Effects of resistance training on metabolic and cardiovascular responses to a maximal cardiopulmonary exercise test in Parkinson`s disease

ABSTRACT: Objective: To evaluate the effects of resistance training on metabolic and cardiovascular responses during maximal cardiopulmonary exercise testing in patients with Parkinson’s disease. Methods: Twenty-four patients with Parkinson’s disease (modified Hoehn and Yahr stages 2 to 3) were randomly assigned to one of two groups: Control or Resistance Training. Patients in the Resistance Training Group completed an exercise program consisting of five resistance exercises (two to four sets of six to 12 repetitions maximum per set) twice a week. Patients in the Control Group maintained their usual lifestyle. Oxygen uptake, systolic blood pressure and heart rate were assessed at rest and during cycle ergometer-based maximal cardiopulmonary exercise testing at baseline and at 12 weeks. Assessments during exercise were conducted at absolute submaximal intensity (slope of the linear regression line between physiological variables and absolute workloads), at relative submaximal intensity (anaerobic threshold and respiratory compensation point) and at maximal intensity (maximal exercise). Muscle strength was also evaluated. Results: Both groups had similar increase in peak oxygen uptake after 12 weeks of training. Heart rate and systolic blood pressure measured at absolute and relative submaximal intensities and at maximal exercise intensity did not change in any of the groups. Muscle strength increased in the Resistance Training but not in the Control Group after 12 weeks. Conclusion: Resistance training increases muscle strength but does not change metabolic and cardiovascular responses during maximal cardiopulmonary exercise testing in patients with Parkinson’s disease without cardiovascular comorbidities.


❚ INTRODUCTION
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by nigrostriatal dopaminergic system dysfunction and resultant motor symptoms, such as bradykinesia, resting tremor, rigidity and postural instability. (1,2) Besides motor symptoms, PD patients also tend to have metabolic and cardiovascular dysfunctions either at rest (3)(4)(5)(6) or during stressful events such as exercise. (7)(8)(9)(10) Attenuated metabolic and cardiovascular responses in submaximal and maximal cardiopulmonary exercise testing have recently been reported in patients with PD. (7) Blunted responses to exercise may increase cardiovascular risk in these patients. (11,12) Hence the significance of investigating strategies to offset such impairments.
Resistance training (RT) is recommended to PD patients in order to improve muscle strength, functionality (e.g., walking capacity) and quality of life. (13) Resistance training has also been shown to improve cardiac autonomic dysfunction at rest and during stressful conditions such as orthostatic stress in this population. (14) These findings suggest RT may also enhance cardiovascular responses to exercise. However, this hypothesis remains to be confirmed.
Resistance training has been shown to increase peak oxygen uptake (VO 2peak ) in patients suffering from other conditions (cognitive impairment, hemiparesis, etc). (15,16) Still, in PD patients in particular, RT failed to induce changes in VO 2peak (17,18) and RT-related effect remains to be confirmed. However, assessment of responses to submaximal exercise (i.e., responses at absolute submaximal workloads and ventilatory thresholds) is even more relevant in these patients, since these responses mirror effort intensity associated with daily activities. (19) Fernández-Lezaun et al., reported improvement of responses to submaximal exercise in older adults without PD following RT. (20) Enhanced cardiovascular responses to submaximal RT may improve the quality of life of these patients. (21) Despite the relevance of this topic, to the best of our knowledge the effects of training on responses to submaximal exercise have not been investigated in PD patients to date.
This study was designed to test the hypothesis that RT improves responses obtained at submaximal intensities during maximal cardiopulmonary exercise testing in patients with PD without changing maximal metabolic (i.e., VO 2 ) and cardiovascular (i.e., heart rate -HR and systolic blood pressure -SBP) parameters.

❚ OBJECTIVE
To evaluate the effects of resistance training on metabolic and cardiovascular responses during maximal cardiopulmonary exercise testing in patients with Parkinson's disease.

❚ METHODS Subjects
Volunteers were recruited from Associação Brasil Parkinson. Inclusion criteria were as follows: ≥50 years of age; stages 2 to 3 of the modified Hoehn and Yahr scale; (22) no other neurological disorder, hypertension or cardiovascular disease diagnosis; not taking medications with potential direct cardiovascular effects except for those required to treat PD; no limitations to engage in RT. Patients who experienced changes of type or dose of regular medications during the study, engaged in additional physical exercise programs or attended to less than 80% of RT sessions were excluded. einstein (São Paulo). 2021;19:1-7 This paper was based on data extracted from a larger study approved by the Ethics Committee of the Faculdade de Educação Física e Esporte of Universidade de São Paulo (2011/42) and registered at Brazilian Clinical Trials Registry (RBR-5YC53K). All patients read and signed an informed consent form prior to enrollment. Findings derived from the analysis RT effects on resting conditions have been published. (14) This paper specifically addresses responses during exercise.

Experimental design
This prospective, randomized controlled study with parallel design was conducted at the Faculdade de Educação Física e Esporte of Universidade de São Paulo, between February 2012 and March 2015. Patients with PD were randomly allocated to one of two groups: Control Group (CG) or Resistance Training Group (RTG), as previously described. (14) Physiological responses during maximal cardiopulmonary exercise testing were assessed at baseline (beginning of the study) and at 12 weeks. In the RTG, post-intervention assessments were carried out at least 48 hours after the last training session. Patients were assessed in the "on" state (i.e., action phase of medication).

Experimental procedures
Detailed description of maximal cardiopulmonary exercise testing procedures have been given elsewhere. (7) Tests were conducted on a cycle ergometer (Lode, Corival, Netherlands) by a physician with extensive experience (more than 10 years) in maximal exercise testing. Fifteen to twenty minutes prior to testing, patients were familiarized with the cycle ergometer by pedaling at a comfortable intensity for 2 to 3 minutes. Patients were then allowed to rest until cardiovascular parameters returned to baseline and tested. Individualized ramp protocols were selected to induce fatigue within 8 to 12 minutes of test start. These involved increments ranging from 3 to 15 watts per minute according PD severity and level of physical conditioning. Pedaling frequency ranged from 50 to 60rpm. Tests were discontinued whenever subjects were unable to maintain pedaling frequency. The same ramp increments were used in baseline and 12-week assessments.
Heart rate was recorded at 30-second intervals via continuous 12-lead echocardiogram monitoring (CardioPerfect ® , ST 2001, Netherlands). Auscultatory blood pressure was measured by a blinded technician every 2 minutes using a mercury sphygmomanometer. Respiratory gas exchange was measured by breath-bybreath analysis using a metabolic cart (Medical Graphics Corporation, CPX/D, United States) and data collected at 30-second intervals averaged.
Peak HR, SBP and VO 2 were defined as the highest value obtained during the exercise phase of the test and corresponded to maximal test responses. Responses to submaximal relative intensities were assessed at ventilatory thresholds (i.e., anaerobic threshold -AT -and respiratory compensation point -RCP) (23,24) determined by two independent experts, with discrepancies solved by consensus. Responses to submaximal absolute intensities were assessed by comparing the slope of the linear regression line between physiological parameters (VO 2 , HR and SBP values) recorded at baseline and after 12 weeks of exercise practice. (25) Regression was based on values measured during exercise. Individual linear regression slope lines were used in the analysis.

Interventions
The RT program consisted of two exercise sessions per week with a rest period of 3 to 4 days in-between. Training sessions were supervised by an experienced strength coach. The RT program included lower limb (horizontal leg press, squat and rotary calf) and upper limb (lat pulldown and chest press) resistance exercises. Training load increased progressively from two to four sets of six to 12 repetition maximum (RM), as detailed elsewhere. (14) Training load increments were as follows: first and second weeks, two sets of 10-12 RM; third and fourth weeks, three sets of 10-12 RM); fifth and sixth week, three sets of 8-10 RM; seventh to tenth week, four sets of 8-10 RM; 11 st and 12 nd weeks, four sets of 6-8 RM. The rest period between exercises and sets was 2 minutes. Workload increased progressively throughout the intervention period. Load increments were introduced whenever patients were able to execute two consecutive sessions with the same load.
Patients in the CG were instructed to maintain their usual lifestyle during the experimental period and were evaluated at baseline and at 12 weeks only. einstein (São Paulo). 2021;19:1-7

Muscle strength
Resistance training efficacy was estimated according to muscle strength. After two familiarization sessions 48 hours apart, muscle strength was assessed using the 1RM test in the leg press exercise, as per the Brown et al., protocol (26) and details given elsewhere. (14) Muscle strength was reassessed at 12 weeks.

Statistical analysis
Data normality and homogeneity were investigated using the Shapiro-Wilk and Levene test respectively. Data were submitted to logarithmic transformation as needed (i.e., HR peak , HR slope and VO 2slope ). Patient characteristics were compared between groups using the t or the χ 2 test. Two-way mixed design analysis of variance (ANOVA -análise de variância) using group (CG versus RTG) as a between main factor and time (baseline and 12 weeks) as a within main factor was conducted to examine the effects of RT. Whenever F-values were significant, the Newman-Keuls post-hoc test was used for multiple comparisons. Variables (i.e., SBP) that differed between groups at baseline were submitted to covariance analysis (ANCOVA -análise de covariância) using baseline values as covariates. Effect size (ES) was calculated for each outcome using Cohen's d. (27) Effect size was categorized as small (ES≤0.49), medium (ES 0.50-0.79) or large (ES≥0.80). The level of significance was set at p<0.05. Data were expressed as means±standard deviation.

❚ RESULTS
Forty-four PD patients signed the informed consent form. Of these, 30 were randomly allocated to the RTG (n=15) or the CG (n=15). Four patients in the CG and two patients in the RTG dropped out of the study during the intervention period. A total of 24 patients completed the study (11 and 13 patients, CG and RTG, respectively) and had their data analysed (Figure 1).
Baseline VO 2peak did not differ between groups. However, both groups experienced similar significant increase in VO 2peak after the intervention (F [1,22] = 0.0338; p=0.86 and p<0.01, interaction effect and main effect of time respectively) ( Table 2). Resting VO 2peak AT and RCP were also similar between groups at baseline and remained unchanged over time. Likewise, peak VO 2 increase according to workload increments (slope line between VO 2 and workload) was similar between groups and remained unchanged over time.
Heart rate measured at rest, AT, RCP and maximal exercise, and HR slope increment per watt during testing were similar between groups and remained unchanged after 12 weeks of RT. Likewise, SBP measured at, RCP and maximal exercise, and SBP slope increment per watt during testing did not differ between groups and did not change after 12 weeks of RT.

DISCUSSION
The main finding of this study was that RT increased lower limb muscle strength but had no impact on metabolic and cardiovascular responses obtained at maximal or absolute and relative submaximal intensities during maximal cardiopulmonary exercise testing in patients with PD. Lower limb muscle strength increase in RTG relative to the CG emphasizes the effectiveness of the training protocol employed in this study. Similar findings have been reported in previous studies, (17,18) in which lower limb strength also increased after RT. Neuroplastic changes in the primary motor cortex and neural adaptation to RT may explain the initial increase in lower limb strength in these patients. (28)(29)(30) Such strength gains may be of clinical significance in this population, given muscle mass and strength losses are correlated with poorer quality of life in patients with PD. (31) Significant similar VO 2peak increase at 12 weeks in both groups indicates improvements cannot be attributed to the RT program. In fact, the increase observed in the CG suggests a learning effect of multiple tests. A previous study (32) with PD patients submitted to three maximal cardiopulmonary exercise tests on different days revealed significant increases in VO 2peak between the first and the second test. Patients in this study may have experienced similar effects.
The lack of effect of RT on VO 2peak is in keeping with previous studies that also failed to detect changes in VO 2peak in response to RT in patients with PD. (17,18) This finding is also consistent with a previous study conducted by this research group, (25) in which VO 2peak remained unchanged after 16 weeks of resistance and power training in healthy elderly. In contrast, studies conducted with other populations of adult patients with neurological impairments or chronic neurologic diseases (cognitive impairments or chronic hemiparesis) reported VO 2 increase after RT. (15,16) This discrepancy may reflect different pathophysiological changes in different neurological diseases and their respective impact on patient response to RT. Therefore, it could be argued that, at least in patients with mild to moderate stage PD, RT has no effect on VO 2peak .
A differential of this study was the investigation of submaximal exercise parameters which are less impacted by motor disabilities associated with PD. (33) For this purpose, patients were assessed at both absolute and relative submaximal exercise intensities. Responses to absolute submaximal intensity were assessed according to metabolic and cardiovascular changes in response to workload increments, whereas responses to relative submaximal intensity were assessed at AT and RCP. Contrary to the research hypothesis, RT had no impact on VO 2 , HR or SBP responses at absolute and relative submaximal intensities. This finding is congruent with a previous study addressing responses to RT at absolute and relative submaximal intensities in subjects without PD. (25) Therefore, is spite selection of parameters which are less affected by the disease-related limitations, this study failed to demonstrate significant impacts of RT on responses during progressive exercise testing. Enhanced metabolic and cardiovascular responses during maximal cardiopulmonary exercise testing are associated with better quality of life in patients with PD. Such responses have been obtained with aerobic training in this population. (18,34) Still, RT can improve muscle strength, functionality (e.g., walking capacity) and quality of life in patients with PD. (17,18,26,28,29,33,35) Findings of this study support recommendations of combined aerobic and strength training in exercise programs designed for patients in the mild to moderate stages of PD.

Study limitations
This study has some limitations. Exclusion of patients diagnosed with hypertension or any other cardiovascular disease limited sample size. However, such exclusions were deemed important to tease out the effects of RT on metabolic and cardiovascular changes inherent to PD. Also, selected patients were at stages 2 to 3 of the modified Hoehn & Yahr scale. Therefore, findings may not apply to patients in other stages of PD.

❚ CONCLUSION
Twelve weeks of resistance training improves lower limb muscle strength but does not affect metabolic or cardiovascular responses obtained at submaximal and maximal intensities during maximal cardiopulmonary exercise testing in patients with Parkinson's disease with no cardiovascular comorbidities.