The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)

Marcelo Carvalho Vieira; Fernanda de Souza Nogueira Sardinha Mendes; Paula Simplício da Silva; Gilberto Marcelo Sperandio da Silva; Flavia Mazzoli-Rocha; Andrea Silvestre de Sousa; Roberto Magalhães Saraiva; Marcel de Souza Borges Quintana; Henrique Silveira Costa; Vitor Barreto Paravidino; Luiz Fernando Rodrigues, Junior; Alejandro Marcel Hasslocher-Moreno; Pedro Emmanuel Alvarenga Americano do Brasil; Mauro Felippe Felix Mediano

doi:10.1371/journal.pone.0279086

. 2022 Dec 15;17(12):e0279086. doi: 10.1371/journal.pone.0279086

The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)

Marcelo Carvalho Vieira ^1,^2,^*, Fernanda de Souza Nogueira Sardinha Mendes ¹, Paula Simplício da Silva ¹, Gilberto Marcelo Sperandio da Silva ¹, Flavia Mazzoli-Rocha ¹, Andrea Silvestre de Sousa ¹, Roberto Magalhães Saraiva ¹, Marcel de Souza Borges Quintana ¹, Henrique Silveira Costa ³, Vitor Barreto Paravidino ^4,⁵, Luiz Fernando Rodrigues Junior ^6,⁷, Alejandro Marcel Hasslocher-Moreno ¹, Pedro Emmanuel Alvarenga Americano do Brasil ¹, Mauro Felippe Felix Mediano ^1,⁶

Editor: Gerson Cipriano Jr⁸

¹Evandro Chagas National Institute of Infectious Disease, Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil

²Center for Cardiology and Exercise, Aloysio de Castro State Institute of Cardiology, Rio de Janeiro, Rio de Janeiro, Brazil

³Department of Physical Therapy, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, Minas Gerais, Brazil

⁴Institute of Social Medicine, State University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil

⁵Department of Physical Education and Sports, Naval Academy, Rio de Janeiro, Rio de Janeiro, Brazil

⁶Department of Research and Education, National Institute of Cardiology, Rio de Janeiro, Rio de Janeiro, Brazil

⁷Department of Physiological Sciences, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil

⁸University of Brasilia, BRAZIL

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: vieiramc@yahoo.com.br

Roles

Marcelo Carvalho Vieira: Formal analysis, Visualization, Writing – original draft, Writing – review & editing

Fernanda de Souza Nogueira Sardinha Mendes: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Writing – review & editing

Paula Simplício da Silva: Conceptualization, Data curation, Investigation, Writing – review & editing

Gilberto Marcelo Sperandio da Silva: Conceptualization, Data curation, Investigation, Writing – review & editing

Flavia Mazzoli-Rocha: Writing – review & editing

Andrea Silvestre de Sousa: Conceptualization, Data curation, Investigation, Writing – review & editing

Roberto Magalhães Saraiva: Conceptualization, Data curation, Investigation, Writing – review & editing

Marcel de Souza Borges Quintana: Formal analysis, Writing – review & editing

Henrique Silveira Costa: Writing – review & editing

Vitor Barreto Paravidino: Writing – review & editing

Luiz Fernando Rodrigues Junior: Writing – review & editing

Alejandro Marcel Hasslocher-Moreno: Conceptualization, Data curation, Investigation, Writing – review & editing

Pedro Emmanuel Alvarenga Americano do Brasil: Conceptualization, Data curation, Investigation, Writing – review & editing

Mauro Felippe Felix Mediano: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Gerson Cipriano Jr: Editor

PMCID: PMC9754173 PMID: 36520825

Abstract

Studies investigating the association between functional capacity and quality of life (QoL) in individuals with chronic Chagas cardiomyopathy (CCC) usually do not include a gold-standard evaluation of functional capacity, limiting the validity and the interpretation of the results. The present study is a cross-section analysis aiming to evaluate the association between functional capacity (quantified by cardiopulmonary exercise test [CPET]) and QoL in individuals with CCC. QoL was assessed using the SF-36 questionnaire. Sociodemographic, anthropometric, clinical, cardiac function and maximal progressive CPET variables were obtained from PEACH study. Generalized linear models adjusted for age, sex, and left ventricular ejection fraction were performed to evaluate the association between CPET variables and QoL. After adjustments, VO₂ peak and VO₂ AT were both associated with physical functioning (β = +0.05 and β = +0.05, respectively) and physical component summary (β = +0.03 and β = +0.03, respectively). Double product was associated with physical functioning (β = +0.003), general health perceptions (β = +0.003), physical component summary (β = +0.002), and vitality (β = +0.004). HRR≤12bpm was associated with physical functioning (β = -0.32), role limitations due to physical problems (β = -0.87), bodily pain (β = -0.26), physical component summary (β = -0.21), vitality (β = -0.38), and mental health (β = -0.19). VE/VCO₂ slope presented association with all mental scales of SF-36: vitality (β = -0.028), social functioning (β = -0.024), role limitations due to emotional problems (β = -0.06), mental health (β = -0.04), and mental component summary (β = -0.02). The associations between CPET variables and QoL demonstrate the importance of CPET inclusion for a more comprehensive evaluation of individuals with CCC. In this setting, intervention strategies aiming to improve functional capacity may also promote additional benefits on QoL and should be incorporated as a treatment strategy for patients with CCC.

Introduction

Chagas disease (CD) is a parasitic infection caused by the protozoan Trypanosoma cruzi [1] and considered a neglected disease by the World Health Organization [2]. Traditionally restricted to rural underdeveloped areas of Central and South America, the increase of migratory flow observed in last decades transformed CD into a health issue in several nonendemic countries [1,3].

During the chronic phase, approximately 20 to 40% of the CD infected individuals may develop the cardiac form of the disease, a condition usually known as chronic Chagas cardiomyopathy (CCC) [4,5]. CCC is characterized by a persistent inflammatory process and the development of myocardial fibrosis, leading to arrhythmias, thromboembolism, and heart failure (HF) [5,6] that negatively impact the quality of life (QoL).

Recently, improvements on QoL have become a therapeutic goal for the management of patients with several chronic diseases, with its evaluation gaining progressively importance [7,8], despite the lack of standardization of the results from longitudinal analysis which may compromise the comparison of results between trials and jeopardize their clinical applications [9]. QoL can predict death and hospitalization in individuals with HF [10], as well as adverse cardiovascular outcomes in CCC patients [11]. Individuals with CD present lower scores of QoL [12–19] and individuals with CCC present lower QoL when compared to healthy individuals [14], to those with the indeterminate form of CD [12,16], and to those with HF from other etiologies [15,20,21].

The association between functional capacity and QoL has been previously demonstrated in individuals with HF [22] and CCC [23–30]. However, studies investigating this association in individuals with CCC usually included submaximal evaluations and indirect measures of functional capacity, limiting the validity and the interpretation of the results obtained until now. Therefore, the study of the association between QoL and functional capacity measured by cardiopulmonary exercise test (CPET), the gold standard method that directly assesses functional capacity by gas exchange ratio [31], can provide a more accurate and precise information of individuals with CCC, allowing the development of tailored strategies to improve QoL in this population.

Methods

Study design

This is a secondary analysis using cross-sectional baseline data from PEACH study, a single center, superiority randomized parallel-group clinical trial of exercise training versus a control group with no exercise training, conducted from March 2015 to January 2017 at the Evandro Chagas National Institute of Infectious Diseases (INI) of Oswaldo Cruz Foundation (Fiocruz). The sample comprised 30 CD patients (confirmed by two distinct serological tests) of both sexes, older than 18 years, with CCC, left ventricular ejection fraction (LVEF) <45% or HF symptoms (CCC stages B2 or C), New York Heart Association class I or II for at least three months, and clinically stable and under optimal medical therapy according to HF guidelines for at least six weeks. Exclusion criteria were motor or musculoskeletal limitations that preclude the exercise training, pregnancy, unavailability to attend exercise sessions 3 times a week, practice of regular exercise training (>1 week) in the three months prior to the study, smoking, or evidence of non-CCC cardiomyopathies. A complete description and the main results of the PEACH study have been previously published [32,33].

Measurements

Sociodemographic and clinical variables were assessed during the initial assessment, together with a maximal progressive CPET, QoL questionnaire, anthropometric and cardiac function evaluations, which were performed within a one-week range.

Sociodemographic variables were obtained through interviews and included age, sex, income, schooling, and self-reported race. Income was stratified into two categories (<2 and ≥2 minimum wages per month). Schooling included the years of formal study, stratified into three categories (<5 years, 5–9 years, and >9 years). Clinical variables were obtained from medical records and included stage of CCC, presence of arterial hypertension, diabetes mellitus, dyslipidemia, history of stroke, presence of arrhythmias, cardiac devices, and medications.

QoL was assessed using the Medical Outcomes Study 36-Item Short-form of Health Survey (SF-36) questionnaire [34,35], translated into Portuguese and validated for the Brazilian population [36], by a single interviewer. SF-36 is a generic multidimensional instrument, composed of 36 questions, referring to the four-week period prior to the interview, and divided into eight different scales: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and mental health. These scales define two summary scores: physical component summary (PCS) and mental component summary (MCS). Participants receive a final score ranging from zero (worst QoL) to 100 (best QoL) [34,35].

Maximal symptom-limited CPET was performed in a treadmill (Inbramed, Brazil) with a ramp protocol and active recovery, using a VO₂₀₀₀ gas analyzer (MedGraphics, St. Paul, MN) connected to a computerized Ergo PC Elite system (Micromed, Brazil), with patients under use of their standard medications. The following CPET variables were assessed: oxygen consumption at peak of exercise (VO₂ peak), percent achieved of predicted oxygen uptake at peak of exercise (%PPVO₂), oxygen consumption at anaerobic threshold (VO₂ AT), double product, minute ventilation-carbon dioxide production relationship (VE/VCO₂ slope), O₂ pulse, oxygen uptake efficiency slope (OUES), and heart rate recovery at the first minute (HRR). The VO₂ peak was defined as the highest value 30 seconds before or after the maximum effort or the plateau in oxygen uptake, and the anaerobic threshold (AT) by the V-slope method together with the ventilatory equivalents for VO₂ and carbon dioxide production (VCO₂), used to identify ventilatory thresholds [37]. The double product was calculated as a product of heart rate and systolic blood pressure at the peak of exercise. HRR was defined as the difference between maximal exercise heart rate and the heart rate at the first minute in the recovery phase, stratified into two categories (≤12 beats and >12 beats) [38]. The Ergo PC Elite software determined the other variables obtained on the CPET.

The anthropometric evaluation consisted of measurements of height, weight, and waist-to-hip ratio [39]. Body mass index (BMI) was calculated as the ratio of weight (kg) to height squared (m²) and classified according to WHO definition [40].

Cardiac function was assessed by transthoracic echocardiogram following the American Society of Echocardiography recommendations, using a phased-array ultrasound system (Vivid 7, GE Medical Systems, Milwaukee, WI) equipped with a M4S phased-array transducer [41]. LVEF was determined using the modified Simpson’s rule.

Data analysis

Descriptive analysis of sociodemographic, anthropometric, clinical, cardiac function and CPET variables consisted of mean and standard deviation for continuous variables and frequency and percentage for categorical variables. Descriptive analysis of QoL scores consisted of mean, standard deviation and range. The association between CPET variables (exposure variables) and QoL scales (outcomes) was determined by generalized linear models with gamma distribution and log-link function that accounts for skewed and heteroscedastic residuals distribution. Regression models were performed without adjustments and adjusted for age, sex, and LVEF that were considered as potential confounders according to the literature [5]. The partial eta-squared (partial η2), the proportion of variance in the dependent variable explained by each term in the model, were determined for each CPET variable in separate unadjusted and adjusted models.

The Research Electronic Data Capture (REDCap) web application was used for data management and the data analysis was conducted using R software (version 3.6.2). An association matrix graph was built to visually demonstrate the eta-squared for the association between CPET variables and scales and summary scores of SF-36 using the command ggplot2 in R Studio software. Statistical significance was set at p≤0.05 for all analyses.

Ethical considerations

All participants read and signed a written informed consent, and received information about the goals and procedures of the study. The study was performed in accordance with the resolution 466/2012 of the Brazilian National Council of Health and was approved by the Evandro Chagas National Institute of Infectious Diseases Research Ethics Committee (CAAE: 38038914.6.0000.5262; report number 3.165.034) in February 27^th, 2015. The clinical trial was registered at ClinicalTrials.gov (NCT02517632).

Results

The characteristics of the patients included in the study are shown in Table 1. Briefly, the mean age was 59.8 ± 10.0 years, with 66.7% males, 60.0% non-white, 56.7% in the low-income group, and 86.7% had up to nine years of schooling. The majority (73.3%) was classified as stage C of CCC (with HF).

Table 1. Characteristics of participants included in the study (n = 30).

Variable	Frequency (percentage) or Mean ±standard deviation
Sociodemographic variables
Age (years)	59.8 ±10.0
Sex (%)
Female	10 (33.3)
Male	20 (66.7)
Income (%)
< 2 minimum wage	17 (56.7)
≥ 2 minimum wage	13 (43.3)
Schooling (%)
<5 years	13 (43.3)
5–9 years	13 (43.3)
>9 years	4 (13.3)
Race (%)
White	12 (40.0)
Mulatto	14 (46.7)
Black	3 (10.0)
Indigenous	1 (3.3)
Clinical variables
Clinical form of CCC (%)
B2 (without heart failure)	8 (26.7)
C (with heart failure)	22 (73.3)
Hypertension (%)	1 (3.3)
Diabetes Mellitus (%)	5 (16.7)
Dyslipidemia (%)	8 (30.0)
Previous stroke (%)	5 (16.7)
Arrhythmia (%)	22 (73.3)
Cardiac device (%)	14 (46.7)
LVEF (%)	33.1 ±7.8
Medications (%)^†
Beta-blocker	28 (93.3)
Diuretics	22 (73.3)
Angiotensin-converting enzyme inhibitors	16 (53.3)
Aldosterone antagonist	15 (50.0)
Anticoagulants	14 (46.7)
Angiotensin receptor blockers	12 (40.0)
Digital	7 (23.3)
Amiodarone	6 (20.0)
Anthropometric variables
Weight (Kg)	66.5 ±14.0
Height (m)	1.60 ±0.1
BMI (Kg/m²)	25.4 ±5.2
BMI classification (%)
Underweight	2 (6.7)
Eutrophic	14 (46.7)
Overweight	9 (30.0)
Obese	5 (16.7)
Waist-to-hip ratio
Female	0.88 ±0.09
Male	0.92 ±0.07
CPET variables
VO₂ peak (ml.kg^-1.min^-1)	16.5 ±5.6
%PPVO₂	55.5 ±15.6
VO₂ AT (ml.kg^-1.min^-1)^¥	14.8 ±4.2
Double product (mmHg.bpm) x10²	135.5 ±50.7
O₂ Pulse (L/sys)	10.1 ±3.6
VE/VCO₂ slope	29.3 ±6.3
OUES	1.4 ±0.7
HRR ≤ 12 bpm (%)	53.3 (16)

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CCC: Chronic Chagas cardiomyopathy; LVEF: Left ventricular ejection fraction; BMI: Body mass index; CPET: Cardiopulmonary exercise test; VO₂ peak: Oxygen consumption at peak exercise; %PPVO₂: Percent achieved of predicted oxygen uptake at peak exercise; VO₂ AT: Oxygen consumption at anaerobic threshold; VE/VCO2 slope: Minute ventilation-carbon dioxide production relationship; OUES: Oxygen uptake efficiency slope; HRR: First-minute heart rate recovery.

^¥ VO₂ AT: n = 17.

^† Medications: Beta-blocker: Carvedilol; Diuretics: Furosemide and hydrochlorothiazide; Angiotensin-converting enzyme inhibitors: Enalapril and captopril; Aldosterone antagonist: Spironolactone; Anticoagulants: Warfarin; Angiotensin receptor blockers: Losartan; Digital: Digoxin.

The prevalence of hypertension was 3.3%, diabetes mellitus was 16.7%, dyslipidemia was 30.0%, and history of stroke was 16.7%. Most participants (73.3%) presented arrhythmia and 46.7% used a cardiac device. The mean LVEF was 33.1% (± 7.8). Regarding medications in use, 93.3% of the participants were treated with beta-blockers, 93.3% with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 50% with aldosterone antagonist, and 73.3% were taking diuretics. For the variables from CPET, the mean VO₂ peak was 16.5 (± 5.6) ml.kg^-1.min^-1, VO₂ AT was 14.8 (± 4.2) ml.kg^-1.min^-1, and VE/VCO₂ slope was 29.3 (± 6.3). Sixteen individuals (53.3%) presented HRR equal to or lesser than 12 bpm (Table 1).

The description of QoL scores by each scale is depicted in Table 2. Overall, patients presented lower scores for the scales related to physical aspects in comparison to those related to mental aspects. The role limitations due to physical problems (60.0 ± 45.3) and general health perceptions (62.2 ± 22.2) presented the lowest scores, while social functioning (83.1 ± 23.6) and mental health (81.2 ± 20.2) achieved the highest scores. The summary scores were 43.0 (± 9.8) for PCS and 53.0 (± 11.7) for MCS.

Table 2. Quality of life assessed by SF-36 (n = 30).

Variable	Mean ±standard deviation	Range
SF-36 QoL Scales
Physical functioning	65.8 ±26.5	15–100
Role limitations due to physical problems	60.0 ±45.3	0–100
Bodily pain	73.5 ±23.6	31–100
General health perceptions	62.2 ±22.2	25–100
Physical Component Summary	43.0 ±9.8	24–59
Vitality	66.8 ±26.8	5–100
Social functioning	83.1 ±23.6	13–100
Role limitations due to emotional problems	65.6 ±43.3	0–100
Mental health	81.2 ±20.2	12–100
Mental Component Summary	53.0 ±11.7	19–66

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SF-36: Medical Outcomes Study 36-Item Short-form of Health Survey; QoL: Quality of life.

Table 3 presents the association between CPET variables and physical scales of QoL. After adjustments for potential confounders, VO₂ peak and VO₂ AT were both positively associated with physical functioning (β = +0.05 95%CI +0.03 to +0.07 and β = +0.05 95%CI +0.02 to +0.08, respectively) and PCS (β = +0.03 95%CI +0.01 to +0.05 and β = +0.03 95%CI +0.01 to +0.06, respectively). Double product was positively associated with physical functioning (β = +0.003 95%CI +0.000 to +0.007), general health perceptions (β = +0.003 95%CI +0.000 to +0.006), and PCS (β = +0.002 95%CI +0.000 to +0.004), whilst HRR ≤ 12 bpm was negatively associated with physical functioning (β = -0.32 95%CI -0.61 to -0.04), role limitations due to physical problems (β = -0.87 95%CI -1.53 to -0.21), bodily pain (β = -0.26 95%CI -0.49 to -0.04), and PCS (β = -0.21 95%CI -0.38 to -0.05). The CPET variables that most explained the QoL variation in the adjusted models were VO₂ AT (50% for physical functioning and 36% for PCS) and VO₂ peak (31% for physical functioning and 21% for PCS).

Table 3. Association between CPET variables and QoL physical related scales.

CPET variables	SF-36 Physical functioning domain
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.05 (+0.03 to +0.07)	0.38	+0.05 (+0.02 to +0.09)	0.31
%PPVO₂	+0.02 (+0.01 to +0.03)	0.42	+0.02 (+0.01 to +0.03)	0.33
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.04 (+0.02 to +0.06)	0.48	+0.05 (+0.02 to +0.08)	0.50
Double product (x10^-2)	+0.004 (+0.001 to +0.007)	0.21	+0.003 (+0.000 to +0.007)	0.15
O₂ Pulse (ml/sys)	+0.036 (-0.005 to +0.076)	0.10	+0.022 (-0.026 to +0.069)	0.03
VE/VCO₂ slope	-0.024 (-0.047 to -0.001)	0.13	-0.018 (-0.044 to +0.009)	0.06
OUES (x10^-3)	+0.29 (+0.07 to +0.50)	0.19	+0.24 (-0.06 to +0.54)	0.09
HRR ≤ 12 bpm (%)	-0.23 (-0.52 to +0.06)	0.08	-0.32 (-0.61 to -0.04)	0.16
	SF-36 Role limitations due to physical problems scale
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.05 (-0.01 to +0.10)	0.09	+0.06 (-0.02 to +0.15)	0.09
%PPVO₂	+0.021 (+0.001 to +0.041)	0.13	+0.023 (-0.004 to +0.050)	0.10
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.055 (-0.003 to +0.114)	0.19	+0.065 (-0.017 to +0.146)	0.17
Double product (x10^-2)	+0.006 (0.000 to +0.012)	0.11	+0.006 (-0.001 to +0.013)	0.10
O₂ Pulse (ml/sys)	+0.04 (-0.04 to +0.12)	0.04	+0.03 (-0.06 to +0.13)	0.02
VE/VCO₂ slope	-0.02 (-0.07 to +0.02)	0.03	-0.02 (-0.07 to +0.03)	0.02
OUES (x10^-3)	+0.41 (-0.04 to +0.86)	0.10	+0.46 (-0.18 to +1.09)	0.07
HRR ≤ 12 bpm (%)	-0.52 (-1.11 to +0.08)	0.09	-0.87 (-1.53 to -0.21)	0.21
	SF-36 Bodily pain scale
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.020 (-0.001 to +0.041)	0.11	+0.01 (-0.02 to +0.04)	0.02
%PPVO₂	+0.005 (-0.003 to +0.012)	0.05	+0.004 (-0.005 to +0.014)	0.03
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.02 (-0.01 to +0.05)	0.14	+0.01 (-0.03 to +0.05)	0.02
Double product (x10^-2)	+0.002 (-0.001 to +0.004)	0.07	+0.002 (0.000 to +0.005)	0.13
O₂ Pulse (ml/sys)	0.00 (-0.03 to +0.03)	0.00	-0.01 (-0.05 to +0.03)	0.01
VE/VCO₂ slope	-0.017 (-0.035 to +0.002)	0.10	-0.014 (-0.035 to +0.007)	0.06
OUES (x10^-3)	+0.07 (-0.11 to +0.25)	0.02	+0.04 (-0.19 to +0.28)	0.01
HRR ≤ 12 bpm (%)	-0.14 (-0.38 to +0.09)	0.05	-0.26 (-0.49 to -0.04)	0.18
	SF-36 General health perceptions scale
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.01 (-0.01 to +0.03)	0.02	+0.02 (-0.01 to +0.06)	0.07
%PPVO₂	+0.005 (-0.003 to +0.013)	0.05	+0.007 (-0.004 to +0.018)	0.05
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.03 (-0.01 to +0.06)	0.11	+0.047 (-0.004 to +0.098)	0.22
Double product (x10^-2)	+0.003 (0.000 to +0.005)	0.15	+0.003 (0.000 to +0.006)	0.16
O₂ Pulse (ml/sys)	+0.02 (-0.01 to +0.06)	0.06	+0.03 (-0.01 to +0.07)	0.07
VE/VCO₂ slope	-0.01 (-0.03 to +0.01)	0.05	-0.02 (-0.04 to +0.01)	0.06
OUES (x10^-3)	+0.15 (-0.04 to +0.35)	0.08	+0.26 (-0.02 to +0.53)	0.12
HRR ≤ 12 bpm (%)	-0.27 (-0.52 to -0.01)	0.13	-0.27 (-0.54 to +0.01)	0.12
	SF-36 Physical Component Summary
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.02 (+0.01 to +0.03)	0.21	+0.03 (+0.01 to +0.05)	0.21
%PPVO2	+0.007 (+0.002 to +0.012)	0.23	+0.008 (+0.002 to +0.015)	0.21
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.023 (+0.005 to +0.041)	0.29	+0.032 (+0.008 to +0.057)	0.36
Double product (x10^-2)	+0.002 (+0.001 to +0.004)	0.22	+0.002 (0.000 to +0.004)	0.20
O₂ Pulse (ml/sys)	+0.02 (-0.01 to +0.04)	0.06	+0.01 (-0.02 to +0.04)	0.03
VE/VCO₂ slope	-0.01 (-0.02 to +0.01)	0.04	-0.01 (-0.02 to +0.01)	0.02
OUES (x10^-3)	+0.14 (+0.01 to +0.26)	0.14	+0.15 (-0.02 to +0.32)	0.11
HRR ≤ 12 bpm (%)	-0.18 (-0.34 to -0.02)	0.15	-0.21 (-0.38 to -0.05)	0.21

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Estimates in bold are statistically significant.

^§Model adjusted for age, sex, and left ventricular ejection fraction.

^¥VO₂ AT: n = 17.

CPET: Cardiopulmonary exercise test; QoL: Quality of Life; SF-36: Medical Outcomes Study 36-Item Short-form of Health Survey; VO₂ peak: Oxygen consumption at peak exercise; %PPVO₂: Percent achieved of predicted oxygen uptake at peak exercise; VO₂ AT: Oxygen consumption at anaerobic threshold; VE/VCO₂ slope: Minute ventilation-carbon dioxide production relationship; OUES: Oxygen uptake efficiency slope; HRR: First-minute heart rate recovery.

The association between CPET variables and mental scales of QoL is presented in Table 4. After adjustments for potential confounders, VE/VCO₂ slope presented a negative association with all mental scales of SF-36: vitality (β = -0.028 95%CI -0.055 to -0.002), social functioning (β = -0.024 95%CI -0.044 to -0.003), role limitations due to emotional problems (β = -0.06 95%CI -0.12 to +0.01), mental health (β = -0.04 95%CI -0.06 to -0.02), and MCS (β = -0.02 95%CI -0.04 to -0.01). HRR ≤ 12 bpm was negatively associated with vitality (β = -0.38 95%CI -0.68 to -0.08) and mental health (β = -0.19 95%CI -0.38 to -0.01). Double product was positively associated with vitality (β = +0.004 95%CI 0.000 to +0.007). The CPET variables that most explained the QoL variation in the adjusted models were VE/VCO₂ slope (45% for mental health and 31% for MCS) and HRR ≤ 12 bpm (20% for vitality).

Table 4. Association between CPET variables and QoL mental related scales.

CPET variables	SF-36 Vitality scale
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.03 (+0.003 to +0.055)	0.14	+0.03 (-0.01 to +0.07)	0.09
%PPVO₂	+0.012 (+0.002 to +0.021)	0.17	+0.010 (-0.002 to +0.022)	0.09
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.02 (-0.01 to +0.05)	0.08	+0.02 (-0.03 to +0.06)	0.05
Double product (x10^-2)	+0.004 (+0.001 to +0.007)	0.18	+0.004 (0.000 to +0.007)	0.15
O₂ Pulse (ml/sys)	+0.02 (-0.02 to +0.06)	0.04	+0.02 (-0.03 to +0.07)	0.02
VE/VCO₂ slope	-0.029 (-0.052 to -0.006)	0.18	-0.028 (-0.055 to -0.002)	0.15
OUES (x10^-3)	+0.19 (-0.03 to +0.42)	0.09	+0.18 (-0.13 to +0.49)	0.05
HRR ≤ 12 bpm (%)	-0.28 (-0.58 to +0.02)	0.11	-0.38 (-0.68 to -0.08)	0.20
	SF-36 Social functioning scale
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.016 (-0.003 to +0.035)	0.09	+0.010 (-0.018 to +0.038)	0.02
%PPVO₂	+0.005 (-0.002 to +0.012)	0.06	+0.004 (-0.005 to +0.013)	0.03
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.02 (-0.01 to +0.05)	0.09	+0.01 (-0.04 to +0.05)	0.01
Double product (x10^-2)	+0.002 (0.000 to +0.004)	0.08	+0.002 (-0.001 to +0.004)	0.09
O₂ Pulse (ml/sys)	0.00 (-0.03 to +0.03)	0.00	-0.02 (-0.05 to +0.02)	0.03
VE/VCO₂ slope	-0.024 (-0.040 to -0.007)	0.21	-0.024 (-0.044 to -0.003)	0.17
OUES (x10^-3)	+0.09 (-0.06 to +0.25)	0.05	+0.06 (-0.17 to +0.29)	0.01
HRR ≤ 12 bpm (%)	-0.14 (-0.35 to +0.06)	0.06	-0.22 (-0.45 to +0.01)	0.12
	SF-36 Role limitations due to emotional problems scale
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.041 (-0.005 to +0.087)	0.10	+0.030 (-0.042 to +0.102)	0.03
%PPVO₂	+0.016 (-0.001 to +0.033)	0.11	+0.011 (-0.012 to +0.035)	0.03
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.04 (-0.01 to +0.09)	0.13	+0.01 (-0.08 to +0.09)	0.00
Double product (x10^-2)	+0.005 (-0.001 to +0.010)	0.10	+0.007 (0.000 to +0.014)	0.13
O₂ Pulse (ml/sys)	+0.04 (-0.03 to +0.11)	0.05	+0.03 (-0.06 to +0.12)	0.02
VE/VCO₂ slope	-0.05 (-0.10 to -0.01)	0.18	-0.06 (-0.12 to -0.01)	0.16
OUES (x10^-3)	+0.29 (-0.08 to +0.67)	0.08	+0.32 (-0.27 to +0.91)	0.04
HRR ≤ 12 bpm (%)	-0.16 (-0.64 to +0.31)	0.02	-0.36 (-0.96 to +0.24)	0.05
	SF-36 Mental health scale
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.013 (-0.003 to +0.030)	0.08	+0.006 (-0.017 to +0.029)	0.01
%PPVO₂	+0.006 (0.000 to +0.012)	0.12	+0.003 (-0.005 to +0.010)	0.02
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.012 (-0.021 to +0.045)	0.03	-0.002 (-0.047 to +0.042)	0.00
Double product (x10^-2)	+0.001 (0.000 to +0.003)	0.07	+0.001 (-0.001 to +0.003)	0.05
O₂ Pulse (ml/sys)	+0.01 (-0.01 to +0.04)	0.02	+0.01 (-0.02 to +0.04)	0.01
VE/VCO₂ slope	-0.04 (-0.05 to -0.02)	0.44	-0.04 (-0.06 to -0.02)	0.45
OUES (x10^-3)	+0.10 (-0.04 to +0.24)	0.07	+0.08 (-0.11 to +0.27)	0.03
HRR ≤ 12 bpm (%)	-0.12 (-0.31 to +0.06)	0.06	-0.19 (-0.38 to -0.01)	0.15
	SF-36 Mental Component Summary
	Unadjusted		Adjusted^§
	β (95% CI)	eta-squared	β (95% CI)	eta-squared
VO₂ peak (ml.kg^-1.min^-1)	+0.010 (-0.004 to +0.025)	0.06	+0.005 (-0.016 to +0.025)	0.01
%PPVO₂	+0.004 (-0.001 to +0.010)	0.09	+0.002 (-0.005 to +0.009)	0.01
VO₂ AT (ml.kg^-1.min^-1)^¥	+0.01 (-0.02 to +0.04)	0.03	-0.01 (-0.04 to +0.03)	0.01
Double product (x10^-2)	+0.001 (0.000 to + 0.003)	0.09	+0.001 (0.000 to +0.003)	0.09
O₂ Pulse (ml/sys)	+0.008 (-0.015 to +0.030)	0.02	+0.004 (-0.023 to +0.030)	0.00
VE/VCO₂ slope	-0.02 (-0.03 to -0.01)	0.31	-0.02 (-0.04 to -0.01)	0.31
OUES (x10^-3)	+0.08 (-0.04 to +0.20)	0.06	+0.07 (-0.10 to +0.24)	0.03
HRR ≤ 12 bpm (%)	-0.08 (-0.24 to +0.08)	0.04	-0.14 (-0.30 to +0.03)	0.10

Open in a new tab

Estimates in bold are statistically significant.

^§Model adjusted for age, sex, and left ventricular ejection fraction.

^¥VO₂ AT: n = 17.

Fig 1 illustrates the eta-squared for the association between CPET variables and scales and summary scores of SF-36.

Discussion

The present study demonstrated a significant association between several CPET variables and QoL in patients with CCC. The variables that most explained the variation in the physical scales of QoL were VO₂ AT and VO₂ peak, whilst the variables that most explained the variation in the mental scales of QoL were VE/VCO₂ slope and HRR ≤ 12 bpm. Overall, physical scales presented lower scores in comparison to mental scales of QoL, which may reflect the impaired functional capacity observed in individuals with CCC [42].

The use of normative QoL values can provide important insights about the QoL status of a specific group, allowing the comparison with other populations [43]. In this sense, comparing the SF-36 results from our sample with the Brazilian normative data [44], CCC patients presented lower QoL values than the general population for physical functioning, role limitation to physical problems, general health perceptions, and role limitation to emotional problems scales, as well as in the PCS. However, previous studies showed different results for the physical functioning scale [11,14,15,27,45,46], with mean scores ranging from 18.8 [45] to 85.0 [14,27]. The differences observed across studies may be explained by the heterogeneity of the studied groups in terms of clinical characteristics, cardiac function, functional class, and geographical origin.

Regarding the association between CPET variables and QoL, some interesting findings were observed. VO2 peak, %PPVO₂ and VO2 AT correspond to maximal and submaximal parameters of functional capacity, respectively [31]. In the present study, all these three parameters were positively associated with physical functioning and PCS. Similarly, other studies identified an association between QoL and functional capacity in individuals with CCC [23–30], although most of them used field tests [23,24,28,29] or questionnaires [30] to estimate the functional capacity. In line with our results, Andersen et al. (2018) found a positive correlation between VO2 AT and PCS in patients with cardiac disease [47]. On the other hand, Ritt et al. (2013) and Costa et al. (2014), found a significant correlation between VO2 peak and QoL measured, respectively, by Minnesota Living with Heart Failure Questionnaire (MLHFQ) and SF-36 in patients with CCC [26,27]. In addition, Ritt et al. (2012) identified a significant difference in the QoL between the groups with VO2 peak > and ≤ 12 ml.kg-1.min-1 (a threshold for indication of heart transplantation), with greater QoL scores being observed among those individuals in the greater VO2 peak group [25].

Other CPET variables were also associated with some QoL scales in our study. VE/VCO₂ slope and OUES represent the ventilatory efficiency [48], and its association with prognosis in HF [49,50] and in CCC [26] has already been demonstrated. Nogueira et al. (2010) examined 46 HF patients (28.3% with CCC) and found a significant negative correlation between peak VE/VCO₂ slope and role limitations due to physical problems scale of SF-36 [22]. In contrast, Arena et al. (2002) and Ritt et al. (2013) did not find any association between VE/VCO₂ slope and OUES with QoL measured through the MLHFQ in patients with HF [26,51]. Likewise, in the present study, neither VE/VCO₂ slope nor OUES showed any significant association with the physical scales of QoL. The unexpected poor correlation between VE/VCO₂ slope and physical scales of QoL can be explained by the high percentage (77%) of patients with normal VE/VCO₂ slope levels (<32.5) in the studied population [26], with a low impact on the ability to perform the activities that are evaluated in the SF-36 instrument. On the other hand, VE/VCO₂ slope (but not OUES) was inversely associated with all mental components of SF-36. Considering that most patients presented normal VE/VCO₂ slope levels, we can speculate that variations in normal levels of VE/VCO₂ slope may have impacted the performance of submaximal activities that required efforts greater than those activities evaluated in the physical scales of SF-36, negatively impacting the emotional aspects of QoL by the inability to perform these more physically demanding activities on daily living.

Autonomic dysfunction has been demonstrated in CCC patients [52,53] and may be identified by a blunted HRR after the peak exercise [54]. Low HRR after exercise tests has been demonstrated as evidence of poor prognosis and greater disease severity in patients with HF [55,56], even in submaximal tests [57], and may indicate the presence of autonomic dysfunction [38]. In the present study, HRR ≤ 12 bpm was inversely associated with both physical (physical functioning, role limitations due to physical problems, pain, and PCS) and mental (vitality and mental health) scales of SF-36. The possible mechanism to explain this finding may be the better autonomic regulation allowing a more adequate adjustment of heart rate and peripheral blood flow, which may result in optimization of peripheral energy consumption and reduction of the sensation of dyspnea and fatigue [58]. To our knowledge, there is no previous evidence about the relationship between autonomic modulation and QoL in HF patients, despite some studies have shown that treatments aimed at improving autonomic regulation promoted an increase in QoL [59–62]. Nevertheless, our results are in line with those from van den Berg et al. (2001), that found an association between several autonomic function variables (deep breathing, isometric handgrip, standing up, head up tilting, and baroreflex sensitivity) and physical functioning, general health perceptions, vitality, and role limitations due to emotional problems scales of SF-36 in a sample of patients presenting paroxysmal atrial fibrillation [63].

In the present study, the double product was positively associated with physical functioning, general health perceptions, PCS, and vitality. Since the correlation between double product and VO₂ peak has already been demonstrated [64], we speculate that this association, especially on scales related to physical aspects, occurred because the higher value of the double product may express a higher functional capacity.

The major strength of our study was the inclusion of the CPET, the gold standard measure of functional capacity, which may allow for a more accurate assessment of the association between functional capacity and QoL in CCC patients. However, the small sample size was a limitation, with an a posteriori analysis demonstrating statistical power ranging from 5% to 97% (S1 Table). Moreover, our sample consisted of patients from an urban cohort and regularly followed at the outpatient clinic of a national reference center for the treatment of infectious disease, which may limit the applicability of the results for other populations. Besides that, the high-quality health care provided during the follow-up at a referral center may have positively affected the patients’ perception of QoL. Although the use of beta-blockers does not appear to alter exercise capacity in maximal and submaximal tests, there appears to be a favorable effect on the VE/VCO2 slope [65]. Thus, as most of our sample was using beta-blockers (93.3%), this may have influenced the CPET response. Overweight and obesity are other variables that may influence the exercise test results [66] and were not included in the statistical model as potential confounders. Finally, depression may be an important confounding factor for QoL in individuals with CD [13,67] and was not assessed in the present study.

Conclusions

The associations between CPET variables and QoL, especially for VO₂ AT and VO₂ peak with the physical scales, and VE/VCO₂ slope and HRR ≤ 12 bpm with the mental scales, reinforce the importance of CPET inclusion for a more comprehensive evaluation of individuals with CCC, when available. In this setting, intervention strategies aiming to improve functional capacity may also promote additional benefits on QoL and should be incorporated as a treatment strategy for patients with CCC.

Supporting information

S1 Table. Study power for adjusted models.

(DOCX)

Click here for additional data file.^{(24.5KB, docx)}

Data Availability

The data underlying the results presented in the study are available at osf.io/gkavb.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0279086.r001

Decision Letter 0

Gerson Cipriano Jr

26 Aug 2022

PONE-D-22-07420

The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)

PLOS ONE

Dear Dr. Vieira,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Dear Dr. Marcelo Carvalho Vieira

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit, but is not suitable for publication as it currently stands. Therefore, my decision is "Major Revision.” We invite you to submit a revised version of the manuscript that addresses the points below:

I am returning your manuscript with four reviews. The reviewers came to different conclusions about the paper, as you will see. After reading the reviews and looking at the manuscript, I am afraid that I have to concur with the more critical review. I am sorry I cannot be more positive at the moment, but as I have noted, all is not lost. It requires a lot of work and a major revision that I believe that you may need more time to work on the manuscript for a resubmission if you so wish to do so.

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Gerson Cipriano Jr., PT, MsC, Ph.D.

Academic Editor

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Review Comments to the Author

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Reviewer #1: The present is an interesting paper aiming to evalaute and standardize evaluation of patients with Chagas Disease

Some issues remain to be address

1)in the abstract some numerical data regarding HR/OR should be added (at least those more relevant)

2) In the introduction it should be better specified the importance of a "standardization"of QoL.

3) was the present analysis pre-specified or not?

4) Usually evaluation with time consuming questionare is challenging. Who asked the questions to the patients? DO authors recorded a % of complete or not answers?

5) regarding CPET did authors recorded % of medications?

6) Did authors performed a MRI to these patients or not?

7) due to reduced sample size, did authors checked for normality?

8) the rest of the statistical anakysis is correct. Usually i do not like when authors correct for "variables knowm in literature", anyway in this case it is accpetable due to reduced sample size. Please comment

Reviewer #2: The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY) - PONE-D-22-07420

1. I suggest the authors put the of the CEP number 2908991, once the CAAE is just a number generated to identify the research project that enters for ethical consideration in the CEP.

2. Consider to mention that this is an arm of a clinical study, since in the clinical trails the main objectives were to evaluate interventions such as exercise, nutritional counseling and pharmaceuticals and not the association of cardiopulmonary variables and quality of life.

3. Was an a priori sample calculation performed? If yes, what was the outcome variable used? If not, I suggest calculating the test power.

I understand that as this is an arm of a clinical study, the sample size calculation is not presented and/or applied to the study in question.

Reviewer #3: In the present study the authors analize the correlation between quality of life and exercise performance in patients with Chagas cardiomyopathy. The study is confirmatory of this assosiation in heart failure patients, albeit, as far as I know, not previously evaluated in patients with Chagas cardiomyopathy.

The study is well presented, but I suggest the authors to add among the variables VO2 reported as a percent of predicted.

The same for the VE/VCO2 relationship slope.

The discussion is by far too long and I believe that it should be shortened. Specifically all the parts about autonomic disfunction is mainly speculative and should be deleted.

Reviewer #4: The study entitled "the association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)" is well written and presents an interesting topic of a neglected disease with reflections on other cardiomyopathies. Some aspects need further clarification.

1. Can you provide the interval between CPET and Echocardiography. This is relevant to ascertain that it may reflect precisely its relation to CPET.

2. On page 8 line 190, you stated that a HRR<12bpm is probably related to autonomic dysfunction. I suggest considering and presenting data corroborating that. A non-trained individual may present a reduced HRR so looking at a VO2 may help exclude that possibility.

3. Was the CPET performed using Beta-blockers? If not, please insert that information. If they were performed using the medications I suggest a paragraph about the possible impact on the results, since nearly all sample was taking them. IT may be a study limitation.

4. Age, gender, and LVEF were your potential confounders, but the literature also presents overweight and obesity as potential confounders (PLoS One. 2021; 16(8): e0255724.). Why you did not consider them? Nearly half of your sample has overweight or obese. Please comment on that.

5. Although the discussion is comprehensive, I suggest a paragraph on study limitations, discussing beta blockers and overweight impact and the absence of a direct evaluation of the autonomic function, as well as the small sample evaluated.

**********

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Reviewer #1: Yes: Fabrizio D'Ascenzo

Reviewer #2: Yes: Daniela Bassi Dibai

Reviewer #3: Yes: oiergiuseppe agostoni

Reviewer #4: No

**********

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PLoS One. 2022 Dec 15;17(12):e0279086. doi: 10.1371/journal.pone.0279086.r002

Author response to Decision Letter 0

1 Nov 2022

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf".

Response: Thanks for the notice. We have reviewed the manuscript and ensured that it meets all PLOS ONE style requirements.

2) In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

Response: We apologize for the misunderstanding. The dataset is now available at osf.io/gkavb. Thanks for updating the respective statement.

3) We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

We will update your Data Availability statement on your behalf to reflect the information you provide.

Response: We apologize for the misunderstanding. The dataset is now available at osf.io/gkavb. Thanks for updating the respective statement.

Reviewer 1: The present is an interesting paper aiming to evaluate and standardize evaluation of patients with Chagas Disease. Some issues remain to be address.

1) In the abstract some numerical data regarding HR/OR should be added (at least those more relevant)

Response: We thank the reviewer for the suggestion. We added the β coefficients for all the significant variables in the abstract.

2) In the introduction it should be better specified the importance of a "standardization" of QoL.

Response: We appreciated the reviewer suggestion. We added a sentence highlighting the importance of HRQoL standardization.

3) Was the present analysis pre-specified or not?

Response: This is a secondary analysis from the PEACH clinical trial using the baseline data. This information was included in the manuscript.

4) Usually evaluation with time consuming questionnaire is challenging. Who asked the questions to the patients? Do authors recorded a % of complete or not answers?

Response: The same investigator was responsible for the application of the questionnaires in all patients, which took approximately 20 to 30 minutes. No patient failed to answer the questionnaire. This information was included in the manuscript.

5) Regarding CPET did authors recorded % of medications?

Response: The CPET was performed with patients taking all their medications. This information was included in the manuscript. The medications in use by the patients at the time of CPET are described in the Table 1.

6) Did authors perform a MRI to these patients or not?

Response: MRI is not a standard exam for evaluation of Chagas cardiomyopathy and was not performed in any patient.

7) Due to reduced sample size, did authors checked for normality?

Response: We use generalized linear models with gamma distribution and log-link function that accounts for skewed and heteroscedastic residuals distribution. This information is included in the manuscript.

8) The rest of the statistical analysis is correct. Usually I do not like when authors correct for "variables known in literature", anyway in this case it is acceptable due to reduced sample size. Please comment

Response: Many thanks for the comment. Age, sex, and left ventricle ejection fraction are the variables most related to prognosis in Chagas cardiomyopathy and, because of this, they were considered in our model as potential confounders.

Reviewer 2

1) I suggest the authors put the of the CEP number 2908991, once the CAAE is just a number generated to identify the research project that enters for ethical consideration in the CEP.

Response: We appreciated the reviewer suggestion. We added the report number after the CAAE.

2) Consider to mention that this is an arm of a clinical study, since in the clinical trails the main objectives were to evaluate interventions such as exercise, nutritional counseling and pharmaceuticals and not the association of cardiopulmonary variables and quality of life.

Response: We thank the reviewer for this comment. We rephrased this sentence in the methods section in order to improve clarity.

3) Was an a priori sample calculation performed? If yes, what was the outcome variable used? If not, I suggest calculating the test power. I understand that as this is an arm of a clinical study, the sample size calculation is not presented and/or applied to the study in question.

Response: The sample size was calculated only for the clinical trial to detect a clinically significant difference between groups in peak VO2. We calculated the study power for the analysis performed in this secondary analysis, which ranged from 5% to 97%. Please see supplementary table. This information was included in the manuscript.

Reviewer 3: In the present study the authors analyze the correlation between quality of life and exercise performance in patients with Chagas cardiomyopathy. The study is confirmatory of this association in heart failure patients, albeit, as far as I know, not previously evaluated in patients with Chagas cardiomyopathy.

1) The study is well presented, but I suggest the authors to add among the variables VO2 reported as a percent of predicted.

Response: We thank the reviewer for the suggestion. We include the variable in the analysis as suggested. The results are described in the text, in Tables 1 and 3 and in Figure 1.

2) The same for the VE/VCO2 relationship slope.

Response: Mean and standard deviation of the VE/VCO2 slope of participants included in the study were presented in the Table 1. The association between VE/VCO2 slope and QoL scales were presented in the Tables 3 and 4.

3) The discussion is by far too long and I believe that it should be shortened. Specifically all the parts about autonomic disfunction is mainly speculative and should be deleted.

Response: We thank the reviewer for this comment. However, although we do agree that the explanations for our findings on autonomic modulation are hypothetical, they are supported by some references cited in the text. We believe that these mechanisms should be presented, even to stimulate further research on the subject.

Reviewer 4: The study entitled "The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)" is well written and presents an interesting topic of a neglected disease with reflections on other cardiomyopathies. Some aspects need further clarification.

1) Can you provide the interval between CPET and Echocardiography? This is relevant to ascertain that it may reflect precisely its relation to CPET.

Response: Thank you for the question. CPET and echo were performed within one-week range. This information was included in the manuscript.

2) On page 8 line 190, you stated that a HRR<12bpm is probably related to autonomic dysfunction. I suggest considering and presenting data corroborating that. A non-trained individual may present a reduced HRR so looking at a VO2 may help exclude that possibility.

Response: We thank the reviewer for this comment. It has been demonstrated that a blunted heart rate recovery after exercise testing is a predictor of mortality, both in individuals without cardiovascular disease (Cole et al., 1999) and in individuals with heart failure (Bilsel et al., 2006; Arena et al., 2010). Moreover, Imai et al. (1994) demonstrated that heart rate recovery after exercise testing is blunted in heart failure patients even when compared to age-matched normal control individuals, which presented a statistically significant lower VO2. All the above cited references are included in our paper. We made changes to the text to clarify this point.

3) Was the CPET performed using Beta-blockers? If not, please insert that information. If they were performed using the medications I suggest a paragraph about the possible impact on the results, since nearly all sample was taking them. It may be a study limitation.

Response: Yes, the CPET was performed with patients taking all their medications, including beta-blockers (93.3%) when applicable. We have included a sentence on study limitations on the impact of beta-blocker use on CPET responses.

4) Age, gender, and LVEF were your potential confounders, but the literature also presents overweight and obesity as potential confounders (PLoS One. 2021; 16(8): e0255724.). Why did you not consider them? Nearly half of your sample has overweight or obese. Please comment on that.

Response: We thank the reviewer for the suggestion. Although overweight/obesity has an influence on the CPET response, we chose to include as potential confounders those variables whose impact on the morbidity and mortality of patients with CCC has already been reported in the literature, such as age, gender, and LVEF. In addition, the small sample size prevented us from including more confounding variables in the statistical model.

5) Although the discussion is comprehensive, I suggest a paragraph on study limitations, discussing beta blockers and overweight impact and the absence of a direct evaluation of the autonomic function, as well as the small sample evaluated.

Response: Thank you very much for the suggestion. We have expanded the section on study limitations to include the reviewer's suggestions.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(23.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0279086.r003

Decision Letter 1

Gerson Cipriano Jr

18 Nov 2022

PONE-D-22-07420R1The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)PLOS ONE

Dear Dr. Vieira,

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Thank you for submitting your paper to PlosOne. We have now completed our review.This original research aimed to evaluate the association between functional capacity (quantified by cardiopulmonary exercise test [CPET]) and QoL in individuals with CCC.

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PLoS One. 2022 Dec 15;17(12):e0279086. doi: 10.1371/journal.pone.0279086.r004

Author response to Decision Letter 1

22 Nov 2022

To Editorial Board of PLOS ONE

Dear Editor-in-Chief,

Manuscript ID: PONE-D-22-07420

Title: The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)

Dear editor,

Thank you very much for giving us the opportunity to review our Figure 1. The figure has been revised according to PLOS ONE’s “Figure preparation instructions” and the figure file has been uploaded to the PACE digital diagnostic tool to meet journal requirements. We hope the paper is now suitable for publication at PLOS ONE. Please, feel free to contact me in case of any addition doubt.

Thank you for your consideration.

Sincerely yours,

Marcelo Carvalho Vieira, BPhEd., MSc., PhD

Evandro Chagas National Institute of Infectious Disease, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil

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PLoS One. doi: 10.1371/journal.pone.0279086.r005

Decision Letter 2

Gerson Cipriano Jr

1 Dec 2022

The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)

PONE-D-22-07420R2

Dear Dr. Vieira,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Gerson Cipriano Jr., PT, MsC, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0279086.r006

Acceptance letter

Gerson Cipriano Jr

6 Dec 2022

PONE-D-22-07420R2

The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)

Dear Dr. Vieira:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Gerson Cipriano Jr.

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Study power for adjusted models.

(DOCX)

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Data Availability Statement

The data underlying the results presented in the study are available at osf.io/gkavb.

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PERMALINK

The association between variables of cardiopulmonary exercise test and quality of life in patients with chronic Chagas cardiomyopathy (Insights from the PEACH STUDY)

Marcelo Carvalho Vieira

Fernanda de Souza Nogueira Sardinha Mendes

Paula Simplício da Silva

Gilberto Marcelo Sperandio da Silva

Flavia Mazzoli-Rocha

Andrea Silvestre de Sousa

Roberto Magalhães Saraiva

Marcel de Souza Borges Quintana

Henrique Silveira Costa

Vitor Barreto Paravidino

Luiz Fernando Rodrigues Junior

Alejandro Marcel Hasslocher-Moreno

Pedro Emmanuel Alvarenga Americano do Brasil

Mauro Felippe Felix Mediano

Roles

Abstract

Introduction

Methods

Study design

Measurements

Data analysis

Ethical considerations

Results

Table 1. Characteristics of participants included in the study (n = 30).

Table 2. Quality of life assessed by SF-36 (n = 30).

Table 3. Association between CPET variables and QoL physical related scales.

Table 4. Association between CPET variables and QoL mental related scales.

Fig 1. Association matrix between CPET variables and quality of life (SF-36).

Discussion

Conclusions

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Gerson Cipriano Jr

Roles

Author response to Decision Letter 0

Decision Letter 1

Gerson Cipriano Jr

Roles

Author response to Decision Letter 1

Decision Letter 2

Gerson Cipriano Jr

Roles

Acceptance letter

Gerson Cipriano Jr

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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