Simpósio Doença de Chagas

22/11/2019

Prof. Dr. Martino Martinelli

Fibrose e risco em Chagas

martinomartinelli@uol.com.br

Fibrose/cicatrizHipertrofiaInflamação miocárdicaAlteração da repolarização

Fibrose/cicatrizIsquemiaDilatação VE/stress parede

Fibrose/cicatrizAlt. da regulação do cálcio

Dilatação VE/ stress paredeHipertrofia

Fatores de RiscoIdade,HAS,DM,

tabagismo,obesidade,doença renal,inflamação

genética CMDCMI

Estabilizadoresde membrana,

N3 PUFA, magnésio,

NEFA

PredisposiçãoGenética

automaticidadecondução

repolarização

MSC

ativação simpática, isquemia,stress emocional;

fluxo de eletrólitos,stress hemodinâmico

TV/FV

Morte Súbita Cardíaca

Substratovulnerável

Rajat Deo;Circulation 2012;125:620-637

Cardiomiopatia Isquêmica Cardiomiopatia Dilatada

Cardiomiopatia Hipertrófica Cardiomiopatia Chagásica

Substrato Vulnerável

Imagens cedidas por Dra. Vera Demarchi Aielo

Laboratório de Anatomia Patológica do InCor

Ventrículo esquerdo e aorta abertos

Nota-se dilatação ventricular e

Trombose no ápice do VE.

Corte histológico do miocárdio corado hematoxilina-eosina

Cardiomiopatia Chagásica

miocardite crônica com fibrose intersticial

Cardiomiócito com ninho de amastigotas do T.Cruzi

Substrato Vulnerável

Inflammation andfibrosis predominance;parasite persistence

Nerve endings

Low-gradeparasitaemia

T.Cruzi antigens

Several receptors

Cardiac fibrosis markersMarker Role in fibrosis

TGF‐β Promotes myocyte hypertrophy and extracellular

matrix deposition

IL‐1β -TNF‐α Promote myocardial hypertrophy and induce

cardiomyocyte apoptosis

MMP‐2 Potential biomarker for initial fibrosis in patients with

Chagas disease

MMP‐9 Potential biomarker for fibrosis in patients with chronic

Chagas cardiomyopathyGal‐3 Regulates inflammatory and fibrotic responses

Myocardial damage and fibrosis

CDI (20) CCC (17) FI (20) Gene Chr Start Ref Alt

20 0 1 CACNA1B 9 140777306 C G20 0 0 KCNC3 19 50832152 T C20 0 1 KCNJ12 17 21318952 A G20 0 0 HLA-B 6 31323953 C G20 0 0 HLA-DQB2 6 32725619 T C20 0 0 HLA-DRB1 6 32549475 T C20 0 0 HLA-DRB1 6 32549501 A C20 0 0 HLA-DRB1 6 32549611 T A20 0 0 HLA-DRB1 6 32557483 T C20 0 0 MMP12 11 102738793 - T Stawski L 201420 0 0 MMP12 11 102738795 G T20 0 0 MMP17 12 132313098 - GCTGCCGCT Liang B, 2017

Estudo de Polimorfismos

Marcadores genéticos

Apesar das evidências sobre a relação entre moléculas inflamatórias e produção de fibrose, ainda não foi estabelecida uma associação nítida e definitiva que aponte um potencial

biomarcador não invasivo da deposição de colágeno. É crucial continuar a buscando biomarcadores não invasivos preditores de fibrose cardíaca.

Gulati A. et al, JAMA 2013;309(9):896-908

Apical (a), mid (b) and basal

(c) short-axis images of a

Chagas’ heart disease patient

in the indeterminate phase

(patient 54, IND) with T2w

(left column), cine SSFP for

anatomical reference (mid

column) and LGE (right

column).

Red arrows indicate

increased myocardial signal

intensity (T2W Ratio: 2.5). On

the apical short-axis slice one

can see a positive T2w image

without correspondent LGE

Conclusion: there is a good biological correlation with presence

of myocardial fibrosis, severity of Chagas’ heart disease, NYHA

functional class, left ventricular ejection fraction

Torreão et al JCMR 2015;17:97 DOI 10.1186/s12968-015-0200-7

Freitas et al; International Journal of Cardiology 102(2005)239-247

CHD: 220

Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas heart disease

EtiologyChagasic/idiopathic <0.0001 2.267 [1.671, 3.076]Chagasic/hypertensive <0.0001 2.725 [1.823, 4.074]Chagasic/ischemic <0.0001 2.531 [1.695, 3.778]Chagasic/others <0.0001 2.976 [1.936, 4.573]

Chagas heart disease

N:1220

SubstratoTV/FV

Corte SagitalCoração Chagásico

Morte Súbita Cardíaca Cardiopatia Chagásica Crônica

Miocárdio Inflamado

Miocárdio Normal

Fibrose Miocárdica

Istmo

Tecido Cardíaco

Hematoxiline& eosine

RM, masc, 55a, funcionário público, RJ

CCC ; NYHA classe II; FEVE: 42%

Síncope Inexplicada:

Fibrose miocárdica extensa: CDI indicado

Teste ErgométricoHolter 24h

RM, masc, 55a, funcionário público, RJ

CCC ; NYHA classe II; FEVE: 42%

Seguimento Clínico

Fibrose miocárdica: parede lateral

TRC não-indicada

EPL, 67a, casado, porteiro, natural de PR CCC,NYHA CFIII, BRE, FEVE 35%

RMCRealce Tardio

Tratamento clínico otimizado

Journal of the American College of CardiologyLong-Term Prognostic Value of Myocardial Fibrosis in Patients With Chagas

Cardiomyopathy

avaliar o papel da FM na predição de eventosadversos ou mortalidade total

estudo retrospectivo observacional de dados clinicos em pacientes que realizaram RMC

combinação de mortalidade por todas as causas , TC, MP, choques apropriados do CDI, MSC abortada

Desfecho Primário:

Desfecho Secundário:

Objetivo:

Método:

idade: 53.6 ± 11.5 a,

genero: 53.9% feminino

Seguimento: 5.05 anos

mortalidade por todas as causas

N: 130

Journal of the American College of CardiologyLong-Term Prognostic Value of Myocardial Fibrosis in Patients With Chagas

Cardiomyopathy

Principais AchadosFibrose Miocárdica é preditor independente de mau prognóstico

na CCC; 12,3 g é o valor de carga determinante de maior mortalidade .

Fibrose e Risco em ChagasSumário

1- As evidências científicas sobre associação de fibrose miocárdica à RMC e disfunção ventricular, IC e mortalidade cardíaca são claras;

2- Com relação à taquiarritmia ventricular, a documentação da fibrose miocárdica atesta apenas a presença de um importante componente do seu substrato;

3- A carga de fibrose miocárdica superior a 12 g é fator independente de maior mortalidade ;

4- Não existem evidências científicas sobre associação de fibrose miocárdica `RMC com morte súbita cardíaca;

5- A busca de outros marcadores não invasivos deve persistir.

Obrigado!

BackgroundMyocardial fibrosis (MF) according to cardiac magnetic resonance (CMR) is a frequent finding in Chagas cardiomyopathy and has been associated with risk factors of poor outcome.ObjectivesThe goal of this study was to determine the prognostic value of MF in predicting combined hard events or all-cause mortality.MethodsPatients with Chagas cardiomyopathy who had a previous CMR evaluation were included, and clinical follow-up was retrospectively obtained. The primary outcome was a combination of all-cause mortality, heart transplantation, antitachycardia pacing or appropriate shock from an implantable cardioverter-defibrillator, and aborted sudden cardiac death; the secondary outcome was all-cause mortality.ResultsA total of 130 patients were included; mean age was 53.6 ± 11.5 years, and 53.9% were female. The majority of patients reported no symptoms of heart failure or arrhythmia, but electrocardiographic and echocardiographic abnormalities were common. On CMR, left ventricular dilatation and dysfunction were frequent, and MF was found in 76.1%, with a mean mass of 15.2 ± 16.5 g. Over a median follow-up of 5.05 years, 58 (44.6%) patients reached the combined endpoint, and 45 (34.6%) patients died. MF was associated with the primary outcome as a continuous variable (adjusted hazard ratio: 1.031; 95% CI: 1.013 to 1.049; p = 0.001) and as a categorical variable (MF ≥12.3 g) (adjusted hazard ratio: 2.107; 95% CI: 1.111 to 3.994; p = 0.022), independently from the Rassi risk score. MF expressed as a continuous variable was also associated with all-cause mortality (adjusted hazard ratio: 1.028; 95% CI: 1.005 to 1.051; p = 0.017) independently from the Rassi risk score.ConclusionsMF is an independent predictor of adverse outcome in Chagas cardiomyopathy. Our data may support the use of CMR in better risk-stratifying this population and possibly guiding therapy.Central Illustration

Long-Term Prognostic Value of Myocardial

Fibrosis in Patients With Chagas Cardiomyopathy

Left Ventricular Scar and Prognosis in Chronic Chagas CardiomyopathyGustavo J. Volpe, Henrique T. Moreira, Henrique S. Trad, Katherine C. Wu, Maria Fernanda

Braggion-Santos, Marcel K. Santos, Benedito C. Maciel, Antonio Pazin-Filho, José Antonio

Marin-Neto, João A.C. Lima and André Schmidt

Journal of the American College of Cardiology

Volume 72, Issue 21, November 2018DOI: 10.1016/j.jacc.2018.09.035

AbstractBackground Patients with chronic Chagas cardiomyopathy (CCC) have pronounced myocardial fibrosis, which may predispose to sudden cardiac death, despite well-preserved global left ventricular (LV) systolic function. Cardiac magnetic resonance can assess myocardial fibrosis by late gadolinium enhancement (LGE) sequences.Objectives This prospective study evaluated if the presence of scar by LGE predicted hard adverse outcomes in a cohort of patients with CCC.Methods A prospective cohort of 140 patients with CCC (52.1% female; median age 57 years [interquartile range: 45 to 67 years]) were included. Cardiac magnetic resonance cine and LGE imaging were performed at enrollment with a 1.5-T scanner. The primary endpoint was the combination of cardiovascular death and sustained ventricular tachycardia. The secondary endpoint was the combination of cardiovascular death, sustained ventricular tachycardia, or cardiovascular hospitalization during follow-up.

Results After a median of 34 months (interquartile range: 24 to 49 months) of follow-up, 11 cardiovascular deaths, 3 episodes of sustained ventricular tachycardia, and 20 cardiovascular hospitalizations were recorded. LGE scar was present in 71.4% of the patients, with the lateral, inferolateral, and inferior walls most commonly affected. Patients with positive LGE had lower LV ejection fraction and higher LV end-diastolic volume and LV mass than patients without LGE. No difference in other cardiovascular risk factors was noted. Patients with scar had higher event rates compared with those without scar for the primary (p = 0.043) and the secondary (p = 0.016) endpoint. In multivariable analysis, age and LGE area were related to primary outcome; age and lower LV ejection fraction were related to the secondary outcome. The pattern of LGE myocardial fibrosis was transmural, focal, or diffuse scar in approximately one-third of patients with positive LGE, and no pattern was specifically related to outcomes.Conclusions In patients with CCC, presence of scar by LGE is common and is strongly associated with major adverse outcomes.

Left Ventricular Scar and Prognosis in Chronic Chagas CardiomyopathyGustavo J. Volpe,

CDI (20) CCC (17) FI (20) Gene Chr Start Ref Alt

20 0 1 CACNA1B 9 140777306 C G20 0 0 KCNC3 19 50832152 T C20 0 1 KCNJ12 17 21318952 A G20 0 0 HLA-B 6 31323953 C G20 0 0 HLA-DQB2 6 32725619 T C20 0 0 HLA-DRB1 6 32549475 T C20 0 0 HLA-DRB1 6 32549501 A C20 0 0 HLA-DRB1 6 32549611 T A20 0 0 HLA-DRB1 6 32557483 T C20 0 0 MMP12 11 102738793 - T Stawski L 201420 0 0 MMP12 11 102738795 G T20 0 0 MMP17 12 132313098 - GCTGCCGCT Liang B, 2017

Grupos de Pacientes

GI- CCC com TVS/CDI (N=20)

GII- CCC sem disfunção /TV (N=17)

GIII- Forma indeterminada (N=20)

• CACNA1B aumenta tonus simpático e reduz tônus parasimpático;

• Mutação CACNA1B R1389H afeta a taxa de fluxo de Ca++ nos canais ionicos;

• Mutação no CACNA1B R1389H aumenta tônus simpático;

• Mutação no CACNA1B R1389H pode agravar ocorrência de TV/FV

GI GII GIII

Variantes em genes potencialmente relevantes para a arritmia ventricular

Polimorfismo Genético na CCC

Prof. Edécio Cunha

CCCDistúrbios de Condução e

Arritmias Ventriculares

Fibrose Miocárdica

Genética

Endpoints

Follow-up6,12,18,24 meses *

Escore de Risco Mortalidade

*Exame clínicoRegistros no DCEI

Projeto GENOMICHS

Bloqueador de Cálcio específico

MP, CDI prevenção e secundária, TRC

Marcadores Clínicos e Biológicos

CMI

Imagem cedida por Dra. Maria Higuchi Imagem cedida por Dra. Maria Higuchi

CMD

Hipertrofia difusa de cardiomiócitos e discreta fibrose.

Algumas fibras mostram-se afiladas (setas).

Extensa substituição fibrosa do miocárdio (matriz rósea).

Trombos superajuntados (setas).

Polimorfismo Genético na CCC

33

Cardiomiopatia x Forma indeterminada(n=845) Modelo aditivo

Modelo recessivo

Modelo Dominante

Additif Dominant récessif

SNP POSITIONAllèle

ancestrale

Allèle muté

OR P OR P OR P Gène Localisation

rs78158283

chr3:24502985

G A 0,1359,07E-

060,135

9,07E-06

THRB intronrs1155966

95chr3:2453150

9T G 0,132

3,11E-06

0,1323,11E-

06

rs1852211chr3:1192747

49G A 0,465

4,61E-07

0,38573,61E-

07CD80 intron

rs1997421chr3:7774095

4T C 0,1803 3,16E-06

ROBO1 -ROBO2

intergénique

rs2153251chr6:1494052

18C T 0,2975 1,11E-06

UST - TAB2 intergéniquers9498206

chr6:149407165

C T 0,32 3,89E-06

rs6974790chr7:5533994

8C T 0,2443 3,08E-06 EGFR - LANCL2 intergénique

rs7014898chr8:7310440

7T C 0,4873

1,02E-06

0,4254,24E-

06MSC - KCNB2 intergénique

rs79378068

chr9:13284056

A G 0,28456,82E-

060,3162

7,70E-06

MPDZ - NFIB intergénique

rs12683673

chr9:7151012 G A KDM4C intron

rs79796987

chr15:52512344

G A 0,35988,76E-

060,3372

9,58E-06

MYO5C intron

rs1440473chr18:530103

32C T 0,5486

8,20E-06

0,3963 2,67E-06 TCF4 intron

Polimorfismo genético em canal iônico (KCNB2) e expressão gênica de canais Na, K e Ca no miocárdio

associados a distúrbios de condução e arritmias ventriculares

Morte Súbita Cardíacafisiopatogenia

Rajat Deo;Circulation 2012;125:620-637

E.Zaklayazminskaya; Gene 517(2013) 1-11

Inherited- Genetic

Ion Channel subunit genes

Channel regulatory protein genes

SCD VT/VFVT/VF

D. Primariamente Genéticas D. Adquiridas