
==== Front
Diabetol Metab Syndr
Diabetol Metab Syndr
Diabetology & Metabolic Syndrome
1758-5996
BioMed Central London

39272115
1464
10.1186/s13098-024-01464-z
Research
Type 2 diabetes mellitus negatively affects the functional performance of 6-min step test in chronic heart failure: a 3-year follow-up study
Santos-de-Araújo Aldair Darlan 1
Bassi-Dibai Daniela 2
Dourado Izadora Moraes 1
da Luz Goulart Cássia 3
Marinho Renan Shida 4
de Almeida Mantovani Jaqueline 1
de Souza Gabriela Silva 1
dos Santos Polliana Batista 5
Roscani Meliza Goi 6
Phillips Shane A. 7
Borghi-Silva Audrey audrey@ufscar.br

1
1 https://ror.org/00qdc6m37 grid.411247.5 0000 0001 2163 588X Cardiopulmonary Physiotherapy Laboratory, Universidade Federal de São Carlos, Federal University of Sao Carlos Rodovia Washington Luiz, São Carlos, SP 13565-905 Brazil
2 grid.442152.4 0000 0004 0414 7982 Management in Health Programs and Services, Universidade CEUMA, São Luís, MA Brazil
3 https://ror.org/02xfp8v59 grid.7632.0 0000 0001 2238 5157 Health Sciences and Technologies, Universidade de Brasília, Brasília, DF Brazil
4 https://ror.org/036rp1748 grid.11899.38 0000 0004 1937 0722 Inter-Units of Bioengineering, University of São Paulo, São Carlos, SP Brazil
5 Morgana Potrich Faculty, Mineiros, GO Brazil
6 https://ror.org/00qdc6m37 grid.411247.5 0000 0001 2163 588X Department of Medicine, Universidade Federal de São Carlos (UFSCar), Sao Carlos, SP Brazil
7 https://ror.org/02mpq6x41 grid.185648.6 0000 0001 2175 0319 Department of Physical Therapy, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL USA
14 9 2024
14 9 2024
2024
16 22918 7 2024
2 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) present a decrease in functional capacity due to the intrinsic nature of both pathologies. It is not known about the potential impact of T2DM on functional capacity when assessed by 6-min step test (6MST) and its effect as a prognostic marker for fatal and non-fatal events in patients with CHF.

Objective

to evaluate the coexistence of T2DM and CHF in functional capacity through 6MST when compared to CHF non-T2DM, as well as to investigate the different cardiovascular responses to 6MST and the risk of mortality, decompensation of CHF and acute myocardial infarction (AMI) over 36 months.

Methods

This is a prospective cohort study with 36 months of follow-up in individuals with T2DM and CHF. All participants completed a clinical assessment, followed by pulmonary function testing, echocardiography, and 6MST. The 6MST was performed on a 20 cm high step and cardiovascular responses were collected: heart rate, systemic blood pressure, oxygen saturation, BORG dyspnea and fatigue. The risk of mortality, acute myocardial infarction and decompensation of CHF was evaluated.

Results

Eighty-six participants were included. The CHF-T2DM group had a significantly lower functional capacity than the CHF non-T2DM group (p < 0.05). Forced Expiratory Volume in one second (L), ejection fraction (%), gender and T2DM influence and are predictors of functional capacity (p < 0.05; adjusted R squared: 0.419). CHF-T2DM group presented a higher risk of mortality and acute myocardial infarction over the 36 months of follow-up (p < 0.05), but not to the risk of decompensation (p > 0.05).

Conclusion

T2DM negatively affects the functional performance of 6MST in patients with CHF. Gender, ejection fraction (%), FEV1 (L) and T2DM itself negatively influence exercise performance.

Keywords

Step test
Prognosis
Chronic heart disease
Diabetes
Mortality
http://dx.doi.org/10.13039/501100001807 Fundação de Amparo à Pesquisa do Estado de São Paulo 15/26501-1 Borghi-Silva Audrey issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Common, highly prevalent, closely related and frequently associated, CHF and T2DM have a bidirectional relationship, that is, the origin and evolution of each pathology can be mutually influenced [1–4]. The interactions between both diseases is widely known [5, 6], however, the treatment approach continues to be a challenge, from screening to optimizing therapeutic decision-making that addresses aspects of rehabilitation of these individuals due to the high rate of morbidity and mortality and the heterogeneous clinical presentation of both conditions [1, 6, 7].

In both diseases, exercise capacity has been adopted as an important outcome and the main guidelines and international campaigns have drawn attention to the importance of this assessment and the inclusion of this outcome in therapeutic optimization [8–11]. Since the results that reflect exercise capacity have discriminative prognostic value for mortality risk, risk of unfavorable outcomes, the assessment of treatment efficacy in both conditions is highly desirable [12–14].

When it comes to exercise capacity, cardiopulmonary exercise testing (CPET) has established itself as the most effective tool for assessing this outcome [10, 15], however, the arsenal of equipment used and the need for a team that involves trained professionals led scientists to develop options that could reflect the CPET's ability to exercise in a more economically accessible and simple, but not replaceable [16, 17]. The 6-min step test (6MST) has gained notoriety and clinical and scientific popularity due to its practicality and simple, low-cost and easily available alternative option, especially in environments where the most sophisticated resources and equipment for achieving the gold standard are not available, in addition to having an important correlation with CPET [16, 18]. In both individuals with CHF [16] and individuals with T2DM [18], the reliability and validity of the 6MST has already been scientifically proven and the test has strong concurrent validity when compared to the CPET.

Undoubtedly, both disease negatively impact on exercise capacity, affecting the cardiovascular, respiratory and metabolic dynamic for the supply of oxygen to peripheral muscles [19, 20]. However, although the coexistence of T2DM and CHF has been growingly reported, description of fatal and nonfatal events and its relation with functional (in)capacity considering the presence of both conditions is still scarce. Therefore, the objective of this investigation is to evaluate whether individuals with CHF with T2DM have worse functional capacity when compared to a group with CHF without T2DM. Secondarily, we aimed to investigate the different cardiovascular responses presented in both groups and the risk of mortality, decompensation of heart failure and acute myocardial infarction over 36 months. Our hypothesis is, based on all the previously described aspects, that T2DM not only negatively affects the functional performance of individuals with CHF, but also presents itself as an independent factor for reducing functional capacity in the 6MST, worse cardiovascular responses and presents greater mortality, decompensation of CHF and acute myocardial infarction risk.

Methodology

Study design

This is a prospective longitudinal investigation with a follow-up of 3 years (36 months) carried out by the Cardiopulmonary Physiotherapy Laboratory (LACAP) of the Federal University of São Carlos—UFSCar, located in São Carlos, SP, Brazil. The participant recruitment process took place between December 2017 and November 2020. The university's ethics committee previously approved the development of the investigation under protocol number 5.188.654 and the research followed the principles of the Declaration of Helsinki. The STrengthening the Reporting of OBservational Studies in Epidemiology (STROBE) guideline was used to conduct the study [21]. All participants were informed about the research objectives and gave their informed consent before being evaluated.

Participants

The Cardiology Outpatient Clinics of the Medical Specialties Center (CEME) and the São Carlos University Hospital (HU-UFSCar) were used to actively search for participants eligible for the investigation. We included patients over 40 years of age, confirmed diagnosis of heart failure with left ventricular ejection fraction below 50% by echocardiography, with or without clinical diagnosis of T2DM, clinical stability and absence of medication changes in the last 3 months. Those aged over 80 years, diagnosed with heart failure with preserved ejection fraction, history of cardiovascular events in the last 6 months, decompensation of the disease in the last 3 months, presence of any implantable cardiac pacemaker, unstable angina, diagnosis of any neoplasms, uncontrolled systemic arterial hypertension, cognitive impairment or lack of understanding of the study proposal were excluded of study.

Initial assessment

Initially, a prior anamnesis was carried out using an assessment form developed by the laboratory and researchers involved so that personal information, associated pathologies and medications used were collected. The medical records of the included patients were also used as a tool to search for important information.

Anthropometric variables

To estimate the height of participants, a stadiometer (Welmy R-110, Santa Bárbara do Oeste, São Paulo, Brazil) was used. Body mass in kilograms (kg), body fat mass (kg), body fat percentage (%) and skeletal muscle mass (kg) were determined through bioelectrical impedance analysis, using the InBody 720 device. Participants were instructed to fast for at least 4 h, wear light clothing, remove all metallic objects in contact with the body, urinate before the exam, avoid drinking alcoholic beverages for 12 h and not perform strenuous physical exercise the day before the evaluation. During the examination, participants were positioned in an upright position, barefoot, with their shoulders slightly abducted and their elbows flexed at approximately 15°, as recommended by the manufacturer (BIOSPACE, 2004). The Body Mass Index (BMI) was calculated by dividing body mass (kg) by height squared in meters (kg/m2). The BMI classification was established as follows: low weight (15–19.9 kg/m2); normal weight (20–24.9 kg/m2); overweight (25–29.9 kg/m2); obesity I (30–34.9 kg/m2); obesity II (35–39.9 kg/m2); and obesity III (≥ 40 kg/m2)[22].

Minnesota Questionnaire

Previously validated for the Brazilian population [23], this questionnaire consists of 21 questions relating to the limitations associated with heart failure considering the last month. The answers to each question range from 0 to 5, where 0 represents no limitations and 5 the maximum limitation. These questions involve a physical dimension (1–7, 12 and 13), which are highly related to dyspnea, fatigue; emotional dimension (17- 21); and other issues (number 8, 9, 10, 11, 14, 15 and 16) which, together with the previous dimensions, form the total score.

New York Heart Association—NYHA

The New York Heart Association (NYHA) functional classification was used to assess the severity of functional limitations resulting from the CHF condition based on the symptoms experienced by the participant during physical activity. It allows stratifying the degree of limitation imposed by it: class I—absence of symptoms during daily activities, with limitation in efforts similar to that expected in healthy individuals; class II—symptoms triggered by daily activities; class III—symptoms triggered by activities less intense than everyday activities; class IV—symptoms at rest [24].

Pulmonary function—spirometry

The assessment of lung function was conducted using spirometry (Masterscreen Body, Mijnhardt/Jäger, Würzburg, Germany) by a previously trained researcher, following conventional techniques and the acceptability and reproducibility guidelines of the American Thoracic and European Respiratory Societies (ATS/ERS). At least three slow and forced maneuvers considered acceptable and reproducible were performed, as recommended, and repeated 20 min after administration of 400 µg of Albuterol Sulfate. Participants with overlapping chronic obstructive pulmonary disease were diagnosed according to the GOLD criteria (post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio < 0.70) [25, 26].

Transthoracic echocardiogram

The transthoracic echocardiogram was performed by a cardiologist, using an ultrasound device with a 3 MHz transducer (Phillips, HD11 XE, Bothell, Washington, United States) according to recommendations [27]. The end systolic and diastolic diameter of the left ventricle, early diastolic mitral filling velocities (E wave), early diastolic velocity of the mitral annulus (E' wave) and left ventricular ejection fraction (LFEV) were obtained using the Simpson method [28].

6-min step test—6MST

The 6MST has been previously validated for individuals with CHF [16]. Prior to the test, upon arrival at the laboratory, participants were informed about the nature and dynamics of the test so that any doubts regarding carrying it out could be clarified. Then, they underwent a period of 4 min of rest (2 min sitting and 2 min standing) so that vital signs could be collected (resting heart rate [HR], peripheral oxygen saturation [SpO2] and blood pressure systemic) in addition to perceived exertion for dyspnea and fatigue of the lower limbs using the BORG 10 scale in each position. At the end of the 4 min, they were instructed to go up and down a single step with a height of 20 cm (cm) in a self-paced manner, being allowed to slow down, if necessary, and even interrupt the test to rest. Verbal encouragement commands were used for each minute of testing and the time remaining until completion. The step numbers were counted from the beginning to the end of the 6-min time and recorded. Vital signs collected prior to the test, as well as feelings of lower limb fatigue and dyspnea were obtained immediately at the end of the test and the 6th min of recovery.

Despite being considered a test of a submaximal nature, some criteria for interrupting the exam were adopted so that the integrity of the patient's health was guaranteed: reaching 85% of maximum HR, arterial oxygen saturation ≤ 87%, systolic blood pressure (SBP) greater than 170 mmHg and DBP greater than 110 mmHg, BORG score greater than 7 for dyspnea and lower limb fatigue, anginal pain > 2, dizziness, vertigo and nausea. The prediction of functional performance of participants in the 6MST for the Brazilian population was made using the equations proposed by Arcuri et al.[29] 6MST = 209 – (1.05 × age) for men and 6MST = 174 – (1.05 × age) for women, where age is expressed in years; and Albuquerque et al.[30] 6MST = 106 + (17.02 × [0:woman; 1:man]) + (− 1.24 × age) + (0.8 × height) + (− 0.39 × weight) where 6MST is expressed in number of steps; age, in years; height, in cm; and weight, in kg.

Participants follow-up

Information on mortality, AMI and acute decompensated heart failure was collected through periodic telephone calls every 6 months and/or through hospital records from the date of the patient's initial evaluation in the laboratory. According to the European Society of Cardiology [28], acute decompensation of heart failure was understood as a rapid or gradual clinical presentation of the signs and symptoms of heart failure at rest, severe enough to cause unplanned office visits, emergency room visits or hospitalization requiring urgent assessment and subsequent initiation or intensification of treatment that includes therapies or procedures.

Statistical analyses

Data are presented as mean and standard deviation or absolute values and percentages of occurrence when appropriate. The Kolmogorov–Smirnov test was used to verify the normality of the data. For the analysis between the groups test T for independent samples was used when the data presented a normal distribution. When the data presented a non-parametric distribution, the Mann–Whitney test was used. The χ2 test was used to compare categorical variables. Kaplan–Meier analysis was used to test the risk of all-cause mortality, acute decompensated heart failure, and acute myocardial infarction over 36 months of follow-up. Differences between curves were evaluated using the Log-rank test, Breslow and Tarone-Ware.

The covariates included in the present analysis constitute a broad spectrum of factors associated with unfavorable outcomes (mortality, decompensation of heart failure and AMI). Univariate linear regression analyses were performed to verify the association between the independent variables and the dependent variable (steps in the 6MST) [31]. For the multiple linear regression model, variables that presented a p-value < 0.20 in the univariate analysis were selected as covariates [32]. Comparisons of 6MST performance and cardiovascular responses between groups were expressed as mean, standard deviation (SD), mean difference (MD), and effect size calculated using Cohen’s d, with the categorization based on the values established by Cohen [33]. The effect size was calculated based on the Cohen d, according to the website: <https://www.psychometrica.de/effect_size.html>. It was considered the following interpretation of the d value: 0.2 (weak), 0.5 (moderate) and > 0.8 (large effect size) [33]. Raincloud plots were produced using the JASP 0.18.2 software [34] for data visualization of the step test performance and predictive values <https://jasp-stats.org/>. All analyzes were performed using GraphPad Software, Inc. (2019). GraphPad Prism (versão 8.0.1). San Diego, CA <https://www.graphpad.com>. The probability of type 1 error occurrence was established at 5% for all tests (p < 0.05).

Results

Initially, one hundred and twenty-one participants were recruited, however thirty-five were not included. Finally, eighty-six participants were included: 34 CHF-T2DM group and 52 in CHF non-T2DM group (Fig. 1). Information about the characteristics of the sample included in the study can be viewed in Table 1. The groups did not differ in terms of age (years), sex distribution and height (m). However, the CHF-T2DM group had higher body weight and BMI when compared to the CHF non-T2DM and, consequently, a greater number of participants with obesity (65%) (class I [40%], class II [18%] and class III [5%]). Additionally, this same group had a higher prevalence of coronary artery disease (12%), dyslipidemia (72%), use of beta-blockers (85%) and lower LVEF (%). No statistically significant differences were observed in the outcomes of quality of life (Minnesotta questionnaire), functional classification (NYHA) and lung function (spirometry). In total, 14 individuals died over the 36 months of follow-up (9 in the CHF-T2DM group and 5 in the CHF non-T2DM). Furthermore, 13 individuals progressed to acute decompensation of heart failure and 10 to AMI.Fig. 1 Flowchart

Table 1 General characteristics of the study sample at initial assessment (n = 86)

Variables	All volunteers
(n = 86)	CHF Non-diabetics
(n = 52)	CHF Diabetics
(n = 34)	P value	
Age (years)	62 ± 11	62 ± 12	62 ± 11	0.688	
Gender					
 Male, n (%)	64 (74)	41 (79)	23 (68)	0.181	
 Female, n (%)	22 (26)	11 (21)	11 (32)	
Body Mass (kg)	78.82 ± 17.89	75.27 ± 16.49	84.24 ± 18.80	0.022*	
Height (m)	1.66 ± 0.09	1.66 ± 0.08	1.65 ± 0.10	0.709	
BMI (kg/m2)	28.72 ± 6.07	27.36 ± 5.72	30.79 ± 6.09	0.010*	
 Normal	24 (28)	18 (35)	6 (18)	0.009*	
 Overweight	27 (31)	21 (40)	6 (18)	
 Obesity class I	22 (26)	8 (15)	14 (41)	
 Obesity class II	10 (12)	4 (8)	6 (18)	
 Obesity class III	3 (3)	1 (2)	2 (5)	
Death patients, n (%)	14 (16)	5 (10)	9 (26)	0.038*	
 COVID-19, n (%)	2 (14)	1 (20)	1 (11)	
 Decompensation, n (%)	8 (58)	4 (80)	4 (45)	
 Renal insufficiency, n (%)	1 (7)	0 (0)	1 (11)	
 Diabetes complication, n (%)	1 (7)	0 (0)	1 (11)	
 AMI, n (%)	2 (14)	0 (0)	2 (22)	
Decompensation, n (%)	13 (15)	5 (10)	8 (24)	0.078	
AMI, n (%)	10 (12)	3 (6)	7 (21)	0.036*	
Risk factors, n (%)					
 Atrial Fibrillation	18 (20)	8 (15)	10 (29)	0.117	
 Asma	11 (13)	4 (8)	7 (21)	0.061	
 Atherosclerosis	3 (3)	1 (2)	2 (6)	0.344	
 Coronary artery disease	5 (6)	1 (2)	4 (12)	0.047*	
 Hypertension	65 (76)	42 (81)	23 (67)	0.344	
 Depression	16 (19)	9 (17)	7 (21)	0.605	
 COPD	21 (24)	13 (25)	8 (24)	0.877	
 Obesity	35 (41)	13 (25)	22 (65)	 < 0.001*	
 Dyslipidemia	40 (47)	17 (33)	23 (72)	 < 0.001*	
 Deep vein thrombosis	4 (5)	1 (2)	3 (9)	0.119	
 Stress	20 (23)	15 (29)	5 (15)	0.167	
 Type 2 Diabetes					
 Alcoholism	5 (6)	4 (8)	1 (3)	0.390	
 Thyroid Disease	12 (14)	7 (13)	5 (15)	0.783	
 Obstructive Sleep Apnea Syndrome	9 (10)	7 (13)	2 (6)	0.299	
 Current Smokers	14 (16)	10 (19)	4 (12)	0.421	
 Ex-smokers	42 (49)	25 (48)	17 (47)	0.653	
Minnesota questionnaire		27.45 ± 21.34	31.66 ± 19.73	0.378	
NYHA, n (%)					
 I	35 (41)	20 (38)	15 (44)	0.603	
 II	35 (41)	24 (46)	11 (32)	
 III	14 (17)	7 (13)	7 (21)	
 IV	2 (2)	1 (2)	1 (3)	
Pulmonary Function					
 FEV1 (L)	2.40 ± 0.74	2.45 ± 0.77	2.32 ± 0.69	0.473	
 FEV1 (%)	76.00 ± 30.73	75.28 ± 32.98	77.13 ± 27.26	0.789	
 FVC (L)	3.30 ± 0.89	3.40 ± 0.95	3.15 ± 0.81	0.216	
 FVC (%)	91.12 ± 17.59	92.71 ± 18.88	88.75 ± 15.40	0.335	
 FEV1/FVC	0.66 ± 0.24	0.64 ± 0.26	0.69 ± 0.21	0.343	
Echocardiogram					
 LV end-diastolic diameter (mm)	58.15 ± 11.00	57.38 ± 10.46	59.44 ± 11.94	0.444	
 LV end-systolic diameter (mm)	46.52 ± 11.66	44.98 ± 11.07	49.08 ± 12.38	0.159	
 Mitral E wave (cm/s)	72.46 ± 24.20	69.86 ± 23.26	77.67 ± 25.89	0.268	
 Mitral E’ wave (cm/s)	7.43 ± 2.49	7.93 ± 2.36	6.53 ± 2.53	0.063	
 LVEF, %	39.60 ± 8.20	41.29 ± 7.81	37.03 ± 8.23	0.018*	
Medications, n (%)					
 SABA	7 (8)	4 (8)	3 (9)	0.786	
 LABA	5 (6)	2 (4)	3 (9)	0.298	
 LAMA	2 (2)	2 (4)	0 (0)	0.262	
 Bronchodilator	12 (14)	8 (15)	4 (12)	0.714	
 ACE inhibitors	55 (64)	31 (60)	24 (70)	0.300	
 Calcium channel blocker	1 (1)	0 (0)	1 (3)	0.728	
 Diuretics	66 (77)	37 (71)	29 (85)	0.129	
 Oral hypoglycemic agents	26 (30)	0 (0)	26 (76)	 < 0.001*	
 Anticoagulant	53 (62)	33 (63)	20 (62)	0.923	
 Digoxin	14 (17)	9 (17)	5 (15)	0.890	
 Beta blocker	69 (81)	40 (77)	29 (85)	0.049*	
 Statins	35 (41)	18 (35)	17 (48)	0.071	
Values are mean ± SD or absolute values (%)

CHF chronic heart failure, %: percentage, kg kilos, m meter, BMI body mass index, acute myocardial infarction, COPD Chronic Obstructive Pulmonary Disease, DASI Duke Activity Status Index, VO2 oxygen uptake, NYHA New York Heart Association, FEV1 forced expiratory volume in 1 s, L liters, FVC forced vital capacity, LV left ventricular; millimeter, cm centimeter, Mitral E/E’ ratio early diastolic mitral filling velocity/ early diastolic mitral annular velocity, LVEF left ventricular ejection fraction, SABA short-acting β-agonist, LABA long-acting β-agonist, LAMA long-acting muscarinic antagonists, ACE angiotensin-converting inhibitors

*p < 0.05 Statistical significance for Student’s t-test, Mann–Whitney test or χ2 test

In Fig. 2, when we evaluated functional performance comparing to 6MST in both groups, we observed that the CHF-T2DM group had a significantly lower functional capacity than the CHF non-T2DM group (60 ± 29 versus 87 ± 31; Cohen’s d = 0.875) and that they achieved an average percentage of 45 ± 20 versus 64 ± 22 when considering the prediction equation by Arcuri et al., and 43 ± 19 versus 60 ± 19 when considering the prediction equation by Albuquerque et al. Regarding cardiovascular responses (Table 2), we only found a lower heart rate chronotropic response by heart rate in beats per minute in the CHF-T2DM (bpm) at peak exercise (97 ± 26 versus 108 ± 21; Cohen’s d: 0.476).Fig. 2 Raincloud plots for functional capacity by 6MST and predicted values in CHF non-T2DM and CHF-T2DM. CHF non-T2DM chronic heart failure without type 2 diabetes mellitus, CHF-T2DM chronic heart failure with type 2 diabetes mellitus, % percentage, n number in absolute value, p < 0.05: statistical significance

Table 2 Cardiovascular responses through 6MST

Variables	CHF Non-T2DM n = 52)	CHF T2DM (n = 34)	Mean Difference	Cohen D	P value	
HR (bpm) rest	72 ± 12	68 ± 12	− 4.00	0.333	0.144	
HR (bpm) peak	108 ± 21	97 ± 26	− 11.00	0.476	0.030*	
HR (bpm) rec 1’	− 20 ± 17	− 17 ± 17	− 3.00	0.176	0.392	
SBP (mmHg) rest	118 ± 12	121 ± 16	3.00	0.219	0.367	
SBP (mmHg) peak	147 ± 20	146 ± 25	− 1.00	0.045	0.939	
DBP (mmHg) rest	78 ± 9	79 ± 9	− 1.00	0.111	0.859	
DBP (mmHg) peak	86 ± 19	89 ± 15	− 3.00	0.171	0.497	
SpO2 (%) rest	96 ± 2	96 ± 2	0.00	0.000	0.907	
SpO2 (%) peak	95 ± 3	95 ± 3	0.00	0.000	0.821	
BORG Dyspnea rest	0.1 ± 1.00	0.5 ± 1.00	− 0.40	0.238	0.112	
BORG Dyspnea peak	3 ± 2	3 ± 3	0.02	0.00	0.989	
BORG fatigue lower limbs rest	0.1 ± 0.7	0.1 ± 0.5	− 0.02	0.00	0.837	
BORG fatigue lower limbs peak	3 ± 3	3 ± 2	− 0.30	0.00	0.589	
Values are mean ± Standard Deviation

CHF chronic heart failure, 6MST six-minute step test, % percentage, HR heart rate, bpm beats per minute, rec recovery, SBP systolic blood pressure, mmHg millimeters of mercury, DBP diastolic blood pressure, SpO2 peripheral oxygen saturation

*Statistical difference between groups highlighted in bold (p < 0.05)

The univariate linear regression model (Table 3) revealed that FEV1 (L), ejection fraction (%), gender and T2DM influence and are predictors of approximately 42% functional capacity (p < 0.05; adjusted R squared: 0.419). Secondarily, when we analyzed the Kaplan–Meier curves, we observed that the CHF-T2DM presented a higher risk of mortality (Fig. 3) and acute myocardial infarction (Fig. 4) over the 36 months of follow-up (p < 0.05 to Log-rank, Brelow and Tarone-ware), however, regarding the risk of heart failure decompensation (Fig. 5), there was no statistically significant difference between the groups (p > 0.05 to Log-rank, Brelow and Tarone-ware).Table 3 Stepwise multiple linear regression model for the six-minute step test

Dependent variable: steps from 6MST	
Variables	β	Std. error	t	p value	CI 95%	
Intercept	− 36.258	18.952	− 1.913	0.060	− 74.039, 1.523	
FEV1 (L)	25.583	4.381	5.840	0.008	16.851, 34.316	
Ejection Fracion (%)	0.875	0.411	2.125	0.037	0.054, 1.695	
[T2DM = 0]	18.990	6.152	3.087	0.003	5.556, 36.191	
[T2DM = 1]	0a						
[Gender = 0 Female]	20.873	4.381	5.840	 < 0.001	16.851, 34.316	
[Geeder = 1 Male]	0a						
R squared 0.450; Adjusted R Squared: 0.419

6MST six-minute step test, FEV forced expiratory volume, L liter, m meter, % percentage, T2DM diabetes mellitus type 2, β beta, std standard, CI confidence interval

aThis parameter is set to zero because it is redundant

Fig. 3 Kaplan–Meier curve for mortality over a period of 36 months. CHF chronic heart failure, %: percentage

Fig. 4 Kaplan–Meier curve for acute myocardial infarction over a period of 36 months. CHF chronic heart failure, % percentage

Fig. 5 Kaplan–Meier curve for acute decompensation over a period of 36 months. CHF chronic heart failure, % percentage

Discussion

The main results of this investigation are associated with some important aspects: (1) for the first time, the impact of T2DM on CHF was investigated considering the performance and cardiovascular variables of 6MST; (2) we confirmed our hypothesis that the association of T2DM and CHF presents worse functional capacity compared to the CHF non-T2DM group; (3) secondarily, we observed a higher risk of mortality and AMI in the CHF-T2DM over 36 months of follow-up.

The heterogeneous presentation of CHF, that is, concomitant with other risk factors that contribute to the increase in unfavorable outcomes, with consequent development of disabling functional limitations [28, 35]. Particularly, in individuals affected by CHF, the decrease in functional capacity is linked to multifactorial mechanisms that involve, above all, early anaerobic metabolism resulting from a combination of reduced blood flow in skeletal muscle, decreased aerobic enzymes in skeletal muscle, morphological and functional changes of musculoskeletal fibers and inefficiency of the cardiovascular and respiratory system [36–38]. T2DM, in turn, presents peculiar characteristics that compromise exercise capacity in this population, mainly associated with ineffective glucose uptake, mitochondrial imbalance and the transition from oxidative to glycolytic fiber type [39, 40].

Paradoxically to the physiological limitations mentioned above, the effort required to perform the 6MST requires vertical displacement and the involvement of large muscle groups that demand greater cardiovascular stress when compared, for example, to the 6-min walk test, leading to an increase extraction oxygen [16, 29]. Considering oxygen uptake, it is nothing new that, individually, both diseases present a decrease in functional capacity when evaluated by field and laboratory tests. In individuals with CHF, whether with a reduced ejection fraction or with its preservation, different methods that reflect this outcome indicate functional impairment over time [41, 42]. The same reasoning can be observed in patients with T2DM [40, 43].

Previously, and in an unprecedented way, an investigation proved that in individuals with CHF the addition of T2DM is associated with a reduction in the distance covered during the 6-min walk test (6MWT) in addition to being an independent determinant of worse performance in the group with coexistence of both pathologies [44]. Still considering the phenotypic nature of CHF presentation, recently, a group of researchers observed that T2DM demonstrated to be the strongest predictor of limited exercise capacity in CHF and preserved ejection fraction when also assessed by the 6MWT [45].

In healthy individuals, variables such as weight (kg), height (cm), age (years) and gender influence 6MST performance and explained at least 42% of the variability in functional capacity [30]. Parallel to this, our results point to an influence of gender, T2DM, ejection fraction (%) and FEV1 (L) and, undoubtedly, we need to recognize how much each variable makes sense in our regression model since current literature has demonstrated the influence of each of them on exercise capacity. The influence of gender is associated with the nature of the physiological difference that men and women present in the cardiovascular, respiratory and musculoskeletal systems, both in healthy individuals and in individuals affected by heart failure [46, 47]. In turn, airflow limitation, more specifically when assessed by FEV1 (L), contributes to functional performance in this population also being compromised. The contribution of lung function to exercise capacity in patients with CHF has been previously discussed and accounts for approximately 30% of maximal exercise capacity during CPET [48].

Our sample presented some important characteristics that deserve discussion. At first, we must keep in mind that the majority of people affected by T2DM are overweight or obese [3]. Although there is a paradoxical relationship, that is, inversely proportional, between weight gain and 6MST performance, in practical terms, when we talk about T2DM it is practically utopian to disregard overweight or obesity in this population due to the close relationship between these two outcomes [30]. We minimally understand the importance of controlling the variable that reflects obesity in both groups so that this bias is minimized, but this may reflect a small portion of the population affected by CHF-T2DM since the coexistence of both pathologies is highly prevalent [49] and that obesity is strongly connected to T2DM [3]. Nevertheless, the impact of T2DM culminates in structural and functional changes in the heart muscle that lead to exercise intolerance in patients with CHF and, not surprisingly, the CHF-T2DM group showed a lower left ventricular ejection fraction that may be a reflection of coexistence of both diseases [20].

When we considered the characterization of our sample using the NYHA scale, we observed that most participants were categorized as NYHA I and II. Curiously, there was a significant risk of mortality and AMI in our sample, revealing a true paradox, as these functional classes typically reflect better functional capacity. Since our patients were followed during a pandemic period, we hypothesize several possible explanations for these unfavorable outcomes: (a) COVID-19 infection and its deleterious effects, leading to an increased risk of AMI and mortality [50]; (b) the impact of lockdown on increasing the risks associated with these outcomes [51]; (c) limited discrimination of the NYHA classification [52].

Clinically, our results contribute not only to recognizing the impact of T2DM in individuals with CHF on 6MST performance, but mainly so that the results can be used in more precise therapies that consider the nature of the coexistence of both pathologies once the evaluation of this outcome. It is routinely used for prognostic, diagnostic, pharmacological optimization, monitoring of disease progression and investigation of functional decline.

Limitations

This is a study with some limitations that deserve to be described. It was not possible to characterize the sample according to metabolic outcomes such as fasting blood glucose or glycated hemoglobin and we also do not have information about the time of diagnosis of T2DM.

Conclusion

T2DM negatively affects the functional performance of 6MST in patients with CHF. Sex, ejection fraction (%), FEV1 (L) and T2DM itself negatively influence this outcome and must be considered within the evaluation.

Acknowledgements

To the patients who participated in the research. To the Coordination for the Improvement of Higher Education Personnel (CAPES), National Council for Scientific and Technological Development (CNPq) and São Paulo Research Foundation (FAPESP) for maintaining the postgraduate programs in Brazil. University Hospital of Federal University of São Carlos—SP-Brazil (HU-UFSCar) Brazilian Company of Hospital Services (EBSERH). Professor Ph.D. Audrey Borghi-Silva is CNPq Research Productivity Scholarship—Level 1B.

Author contributions

Study design: ADS, DB, IMD, CLG, RSM, JAM, GSS, PBS, MGR, SAP, AB. Conceptualization: ADS, DB, IMD, CLG, RSM, JAM, GSS, PBS, MGR, SAP, AB. Methodology: ADS, DB, IMD, CLG, RSM, JAM, GSS, PBS, MGR, SAP, AB. Data collection: ADS, DB, IMD, CLG, RSM, JAM, GSS, PBS, MGR, SAP, AB. Data analysis and interpretation: ADS, DB, IMD, CLG, RSM, JAM, GSS, PBS, MGR, SAP, AB. Initial manuscript writing: ADS, DB, IMD, CLG, RSM, JAM, GSS, PBS, MGR, SAP, AB. All the authors read and approved the final manuscript.

Funding

This work was supported by São Paulo Research Foundation (FAPESP Process 15/26501-1).

Availability of data and materials

The set of data generated and/or analyzed during the present study are available through the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee on Research of Universidade Federal de São Carlos (number 5.188.654).

Consent for publication

An informed consent was obtained from all the individuals included in the study. All participants agreed to publish.

Competing interests

The authors do not have any relevant financial or nonfinancial interest to disclose. The authors declare that there is not any conflict of interest.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Elendu C Amaechi DC Elendu TC Ashna M Ross-Comptis J Ansong SO Heart failure and diabetes: understanding the bidirectional relationship Medicine (Baltimore) 2023 102 E34906 10.1097/MD.0000000000034906 37713837
Elendu C, Amaechi DC, Elendu TC, Ashna M, Ross-Comptis J, Ansong SO, et al. Heart failure and diabetes: understanding the bidirectional relationship. Medicine (Baltimore). 2023;102:E34906.37713837 10.1097/MD.0000000000034906
2. Palazzuoli A Iacoviello M Diabetes leading to heart failure and heart failure leading to diabetes: epidemiological and clinical evidence Heart Fail Rev 2023 28 585 10.1007/s10741-022-10238-6 35522391
Palazzuoli A, Iacoviello M. Diabetes leading to heart failure and heart failure leading to diabetes: epidemiological and clinical evidence. Heart Fail Rev. 2023;28:585.35522391 10.1007/s10741-022-10238-6
3. Theofilis P Oikonomou E Tsioufis K Tousoulis D Diabetes mellitus and heart failure: epidemiology, pathophysiologic mechanisms, and the role of SGLT2 inhibitors Life 2023 13 497 10.3390/life13020497 36836854
Theofilis P, Oikonomou E, Tsioufis K, Tousoulis D. Diabetes mellitus and heart failure: epidemiology, pathophysiologic mechanisms, and the role of SGLT2 inhibitors. Life. 2023;13:497.36836854 10.3390/life13020497
4. Sugandh F Chandio M Raveena F Kumar L Karishma F Khuwaja S Advances in the management of diabetes mellitus: a focus on personalized medicine Cureus. 2023 15 e43697 37724233
Sugandh F, Chandio M, Raveena F, Kumar L, Karishma F, Khuwaja S, et al. Advances in the management of diabetes mellitus: a focus on personalized medicine. Cureus. 2023;15:e43697.37724233
5. Thomas MC Type 2 diabetes and heart failure: challenges and solutions Curr Cardiol Rev 2016 12 249 10.2174/1573403X12666160606120254 27280301
Thomas MC. Type 2 diabetes and heart failure: challenges and solutions. Curr Cardiol Rev. 2016;12:249.27280301 10.2174/1573403X12666160606120254
6. Htay T Soe K Lopez-Perez A Doan AHA Romagosa MA Aung KK Mortality and cardiovascular disease in type 1 and type 2 diabetes Curr Cardiol Rep 2019 21 1407 10.1007/s11886-019-1133-9
Htay T, Soe K, Lopez-Perez A, Doan AHA, Romagosa MA, Aung KK. Mortality and cardiovascular disease in type 1 and type 2 diabetes. Curr Cardiol Rep. 2019;21:1407.10.1007/s11886-019-1133-9
7. Bytyçi I Bajraktari G Mortality in heart failure patients Anatol J Cardiol 2015 15 63 10.5152/akd.2014.5731 25550250
Bytyçi I, Bajraktari G. Mortality in heart failure patients. Anatol J Cardiol. 2015;15:63.25550250 10.5152/akd.2014.5731
8. Colberg SR Sigal RJ Yardley JE Riddell MC Dunstan DW Dempsey PC Physical activity/exercise and diabetes: a position statement of the American Diabetes Association Diabetes Care 2016 39 2065 10.2337/dc16-1728 27926890
Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2016;39:2065.27926890 10.2337/dc16-1728
9. Flotyńska J, Szybiak W, Naskręt D, Zozulińska-Ziółkiewicz D, Grzelka-Woźniak A, Uruska A. Methods of Assessment of Physical Capacity in People with Diabetes Mellitus Type 1. Curr Diabetes Rev . 2024;20.
10. Herdy AH Ritt LEF Stein R de Araújo CGS Milani M Meneghelo RS Cardiopulmonary exercise test: background, applicability and interpretation Arq Bras Cardiol 2016 107 467 27982272
Herdy AH, Ritt LEF, Stein R, de Araújo CGS, Milani M, Meneghelo RS, et al. Cardiopulmonary exercise test: background, applicability and interpretation. Arq Bras Cardiol. 2016;107:467.27982272
11. Heidenreich PA Bozkurt B Aguilar D Allen LA Byun JJ Colvin MM 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines J Am Coll Cardiol 2022 79 e263 421 10.1016/j.jacc.2021.12.012 35379503
Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79:e263-421.35379503 10.1016/j.jacc.2021.12.012
12. Huang WM Chang HC Chen CN Huang CJ Yu WC Cheng HM Symptom-limited exercise capacity is associated with long-term survival Medicine (Baltimore) 2023 102 E34948 10.1097/MD.0000000000034948 37773832
Huang WM, Chang HC, Chen CN, Huang CJ, Yu WC, Cheng HM, et al. Symptom-limited exercise capacity is associated with long-term survival. Medicine (Baltimore). 2023;102:E34948.37773832 10.1097/MD.0000000000034948
13. Zisman-Ilani Y Fasing K Weiner M Rubin DJ Exercise capacity is associated with hospital readmission among patients with diabetes BMJ Open Diabetes Res Care 2020 8 1771 10.1136/bmjdrc-2020-001771
Zisman-Ilani Y, Fasing K, Weiner M, Rubin DJ. Exercise capacity is associated with hospital readmission among patients with diabetes. BMJ Open Diabetes Res Care. 2020;8:1771.10.1136/bmjdrc-2020-001771
14. Nojima H Yoneda M Watanabe H Yamane K Kitahara Y Sekikawa K Association between aerobic capacity and the improvement in glycemic control after the exercise training in type 2 diabetes Diabetol Metab Syndr 2017 9 63 10.1186/s13098-017-0262-9 28828040
Nojima H, Yoneda M, Watanabe H, Yamane K, Kitahara Y, Sekikawa K, et al. Association between aerobic capacity and the improvement in glycemic control after the exercise training in type 2 diabetes. Diabetol Metab Syndr. 2017;9:63.28828040 10.1186/s13098-017-0262-9
15. Myers J Arena R Cahalin LP Labate V Guazzi M Cardiopulmonary exercise testing in heart failure Curr Probl Cardiol 2015 40 322 372 10.1016/j.cpcardiol.2015.01.009 26096801
Myers J, Arena R, Cahalin LP, Labate V, Guazzi M. Cardiopulmonary exercise testing in heart failure. Curr Probl Cardiol. 2015;40:322–72.26096801 10.1016/j.cpcardiol.2015.01.009
16. Marinho RS Jürgensen SP Arcuri JF Goulart CL Dos Santos PB Roscani MG Reliability and validity of six-minute step test in patients with heart failure Brazilian J Med Biol Res 2021 54 e10514 10.1590/1414-431x2020e10514
Marinho RS, Jürgensen SP, Arcuri JF, Goulart CL, Dos Santos PB, Roscani MG, et al. Reliability and validity of six-minute step test in patients with heart failure. Brazilian J Med Biol Res. 2021;54:e10514.10.1590/1414-431x2020e10514
17. Giannitsi S Bougiakli M Bechlioulis A Kotsia A Michalis LK Naka KK 6-minute walking test: a useful tool in the management of heart failure patients Ther Adv Cardiovasc Dis 2019 13 1 10 10.1177/1753944719870084
Giannitsi S, Bougiakli M, Bechlioulis A, Kotsia A, Michalis LK, Naka KK. 6-minute walking test: a useful tool in the management of heart failure patients. Ther Adv Cardiovasc Dis. 2019;13:1–10.10.1177/1753944719870084
18. Lee MC Validity of the 6-minute walk test and step test for evaluation of cardio respiratory fitness in patients with type 2 diabetes mellitus J Exerc Nutr Biochem 2018 22 49 10.20463/jenb.2018.0008
Lee MC. Validity of the 6-minute walk test and step test for evaluation of cardio respiratory fitness in patients with type 2 diabetes mellitus. J Exerc Nutr Biochem. 2018;22:49.10.20463/jenb.2018.0008
19. Poole DC Richardson RS Haykowsky MJ Hirai DM Musch TI Exercise limitations in heart failure with reduced and preserved ejection fraction J Appl Physiol 2018 124 208 10.1152/japplphysiol.00747.2017 29051336
Poole DC, Richardson RS, Haykowsky MJ, Hirai DM, Musch TI. Exercise limitations in heart failure with reduced and preserved ejection fraction. J Appl Physiol. 2018;124:208.29051336 10.1152/japplphysiol.00747.2017
20. Nesti L Pugliese NR Sciuto P Natali A Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach Cardiovasc Diabetol 2020 19 134 10.1186/s12933-020-01109-1 32891175
Nesti L, Pugliese NR, Sciuto P, Natali A. Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach. Cardiovasc Diabetol. 2020;19:134.32891175 10.1186/s12933-020-01109-1
21. Malta M Cardoso LO Bastos FI Magnanini MMF da Silva CMFP STROBE initiative: guidelines on reporting observational studies Rev Saude Publica 2010 44 559 565 10.1590/S0034-89102010000300021 20549022
Malta M, Cardoso LO, Bastos FI, Magnanini MMF, da Silva CMFP. STROBE initiative: guidelines on reporting observational studies. Rev Saude Publica. 2010;44:559–65.20549022 10.1590/S0034-89102010000300021
22. Nuttall FQ Body mass index: obesity, BMI, and health: a critical review Nutr Today 2015 50 117 10.1097/NT.0000000000000092 27340299
Nuttall FQ. Body mass index: obesity, BMI, and health: a critical review. Nutr Today. 2015;50:117.27340299 10.1097/NT.0000000000000092
23. Carvalho VO Guimarães GV Carrara D Bacal F Bocchi EA Validação da versão em português do Minnesota Living with Heart Failure Questionnaire Arq Bras Cardiol 2009 93 39 44 10.1590/S0066-782X2009000700008 19838469
Carvalho VO, Guimarães GV, Carrara D, Bacal F, Bocchi EA. Validação da versão em português do Minnesota Living with Heart Failure Questionnaire. Arq Bras Cardiol. 2009;93:39–44.19838469 10.1590/S0066-782X2009000700008
24. Rohde LEP Montera MW Bocchi EA Clausell NO de Albuquerque DC Rassi S Diretriz brasileira de insuficiência cardíaca crônica e aguda Arq Bras Cardiol 2018 111 436 539 30379264
Rohde LEP, Montera MW, Bocchi EA, Clausell NO, de Albuquerque DC, Rassi S, et al. Diretriz brasileira de insuficiência cardíaca crônica e aguda. Arq Bras Cardiol. 2018;111:436–539.30379264
25. De Castro Pereira CA Sato T Rodrigues SC New reference values for forced spirometry in white adults in Brazil J Bras Pneumol 2007 33 397 406 17982531
De Castro Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in white adults in Brazil. J Bras Pneumol. 2007;33:397–406.17982531
26. Graham BL Steenbruggen I Barjaktarevic IZ Cooper BG Hall GL Hallstrand TS Standardization of spirometry 2019 update. An Official American Thoracic Society and European Respiratory Society Technical Statement Am J Respir Crit Care Med 2019 200 e70 10.1164/rccm.201908-1590ST 31613151
Graham BL, Steenbruggen I, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand TS, et al. Standardization of spirometry 2019 update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200:e70.31613151 10.1164/rccm.201908-1590ST
27. Mitchell C Rahko PS Blauwet LA Canaday B Finstuen JA Foster MC Guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the American Society of Echocardiography J Am Soc Echocardiogr 2019 32 1 64 10.1016/j.echo.2018.06.004 30282592
Mitchell C, Rahko PS, Blauwet LA, Canaday B, Finstuen JA, Foster MC, et al. Guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the American Society of Echocardiography. J Am Soc Echocardiogr. 2019;32:1–64.30282592 10.1016/j.echo.2018.06.004
28. McDonagh TA Metra M Adamo M Gardner RS Baumbach A Böhm M 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC Rev Esp Cardiol (Engl Ed). 2022 75 523 35636830
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Rev Esp Cardiol (Engl Ed). 2022;75:523.35636830
29. Arcuri JF Borghi-Silva A Labadessa IG Sentanin AC Candolo C Di Lorenzo VAP Validity and reliability of the 6-minute step test in healthy individuals: a cross-sectional study Clin J Sport Med 2016 26 69 75 10.1097/JSM.0000000000000190 25706661
Arcuri JF, Borghi-Silva A, Labadessa IG, Sentanin AC, Candolo C, Di Lorenzo VAP. Validity and reliability of the 6-minute step test in healthy individuals: a cross-sectional study. Clin J Sport Med. 2016;26:69–75.25706661 10.1097/JSM.0000000000000190
30. Salles Albuquerque V Dal Corso S Pereira do Amaral D Medina Dutrade Oliveira T Fonseca Souza G Naara Silva de Souza R Normative values and reference equation for the six-minute step test to evaluate functional exercise capacity: a multicenter study J Bras Pneumol 2022 10.36416/1806-3756/e20210511
Salles Albuquerque V, Dal Corso S, Pereira do Amaral D, Medina Dutrade Oliveira T, Fonseca Souza G, Naara Silva de Souza R, et al. Normative values and reference equation for the six-minute step test to evaluate functional exercise capacity: a multicenter study. J Bras Pneumol. 2022. 10.36416/1806-3756/e20210511.10.36416/1806-3756/e20210511
31. Anderson TW, Theodore W. An introduction to multivariate statistical analysis. 2003;721. Available from: https://www.wiley.com/en-us/An+Introduction+to+Multivariate+Statistical+Analysis%2C+3rd+Edition-p-9780471360919.
32. Maldonado G Greenland S Simulation study of confounder-selection strategies Am J Epidemiol 1993 138 923 936 10.1093/oxfordjournals.aje.a116813 8256780
Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol. 1993;138:923–36. 10.1093/oxfordjournals.aje.a116813.8256780 10.1093/oxfordjournals.aje.a116813
33. Cohen J Statistical power analysis for the behavioral sciences Stat Power Anal Behav Sci 2013 10.4324/9780203771587
Cohen J. Statistical power analysis for the behavioral sciences. Stat Power Anal Behav Sci. 2013. 10.4324/9780203771587.10.4324/9780203771587
34. JASP—Free and User-Friendly Statistical Software (version 0.18.2). Available from: https://jasp-stats.org/.
35. Roh J Hill JA Singh A Valero-Muñoz M Sam F Heart failure with preserved ejection fraction: heterogeneous syndrome, diverse preclinical models Circ Res 2022 130 1906 1925 10.1161/CIRCRESAHA.122.320257 35679364
Roh J, Hill JA, Singh A, Valero-Muñoz M, Sam F. Heart failure with preserved ejection fraction: heterogeneous syndrome, diverse preclinical models. Circ Res. 2022;130:1906–25.35679364 10.1161/CIRCRESAHA.122.320257
36. Sullivan MJ Hawthorne MH Exercise intolerance in patients with chronic heart failure Prog Cardiovasc Dis 1995 38 1 22 10.1016/S0033-0620(05)80011-8 7631018
Sullivan MJ, Hawthorne MH. Exercise intolerance in patients with chronic heart failure. Prog Cardiovasc Dis. 1995;38:1–22.7631018 10.1016/S0033-0620(05)80011-8
37. Tucker WJ Haykowsky MJ Seo Y Stehling E Forman DE Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function Curr Heart Fail Rep 2018 15 323 331 10.1007/s11897-018-0408-6 30178183
Tucker WJ, Haykowsky MJ, Seo Y, Stehling E, Forman DE. Impaired exercise tolerance in heart failure: role of skeletal muscle morphology and function. Curr Heart Fail Rep. 2018;15:323–31.30178183 10.1007/s11897-018-0408-6
38. Zizola C Schulze PC Metabolic and structural impairment of skeletal muscle in heart failure Heart Fail Rev 2013 18 623 630 10.1007/s10741-012-9353-8 23065040
Zizola C, Schulze PC. Metabolic and structural impairment of skeletal muscle in heart failure. Heart Fail Rev. 2013;18:623–30. 10.1007/s10741-012-9353-8.23065040 10.1007/s10741-012-9353-8
39. Bassi-Dibai D Santos-de-Araújo AD Dibai-Filho AV de Azevedo LFS Goulart CDL Luz GCP Rehabilitation of individuals with diabetes mellitus: focus on diabetic myopathy Front Endocrinol (Lausanne). 2022 13 869921 10.3389/fendo.2022.869921 35498435
Bassi-Dibai D, Santos-de-Araújo AD, Dibai-Filho AV, de Azevedo LFS, Goulart CDL, Luz GCP, et al. Rehabilitation of individuals with diabetes mellitus: focus on diabetic myopathy. Front Endocrinol (Lausanne). 2022;13:869921.35498435 10.3389/fendo.2022.869921
40. Bilak JM, Gulsin GS, McCann GP. Cardiovascular and systemic determinants of exercise capacity in people with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2021;12.
41. Meyer K Westbrook S Schwaibold M Hajric R Lehmann M Roskamm H Cardiopulmonary determinants of functional capacity in patients with chronic heart failure compared with normals Clin Cardiol 1996 19 944 948 10.1002/clc.4960191208 8957598
Meyer K, Westbrook S, Schwaibold M, Hajric R, Lehmann M, Roskamm H. Cardiopulmonary determinants of functional capacity in patients with chronic heart failure compared with normals. Clin Cardiol. 1996;19:944–8.8957598 10.1002/clc.4960191208
42. Fuentes-Abolafio IJ Stubbs B Pérez-Belmonte LM Bernal-López MR Gómez-Huelgas R Cuesta-Vargas AI Physical functional performance and prognosis in patients with heart failure: a systematic review and meta-analysis BMC Cardiovasc Disord 2020 20 512 10.1186/s12872-020-01725-5 33297975
Fuentes-Abolafio IJ, Stubbs B, Pérez-Belmonte LM, Bernal-López MR, Gómez-Huelgas R, Cuesta-Vargas AI. Physical functional performance and prognosis in patients with heart failure: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2020;20:512.33297975 10.1186/s12872-020-01725-5
43. Kuziemski K Słomiński W Jassem E Impact of diabetes mellitus on functional exercise capacity and pulmonary functions in patients with diabetes and healthy persons BMC Endocr Disord 2019 19 2 10.1186/s12902-018-0328-1 30606177
Kuziemski K, Słomiński W, Jassem E. Impact of diabetes mellitus on functional exercise capacity and pulmonary functions in patients with diabetes and healthy persons. BMC Endocr Disord. 2019;19:2.30606177 10.1186/s12902-018-0328-1
44. Ingle L Reddy P Clark AL Cleland JGF Diabetes lowers six-minute walk test performance in heart failure J Am Coll Cardiol 2006 47 1909 1910 10.1016/j.jacc.2006.02.005 16682322
Ingle L, Reddy P, Clark AL, Cleland JGF. Diabetes lowers six-minute walk test performance in heart failure. J Am Coll Cardiol. 2006;47:1909–10.16682322 10.1016/j.jacc.2006.02.005
45. Berisha-Muharremi V Henein MY Dini FL Haliti E Bytyçi I Ibrahimi P Diabetes is the strongest predictor of limited exercise capacity in chronic heart failure and preserved ejection fraction (HFpEF) Front Cardiovasc Med. 2022 9 883615 10.3389/fcvm.2022.883615 35694665
Berisha-Muharremi V, Henein MY, Dini FL, Haliti E, Bytyçi I, Ibrahimi P, et al. Diabetes is the strongest predictor of limited exercise capacity in chronic heart failure and preserved ejection fraction (HFpEF). Front Cardiovasc Med. 2022;9:883615.35694665 10.3389/fcvm.2022.883615
46. Rozenbaum Z Granot Y Sadeh B Havakuk O Arnold JH Shimiaie J Sex differences in heart failure patients assessed by combined echocardiographic and cardiopulmonary exercise testing Front Cardiovasc Med. 2023 10 1098395 10.3389/fcvm.2023.1098395 36815019
Rozenbaum Z, Granot Y, Sadeh B, Havakuk O, Arnold JH, Shimiaie J, et al. Sex differences in heart failure patients assessed by combined echocardiographic and cardiopulmonary exercise testing. Front Cardiovasc Med. 2023;10:1098395.36815019 10.3389/fcvm.2023.1098395
47. Herdy AH Uhlendorf D Reference values for cardiopulmonary exercise testing for sedentary and active men and women Arq Bras Cardiol 2011 96 54 59 10.1590/S0066-782X2010005000155 21109909
Herdy AH, Uhlendorf D. Reference values for cardiopulmonary exercise testing for sedentary and active men and women. Arq Bras Cardiol. 2011;96:54–9.21109909 10.1590/S0066-782X2010005000155
48. Dimopoulou I Tsintzas OK Daganou M Cokkinos DV Tzelepis GE Contribution of lung function to exercise capacity in patients with chronic heart failure Respiration 1999 66 144 149 10.1159/000029356 10202318
Dimopoulou I, Tsintzas OK, Daganou M, Cokkinos DV, Tzelepis GE. Contribution of lung function to exercise capacity in patients with chronic heart failure. Respiration. 1999;66:144–9.10202318 10.1159/000029356
49. Echouffo-Tcheugui JB Xu H DeVore AD Schulte PJ Butler J Yancy CW Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from get with the guidelines-heart failure registry Am Heart J 2016 182 9 20 10.1016/j.ahj.2016.07.025 27914505
Echouffo-Tcheugui JB, Xu H, DeVore AD, Schulte PJ, Butler J, Yancy CW, et al. Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from get with the guidelines-heart failure registry. Am Heart J. 2016;182:9–20.27914505 10.1016/j.ahj.2016.07.025
50. Zuin M Rigatelli G Battisti V Costola G Roncon L Bilato C Increased risk of acute myocardial infarction after COVID-19 recovery: a systematic review and meta-analysis Int J Cardiol 2023 372 138 10.1016/j.ijcard.2022.12.032 36535564
Zuin M, Rigatelli G, Battisti V, Costola G, Roncon L, Bilato C. Increased risk of acute myocardial infarction after COVID-19 recovery: a systematic review and meta-analysis. Int J Cardiol. 2023;372:138.36535564 10.1016/j.ijcard.2022.12.032
51. Chagué F Boulin M Eicher JC Bichat F Saint Jalmes M Cransac-Miet A Impact of lockdown on patients with congestive heart failure during the coronavirus disease 2019 pandemic ESC Hear Fail. 2020 7 4420 10.1002/ehf2.13016
Chagué F, Boulin M, Eicher JC, Bichat F, Saint Jalmes M, Cransac-Miet A, et al. Impact of lockdown on patients with congestive heart failure during the coronavirus disease 2019 pandemic. ESC Hear Fail. 2020;7:4420.10.1002/ehf2.13016
52. Caraballo C Desai NR Mulder H Alhanti B Wilson FP Fiuzat M Clinical implications of the New York Heart Association Classification J Am Hear Assoc Cardiovasc Cerebrovasc Dis. 2019 8 e014240
Caraballo C, Desai NR, Mulder H, Alhanti B, Wilson FP, Fiuzat M, et al. Clinical implications of the New York Heart Association Classification. J Am Hear Assoc Cardiovasc Cerebrovasc Dis. 2019;8:e014240.
