pregnant women and those with advanced disease with cardiac or cardiobigestive involvement.² However, for pregnant women with acute and severe clinical findings of CD (myocarditis or meningoencephalitis),⁸ a decision about that ethical dilemma has to be made.²

In one of the eleven WHO public health global campaigns, the 72nd World Health Assembly approved, on May 24, 2019, the designation of a World Chagas Disease Day aimed at raising public awareness on this NTD.³⁶ In addition, the WHO's road map for NTD identified three strategic actions to eliminate the disease: action 1 – engage with public institutions/agencies involved in prevention and control in different countries (ministries of health) to recognize CD as a public health problem and establish policies and effective actions of prevention, control, care, and surveillance in all endemic territories; action 2 – qualify medical care, from permanent education during service to integrated action across the entire care network; and action 3 – ensure that countries where within-household/ extra-household vector transmission still occurs, comply with the protocols of prevention, control, and surveillance.⁶²

It is noteworthy that society is increasingly participating in this endeavor. Social movements are engaging and taking a leading role in CD globally, as well as coordinating with other movements directed at NTD, in an effort to preserve fundamental rights such as access to health.²,³⁴ Those movements get together in a wider Social Forum to tackle NTD in Brazil.⁴⁹ In addition, those movements related to CD make up an international federation (FINDECHAGAS – Federação Internacional de Associações de Pessoas Afetadas pela Doença de Chagas [https://findeChagas.org/home-po/]) representing endemic and nonendemic countries.²,³⁴

## 2.2. World Distribution of Chagas Disease

In the 21st century, CD maintains an epidemiological pattern of endemicity in 21 Latin-American countries, with approximately 70 million individuals at risk for exposure to *T. cruzi* infection. There is relative difficulty in establishing more precise estimates in the context of a NTD, raising uncertainty. However, the currently available estimates have been fundamental to subsidize agendas for CD control. The WHO estimates 6-7 million infected individuals around the world, most in Latin America, indicating a reduction of approximately 65% as compared to 1980 (17 million).

Approximately 63% of those cases are in countries of the Southern Cone Initiative, mainly Argentina (1.5 million),

Brazil (1.2 million), Mexico (880 thousand) and Bolivia (610 thousand).³⁸,³⁹,⁶³ Chart 2.1 shows the different patterns of epidemiological indicators of CD in Latin America at different times.

However, those global data differ from the individual estimates in several countries, hindering the exact establishment of CD prevalence in the Americas.² In addition, under-reporting of cases and not reporting deaths due to CD represent critical obstacles, because they prevent the adoption of control measures more adjusted to local realities based on epidemiological surveillance.³⁴,⁶⁴,⁶⁵

Despite these difficulties, the development of regional initiatives, coordinated to interrupt *T. cruzi* transmission, was able to expressively reduce the global prevalence of CD.²,³⁴,⁶⁶,⁶⁷ The agreed goals to eliminate transmission by the major vector species (*Triatoma infestans*) and by blood transfusion was achieved by several countries based on initiatives since the 1990 decade, with a significant reduction in the number of new cases; however, some critical areas of transmission still persist.²,⁶⁶,⁶⁸,⁶⁹

The current challenges are even more important. Only 10%-30% of the individuals affected by CD are aware of their diagnosis, which contributes to the fact that only 1% of those requiring etiological treatment have actual access to it, maintaining morbidity, mortality, and social cost at high levels, with impairment of quality of life.³⁶,⁴³,⁵⁴,⁵⁶,⁶⁰ Furthermore, in most areas where vectorial interruption or transmission reduction was achieved, the population affected is getting older, increasing the burden of morbidity and mortality due to the coexistence of chronic-degenerative diseases, mostly cardiovascular diseases.⁴¹,⁶⁶,⁷⁰⁻⁷² In the elderly population, CCD remains a strong predictor of higher risk for death.⁷⁰

<table><caption>**Chart 2.1 – Changes in mortality, prevalence, and incidence of Chagas disease (vector and congenital transmission) in 21 endemic countries in Latin America, in 1980–1985, 2005, and 2010.**</caption><thead><tr><th>PARAMETERS - ESTIMATES</th><th>1980-1985</th><th>2005</th><th>2010</th></tr></thead><tbody><tr><td>Number of deaths/ year</td><td>> 45 000</td><td>12 500</td><td>12 000</td></tr><tr><td>Number and percentage of infected individuals</td><td>17 395 000 (4.3%)</td><td>7 694 500 (1.4%)</td><td>5 742 167 (1.1%)</td></tr><tr><td>New cases/year – total</td><td>700 000</td><td>55 585</td><td>38 593</td></tr><tr><td>New cases/year – vector transmission</td><td>> 500 000</td><td>41 200</td><td>29 925</td></tr><tr><td>New cases/ year – congenital transmission</td><td>7000 - 49 000</td><td>14 385</td><td>8668</td></tr><tr><td>Number and percentage of total population at risk</td><td>92 895 000 (25.0%)</td><td>108 595 000 (20.4%)</td><td>70 199 360 (12.9%)</td></tr></tbody></table>

Source: Adapted from Dias et al., 2016;² WHO, 2002;³⁸ PAHO, 2006;³⁹ and WHO, 2015.⁶³
# Guidelines

Despite the significant reduction in prevalence, approximately 10-15 thousand deaths related to CD are reported every year,²,³,⁶,⁹,⁵⁹ although a significant reduction has been observed, considering the recording of over 45 thousand deaths annually in the 1980 decade. However, mortality still remains high,⁶³,⁶⁵,⁷⁰,⁷³ contributing to maintain CD a public health problem.⁴⁴,⁷⁰,⁷⁴,⁷⁵

Beyond the classically endemic areas in Latin America, CD has been progressively reported in nonendemic countries (some in Europe, USA, Australia, and Japan), because of the migration movements associated with political-institutional, sanitary, environmental, and economic crises in some countries.²,⁴²,⁶⁷,⁷⁶⁻⁸¹

Those global estimates are supported by recent data originating from countries, such as Spain, where, although the disease is not endemic, there is active research and focus on public health measures for control. In Spain, they estimated for 2018 over 55 thousand of the almost 2.6 million migrants from endemic countries (54% from Bolivia) living with CD, an estimated prevalence of 2.1%. Approximately 70% of migrants did not have an established diagnosis and most were not treated, 83% were older than 15 years and 60% were children.⁸²

In addition, those populations live in precarious conditions, are socially vulnerable because of social and economic restrictions that hinder access to healthcare, which is aggravated by the poor professional experience in the specific health sector.⁴²,⁶¹,⁶⁷,⁷⁷,⁸⁰,⁸¹ It is worth noting that *T. cruzi* can act as an opportunistic microorganism in individuals with other immunosuppression-associated pathologies, resulting in life-threatening clinical syndromes due to RCD.¹,⁸³,⁸⁴

In those nonendemic contexts, the likelihood of *T. cruzi* transmission through blood transfusion has been more and more recognized. Although CD is rarely defined as a public health problem in nonendemic countries, in the past 10 years several blood centers implemented measures to mitigate the risk related to blood safety based on the recognition of epidemiological risk factors associated with Latin-American immigrants and the adoption of serological tests for screening.⁴²,⁷⁹

In endemic contexts, the control of two transmission modes (vectorial and transfusion) puts into perspective the congenital mode, responsible for almost one third of the new infections in 2010.⁴¹,⁶³,⁶⁹,⁸⁵⁻⁸⁷ In endemic regions, 1.12 million women at reproductive age are estimated to be infected,⁵⁹ and the mean congenital transmission rate is estimated as 5%, mainly in high-risk endemic areas.⁵⁹,⁸⁸ Because the access to diagnosis of *T. cruzi* infection in mothers or newborn babies is limited in most endemic areas, the prevalence in pregnant women and newborns can be underestimated.⁵⁹,⁸⁸ Even with such limitations, the incidence is estimated at 8000 to 15 000 cases of congenital transmission per year in Latin America.⁸⁵ Of note, that mode of transmission has played a central role in maintaining *T. cruzi* infection in nonendemic areas.⁵⁹,⁶³,⁸⁶,⁸⁷ Thus, the occurrence of congenital infection can sustain *T. cruzi* transmission indefinitely, even in countries without the classic vectorial mode.⁸⁶,⁸⁸

To prevent congenital transmission in endemic areas, it is essential to guarantee access to diagnosis and etiological treatment to girls and women at reproductive age before pregnancy.⁵⁷,⁵⁹,⁸⁹ In addition, the diagnosis of *T. cruzi* infection in pregnant women during the prenatal period, favoring the early screening of the newborn infection, as well as the diagnosis of infection in newborns from infected mothers, enabling the implementation of etiological treatment, would be highly effective and safe measures.⁴¹,⁵⁷,⁵⁹,⁸⁵,⁸⁶,⁸⁸,⁸⁹

Oral transmission, on the other hand, has been reported particularly in the Amazonian region and subtropical Andes,⁹⁰ playing an important role in the appearance of acute cases in the Brazilian Amazonian region and Venezuela.²,⁴⁸,⁹⁰ In those scenarios, mortality is higher during the acute phase as compared to that of acute cases caused by the classic vectorial transmission.²,⁴⁷,⁴⁸ Acute CD orally transmitted has considerable lethality in the first year after infection,⁴⁸ as discussed in another chapter of this guideline.

## 2.3. Overview of Chagas Disease in Brazil

In the 21st century, it is unequivocally important to sustain CD surveillance and control in all its evolutionary clinical phases, considering as criteria, the magnitude, spread potential, transcendence, vulnerability, and Brazil's international commitments.²,³⁴,⁶⁹,⁹¹ As a country of continental dimensions, throughout this century Brazil has undergone demographic, social, economic, and environmental changes, failing to overcome the critical socioeconomic and regional inequalities.²,³³,⁵²

However, Brazil has a public, universal, and democratic unified health system (SUS), whose quality should continue to enhance constantly, aimed at ensuring the access to health for all individuals, a right established in the 1988 Federal Constitution 1988.²,³³,⁴⁹,⁹²

In that context, CD remains the NTD with the highest morbidity and mortality burden, particularly among elderly men and those who had lived in important endemic areas of vectorial transmission.⁷³,⁷⁴,⁷⁵ Considering Brazil's extension and diversity, with implications in the ecological, demographic, social, and economic dynamics of the regions, there are multiple clinical, epidemiological, and operational scenarios for disease control.²,³⁴

Vectorial control in endemic areas had a significant impact on both blood transfusion and congenital transmissions,⁶⁴,⁶⁹,⁸⁷ but the current weakening of the entomological surveillance operations in endemic municipalities is worrisome. The certification of interruption of Chagas disease transmission by the major domestic vector, *T. infestans*, was issued in 2006 by the Pan American Health Organization (PAHO), within the Southern Cone Initiative.²,³⁴ Despite advances, the risk of CD transmission by vectors persists and has been assessed under different perspectives because of several factors, such as the existence of autochthonous triatomine species with a high potential of colonization, the presence of wild and domestic reservoirs of *T. cruzi*, the increasing proximity between human populations and those environments, in addition to the persistence of residual *T. infestans* foci, even in specific areas of the Bahia state, and the limitation of entomological surveillance actions.²,³⁴
In Brazil, in 1980-1985, 6 180 000 (4.2%) individuals were estimated to be infected with *T. cruzi*, and, in 2000, 1 900 000 (1.0%).³⁸,³⁹ The WHO's most recent estimates indicate in 2010 1 156 821 infected individuals with *T. cruzi* (0.6%).⁶³ However, the limitation of population-based studies hinders more realistic assessments about the magnitude of CD in Brazil.⁶⁴ Thus, some studies based on systematic reviews and meta-analyses of data available in Brazil have estimated the number of infected individuals ranging from 1.9 to 4.6 million, figures that might be closer to the current variation from 1.0% to 2.4% of the population.²,⁶⁴ Based on those proportions, the number of Brazilians infected with *T. cruzi* estimated for 2020 is 1 365 585 to 3 213 142, of whom, 136 559 to 321 314 individuals with the chronic digestive form and 409 676 to 963 943 with the chronic cardiac form. Regarding the IFCD, the population estimated with *T. cruzi* infection ranged from 819 350 to 1 927 885 individuals.² Chart 2.2 shows the projections of the numbers of *T. cruzi* infected individuals and cases in the chronic phase of CD with cardiac and digestive forms in Brazil from 2020 to 2055.

The prevalence of *T. cruzi* infection in pregnant women in Brazil in 2010 was estimated as 1.1% (34 629 women), with a mean of 589 newborns with congenital infection (transmission rate of 1.7%),⁸⁷ similar to the WHO's estimate (571 cases).⁶³ The congenital transmission rate is lower (1.5-2.0%) as compared to the mean of 5% observed in other Southern Cone countries, such as Argentina, Paraguay and Bolivia. Such findings suggest that the presence of TcII associates with lower transmission as compared to that of TcV, which predominates in the Southern region of Brazil and those countries.²,⁵⁷

Based on data from the Notifiable Diseases Information System (SINAN), the occurrence of cases of acute CD has been the aim of epidemiological surveillance, according to the Brazilian Ministry of Health definition of “case”. From 2007 to 2019, 3060 cases of acute CD (mean of 222 cases/year) were confirmed in 219 municipalities.³⁴ In 2020, 146 cases were confirmed, mainly in the North region, with case

fatality rate of 2% (3/146 - all deaths in the Pará state). The most frequently reported mode of transmission in Brazil in the past 15 years in cases of acute CD was the oral one,³⁴,⁹³ revealing the operational limitations of the surveillance process in Brazil, which have induced changes in the epidemiological profile of the disease in the past decade.²,⁹⁰

The CD mortality burden in Brazil persists significantly high, despite the control actions implemented. Mortality is known to be more expressive at ages 50 to 64 years and older cohorts, probably due to the effects of the period of intensification of vectorial control actions, in addition to demographic changes.³⁵,⁷⁵ The differences observed between regions, especially with higher burden in the West-Central and Southeast regions, indicate socioeconomic inequities and different patterns of access to healthcare services in the SUS.³⁵,⁷³ The South region shows a reduction in the trend of mortality, the North region, an increase, while the Northeast region has no defined trend.³⁵,⁷⁴

It is worth noting that the North region concentrates the majority of the new cases reported in the country.³⁴,⁴⁷,⁹³ In addition to the probable underreporting of cases not associated with domiciliary vectorial transmission, that region had little impact from the systematic actions for triatomine control. This is justified because the local cycle of *T. cruzi* transmission does not involve vectors with the ability of domiciliation, but is sustained in an enzootic cycle, with wild vectors implicated in cases associated with oral or extra-household vector transmission.²,⁴⁷,⁴⁸,⁶⁰,⁷³ Thus, it is reasonable to estimate that the accumulation of hundreds or even thousands of cases of *T. cruzi* infection over time in the Amazonian region might be contributing to this specific epidemiological pattern.⁴⁷

Chagas disease continues to have a strong impact on Social Security and the services of the National Institute for Social Security (INSS) in the Brazilian states with higher prevalence,³⁴ particularly as the affected population ages.²,⁷² The global analysis for the 2030-2034 period indicates a progressive decline in mortality (over 75% as compared to that in 2010-2014), mainly

<table><caption>Chart 2.2 – Projections of the number of individuals infected with *T. cruzi* and of individuals with chronic Chagas disease in the cardiac and digestive forms in Brazil, 2020–2055.*</caption><thead><tr><th rowspan="2">YEAR</th><th rowspan="2">ESTIMATE OF THE BRAZILIAN POPULATION</th><th colspan="3">AGE GROUP OF REFERENCE</th><th colspan="2">ESTIMATE OF THE NUMBER OF INFECTED INDIVIDUALS</th><th colspan="2">ESTIMATE OF INDIVIDUALS WITH THE DIGESTIVE FORM</th><th colspan="2">ESTIMATE OF INDIVIDUALS WITH THE CARDIAC FORM</th></tr><tr><th>AGE GROUP</th><th>POPULATION</th><th>%</th><th>INFECTION 1.02%</th><th>INFECTION 2.4%</th><th>INFECTION 1.02%</th><th>INFECTION 2.4%</th><th>INFECTION 1.02%</th><th>INFECTION 2.4%</th></tr></thead><tbody><tr><td>2020</td><td>212 077 375</td><td>≥ 25</td><td>133 880 929</td><td>63.1</td><td>1 365 585</td><td>3 213 142</td><td>136 559</td><td>321 314</td><td>409 676</td><td>963 943</td></tr><tr><td>2025</td><td>218 330 014</td><td>≥ 30</td><td>127 334 466</td><td>58.3</td><td>1 298 812</td><td>3 056 027</td><td>129 881</td><td>305 603</td><td>389 644</td><td>916 808</td></tr><tr><td>2030</td><td>223 126 917</td><td>≥ 35</td><td>120 096 221</td><td>53.8</td><td>1 224 981</td><td>2 882 309</td><td>122 498</td><td>288 231</td><td>367 494</td><td>864 693</td></tr><tr><td>2035</td><td>226 438 916</td><td>≥ 40</td><td>112 013 898</td><td>49.5</td><td>1 142 542</td><td>2 688 334</td><td>114 254</td><td>268 833</td><td>342 763</td><td>806 500</td></tr><tr><td>2040</td><td>228 153 204</td><td>≥ 45</td><td>102 983 115</td><td>45.1</td><td>1 050 428</td><td>2 471 595</td><td>105 043</td><td>247 160</td><td>315 128</td><td>741 479</td></tr><tr><td>2045</td><td>228 116 279</td><td>≥ 50</td><td>92 984 144</td><td>40.8</td><td>948 438</td><td>2 231 619</td><td>94 844</td><td>223 162</td><td>284 531</td><td>669 486</td></tr><tr><td>2050</td><td>226 347 688</td><td>≥ 55</td><td>82 097 220</td><td>36.3</td><td>837 392</td><td>1 970 333</td><td>83 739</td><td>197 033</td><td>251 218</td><td>591 100</td></tr><tr><td>2055</td><td>222 975 532</td><td>≥ 60</td><td>70 485 475</td><td>31.6</td><td>718 952</td><td>1 691 651</td><td>71 895</td><td>169 165</td><td>215 686</td><td>507 495</td></tr></tbody></table>

<footnote>*For infection rates of 1.02% and 2.4%, and considering 30% of patients with the cardiac form and 10% with the digestive form of Chagas disease. Source: Adapted from Dias et al., 2016²</footnote>
# Guidelines

among the youngsters, ranging from 86%, in the age group from 20 to 24 years, to 50% in those aged 80 years and more.⁷⁵ It is worth noting the significant reduction in the quality of life of individuals with CD and their families.⁴³

Integrated actions of care, surveillance and control of CD in PHC have been fundamental and strategic to reduce the morbidity and mortality burden, mainly in endemic territories, expanding access to diagnosis and etiological treatment.²,³⁴,⁴⁴,⁵⁸,⁷⁵ The PAHO document "Chronic Care for Neglected Infectious Diseases: Leprosy/Hansen's Disease, Lymphatic Filariasis, Trachoma, and Chagas Disease – A guide for morbidity management and disability prevention for primary health care services" is a landmark, because it highlights several fundamental aspects in the care of individuals with CD, aiming at providing PHC teams with tools, and reinforces the importance of integrated surveillance actions.⁴⁴

## 2.4. Epidemiological Surveillance in Brazil

Epidemiological surveillance for CD comprises necessarily integrated actions that involve approaching human cases, vectors, and reservoirs, maintaining an interface with the healthcare network and special emphasis on the PHC role.²,³⁴,⁹¹,⁹³

The major objectives of the epidemiological surveillance actions for CD in Brazil are as follows: 1) to early detect cases of acute CD for proper etiological treatment and application of measures to prevent the occurrence of new cases; 2) to conduct an epidemiological investigation of all acute cases, aiming to identify the mode of transmission and adopt proper control measures; 3) to monitor *T. cruzi* infection in the human population by use of PHC screening programs, periodical serological inquiries in strategic populations, and analysis of the screening process of candidates for blood donation in blood centers; 4) to monitor the morbidity and mortality profile of CD, outlining actions to strengthen the healthcare network for infected individuals; 5) to maintain transmission by *T. infestans* eliminated and that by other important species under monitoring/control; and 6) to integrate actions of sanitary, environmental, vectorial, and reservoir surveillance with epidemiological surveillance actions.²,⁹³

The data available on the epidemiological surveillance of human cases do not enable estimating the nosological magnitude of American trypanosomiasis. Only 10-20% of the acute CD cases are estimated to be reported.²,⁴⁷ Up to May 2020, when the chronic phase of CD was included as an event of interest for epidemiological surveillance, by use of mandatory reporting of cases (Ordinance nº 1.061, of May 18, 2020), only the traditional surveillance of cases in the acute phase was performed and included in the National List of Notifiable Diseases of Mandatory and Immediate Reporting.³⁴,⁹³ This enlargement in the surveillance scope is very important for our country to reach national recognition of patterns of disease occurrence and can be followed by other endemic countries. This new process of epidemiological surveillance is expected to be implanted in the entire Brazilian territory by 2022.

More recently, to recognize the magnitude of chronic CD in the country, the importance of rearticulating and integrating health surveillance actions have been discussed, aimed at the development of a large hierarchical network of health services in several territories to guarantee access for millions of *T. cruzi* infected individuals.⁴⁴,⁹¹,⁹⁴ To elaborate a prioritization model of municipalities for chronic CD surveillance, a team of the Ministry of Health conducted a preliminary multicriteria decision analysis based on three indices built from the following indicators: (a) epidemiological, directly related to chronic CD; (b) resulting from the progression of chronic CD; and (c) related to access to health services. The model defined as the most suitable was composed by 1345 municipalities of intermediate priority, 1003 of high, and 601 of very high priority for chronic CD, mainly in the Southeast and Northeast regions of the country.⁹⁴

After that, the Ministry of Health proposed the elaboration of an index of vulnerability for chronic CD to evidence areas at higher risk for morbidity and mortality in that phase of the disease, taking into consideration contexts of limited access to the healthcare service network, with low diagnostic suspicion and case detection and limitation of the quality of life of the individuals affected.⁹¹ Thus, three subindices were developed from the three indicators integrated in the previous analysis.⁹¹,⁹⁴ The value of the index can range from 0 to 1, and the closer to the value '1', the higher the vulnerability for chronic CD (Figure 2.1).⁹¹

An additional perspective of CD surveillance in Brazil leads to the recommendation that an anti-*T. cruzi* antibody testing request should be made available to every infected individual with the human immunodeficiency virus (HIV) or with acquired immunodeficiency syndrome (AIDS), based on the existence of epidemiological antecedent. This recommendation has been debated more recently in other countries, such as the USA.⁹⁵ It is worth noting that, for the purpose of epidemiological surveillance, since 2004 Brazil has inserted RCD in the list of diseases indicative of AIDS in the presence of HIV infection, from the definitive diagnosis of meningoencephalitis and myocarditis associated with CD.²,⁸³,⁸⁴

## 2.5. Association of Chagas Disease with COVID-19

The emergence of COVID-19, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has brought serious and unprecedented global challenges for the national health systems and humankind.⁴²,⁸⁰,⁹⁶,⁹⁷ Its pandemic character has been compounded by its high infectivity, even in its asymptomatic phases, leading to its rapid spread.⁹⁸,⁹⁹

As the COVID-19 global pandemic advances, it disproportionately impacts more and more socially vulnerable populations,⁸⁰,⁹⁸,⁹⁹ which already bear a significant morbidity and mortality burden for NTD. Thus, the analysis of the current context of NTD provides relevant possibilities to approach gaps in COVID-19 control, because it is an important referential for the progress in responding to the needs of more vulnerable populations. Success in responding to COVID-19 control without reducing the NTD burden concomitantly points to flaws in the sustainability of the national health systems to maintain that control.⁹⁷
<figure><img src="image_2.png" /><figcaption>**Figure 2.1** – Spatial distribution of chronic Chagas disease (CCD) vulnerability index according to the federative units (FU) and Distrito Federal (A) and health macroregions (B). Source: CGZV/Deidt/SVS</figcaption></figure>

The concomitance of CD is particularly worrisome because it can cause cardiac, gastrointestinal, neurological and other complications, increasing susceptibility to COVID-19.⁷¹,¹⁰⁰⁻¹⁰² The highest prevalence of comorbidities seems to be related to a worse prognosis in coinfection.¹⁰² Since the appearance of the pandemic caused by SARS-CoV-2, the cardiovascular involvement has been identified as a frequent complication of COVID-19.⁹⁶,¹⁰⁰ However, there is little evidence on the effects of COVID-19 on individuals with CD.¹⁰⁰,¹⁰²⁻¹⁰⁴ Some studies have reported that COVID-19 may add new challenges in guaranteeing access to total healthcare (diagnosis and treatment, as well as throughout the full disease cycle) to those individuals and in the necessary development of new research analyzing the implications of SARS-CoV-2 coinfection.⁹⁷,¹⁰³

In addition, both diseases are similar regarding the susceptibility to risk factors, molecular patterns associated with the pathogen, recognition of glycosaminoglycans, inflammatory process, vascular hypercoagulability, microthrombosis and endotheliopathy, and, thus, may require treatments with similar principles.¹⁰⁵ However, it is worth noting the importance of considering the disease's different clinical forms and specific pathophysiological mechanisms associated.¹⁰² Thus, despite some similarity regarding pathophysiology, which involves high risk of thromboembolism in COVID-19 and in the chronic cardiomyopathy of Chagas disease (CCCD), cautiousness is required regarding the recommendation of immediate treatment for CD with anticoagulant drugs, whose potential benefit should be restricted to clinical scenarios in which there is a favorable adequate risk relation of hemorrhage versus thrombosis with the use of those drugs. Such principles are discussed in another chapter of this guideline.

Some studies have pointed to high levels of comorbidity in cases of CD associated with severe forms of COVID-19. It is important to emphasize that those comorbidities reflect the more advanced ages of the populations that are specially impacted by CD and COVID-19.⁷¹,¹⁰⁰⁻¹⁰² Although more than 80% of the cases of COVID-19 are mild or asymptomatic, severe cases have been more frequent among elderly and individuals with comorbidities, while, for CD, elderly with chronic cardiomyopathy are at a higher risk of death, which is partially justified by its association with age or other chronic conditions and by social poverty.⁷¹,¹⁰⁰

Although coinfection might be associated with a higher risk for complications, with a worse clinical prognosis, a multicenter prospective study with 37 hospitals in 17 municipalities of 5 Brazilian states (Minas Gerais, Pernambuco, Rio Grande do Sul, Santa Catarina, and São Paulo) reported that there was no significant differences in the clinical presentation nor in the outcomes of cases with CD as compared to controls, despite the evidence in the beginning of the study of higher frequency of chronic HF and atrial fibrillation (AF). In addition, that study reported lower level of reactive C protein among participants with CD.¹⁰⁴

The higher social vulnerability of individuals with CD in the context of poverty can be increased by COVID-19, because of its political-economic impacts.⁸⁰,⁹⁷⁻⁹⁹ The significant increase of extreme poverty around the world in the past decade compounds the challenge of access to healthcare for individuals with CD.⁷¹,¹⁰¹,¹⁰⁶

In addition, individuals with CD might be afraid to search care because of fear of exposure to COVID-19, postponing the solution for complications related to disease and increasing the emotional burden of the disease due to the associated
# Guidelines

worries. And all that is compounded by the weakening, disorganization, and overload of the national health systems.⁷¹

Brazil is one of the countries with the highest COVID-19 morbidity and mortality burdens and has called negative attention in the international scenario because of its lack of coordination and leadership regarding the COVID-19 surveillance and control actions.⁹²,⁹⁹,¹⁰⁷ Moreover, the inequity of COVID-19 expression in Brazil has been evidenced by the excessive mortality of black/mixed heritage individuals of all age groups.⁹⁹,¹⁰⁸ These racial disparities can be justified by historically determined socioeconomic conditions, which usually define who can maintain social distancing and avoid exposure to SARS-CoV-2.⁷¹,⁹⁹,¹⁰⁸

In addition, the risk of death from COVID-19 showed a wide range in the pandemic initial stages, with increased vulnerability of the peripheral areas, where the most vulnerable communities are found, jeopardizing the health system's ability to respond and increasing the inequities in health care.⁹⁹,¹⁰⁶

Through the informative note nº 9 from 2020 (CGZV/ DEIDT/SVS/MS), recommendations from the Ministry of Health were established in Brazil to adapt surveillance and healthcare actions for individuals with CD considering the COVID-19 epidemiological situation.¹⁰⁹ Despite those orientations, the specific Epidemiological Bulletin from the Ministry of Health raised the possibility of impact of the COVID-19 pandemic on the morbidity and mortality profile and surveillance actions for CD in Brazil.⁹³

That bulletin points to evidence of cardiovascular diseases as critical risk factors for higher severity of the clinical syndrome associated with COVID-19. Based on that, individuals with CD should be considered a population at higher risk for worse clinical progression of COVID-19, requiring more careful attention by the SUS during the pandemic.⁹³

In addition, that epidemiological bulletin from March to August 2020 reported 1746 deaths in Brazil with CD as the underlying cause of death (data from the Brazilian Mortality Information System), 29 of which cited COVID-19 or severe acute respiratory syndrome as an aggravating condition or a condition contributing directly or indirectly to the causal chain of death (parts I and II of the certificate of death), with a higher proportion in the Southeast and Northeast regions.⁹³ During that period, 125 691 deaths from COVID-19 were reported, in 207 of which (0.2%) CD was mentioned as the condition contributing to death (part II of the certificate of death), with a higher proportion in the Southeast and Northeast regions. Most of those deaths occurred in female individuals (52.7%), of mixed heritage (42.0%), with a mean age of 74 years (SD±11.36), and in the age group over 75 years (53.0%).⁹³

Some hypotheses point to *T. cruzi* and SARS-CoV-2 coinfection as an important uninvestigated causal binomial of death in CD endemic regions.¹⁰¹

The regionalized temporal trend analysis in the country, from 2009 to 2019, reveals propensity for a statistically significant reduction in the specific coefficient of mortality from the disease. However, a tendency to increase was

observed in the coefficient of incidence of acute phase cases, which was statistically significant in the North region; however, in 2020, the number of cases reported was lower than that foreseen.⁹³

Regarding diagnosis, a 24% reduction was observed in the number of requests for laboratory tests for CD diagnosis processed in 2020 as compared to the mean from 2017 to 2019.⁹³ In addition, a reduction in treatment was observed, evidenced by the reduction in benznidazole distribution and the entomological surveillance assessment in the state coordinations,⁹³ indicating a possible reduction in the sensitivity of the healthcare and surveillance network, probably related to directing municipal and state efforts to fight the COVID-19 pandemic.

Even with guidance on the need to readapt the entomological surveillance activities in the context of COVID-19,¹⁰⁹ the reports of state representatives indicate that, in many territories, the foreseen control activities for 2020 could not be performed, not even partially.⁹³

Finally, because of the recent evidence that cardiovascular sequelae persist in the long term in individuals with COVID-19,¹¹⁰ this could be even more ominous for those individuals already with CCCD when they get infected with SARS-CoV-2.

## 2.6. Final Reflection on the Current Chagas Disease Epidemiological Scenario

Recent publications by researchers and managers from both nonendemic¹¹¹,¹¹² and endemic countries,¹¹³,¹¹⁴ indicate the pressing need to adopt comprehensive policies regarding public health to effectively control the inter-human transmission of the *T. cruzi* infection and to reach an optimal level of care for already infected individuals, focused on providing both diagnostic and therapeutic opportunities.

# 3. Pathogenesis of Cardiomyopathy of Chagas Disease

## 3.1. Introduction

The CCCD pathogenesis is still object of intense debate. In the acute phase of CD, the intense tissue parasitism has always been recognized as an essential mechanism; however, in the chronic phase, this has not occurred and other pathogenetic hypotheses predominated during the second half of the 20th century. It was only from the year 2000 on that the notion of the persistence of the parasite in the myocardial has consolidated as the primordial mechanism for the CCCD installation. This rescued the concept of CD as a truly infectious entity and that of CCCD as caused by a low-intensity, but virtually incessant, focal inflammatory process. The tissue aggression, causing necrosis and reactive and repairing fibrosis, is directly stimulated by *T. cruzi* and the adverse immune reaction to parasite persistence.

The prognosis of CCCD is usually more ominous than that of non-inflammatory cardiomyopathies. The identification of prognostic factors and therapeutic targets is critically dependent on that knowledge. The direct lysis of infected
cells is significant mainly during the acute phase of the infection, when intracellular parasites are abundant and myocarditis is usually diffuse and intense. On the other hand, chronically infected individuals have a clearly different disease progression. Decades after the infection, approximately 60% of infected individuals remain free from clinical manifestations of the disease for their entire life (stage A - IFCD), 10% develop gastrointestinal disease, and 30% develop CCCD, which can be classified into stages B1/B2 (less advanced cardiomyopathy) or C/D (severe cardiomyopathy), as detailed in another chapter of this guideline.

The major pathogenic hypotheses to explain the beginning and progression of CCCD include: 1) direct parasite-induced damage to the tissues; 2) indirect inflammatory/ immune damage to the tissues; 3) neurogenic disorders; 4) microvascular disorders. The neurogenic hypothesis was based on intracardiac neuronal depletion and consequent dysautonomia, but there are unavoidable obstacles to the postulated cardiopathy resulting from parasympathetic deprivation ('parasympathetic-deprived' cardiopathy). Evidence from experimental models and human disease indicates that inflammatory infiltrates are the major cause of damage to the cardiac tissue. However, more recent evidence has shown that genetic susceptibility and mitochondrial damage are important parts in the CCCD pathogenesis. Cardiac microcirculatory lesions have been reported in CCCD, but microvascular ischemia can result from the action of inflammatory mediators and constitute a mechanism of positive feedback, potentializing the inflammatory and mitochondrial damages, as discussed in the following section.

## 3.2. Immune Dynamics and Differential Progression to Chronic Cardiomyopathy of Chagas Disease

In the acute phase of the infection, which has been investigated in more details in murine models, parasitemia and intense parasitism of the tissues trigger a strong immune response. Initially there is innate immune response, followed by that depending on cytotoxic T lymphocytes and T lymphocytes that produce inflammatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), and specific anti-T. cruzi antibodies that partially control the parasitism, establishing persistent, although low-grade, infection.¹¹⁵,¹¹⁶

Different lineages of mice infected with the same lineage of *T. cruzi* show different severities of CCCD, characterized by electrocardiographic and echocardiographic changes, associated with varied serum levels of TNF-α and nitric oxide, suggesting that variations in the host's genetics can determine chronic disease severity.¹¹⁷,¹¹⁸

Persistent parasitic stimulation induces the systemic production of IFN-γ and TNF-α in individuals with chronic CD, which is particularly intense in those with CCCD as compared to those with the IFCD.¹¹⁹,¹²⁰ A relation between the intensity of the acute phase of *T. cruzi* infection and the severity of its chronic phase has been proposed. Patients with CCCD have diffuse myocarditis (rich in macrophages, CD8+ cytotoxic lymphocytes and CD4+ T lymphocytes) with fibrosis and hypertrophy. Myocarditis is due to both *T. cruzi*-specific

lymphocytes and autoimmune T lymphocytes, which produce large amounts of IFN-γ and TNF-α. In CCCD, IFN-γ plays a central pathogenic role by inducing cell damage via several mechanisms, while other inflammatory mediators also act.

Recent review on systemic and heart-specific immune alterations has shown that patients with CCCD have a characteristic inflammatory cytokine profile.¹¹⁵ Significant systemic immune effects were observed in the peripheral blood of patients with chronic CD, which are associated with the distinct clinical forms. It is important to note that qualitative differences are clearly observed in the systemic cellular responses of patients with the IFCD and cardiac clinical form. Those differences are influenced by an immune-regulated cytokine network, which orchestrates the immune response. While individuals with IFCD have a balanced immune-regulatory profile modulated by the production of interleukin (IL)-10,¹²¹ patients with CCCD have an increased frequency of CD4+ and CD4-CD8- T cells producing IFN-γ, as well as increased levels of circulating TNF-α in the peripheral blood.¹²²

In addition, the expression of IFN-γ is elevated in patients with the DCM form of CD as compared to the still nondilated form of CCCD.¹²³,¹²⁴ Also, patients with CCCD have reduced numbers of circulating Th17 T cells¹²⁵,¹²⁶ and of monocytes producing IL-10,¹²⁷ CD4+CD25+ regulatory T cells (Tregs),¹²⁸⁻¹³² as well as reduced levels of Ebi/IL-27p28¹³³ as compared to individuals with the IFCD (Figure 3.1). Such immune-regulatory alterations correlate with contractile depression, because the high frequency of cells producing IFN-γ and TNF-α is associated with low LVEF.¹³⁴,¹³⁵

On the other hand, higher numbers of cells producing IL-17 and IL-10 are associated with the preservation of LVEF within the normal range.¹³⁶⁻¹³⁸ Self-reactive B cells¹³⁹ and subpopulations of B cells associated with potentially protective or pathogenic responses were identified in patients with CD.¹⁴⁰ In addition, the production of lytic antiparasite antibodies was proposed as a mechanism to control parasites.¹⁴¹ Activation of monocytes,¹²⁷,¹⁴²,¹⁴³ CD4+ T cells with T-cell-specific receptors,¹³⁶⁻¹³⁸ CD8+ T cells¹⁴⁴⁻¹⁴⁷ and other less numerous but very active T cell populations, such as CD4-CD8- T cells, was shown in patients with CD.¹³⁵,¹⁴⁸

An exacerbated Th1 response in the peripheral blood of patients with CCCD reflects on the inflammatory infiltrate rich in Th1 secreting predominantly IFN-γ and TNF-α, with lower production of IL-4, IL-6, IL-7, IL-15, IL-18, as evidenced in immunohistochemistry and mRNA expression studies.¹²³,¹⁴⁹⁻¹⁵³ In the cardiac tissue of patients with CCCD, IFN-γ is the most upregulated cytokine. Thus, a significant expression of T-bet, Th1 transcription factor, is observed in the myocardium of patients with CCCD.¹⁵⁴

In addition, there is a positive correlation between the T-bet gene expression and dilatation of the left ventricle, corroborating the pathogenic role of T cells producing IFN-γ. However, the mRNA expression of GATA3, RORγT and FoxP3, T cell subset that defines transcription factors of Th1, Th2, Th17, and Treg populations, with their cytokines IL-4, IL-13, IL-17, IL-10, and molecular markers (FoxP3 and CTLA4), was low or undetectable.¹⁵⁴
<figure><img src="image_3.png" /><figcaption>**Figure 3.1** – Pathogenic events in the progression of chronic cardiomyopathy of Chagas disease (CCCD). (A): events in the acute phase of Chagas disease (CD); (B): primary pathogenic events in the chronic phase of CD, with the fundamental stages and clinical manifestations (see the CD natural history chapter); (C) events and pathophysiological disorders in more advanced phases of CD. miRNA: microRNA.</figcaption></figure>

The number of CCR5+ CXCR3+ Th1 T cells producing IFN-γ is higher in patients with CCCD than in those with the IFCD,¹⁵⁵ and those same cells were identified in the cardiac tissue of patients with CCCD, along with their chemokine receptors (CCL3-5, CXCL9 and CXCL10, respectively). CCL5 and CXCL9 were the most often expressed chemokines and the severity of myocardial inflammation correlated positively with the mRNA expression of CXCL9.¹⁵¹,¹⁵⁶

In animal models of CCCD, in the acute and chronic phases of *T. cruzi* infection, CCL3, CCL4 and CCL5, acting via CCR1 or CCR5, control the migration of T cells and macrophages to the cardiac tissue, leading to cardiomyocyte damage, conduction abnormalities, and ventricular dysfunction.¹⁵⁷,¹⁵⁸ This suggests that Th1 chemoattractive chemokines locally produced play a significant role in the selective accumulation of Th1 T cells in the heart in the CCCD. In addition, it indicates that there is essentially no regulation via either T cells or regulatory cytokines in the myocardium infiltrated with Th1 of patients with CCCD.

The low regulation could explain the inflammatory infiltrate destructiveness, most probably due to the excessive collateral damage caused by the T cells producing IFN-γ. The non-antagonism to IFN-γ in patients with CCCD might be related to the decreased number of the T cells producing IL10 and Ebi/IL27R and regulatory ones, all able to suppress the production of IFN-γ and/or differentiation of Th1 T cells.

### 3.3. Myocardial Mitochondrial Dysfunction and Chronic Cardiomyopathy of Chagas Disease

Wan et al. were the first to implicate myocardial mitochondrial dysfunction and oxidative stress in the pathogenesis of CCCD in murine models.¹¹⁵,¹⁵⁸ The remarkable similarity between cardiac, digestive, and autonomic disorders in the mitochondriopathies (15% develop gastrointestinal motility disorders and 40% develop cardiomyopathy and arrhythmia),¹⁵⁹,¹⁶⁰ as well as the broad clinical spectrum of symptomatic CD,¹⁶¹ suggest
mitochondrial dysfunction as a fundamental component of
the CCCD pathogenesis.

In CCCD, the myocardium shows signs of reduced
mitochondrial activity and energy production. The reduction
in mitochondrial ribosomal RNA¹⁵¹ and mitochondrial
DNA,¹⁶² in addition to other observations (not published) and
*in vivo* production of adenosine triphosphate (ATP),¹⁶³ has
been described in the myocardium of patients with CCCD.

The myocardial levels and activity of the enzymes
of the mitochondrial energy metabolism, ATP synthase
and creatine kinase, are even lower than those in other
cardiomyopathies,¹⁶⁴ which could contribute to the worse
prognosis associated with CCCD. The discovery of the
association of CCCD with rare variants of mitochondrial
genes, described in more details in this chapter, supports
the role played by mitochondrial dysfunction in the
myocardial injury of patients with CCCD and can be a
mechanism to perpetuate the inflammation and damage in
cardiomyocytes.¹¹⁵,¹⁶¹

Recent studies have shown the modulation of the
expression of some microRNAs (miRNAs), molecules that
specifically control the translation of mRNA in the cardiac
tissue of patients with CCCD¹⁶⁵,¹⁶⁶ and in the murine acute
infection by *T. cruzi*.¹⁶⁷

In addition, the discoveries in *T. cruzi*-infected mice
genetically deficient in microRNA-155 have supported the
relationship of miRNA with infection control and production
of inflammatory cytokines.¹⁶⁸

**3.4. Genetics in Chronic Cardiomyopathy of Chagas Disease**

Finding that approximately 30% of the patients with CD
develop chronic cardiomyopathy and the presence of family
cases of CCCD¹⁶⁹ have suggested the participation of genetic
factors in the different progressions of the disease. Patients
with CCCD have more intense inflammatory response than
those with the IFCD, who seem to have a better regulated
immune response.

Given the importance of the inflammatory mechanisms in
the pathogenesis of CCCD, several studies have focused the
common or frequent polymorphisms in the genes related to
inflammatory and immune responses, thus causing important
variations in the expression of inflammatory cytokines and
chemokines involved in the disease's pathogenesis. Each
common or frequent polymorphism is typically responsible
for small phenotypic effects (approximately 10% of the
population/phenotype).

A recent review of 145 association studies on candidate
polymorphisms in 76 genes has revealed 62 single nucleotide
polymorphisms (SNPs) of 44 genes to be associated with the
CCCD phenotype.¹¹⁵ Of those, SNP in 8 genes were associated
with the severity of CCCD: SNPs in genes IL17a, IL18, IL27b/
Ebi3, CCR2, CXCL9, CXCL10, and MICA were more frequent
in patients with CCCD and significant left ventricular (LV)
dysfunction (LVEF < 40%) as compared to other patients with
CCCD.

Two genome association studies were performed using the
GWAS (Genome Wide Association Study) technique, comparing

CCCD and IFCD, one in 2013,¹⁷⁰ involving 600 patients with
CD, and the other in 2021, involving 3413 individuals.¹⁷¹
Only the latter revealed a significant single variant in the entire
genome (p < 10⁻⁸) close to the SAC3D1 gene.

A recent study has assessed the role of rare gene variants
in the progression to CCCD in nuclear families with multiple
cases of CD by using whole exome sequencing.¹⁷² In the
six families studied, 22 rare high-impact non-synonymous
heterozygous pathogenic variants were found associated with
CCCD, located in 20 genes. Only seropositive individuals
with the pathogenic genetic variants developed CCCD, but
neither seropositive individuals without the genetic variants
nor seronegative siblings with the pathogenic genetic
variants did. There was a significant accumulation of specific
variants of CCCD (86%) in mitochondrial or inflammation-
related genes. In addition, all families studied showed at
least one gene variant linked to CCCD. The results of that
study indicated that the gene contribution to cause CCCD
is polygenic and mediated by several rare genetic variants
that differ in the families, being related to mitochondrial
changes and inflammation.

The results indicate that mitochondrial dysfunction and
inflammation, key-processes in the CCCD pathophysiology,
are at least partially genetically determined. This can depend
on a double-aggression mechanism. Thus, IFN-γ and
proinflammatory cytokines induced by chronic infection
would trigger mitochondrial dysfunction and clinical disease in
patients with gene variants that cause subclinical impairment
of mitochondrial function in organs of high metabolic
demand, such as heart and myenteric ganglion neuronal cells.
Mitochondrial lesion can be the mechanism that perpetuates
the tissue inflammatory changes because of the release of inner
components of damaged mitochondria by innate immune
response. Figure 3.2 shows the highlights of the inflammatory
key points associated with CCCD progression.

**3.5. Coronary Microvascular Disorder**

There is increasing evidence, both clinical and experimental,
of coronary microvascular abnormalities in the pathogenesis
of CCCD. Several studies have indicated that the myocardial
damage might result from microvascular changes mainly
associated with inflammation, which lead to myocardial
ischemia and necrosis with occasional reparative fibrosis.¹⁷³⁻¹⁷⁶

The first evidence that coronary microcirculation disorders
may play a role in the myocardial damage of CD in humans
has been obtained from postmortem studies describing
severe vascular changes, with intimal hyperproliferation, wall
thickening, and obstruction of the small intramural coronary
arterioles in hearts of patients with CCCD.¹⁷⁷,¹⁷⁸ In addition,
the myocardial fibers in the proximity of the vascular lesions
showed myocytolysis, a cellular lesion closely related to
myocardial ischemia.

In a more recent study, Higuchi et al. have described coronary
microcirculatory changes with vascular dilation and rarefaction in
hearts of patients with CCCD, which differed from those usually
observed in patients with idiopathic DCM.¹⁷⁹

Thus, observations from postmortem studies strongly
suggest the participation of microvascular ischemia in the
<figure><img src="image_4.png" /><figcaption>Figure 3.2 – Interactions between immune, microvascular, and neurogenic mechanisms in the chronic cardiomyopathy of Chagas disease.</figcaption></figure>

genesis of the inflammatory foci and myocytolysis, which lead to reparative fibrosis, the fundamental histopathological features of CCCD.

In the clinical scenario, studies using myocardial perfusion scintigraphy have shown high prevalence (30% to 50%) of perfusion defects in patients with CCCD and angiographically normal coronary arteries, strongly suggesting the presence of coronary microvascular dysfunction.¹⁸⁰⁻¹⁸³ In addition, several studies have shown that the myocardial perfusion defects were topographically related to LV wall motion impairment occurring in patients in the early phases of CCCD with no other evidence of cardiac impairment,¹⁸³ suggesting that microvascular ischemia is an early disorder in the disease progression, preceding regional ventricular dysfunction and possibly related to hibernating or stunned myocardium induction. Similar results were obtained in studies with doppler ECHO, showing reduction in the coronary vasodilation reserve, a microvascular dysfunction index, in patients with the IFCD as compared to normal controls.¹⁸⁴

A retrospective longitudinal study using myocardial perfusion scintigraphy in patients with CCCD has shown that microvascular ischemia is topographically related to areas that develop myocardial fibrosis during the disease progression. These results support the hypothesis that microvascular ischemia can be directly involved in the mechanism that leads to regional fibrosis and LV systolic dysfunction progression in CCCD.¹⁸¹

More recent studies in an experimental model of Syrian hamsters chronically infected by *T. cruzi* have shown, using high-resolution myocardial perfusion scintigraphy *in vivo*, a close topographic relation between myocardial perfusion defects at rest with histological evidence of inflammation and

regional/global LV systolic dysfunction.¹⁸⁵ In addition, another study with that experimental model has confirmed, by use of positron emission tomography computed tomography (PET/CT) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), that the regions with myocardial hypoperfusion at rest corresponded to areas with viable myocardium and inflammation.¹⁸⁶

Another recent study with the same model of hamsters chronically infected by *T. cruzi* has shown that the prolonged use of dipyridamole, a vasodilating agent of the coronary microcirculation, was associated with a significant reduction in myocardial perfusion defects at rest, indirectly supporting the presence of viable, but hypoperfused myocardium caused by coronary microcirculation dysfunction in experimental CCCD.¹⁸⁷

The mechanisms potentially involved in the genesis of coronary microvascular dysfunction in CCCD are: 1. Functional changes in the coronary tree, with increased vasoreactivity and spasm of small intramural arterial branches;¹⁸⁸,¹⁸⁹ 2. Endothelial lesions caused directly by parasitic aggression;¹⁹⁰ 3. Functional and structural changes induced by substances secreted by the inflammatory infiltrate in the myocardial tissue close to the coronary microvessels, mainly endothelin and cytokines. This late mechanism is supported by studies evidencing that myocardial inflammation changes are associated with the occurrence of platelet plugs, obstructive proliferation of the vascular intimal layer, and microarteriolar spasm.¹⁹¹

### 3.6. Cardiac Denervation

Autonomic cardiac denervation is an important characteristic of CCCD and was first described in human postmortem studies showing intense intramural neuronal depopulation, greater than that observed in any other cardiovascular disease.¹⁹²,¹⁹³ This discovery has been confirmed in studies
with experimentally *T. cruzi*-infected animals, showing cardiac neuronal parasitism associated with periganglionitis and degenerative abnormalities in Schwann cells and nervous fibers.¹⁹⁴,¹⁹⁵ It is worth noting that the neural depopulation also affects the intramural ganglia of several digestive system organs, mainly the esophagus and colon, which is clearly implicated in the pathophysiology of megaesophagus and megacolon of CD.

Neuronal depopulation in CCCD has been postulated to occur during the acute phase of the infection, secondary to the direct parasitism of neurons, the degeneration caused by periganglionic inflammation, and the antineuronal autoimmune reaction.¹⁹⁶,¹⁹⁷ There is evidence that the damage can continue in the chronic phase because of the localized inflammation.

Several functional abnormalities of the autonomic reflex control of heart rate (HR) in patients with CCCD have been described as a consequence of the anatomically detected autonomic cardiac denervation.¹⁹⁸⁻²⁰¹ Patients with CCCD have deprivation of the tonic inhibitory action of the parasympathetic system in the sinus node and also lack of the vagal-mediated mechanism to respond with rapid bradycardia or tachycardia to transient blood pressure or venous return changes.²⁰² Dysautonomia in patients with CCCD can be detected before the development of ventricular dysfunction, as well as in the early stage of the chronic phase and even in the indeterminate and digestive forms of CD.²⁰³,²⁰⁴

More recently, ¹²³I-MIBG myocardial scintigraphy has been used in patients with CD to provide accurate information on the integrity of the sympathetic nervous fibers within the LV myocardium.¹⁸³ In that study, 37 patients were investigated by use of ¹²³I-MIBG imaging and the results were correlated with myocardial perfusion and regional LV wall motion impairment. Defects in ¹²³I-MIBG uptake were observed in most patients: 33% of those with a normal ECG and normal ECHO and 77% of those with regional LV wall motion impairment. In addition, patients with more severe ventricular dysfunction had a higher prevalence of defects in the ¹²³I-MIBG uptake (92%). There was a clear topographic correlation of the myocardial sympathetic denervated areas, perfusion myocardial defects, and regional LV wall motion abnormalities.

Another study using ¹²³I-MIBG scintigraphy has shown strong topographic concordance between myocardial sympathetic denervated areas and myocardial hypoperfusion areas during stress.²⁰⁵ Those results indicated that sympathetic denervation is an early disorder in the CCCD pathophysiology, preceding the development of LV regional contractile abnormalities or global contractile dysfunction. This hypothesis has been corroborated by the results of an independent study evidencing abnormal ¹²³I-MIBG absorption in most patients with CD without any sign of cardiac involvement.²⁰⁶

In addition, clinical studies have reported a quantitative relation between the extension of myocardial denervation, using ¹²³I-MIBG imaging, and the risk for malignant ventricular arrhythmias. This is a clinically relevant aspect because it associates the presence and extension of sympathetic denervation with severe arrhythmia in patients with CCCD and it is potentially implicated as the mechanism of sudden death.²⁰⁷,²⁰⁸

Despite the extensive documentation of conspicuous autonomic denervation in the early stages of CD and the recent demonstration of its potential participation in the mechanism that triggers severe ventricular arrhythmias, the “neurogenic theory” still lacks demonstration of the pathophysiological links between those phenomena and the essential myocardial lesions in CCCD.

Autonomic denervation has also been proposed to be associated with coronary microvascular spasm and trigger myocardial ischemia, leading to myocardial necrosis. However, that mechanism still awaits more clear evidence. Figure 3.2 shows the interaction of inflammation with microvascular and neurogenic mechanisms.

### 3.7. Final Considerations

The pathogenesis of CCCD is still an enigma consisting of multiple complex aspects related to the variety of pathogens, as well as to the host's genetics and immune system, as shown in Figures 3.1 and 3.2. In addition, there is recent evidence that the several gaps in the knowledge about the parasite's life cycle in the human host and vector should be revisited and clarified, enabling the identification of more appropriate targets for more effective therapies, as well as their use in guided research.²⁰⁹

## 4. Cardiomyopathy Pathophysiology - Acute and Chronic Phases

### 4.1. Introduction

The pathophysiology of CCD can be briefly described as follows. In the acute phase, most *T. cruzi*-infected individuals can progress with diffuse myocarditis of low intensity, which does not associate with severe cardiovascular disorders, being not even diagnosed. In rare patients, acute inflammation can lead to a significant loss of myocardial contractility, with chamber dilatation and HF with biventricular ejection fraction reduction, sometimes with concomitant electrical disorders (conduction blocks, extrasystoles) and pericardial effusion. Such changes are usually self-limited to a few weeks, not causing clinically manifest sequelae.

Cardiac damage in the chronic phase, however, results from fundamental changes (inflammation, necrosis, and fibrosis) caused directly or indirectly by *T. cruzi* in the specialized conduction tissue, in the contractile myocardium, and in the intramural autonomic system.

The frequent impairment of sinus and atrioventricular nodes, as well as of the His bundle, due to inflammatory, degenerative, and fibrotic changes leads to sinus dysfunction and varied atrioventricular and intraventricular blocks. By being more individualized structures, the right branch and the left anterosuperior fascicle are more vulnerable and more frequently damaged. Inflammatory foci and fibrotic areas in the ventricular myocardium, especially in apical, posterolateral and inferobasal regions, can produce electrophysiological changes and favor the appearance of reentry, the major electrophysiological mechanism of malignant ventricular tachyarrhythmias, which cause sudden death even in patients without previous HF and without severe LV systolic dysfunction.
Another very common consequence of myocardial lesions is biventricular dysfunction, characteristic of CCCD. Initially, there is regional impairment, similar to that occurring in the cardiopathy due to coronary obstruction, but dilation and generalized hypokinesia, usually of both ventricles, gradually occur, conferring the hemodynamic pattern of DCM to CCCD. In more advanced phases of the natural history, there are global cardiac dilation and marked cardiac mass increase, due to the combination of myocardial hypertrophy and fibrosis at degrees varying from patient to patient.

From the earliest phases, dyssynergies or ventricular aneurysms predispose to thromboembolic complications. In advanced stages, global dilation, venous stasis, and AF are additional factors that propitiate thrombus formation and consequent pulmonary and systemic embolism, such as in the central nervous system, where they cause stroke. In addition to malignant arrhythmias and refractory HF, CCCD can cause embolism to the pulmonary circuit and several systemic organs, resulting in renal, splenic, and mesenteric infarctions, or embolism to the arteries of the limbs.

Such characteristics of the CCCD pathophysiology can be understood as resulting from important pathogenic mechanisms, such as those approached in the chapter of pathogenesis, with the additional emphasis on aspects described in the next section.

## 4.2. Myocardial Parasitism and Immune Response

The infectious-parasitic disease caused by *T. cruzi*, CD, has its natural history divided into acute and chronic phases.³⁷,⁴⁶ The acute phase is usually oligosymptomatic with unspecific symptoms, but 5-10% of the cases can have more expressive symptoms in the presence of intense parasitemia,²¹⁰ with fever and lesion in the pathogen inoculation site. It can complicate with meningoencephalitis, myocarditis, and other manifestations.

Four to eight weeks after the infection, when the parasitemia drops to undetectable levels and the acute phase symptoms disappear, begins the chronic phase, which usually lasts for several decades. In the chronic phase, 60-70% of the individuals have no symptom, and the routine additional tests related to the heart and digestive system show no abnormality. That is the IFCD.²¹¹ The other chronically infected patients develop the determined forms, with cardiac and/or digestive impairment.⁴⁶,²¹²

### 4.2.1. Immune Response in the Acute Phase

Since the acute phase, CD has a multifactorial pathophysiology, in which the immune and primary inflammatory (triggered by *T. cruzi* itself) mechanisms play a fundamental role.²¹³,²¹⁴

In the acute phase, there is exposure of the *T. cruzi* surface molecules to the receptors of macrophages and dendritic cells, causing the activation of innate immunity cells, such as neutrophils and NK lymphocytes (natural killers), which will trigger intense inflammatory response aimed at controlling parasitemia. Innate immunity activation generates intense secretion of pro-inflammatory cytokines, such as TNF-α, IFN-γ, and several interleukins, especially IL-10.¹¹⁹,²¹⁵ That intense inflammatory response resulting from the activation of innate

immunity cells and production of pro-inflammatory mediators, although crucial to control the infection, contributes to cause direct lesion to the cardiomyocytes – also attacked by the usually conspicuous tissue parasitism. This pathophysiologic set represents the typical diffuse myocarditis of the acute phase of CD, which, in most cases, has a benign and self-limited course.

After the intense inflammatory phase, causing a reduction in parasitemia and tissue parasitism, the macrophages and dendritic cells that phagocyted *T. cruzi* trigger the humoral and cellular immune responses, with activation of B and T lymphocytes. The chronic phase, thus, begins in most patients who did not eliminate the parasite in the acute phase window of opportunity.²¹⁶

### 4.2.2. Immune Response in the Chronic Phase

The presence of the parasite's DNA in the myocardium,¹⁴⁹,²¹⁷ as well as the cross-recognition by CD4+ T cells of *T. cruzi* antigens and amino acid sequences of cardiac myosin are important aspects of the pathophysiology of myocardial dysfunction during the chronic phase.²¹⁸

Regarding the cellular immune response, infected macrophages present *T.cruzi* antigens from cross-reaction with the heart to CD4+ T lymphocytes, which migrate to the heart, producing inflammatory cytokines that increase the recruiting and activation of immune system cells, triggering late hypersensitivity reaction. Of the inflammatory cytokines, TNF-α and IFN-γ are significantly increased in patients with CCCD.¹¹⁹,¹²⁴

A recent study has directly compared the T lymphocytic subpopulation in individuals with CCCD and idiopathic DCM, evidencing a clear difference in the immunoregulatory profile and higher immune activation in CCCD, although those two conditions have similar hemodynamic characteristics.²¹⁹

Several factors are implicated in the etiopathogenesis of CD in the heart, but, regardless of the major mechanisms of tissue damage, the common final pathway is intense inflammatory infiltrate and reactive and reparative myocardial fibrosis. The structural, geometrical, and functional cardiac disorganization essentially results from myocardial necrosis and consequent replacement by fibrous tissue, damaging the perivascular and interstitial content, important histopathological markers of CD.

Such alterations are sufficient to cause dilation and consequent biventricular contractile dysfunction, and the myocardial fibrosis is far more intense as compared to that of other cardiomyopathies. Complex mechanisms activate the cascade of cellular and molecular response, intensifying the inflammatory response, oxidative stress, and progressive loss of cardiomyocytes through necrosis and/or apoptosis, in addition to promoting overload and further dysfunction of the residual myocardium.²⁰⁰,²²⁰

## 4.3. Autonomic Nervous System Alterations in Chagas Disease: Evidence from Histopathological Studies

Anatomical pathological and functional changes of the autonomic nervous system, at various severity levels, have been described in humans and experimental animals since the initial studies by Carlos Chagas and collaborators.¹⁷⁶,²⁰⁰,²²¹⁻²²⁹
Such changes have been reported to be more conspicuous in patients with CD as compared to that occurring, at a lower level, in other cardiomyopathies.²³⁰,²³¹ However, despite being one of the most remarkable aspects in the CD pathophysiology, the actual etiopathogenetic role of those changes, including those described in the inter-trunk cardiac plexus, remains uncertain.

Directly dependent on the *T. cruzi* infection, those changes, such as ganglionitis, periganglionitis, neuritis, and perineuritis, cause a significant ganglionic density reduction and neural depopulation in experimental animal models²²³ and patients with CD.²²⁴ Based on studies with experimental models, those anatomical pathological changes in the inter-trunk cardiac plexus have been postulated to occur predominantly during the acute phase of the infection²²⁵,²²⁶ and to continue in the chronic phase at lower intensity.²²⁷,²²⁸ Such changes result from four factors acting in isolation or combination: direct parasitism of neurons,²²⁹ intense periganglionic inflammatory process,²²¹ autoimmune antineural reaction,²³² and periganglionic microvascular dysfunction.²³³

Damage to the autonomic structures can be partially compensated, because the autonomic neurons, within limits, maintain a certain ability to functionally recover.²²⁷ In addition, sympathetic reinnervation has been reported in humans during the chronic phase of CD after procedures, such as cardiac transplantation (CTX)²³⁴ and stem-cell therapy.²³⁵

However, restoration of the functional neuroeffector junctions, due to axonal regeneration during the chronic phase, is disorganized, random, and incomplete. The parasympathetic innervation has a similar behavior: there is marked destruction of nervous fibers, with a reduction in the cardiac acetylcholine levels during the acute phase, followed by disorganized, random, and incomplete functional restoration during the chronic phase.²²⁷ Several physiological and pharmacological tests have evidenced abnormal functional responses, supporting that pathophysiological hypothesis.¹⁶¹

Neuronal depopulation occurs predominantly in the parasympathetic intramural ganglia of the heart and myenteric plexuses.²²¹⁻²²⁸ Thus, a theory was initially formulated that a 'parasympathetic-deprived' cardiopathy would install in the heart, in other words, there would be an actual "cardioneuropathy induced by a relative non-antagonized excess of catecholamines".²²¹,²²³ According to that pathophysiological theory, the heart, unprotected due to the absence of the moderator parasympathetic effect, would be subjected to the stress of the intense toxic stimulation of the adrenergic system.

However, several pieces of evidence hinder the confirmation that a "catecholamine-induced cardioneuropathy" decisively contributes to the pathogenesis of the cardiac form of CD. In contrast, it is virtually impossible to eliminate the possibility of the involvement of that mechanism in the process. Even more important, there would be signs that the vagal-cholinergic pathway plays a fundamental direct role in preventing the cardiac impairment that occurs in CD.²²⁹

Among the obstacles to the 'parasympathetic-deprived' theory and despite the predominant vagal dysfunction, there is the finding of the concomitant attenuation of the adrenergic regulation of the sinus node-mediated cardiac

chronotropism.¹⁷⁶,²³⁶ Furthermore, at the myocardial level, sympathetic denervation is described in I-MIBG scintigraphy of the heart.¹²³ Disorders in that radiotracer uptake, which reflects the adrenergic integrity at ventricular level, tend to intensify as the disease progresses.²⁰⁵ Those studies evidence strong association between the sympathetic denervation areas, wall motion abnormalities, and myocardial hypoperfusion in many patients, contributing to the installation of potentially fatal arrhythmias. Studies on *T. cruzi* infection in humans and experimental models with Syrian hamsters have suggested that the sympathetic autonomic denervation and microvascular dysfunction are closely related and active in the initial stages of CCCD.¹⁸³,²⁰⁵

Additional aspects related to the complex dysautonomic pathophysiology observed in CD involve the so-called anti-inflammatory cholinergic pathway. The conceptual base resides in the evidence that the inflammatory process in CD influences and is influenced by the immune-mediated autonomic balance.²³⁷⁻²³⁹ Thus, attenuation of the cytotoxicity of T lymphocytes by cholinergic-muscarinic stimulation was observed, and afferent and efferent signs that would compose an arch, the "neuroimune" or "inflammatory" reflex, were postulated.

According to that concept, the nervous and immune systems communicate in a two-way manner and use that interaction to mediate the cytokines and neurotransmitters they have in common. The efferent pathway of the central nervous system would act on the immune system through its parasympathetic component, making the anti-inflammatory cholinergic pathway. The parasympathetic system innervates the organs of the immune system and its mediator, acetylcholine, acts on that system cells, especially macrophages, by activating the acetylcholine receptor.²⁴⁰ In the CD context, it was hypothesized that the cardiac parasympathetic tonus depression could contribute to exacerbate inflammation during the chronic phase, a pathophysiological conception that goes back to the beginning of the investigations about CD.²²⁹

The mechanisms that induce autonomic dysfunction in CD include the production of circulating autoantibodies, particularly against cholinergic receptors (Ac-M), as well as against adrenergic receptors (Ac-β).²⁴⁰ Such antibodies are postulated to result from antigenic mimicry (cross-reaction between the P ribosomal protein of *T. cruzi* and the human ribosomal protein),²⁴¹⁻²⁴³ and the disorders mediated by circulating autoantibodies can confer particular characteristics to the CD dysautonomia as compared to other neuronal affections.²³³,²⁴⁴⁻²⁴⁶

### 4.4. Chagas Disease Pathophysiology Dependent on the Parasite and Human Host Genetic Characteristics

The development of an infectious disease is usually a complex phenomenon related to several factors of the environment, the infectant pathogen, and the host. Thus, the assessment of the genetic characteristics of the host and pathogen can contribute to solve the enigma: why approximately 30% of the infected individuals develop CCCD, while the rest remains asymptomatic and without clinical manifestations for the entire life.
# Guidelines

The genetic diversity of *T. cruzi* recognizes seven discrete typing units (DTU), TcI-TcVI and Tcbat.²⁴⁷ This genetic diversity is a potential target for innovation in new trypanocidal drugs.²⁴⁸

Recent research has indicated that the parasite strains detected in patients, regardless of their clinical presentation, reflect the major circulating DTU in the domestic transmission cycles of a certain region. Recent systematic review and meta-analysis of *in vitro* studies has evidenced that, despite the preliminary signs of relevant differences in the parasite's sensitivity to the etiological treatment, there is significant heterogeneity in the results, even considering only studies on the sensitivity of several *T. cruzi* DTU to a single trypanocidal drug, benznidazole, which hinders the accurate identification of more and less sensitive parasite's strains to treatment.²⁴⁹

In several studies of micro-outbreaks of orally transmitted parasites, wild strains are implicated. Because of the genotypic and phenotypic differences of *T. cruzi* strains and the different geographical distribution of DTU in humans, there are regional variations in the sensitivity of the serological tests, causing potential implications in the response to parasiticide treatment options.²⁵⁰

Such genotypic characteristics have been recently summarized to clarify their potential associations with clinical manifestations of CD, emphasizing the persistence of significant uncertainties regarding knowledge as well as of relevant challenges in those research lines.²⁵¹

Similarly, studies of genetic polymorphism have focused the host's characteristics that influence the development and severity of the clinical presentations. In that context, the SNPs are defined when at least two alternative nucleotides occur in the genome at significant frequency (usually > 1%). The SNPs show Mendelian inheritance and are used as genetic markers.²⁵²

Several studies have assessed the human genetic polymorphism and included correlations with elements of the immune response, adaptive and regulatory, during *T. cruzi* infection.²⁵³ The TNF polymorphism is one of the most studied in CD. In Brazil, a reduction in the survival of patients with the TNF-308A allele or TNFa2 microsatellite allele has been reported,²⁵⁴ but no association was found between the TNF-308 polymorphism and the CD clinical presentations.²⁵⁵ Similarly, another study in Peruvian patients, comparing those with CD versus control individuals without *T. cruzi* infection, has shown no major association of the TNF-308, -244, and -238 polymorphisms with CD.²⁵⁶

In contrast to that described for mediators related to the immune profile, the genetic assessment related to the angiotensin-converting-enzyme system evidenced some disagreement, but the DD genotype has been associated with a higher risk for HF and mortality in the myocardial disease of ischemic etiology.²⁵⁷

In another cohort study, in HF due to idiopathic cardiomyopathy, the DD genotype has been shown to remain a predictor of mortality.²⁵⁸ In two different populations with CD, including a Brazilian one, no valid association regarding those polymorphisms has been observed.²⁵⁹,²⁶⁰ However, in another population from the Brazilian northeastern region, a higher prevalence of the I/D polymorphism has been reported

in patients with HF as compared to asymptomatic patients with CD.²⁶¹ Such discrepancies can be due to the fact that final phenotypes are considered dependent on environmental factors,²⁶² requiring large samples to demonstrate effects of the genes involved in complex traces, such as those in the complicated clinical syndromes, such as HF of CD etiology.

More recent studies on genetic aspects and using GWAS technology have involved bigger samples and generated more consistent and relevant information. For example, previously the SNPs have not been strongly associated with CCCD.¹⁷⁰ But a recent meta-analysis has revealed the association with CCCD development in rs2458298, nearby the SAC3D1 gene, indicating the host's genetic variability as a susceptibility factor to CCCD development after *T. cruzi* infection.¹⁷¹

## 4.5. Peculiar Histopathology of Chagas Disease

In the acute phase of the infection, the parasite's adhesion to and penetration into the host's cells occur via lecithins that bind to carbohydrate residues attached to the host cell membrane, mainly the sialic acid. Recent review about the family of human galactoside-binding proteins, called galectins, has reported on their significant participation in the innate and adaptive immunomodulation to *T. cruzi* infection, with potential pathophysiological and therapeutical implications.²⁶³

Inside the host's cells, trypomastigote forms transform into amastigote forms, but, for as long as the parasitized cells remain intact, no local inflammatory reaction is observed. When the parasitized cell ruptures, epi-, trypo-, and amastigote forms of the parasite, intact or degenerated, are released, along with cell components that act as immunogens (mitochondria, myofibril remnants), to the extracellular medium, stimulating the presence of inflammatory mediators, which cause vasodilation and increase vascular permeability, factors typically implicated in the inflammatory process exacerbation.

In the early acute phase, the inflammation is focal, topographically associated with intense parasitism, and can coalesce and become diffuse. In contrast, the chronic phase is more obscure and complex, because, although there is active inflammatory reaction, the parasitism is scarce and cannot completely explain the inflammatory foci. Thus, the hypothesis of late hypersensitivity and autoimmunity has been raised to explain the maintenance of inflammation and lesions in the chronic phase of the disease by: (1) molecules of the parasite and of the cardiomyocytes are structurally similar, which could explain common antigenic properties and immune cross-reaction: *in vitro*, *T. cruzi*-sensitized lymphocytes have a cytotoxic action against cardiomyocytes; (2) the mononuclear inflammatory infiltrate and occasional formation of granulomas suggest the possibility of late hypersensitivity reaction.

These more controversial pathophysiological aspects of the inflammatory lesions of the CCCD have been partially clarified in recent studies using more sensitive tests to detect the parasite. Such tests suggest that, even scarce, the parasite persistence in the tissues is a continuous source of antigens, which can mediate the low-grade, but incessant, inflammatory response.

Techniques of molecular biology, such as polymerase chain reaction (PCR), applied to myocardial fragments of patients
with CCCD have shown *T. cruzi* DNA in inflammatory foci in almost all cases studied. In addition, the accumulation of CD8+ T lymphocytes, which predominate in chronic myocarditis, correlates with the focal presence of parasite antigens. In addition to the degenerated trypanosomes, the cell rupture can cause the release of microorganisms that were in the *T. cruzi* cytoplasm. This hypothesis is based on the observation of endomyocardial biopsies of patients with CCCD showing electron-lucent microparticles and nanovesicles containing DNA from archaea – the oldest microorganisms in nature that can parasitize trypanosomes – in the region of inflammatory foci.²⁶⁴

Archaea, numerous in the serum of patients with HF due to CD, are associated with inflammation, because they uptake interstitial proteins and generate immune response with CD8+ T lymphocytes, with no response of CD4+ T cells. Lipidic archaea are increased in the IFCD, as well as protecting exosomes that capture AMZ1 (archaea-specific metalloprotease) from the external medium, preventing the activation of enzymes and protecting against collagen degradation and inflammation. Thus, according to that hypothesis, archaea could play a fundamental role in the myocardial inflammation and microcirculation dilation.²⁶⁵

Still, from the histopathological viewpoint, former studies have evidenced that *T. cruzi* has tropism for the adipose tissue, which can be another pathophysiological link of the extensive inflammatory changes present in the chronic phase and explored as a therapeutic target.²⁶⁶⁻²⁶⁸

## 4.6. Coronary Microcirculation Injury

Several clinical manifestations in patients with CCCD mimic those of coronary obstructive disease: 30-40% of those patients have chest pain, which is usually atypical with no clear relation to physical exertion and variable duration, for long symptomatic periods. Those patients' ECG usually show ST-T alterations and areas of electrical inactivity, simulating changes due to ischemia and/or myocardial infarction. More characteristically, patients with CCCD usually show ventricular wall motion abnormalities similar to those due to necrosis and infarction associated with coronary obstructions. Finally, several myocardial perfusion disorders have been described in the different phases of the CCCD.

Of note, all those structural and functional changes are found in the presence of angiographically normal subepicardial coronary arteries with no early detectable atherosclerosis on computed tomography angiography.²⁶⁹ These pathophysiological changes are attributed to coronary structural and regulatory abnormalities at microvascular level. Histologically, extreme vasodilation, not seen in other DCMs, has been described, with a reduction in distal perfusion pressure, myocytolysis, and ischemia in borderline regions of double coronary irrigation (vascular watershed zones, such as the *crux cordis* region, in which the septal artery, a branch of the anterior descending artery, competes with a branch originating from the right coronary artery), postulated as more susceptible to ischemia.²⁷⁰ Such ischemic lesions are believed to contribute to the installation of akinetic areas and ventricular aneurysms, such as apex thinning and typical

inferolateral fibrosis frequently detected as the origin of sustained ventricular tachycardia (SVT).

A common consequence of those microcirculatory disorders is fibrosis, which develops slowly and progressively, with interstitial deposition of fibronectin, laminin, and collagen, leading to expansion and distension of the extracellular matrix, contributing to the progressive loss of myocardial contractile activity and appearance of cardiac arrhythmias. There is no other human myocarditis in which fibrosis develops so intensely and with so peculiar characteristics as that of the CCCD.²⁷¹

## 4.7. Potential Therapeutic Applications of Pathophysiological Targets in Chronic Cardiomyopathy of Chagas Disease

Several recent investigations have focused on some pathophysiological changes that can be therapeutic targets to favorably influence the *T. cruzi*-infection natural history or even CCCD. The parasite life cycle itself, through new knowledge of its interaction with the human host, and the vector as an intermediate host, with the better understanding of its genetic characteristics, can be revisited to assess the therapeutic possibilities of the trypanocidal effect.²⁰⁹

However, the most recently identified perspectives reside in the possibility of inflammatory response modulation. In the IFCD and CCCD, several mechanisms of inflammatory activation of IL-1Beta have been shown.¹⁴³ Thus, after a preclinical study evidencing a reduction in fibrosis with the transforming growth factor-beta inhibitor,¹⁵⁷ that cytokine antagonism has become an important therapeutic target in the context.²⁷²

In addition, there is evidence that the clinical forms of CD (IFCD and CCCD) involve different subpopulations of CD4- and CD8- immune memory cells, raising the possibility of a new anti-inflammatory strategy to control CD in the heart.²⁷³ An extensive analysis of several aspects hypothetically related to multiple strategies to control the parasite and its inflammatory consequences has been recently reported to improve the prognosis of infected individuals.²⁷⁴

In another line of research about natural drugs with strong anti-inflammatory and antioxidant activity, such as curcumin and resveratrol, the results with experimental animals have been reviewed, encouraging future initiatives in humans.²⁷⁵ A pioneer randomized study with a small sample of 37 patients with CCCD has assessed the therapy with granulocyte-colony stimulating factor (G-CSF), which is clinically used to support chemotherapy and bone marrow transplantation and has shown promising results in *T. cruzi*-infected mice. That study has reported good tolerability to treatment for 1 year, suggesting that further studies with G-CSF should be conducted in humans with CCCD.²⁷⁶

Finally, the genetic polymorphism, which pathophysiologically regulates the levels of pro- and anti-inflammatory factors (as exemplified by IL-10), has been recently revisited in a meta-analysis of several studies with some subpopulations of *T. cruzi*-infected individuals. The aim was to identify biomarkers to predict the risk of developing CCCD and to monitor the evolution and therapeutic interventions in that context.²⁷⁷
## 5. Natural History

### 5.1. Acute Myocarditis of Chagas Disease

The incidence of the acute myocarditis of CD depends on the parasite load and strain, host, and infection transmission mode (oral or classic vectorial mainly). Depending on the diagnostic tool, the detection of myocarditis can vary from 40% to 100% in the acute phase of *T. cruzi* infection.²⁷⁸⁻²⁸¹

As already discussed in the chapter on the pathogenesis of CD, the anatomical pathology of the acute phase is directly related to the parasitism of the cardiac cells, the inflammatory reaction immediately evoked by the infectious process, and the consequent microcirculatory impairment.²⁸² There are inflammatory lesions in the myocardium, endocardium, pericardium, and intramural autonomic nervous system of the heart and several other organs, similarly to those observed in viral myocarditis. The hematoxylin-eosin and Giemsa stains can easily evidence amastigote forms of the parasite.²⁸³,²⁸⁴

A characteristic finding is the presence of small nodules lined up as beads in a rosary, which is called moniliform epicarditis. Despite the true pancarditis, the cardiac valves, typically avascular structures, are often spared. The severity of the cardiac lesions is influenced by the infection transmission mode (oral or classic vectorial). In most cases, the infection has a benign course, being virtually oligosymptomatic, or, less often, very severe, leading to death.²⁸³⁻²⁸⁵

Recently, the most studied clinical aspects have been those related to the myocarditis caused by oral *T. cruzi* transmission (ingestion of foods not sanitarily prepared and contaminated by macerated triatomine bugs or by their excrementa). Subclinical aspects have been frequent. Acute inflammation can begin right before the fever subsides, which usually occurs within 15 to 20 days from the disease beginning.²

Some patients, similarly to that occurring in viral myocarditis, can manifest chest pain, dyspnea, and palpitations, sometimes imitating coronary artery disease symptoms.²⁸⁶ Tachycardia is usually present, and, in most severe cases, symptoms and signs of acute HF can be observed, particularly the C hemodynamic profile (poor tissue perfusion and pulmonary and/or systemic congestion).²⁸⁷ The ECG shows unspecific ventricular repolarization changes, low-voltage QRS complexes, supra- or ventricular extrasystoles, and even sustained ST-segment elevation. Atrioventricular or even intraventricular conduction disorders, common in the chronic phase, are less frequent in the acute myocarditis.²⁷⁹,²⁸⁸

The ECHO frequently detects pericardial effusion of variable proportions, with diffuse hypocontractility of both ventricles, which is an attribute of the most severe cases of myocarditis.²⁸⁹

The most accepted hypothesis for the fatal outcome of a significant number of orally infected patients is due to large inoculation, with ingestion of a high parasite load, in addition to the easy intense penetration of parasites

through the gastrointestinal mucosa, very permeable to *T. cruzi*.⁴⁸,²⁹⁰ In a study involving 126 individuals aged < 18 years, most of whom (68.3%) diagnosed with the acute form after oral transmission and followed up for 10.9 years, the evolution was considered benign, although 2.4% persisted with cardiac changes.²⁹¹

The natural history of the acute phase of CD caused by the classic vector transmission (excrementa of the hematophagous bug) includes a high number of individuals whose infection is not even diagnosed because they are asymptomatic or oligosymptomatic and progress to practically spontaneous remission. In a reduced number of cases, the acute *T. cruzi* infection can be fatal (estimated as 3-5% of the symptomatic cases, due to myocarditis and/or fulminant meningoencephalitis).

The natural history of the acute phase myocarditis caused by classic vectorial transmission²⁹²,²⁹³ is less clear than that registered for the micro outbreaks recently observed after oral transmission. However, it is evident that more symptomatic cases have unfavorable outcomes because of their association with a more intense acute myocarditis.²⁹⁴ But, most importantly, the large majority of individuals acutely infected by *T. cruzi* usually progress to the chronic phase, being characterized as having the IFCD.

The natural history of the acute myocarditis of CD and IFCD is yet to be clarified. Some studies have properly assessed that evolution. However, several influences can bias the results, such as the affected population's age range, transmission mode, parasite load and strain, follow-up duration, and previous etiological treatment, which can completely and favorably change the natural history.

A cross-sectional study conducted in the municipality of Bambuí, Minas Gerais state, in the 1940-1950 decades, on the acute phase of CD diagnosed after classic vectorial transmission, has reported 8.3% of case-fatality in the acute phase of children < 10 years of age. Of 130 individuals followed up from 1 to 3 years after the acute phase, 71.5% showed no ECG changes and 30% had normal cardiac dimensions. After 3 to 5 years, those numbers were 65.7% and 87.5%, respectively. It is worth noting that the population sample was basically formed by children in the post-world war-II period, who received no etiological treatment.²⁹³,²⁹⁵,²⁹⁶

A more recent study on the natural history of CD has assessed two groups of patients: one followed up since the diagnosis in the acute phase and the other followed up from the IFCD onward. The study has assessed the risk of developing CCCD by use of systematic review and meta-analysis of 32 studies. The following were considered for the diagnosis of CCCD: appearance of arrhythmias or ECG changes; evidence of ventricular contractile abnormalities on ECHO; and death associated with CD. After the acute phase, the estimated annual risk of progression to chronic cardiopathy was elevated, 4.6% (95% CI, 2.7%-7.9%; I² = 86.6%; τ² [*In scale*] = 0.4946). For the individuals followed up from the IFCD on, that risk was 1.9% (95% CI, 1.3%-3.0%; I² = 98.0%; τ² [*In scale*] = 0.9992).²⁹⁷

Observational studies characterize myocarditis either as a potential underdiagnosed cause of acute HF that could
progress to sudden death or, more commonly, as DCM. The prognosis is considered good in the short term for the group of individuals with no clinical manifestation of cardiac impairment, or when there is complete remission of the biventricular myocardial depression. There is no evidence of how many patients with clinically detected myocarditis in the acute phase recover ventricular function, but develop DCM in the long term. However, much older studies have reported a considerably poorer prognosis of patients whose acute phase was manifested and disease diagnosed than that of patients whose acute myocarditis passed unnoticed.²⁹³,²⁹⁵,²⁹⁶

There is evidence through anecdotal cases and WHO records that some individuals with acute myocarditis progress directly to the chronic phase with severe clinical manifestations, without the characteristically long period of IFCD.³⁸ Finally, similarly to myocarditis of other etiologies, access to low-cost diagnostic tools is currently being assessed to predict the risk of cardiovascular events and guide therapy. In addition to the limited access, the actual role of myocardial biopsy and CMRI to approach patients with suspicion of acute myocarditis of CD remains to be determined.²⁹⁸

## 5.2. The Indeterminate Form and Clinical Syndromes of Chronic Cardiomyopathy of Chagas Disease

### 5.2.1 Natural History of the Chronic Phase of Chagas Disease

After the acute phase, untreated *T. cruzi*-infected individuals progress to the indeterminate form of the chronic phase, also called IFCD.²⁹⁹,³⁰⁰ This form is classically defined by evident *T. cruzi* infection, confirmed by serology or parasitology test, in the absence of the disease's symptoms and physical signs, in addition to lack of abnormalities on ECG at rest and on chest, esophagus, and colon radiologic study.³⁰¹ Patients with the IFCD have an excellent medium-term prognosis (5 to 10 years of follow-up), and deaths among them are very rare and probably not more frequent than those occurring in sex- and age-matched individuals not infected by *T. cruzi*.²⁹⁹,³⁰⁰

Although several individuals can remain indefinitely in the IFCD, in others, some decades after the acute infection, CD becomes clinically evident with disorders in specific organs, mainly heart, esophagus, and colon, characterizing the determined chronic clinical forms: cardiac, digestive, or mixed (cardiodigestive).

Epidemiological studies in endemic areas, observation in blood donors, and meta-analysis results, after systematic review, have shown that approximately 2% of the patients progress annually from IFCD to a clinical form of CD.²⁹⁷,³⁰² In Brazil, 20% to 30% of the patients are estimated to develop the cardiac form, 5% to 8%, esophageal disorders, and 4% to 6%, colonic disorders. With population aging, a greater part of infected individuals tends to develop the cardiac form, although recognition of the real prevalence is hindered by the coexistence of other cardiovascular diseases associated with aging.³⁰³ The clinical manifestations of CD differ significantly in different Latin-American regions,

and digestive syndromes are less often reported outside Brazil. From the epidemiological and clinical viewpoints, chronic cardiomyopathy is the most important form of CD because of its high morbidity and mortality and consequent medical and social impacts.

### 5.2.2. Indeterminate Form of Chagas Disease: Importance of the Concept and Abnormalities on More Sophisticated Additional Tests

The term “indeterminate form” was used, for the first time, by Carlos Chagas in 1916 to designate *T. cruzi* infection in the “absence of any clinical syndrome” of CD.²²⁹ Its possibility for progression to cardiac and/or digestive disease was originally described by Eurico Villela and Carlos Chagas in 1923³⁰⁴ and highlighted in the 1950 decade by Laranja et al.³⁰⁵ Those authors defined IFCD as the 10-to-30-year asymptomatic period extending from the end of the acute phase to the late initiation of cardiopathy from chronic infection.

Since then, several authors have used different terms to refer to that stage of CD, such as latent, asymptomatic, subclinical, laboratory, or “potentially cardiac” form, with no strict standardization of the diagnostic criteria, leading to different and even conflicting interpretations of the real meaning of the IFCD.

In 1984, a group of experts met in the city of Araxá, Minas Gerais state, to elaborate a consensus document reassuring the IFCD concept validity, as well as defining the objective diagnostic criteria previously cited.³⁰¹ The consensus emphasized that the presence of alterations identified on the most sophisticated investigative tests does not invalidate the previously presented concept, reinforcing the good medium-term prognosis of the cases, as confirmed by clinical follow-up as well as by ECG and ECHO.²¹¹

As there is still criticism about the IFCD concept, some suggestions for its modification have been made, such as replacement of ‘normal findings on chest X-ray’ by ‘normal findings on ECHO’ to define IFCD presence.³⁰⁶ Elimination of the term has been even suggested, with its replacement by ‘chronic CD with no evident pathology’, when not only conventional ECG and chest radiography, but routinely performed doppler ECHO, Holter, and exercise testing resulted normal.¹¹ However, the classical concept of IFCD has been reassured in national and international guidelines.²,⁷

It is worth noting that, in clinical practice and epidemiological studies, patients with CD, normal findings on ECG and chest X-ray, and no digestive manifestations, do not routinely undergo gastrointestinal tract radiological assessment. This has led to the operational concept of “chronic CD with no apparent cardiopathy”, because the classical definition of IFCD requires the radiological assessment of the esophagus and colon.²⁹⁹

As the investigative methods became more sophisticated, several alterations, usually discrete and with no prognostic implication, could be detected in those individuals, as reported in studies with Doppler ECHO, radionuclide ventriculography, exercise test, cardiopulmonary exercise test, autonomic tests, and ambulatorial ECG.²⁰⁴,²⁹⁹,³⁰⁷,³⁰⁸ In
addition, invasive methods, such as endomyocardial biopsy, have shown histological changes in a substantial number of patients with IFCD, but at low intensity. Of 33 patients with IFCD undergoing endomyocardial biopsy, 60% have shown degenerative changes, fiber volume alterations, interstitial edema, inflammatory infiltrate, and fibrosis in small amount.³⁰⁹

Currently, CMRI provides the same data, with the advantage of being noninvasive.³¹⁰,³¹¹ In addition, more sensitive echocardiographic methods, such as tissue Doppler³¹² and myocardial global longitudinal strain (GLS)³¹³ with speckle tracking echocardiography (STE), have shown alterations in patients with IFCD. However, such studies have not had sufficient follow-up to define if patients with those mild alterations would progress in a different way, and, eventually, to ventricular dysfunction.

## 5.2.3. Progression to Chronic Cardiomyopathy

For the past 60 years, the risk of chronic cardiomyopathy development has been assessed in cohort studies, which have been gathered in a recent systematic review and meta-analysis.²⁹⁷ The following cardiac primary outcomes were considered in that systematic review: (1) development of symptoms, in general, or of HF, specifically; (2) development of structural cardiomyopathy or cardiac arrhythmias, as observed in abnormal ECG or echocardiographic findings; and (3) presence of complications due to severe cardiomyopathy, such as sudden death, death associated with advanced HF, pulmonary embolism, or stroke. Twenty-three studies have reported observational longitudinal findings for patients with IFCD. Most of them were prospective cohorts conducted in Brazil or Argentina between 1960 and 2005. In studies with information on age group, the means ranged from 10 years to 44 years, the general mean being 31 years. The mean follow-up duration was 8.5 years, varying from 3 years to 18 years. That study concluded that the estimated annual combined rate of progression to CCCD was 1.9% (95% CI, 1.3% – 3.0%). The cumulative probabilities of cardiomyopathy evidence were approximately 17% and 31% in 10 years and 20 years, respectively.²⁹⁷

Although the rate of progression to cardiomyopathy is well defined, several doubts persist about the mechanisms involved in disease progression. In that same systematic review,²⁹⁷ the authors found no difference regarding the rate of progression based on the investigation year (before or after 1985), study size (n > or < 200 participants), participants' mean age (n < or > 32 years), or sex predominance. However, in studies originated from Brazil, the annual rate of progression to cardiomyopathy was significantly higher (2.3%; 95% CI, 1.2% – 4.3%) as compared to those from studies from other South-American countries (1.1%; 95% CI, 0.5% – 2.4%; *p* = 0.05), reinforcing the importance of regional differences in disease course.

In addition, the authors have reported that the subgroup receiving antiparasite treatment had an estimated annual combined rate of progression to cardiomyopathy significantly lower (1.0%; 95% CI, 0.5% – 1.9%) as compared to the

subgroup not receiving etiological treatment (2.3%; 95% CI, 1.5% – 3.5%; *p* = 0.03).²⁹⁷

Those results corroborate with the general pathophysiological notion that there is substantial evidence that parasite persistence (load) is a fundamental factor for IFCD progression to CCCD. A reference study³¹⁴ with a murine model of *T. cruzi* infection has shown that parasite persistence correlates with the presence of cardiac disease, while parasite elimination from the tissues is associated with inflammation improvement.

Subsequent studies have shown that inflammation and fibrosis extension, as well as disease severity, are associated with persistence of the parasite DNA in cardiac lesions observed in patients with CD.³¹⁵,³¹⁶ The presence of parasitemia correlates significantly with known markers of disease progression, such as prolonged QRS, reduced LVEF, and higher levels of troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP).³¹⁷

In a cohort with 1813 patients with CCCD, those previously treated with benznidazole showed a significantly reduced parasitemia, lower prevalence of severe cardiomyopathy markers, and lower mortality after a 2-year follow-up.³¹⁸ Additional results of the NIH-REDS2 cohort, with a mean 8.7-year follow-up of the original cohort,³¹⁹ have shown that the incidence of cardiomyopathy in *T. cruzi* seropositive blood donors was 13.8 (95% CI, 9.5-19.6) events/1000 per year (32/262, 12%) as compared to 4.6 (95% CI, 2.3-8.3) events/1000 per year (11/277, 5%) in seronegative controls, with a difference in the absolute incidence of *T. cruzi* infection of 9.2 (95% CI, 3.6-15.0) events/1000 per year. Anti-*T. cruzi* antibody levels at the beginning of the study, an indirect measure of parasite load, were associated with the development of cardiomyopathy, with adjusted odds ratio of 1.4 (95% CI, 1.1-1.8) per unit of increase in antibody levels.³¹⁹

The importance of parasite persistence for the development of CCCD is corroborated by an extensive nonrandomized clinical trial by Viotti et al.³²⁰ showing that treatment with benznidazole, as compared to absence of etiological treatment, was associated with a reduction in the progression of CD and an increase in negative seroconversion. Other observational studies have reported similar results.³²¹⁻³²³

There is yet evidence that, once the cardiopathy is established, tissue parasitism loses importance for the disease's clinical course, and immune damages to the tissues predominate. According to this hypothesis, once the cardiopathy is established and the tissue parasite factor is eliminated, there would no longer be a chance of reversion to a less ominous natural history, because irreversible lesions would already be installed. Thus, the prospective, multicenter, randomized BENEFIT study, involving 2854 patients with CCCD receiving benznidazole or placebo for as long as 80 days and with a mean follow-up of 5.4 years, has shown that the use of the trypanocidal drug reduced parasitemia, but did not significantly influence clinical cardiac deterioration as compared to a control group.³²⁴ Those results have been object of divergent and
complementary discussions and interpretations,³²⁵ and the importance of parasite persistence in patients with established cardiopathy remains controversial, as detailed in the chapter of etiological treatment in this guideline.

### 5.2.4. Clinical Forms of Chronic Cardiomyopathy of Chagas Disease

The natural history of CCCD is characteristically slow and progressive, although occasionally more abrupt. Its clinical manifestations vary from asymptomatic ('silent' cardiopathy) to severe findings, with refractory HF, rhythm disorders, and thromboembolic phenomena, the three major clinical syndromes.³²⁶ The most important symptoms are: dyspnea on exertion, fatigue, palpitations, dizziness, syncope, chest pain (angina, usually atypical), and lower limb edema.

The physical examination reveals one or more abnormalities: systolic murmur of mitral and/or tricuspid regurgitation; splitting of the second heart sound, usually associated with right bundle branch block (RBBB); diffuse and displaced apical thrust; and arrhythmias, extrasystoles being the most common ones.

#### 5.2.4.1 Abnormalities on Complementary Tests

The ECG in CD has fundamental diagnostic and prognostic values.³²⁷,³²⁸ The absence of electrocardiographic changes, however, is no absolutely reliable indicator of the cardiac impairment absence.²⁹⁹ The RBBB, isolated or in association with other changes, is the most common electrocardiographic abnormality.³²⁹,³³⁰ It is more typically associated with left anterior fascicular block (LAFB) and ventricular extrasystoles (VE). The QRS duration is directly related to the LV size and inversely related to LVEF.³³¹ A QRS duration > 120ms and QT interval > 440ms have moderate accuracy to predict reduced LVEF in patients with CD.³³²

The ECG abnormalities most frequently associated with LVEF reduction in CD are frequent supraventricular and ventricular extrasystoles, AF, intraventricular blocks, pathologic Q waves, and ST-T alterations.³³²,³³³ The combination of intraventricular conduction disorders with extrasystoles or sinus bradycardia associates with both LVEF reduction and LV volume increase.³³⁴ It is worth noting that the electrocardiographic changes caused by CD tend, in older individuals, to add to those caused by the biological aging process itself.³⁰³ A more detailed presentation of the ECG changes of CCCD and of those not sufficient to make that diagnosis is found in other chapters of this guideline.

Chest radiography is an important test to diagnose patients with CCCD, enabling the assessment not only of the enlargement of cardiac chambers, but, especially, of the pulmonary congestion grade, an imperceptible change on usual ECHO.³³⁵,³³⁶ There is low correlation between the cardiac silhouette enlargement on chest radiography and the systolic ventricular dysfunction degree.³³⁵ However, cardiomegaly detected based on cardiothoracic index (CTI) > 0.5 on radiography correlates better with LV diastolic diameter (LVDD) increase, suggesting the presence of LV systolic dysfunction.³³⁷

In CCCD, the radiological findings are similar to those detected in other DCMs. However, an interesting particularity refers to a fact described by clinicians decades ago: several patients with evident systemic congestion, including ascites, hepatomegaly, and anasarca, show a clear disproportion between the advanced cardiomegaly and pulmonary congestion that is usually mild or even absent.³³⁶

For decades, transthoracic ECHO has been an important tool for the diagnosis and follow-up of patients with the different forms of CD.³³⁸,³³⁹ It is the most often used noninvasive test to assess cardiac function because of its wide availability and high reliability regarding performance and interpretation, as well as its relatively low cost. It enables determining the evolutionary status of the disease, as well as the most subtle cardiac impairment alterations, especially in the less advanced phases of cardiomyopathy. In CCCD, up to 13% of the patients in stage B (see HF classification) have a characteristic regional deficit, despite preserved global biventricular systolic function.³⁴⁰ It is worth noting that such isolated regional LV motion alterations evidence poor prognosis, as observed in serial studies with ECHO.³⁴¹,³⁴²

Of several parameters analyzed, the most important ones are: LVEF, left atrial diameter, left atrial volume, systolic and diastolic LV diameters, diastolic function, right ventricular (RV) systolic function, global and regional LV contractility, global RV contractility, and presence of apical aneurysm.

The RV echocardiographic analysis is hindered by technical difficulties regarding the RV chamber itself and the essence of the ultrasonographic method. Thus, RV dysfunction is more often evidenced when there is concomitant and significant LV involvement.³⁴³,³⁴⁴ Despite this pathophysiological notion, evidence derived from studies using other methods, such as radionuclide ventriculography, CMRI, and more specialized ECHO, indicates that some patients with CCCD have early important isolated RV morphofunctional changes.²⁰³,³⁴⁵⁻³⁴⁸ In such conditions, in the absence of concomitant LV pathological involvement and while the impedance of the pulmonary circuit remains reduced, the RV dysfunction might remain unnoticed because the LV vis-a-tergo is sufficient to maintain the flow and pulmonary vascular resistance normal, as reported in a publication on the subject.³⁴⁹

Finally, when present in the natural history of the disease, the clinically manifest RV systolic dysfunction significantly worsens the prognosis of patients with CCCD.³⁵⁰

#### 5.2.4.2. Cardiac Arrhythmias

Cardiac arrhythmia is an extremely common manifestation of CCCD, and ventricular ectopic activity predominates since the early phases of its natural history. Ventricular extrasystoles have been shown in 15% to 55% of individuals with positive serology for T. cruzi. When patients with ECG changes at rest and manifest HF undergo dynamic electrocardiography assessment, almost all of them (99%) have VEs, which, in 87% of the patients, are multiform or present as repetitive (paired) forms or even as nonsustained ventricular tachycardia (NSVT), that is, three or more successive ventricular ectopic beats, lasting less than 30 seconds.³⁵¹