Noninvasive investigation of the cardiodynamic response to 6MWT in people after stroke using impedance cardiography

Fang Liu; Alice Y M Jones; Raymond C C Tsang; Yao Wang; Jing Zhou; Mingchao Zhou; Yulong Wang

doi:10.1371/journal.pone.0233000

. 2020 Jun 17;15(6):e0233000. doi: 10.1371/journal.pone.0233000

Noninvasive investigation of the cardiodynamic response to 6MWT in people after stroke using impedance cardiography

Fang Liu ^1,^#, Alice Y M Jones ^2,^3,^‡,^*, Raymond C C Tsang ^4,^‡, Yao Wang ^1,^5,^#, Jing Zhou ^1,^#, Mingchao Zhou ^1,^#, Yulong Wang ^1,^#

Editor: Shane Patman⁶

PMCID: PMC7299376 PMID: 32555655

Abstract

This is a cross-section observational study that investigated the cardiodynamic response to a 6-minute walk test (6MWT) in patients after stroke using impedance cardiography (ICG). Patients diagnosed with stroke were invited to participate in a 6MWT on consecutive days. Heart rate (HR), cardiac output (CO), stroke volume (SV) and cardiac index (CI) were measured by ICG using the PhysioFlow^® PF07 Enduro^TM at 1-second intervals for 10 minutes prior to, during and for 10 minutes after each 6MWT. Oxygen saturation, perceived exertion score (modified Borg scale) and the distance covered at the end of each 6MWT were recorded. Twenty-nine patients (mean age 55.6±10.9 years) completed the study. The mean duration of stroke after diagnosis was 14.4±19.1 months. There were no differences in the measured data between the first and second 6MWT (mean intraclass correlation coefficient (ICC) range: 0.87–0.95). The 6 minute walk distance (6WMD) covered in the two 6MWTs was 246±126 and 255±130m respectively (p>0.05). Mean measured data for each subject at rest, and at the end of the better performed 6MWT were, respectively: HR 78±11 and 100±18 bpm; CO 5.5±1.2 and 8.9±2.6 l/min, SV 71.3±16 and 89.3±18.6 ml/beat and CI 3.0±0.6 and 4.9±1.3 l/min/m². After commencement of the 6MWT, the increase in SV took 30 sec before the rise approaching a plateau, whereas HR, CO and CI continued to rise steeply for 90 sec before leveling off to a steady rise. After completion of the 6MWT, all parameters had returned to baseline by a mean of 3.5 min. Sub-group analysis showed that the increase in cardiac output was predominantly contributed by an increase in heart rate in participants diagnosed with stroke for less than 1 year, whereas both stroke volume and heart rate contributed similarly to the increase in cardiac output in participants with diagnosis of stroke for longer than 1 year. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) both returned to baseline within 2 minutes post 6MWT. HR recorded at the end of the 6MWT was 60.8±10.6% of the predicted maximal heart rate and perceived exertion score was 5±2. Correlations between 6MWD and HR, and between 6MWD and SV were weak, with correlation coefficients Spearman’s rho (r_s) =0.46, and 0.42, respectively (p<0.05). Correlation between 6MWD and CO and CI were higher (r_s= 0.66 and 0.63, respectively (p<0.01)). This is the first study to report cardiac responses during a 6MWT in stroke patients. ICG is a reliable, non-invasive, repeatable method of measuring cardiodynamic data in stroke patients.

Introduction

Neurological deficits associated with stroke often lead to significant physical disability [1], resulting in low ambulatory activity and poor cardiovascular fitness [2]. Low cardiovascular fitness in stroke survivors may not only lead to low social participation, effecting quality of life [3], but may also worsen underlying cardiovascular and metabolic risk factors such as hypertension, obesity, diabetes and dyslipidemia, resulting in an increased risk of recurrent stroke [4]. To counteract the decline in aerobic fitness in this population, rehabilitation programs to improve aerobic capacity in people post stroke have been recommended [5,6]. Appropriate prescription of an effective exercise program requires accurate monitoring and evaluation of aerobic capacity. Assessment of peak oxygen uptake (VO₂peak) by indirect calorimetry during progressive cardiopulmonary exercise testing (CPET) is the gold standard for evaluation of aerobic capacity [7], however this is invariably impractical in patients with stroke. Stroke-specific impairments such as muscle weakness, fatigue, poor balance, contracture and spasticity often limit the patient reaching their maximum capacity using these standard exercise tests. The mean VO_2peak measured during a 6MWT is similar to cycle graded exercise test value [8]. In clinical practice, the 6-minute walk test (6MWT) is therefore often used as a sub-maximal test to assess walking capacity and cardiovascular fitness in this group of patients [9–11]. Whether 6MWT is an adequate measure of aerobic fitness has been queried [12], but there is strong evidence to support the reliability and construct validity of using the 6MWT in people after stroke [13,14]. Heart rate was reportedly 85% of maximum at the end of a 6MWT, while oxygen consumption was 70% of peak values, after a progressive, standardized exercise test, in patients with stroke [15, 16]. These studies suggest that the 6MWT induces a significant aerobic challenge in a stroke patient.

While the 6MWT reflects the aerobic capacity of a patient after stroke, the cardiodynamic parameters (stroke volume, cardiac output and cardiac index) which determine exercise capacity during a 6MWT, have not been reported in people after stroke. Impedance cardiography (ICG) is an established noninvasive technique used to measure various indices of cardiovascular function and correlates closely with invasive techniques using dye dilution [17]. The validation and recent advances in clinical applications of ICG are well described [18,19], although the role of ICG was not shown to be superior to echocardiography [20]. ICG measurements during a 6MWT in people after stroke however have not been reported.

The objectives of this study in people with stroke were to investigate: (1) the cardiodynamic responses prior, during and after 6MWT using ICG; and (2) the relationship between the 6-minute walk distance (6MWD) and the cardiodynamic parameters during the 6MWT. Lastly, the variability of ICG data measured between two 6MWTs was also examined.

Material and methods

Approval to conduct this study was obtained from the Institutional Review Board of Shenzhen Second People’s Hospital (Ethics approval number: 20190605016-FS20190629008). The protocol for this study is available at dx.doi.org/10.17504/protocols.io.6s2hege

Study design

This study adopts a cross-section observational design involving patients diagnosed with stroke and received regular medical follow ups from July 1^st to August 31^st 2019, at the Rehabilitation Department at the Shenzhen Second People’s Hospital, China. Patients were invited to undertake two 6MWTs in consecutive days at the hospital, during which cardiodynamic parameters were measured by ICG.

Inclusion and exclusion criteria

The inclusion criteria were: (1) age ≥ 18 years, (2) clinically diagnosed with ischemic and/or hemorrhagic stroke, (3) time lapsed after stroke diagnosis ≥ 1 month, (4) patient able to independently ambulate with or without an assistive device for ≥ 100 meters, (5) medically stable and with no significant pain limitations, (6) able to clearly comprehend exercise testing instructions.

The exclusion criteria were: (1) patients prescribed with regular beta blockers or those requiring beta blocker at the time of the study; (2) other neurological or orthopaedic conditions that may cause motor deficit (e.g. fracture, degenerative joint changes, or clinical instability of the hip or knee joint), (3) psychiatric impairment, such as severe depression or panic disorder, (4) pregnancy, (5) uncontrolled hypertension, arrhythmia, or an unstable cardiovascular status as advised by the attending physician.

Sample size

Sample size was estimated by Pass 11 (NCSS, LLC, Kaysville, Utah). To achieve a power of 0.8 and intraclass correlation coefficient value > 0.5 for reliability, the minimum estimated number of participants was 22. Allowing for a possible withdrawal rate of 20%, a minimum of 27 participants was deemed necessary [21].

Procedure

The aims and procedures of the study were explained to the participants and written informed consent obtained. Demographic data for each participant including age, gender, height, weight, body mass index (BMI) and lean body mass were recorded. The stroke diagnosis, time elapsed after stroke diagnosis, past medical history (e.g. hypertension, diabetes mellitus, cardiovascular disease, lipidemia, kidney disease, pulmonary disease), the National Institute of Health Stroke Scale (NIHSS) and Modified Rivermead Mobility Index (MRMI) were retrieved from each patient’s medical record [22, 23].

Participants were invited to perform a 6MWT at the cardiopulmonary laboratory of the hospital on two consecutive days at a time > 2 hours after a light meal. Participants were requested to avoid caffeine-containing products, nicotine, and alcohol for at least 12 hours before attending the laboratory. The patients performed the 6MWT in a 30m indoor hallway located immediately outside the laboratory. The 6MWT was conducted according to the standard protocol recommended by the American Thoracic Society (ATS) [11]. Prior to the 6MWT, each participant was asked to rest in a sitting position for 10 minutes during which hemodynamic parameters (ICG, see below), oxygen saturation (SpO₂) (Heal Force pulse oximeter, POD-3, China), blood pressure (BP) (OMRON electronic blood pressure monitor, U30, China), perceived fatigue sensation (modified Borg 0–10 Scale [24]), were recorded. Blood pressure was measured immediately before and after the 6MWT, and at 2-minute intervals during the 10-minute rest period after the 6MWT. SpO₂ was measured immediately before, at each minute during, and at the end of the 6MWT. Perceived exertion level was recorded immediately before and at the end of 6MWT.

Measurement of cardiac parameters

Heart rate (HR), stroke volume (SV), cardiac output (CO) and cardiac index (CI) were measured by Impedance cardiography using the PhysioFlow®PF07 Enduro^TM (PhysioFlow Enduro, Paris, France). Auto-calibration of the machine was performed as instructed by the manufacturer, prior to data collection. The Enduro^TM is a portable, non-invasive device that adopts real-time wireless monitoring of morphology-based impedance cardiography signals via a blue tooth USB adapter. Variations in the impedance signal during cardiac ejection generates a specific waveform from which the SV is calculated when an alternating high-frequency, low magnitude current is passed across the thorax [25]. CO (l/min) is calculated by multiplication of the SV and HR, cardiac index (CI) is computed by dividing the CO by calculated body surface area based on height and weight of the patient; heart rate, and R-R interval were derived from the electrocardiograph (ECG) [26]. HR, SV, CO, CI data were computed by the Enduro^TM at 1-second intervals from 10 min prior, during, and for 10 min after the 6MWT.

Electrode placement

Electrode placement was conducted as described by Tonelli and colleagues [27] (Fig 1).

Data analyses

HR, SV, CO, CI were averaged every 10 seconds. The data at rest, at every 30^th sec during the 6MWT, and for 10 minutes during recovery, were collected for analysis. All data were analyzed using IBM SPSS Statistics for Windows, Version 23.0 (Armonk, NY: IBM Corp). Demographic data and clinical characteristics for all participants were summarized using descriptive statistics. Wilcoxon signed rank test was used to compare the differences between the first and the second 6MWT for SpO₂, Borg score and 6MWD data. Changes in variables, the time taken for each parameter to reach a steady plateau and the time taken to return to baseline, were analyzed using repeated-measures ANOVA with post-hoc Least Significant Difference (LSD) analysis. The intraclass correlation coefficient (ICC_1,1) [28] for parameters recorded between the first and second 6MWT was calcuated by a one-way random-effects model. Standard error of measurement (SEM) was calculated by taking the square root of the mean square error of repeated measurements ( $\sqrt M S E$ ) [29]. Correlation analysis was conducted using Spearman’s rho (r_s) to determine the relationship between 6MWD and cardiac variables at the end of the 6MWT. The predicted maximal heart rate was estimated by applying the formula, 220 minus age. The time elapsed since their stroke event in our participant cohort ranged from 1 month to >60 months. Subgroup analysis with linear regression was performed in participants whose elapsed time since stroke was ≤12 months or >12 months, using CO as the dependent variable and HR change and SV change as covariates to determine whether HR or SV was the main determinant factor for changes in CO.

All patient records were locked in special storage by the chief investigator LF. Data entered for analysis were de-identified.

Results

Thirty-one subjects were recruited for the study. Two subjects were unable to return for a second 6MWT as they had been transferred to another hospital. A total of 29 patients (mean age 55.6±10.9 years) completed both 6MWTs. Patient demographics and clinical characteristics are displayed in Table 1. There was no statistical difference in recorded haemodynamic data between the first and second 6MWT; intraclass correlation coefficient (ICC) range was 0.87–0.95 (S1 Table). The mean distance covered in the second 6MWTs was slightly higher compared to the first test, but this did not reach a statistical significance [mean distance covered in the two tests was 246±126 and 255±130m, respectively (p>0.05)]. For each subject, the data recorded in the ‘better’ walk test were used to describe the cardiodynamic response to a 6MWT. SV rose quickly during the first 30 sec, while HR, CO and CI continued to rise sharply till 90 sec before the rise became steadier and approaching a plateau; all parameters had returned to baseline by a mean of 3.5 min post 6MWT (S2 Table). Graphical presentations of the changes in parameters are displayed in Fig 2. Mean cardiodynamic data are illustrated in S3 Table.

Table 1. Demographic data of the 29 participants.

Data in n(%) or mean±SD.

Gender	Male = 21 (72.4%)
Gender	Female = 8 (27.6%)
Age (years)	55.6±10.9
Height (cm)	168.4±8.1
Weight (kg)	70.2±9.8
Lean body mass (kg)	52.3±7.1
Diagnosis
Cerebral hemorrhage	11 (37.9%)
Cerebral infarction	18 (62.1%)
Duration of stroke (months)
mean	14.4±19.1
1–3	9 (31.1%)
4–12	10 (34.5%)
13–24	5 (17.2%)
48–60	5 (17.2%)
With hypertension	23 (79.3%)
With diabetes	6 (20.7%)
With hyperlipidemia	12 (41.4%)
Ambulation status
Free	24 (82.8%)
With a cane	5 (17.2%)
NHISS score	4.3±2.9
MRMI score	36.7±3.5

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NHISS = National Institutes of Health Stroke Scale; MRMI= Modified Rivermead Mobility Index

Oxygen saturation remained stable throughout the 6-minute walk. Blood pressures immediately before and after 6MWT are displayed in S2 Table. Rate of exertion at the end of the 6MWT expressed as a modified Borg scale, was 5±2 on both days. HR recorded at the end of the 6MWT was 60.8±10.7% of the predicted maximal heart rate. Correlations between 6MWD and HR, and between 6MWD and SV were weak, (correlation coefficients r_s=0.46, and 0.42, respectively (p<0.05)). Correlation between 6MWD and CO, and with CI, were higher (r_s=0.66 and 0.63, respectively) (p<0.01) (S4 Table). Table 2 illustrates previous reported cardiodynamic parameters measured during a 6MWT [5, 22, 27, 30–33] compared to data reported in the current study.

Table 2. Heart rate and cardiodynamic parameters during a 6MWT reported in previous literature in comparison to data recorded in the current study.

Reference	current study	Muren et al [32]	Pradon et al [31]	Kubo et al [22]	Salbach et al [5]	Harmsen et al [30]	Someya et al [33]		Tonelli et al [27]
Age	55.6±10.9	58±9	53.4±13.7	72±10.7	71.1±9.7	53.0±8.9	20.5±0.7	60.2±6.1	51.8±15	49 ± 11
Pathology	Stroke	Stroke	Stroke	Stroke	Stroke	ASAH	Young adults	Elderly	Healthy	PH
Mean Duration of stroke	14.4±19.1 (mon)	60 ±27 (mon)	16±8 (mon)	5.1 ± 2.6 (days)	2.0 ± 1.1 (years)	-	-	-	-	-
6MWD (m)	255±130	353	273.8	331.8	254.9	498	541	533	560	380
HR-rest (bpm)	78±11	80±12	72.3±11.1	74.6 ±12.2	76.1 ± 10.1	-	75.8±12.0	77.3±11.6	76±14	83±12
HR-end of 6MWT	100±18	105±19	106.21±21.41	82.1±14.3	103.7 ± 13.0	114±20	117.4±26.7	121.0±21.8	127±18	117±20
HR change (%)	28.7±22.1	31.25	46.92	10.05	36.27	-	54.88	56.53	67.11	40.96
SV-rest (ml)	71.3±16	-	-	-	-	-	89.4±22.1	68.9±11.6	62±19	51±17
SV-end of 6MWT (ml)	89.3±18.6	-	-	-	-	-	111.3±27.3	102.9±15.2	95±26	75±22
SV change (%)	26.1±14.2	-	-	-	-	-	24.50	49.35	53.23	47.06
CO-rest (l/min)	5.5±1.2	-	-	-	-	-	6.6±1.3	5.3±1.1	-	-
CO-end of 6MWT (l/min)	8.9±2.6	-	-	-	-	-	12.7±2.9	12.5±2.9	-	-
CO change (%)	64.1±40.5	-	-	-	-	-	92.42	135.85	-	-
CI-rest (l/min/m²)	3.0±0.6	-	-	-	-	-	4.0±0.6	3.4±0.6	2.3±0.9	2.3±0.7
CI-end of 6MWT (l/min/m²)	4.9±1.3	-	-	-	-	-	7.6±1.4	7.9±1.7	5.9±1.7	4.9±1.5
CI change (%)	63.3±41.1	-	-	-	-	-	90	132.35	156.52	113.04
%MHR at end of 6MWT	60.8±10.6	-	-	-	-	67%	59%	76%	-	-
Borg scale at end of 6MWT	5±2/10	-	11.4/20	2.2/10	3.1/10	-	-	-	1.2/10	2.6/10

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6MWD=6 minute walk distance; 6MWT=6 minute walk test; HR=heart rate; SV=stroke volume; CO=cardiac output; CI=cardiac index; mon=months; numbers in brackets are reference number; ASAH= aneurysmal subarachnoid hemorrhage; PH=pulmonary hypertension; %MHR= percentage of predicted maximal heart rate.

Subgroup analysis showed that if the time elapsed since the stroke event was 12 months or less, the change in HR contributed 60% to the increase in CO with 6MWT exercise, while the unique SV contribution to the increase in CO, was only 12%. In the 10 participants in whom > 12 months had elapsed since their stroke, HR and SV increase contributed equally to CO increase with exercise (Table 3). Although the BSA derived from height and weight data differed, there was no significant between-group difference in age, BMI, haemodynamic variables at rest or at the end of the 6MWT (S5 Table). Age and gender were initially included as independent variables in the regression analysis, however they were eliminated from the regression model due to statistical non-significant effect. Fig 3 illustrates the cardiodynamic responses to the 6MWT in the two groups.

Table 3. Linear regression using cardiac output change as dependent variable and HR change or SV change as covariates.

	Time elapsed after stroke less than 1 year (n=19)	Time elapsed after stroke over 1 year (n=10)	Total (n=29)
HR change standardized beta coefficient	0.821	0.559	0.695
SV change standardized beta coefficient	0.361	0.539	0.474
HR change semipartial correlation	0.777	0.425	0.626
SV change semipartial correlation	0.342	0.410	0.427
HR change unique contribution to CO change (%)	60	18	39
SV change unique contribution to CO change (%)	12	17	18
6MWD (m)	265±136.3	222±121.5	255±130

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6MWD=6-minute walk distance; 6MWT=6-minute walk test; HR=heart rate; SV=stroke volume; CO=cardiac output; CI=cardiac index

Fig 3 — Solid line= time elapsed after stroke less than 1 year; dotted line=time elapsed after stroke longer than 1 year.

Discussion

There are studies reporting the heart rate changes during a 6MWT in people after stroke [22,31,32], but this is the first study to report changes in stroke volume, cardiac output, cardiac index, together with heart rate, in a stroke population during a 6MWT. The mean distance covered by our cohort of patients was 255m; which was slightly less, but comparable to 274m reported by Pradon and colleagues in a cohort of stroke patients of similar age [31]. While the 6MWDs were similar, the increase in heart rate at the end of the 6MWT in our patient cohort was 29%, compared to 47% reported in Pradon’s study (Table 2). The subjective rate of exertion was 5/10 (modified Borg scale) in our cohort and 11/20 (Borg scale) in Pradon’s study. It would appear that Pradon’s cohort achieved similar distance to our cohort with a higher increase in heart rate but lower rate of perceived exertion. The perceived exertion level reported by our subjects was equivalent to an intensity level described as ‘hard’, although the peak HR generated was only 60% of the subject’s predicted maximal heart rate. All our participants were able to mobilise independently with or without a walking stick, although some were unable to independently negotiate stair climbing. The mean MRMI score of our participants was 36.7; very close to the full scale of 40, reflecting the high level of independence during transfers and walking. With no cardiodynamic data available from Pradon’s study for comparison, we are unable to explain the differences between ours and Pradon’s study, but it may be worthy to note that, unlike in western countries, stroke rehabilitation programs for patients in China are relatively undemanding and mainly involved leisure walking and passive limb exercise. This may explain the higher perceived exertion score in our patients during the 6MWT; as they were not accustomed to such a strenuous challenge. Muren and colleagues [32] report a lower percentage (31%) increase in heart rate, similar to our cohort, but Muren’s subjects were slightly older (58 years) and with a longer elapsed time since their stroke event.

Application of ICG measurement during a 6MWT allows a more informed analysis of the correlation between the 6MWD and HR, SV, CO and CI. Our study showed that in a population of people after stroke, the 6MWD demonstrated a positive correlation with HR, SV, CO and CI (S4 Table). The relationship between 6MWD and HR and CI, reported in subjects with pulmonary hypertension by Tonelli and colleagues [27], was very similar to ours. However, the coefficient values for SV and CO were not provided by these authors. The correlation between 6MWD and HR and CO in healthy adults reported by Someya and colleagues was comparable to our findings [33], but their study showed that the 6MWD was not correlated with stroke volume. We posit that this may be because the correlation data in Someya’s subjects were pooled from both young and elderly subjects, and that the SV in their young subjects did not change during the 6MWT [33].

Someya and colleagues compared changes in haemodynamic variables between young and elderly healthy subjects after a 6MWT [33]. Their data demonstrated that the increase in HR took more than 60s in the elderly, but took less than 30s to reach a plateau in the young, the authors explained this being the reason of the slower response to changes in cardiac output in their elderly subjects. Data from our stroke subjects showed that HR took 90sec to rise before reaching a more steady state, while the increase in SV steadied after only 30 seconds into the 6MWT. As the patterns of increase in HR and CO were similar (S2 Table), this suggests that the increase in CO during the 6MWT was met by an increase in HR rather than SV in our subject cohort. This proposition is supported by results of linear regression analysis as reported by Tonelli et al [27]. Although Tonelli et al [27] and Somya et al [32] do not report data obtained from people after stroke, their work explains the analysis of cardiodynamic responses acquired using ICG during a 6MWT.

The range of time elapsed since the stroke event was large in our cohort. While the changes in CO were similar in the two sub-cohorts during the 6MWT, analysis of our data showed that the unique contribution to CO by HR was much higher (60%) in the group where the onset of their stroke event occurred < 12 months, compared to the 18% contribution in those subjects where the elapsed time after stroke diagnosis longer than 1 year (Table 3). In the group with time elapsed after stroke > 12 months, SV changes in contribution to CO were greater than those with shorter time elapsed after stroke diagnosis, although the difference is less dramatic (17% vs 12%) (Table 3). A lower contribution of SV to haemodynamic response may be associated with poorer diastolic function [34], and left ventricular diastolic dysfunction associated with poor functional outcomes and vascular events has been reported in a stroke population [35]. Exercise training improves ventricular systolic and diastolic function [36], thus we speculate that the diastolic function of those persons in our patient cohort with a longer elapsed time after stroke may have improved in accord with the longer exposure to exercise training, thereby contributing to the increase in CO during the 6MWT. This might further endorse the role of ICG in investigation of the effect of rehabilitation in people after stroke.

Despite a slight increase in the distance covered over the second 6MWT, there was no statistically significant difference in the distance covered. This is not surprising because the reliability of a 6MWT is high and hence a single 6MWT is recommended in people after stroke [14]. Notwithstanding a small ‘practice effect’ of the two 6MWT, the high ICC values of ICG data recorded on consecutive days provide support for the reliability of ICG measurement of cardiodynamic variables.

One limitation of our study is the small sample size and that we have a large range of time elapsed since the stroke event in our subject cohort. The number of subjects with onset of stroke duration >12 months was only 10. While our data suggest the increase in CO was predominantly a consequence of HR increase in subjects where the time elapsed after stroke was less than 1 year, the data failed to reach statistical significance, possibly due to the small sample size. Linear regression analysis showed no effect of age and gender on our measured cardiodynamic variables, again probably due to the small sample size. Age and gender can influence cardiovascular function [37,38], and further studies with a larger sample size are required to explore any effect of age and gender on cardiodynamic parameters, measured by ICG, in response to exercise training, in patients recovering from stroke.

Conclusion

This is the first study to report changes in cardiodynamic parameters during a 6MWT in a cohort of stroke patients using impedance cardiography. We demonstrated that 6MWD correlated with the increase in CO and that this increase was in response to a change in HR rather than SV in participants with diagnosis of stroke less than 1 year, however in participants with diagnosis of stroke greater than 1 year, stroke volume and heart rate both contributed similarly to the increase in cardiac output. Findings of this current study suggests further investigation of cardiodynamic response to exercise in stroke patients by impedance cardiography are warranted.

Supporting information

S1 Checklist. STROBE statement—checklist of items that should be included in reports of observational studies.

(DOCX)

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S1 Table. ICC data.

(DOCX)

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S2 Table. Time for each variable returned to baseline.

(DOCX)

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S3 Table. Mean cardiodynamic data.

(DOCX)

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S4 Table. Correlation between 6MWD and cardiodynamic parameters at the end of 6MWT.

(DOCX)

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S5 Table. Comparison of characteristics in subjects with time elapsed since stroke diagnosis longer or shorter than 1 year.

(DOCX)

Click here for additional data file.^{(15KB, docx)}

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was funded by a grant from Sanming Project of Medicine in Shenzhen awarded to YM (No. SZSM201512011).

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PLoS One. doi: 10.1371/journal.pone.0233000.r001

Decision Letter 0

Shane Patman

2 Jan 2020

PONE-D-19-24687

Noninvasive investigation of the cardiodynamic response to 6MWT in people with stroke using impedance cardiography

PLOS ONE

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Reviewer #1: Partly

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: The subject of this paper is interesting and the attempt to use impedance cardiography in dynamic exercise tests is valuable. However, the scientific value of the concept of the study is not very high and methods have some important limitations.

1. Title (and whole article): The formula „patient with stroke” is for me misleading. It would be better „patients after stroke”, they were not with acute stroke.

2. Abstract: „better performed 6MWT”? was it always „better performed 6MWT”? From methods section I can conclude it was the second test, I suppose it was not better test for every subject. It should be explained.

3. Introduction – verse 67-69 – what is the purpose to put the sentence … „We hypothesized….” What it means in the context of the aims? Why did you hypothesize like that? How it is related with the paper aim?

4. Methods – in my opinion it is not enough to perform two 6MWT to prove that the method is repeatable. It was shown by previous researchers that in the second test distance is usually longer then in the first test.

5. Methods – inclusion/exclusion criteria (verse 82-92) – „duration of stroke”? – see comment 1.; „patients on beta blocker” – ever? While tested? ; „uncontrolled hypertension” – what cut-off, if all subjects presented normal BP? What was the mean value of BP before 6MWT?

6. Methods – were you really able to keep the temperature 23 C and humidity 60% (verse 110-111) at „hospital hallway”?

7. Methods – verse 162-164 – what variables were chosen for linear regression models, besides SV and CO? Where are the results of linear regression mentioned in verse 281-283 (with age and gender)?

8. Were there any withdrawals? The assumption for sample size was 20%.

9. Results – for summary description of study group statistics the word „mean” should by applied, i.e. „by MEAN 3,5 min…”

10. Patients functional/neurological state should be described in detail and commented if it could influence the capability to perform the 6MWT. It might influence the results and explain low max HR, what is discussed in verse 242-244.

11. NHISS and MRMI scores should be described in Methods.

12. Table 2 – the differences in HR between current study and most of other should be commented, some studies (ref. 29, 35) evaluated SV, CO, CI, it should be commented (what method, why your .

13. Table 2 – „EF change (%)” – it should be explained – is it value of EF change on units (%) or relative change in % of basal EF.

14. Table 3 is to complictated, some data should not be presented. The description

15. Discussion – verse 248-251 – repeated results.

16. Discussion verse 255-257 – the descirption of Tonelli study should be more correlated with previous text.

17. Discussion – verse 258-262 , related to Fig 2 – where are the results for 12 months?

18. What is „chronc stroke”? verse 280? What does suport the sentence „increase in CO was predominantly a consequence od SV increase …” verse 279-280

19. The abbrreviations should be introduced with first use and than used within further text.

20. Conclusions – it was not supported by the results that „SV contributed more when the time elapsed since stoke….” Verse 292. For SV it was 17%, for HR 18%.

21. In my opinions Figures 1 and 4 should be omitted.

Reviewer #2: Manuscript is interesting and valuable. However, I have some questions and comments.

Line 16-17 "whereas HR, CO and CI continued to rise for 90 sec before plateau." Statement is unclear.

Line 130 Are you sure you mean CO not CI? You are writing about "body surface area ". Besides, heart rate was measured based on and R-R interval that derived from the electrocardiograph (ECG) not CO. Please correct.

Line 136 -141 Please do not duplicate information. Figure with arrangement of electrodes is enough, without description in main text. Do you have a one picture with the device placed on the patient with the electrodes?

Table 1 How many patients have been diagnosed with coronary artery disease, HFpEF and other serious cardiac diseases? Were there any differences in subgroups?

Line 176-177 I do not agree with "SV reached a steady plateau at 30 sec into the 6MWT, while HR, CO and CI reached a plateau after 90 sec". This is a non-physiological mechanism. An increase in HR and CO is observed until the end of 6MWT. Figure 3 and Figure 5 prove this. The increase in these parameters is not large, but seems continuous and gradual. Of course, I agree that the increase in CO is mainly the result of an increase in HR and not SV, and SV quickly reached plateau. This is a valuable observation.

Line 132 What is the value of haemodynamic parameters obtained in 1 second intervals during ICG? Is the average of value of parameters of the number of heartbeat in such an interval or the current value every 1 second? Please consider if beat-to-beat recorded data would be more reliable, especially when HR> 120 / min. Have additional ventricular or supraventricular beats been observed or have they occurred in past medical history? Did you observe artifacts while recording ICG data?

Table 2 How did you count the Ejection Fraction at rest and at the end of 6MWT? Was echocardiography performed? Please complete the description of the methodology.

Fig 4. Figure 4 seems to be useless, because you did not assess blood pressure during 6MWT or systemic vascular resistance. Values blood pressure at rest, at the end of the effort, and possibly the time to return it to baseline will be enough.

Fig5. We observe a big discrepancy between CO and CI. Did the subgroups differ significantly between BSA and BMI?

Line 243-244 Do you have any data on the difference in activity between subgroups? Was rehabilitation in the subgroup > 12 months after the stroke performed? Were they more fit, physically active?

**********

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Reviewer #1: No

Reviewer #2: Yes: Małgorzata Kurpaska MD, PhD, Military Institute of Medicine, Warsaw, Poland

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PLoS One. 2020 Jun 17;15(6):e0233000. doi: 10.1371/journal.pone.0233000.r002

Author response to Decision Letter 0

5 Feb 2020

Responses to reviewers have been included in the 'Rebuttal letter' as well.

Reviewer #1:

We are grateful for Reviewer 1’s valuable comments. Please see our response to each point raised.

1. Title (and whole article): The formula „patient with stroke” is for me misleading. It would be better „patients after stroke”, they were not with acute stroke.

We have now modified the reference to our patients and changed ‘patients with stroke’ to patients after stroke.

2. Abstract: better performed 6MWT”? was it always „better performed 6MWT”? From methods section I can conclude it was the second test, I suppose it was not better test for every subject. It should be explained.

All except 3 patients performed slightly better in the second 6MWT. We have used the data from the ‘better’ performed 6MWT for each patient. We have now further clarified this in the abstract (line 14-15).

This sentence is now deleted

Despite a slight increase in the distance covered over the second 6MWT, there was no statistically significant difference in the distance covered. This suggests that the ‘practice effect’ of the two 6MWTs was only small. The high ICC values of ICG data recorded on consecutive days provides support for the reliability of ICG measurement of the cardiodynamic variables. We have explained this further in the discussion. Please refer to page 16, lines 285-288.

5. Methods – inclusion/exclusion criteria (verse 82-92) – „duration of stroke”? – see comment 1.; “patients on beta blocker” – ever? While tested? ; „uncontrolled hypertension” – what cut-off, if all subjects presented normal BP? What was the mean value of BP before 6MWT?

We have further clarified our inclusion and exclusion criteria. “Duration of stroke” is replaced with ‘time elapsed after stroke diagnosis’; “patients on beta blocker” is replaced with ‘patients prescribed with regular beta blockers or those required beta blocker at the time of the study’; “uncontrolled hypertension” is ‘as advised by the attending medical practitioner’. Please refer to page 6, line 88-93. BP values before the 6MWT are displayed in the supplementary data table: S2 Table.

6. Methods – were you really able to keep the temperature 23 C and humidity 60% (verse 110-111) at „hospital hallway”?

The 6MWTs were conducted in an indoor corridor outside the laboratory. The temperature and humidity were controlled throughout the whole hospital. This is clarified on Page 7, line 110-113.

We followed the method of linear regression for similar comparisons, as published by Tonelli et al 2013*. We have initially included Age and gender as independent variables in the linear regression analysis, but as these have no statistically significant effect, these variables were removed from the linear regression model. SV and CO remain the main variables of interest for comparison. We have further explained this in our Result section (page 12, line 210-214). We have also included an extra table which details the characteristics of the two subject groups. Please refer to supplementary table S5 Table.

Only two patients could not complete the second 6MWT. This is now reported at Page 9, line 166-167.

*Tonelli AR, Alkukhun L, Arelli V, Ramos J, Newman J, McCarthy K, et al. Value of impedance cardiography during 6-minute walk test in pulmonary hypertension. Clin Transl Sci. 2013;6(6): 474-480.

8. Results – for summary description of study group statistics the word „mean” should by applied, i.e. „by MEAN 3,5 min…”

The word ‘mean’ is now included in the sentence. Please refer to Page 10, line 178.

9. Patients functional/neurological state should be described in detail and commented if it could influence the capability to perform the 6MWT. It might influence the results and explain low max HR, what is discussed in verse 242-244.

More information on the mobility status of the participants is now included in Table 1. We have also included more details of the mobility status of our subjects in our discussion (page 14, line 243-250)

10. NHISS and MRMI scores should be described in Methods.

The NHISS and MRMI scores were retrieved from the patients’ bed notes. Please refer to page 7, line 105-106, under Procedure in Methods.

11. Table 2 – the differences in HR between current study and most of other should be commented, some studies (ref. 29, 35) evaluated SV, CO, CI, it should be commented (what method, why your .

Comparison with the two studies that evaluated haemodynamic variables during a 6MWT with Impedance Cardiograpy is now discussed in more detail. Please refer to Page 14, line 255-272.

12. Table 2 – „EF change (%)” – it should be explained – is it value of EF change on units (%) or relative change in % of basal EF.

Ejection Fraction was computed by the ICG software. This was not reported in other published studies, so we have now deleted this from Table 2.

13. Table 3 is to complicated, some data should not be presented. The description

Presentation of Table 3 was modelled on Tonelli and Colleagues’ published work. We considered it a meaningful way of expressing the contribution of HR or SV to CO. May we know which data are considered unnecessary?

14. Discussion – verse 248-251 – repeated results.

This sentence is now reworded, and ‘repeated’ results are deleted.

15. Discussion verse 255-257 – the description of Tonelli study should be more correlated with previous text.

The discussion has now been reworded, and comparison with Someya’s work included.

16. Discussion – verse 258-262 , related to Fig 2 – where are the results for 12 months?

Figure 2 presents the pooled data of all 29 subjects. Sub-group analysis comparing changes in subjects with the time elapsed after stroke-diagnosis of shorter or longer than 12 months, are displayed in Figure 3.

17. What is „chronic stroke”? verse 280? What does support the sentence „increase in CO was predominantly a consequence od SV increase …” verse 279-280

The terminology of chronic stroke is no longer used in the text. The paragraph explaining the relationship between CO, SV and HR is now reworded.

18. The abbreviations should be introduced with first use and then used within further text.

We have re-checked that abbreviations are all introduced the first time they appear in the text.

19. Conclusions – it was not supported by the results that „SV contributed more when the time elapsed since stoke….” Verse 292. For SV it was 17%, for HR 18%.

The conclusion is now reworded.

20. In my opinions Figures 1 and 4 should be omitted.

Figures 1 and 4 are now deleted.

Responses to Reviewer# 2

We are grateful for Reviewer 2’s valuable comments, please see our responses to questions raised:

1. Line 16-17 "whereas HR, CO and CI continued to rise for 90 sec before plateau." Statement is unclear.

This sentence is now reworded. Please refer to page 2, line 16-18

2. Line 130 Are you sure you mean CO not CI? You are writing about "body surface area ". Besides, heart rate was measured based on an R-R interval that derived from the electrocardiograph (ECG) not CO. Please correct.

This sentence is now reworded. Please see page 8, line 131-136

3. Line 136 -141 Please do not duplicate information. Figure with arrangement of electrodes is enough, without description in main text. Do you have one picture with the device placed on the patient with the electrodes?

Text description is now deleted as suggested.

4. Table 1 How many patients have been diagnosed with coronary artery disease, HFpEF and other serious cardiac diseases? Were there any differences in subgroups?

The patient history was retrieved from hospital notes. Only 5 patients were diagnosed with coronary artery disease and there was no record of heart failure as a diagnosis. We are of the view that a subgroup analysis of such a small number would not be meaningful.

5. Line 176-177 I do not agree with "SV reached a steady plateau at 30 sec into the 6MWT, while HR, CO and CI reached a plateau after 90 sec". This is a non-physiological mechanism. An increase in HR and CO is observed until the end of 6MWT. Figure 3 and Figure 5 prove this. The increase in these parameters is not large, but seems continuous and gradual. Of course, I agree that the increase in CO is mainly the result of an increase in HR and not SV, and SV quickly reached plateau. This is a valuable observation.

The HR, SV and CO indeed continue to rise till the end of the 6MWT, however, the rise was much steeper in the first 90 sec for HR and the first 30 sec for SV; thereafter then the rise became more gradual (S3 Table, Fig 2). We have reworded the description of this phenomenon. Please refer to page 10, line 176-178.

6. Line 132 What is the value of haemodynamic parameters obtained in 1 second intervals during ICG? Is the average of value of parameters of the number of heartbeat in such an interval or the current value every 1 second? Please consider if beat-to-beat recorded data would be more reliable, especially when HR> 120 / min. Have additional ventricular or supraventricular beats been observed or have they occurred in past medical history? Did you observe artifacts while recording ICG data?

The EnduroTM was used to capture cardiography signals. Signals were recorded at 1-second intervals. We did not observe any abnormal ventricular or supraventricular conduction abnormality.

7. Table 2 How did you count the Ejection Fraction at rest and at the end of 6MWT? Was echocardiography performed? Please complete the description of the methodology.

Ejection fraction was computed by the software. As this was not reported in other studies listed in Table 2, we have now deleted this variable from Table 2.

8. Fig 4. Figure 4 seems to be useless, because you did not assess blood pressure during 6MWT or systemic vascular resistance. Values blood pressure at rest, at the end of the effort, and possibly the time to return it to baseline will be enough.

Figure 4 is now deleted. Blood pressures before and immediately after 6MWT are displayed in S2 Table

9. Fig5. We observe a big discrepancy between CO and CI. Did the subgroups differ significantly between BSA and BMI?

There were no statistical differences in BMI between the two groups. However computed BSA was higher in the group with time elapsed after stroke-diagnosis longer than 12 months. This may explain the higher CI in this group, but the difference in CI did not reach statistical significance. We have now included an additional table (S5 Table) to illustrate the differences in characteristics between the groups.

10. Line 243-244 Do you have any data on the difference in activity between subgroups? Was rehabilitation in the subgroup > 12 months after the stroke performed? Were they more fit, physically active?

Unfortunately, we do not have detailed information on the activity of our patients. We do however know that the subjects with a longer time-elapsed after stroke diagnosis engaged in a longer duration of a walking program. We have included a more detailed discussion of this point. Please refer to page 14, line 243-251.

Attachment

Submitted filename: Responses_Reviewer2.docx

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PLoS One. doi: 10.1371/journal.pone.0233000.r003

Decision Letter 1

Shane Patman

17 Mar 2020

PONE-D-19-24687R1

Noninvasive investigation of the cardiodynamic response to 6MWT in people after stroke using impedance cardiography

PLOS ONE

Dear Professor Jones,

I have been fortunate in being able to continue with the same two content expert peer reviewers from the original submission with this latest review cycle. Both reviewers have noted positive changes with this revised submission, however a few recommendations have arisen from this last peer review, as outlined below.

We would appreciate receiving your revised manuscript by May 01 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Shane Patman, PhD

Academic Editor

PLOS ONE

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Reviewer #1: Thank you for your work aimed to address my comments.

It is rather pilot study on a small sample size.

However, the conclusions are encouraging to perform further research in this area.

Reviewer #2: Thank you for answering my comments raised in a previous round of review. Unfortunately I have a lot of questions and remarks. I hope my comments will be useful and they will serve to improve the manuscript.

1. Line 45-47 The sentence: "The assessment... capacity." is not needed.

2. Line 61 Are you sure that references 15-18 are about exercise ICG?

3. Line 63 References 19-21 I think that more accurate study is for example: doi: 10.1007/s10554-019-01738-y than studies carried out in children.

4. Line 110-111 What is the significance of constant temperature and humidity for 6 MWT, please provide refferences.

5. Line 165-166 and line 169-170 repeated sentence "The distance covered in the second 6MWT was slightly greater than the first 6MWT"

6. Line 190-191 Do you know other studies (on other populations) describing the correlation of 6MWT with SV, HR, CO? Describe in the discussion.

7. Table 2 Are there studies with the use of 6MWT in case of diseases that are etiopathologically close to stroke? Hemodynamic studies during 6MWT or CPET with CAD, with AH, lack of training (sedentary lifestyle)? I understand that the model study was Tonelli's study but the PH pathogenesis is radically different from stroke, unless we are interested in the control group. Please comment on absolute values and parameter changes, are they larger / smaller? What can affect the observed hemodynamic profile in patients after stroke?

8. Line 203-204 The absolute values between the subgroups did not differ significantly, is not it? How can you explain the different percentage of linear regression? Were different trends in parameter changes observed between the subgroups? Which trend of changes is correct? Is any parameter trend a compensatory response? What could be the reason for the different results? Chronotropic failure? SV disability? How can you explain such a difference in the share of HR and SV in CO?

9. In the subgroup > 12 months after stroke, worse physical capacity was observed, but a greater relationship between CO and SV and HR. See DOI: 10.1080/10641963.2018.1523917

10. Line 223 - 228 should be put in the introduction rather than in the discussion.

11. According Ref. 39 "6MWT is not, by itself, an adequate measure of aerobic fitness early after stroke". Please explain the choice of 6MWT as a research method in a different way.

12. Line 230 -237 do not repeat information: The mean distance covered by our cohort of patients was 255m;... comparable to 274 m reported by Pradon" oraz "...that Pradon’s cohort achieved similar distance to our cohort...". Please edit these sentences.

13. Line 186-188 and line 237-239 Does it mean that 6MWT is performed according to the maximum capabilities? What could affect this result?

14. Line 239-242 What is the influence of 6MWT " with or without a walking stick, although some were unable to independently negotiate stair climbing". Please give the references. Was MRMI score result good or poor? Does it influence 6MWT, please give references.

15. Line 250-256 Please at first discuss your results and then comment this on other research. Do not describe other authors's researches.

16. Line 260-266 "Tonelli.... [29]" What does this information bring in to discussion on the hemodynamic response in stroke patients? I understand that you methodologically modeled the study on Tonelli's work, however this can be entered in the methodology. What is the relationship between PH and stroke, how to explain the similarity of hemodynamics?

17. Line 268 "While the changes in CO were similar". Were SV and HR changes also similar?

18. Line 274-278 How do you explain the shorter 6MWTD after a year? Did they exercise more or less? Are you suggesting that stroke patients in the study group had LVDD? In reply to question 4 was: "there was no record of heart failure as a diagnosis". What is the connection to LVDD?

19. Line 279- 280 Is this observation exceptional? See: doi: 10.1164/rccm.200203-166OC, doi: 10.1016/S0002-8703(03)00119-4,

20. Line 288-289 What research was the basis for suspecting a relationship between the age and sex with hemodynamic parameters? Please provide references.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. 2020 Jun 17;15(6):e0233000. doi: 10.1371/journal.pone.0233000.r004

Author response to Decision Letter 1

3 Apr 2020

Responses to Reviewer 2’s Comments

1. Line 45-47 The sentence: "The assessment... capacity." is not needed.

This sentence was not intended to be read in isolation but together with the fact that 6MWT is commonly used for assessment of aerobic capacity in people with stroke. Please see page 4, line 45 to 47.

2. Line 61 Are you sure that references 15-18 are about exercise ICG?

References 15 to 18 are now replaced with a recent review article on clinical application of ICG [new reference 17]. Please kindly see page 5, line 61-63.

3. Line 63 References 19-21 I think that more accurate study is for example: doi: 10.1007/s10554-019-01738-y than studies carried out in children.

We have now deleted the references to paediatric patients and replaced them with more recent publications, including the one suggested by the reviewer [Reference 18].

4. Line 110-111 What is the significance of constant temperature and humidity for 6 MWT, please provide references.

It is well known that variable temperature and humidity may influence exercise performance. Our subject cohort performed the sub-maximal exercise test in an environment where humidity and temperature were controlled. These criteria are not required by the ATS Guideline and so in order not to cause confusion, we have now removed the information on the temperature and humidity.

5. Line 165-166 and line 169-170 repeated sentence "The distance covered in the second 6MWT was slightly greater than the first 6MWT"

The first sentence refers to the ‘mean’ distance recorded and later refers to individual performance. To avoid the confusion, we have removed the second sentence. Please refer to line 166-169.

6. Line 190-191 Do you know other studies (on other populations) describing the correlation of 6MWT with SV, HR, CO? Describe in the discussion.

We have now added a paragraph describing correlation of 6MWT with SV, HR, and CO and compared our data with those reported in other populations. Please refer to page 15, line 250-260.

Table 2 illustrates four studies [31,30,28,5] reporting heart rate changes associated with 6MWT. However SV, CO and CI data were not available in these studies. Our study is the first to report the SV, CO and CI response to a 6MWT in people after stroke. We have now highlighted that the ‘change’ in heart rate refers to an ‘increase’ in heart rate. Please refer to page 14, line 232.

We presume the reviewer is referring to lines 204-213 in the previous version. Linear regression analysis was a method used by Tonelli and colleagues [Reference 25] to determine whether the primary contribution to CO was HR or SV. We considered it meaningful to assess whether people with a longer post-stroke duration responded differently to exercise stress in the form of 6MWT. We have therefore adopted the same statistical method used by Tonelli and colleagues.

9. In the subgroup > 12 months after stroke, worse physical capacity was observed, but a greater relationship between CO and SV and HR. See DOI:

10.1080/10641963.2018.1523917

The reference suggested by the reviewer compared exercise capacity assessed via a 6MWT and cardiopulmonary exercise test with haemodynamic assessment via ICG in patients with arterial hypertension. The study concluded that ICG is a reliable method for assessing cardiovascular response to exercise. We are unsure how this relates to physical capacity in our subjects >12months after stroke.

10. Line 223 - 228 should be put in the introduction rather than in the discussion.

We have now rewritten the first paragraph of our Discussion. Please refer to lines 221-228.

11. According Ref. 39 "6MWT is not, by itself, an adequate measure of aerobic fitness early after stroke". Please explain the choice of 6MWT as a research method in a different way.

Justification for the use of 6MWT in the assessment of cardiorespiratory fitness for people after stroke, is now included with an additional reference. Please see lines 221-228.

We were confused as to whether the reviewer prefers us using the absolute values to illustrate our discussion point or a ‘similar’ distance statement was sufficient. The second sentence, which appears to reiterate that a similar distance was covered in both studies, is in fact necessary to highlight that ‘despite the similar distance’, the reported rate of perceived exertion was very different. Please refer to line 230-236.

13. Line 186-188 and line 237-239 Does it mean that 6MWT is performed according to the maximum capabilities? What could affect this result?

It is expected that a 6MWT is performed at the subject’s maximum capacity. While the VO2peak achieved at the end of a 6MWT is very similar to that obtained from a cycle graded exercise test (for example current reference 35), a graded cardiopulmonary exercise test remains the gold standard for assessment of maximum capacity. We followed the ATS guideline and delivered standard instructions to our subjects to attain their maximum performance. The results (% MHR at the end of 6MWT) are comparable to data reported by others, so we do not anticipate a problem with this methodology. The aim of our study was to illustrate that ICG can be used to measure haemodynamic parameters during a 6MWT and easily applied in a clinical setting. Construct validity of 6MWT performance as a measure of functional walking capacity in people with acute, subacute and chronic stroke has been well established [Reference36], and is beyond the scope of this current study.

Our subjects were able to mobilize independently although a few required a walking cane. The number of those who required a walking cane is small and therefore subgroup analysis is not appropriate. ATS guidelines only require a record of whether the subject required a walking aid or not. Table 1 illustrates the high MRMI score in our patients. This is further explained in the discussion (please refer to page 14, line 240-241). The MRMI score reflects the mobility level of our cohort and correlates well with physical function variables such as range of movement and sensory function (doi:10.1589/jpts.28.2389). That being said, it is not a measurement tool for aerobic capacity. Detailed investigation of the relationship between MRMI and 6MWD is beyond the scope of our study.

15. Line 250-256 Please at first discuss your results and then comment this on other research. Do not describe other authors's researches.

We appreciate this may be true in most circumstances, however in our view, the concept would be more difficult for the readership to grasp if we commenced with data from a population of stroke survivors. We consider it is easier to first explain the scenario in a normal healthy population in various age groups.

We have now deleted the paragraph reiterating the linear regression method employed by Tonelli.

17. Line 268 "While the changes in CO were similar". Were SV and HR changes also similar?

Yes, all changes were similar. Please refer to supplementary table 5. ( S5 Table 5).

The shorter 6MWD shown in Table 3 does not refer to a shorter 6MWD ‘after a year’. Please refer to Table 1, which shows that the duration of post stroke time in our subjects ranged from 1 month to 60 months. These sentences only postulate that diastolic function in patients after stroke may be influenced by exercise or activities. We did not at all suggest that our patients have left ventricular diastolic dysfunction. We have reworded the respective sentence to reflect our speculation. Please see page 16, line 281-282.

19. Line 279- 280 Is this observation exceptional? See: doi: 10.1164/rccm.200203-166OC, doi: 10.1016/S0002-8703(03)00119-4,

The learning effect with 6MWT is well documented in people with respiratory disease, however in people after stroke, reliability was shown to be excellent with one 6MWT trial and a single 6MWT is recommended in people after stroke (Reference 36). This is now highlighted in the Discussion, page 16, line 284-286.

20. Line 288-289 What research was the basis for suspecting a relationship between the age and sex with hemodynamic parameters? Please provide references.

We have now included two references [39,40] to support our view that age and gender influence cardiovascular function parameters. Please see page 17, line 295-296.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(28.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0233000.r005

Decision Letter 2

Shane Patman

17 Apr 2020

PONE-D-19-24687R2

Noninvasive investigation of the cardiodynamic response to 6MWT in people after stroke using impedance cardiography

PLOS ONE

Dear Professor Jones,

We would appreciate receiving your revised manuscript by Jun 01 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Shane Patman, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

As academic editor I have been fortunate, even during this uncertain worldly times, to have secured consistency with reviewers for this R2 submission. Reviewer 2 remains with some significant concerns, as outlined below, which require further opportunity for rebuttal commentary from authors at this stage

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: I have no additional comments. All previous comments were addressed well. The manuscript is now correct .

Reviewer #2: Major Comments:

The manuscript is valuable in terms of methodology and results. Unfortunately, I have the impression that you are completely unable to explain whether the observed hemodynamic reaction is correct or not, whether it have been observed in other groups (not in PH!) already and what is clinical significance of your observations. I have no doubts about the 6MWT methodology. The intention of my questions 6 - 9 and 13 and 18 was a broader view on the obtained results in order to supplement and improve the discussion on their basis. Compare the obtained hemodynamic results to the results obtained in other, more pathophysiologically related diseases to stroke such as CAD or AH.

Ad Q 9:

Do you know the entire manuscript? In this manuscript DOI 10.1080/10641963.2018.1523917:

Stronger correlations were observed between absolute value of VO2 and HR and VO2 and CO at peak exercise and changes in all of the evaluated parameters in subgroup of patient and reduced exercise capacity than with normal peak VO2 (>80% pred.)

I think this information is worth of consideration in the discussion.

Line 273-280

What can be the reason for the different contribution to CO by HR and SV observed by Comparing subgroups of patients: "time elapsed after stroke less than 1 year" and "time elapsed after stroke over 1 year"? Information on left ventricular dysfunction is insufficient in my opinion.

Minor Comments:

Line 223-230 Good justification for the choice of method. It is recommended to move this fragment to the introduction as before. Please discuss the results in the discussion.

Line 242 Please complete the discussion with the sentence: The MRMI score reflects the mobility level of our cohort and correlates well with physical function variables such as range of movement and sensory.

Line 281 Please replace "but" with "and".

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Attachment

Submitted filename: Review 3.docx

Click here for additional data file.^{(12.6KB, docx)}

PLoS One. 2020 Jun 17;15(6):e0233000. doi: 10.1371/journal.pone.0233000.r006

Author response to Decision Letter 2

20 Apr 2020

Responses to Reviewer 2’s comments

Major Comments:

We are disappointed that Reviewer 2 has the misconception that we are ‘completely unable’ to explain whether the observed hemodynamic reaction is correct or not and ‘whether it have been observed in other group (not in PH!)’.

We believe that Reviewer 2 appears to have failed to give appropriate weight to the primary aims of our study.

Our paper aims to report the cardiodynamic parameters recorded by Impedance Cardiography (ICG) DURING a 6MWT in a cohort of people after stroke. Our paper is the first to report SV, CO, CI during a 6MWT. The manuscript describes cardiodynamic parameters recorded by ICG during a 6MWT. There are limited publications from which to draw a reference and none for direct comparison, but our focus is cardiac parameters recorded DURING a 6MWT.

In a nutshell, our study describes the rationale for obtaining cardiodynamic data during a common clinical aerobic capacity test for people after stroke; explains how ICG was applied; reports the data recorded; and compares our data (recorded by ICG DURING a 6MWT) with reported literature on cardiodynamic variables obtained by ICG DURING a 6MWT in other patient cohorts.

The focus of our paper was on the potential role for ICG in the examination of cardiodynamic function in stroke patients. Tonelli et al. 2013 and Someya et al. 2015 were two excellent papers that describe clearly how to determine whether the main contributor to CO is SV or HR. Therefore, although these papers do not describe data from people with stroke, their work explains the analysis of cardiodynamic responses acquired by ICG during a 6MWT, highlighting the potential for ICG in further investigation during stroke rehabilitation; we believe their work is worthy of consideration.

In short, the focus of this article is not the cardiodynamics and aerobic capacity of people with stroke, but the measuring capability of ICG during a 6MWT in people with stroke.

Ad Q 9:

Do you know the entire manuscript? In this manuscript DOI 10.1080/10641963.2018.1523917:

I think this information is worth of consideration in the discussion.

Yes, we have considered and understand this article. This article described the cardiodynamic parameters obtained by ICG during a cardiopulmonary exercise test (CPET). The subjects also were subjected to a 6MWT. The correlation between the 6-minute walk distance (6MWD) achieved and the peak VO2, HR, SV and CO obtained during the CPET was investigated. This paper did NOT access cardiodynamic data DURING a 6MWT and therefore is irrelevant to the focus of our paper. This article forms the basis of the second phase of our study, which compares cardiodynamic data obtained by ICG during CPET and ICG data obtained during 6MWT.

Line 273-280

In our discussion we suggest that the lesser contribution of SV to CO might be associated with diastolic dysfunction. The contribution of SV to CO appeared to be higher in the patients in our cohort with the opportuity for a longer period of rehabiliation training. This does nothing more than invite further investigation of the contributions of SV and HR to CO in response to exercise training. ICG is a convenient modality to determine this information. It is not the aim of our paper to discuss left ventricular dysfunction in our subject cohort.

Minor Comments:

Line 223-230 Good justification for the choice of method. It is recommended to move this fragment to the introduction as before. Please discuss the results in the discussion.

Line 281 Please replace "but" with "and".

The above has been addressed accordingly.

Attachment

Submitted filename: Respose to Reviewer 2-rev3.pdf

Click here for additional data file.^{(96.1KB, pdf)}

PLoS One. doi: 10.1371/journal.pone.0233000.r007

Decision Letter 3

Shane Patman

28 Apr 2020

Noninvasive investigation of the cardiodynamic response to 6MWT in people after stroke using impedance cardiography

PONE-D-19-24687R3

Dear Dr. Jones,

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

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Shane Patman, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: (No Response)

**********

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

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

PLoS One. doi: 10.1371/journal.pone.0233000.r008

Acceptance letter

Shane Patman

8 May 2020

PONE-D-19-24687R3

Noninvasive investigation of the cardiodynamic response to 6MWT in people after stroke using impedance cardiography

Dear Dr. Jones:

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

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

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Assoc Prof Shane Patman

Academic Editor

PLOS ONE

Associated Data

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

Supplementary Materials

S1 Checklist. STROBE statement—checklist of items that should be included in reports of observational studies.

(DOCX)

Click here for additional data file.^{(36KB, docx)}

S1 Table. ICC data.

(DOCX)

Click here for additional data file.^{(15.4KB, docx)}

S2 Table. Time for each variable returned to baseline.

(DOCX)

Click here for additional data file.^{(17.2KB, docx)}

S3 Table. Mean cardiodynamic data.

(DOCX)

Click here for additional data file.^{(18.8KB, docx)}

S4 Table. Correlation between 6MWD and cardiodynamic parameters at the end of 6MWT.

(DOCX)

Click here for additional data file.^{(13.4KB, docx)}

S5 Table. Comparison of characteristics in subjects with time elapsed since stroke diagnosis longer or shorter than 1 year.

(DOCX)

Click here for additional data file.^{(15KB, docx)}

Attachment

Submitted filename: review.docx

Click here for additional data file.^{(12.3KB, docx)}

Attachment

Submitted filename: Responses_Reviewer2.docx

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Attachment

Submitted filename: Response to reviewers.docx

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Attachment

Submitted filename: Review 3.docx

Click here for additional data file.^{(12.6KB, docx)}

Attachment

Submitted filename: Respose to Reviewer 2-rev3.pdf

Click here for additional data file.^{(96.1KB, pdf)}

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Noninvasive investigation of the cardiodynamic response to 6MWT in people after stroke using impedance cardiography

Fang Liu

Alice Y M Jones

Raymond C C Tsang

Yao Wang

Jing Zhou

Mingchao Zhou

Yulong Wang

Roles

Abstract

Introduction

Material and methods

Study design

Inclusion and exclusion criteria

Sample size

Procedure

Measurement of cardiac parameters

Electrode placement

Fig 1. Placement of electrodes (with patient consent).

Data analyses

Results

Table 1. Demographic data of the 29 participants.

Fig 2. Cardiodynamic changes at rest, during and post 6MWT.

Table 2. Heart rate and cardiodynamic parameters during a 6MWT reported in previous literature in comparison to data recorded in the current study.

Table 3. Linear regression using cardiac output change as dependent variable and HR change or SV change as covariates.

Fig 3. Cardiodynamic changes during the 6MWT in participants post-stroke duration of less or longer than 1 year.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Shane Patman

Roles

Author response to Decision Letter 0

Decision Letter 1

Shane Patman

Roles

Author response to Decision Letter 1

Decision Letter 2

Shane Patman

Roles

Author response to Decision Letter 2

Decision Letter 3

Shane Patman

Roles

Acceptance letter

Shane Patman

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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