Abstract

Introduction:

The clinical–epidemiological profile of Chagas disease (CD) has changed over the past decades, leading to decreased levels of physical activity (PA), which may be associated with changes in markers of subclinical atherosclerosis. This study aimed to investigate the association between PA levels and carotid intima–media thickness (CIMT), the presence of carotid atherosclerotic plaque (CAP), and the amount of epicardial adipose tissue (EAT) in patients with chronic CD.

Methods:

This cross-sectional study included patients with chronic CD. The PA level was determined using the short version of the International Physical Activity Questionnaire (IPAQ-short). CIMT and CAP were assessed using Doppler ultrasound of the carotid arteries. The amount of EAT was assessed using transthoracic echocardiography. Linear and binomial logistic regression models were used.

Results:

The median age of the 349 participants was 62 years (54.0–69.0), 56.5% were women, and 79.5% were non-white, with 67.6% having <9 years of schooling. The most common clinical form of CD was the cardiac form without heart failure (HF) (53.9%). Median CIMT values were 0.65 mm (left) and 0.66 mm (right). CAP was present in 46.4% of participants, and the median EAT was 5.0 mm. No statistically significant association was observed between PA levels and CIMT, the presence of CAP, or the amount of EAT.

Conclusion:

PA levels were not associated with the markers of subclinical atherosclerosis in individuals with chronic CD.

Introduction

Chagas disease (CD) is a parasitic infectious disease caused by the flagellated protozoan Trypanosoma cruzi, affecting approximately 8 million people worldwide (1, 2). The main clinical manifestation of chronic CD is chronic Chagas cardiomyopathy (CCC), which occurs in 20–40% of infected individuals and is associated with high levels of morbidity and mortality (3, 4). This condition is characterized by clinical manifestations such as heart failure, thromboembolism, stroke, arrhythmias, cardiac conduction system block, and sudden death (4). The main non-cardiac complications of CD are megaesophagus and megacolon, which can occur in approximately 10–20% of cases (5).

Over the past decades, improvements in treatment have allowed many individuals with CD to live longer, resulting in an aging patient population (5). In parallel, many individuals with CD have migrated from rural areas to major urban centers, leading to lifestyle changes (6), such as reduced levels of physical activity (PA) (7), which, in turn, increase the risk of atherosclerosis and, consequently, cardiovascular diseases (8). Despite the widely known benefits of PA, low levels of PA are found in individuals with chronic health conditions, including CD (9). Considering that low PA levels are an important risk factor for cardiovascular health, it is necessary to evaluate whether PA levels are associated with markers of subclinical atherosclerosis, such as common carotid artery intima–media thickness (CIMT), carotid atherosclerotic plaques (CAPs), and the amount of epicardial adipose tissue (EAT), in patients with chronic CD. To the best of our knowledge, no previous study has explored this relationship in this population. Thus, this study aimed to investigate the association between PA levels and markers of subclinical atherosclerosis in individuals with chronic CD. We hypothesized that, among individuals with chronic CD, lower levels of PA would be associated with worse markers of subclinical atherosclerosis.

MethodsStudy design and population

This is an observational cross-sectional study conducted from June 2014 to March 2017, including participants of both sexes aged >18 years, with chronic CD diagnosed by two concurrently positive serological tests (enzyme-linked immunosorbent assay and indirect immunofluorescence). All patients were under clinical follow-up at the outpatient center of the Evandro Chagas National Institute of Infectious Disease/Oswaldo Cruz Foundation, a national reference center for the treatment and research of infectious and tropical diseases in Rio de Janeiro, Brazil. Participants were excluded if they presented with heart disease of non-Chagas etiology, autoimmune disorders, cancer, other infectious diseases at the time of study recruitment, severe cognitive impairments, current use of chronic anti-inflammatory agents or corticosteroids, or pregnancy.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki, revised in 2013, and with the Brazilian National Health Council Resolution 466/2012. The study was approved by the Institutional Review Board of the Evandro Chagas National Institute of Infectious Disease (CAAE: 22985313.8.0000.5262). All participants received information about the objectives and procedures of the study and agreed to participate by signing an informed consent form.

Study procedures and measurement tools

Patients were invited to participate during their regular clinic visits and were required to complete the study procedures in two visits within 1 month. During the first visit, patients signed the informed consent form and underwent assessments of sociodemographic, clinical, and lifestyle-related variables. During the second visit, Doppler ultrasound of the carotid arteries and transthoracic echocardiography were performed to assess CIMT, the presence of CAP, and the amount of EAT. Trained staff administered the questionnaires and performed the anthropometric measurements. The same cardiologist, blinded to the PA data, performed all Doppler ultrasound examinations of the carotid arteries and the transthoracic echocardiogram using a GE Medical Systems Vivid 7 vascular ultrasound device with a 7–10-MHz frequency transducer, as guided by an experienced echocardiographer who was also blinded to the PA data.

Physical activity assessment

The level of PA was determined using the short version of the International Physical Activity Questionnaire (IPAQ), adapted and validated for use in the Brazilian population (10, 11). The total volume of PA was calculated using metabolic equivalent of the task (MET)-min/week and stratified into tertiles for analytical purposes (high, intermediate, and low). To calculate the level of PA in MET-min/week, the MET value of each activity was multiplied by the total duration of the activity in minutes and then by the number of times the activity was performed per week. The MET values assigned were 3.3 METs for walking, 4.0 METs for moderate activities, and 8.0 METs for vigorous activities. The total volume of PA was calculated by summing the MET-min/week from walking, moderate activities, and vigorous activities, while the volume of moderate-to-vigorous PA was calculated by summing only the moderate and vigorous activities. The data were limited to a maximum time of 180 min per day, allowing a maximum of 21 h of PA per week for each category, as recommended in the IPAQ scoring protocol guidelines (12). The level of PA was also assessed as a continuous variable, considering the variation of each 100 MET-min/week, which represents approximately 20 min of brisk walking per week, or approximately 3 min of brisk walking per day, every day of the week.

Carotid intima–media thickness

The CIMT was assessed by echo-Doppler ultrasound of the distal common carotid artery, 2 cm from the carotid bifurcation, performed in both arteries (right and left) using a 7–10-MHz frequency transducer in a two-dimensional (2D) mode, with longitudinal and transverse sections. The CIMT was obtained by measuring the distance between two echogenic lines representing the lumen–intima and media–adventitia interfaces of the arterial wall (13).

Presence of carotid atherosclerotic plaque

The presence of CAP was assessed by Doppler ultrasound of the common and internal carotid arteries on both the right and left sides. Examinations were performed in 2D mode using transverse and longitudinal sections with a 7–10 MHz frequency transducer. The presence of CAP was defined as a focal wall thickening exceeding 50% of the surrounding carotid segment or a CIMT measurement greater than 1.5 mm (13).

Epicardial adipose tissue

The amount of EAT was assessed using a 3.5-MHz frequency transducer in two-dimensional mode. EAT thickness was calculated by measuring the echo-free space between the myocardium of the free wall of the right ventricle and the visceral pericardium at end-systole, perpendicular to the aortic annulus, in the parasternal echocardiographic window of the long axis (14).

Covariates

Sociodemographic, lifestyle, and clinical covariates were obtained to characterize the study population and address potential confounding factors in the studied associations. Information on age, sex, schooling, and ethnicity was obtained during the interviews. Age was calculated as the difference between the date of the interview and the date of birth and was considered as a continuous variable. Based on the formal years of study, schooling was categorized into < 9 years, 9–12 years, and > 12 years. Ethnicity was self-reported and categorized as white and non-white (Black, mixed ethnicity, Asian, and Indigenous individuals). Smoking status was classified as current/former smoker or never smoker. Alcohol consumption was categorized as current/former drinker or never drinker. Sleep hours were determined through a direct question and treated as a continuous variable. Food consumption was assessed using a 24-h recall that consisted of the identification and quantification of all food and beverages consumed on the day before the interview. Macronutrients were calculated using Diet Win Professional Version 2008 software.

Comorbidities (hypertension, diabetes, dyslipidemia, and obesity) were obtained using information from medical records and anthropometric measurements during the clinical evaluation. The clinical classification of CD was based on clinical, electrocardiographic, and digestive examinations, and participants were categorized as having the indeterminate form, CCC without heart failure, CCC with heart failure, or the digestive form, in accordance with the Brazilian Consensus on CD (15).

Data analysis

For descriptive data analysis, medians were used, with an interquartile range (25th–75th) for continuous variables and absolute frequencies and percentages for categorical variables. The comparison of clinical, sociodemographic, and lifestyle characteristics between tertiles of PA levels was performed using Cuzick’s trend tests for continuous variables and Jonckheere–Terpstra test for categorical variables. Linear regression and binomial logistic regression models were used to assess the association between PA levels (considered as a categorical variable [PA tertiles] and as a continuous variable [increments of 100 MET-min/week]) and CIMT and EAT (as continuous variables), as well as the presence of CAP (a binary categorical variable). Both unadjusted and adjusted models were fitted to account for potential confounding variables. The minimum set of adjustment variables was identified using a directed acyclic graph (DAG) and included age, sex, ethnicity, schooling, smoking, hypertension, diabetes mellitus, dyslipidemia, food intake (carbohydrates, lipids, and proteins), and stages of CCC (without CCC, CCC without HF, or CCC with HF), as illustrated in Supplementary Figure 1, created using the Dagitty program (available at https://dagitty.net/).

Results

Of the 397 patients initially included, 48 were excluded for the following reasons: 6 had other infectious diseases, 3 had autoimmune diseases, 6 had cancer, 8 had non-Chagas cardiomyopathy, 5 were using anti-inflammatory drugs or corticosteroids, 8 were lost to follow-up, and 12 had missing data for CIMT, CAP, or EAT, resulting in a final analytic sample of 349 participants (Supplementary Figure 2).

Table 1 shows the characteristics of patients, both overall and stratified by tertiles of total PA. The median age was 62 years, with approximately half (56.5%) of them being women and a predominance of <9 years of schooling (67.6%). The prevalence of comorbidities was 67.6% for hypertension, 53.9% for dyslipidemia, and 25.5% for obesity. The most common clinical form of CD was the cardiac form without HF, at 53.9%. The median total PA level was 1,548.0 MET-min/week, while moderate-to-vigorous PA had a median of 720.0 MET-min/week. The median CIMT was 0.65 mm on the left side and 0.66 mm on the right side. CAP was present in 46.4% of participants. The median EAT was 5.0 mm. Considering the characteristics according to the tertiles of PA, there was a trend toward lower age with higher levels of PA, along with reduced CIMT values and a lower proportion of patients with CAP (Table 1).

VariablesTotal
(n = 349; 100%)Total PA tertiles†p-value*Lowest
(n = 117; 33.6%)Intermediate
(n = 116; 33.2%)Highest
(n = 116; 33.2%)Age in years (median; IQR)62.0 (54.0–69.0)64.0 (56.0–71.0)63.0 (53.0–68.5)60.0 (51.5–65.0)<0.001Women (%; n)56.5 (197)59.0 (69)54.3 (63)56.0 (65)0.65White race (%; n)21.5 (75)21.4 (25)22.4 (26)20.7 (24)0.90Schooling (%; n)<9 years67.6 (236)70.9 (83)72.4 (84)59.5 (69)0.069–12 years18.6 (65)16.2 (19)17.2 (20)22.4 (26)0.22>12 years13.8 (48)12.8 (15)10.3 (12)18.1 (21)0.24Sleep hours (median; IQR)7.0 (6.0–8.0)7.0 (5.0–8.0)6.0 (5.3–8.0)7.0 (6.0–8.0)0.74Weight in kg (median; IQR)67.5 (59.4–78.6)66.3 (58.5–76.3)67.9 (60.2–79.4)68.3 (61.2–78.3)0.22Height in m (median; IQR)1.60 (1.53–1.65)1.57 (1.53–1.63)1.60 (1.53–1.65)1.60 (1.55–1.66)0.99BMI Kg/m2 (median; IQR)26.8 (23.9–30.0)26.3 (23.1–30.9)27.0 (24.3–30.2)27.0 (24.0–29.8)0.70Waist circumference in cm (median; IQR)89.9 (82.1–98.3)90.5 (81.2–97.2)90.5 (81.2–97.2)89.7 (80.8–98.7)0.80Number of comorbidities (median; IQR)2.0 (1.0–2.0)2.0 (1.0–3.0)2.0 (1.0–2.0)2.0 (1.0–2.0)0.15Hypertension (%; n)67.6 (236)66.7 (78)71.6 (83)64.7 (75)0.74Diabetes mellitus (%; n)20.9 (73)23.9 (28)19.8 (23)19.0 (22)0.35Dyslipidemia (%; n)53.9 (188)58.1 (68)55.2 (64)48.3 (56)0.13Obesity (%; n)25.5 (89)27.4 (32)26.7 (31)22.4 (26)0.38Previous use of benznidazole (%; n)9.2 (32)7.7 (9)10.3 (12)9.5 (11)0.63Smoking (%; n)46.7 (163)49.6 (58)51.7 (60)38.8 (45)0.10Alcohol consumption (%; n)39.5 (138)44.4 (52)37.0 (43)37.0 (43)0.24Food consumption in grams (median; IQR)Carbohydrates175.9 (137.6–240.2)175.0 (125.7–238.8)176.0 (138.8–237.0)184.6 (140.4–246.3)0.43Lipids34.9 (25.1–48.6)35.0 (27.3–49.0)32.7 (24.9–43.1)40.0 (21.7–51.6)0.76Proteins61.9 (45.8–81.2)48.3 (61.1–79.5)61.7 (44.0–81.4)65.5 (46.8–87.5)0.43Fiber16.6 (11.3–23.4)15.9 (11.2–23.0)16.7 (10.9–24.4)17.0 (11.7–23.0)0.58Clinical form (%; n)Indeterminate26.9 (94)22.2 (26)28.4 (33)30.2 (35)0.17Cardiac57.0 (199)53.9 (63)60.3 (70)56.9 (66)0.63Digestive3.7 (13)4.3 (5)4.3 (5)2.6 (3)0.49Mixed12.3 (43)19.7 (23)6.9 (8)10.3 (12)0.03CCC stage (%; n)Without CCC30.7 (107)26.5 (31)32.8 (38)32.8 (38)0.29CCC without HF (stages A, B1, and B2)53.9 (188)57.2 (67)49.1 (57)55.2 (64)0.74CCC with HF (stages C and D)15.5(54)16.2 (19)18.1 (21)12.0 (14)0.38Carotid intima–media thickness in mmLeft0.65 (0.58–0.76)0.68 (0.59–0.80)0.65 (0.57–0.76)0.61 (0.58–0.71)0.05Right0.66 (0.59–0.77)0.68 (0.60–0.80)0.66 (0.60–0.78)0.61 (0.57–0.73)0.01Carotid atherosclerotic plaque (%)46.4 (162)52.1 (61)47.4 (55)39.7 (46)0.05Epicardial adipose tissue in mm5.0 (4.0–6.0)5.0 (4.0–6.0)5.0 (4.0–6.0)4.0 (3.0–6.0)0.33

Characteristics of patients stratified by tertiles of total activity level (n = 349).

PA: physical activity; MET: metabolic equivalent of the task; IQR: interquartile range of 25–75%; BMI: body mass index; CCC: chronic Chagas disease; HF: heart failure. * Cuzixk’s test for trends in continuous variables/Jonckheere–Terpstra’s test for trends in categorical variables. † PA total MET-min/week (median; IQR: 25–75%): total: 1548.0 (690.0–3066.0); low: 462.0 (120.0–690.0); intermediate: 1561.5 (1271.0–1803.5); high: 4290.0 (3132.5–5733.0).

Table 2 shows the characteristics of CIMT, CAP, and EAT stratified by sex, age, and CCC stage groups. Overall, older individuals (≥65 years) showed higher CIMT values both on the left (0.61 vs. 0.71 mm; p < 0.0001) and the right (0.61 vs. 0.73 mm; p < 0.0001) sides and greater EAT (4.0 vs. 6.0 mm; p < 0.0001) than those aged < 65 years. Additionally, reduced EAT values were observed among individuals with CCC with heart failure compared to those without CCC and those with CCC without heart failure (4.0 vs 5.0 vs 5.0 mm, respectively; p < 0.04) (Table 2).

VariablesSexp-valueAgep-valueCCC stagep-valueMenWomen<65 years≥65 yearsWithout CCCCCC without HFCCC with HFCIMT (mm)Left0.68
(0.59–0.80)0.63
(0.58–0.74)0.100.61
(0.56–0.70)0.71
(0.60–0.90)<0.0010.61
(0.56–0.74)0.67
(0.60–0.79)0.66
(0.58–0.76)0.19Right0.63
(0.59–0.78)0.66
(0.58–0.76)0.700.61
(0.56–0.70)0.73
(0.64–0.88)<0.0010.63
(0.58–0.73)0.67
(0.60–0.79)0.64
(0.58–0.73)0.46CAP (%)44.1 (67)48.2 (95)0.4429.6 (63)72.8 (99)<0.00140.2 (43)52.7 (99)37.0 (20)0.66EAT (mm)4.5
(3.0–6.0)5.0
(4.0–6.0)0.074.0
(3.0–6.0)6.0
(4.0–7.0)<0.0015.0
(3.0–6.0)5.0
(4.0–6.0)4.0
(3.0–5.0)0.04

Characteristics of CIMT, CAP, and EAT stratified by groups of sex, age, and stages of CCC (n = 349).

CIMT: carotid intima–media thickness; CAP: carotid atherosclerotic plaque; EAT: epicardial adipose tissue in mm.

Table 3 shows the estimates for the association between total PA levels and CIMT, the presence of CAP, and the amount of EAT. In the unadjusted analysis, a statistically significant association was observed between the highest PA tertile and lower left (β = −0.49; 95%CI -0.93 to −0.005) and right (β = −0.05; 95%CI -0.09 to −0.01) CIMT. However, these associations did not remain statistically significant after adjusting for potential confounding variables (Table 3). Similar results were observed for the adjusted associations between total PA levels and CIMT, the presence of CAP, and the amount of EAT in the different subgroups of sex, age, and CCC stage (Figure 1).

Total PA tertiles (MET-min/week)Low
(n = 117)Intermediate
(n = 116)High
(n = 116)Continuous
Per 100 MET-min/week
(n = 349)β (95% CI)CIMT leftNot adjustedReference−0.29 (−0.73 to +0.15)−0.49 (−0.93 to −0.005)−0.0004 (−0.0001 to +0.0004)Adjusted*−0.01 (−0.05 to +0.03)−0.02 (−0.06 to +0.03)+0.0002 (−0.001 to +0.001)CIMT rightNot adjustedReference−0.01 (−0.05 to +0.03)−0.05 (−0.09 to −0.01)−0.001 (−0.002 to +0.0003)Adjusted*+0.01 (−0.03 to +0.05)−0.01 (−0.05 to +0.02)−0.0003 (−0.001 to +0.0004)EATNot adjustedReference+0.09 (−0.41 to +0.59)−0.15 (−0.65 to + 0.35)−0.01 (−0.02 to +0.001)Adjusted*+0.21 (−0.24 to +0.68)+0.16 (−0.30 to +0.63)−0.002 (−0.01 to +0.01)OR (95%CI)CAPNot adjustedReference0.82 (0.49 to 1.39)0.60 (0.36 to 1.01)0.99 (0.99 to 1.01)Adjusted*1.19 (0.63 to 2.21)1.04 (0.55 to 1.96)1.00 (0.99 to 1.02)Moderate-to-vigorous PA Tertiles (MET-min/week)Low
(n = 117)Intermediate
(n = 116)High
(n = 116)Continuous
Per 100 MET-min/week
(n = 349)β (95% CI)CIMT leftNot adjustedReference−0.008 (−0.05 to +0.04)−0.04 (−0.09 to +0.001)−0.0006 (−0.002 to +0.0004)Adjusted*+0.01 (−0.03 to +0.06)−0.01 (−0.05 to +0.03)+0.0002 (−0.0008 to +0.001)CIMT rightNot adjustedReference−0.01 (−0.05 to +0.03)−0.05 (−0.09 to −0.06)−0.001 (−0.002 to −0.0002)Adjusted*+0.02 (−0.02 to +0.05)−0.006 (−0.04 to +0.03)−0.0001 (−0.001 to +0.001)EATNot adjustedReference+0.07 (−0.42 to +0.60)−0.25 (−0.75 to +0.26)−0.01 (−0.02 to +0.0005)Adjusted*+0.30 (−0.16 to +0.76)+0.04 (−0.43 to +0.51)−0.005 (−0.02 to +0.01)OR (95%CI)CAPNot adjustedReference0.63 (0.38 to 1.05)0.71 (0.42 to 1.20)0.99 (0.98 to 1.01)Adjusted*0.88 (0.47 to 1.63)1.26 (0.67 to 2.38)1.01 (0.99 to 1.03)

Estimates for the association of total PA level with CIMT, the amount of EAT, and the presence of CAP in patients with CD (n = 349).

*Adjusted for age, sex, race, schooling, smoking, hypertension, diabetes, dyslipidemia, food intake (carbohydrates, lipids, and proteins), and stages of CCC (without CCC, CCC without HF, and CCC with HF); CIMT: carotid intima–media thickness; CAP: carotid atherosclerotic plaque; EAT: epicardial adipose tissue.

Forest plots for the adjusted associations between total PA levels and the amount of EAT, CIMT (left and right), and the presence of CAP in the different subgroups of sex, age, and CCC stage.

Table 3 shows the estimates for the association of moderate-to-vigorous PA levels with CIMT, the presence of CAP, and the amount of EAT. In the unadjusted analyses, a statistically significant association was observed between the highest tertile of PA and lower CIMT in the right carotid artery (β = −0.05; 95% CI -0.09 to −0.06), as well as an association for each increment of 100 MET × minutes per week (β = −0.001; 95% CI -0.002 to −0.0002). However, these associations were not statistically significant after adjustments for potential confounding variables (Table 3).

Discussion

To the best of our knowledge, this is the first study to investigate markers of subclinical atherosclerosis (CIMT, CAP, and EAT) in patients with CD and to evaluate their relationship with PA levels. Our findings revealed CIMT values similar to those reported in other populations in the literature, particularly among asymptomatic adults from low- and middle-income countries (16). These results are also consistent with data from the Brazilian population, as demonstrated by the ELSA-Brasil study (