Association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease: A cross-sectional study.

INTRODUCTION: The risk of malnutrition is an important predictor of functional capacity in the elderly population. However, whether malnutrition is associated with functional capacity in patients with peripheral artery disease (PAD) is poorly known.
PURPOSE: To analyse the association between the risk of malnutrition and functional capacity in patients with PAD.
METHODS: This cross-sectional study included 135 patients with PAD of both genders, ≥50 years old, with symptomatic PAD (Rutherford stage I to III) in one or both limbs and with ankle-brachial index ≤0.90. The risk of malnutrition was assessed by the short form of the Mini Nutritional Assessment-Short Form and patients were classified as having normal nutritional status (n = 92) and at risk of malnutrition (n = 43). Functional capacity was objectively assessed using the six-minute walking test (6MWT, absolute maximal distance and relativized and expressed as a percentage of health subjects), short-physical performance battery (SPPB, balance, gait speed and the sit and stand test) and the handgrip test, and subjectively, using the Walking Impairment Questionnaire and Walking Estimated-Limitation Calculated by History. The association between the risk of malnutrition and functional capacity was analysed using bivariate and multivariate logistic regression adjustments for gender, age, ankle-brachial index, body mass index, use of statins, coronary arterial disease and stroke. For all statistical analyses, significance was accepted at p<0.05.
RESULTS: Thirty-two per cent of our patients were classified with a risk of malnutrition. The risk of malnutrition was associated with the absolute 6MWT total distance (OR = 0.994, P = 0.031) relative 6MWT total distance (OR = 0.971, P = 0.038), lowest SPPB total score (OR = 0.682, P = 0.011), sit and stand (OR = 1.173, P = 0.003) and usual 4-meter walk test (OR = 1.757, P = 0.034).
CONCLUSION: In patients with PAD, the risk of malnutrition was associated with objective measurements of functional capacity.

Introduction

Peripheral artery disease (PAD) is characterised by a systemic arteriosclerotic process, which results in partial or total obstruction in the arteries of the lower limbs [1]. The most common symptom of PAD is claudication [2], consisting of pain or cramp during walking that is relieved at rest. The symptoms of claudication affect about 20 to 50% of patients with PAD, leading to reduced levels of physical activity [3], functional capacity [4] and quality of life [5].

Impaired nutritional status has been considered an additional risk factor for the severity of the PAD [6, 7]. A study by Thomas et al. [8] observed that approximately 78% of patients admitted for vascular surgery were classified as malnourished. Additionally, another study [7] found that 38% of patients submitted to endovascular surgery were malnourished. The risk of malnutrition can be evaluated through Mini Nutritional Assessment-Short Form (MNA-SF), a valid and simple nutritional screening tool [9, 10], which can be easily applied in clinical settings. The MNA-SF consists of six items related to food intake, weight loss, mobility, stress or acute illness, neuropsychological disorders and body-mass index values. The questionnaire score ranges from 0 to 14 points, and individuals are classified as: malnourished (MNA-SF score ≤7), at risk of malnutrition (MNA-SF score ≥8 ≤11) or normal nutritional status (MNA-SF score ≥ 12) [9, 11].

Interestingly, in previous studies risk of malnutrition, an intermediate classification of nutritional status, was associated with reduced functional capacity and lower limb strength in healthy elderly [12] and patients with long-term conditions such as stroke [13], renal failure [14], diabetes [15] and chronic obstructive pulmonary disease [16]. Thus, this study aimed to analyse the association between the risk of malnutrition and functional capacity in patients with symptomatic PAD. Our hypothesis is that malnutrition has an additional factor to functional impairments.

Methods

Study design

This observational cross-sectional study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [17]. Functional capacity was assessed using objective tests (six-minute walk test, Short-Physical Performance Battery and handgrip strength) and subjective tools such as the Walking Impairment Questionnaire (WIQ) and Walking Estimated-Limitation Calculated by History (WELCH). The sample was evaluated according to nutritional status using MAN-SF and was classified as “at risk of malnutrition" and "normal nutritional status". The functional capacity parameters were compared between groups.

Sample and data collection

Patients were recruited at a tertiary center specializing in vascular disease in São Paulo—Brazil. Data collection was carried out between September 2015 and October 2019. All patients were instructed regarding the experimental procedures and signed informed written consent before participation. This study was approved by the ethics committee of Hospital Israelita Albert Einstein, Brazil and Hospital das Clinicas, University of Sao Paulo, Brazil.

We included patients of both genders, ≥50 years old, with symptomatic PAD (Rutherford stage I to III) in one or both limbs, ankle-brachial index ≤0.90 [18]. Patients with non-compressible vessels, amputated limbs and/or ulcers, and low cognitive levels (<17 of the Montreal Cognitive Assessment) [19] were excluded.

Clinical data

A standardised interview was conducted, including an evaluation of sociodemographic information, such as age and gender (male or female) and conditions of comorbidities (doctor-diagnosed history and medications). Current smoking, obesity (body mass index ≥30 kg/m2), diabetes (doctor-diagnosed or use of drugs), hypertension (doctor-diagnosed or antihypertensive drugs), dyslipidaemia (doctor-diagnosed or use of medication) and coronary heart disease (doctor-diagnosed or use of drugs) were assessed.

Dependent variable: Risk of malnutrition

The risk of malnutrition was assessed through the MNA-SF [10], which consists of six questions based on conditions of self-visualization of food intake (0 to 2 points), weight loss (0 to 3 points), mobility (0 to 2 points), psychological stress (0 or 2 points), neuropsychological problems (0 to 2 points) and a measure of body mass index (0 to 3 points). The sum of the points provides scores ranging from 0 to 14. Patients were classified as: ≤ score 7 as "malnourished", score 8 to 11 as "at risk of malnutrition", and score ≥ 12 as "normal nutritional status" [15].

Independent variables

Objective measurements of functional capacity

The six-minute walk test. The 6MWT [20] consists of walking for six minutes in a 30-meter long flat corridor, and patients were encouraged to "walk at the usual pace" and instructed to rest when necessary. The 6MWT total distance was defined as the maximum distance achieved by the patients at the end of the test. In addition, the 6MWT total distance was relativised based on the results of 6MWT performed by healthy individuals using Brito’s et al. equation [21], previously used in patients with PAD [22].

Short Physical Performance Battery. The SPPB [23] comprises a group of tests involving balance, gait speed and the sit and stand test. The balance consisted of the patient remaining in each timed foot position for 10 seconds (feet side by side, semi-tandem and tandem), and the evaluator demonstrated each position. The gait speed consisted of the patient walking for 4 meters twice in a usual and fast way, being the fastest time used for the analysis. The sit and stand test required the initially seated patient to get up from the chair five times with arms flexed over the chest as quickly as possible, and time recorded. Each test score ranged from 0 to 4, and the total score was calculated by adding scores of three tests, ranging from 0 to 12, being 0 in the worst function and 12 in the best function [24].

Handgrip Strength Test. The handgrip strength test was obtained through isometric contractions using a digital dynamometer (EH101, Camry, USA) adjusted and calibrated on a scale from 0 to 100 kgf. The patient was seated with feet resting on the ground, and elbows flexed to 90 degrees and forearms and wrists in a neutral position. Three maximum voluntary contractions of five seconds were performed in both arms with an interval of one minute between each attempt. We considered the highest value for the analysis [25].

Subjective measurements of functional capacity

Walking Impairment Questionnaire. The WIQ [26] is an instrument that provides self-reported indicators of the walking capacity of patients with PAD and claudication symptoms in different situations, such as walking distance, walking speed and ability to climb stairs. The total score ranges from 0 to 100, where 0 represents extreme limitation, and 100 represents no walking difficulties.

Walking Estimated-Limitation Calculated by History. The WELCH [27] is a questionnaire that presents four questions related to the speed and time the patient can walk compared to relatives, friends or individuals of the same age without PAD. The total score ranges from 0 to 100, with 0 indicating a patient who can walk for 30 seconds slower than relatives, friends or colleagues in the same age group, and a score of 100 indicates who can walk for three hours compared to people in the same age group.

Statistical analysis

We describe the data in median (interquartile interval) or frequency. The association between the risk of malnutrition and functional capacity was analysed using bivariate and multivariate logistic regression analysis with adjustment for gender, age, ankle-brachial index, body mass index, use of statins, coronary arterial disease and stroke, which are classical confounders in PAD [28, 29]. The p<0.05 value was considered significant. All statistical analyses were performed with SPSS version 25.0 (IBM Corporation, SPPS Inc, Chicago, IL).

Results

Three hundred and two patients were recruited. However, 31 patients were excluded because they did not answer the MNA-SF questionnaire, and 112 patients were due to the low score on the cognitive assessment, since these patients were probably not able to answer the questionnaires correctly, and this could be a confounding fact in the analyses and 21 excluded for not performing the 6MWT. Furthermore, only three patients were classified as malnourished and were excluded due to the insufficient sample size. Thus, we analysed the data of 135 patients, 68% of patients were classified as having normal nutritional status, and 32% were classified as at risk of malnutrition. The flowchart of the study is shown in Fig 1.

Fig 1

Flowchart of the study.

The characteristics of the patients with normal nutritional status and risk of malnutrition are presented in Table 1.

Table 1

Clinical characteristics of patients with peripheral arterial disease associated with the risk of malnutrition n = 135.

Variables	N	Normal nutritional status	N	Risk of malnutrition	P
Age (years)	92	65 (11)	43	64 (10)	0.780
Sex (men, %)	92	68	43	53	0.092
Weight (kg)	92	74 (19)	43	72 (18)	0.269
Body mass index (kg/m2)	92	27 (5)	43	27 (9)	0.654
Ankle/brachial index	92	0.60 (0.24)	43	0.59 (0.27)	0.850
Risk Factors (%)
Smoke	91	20	43	22	0.763
Hypertension	92	83	43	81	0.769
Diabetes Mellitus	92	54	42	53	0.893
Dyslipidemia	92	76	43	81	0.426
Coronary disease	89	36	41	32	0.580
Stroke	89	9	41	16	0.204
Cancer	86	12	43	13	0.849
Revascularization	86	19	41	12	0.292
Heart failure	88	12	39	12	0.960
Medications (%)
Statins	73	91	32	81	0.118
Vasodilators	73	34	32	31	0.764
Antiplatelet	73	86	32	81	0.507
Beta blockers	73	50	32	37	0.213
Diuretics	73	39	32	50	0.266
ACE inhibitors	73	24	32	18	0.504
ARA	73	29	32	25	0.691
MNA- SF components
Food Intake (0,1,2)	92	2(0)	43	2 (1)	0.000
Weight loss (0,1,2,3)	92	3 (0)	43	1 (2)	0.000
Mobility (0,1,2,3)	92	2 (0)	43	2 (0)	0.196
Psychological/ acute disease (0,2)	92	2 (0)	43	2 (2)	0.013*
Neurophysiological (0,1,2)	92	2 (0)	43	2 (0)	0.022*
BMI classification (0,1,2,3)	92	3 (0)	43	3 (1)	0.005*

The values are presented as median (interquartile range) or relative frequency. BMI—body mass index.; ACE = angiotensin-converting-enzyme; ARA = angiotensin receptor antagonist.

The characteristics and prevalence of risk factors were similar between groups. Patients at risk of malnutrition presented more prevalence of psychological stress/acute diseases (P = 0.013), neuropsychological problems (P = 0.022) and a lower BMI classification (P = 0.005).

Table 2 shows the association between the risk of malnutrition and functional parameters in PAD patients.

Table 2

Logistic regression bivariate and multivariate modelling, associations between at risk of malnutrition and functional parameters in PAD participants.

	Bivariate Model				Adjusted Model
Independent Variables	N	OR	CI 95%	P	N	OR	CI 95%	P
Absolute 6MWT total distance, m	135	0.996	0.993; 1.000	0.056	101	0.994	0.989; 0.999	0.031*
Relative 6MWT total distance, %	135	0.983	0.963: 1.003	0.103	101	0.971	0.944: 0.998	0.038*
SPPB, total score	124	0.783	0.638; 0.961	0.019*	91	0.682	0.509; 0.915	0.011*
Sit and stand 5 times, sec	124	1.098	1.031; 1.170	0.003*	91	1.173	1.056; 1.304	0.003*
4-meter usual walk, m/s	124	1.410	1.016; 1.958	0.040*	91	1.757	1.043; 2.959	0.034*
4-meter fast walk, m/s	124	1.336	0.903; 1.977	0.148	91	1.535	0.888; 2.652	0.125
Handgrip strength, kgf	133	0.980	0.947; 1.014	0.248	100	0.978	0.936: 1.022	0.330
WIQ distance, score	133	0.993	0.977; 1.010	0.434	101	0.987	0.966; 1.009	0.260
WIQ speed, score	133	0.983	0.958; 1.009	0.204	101	0.983	0.949; 1.017	0.322
WIQ stars, score	133	0.992	0.978; 1.007	0.992	101	0.994	0.975; 1.014	0.578
Total WIQ, score	133	0.990	0.964; 1.008	0.213	101	0.982	0.953; 1.013	0.259
WELCH total, score	135	0.983	0.972; 1.008	0.265	101	0.987	0.963; 1.011	0.274

SPPB- Short Physical Performance Battery, WIQ -Walking Impairment Questionnaire, WELCH—Walking Estimated-Limitation Calculated by History. Adjusted model. For gender: Age, ankle-brachial index, body mass index, statins use, diabetes mellitus, coronary arterial disease and stroke.

We observed a significant association between the risk of malnutrition and functional capacity after adjustments in absolute (OR = 0.994; P = 0.031) and relative (OR = 0.971, P = 0.038) values of 6MWT, SPPB (OR = 0.682; P = 0.011) sit and stand test (OR = 1.173, P = 0.003), usual 4-meter (OR = 1.757, P = 0.034).

Discussion

The main findings of this study were; a) 32% of our sample were classified at risk of malnutrition, and; b) the risk of malnutrition was associated with lower walking distance and lower limb strength.

In the present study, we used the MNA-SF questionnaire to assess the risk of malnutrition in PAD patients. This questionnaire has been used in several populations, such as healthy individuals and patients with different chronic diseases [15, 16, 30]. Still, until the present study, MNA-SF was not explicitly used in PAD. Using this questionnaire, we demonstrated that 32% of our patients were classified as at risk of malnutrition. These values are similar to those observed in patients with diabetes mellitus [15] and heart failure [30], with a prevalence of 33% and 30%, respectively.

We demonstrated that the risk of malnutrition was associated with objective measurement of functional capacity analysed by the absolute and relative six-minute walking test, usual 4-meter and sit and stand test, independently of classical PAD confounders. These results demonstrated that nutritional status is related to walking distance and lower limb strength, both crucial components of overall health in PAD patients [31]. Our study did not examine the possible physiological mechanisms, but some hypotheses can explain these associations. Evidence indicates that inadequate nutrition may favour the progression of inflammation in the epithelium [32], due to high blood concentrations of LDL [33] and changes in the immune system [34], such as the release of cytokines and chemokines [35] that contribute to accelerating the atherosclerotic narrowing of the arteries. In addition, low intake of nutrients, especially vitamin D [36], fibers and antioxidants can promote mitochondrial dysfunction, leading to an alteration in ATP synthesis [37], causing impairment in muscle oxygen perfusion [38], altering skeletal muscle function in density, contractility and strength in the lower limbs, which would contribute to the greater functional decline [39].

In the present study, we did not observe the association between the risk of malnutrition with subjective measures of functional capacity using a specific questionnaire for PAD patients such as WIQ and WELCH. One possible explanation is that the subjective method may underestimate the values of functional capacity when compared to objective methods [40]. Furthermore, physical exertion performed in objective methods of function capacity (such as 6MWT and gait speed) can differ from the patient’s daily activity. This might explain the lack of association with self-perception of PAD-induced walking impairments.

Regarding practical implications, our results may draw attention to healthcare providers to determine the nutritional status of patients with PAD, since we observed a high prevalence of risk of malnutrition and being at risk of malnutrition can lead to a significant decline in walking capacity and lower limb strength. As a result, the MNA-SF could be easily applied in clinical practice to identify patients at risk of malnutrition with time efficiency (with an average application time of three minutes), helping to decide on better treatment strategies (nutrition, exercise, etc.) for these patients.

This study has some limitations. This is a cross-section study that does not allow us to establish causality. Due to the small number of cases, malnutrition was not analysed, which could provide information on the magnitude of the outcomes. The use of self-reported assessments is susceptible to information bias.

In conclusion, the risk of malnutrition was associated with lower functional capacity and lower limb strength. These results suggest that assessment of nutritional status could help define therapeutic approaches in symptomatic PAD patients.

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Reviewer #1: 1. The authors are commended for their work.

2. I still continue to see the term "intermittent claudication" used in some (but not all) vascular publications. The nomenclature using the term "intermittent" seems at least to this reviewer, to be outdated. The ACC/AHA guidelines do not refer to it in this way and we don't typically refer to angina as "intermittent angina" so consider just referring to the symptom as "claudication."

3. Abstract, line 40: Revise the sentence "We considered as significant p<0.05" as it is awkward as written.

4. Abstract, line 42: Do the authors mean distance achieved during the six minute walk test, claudication onset time? Please clarify absolute and relative as well, typically six minute walk test distance is a key performance outcome often reported.

5. Abstract, line 43: Lower SPPB total score?

6. Risk of malnutrition and peripheral arterial disease are already in the title so consider different keywords.

7. Introduction, line 62: Minor but change "lower limbs strengths" to "lower limb strength".

8. Were other comorbidities exclusionary? For example, patients with heart failure, previous cardiac and/or peripheral revascularization, those taking medications to treat PAD (cilostazol, etc) were excluded? These and other comorbidities could have had an impact on functional testing so please clarify or perform analyses controlling for these variables.

9. For the six minute walk test, why were patients asked to complete it at their usual pace, rather than as fast as they could?

10. Discussion, lines 225-226: Please revise "worst perfusion".

11. Table 1: Minor, but there is a typo (Phycological).

12. I appreciate Table 2 and the information it provides, but I think it would be helpful for readership to provide a figure(s) to graphically display some of the data if possible.

13. The paper would benefit from additional copy editing for the English language.

Reviewer #2: The manuscript studies the association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease and claudication. The disease process and associated co-morbidities can lead to poor quality diet and low levels of functional capacity sometimes complete immobility, with resultant energy, protein, and micronutrient deficiencies. This research attempts to emphasize that a proper diet maybe improve the functional capacity of patients with peripheral arterial disease and claudication, which implies dietetic care plays a vital role in the management of PAD. Before I can recommend it for publication, the following questions and comments should be addressed.

1)An review published in 2020 year demonstrated that most patients with PAD are overweight or obese, 3/4 under sub-optimal nutritional status and high-fat mass, lower vitamins, and minerals. I suggest the authors explain the definition of malnutrition in people with PAD clearly.

2)I notice that the SPPB is consist of a series test. I suggest the authors explain it in the abstract section briefly. Now, the methods part and the results part are not a one-to-one correspondence.

3)The authors only concluded the association between the risk of malnutrition and objective measurements of functional capacity in patients with peripheral arterial disease and claudication. How about the association between the risk of malnutrition and subjective measurements of functional capacity in patients with peripheral arterial disease and claudication?

4)For the relationship between functional capacity and PAD, I suggest the authors give an explicit explanation.

5)For the relationship between nutritional status and PAD, I suggest the authors give an explicit explanation.

6)For the applicability of MNA-SF in brazil’s PAD, I suggest the authors give an explicit explanation.

7)In lines 72-79, it is not clear why the authors want to invest the association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease and claudication. I suggest the authors give an explicit explanation.

8)In lines 99-101, the inclusion criteria are inconsistent with the abstract section. How about the assessment of claudication？

9)In lines 202-206, the results section, it is not clear the association between the risk of malnutrition and subjective measurements of functional capacity (WIQ, and WELCH) in patients with peripheral arterial disease and claudication, and the balance with the risk of malnutrition.

10)In lines 225-228, it is not clear how nutritional deficiency aggravates the functional capacity in people with PAD and claudication.

11)In lines 244-246, there are some wrong descriptions. it is not clear whether functional capacity is due to nutritional deficiency in this study.

12)In addition, I suggest the authors improve the presentation by considering the following minor changes:

Line 40, “per cent” -> “percent”,

Line 73, the questionnaire used in references 13 and 14 should be MNA instead of MAN-SF.

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Reviewer #1: No

Reviewer #2: Yes: Yameng Li

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10 Jun 2022

May 2022

Dear Editor

The revised version of the manuscript entitled "Association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease: A cross-sectional study" is attached.

We have revised the manuscript following the reviewers' comments and have included changes to the manuscript highlighted in blue text in the marked version of the manuscript. We hope you find this article suitable for publication. Thank you for your time and consideration.

Sincerely,

Reviewer #1: 1. The authors are commended for their work.

2. I still continue to see the term "intermittent claudication" used in some (but not all) vascular publications. The nomenclature using the term "intermittent" seems at least to this reviewer, to be outdated. The ACC/AHA guidelines do not refer to it in this way and we don't typically refer to angina as "intermittent angina" so consider just referring to the symptom as "claudication."

Thanks for your comments. We revised and updated the term "claudication" as requested.

3. Abstract, line 40: Revise the sentence "We considered as significant p<0.05" as it is awkward as written.

Yes, we change the sentence objectively.

4. Abstract, line 42: Do the authors mean distance achieved during the six-minute walk test, claudication onset time? Please clarify absolute and relative as well, typically six-minute walk test distance is a key performance outcome often reported.

Thanks for the questions. We analyzed the six-minute walk test as the maximal distance (absolute) achieved at the end of the test. Further, we have recently expanded the possibility of analysis of the six-minute walk by adjusting the results for a healthy subject (relative) with similar characteristics (Please see: PMID: 32800882).

5. Abstract, line 43: Lower SPPB total score?

Yes, we found significantly lower scores in the SPPB total score in patients at risk of malnutrition and when we analyzed the SPPB separated by all tests. We modified this expression in the text.

6. Risk of malnutrition and peripheral arterial disease are already in the title, so consider different keywords.

Yes, we changed the keywords as requested by the reviewer.

7. Introduction, line 62: Minor but change "lower limbs strengths" to "lower limb strength".

Yes, we corrected the term.

8. Were other comorbidities exclusionary? For example, patients with heart failure, previous cardiac and/or peripheral revascularization, those taking medications to treat PAD (cilostazol, etc.) were excluded? These and other comorbidities could have had an impact on functional testing so please clarify or perform analyses controlling for these variables.

Yes, we reanalyzed and inserted the variables suggested by the reviewer in the manuscript table.

9. For the six-minute walk test, why were patients asked to complete it at their usual pace, rather than as fast as they could?

Because the main limitation of PAD is the pain in the lower limbs during walking, we recommend patients walk at the usual pace to avoid them stopping earlier during the test. In addition, they also were advised by the researchers that the goal of the six-minute walk test is to achieve the greatest distance possible by walking back and forth along a 30 m corridor for six minutes, which is in accordance with the 6MWT recommendation for PAD (please see: 10.1161/CIRCULATIONAHA.114.007002)

10. Discussion, lines 225-226: Please revise "worst perfusion".

Yes, we changed the text and better explained the perfusion time for the vascular aspect.

11. Table 1: Minor, but there is a typo (Phycological).

Thank you, we corrected the word.

12. I appreciate Table 2 and the information it provides. Still, I think it would be helpful for the readership to give a figure(s) to display some of the data, if possible, graphically.

Thank you for your suggestion. Because we used logistic regression analysis, we believe that a table is the most suitable representation method to inform the reader

13. The paper would benefit from additional copy editing for the English language.

Yes, we will insert an editable copy in the English language.

Reviewer #2: The manuscript studies the association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease and claudication. The disease process and associated co-morbidities can lead to poor quality diet and low levels of functional capacity sometimes complete immobility, with resultant energy, protein, and micronutrient deficiencies. This research attempts to emphasize that a proper diet maybe improves the functional capacity of patients with peripheral arterial disease and claudication, which implies dietetic care plays a vital role in the management of PAD. Before I can recommend it for publication, the following questions and comments should be addressed.

1)An review published in 2020 year demonstrated that most patients with PAD are overweight or obese, 3/4 under sub-optimal nutritional status and high-fat mass, lower vitamins, and minerals. I suggest the authors explain the definition of malnutrition in people with PAD clearly.

Thanks for the question. When we seek to better understand malnutrition and PAD, we found that malnutrition, according to the World Health Organization, the term "malnutrition" is related to both the lack of essential nutrients and the imbalance or excess in the intake of nutrients such as carbohydrates. and saturated fats. Yes, we agree with your quote, we found in the studies with the PAD that the patients were overweight, but in the food and/or blood analysis, they had significant nutrient deficiencies that impacted their functional capacity. Low body weight is considered an indicator of malnutrition, let's say "more noticeable", but other factors must be analyzed. We did not find significant differences between the groups regarding weight or BMI.

2)I notice that the SPPB consists of a series test. I suggest the authors explain it in the abstract section briefly. Now, the methods part and the results part are not a one-to-one correspondence.

Yes, we have inserted this item in the abstract. (Line 34)

3)The authors only concluded the association between the risk of malnutrition and objective measurements of functional capacity in patients with peripheral arterial disease and claudication. How about the association between the risk of malnutrition and subjective measures of functional capacity in patients with peripheral arterial disease and claudication?

We did not find significant statistical differences in the subjective measures of functional capacity, which could be explained by the fact that the patient's main limiting factor is the pain when they are walking, thus underestimating their functional capacity in the questionnaire responses. When objectively evaluated, they presented better performance.

4)For the relationship between functional capacity and PAD, I suggest the authors give an explicit explanation.

The presence of claudication symptoms decreases the walking ability of patients with PAD. Pain during walking makes the patient seek strategies to avoid the symptoms of claudication, which is usually done by reducing physical activity levels. A sedentary lifestyle, in turn, impairs the components of physical fitness and indicators of quality of life. In addition, these limitations can lead to loss of independence, increased hospitalization and mortality rates.

5)For the relationship between nutritional status and PAD, I suggest the authors give an explicit explanation.

As demonstrated in studies on PAD, inadequate nutrition may promote the progression of the inflammatory process on the epithelium and changes to the immune system that contributes to atherosclerotic plaque development. And atherosclerotic narrowing of the lower limbs' arteries but related to reduced muscle perfusion and reduced oxygenation that can change skeletal muscle function in density, contractility, and strength that compromise mobility. We have included this explanation in the discussion section.

6)For the applicability of MNA-SF in brazil’s PAD, I suggest the authors give an explicit explanation.

The MNA-SF in Brazil is a validated questionnaire, easy to apply and understand by the patient, and the average application time is only three minutes. We were able to use it during the patient's consultation at the Hospital.

7)In lines 72-79, it is not clear why the authors want to invest the association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease and claudication. I suggest the authors give an explicit explanation.

We choose to study malnutrition because previous studies have been showing that impaired nutritional status has been considered an additional risk factor for the severity of PAD. For example, a study conducted by McDermott demonstrated that deficiency in vitamin D was associated with lower muscle density and poor functional capacity. In another study conducted by Gardner et al. the diet of patients with PAD was monitored according to their national nutritional recommendations and it was shown that about 35% followed an average of 50% of the recommendations and none followed the recommendations completely and low nutrient intake was significantly associated with shorter distances in the six-minute walk test. Thus, malnutrition may be considered a risk factor which can promote a more significant function decline in PAD patients.

8)In lines 99-101, the inclusion criteria are inconsistent with the abstract section. How about the assessment of claudication？

Yes, we added the inclusion criteria in the abstract as the manuscript as suggested by the reviewer. We did not include any questionnaire to assess claudication symptoms.

9)In lines 202-206, the results section, it is not clear the association between the risk of malnutrition and subjective measurements of functional capacity (WIQ and WELCH) in patients with peripheral arterial disease and claudication, and the balance with the risk of malnutrition.

We did not find an association between subjective measures (WIQ and WELCH) and balance and risk of malnutrition. We believe that patients have difficulty with self-perception in reporting their functional capacity and balance because it is a relatively easy test where the patient needs to remain in the position for 10 seconds. Most patients were able to perform this test.

10)In lines 225-228, it is not clear how nutritional deficiency aggravates the functional capacity in people with PAD and claudication.

In the figure below, we seek to explain the possible mechanisms involved in the worsening of PAD in patients at risk of malnutrition. We included the possible mechanisms in the discussion section.

11)In lines 244-246, there are some wrong descriptions. it is not clear whether functional capacity is due to nutritional deficiency in this study.

Thank you for the question. Functional capacity is impaired in patients with PAD, and this finding is established in the literature, but we believe that nutritional status may have an additional factor in this impairment.

12)In addition, I suggest the authors improve the presentation by considering the following minor changes:

Line 40, “per cent” -> “percent”,

Line 73, the questionnaire used in references 13 and 14 should be MNA instead of MAN-SF.

Yes, we made the corrections.

Submitted filename: Response to Reviewers.docx

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4 Jul 2022

Submitted filename: Yameng June 23.Comments to the Authors.docx

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28 Jul 2022

Dear Reviewers

We have revised the manuscript following the reviewers' comments and have included changes to the manuscript and hope to consider it suitable for publication.

Reviewer #1:

2. Abstract line 45: Typo, change “analyzes” to “analyses.”

Thank you very much for the observation. It has been changed in the text. (Line 43).

3. Introduction: PAD is understood to be referring to atherosclerotic plaque development in the lower limbs. Thus consider changing the opening sentence to “…which results in partial or total obstruction in the arteries of the lower limbs.” and delete “…especially in the lower extremities.”

We have changed it according to the reviewer's suggestion. (Line 57).

4. Please include a hypothesis at the end of the Introduction section.

As suggested, we included the study hypothesis at the end of the introduction. (Line 81).

5. Page 5, line 10: “were” is repeated please delete.

Yes, we deleted it. (Line 105 - 107).

6. Page 5 and 6, lines 130-131: Delete the level of accuracy of height and weight measurements. It is awkward as written so if you do want to keep it please revise to clarify.

We followed the reviewer's important suggestion and removed it from the text.

7. Page 6 lines 141-142: Bad grammar in the sentence starting with “The data are…” Please revise.

Thank you, we modified the text. (Line 133 – 136).

8. Page 6 line 151: Why is there a bracket at the end of the sentence ending in “…stand test.”?

Yes, we changed. (Line 143).

9. Page 7 line157: I thought both gender were included so please change the term “his” to include both. Also in the same sentence the statement “…and the time was timed.” is awkward. Did the authors mean and the total time was recorded?

Thank you for this consideration. We have revised the grammar of this paragraph. (Line 147 – 149).

10. “His” seems to continue to be used which needs to be changed.

Yes, we changed.

11. Line 219: missing a period.

Thank you, we changed. (Line 211).

12. It would be helpful for the raw/continuous values of the outcomes were reported (e.g., 6MWT, SPPB, WIQ scores, etc).

Thanks for the comment. The 6MWT is presented in raw and relative data. However, the WIQ and SPPB tests are scored based on calculations.

Reviewer #2: Comments to the Authors

The authors are commended for their work.

For comments 4-6, I suggest the authors make some supplements in the introduction section.

We appreciated the reviewer's suggestions and made the necessary changes.

Submitted filename: Response to Reviewers.docx

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2 Aug 2022

Association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease: A cross-sectional study

PONE-D-22-05299R2

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Submitted filename: Yameng. August.1.Comments to the Authors.docx

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22 Aug 2022

PONE-D-22-05299R2

Association between the risk of malnutrition and functional capacity in patients with peripheral arterial disease: A cross-sectional study

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