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. 2023 Jun 15;5(3):e220112. doi: 10.1148/ryct.220112

Detection of Early Diffuse Myocardial Fibrosis and Inflammation in Chagas Cardiomyopathy with T1 Mapping and Extracellular Volume

Rodrigo J L Melo 1, Antonildes N Assunção Jr 1, Thamara C Morais 1, Cesar H Nomura 1, Mauricio I Scanavacca 1, Martino Martinelli-Filho 1, Felix J A Ramires 1, Fabio Fernandes 1, Barbara M Ianni 1, Charles Mady 1, Carlos E Rochitte 1,✉
PMCID: PMC10316290  PMID: 37404789

Abstract

Purpose

To evaluate myocardial T1 mapping and extracellular volume (ECV) parameters in different stages of Chagas cardiomyopathy and determine whether they are predictive of disease severity and prognosis.

Materials and Methods

Prospectively enrolled participants (July 2013 to September 2016) underwent cine and late gadolinium enhancement (LGE) cardiac MRI and T1 mapping with a precontrast (native) or postcontrast modified Look-Locker sequence. The native T1 and ECV values were measured among subgroups that were based on disease severity (indeterminate, Chagas cardiomyopathy with preserved ejection fraction [CCpEF], Chagas cardiomyopathy with midrange ejection fraction [CCmrEF], and Chagas cardiomyopathy with reduced ejection fraction [CCrEF]). Cox proportional hazards regression and the Akaike information criterion were used to determine predictors of major cardiovascular events (cardioverter defibrillator implant, heart transplant, or death).

Results

In 107 participants (90 participants with Chagas disease [mean age ± SD, 55 years ± 11; 49 men] and 17 age- and sex-matched control participants), the left ventricular (LV) ejection fraction and the extent of focal and diffuse or interstitial fibrosis were correlated with disease severity. Participants with CCmrEF and participants with CCrEF showed significantly higher global native T1 and ECV values than participants in the indeterminate, CCpEF, and control groups (T1: 1072 msec ± 34 and 1073 msec ± 63 vs 1010 msec ± 41, 1005 msec ± 69, and 999 msec ± 46; ECV: 35.5% ± 3.6 and 35.0% ± 5.4 vs 25.3% ± 3.5, 28.2% ± 4.9, and 25.2% ± 2.2; both P < .001). Remote (LGE-negative areas) native T1 and ECV values were also higher (T1: 1056 msec ± 32 and 1071 msec ± 55 vs 1008 msec ± 41, 989 msec ± 96, and 999 msec ± 46; ECV: 30.2% ± 4.7 and 30.8% ± 7.4 vs 25.1% ± 3.5, 25.1% ± 3.7, and 25.0% ± 2.2; both P < .001). Abnormal remote ECV values (>30%) occurred in 12% of participants in the indeterminate group, which increased with disease severity. Nineteen combined outcomes were observed (median follow-up time: 43 months), and a remote native T1 value greater than 1100 msec was independently predictive of combined outcomes (hazard ratio, 12 [95% CI: 4.1, 34.2]; P < .001).

Conclusion

Myocardial native T1 and ECV values were correlated with Chagas disease severity and may serve as markers of myocardial involvement in Chagas cardiomyopathy that precede LGE and LV dysfunction.

Keywords: MRI, Cardiac, Heart, Imaging Sequences, Chagas Cardiomyopathy

Supplemental material is available for this article.

© RSNA, 2023

Keywords: MRI, Cardiac, Heart, Imaging Sequences, Chagas Cardiomyopathy

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Summary

Myocardial T1 and extracellular volume (ECV) values were positively correlated with Chagas disease severity; a higher remote ECV value in indeterminate Chagas disease may represent an early marker of myocardial injury.

Key Points

  • ■ In a prospective observational study of participants with Chagas disease, those with ventricular dysfunction showed higher native T1 and extracellular volume (ECV) values compared with those with normal left ventricular ejection fraction and controls, even areas without late gadolinium enhancement (LGE) (remote myocardium; P < .001 for all).

  • ■ Abnormal remote ECV values (>30%) were present in 12% of participants with indeterminate Chagas disease (asymptomatic, with no cardiac findings) and increased with disease severity (28% in participants with preserved ejection fraction, 93% in those with midrange ejection fraction, and 83% in those with reduced ejection fraction), with higher values being demonstrated in individuals who were LGE-positive.

  • ■ In a survival curve adjusted for covariates, remote T1 times above 1100 msec (99th percentile 1.5-T scanner value) were significantly predictive of combined outcomes (cardioverter defibrillator implant, heart transplant, or death) (hazard ratio, 12 [95% CI: 4.1, 34.2]; P < .001).

Introduction

Chagas disease is a chronic infectious disease caused by Trypanosoma cruzi (1,2). Chronic Chagas cardiomyopathy is the most severe manifestation, occurring in 20%–40% of patients with Chagas disease, and is the leading cause of death in these patients (3). The disease is characterized by chronic, low-intensity myocarditis and ranges from being asymptomatic to resulting in severe clinical outcomes such as ventricular arrhythmias, heart failure, and embolic events (4,5). Diagnosis is based on positive epidemiologic findings, patient history, physical examination findings, serologic test results, and electrocardiographic and imaging findings (4,6).

Cardiac MRI has a fundamental role in the prognostic evaluation of these patients because myocardial fibrosis, which is identified by using the late gadolinium enhancement (LGE) technique, correlates with disease severity and an increased risk of death and arrhythmic events (7–11).

The T1 myocardial mapping and myocardial extracellular volume (ECV) measurements at cardiac MRI (12) have been used to evaluate interstitial and diffuse myocardial fibrosis in several cardiomyopathies. Myocardial T1 values reflect tissue changes, predominantly driven by edema (acute injury or inflammation) and increased interstitial space (fibrosis) and have prognostic value in nonischemic cardiomyopathies (13,14). The ECV reflects the myocardial tissue volume fraction that is not composed of intact cells, including the intracapillary plasma volume. It is calculated by using native and postcontrast T1 times, which are adjusted for hematocrit values (15), and has a reliable correlation with the extracellular matrix as assessed according to histologic characteristics (16–18). Initial data indicate that ECV may have an important prognostic role in the evaluation of cardiomyopathies (19) because it allows for the detection of extracellular matrix expansion, which occurs in the early stages of cardiomyopathy and is not detected with use of LGE techniques. In the early stages of Chagas disease, incipient LGE has already been detected (7,9). However, to our knowledge, T1 mapping and ECV measurements have not yet been correlated prospectively with clinical outcomes; they have only been correlated with the occurrence of nonsustained tachycardia (20).

We sought to investigate the changes in myocardial native T1 and ECV values by using cardiac MRI T1 mapping in different stages of Chagas disease. We also evaluated their correlation with left ventricular (LV) function and the occurrence of combined outcomes (need for an implantable cardioverter defibrillator [ICD], need for cardiac transplant, or death).

Materials and Methods

Study Participants

The institutional review board (local committee for ethics in research) (approval no. 4209/15/036) approved this prospective observational study, and all participants provided written informed consent. The study included participants aged 18 years or older with chronic Chagas disease, as confirmed by at least two serologic examinations, who were clinically monitored at the Cardiomyopathy Unit of the Heart Institute (Instituto do Coração) from July 2013 to September 2016 and underwent follow-up until June 2019. In accordance with established guidelines (4,21), participants were divided into four unpaired groups that were based on the cardiomyopathy severity level: one group with an indeterminate form (asymptomatic with no cardiac findings), one group with cardiomyopathy with preserved ejection fraction (CCpEF) (LV ejection fraction [LVEF] ≥50% and electrocardiographic or echocardiographic findings: bundle branch blocks, premature ventricular contractions occurring more than 10 times per hour, sustained or nonsustained ventricular arrhythmia, and segmental contractility alterations), one group with Chagas cardiomyopathy with midrange ejection fraction (CCmrEF) (LVEF, 40%–49%), and one group with Chagas cardiomyopathy with reduced ejection fraction (CCrEF) (LVEF <40%). Volunteers with no cardiovascular symptoms, matched by age and sex, were enrolled as a control group.

Exclusion criteria were pregnancy, contraindication to cardiac MRI examination, presence of coronary artery disease or high risk for atherosclerotic cardiovascular disease (as determined by the Framingham Risk Score), and presence of concomitant other cardiomyopathies.

All participants underwent, within an interval of up to 30 days before cardiac MRI, electrocardiography, chest radiography, transthoracic echocardiography, and 24-hour Holter monitoring. The Rassi prognostic score was then determined (22). According to current guidelines (4), none of the participants received nifurtimox or benznidazole as an etiologic treatment for Chagas disease.

The data that support the findings of this study are available from the corresponding author on reasonable request.

Image Acquisition

All studies were performed with a 1.5-T MRI scanner (Achieva; Philips Healthcare). Cine and LGE images were obtained as previously described (23,24). In brief, cine parameters were as follows: echo time, 1.5 msec; repetition time, 3.1 msec; flip angle, 60°; and resolution, 1.8 × 2.0 × 8.0 mm. LGE was performed 10 minutes after gadolinium-based contrast material injection at 0.2 mmol/kg (gadoterate meglumine; Dotarem, Guerbet) by using the following parameters: echo time, 3.0 msec; repetition time, 6.1 msec; flip angle, 25°; and resolution, 1.3 × 1.5 × 8.0 mm (23,24). T1 mapping was performed by using an electrocardiographically triggered single-shot modified Look-Locker inversion-recovery (MOLLI) sequence (25,26) with the 3(3)3(3)5 sampling pattern and the following parameters: section thickness, 10 mm; field of view, 300 × 300 mm; acquisition matrix (readout × phase encodings), 152 × 150; flip angle, 40°; minimum inversion time, 60 msec; and inversion time increment, 150 msec. Three MOLLI LV short-axis images (basal, midventricular, and apical) were acquired before and 15 minutes after administration of an intravenous bolus of 0.2 mmol/kg of body weight of gadolinium-based contrast material (gadoterate meglumine; DotaremVR, Guerbet).

Image Analysis

All MRI scans were analyzed by a cardiovascular radiologist (R.J.L.M., 9 years of experience) with level III Society for Cardiovascular Magnetic Resonance training in cardiac MRI, and analysis was conducted by using CVi42 software (Circle Cardiovascular Imaging). The end-systolic and end-diastolic LV volumes, LV mass, and LVEF were measured according to standard methods (27). The left atrial volume index was calculated by using the biplane method. For quantification of LGE, we adopted a semiautomatic thresholding technique in which a signal intensity cutoff value of the mean normal myocardium value ± 5 SDs was used; this technique had the best agreement with findings from visual analysis and seems to have the best correlation with histopathologic findings (28).

Myocardial T1 evaluation was performed by using delimitation of a myocardial region of interest that was obtained by drawing endocardial and epicardial contours, avoiding contamination by blood and extracardiac structures (global analysis). Measurements were performed in basal and midventricular sections, and the values used for statistical analyses were a mean of these two section positions. Apical short-axis T1 maps were excluded from analysis because of a substantial partial-volume effect at this level. Measurements of T1 values were also performed only in myocardial regions free of visually detected LGE (remote analysis) (Fig 1). Careful measures were taken to limit the effect of occasional segments with thin walls and trabeculation at T1 map analysis through meticulous adjustments of regions of interest.

Figure 1:

Examples of native T1, postcontrast T1, extracellular volume (ECV), and late gadolinium enhancement (LGE) midcavity short-axis images in all groups. Rows from top to bottom represent control (CONT) participants and participants with Chagas disease in the indeterminate (IND) form, Chagas cardiomyopathy with preserved ejection fraction (CCpEF), Chagas cardiomyopathy with midrange ejection fraction (CCmrEF), and Chagas cardiomyopathy with reduced ejection fraction (CCrEF). The progressive increase of ECV and focal myocardial fibrosis is visually detected from the top to bottom rows.

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Examples of native T1, postcontrast T1, extracellular volume (ECV), and late gadolinium enhancement (LGE) midcavity short-axis images in all groups. Rows from top to bottom represent control (CONT) participants and participants with Chagas disease in the indeterminate (IND) form, Chagas cardiomyopathy with preserved ejection fraction (CCpEF), Chagas cardiomyopathy with midrange ejection fraction (CCmrEF), and Chagas cardiomyopathy with reduced ejection fraction (CCrEF). The progressive increase of ECV and focal myocardial fibrosis is visually detected from the top to bottom rows.

T1 (longitudinal relaxation time) estimation was enabled by an exponential model and by using the signal intensity and time after inversion for each image as previously described (12,29).

The evaluation of segmental contractility, LGE areas, and T1 mapping was visually performed using the segmentation proposed by the American Heart Association (30).

Outcome Analysis

After MRI scan acquisition, participants were prospectively followed, by medical registry data and telephone, to assess the occurrence of hard outcomes (ICD implant, cardiac transplant, or death).

Statistical Analysis

Data are expressed as the frequencies with percentages and means ± SDs for categorical and continuous variables, respectively. Normality was graphically assessed by using quantile-quantile plots and was confirmed with the Shapiro-Wilk test and/or kurtosis. Comparisons between participants with Chagas disease and the control group for continuous variables were made with use of analysis of variance (or Kruskal-Wallis tests), with Bonferroni correction (or Dunn tests) being used to counteract the multiple comparisons. Categorical variables were compared by using χ2 tests (or Fisher exact tests). Correlations between cardiac MRI features were obtained with use of Spearman tests.

A multivariable Cox proportional hazards regression for the prediction of combined outcomes was used for the following models: model 1, Rassi score greater than 11 (high risk); model 2, Rassi score greater than 11 and LVEF less than or equal to 40%; model 3, Rassi score greater than 11 and LGE greater than or equal to 12%; and model 4, Rassi score greater than 11 and remote native T1 greater than 1100 msec. Comparisons of models 2, 3, and 4 with model 1 were made by using a likelihood ratio test. Comparisons among models 2, 3, and 4 (nonnested) were made with use of the Akaike information criterion. The criterion accounts for both the model fit and the model complexity to reduce the chance of overfitting, and a model with a lower criterion is usually preferred. The cumulative clinical event rate was estimated using Kaplan-Meier curve analysis. A multivariable linear regression was applied for covariate adjustment (hypertension, diabetes, dyslipidemia, smoking, body mass index, left or right bundle brunch block, and atrial fibrillation) to investigate whether differences in LGE and T1 parameters between participant groups remained significant.

Normal T1 and ECV values were obtained from our control group, and images were acquired by using the same scanner and pulse sequence parameters. Cutoffs for native T1 (1100 msec) and ECV (30%) myocardial values were considered the upper 99th percentile for the control group, as recommended in Society for Cardiovascular Magnetic Resonance guidelines (31).

The cutoff value for LVEF is derived from established guidelines for reduced ejection fraction (4). The value of LGE greater than 12% is derived from our group data published by Senra et al (10).

All statistical analyses were performed by using the statistical package R, version 4.1.0 (www.r-project.org; R Foundation for Statistical Computing). All P values were two-tailed, and values less than .05 were considered to indicate statistically significant difference.

Results

Participant Clinical Characteristics

Table 1 summarizes the clinical characteristics of included participants with Chagas disease (n = 90; mean age, 55 years ± 11; 54% men) and control participants (n = 17; mean age, 51 years ± 9; 59% women). Twenty-four patients were excluded (six patients before MRI, nine patients after MRI, and nine patients after image analysis) (Fig 2). There was no evidence of a difference in age or sex between groups. Only one individual in the control group presented with dyslipidemia, and the most prevalent comorbidity in participants with Chagas disease was hypertension (37%), followed by dyslipidemia (30%). The prevalence of hypertension was significantly higher in the indeterminate group than in the other three groups (56% for the indeterminate group vs 33% for CCpEF, 21% for CCmrEF, and 21% for CCrEF [P < .001]) (Table S1).

Table 1:

Baseline Characteristics of Study Participants

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Figure 2:

Flowchart of participant recruitment. ICD = implantable cardioverter defibrillator.

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Flowchart of participant recruitment. ICD = implantable cardioverter defibrillator.

Cardiac MRI Morphologic and Functional Assessment, Focal and Diffuse Myocardial Fibrosis

Indeterminate and control participants had similar right ventricular and LV volumes, masses, and function levels (Table 2). Only one patient in the indeterminate group had positive LGE findings (Fig S1) (participants were divided into groups according to echocardiographic parameters). We found no evidence of a difference in T1 mapping values between participants in the indeterminate group and participants in the control group, but four of 34 participants (12%) in the indeterminate group had a global ECV greater than 30%.

Table 2:

Morphofunctional, LGE, and T1 Mapping Parameters

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Among participants in the other disease subgroups, morphologic and functional parameters were progressively worse with higher disease severity. The prevalence of LGE was 83% in the CCpEF group and 100% in the CCmrEF and CCrEF groups, in which the mean LGE masses were 19.3 and 20.1 g, respectively. Participants with CCmrEF and CCrEF exhibited higher global ECV (35.5% ± 3.6 and 35.0% ± 5.4, respectively) and global native T1 values (1072 msec ± 34 and 1073 msec ± 63, respectively) than did other participants with Chagas disease (CCpEF and indeterminate groups) and control participants (ECV in CCmrEF and CCrEF: P < .001 for all comparisons; native T1 in CCmrEF: P = .01, P = .03, and P = .03, respectively; native T1 in CCrEF: P < .001 for all comparisons). Likewise, values for T1 mapping parameters in myocardial segments without LGE were higher in participants with CCmrEF and CCrEF, but there was no evidence of differences between these two groups. When adjusted for diabetes and hypertension, the significant differences between the CCmrEF and CCrEF groups and the control group remained significant for the LGE percentage and native T1 and ECV values.

Among participants with Chagas disease, LGE and global ECV values had a strong negative correlation with LVEF values (r = −0.78 and r = −0.70, respectively; P < .001 for both). Correlations with LVEF values were weaker for global and remote native T1 values (r = −0.52 and r = −0.45, respectively) (Fig S2).

Clinical Outcomes

During the median follow-up time of 43 months (IQR, 40–46 months), 17 participants with Chagas disease underwent ICD implant, and two died. The proportion of events increased with higher disease severity, reaching 50% (12 participants) in the CCrEF group (Fig 3). Participants who experienced combined outcomes during follow-up had higher Rassi scores (median, 12 [IQR, 8–13] vs 2 [IQR, 0–13]; P < .001), lower LVEF values (36% ± 11 vs 59% ± 18; P < .001), and higher LGE percentages (12% [IQR, 7.6%–17%] vs 0% [IQR, 0%–5%]; P < .001) at baseline compared with participants with no events. Of note, all participants who experienced events had a positive LGE result at baseline. With a lower magnitude, global ECV values (34.7% ± 6 vs 29.2% ± 6; P = .001), native T1 values (1069 msec ± 48 vs 1020 msec ± 58; P = .005), and remote T1 values (1066 msec ± 59 vs 1028 msec ± 59; P = .003) were higher in the group of participants with outcomes. We found no evidence of a difference in remote ECV values between these two groups (Fig 4).

Figure 3:

Bar graph shows clinical outcomes according to Chagas disease group (n = 90). The proportion of events increases with the severity of disease. CCmrEF = Chagas cardiomyopathy with midrange ejection fraction, CCpEF = Chagas cardiomyopathy with preserved ejection fraction, CCrEF = Chagas cardiomyopathy with reduced ejection fraction, ICD = implantable cardioverter defibrillator, IND = indeterminate.

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Bar graph shows clinical outcomes according to Chagas disease group (n = 90). The proportion of events increases with the severity of disease. CCmrEF = Chagas cardiomyopathy with midrange ejection fraction, CCpEF = Chagas cardiomyopathy with preserved ejection fraction, CCrEF = Chagas cardiomyopathy with reduced ejection fraction, ICD = implantable cardioverter defibrillator, IND = indeterminate.

Figure 4:

Box and whisker plots show clinical and cardiac MRI differences between participants with Chagas disease with combined clinical outcomes and participants with Chagas disease without combined clinical outcomes. Participants who had combined outcomes during follow-up had higher Rassi scores, lower left ventricular ejection fraction (LVEF) values, and higher late gadolinium enhancement (LGE) percentages (perc) at baseline than participants with no events. At a lower magnitude, global ECV, native T1, and remote T1 values were found to be statistically higher in the participants with outcomes. Remote ECV was similar between groups. Boxes represents the IQR (ie, 25th–75th percentile), and the horizontal line inside the boxes represents the median value of each parameter. Points outside the boxes represent outliers.

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Box and whisker plots show clinical and cardiac MRI differences between participants with Chagas disease with combined clinical outcomes and participants with Chagas disease without combined clinical outcomes. Participants who had combined outcomes during follow-up had higher Rassi scores, lower left ventricular ejection fraction (LVEF) values, and higher late gadolinium enhancement (LGE) percentages (perc) at baseline than participants with no events. At a lower magnitude, global ECV, native T1, and remote T1 values were found to be statistically higher in the participants with outcomes. Remote ECV was similar between groups. Boxes represents the IQR (ie, 25th–75th percentile), and the horizontal line inside the boxes represents the median value of each parameter. Points outside the boxes represent outliers.

In univariable analysis, Rassi scores greater than 11, LVEF values less than 40%, LGE values greater than 12%, and remote T1 values greater than 1100 msec were independent predictors. However, considering that there were only 19 events, we decided not to use multivariable logistic regression because of the risk of overfitting. Instead, we used the lowest Akaike information criterion value to select model 4 (Rassi score >11 and remote T1 value >1100 msec) as the best-performing model for predicting combined outcomes (Table 3).

Table 3:

Multivariable Cox Proportional Hazards Regression for Prediction of Combined Outcome

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In a survival analysis, Rassi scores greater than 11, LVEF values less than or equal to 40%, LGE values greater than or equal to 12%, and remote native T1 values greater than 1100 msec were predictors of combined outcomes (Fig S3).

Discussion

In this study, we demonstrated the early detection and depiction of progressive changes in myocardial tissue characteristics enabled by myocardial native T1 values and ECV mapping in participants with a spectrum of Chagas cardiomyopathy severity, including in areas of the myocardium without focal fibrosis (LGE-negative or remote regions). Our main findings were the following: (a) global and remote native T1 and ECV values progressively increased from participants with normal to reduced LVEF and were not statistically different among participants with an indeterminate form, those with preserved LVEF, and healthy control participants, and both groups with LV dysfunction (CCmrEF and CCrEF) had a similar increase in global and remote native T1 and ECV values compared with control participants, an increase that remained after pairing for age; (b) remote ECV values were also higher in participants with LGE compared with those without; (c) global and remote ECV values showed a significant negative correlation with LVEF values; (d) native T1 and ECV values progressively increased with disease severity in participants with Chagas disease; and (e) LGE percentages greater than 12%, high-risk Rassi scores, and remote native T1 values greater than 1100 msec were independent predictors of combined outcomes.

These results are in accordance with previously published data (7,9–11,32,33). However, to our knowledge, our study is the first to demonstrate the prognostic power of native T1 values regarding the prediction of hard outcomes (ICD implant, cardiac transplant, or death). Previous data only correlated with the occurrence of nonsustained ventricular tachycardia, as detected with the use of Holter monitoring (20).

Our results demonstrated differences in myocardial native T1 and ECV values between control participants and participants with Chagas disease, even in myocardial regions without LGE, reflecting increases in diffuse myocardial fibrosis. Those differences remained after adjusting for confounders such as age, suggesting that these myocardial tissue changes are not explained solely by histologic changes related to age (34).

Similar to the authors of a previous study demonstrating a correlation between LGE and disease severity (9,10), we found that T1 mapping and ECV findings seem to correlate with the degree of ventricular dysfunction, the presence of focal myocardial fibrosis, and disease severity, which was reinforced by high values even in myocardial areas with no detectable LGE. No evidence of a difference in remote ECV values among participants with an indeterminate form, participants with preserved LVEF, and healthy control participants in our study might reflect the limited sensitivity of the current techniques to detect subtle changes within these subgroups. The limited sample sizes of the subgroups may have also contributed to the lack of statistical differences. Another explanation would be that T1 mapping reflects not only areas of fibrosis but also inflammation or edema as a result of the ECV having a greater correlation with interstitial fibrosis and thus not translating into a prognostic result after multivariable analysis because of its collinearity with the LGE.

The significant increase in myocardial native T1 mapping and ECV in participants with LV dysfunction, even in those with midrange LVEF, parallels data published on other cardiomyopathies, including dilated cardiomyopathies (35,36), myocarditis (37), and infiltrative diseases such as amyloidosis (38). This finding suggests that subtle changes in myocardial structure caused by diffuse fibrosis that may be missed at standard global function analysis can be detected by using native T1 and ECV measurements, even in the absence of myocardial LGE. Thus, anomalies in those parameters may be good stratifiers because they are correlated with alteration in the LVEF.

Moreover, our study showed that the mean global ECV was higher than 30% in about 12% of participants in the indeterminate phase of Chagas disease, which could be of paramount relevance. In larger sample sizes, such as in population studies, the global ECV could be an efficient and highly sensitive tool for detecting patients in the very early phases of Chagas cardiomyopathy (such as the indeterminate phase), who still have incipient myocardial injury and are in a phase before the onset of LV dysfunction or the appearance of LGE. This might open a crucial window of opportunity for investigative studies on many aspects of Chagas disease, including its pathophysiologic characteristics, its risk stratification, and therapies to prevent Chagas cardiomyopathy development and progression.

Our study provides findings related to the pathophysiologic characteristics of Chagas disease, which should motivate further advanced investigations. In particular, the clear increase in remote myocardial native T1 and ECV values observed in participants with CCmrEF and in participants with CCrEF compared with the groups with normal LVEF suggests multiple explanatory pathophysiologic pathways that could be specifically investigated in future studies as follows. A detectable inflammatory process, defined as an increase in the native T1 value, may be due to encroachment by the parasite or an immunologic reaction already present in otherwise normal-appearing myocardial areas. Detectable diffuse myocardial fibrosis, defined as an increase in the ECV, that is already present in the remote myocardium may cause LV dysfunction and remodeling independently of focal myocardial fibrosis (LGE). The severity of the disease pathway in Chagas cardiomyopathy, being a chronic and progressive disease, might have the following sequential or simultaneous steps: an increase in remote native myocardial T1 and ECV values (inflammation and diffuse fibrosis), LGE positivity (focal myocardial fibrosis), and ventricular dysfunction. The final phenotype of Chagas cardiomyopathy might be dependent on these factors and how they interact, which should be investigated in future studies. These characteristics confer a singular pattern to Chagas cardiomyopathy, and the use of T1 mapping and ECV may serve as a tool for earlier diagnosis of myocardial involvement (39). The fact that the myocardial damage is most likely caused by an ongoing inflammatory process opens the possibility of using these techniques to monitor disease progression and investigate potential therapeutic targets to prevent advanced heart failure and death.

Our study had some limitations, including the use of a relatively small cohort from a single center and the absence of histologic correlations, T2 mapping images, and strain analysis. All end points were included on the basis of clinical and echocardiographic recommendations and are, in fact, not related to cardiac MRI findings. Imaging technique limitations, such as the sensitivity to artifacts, cardiac motion, and heart rate variability of the MOLLI sequence with a steady-state free precession–based readout, were minimized by evaluating image quality at the scanner and repeating acquisition as needed to obtain the best possible image quality. Carefully controlled region of interest positioning for myocardial T1 evaluation was performed by using delimitation of a myocardial region of interest, particularly avoiding contamination by blood and extracardiac structures, in participants with Chagas disease with thin and remodeled myocardial walls.

In conclusion, myocardial T1 and ECV values were elevated globally and in LGE-negative myocardial areas and correlated with disease severity in individuals with Chagas disease. Our prospective study demonstrated that higher remote native T1 values (>1100 msec) were significantly and independently predictive of major outcomes. Combining the Rassi score and native T1 value increased the predictive power for cardiovascular events and enabled clear differentiation of the degrees of disease severity. The cardiac MRI features evaluated in our study have the potential to unveil knowledge about the mechanisms of myocardial injury progression in Chagas disease, which remain poorly understood. Our results will likely motivate further investigations into pathophysiologic characteristics, therapeutic pathways, and advanced clinical risk stratification in Chagas disease, which might potentially improve patient prognosis.

Supported in part by the Zerbini Foundation.

Disclosures of conflicts of interest: R.J.L.M. No relevant relationships. A.N.A. No relevant relationships. T.C.M. No relevant relationships. C.H.N. No relevant relationships. M.I.S. No relevant relationships. M.M.F. No relevant relationships. F.J.A.R. No relevant relationships. F.F. No relevant relationships. B.M.I. No relevant relationships. C.M. No relevant relationships. C.E.R. Secretary-treasurer and board member of the Society for Cardiovascular Magnetic Resonance.

Abbreviations:

CCmrEF
Chagas cardiomyopathy with midrange ejection fraction
CCpEF
Chagas cardiomyopathy with preserved ejection fraction
CCrEF
Chagas cardiomyopathy with reduced ejection fraction
ECV
extracellular volume
ICD
implantable cardioverter defibrillator
LGE
late gadolinium enhancement
LV
left ventricular
LVEF
LV ejection fraction
MOLLI
modified Look-Locker inversion recovery

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