Long-term variations of arterial stiffness in patients with obesity and obstructive sleep apnea treated with continuous positive airway pressure

Louis-Marie Galerneau; Sébastien Bailly; Jean-Christian Borel; Ingrid Jullian-Desayes; Marie Joyeux-Faure; Meriem Benmerad; Marisa R Bonsignore; Renaud Tamisier; Jean-Louis Pépin

doi:10.1371/journal.pone.0236667

. 2020 Aug 5;15(8):e0236667. doi: 10.1371/journal.pone.0236667

Long-term variations of arterial stiffness in patients with obesity and obstructive sleep apnea treated with continuous positive airway pressure

Louis-Marie Galerneau ^1,^2,^*, Sébastien Bailly ^1,², Jean-Christian Borel ^1,², Ingrid Jullian-Desayes ^1,², Marie Joyeux-Faure ^1,², Meriem Benmerad ^1,², Marisa R Bonsignore ^3,⁴, Renaud Tamisier ^1,^2,^‡, Jean-Louis Pépin ^1,^2,^‡

Editor: Yu Ru Kou⁵

PMCID: PMC7406029 PMID: 32756570

Abstract

Background

Obstructive sleep apnea (OSA) is associated with cardiovascular co-morbidities and mortality. Arterial stiffness is an independent predictor of cardiovascular risk and mortality, and is influenced by the presence of OSA and related comorbidities. There is a paucity of data regarding long-term evolution of arterial stiffness in CPAP-treated OSA patients. We aimed to prospectively study long term PWV variations and determinants of PWV deterioration.

Methods

In a prospective obese OSA cohort, at time of diagnosis and after several years of follow-up we collected arterial stiffness measured by carotid-femoral pulse wave velocity (PWV), clinical and metabolic parameters, and CPAP adherence. Univariate and multivariate analyses were performed in order to determine contributing factors.

Results

Seventy two OSA patients (men: 52.8%, median age: 55.8 years and median BMI of 38.5 kg/m²) with a prevalence of hypertension: 58.3%, type 2 diabetes: 20.8%, hypercholesterolemia: 33.3%, current or past smoking: 59.7%, were evaluated after a median follow-up of 7.4 [5.8; 8.3] years. Over the period of follow-up, the median increase in PWV was 1.34 [0.10; 2.37] m/s. In multivariate analysis, the increase in PWV was associated with older age (10 extra years was associated with a 5.24 [1.35; 9.12] % increase in PWV) and hypertension (a significant increase in PWV of 8.24 [1.02; 15.57] %). No impact of CPAP adherence on PWV evolution was found.

Conclusion

PWV progression in CPAP-treated OSA patients is mainly related to pre-existing cardio-metabolic comorbidities and not influenced by CPAP adherence. In this high cardiovascular risk population, it is crucial to associated weight management and exercise with CPAP treatment.

Introduction

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete obstruction of the upper airway during sleep, resulting in chronic intermittent hypoxia and sleep fragmentation. OSA is highly prevalent in obese patients with cardio-metabolic comorbidities. [1] The association between OSA and cardiovascular diseases has been clearly demonstrated, OSA being considered as an independent risk factor for cardiovascular and metabolic co-morbidities and mortality. [2–4] Continuous positive airway pressure (CPAP), the first line therapy for OSA, was reported to reduce the incidence of late cardiovascular events in patients with severe OSA in cohort observational studies. [5] However, in the largest recent randomized controlled trials, CPAP treatment did not reduce mortality or the occurrence of late cardiovascular events in intention to treat analyses. [6,7]

Arterial stiffness is an early independent predictor of cardiovascular risk and secondary occurrence of late incident cardiovascular events. [8–10] The gold standard measure of arterial stiffness is carotid-femoral pulse wave velocity (PWV).[11–13] A 1m/s increase in pulse wave velocity is associated with a 15% increase in mortality independently of other usual cardiovascular risk factors. Arterial stiffness has been suggested as having a dose-response relationship with indices of OSA severity. [8,14–16]

Arterial stiffness increases with age and blood pressure levels (BP); [17] and is linked with chronic conditions such as metabolic syndrome, [18] diabetes, [19] or chronic obstructive pulmonary disease (COPD). [20] All these conditions, which contribute to the lifelong increase in arterial stiffness, are highly prevalent in OSA patients. [21] The deterioration in arterial stiffness over time is sustained by intermediary mechanisms such as sympathetic over-activity, endothelial dysfunction, oxidative stress and systemic inflammation that are enhanced by OSA. [12,22]

There remains a debate regarding improvement in arterial stiffness under CPAP treatment. A recent meta-analysis [11] suggested an improvement but data were obtained from non-randomized studies assessing short term CPAP interventions with small sample sizes. [11,14] To date, no study has reported long term variations of arterial stiffness in CPAP-treated OSA patients. The goal of the current study was to prospectively assess the changes in PWV and their determinants in OSA patients treated by CPAP for at least four years (median duration of follow-up 7.5 years).

Materials and methods

Design and study population

Obese patients referred for sleep apnea to the Sleep department of Grenoble Alpes University Hospital between 2007 and 2010 were included in a prospective cohort study. These patients were re-examined after at least 4 years of CPAP treatment, with cardio-metabolic assessments including arterial stiffness. Hypertension was defined following the ESC/ESH guidelines. [23] At inclusion, patients were aged from 20 to 75 years with a body mass index (BMI) > 30 kg/m². Patients with central apnea were excluded.

The study was conducted in accordance with good clinical practice requirements in Europe, French law, ICH E6 recommendations, and the Helsinki Declaration (1996 and 2000). The protocol was approved by an independent Ethics Committee (Comité de Protection des Personnes, Grenoble, France, IRB0006705) and registered on the ClinicalTrials.gov site (NCT02623088). All patients gave their written informed consent.

Sleep study and sleepiness assessment

Overnight polysomnography (PSG) was used to diagnose OSA and characterize severity. [24–26] The apnea-hypopnea index (AHI) was calculated as the number of apnea and hypopnea events per hour of sleep. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS). [27] Mean nocturnal oxygen saturation (SaO₂) and time spent under 90% of SaO₂ were also collected in order to characterize sleep apnea severity. Overnight sleep studies were scored according to international guidelines. [28]

Arterial stiffness assessement

Carotid-femoral PWV, a validated measure of arterial stiffness, was assessed for each patient [12,13] using a Complior device (Alam Medical^®, France). [29] Carotid-femoral PWV is the ratio on distance to transit time between two pressure waves recorded transcutaneously at carotid and femoral arterial sites. The distance travelled by the pulse wave was measured with an external tape-measure across the body surface. For the 30 min-long PWV measurements the subject was fasted and rested and in an elongated supine position. Two electrodes were placed one on the carotid artery and the other on the femoral artery until a quality signal was obtained, characterized by a clear rise of the systolic curve and a smooth diastolic curve for at least 10 seconds. At least two PWV measurements were systematically done. The mean value between the two measurements was retained if the difference between measurements was less than 0.5 m/s. When the difference was above 0.5 m/s, a third measurement was made and the median value of the three measurements was used.

Metabolic and inflammatory biomarkers

On waking, after 10 hours fasting, a peripheral blood sample was drawn. Fasting glucose, HbA1c, serum insulin, lipids, and high-sensitivity C-reactive protein (hsCRP) levels were measured using standard procedures.

Respiratory function

Arterial blood gas measurements and pulmonary function tests (measured using Medisoft^® devices) were performed. Significant airway obstruction was defined as FEV₁/FVC<70%, according to standard definitions. [30]

CPAP treatment

According to French and international recommendations, [31] patients with moderate or severe OSA were treated with CPAP. [2,32] Adherence was defined as a mean CPAP use of at least 4 hours per night. [33] CPAP adherence used for data analysis was corresponding to objective compliance measured in the 3 to 6 months preceding follow-up visit.

Follow-up

After 4 to 9 years of follow-up, new measurements of the same parameters as at baseline were done, except for PSG.

Statistical analysis

Statistical analyses were performed with SAS v9.4 software (SAS Institute Inc., Cary, NC, United States). A p-value < 0.05 was considered as significant. Continuous data are presented as median and interquartile range (IQR) and categorical data as frequency and percentage. A comparison of the main quantitative variables at baseline and at follow-up was performed using a non-parametric Mann-Whitney test. A non-parametric Wilcoxon signed-rank test was used to compare the PWV before and after CPAP use. Due to the non-normality of PWV values, a log-transformation was performed and a log-linear mixed effect model with a patient random effect adjusted for the delay between the two measurements was used to analyze the evolution in arterial stiffness. A univariate analysis between PWV and potentially contributing factors was performed to select variables for the multivariate model. Variables with a p-value less or equal to 0.20 were retained and introduced into the multivariate analysis in association with predefined clinically relevant variables. Adjustment for age, sex and CPAP treatment. Due to the log transformation of the PWV, the final estimate presented in the multivariate analysis corresponded to 100*Beta (where beta was a parameter of the log-linear model and can be directly interpreted as the percent of increase or decrease in the PWV at follow-up). Due to the low number of missing values, a simple imputation method was used to impute missing data: quantitative variables were imputed using the median and qualitative variables were imputed using the most frequent value.

Results

Patient characteristics

As shown in the study flowchart (Fig 1), 107 obese patients were initially included in this prospective cohort. Among them, 91 were followed and treated for OSA and for 72 patients PWV was reassessed at long-term.

At inclusion, patients had a median age of 55.8 [47.4; 62.0] years, 52.8% were men, with a median (IQR) BMI of 38.5 [35.4; 43.1] kg/m². Median (IQR) AHI at diagnosis was 36.1 [23.3; 75.2] events/hour. Patients with hypertension (58.3%), had type 2 diabetes (20.8%) and were current or former smokers (59.7%). Baseline data concerning medical history, comorbidities, arterial blood gases, biological parameters, sleep studies and pulmonary function tests are shown in Table 1. The comparison between imputed and non-imputed datasets is available in S1 Table of the online supplement.

Table 1. Study population characteristics at baseline.

Anthropometric and biological characteristics
Age, (years)	55.8 [47.4–62]
Men	38 (52.8)
BMI, (kg/m²)	38.5 [35.4–43.1]
Hypertension, n (%)	42 (58.3)
Stroke, n (%)	3 (4.2)
Diabetes mellitus, n (%)	15 (20.8)
Hypercholesterolemia, n (%)	24 (33.3)
Smoking, n (%)	40 (59.7)
SBP, (mmHg)	132 [122–140]
DBP, (mmHg)	79.5 [70–85]
HbA1c, (%)	5.8 [5.5–6.3]
Fasting blood Glucose, (mmol/l)	5.7 [5.3–6.2]
Insulinemia, (μUl/ml)	8.7 [6.4–13.3]
hsCRP, (mg/l)	4.2 [2.1–8.9]
Respiratory function
FVC, (% of predicted value)	99 [84–106]
FEV₁, (% of predicted value)	92 [82–103]
FEV₁/ FVC, (%)	80.6 [75.5–84.1]
FEV₁/ FVC < 70%, n (%)	7 (10.1)
TLC, (% of predicted value)	103.5 [96.5–114]
PaCO2, (kPa)	5.3 [5–5.6]
PaO2, (kPa)	10.2 [9.6–11.2]
Sleep disordered breathing
Epworth Sleepiness Scale	12 [8–16]
AHI, (/hour)	36.1 [23.3–75.2]
Mean nocturnal SpO₂, (%)	92 [89–94]
Sleep time spent with SpO₂ < 90%, (% of total sleep time)	11 [2–43]
PWV (m/s)	9.7 [8.5–10.7]

Open in a new tab

Categorical variables are expressed as a percentage and quantitative variables as the median (IQR). AHI, apnea hypopnea index; BMI, body mass index; DBP, diastolic blood pressure; FEV1, Forced Expiratory Volume of the first second of forced expiration; FVC, Forced Vital Capacity; HbA1c, Glycated hemoglobin; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; PWV, Pulse Wave Velocity; SBP, systolic blood pressure; SpO2, oxygen saturation; TLC, Total lung capacity.

Follow-up

The median duration of follow-up was 7.5 years. At baseline, the median value of PWV was 9.7 m/s. At the follow-up PWV assessment, the median value was 10.5 m/s corresponding to a median increase of 1.34 m/s over the follow-up period. There was a significant difference of PWV between and after CPAP use (p<0.01).

CPAP adherence of at least 4 hours/night was recorded for 72% of the patients and the median adherence to CPAP was 6.4 [5.1; 7.5] hours per night (Tables 2 & 3). The medications being used at the time of the follow-up visit are shown in S2 Table of the online supplemental material.

Table 2. Data at the follow-up PWV assessment.

Follow-up time, (years)	7.5 [5.8–8.3]
PWV, (m/s)	10.5 [9.6–12.7]
Patients adherent to CPAP, n (%)	52 (72.2)
Adherence to CPAP, (hours per night)	6.4 [5.1–7.5]
PWV increase during the complete follow-up period, (m/s)	1.34 [0.10–2.37]
PWV increase per year, (m/s per year)	0.19 [0.01–0.36]

Open in a new tab

Categorical variables are expressed as percentage and quantitative variables as median (IQR). PWV, Pulse Wave Velocity.

Table 3. Comparison between baseline and follow-up values.

Variable	Baseline	Follow-up	P
BMI (kg/m²)	38.5 [35.4; 43.1]	38.4 [34.3; 41.9]	0.19
SBP (mmHg)	132 [122; 140]	132 [122; 138]	0.44
DBP (mmHg)	79.5 [70; 85]	74 [68; 81]	<.01
hsCRP (mg/l)	5.8 [5.5; 6.3]	5.9 [5.7; 6.5]	0.61
Fasting Glucose (mmol/l)	5.7 [5.3; 6.2]	6.1 [5.4; 7]	0.02
Insulinemia (μUl/ml)	8.7 [6.4; 13.3]	12.2 [7.9; 16.7]	0.08
hsCRP (mg/l)	4.2 [2.1; 8.9]	4.1 [1.7; 5.8]	0.22
PaCO₂ (kPa)	5.3 [5; 5.6]	4.9 [4.6; 5.2]	<.01
PaO₂ (kPa)	10.2 [9.6; 11.2]	11 [10.1; 11.8]	<.01
Epworth Sleepiness Scale	12 [8; 16]	7 [4; 10]	<.01

Open in a new tab

BMI, body mass index; hs-CRP, high sensitivity C-reactive protein; DBP, diastolic blood pressure; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; SBP, systolic blood pressure.

P: p value for the non-parametric Mann-Whitney test.

Determinants of arterial stiffness deterioration

Univariate analysis

A ten year increase in age was associated with a 7.36% increase in PWV (p<0.01). High blood pressure at baseline was associated with a 12.63% increase in PWV compared to normotensive patients (p<0.01) and having diabetes was associated with a 13.75% increase in PWV compared to patients without diabetes (p<0.01). There was no association between changes in PWV results over the years and BMI or indices of OSA severity at baseline. CPAP adherence was not linked to change in PWV. (Fig 2).

Fig 2 — BMI, body mass index; FEV1, Forced Expiratory Volume in the first second of forced expiration; FVC, Forced Vital Capacity; AHI, apnea hypopnea index; TST, total sleep time, CPAP, continuous positive airway pressure. Interpretation: An increase of ten years in age is associated with a 7.36% increase in PWV. Having high blood pressure at baseline was associated with a 12.63% increase in PWV compared to normotensive patients. Having diabetes was associated with a 13.75% increase in PWV compared to patients without diabetes.

Multivariate analysis

After adjustment for follow-up duration, age, gender, hypertension, diabetes, COPD, and CPAP adherence PWV was shown to increase significantly more in CPAP-treated OSA patients with hypertension (p = 0.03). A trend close to significance was apparent for type 2 diabetic patients (p = 0.08) and with airway obstruction (p = 0.11). The multivariate analysis did not demonstrate a long-term impact of CPAP adherence on PWV evolution (p = 0.54). (Fig 3).

Fig 3 — FEV1, Forced Expiratory Volume of the first second of forced expiration; FVC, Forced Vital Capacity; AHI, apnea hypopnea index; CPAP, continuous positive airway pressure. Interpretation: A 10-year increase in age was associated with a 5.24% increase in PWV. Compared to the baseline PWV value of the multivariate model, this is associated to a significant increase of 0.35m/s of PWV for 10-year age increase. Having hypertension at baseline was associated to a significant increase in PWV of 8.24%.

Discussion

To our knowledge, this is the first study assessing long-term variations (median follow-up 7.5 years) of arterial stiffness in obese OSA CPAP-treated patients. During this period, the median PWV increase under CPAP was 1.34 m/s. In multivariate analysis, PWV progression was significantly dependent of age and hypertensive status. Neither indices of OSA severity at diagnosis nor CPAP adherence contributed significantly to the long-term trajectory of arterial stiffness.

Sleep apnea is known to impact vascular age. [14,34,35] We should compare our obese OSA population (median age 55 years) to the same age group in the general population, they probably show greater arterial stiffness at baseline, as assessed by PWV. The Arterial Stiffness Collaboration [36] reported a median (± 2 SD) PWV of 8.1 (6.3–10.0) m/s for the 50–59 year age group in the healthy population compared to 9.7 [8.5; 10.7] in our study population. A 1 m/s increase in aortic PWV corresponds to a 15% increase in all-cause mortality after adjustment for confounders. [8] This association between OSA and elevated measurements of arterial stiffness had been previously described independently of BP [15,37] or metabolic syndrome. [38] However, in a recent individual patient meta-analysis, [39] we showed that cross-sectional elevated arterial stiffness in patients with OSA is mainly driven by the conventional cardiovascular risk factors; age, BP and the presence of diabetes, while apnea severity indices had limited influence. The current data extend these results by demonstrating that long-term OSA treatment by CPAP does not check the progression in arterial stiffness.

A PWV decrease after CPAP initiation had been reported in several mostly small sample size, uncontrolled and short-term studies. [11] The largest study with a long-term follow-up showed that PWV decreased significantly over the first 6 months of treatment and then gradually increased between 6 and 24 months. [40] As in our study this late increase in PWV might be explained not only by age-related progression in arterial stiffness but also by the long-term burden of uncontrolled co-morbidities.

Hypertension is the main condition associated with PWV progression, with a reciprocal relationship between the two. [36,41–43] Severe OSA and hypertension are both associated with an increase in arterial stiffness, with cumulative effects when the two diseases coexist [14,34,44,45] In morbidly obese OSA patients CPAP has been shown to produce a small but significant reduction in blood pressure in relatively short term randomized controlled trials. [46] The SAVE study showed a non-significant systolic blood pressure difference between CPAP-treated and usual care groups of <1.0 mmHg over a mean follow-up of 3.7 years. [47] Further data on mean BP and visit-to-visit BP variability (BPV) over the first 24-months of the SAVE study have recently been reported. [48] The initial reduction in visit-to-visit BPV and mean BP was lost after 12 months and was associated with a decrease in CPAP adherence. These results are in accordance with our findings, suggesting that non-sustained reductions in mean BP and the relatively small potential effect size of CPAP are not enough to counteract the development of comorbidities and limit arterial stiffness progression. CPAP adherence was relatively high in our study population but no reduction in PWV values was observed. The follow-up long term assessment did not include a PSG as CPAP efficiency was evaluated by the index of residual events downloaded from the CPAP software’s. It is unexpected that the severity of OSA changed dramatically as there was no significant change in BMI (38.5 [35.4; 43.1] versus 38.4 [34.3; 41.9] for baseline and follow-up respectively; Table 3).

Other acknowledged contributors to arterial stiffness progression are type 2 diabetes or glucose intolerance in pre-diabetic states, [19,48] and metabolic syndrome. [49] Again, OSA and metabolic syndrome synergistically act to increase PWV [38] and type 2 diabetes has a major impact toward increasing arterial stiffness in patients with metabolic syndrome. [49,50] In the present study, the association with type 2 diabetes did not reach significance in multivariate analysis, but this can certainly be explained by an insufficient sample size resulting in lack of statistical power.

The combination of COPD and OSA is called “overlap syndrome” [51] and is associated with a worse prognosis compared to that of patients with only one of the two diseases. [52–55] Our data failed to show an independent association between COPD and high arterial stiffness [20,56–58] and additive effects of COPD on the cardiovascular damage seen in patients with OSA. [59]

Conclusion and perspectives

There is an increase in PWV over the study period. In multivariate analysis, determinants of PWV progression are old age and hypertension. Optimal management of OSA-associated comorbidities is needed for patients on CPAP treatment [60,61] in order to slow deterioration in arterial stiffness, reduce the occurrence of late cardiovascular events and to improve survival.

Supporting information

S1 Table. Comparison between imputed and non-imputed datasets.

AHI, apnea hypopnea index; HbA1c, Glycated hemoglobin; hs-CRP, high sensitivity C-reactive protein; DBP, diastolic blood pressure; FEV1, Forced Expiratory Volume of the first second of forced expiration; FVC, Forced Vital Capacity; SBP, systolic blood pressure; SpO2, oxygen saturation; TLC, total lung capacity.

(DOCX)

Click here for additional data file.^{(24.9KB, docx)}

S2 Table. Medication used by patients at the second assessment.

(DOCX)

Click here for additional data file.^{(24.1KB, docx)}

S1 Data

(CSV)

Click here for additional data file.^{(8.1KB, csv)}

S2 Data

(CSV)

Click here for additional data file.^{(6.8KB, csv)}

S3 Data

(CSV)

Click here for additional data file.^{(1.6KB, csv)}

Acknowledgments

Guarantor statement: Jean-Louis Pépin takes responsibility for the content of the manuscript, including the data and analysis. Other contributions: We thank Dr Alison Foote (Grenoble Alpes University Hospital) for critically editing the manuscript.

Abbreviations

AHI: apnea-hypopnea index
BP: Blood pressure
BPV: BP variability
COPD: chronic obstructive pulmonary disease
CPAP: Continuous positive airway pressure
ESS: Epworth Sleepiness Scale
FEV1: Forced Expiratory Volume in the first second of forced expiration
FVC: Forced Vital Capacity
hsCRP: high-sensitivity C-reactive protein
OSA: Obstructive sleep apnea
PWV: Pulse wave velocity
SaO2: Mean nocturnal oxygen saturation
TLC: Total lung capacity

Data Availability

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

Funding Statement

This study was funded by an unrestricted grant from the French National Research Agency (ANR-12-TECS-0010) in the framework of the “Investissements d’avenir” program (ANR-15-IDEX-02), the “e-health and integrated care” Chair of excellence of the University Grenoble Alpes Foundation and the endowment fund “Agir pour les maladies chroniques”. This study was funded in part by ORKYN Society and Périmètre Association.

References

1.Pépin JL, Timsit JF, Tamisier R, Borel JC, Lévy P, Jaber S. Prevention and care of respiratory failure in obese patients. Lancet Respir Med. 2016;4: 407–418. 10.1016/S2213-2600(16)00054-0 [DOI] [PubMed] [Google Scholar]
2.Lévy P, Kohler M, McNicholas WT, Barbé F, McEvoy RD, Somers VK, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primer. 2015; 15015 10.1038/nrdp.2015.15 [DOI] [PubMed] [Google Scholar]
3.Murphy AM, Thomas A, Crinion SJ, Kent BD, Tambuwala MM, Fabre A, et al. Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation. Eur Respir J. 2017;49. [DOI] [PubMed] [Google Scholar]
4.Aron-Wisnewsky J, Clement K, Pépin J-L. Nonalcoholic fatty liver disease and obstructive sleep apnea. Metabolism. 2016;65: 1124–1135. 10.1016/j.metabol.2016.05.004 [DOI] [PubMed] [Google Scholar]
5.Marin JM, Carrizo SJ, Vicente E, Agusti AGN. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365: 1046–1053. 10.1016/S0140-6736(05)71141-7 [DOI] [PubMed] [Google Scholar]
6.McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, et al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med. 2016;375: 919–931. 10.1056/NEJMoa1606599 [DOI] [PubMed] [Google Scholar]
7.Drager LF, McEvoy RD, Barbe F, Lorenzi-Filho G, Redline S, INCOSACT Initiative (International Collaboration of Sleep Apnea Cardiovascular Trialists). Sleep Apnea and Cardiovascular Disease: Lessons From Recent Trials and Need for Team Science. Circulation. 2017;136: 1840–1850. 10.1161/CIRCULATIONAHA.117.029400 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55: 1318–1327. 10.1016/j.jacc.2009.10.061 [DOI] [PubMed] [Google Scholar]
9.Mitchell GF, Hwang S-J, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010;121: 505–511. 10.1161/CIRCULATIONAHA.109.886655 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertens Dallas Tex 1979. 2001;37: 1236–1241. [DOI] [PubMed] [Google Scholar]
11.Vlachantoni I-T, Dikaiakou E, Antonopoulos CN, Daskalopoulou SS, Petridou ET. Effects of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea in arterial stiffness: a meta-analysis. Sleep Med Rev. 2013;17: 19–28. 10.1016/j.smrv.2012.01.002 [DOI] [PubMed] [Google Scholar]
12.Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27: 2588–2605. 10.1093/eurheartj/ehl254 [DOI] [PubMed] [Google Scholar]
13.Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30: 445–448. 10.1097/HJH.0b013e32834fa8b0 [DOI] [PubMed] [Google Scholar]
14.Phillips CL, Butlin M, Wong KK, Avolio AP. Is obstructive sleep apnoea causally related to arterial stiffness? A critical review of the experimental evidence. Sleep Med Rev. 2013;17: 7–18. 10.1016/j.smrv.2012.03.002 [DOI] [PubMed] [Google Scholar]
15.Doonan RJ, Scheffler P, Lalli M, Kimoff RJ, Petridou ET, Daskalopoulos ME, et al. Increased arterial stiffness in obstructive sleep apnea: a systematic review. Hypertens Res Off J Jpn Soc Hypertens. 2011;34: 23–32. 10.1038/hr.2010.200 [DOI] [PubMed] [Google Scholar]
16.Chung S, Yoon I-Y, Lee CH, Kim J-W. The association of nocturnal hypoxemia with arterial stiffness and endothelial dysfunction in male patients with obstructive sleep apnea syndrome. Respir Int Rev Thorac Dis. 2010;79: 363–369. [DOI] [PubMed] [Google Scholar]
17.McEniery CM, Yasmin null, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR, et al. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46: 1753–1760. 10.1016/j.jacc.2005.07.037 [DOI] [PubMed] [Google Scholar]
18.Koivistoinen T, Hutri-Kähönen N, Juonala M, Aatola H, Kööbi T, Lehtimäki T, et al. Metabolic syndrome in childhood and increased arterial stiffness in adulthood: the Cardiovascular Risk In Young Finns Study. Ann Med. 2011;43: 312–319. 10.3109/07853890.2010.549145 [DOI] [PubMed] [Google Scholar]
19.Prenner SB, Chirinos JA. Arterial stiffness in diabetes mellitus. Atherosclerosis. 2015;238: 370–379. 10.1016/j.atherosclerosis.2014.12.023 [DOI] [PubMed] [Google Scholar]
20.Vivodtzev I, Tamisier R, Baguet J-P, Borel JC, Levy P, Pépin J-L. Arterial stiffness in COPD. Chest. 2014;145: 861–875. 10.1378/chest.13-1809 [DOI] [PubMed] [Google Scholar]
21.Lévy P, Bonsignore MR, Eckel J. Sleep, sleep-disordered breathing and metabolic consequences. Eur Respir J. 2009;34: 243–260. 10.1183/09031936.00166808 [DOI] [PubMed] [Google Scholar]
22.Jelic S, Padeletti M, Kawut SM, Higgins C, Canfield SM, Onat D, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation. 2008;117: 2270–2278. 10.1161/CIRCULATIONAHA.107.741512 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36: 1953–2041. 10.1097/HJH.0000000000001940 [DOI] [PubMed] [Google Scholar]
24.International Classification of Sleep Disorders 3rd ed. American Academy of Sleep Medicine. 2014. [DOI] [PMC free article] [PubMed]
25.Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146: 1387–1394. 10.1378/chest.14-0970 [DOI] [PubMed] [Google Scholar]
26.Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med. 2012;8: 597–619. 10.5664/jcsm.2172 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14: 540–545. 10.1093/sleep/14.6.540 [DOI] [PubMed] [Google Scholar]
28.Berry RB, Brooks R, Gamaldo C, Harding SM, Lloyd RM, Quan SF, et al. AASM Scoring Manual Updates for 2017 (Version 2.4). J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med. 2017;13: 665–666. 10.5664/jcsm.6576 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B, Brisac AM, et al. Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies. Hypertension. 1995;26: 485–490. 10.1161/01.hyp.26.3.485 [DOI] [PubMed] [Google Scholar]
30.Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: The GOLD Science Committee Report 2019. Eur Respir J. 2019. [DOI] [PubMed] [Google Scholar]
31.Société de Pneumologie de Langue Française, Société Française d’Anesthésie Réanimation, Société Française de Cardiologie, Société Française de Médecine du Travail, Société Française d’ORL, Société de Physiologie, et al. [Recommendations for clinical practice. Obstructive sleep apnea hypopnea syndrome in adults]. Rev Mal Respir. 2010;27: 806–833. 10.1016/j.rmr.2010.05.011 [DOI] [PubMed] [Google Scholar]
32.Gay P, Weaver T, Loube D, Iber C, Positive Airway Pressure Task Force, Standards of Practice Committee, et al. Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep. 2006;29: 381–401. 10.1093/sleep/29.3.381 [DOI] [PubMed] [Google Scholar]
33.Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc. 2008;5: 173–178. 10.1513/pats.200708-119MG [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Drager LF, Bortolotto LA, Figueiredo AC, Silva BC, Krieger EM, Lorenzi-Filho G. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007;131: 1379–1386. 10.1378/chest.06-2703 [DOI] [PubMed] [Google Scholar]
35.Pépin J-L, Tamisier R, Baguet J-P, Lévy P. Arterial health is related to obstructive sleep apnea severity and improves with CPAP treatment. Sleep Med Rev. 2013;17: 3–5. 10.1016/j.smrv.2012.11.002 [DOI] [PubMed] [Google Scholar]
36.Reference Values for Arterial Stiffness’ Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: “establishing normal and reference values”. Eur Heart J. 2010;31: 2338–2350. 10.1093/eurheartj/ehq165 [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Drager LF, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Chest. 2011;140: 534–542. 10.1378/chest.10-2223 [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Drager LF, Bortolotto LA, Maki-Nunes C, Trombetta IC, Alves MJNN, Fraga RF, et al. The incremental role of obstructive sleep apnoea on markers of atherosclerosis in patients with metabolic syndrome. Atherosclerosis. 2010;208: 490–495. 10.1016/j.atherosclerosis.2009.08.016 [DOI] [PubMed] [Google Scholar]
39.Joyeux-Faure M, Tamisier R, Borel J-C, Millasseau S, Galerneau L-M, Destors M, et al. Contribution of obstructive sleep apnoea to arterial stiffness: a meta-analysis using individual patient data. Thorax. 2018. 10.1136/thoraxjnl-2018-211513 [DOI] [PubMed] [Google Scholar]
40.Saito T, Saito T, Sugiyama S, Asai K, Yasutake M, Mizuno K. Effects of long-term treatment for obstructive sleep apnea on pulse wave velocity. Hypertens Res Off J Jpn Soc Hypertens. 2010;33: 844–849. 10.1038/hr.2010.77 [DOI] [PubMed] [Google Scholar]
41.Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31: 1281–1357. 10.1097/01.hjh.0000431740.32696.cc [DOI] [PubMed] [Google Scholar]
42.Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012;308: 875–881. 10.1001/2012.jama.10503 [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Lin X, Chen G, Qi J, Chen X, Zhao J, Lin Q. Effect of continuous positive airway pressure on arterial stiffness in patients with obstructive sleep apnea and hypertension: a meta-analysis. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol—Head Neck Surg. 2016;273: 4081–4088. 10.1007/s00405-016-3914-8 [DOI] [PubMed] [Google Scholar]
44.Tsioufis C, Thomopoulos K, Dimitriadis K, Amfilochiou A, Tousoulis D, Alchanatis M, et al. The incremental effect of obstructive sleep apnoea syndrome on arterial stiffness in newly diagnosed essential hypertensive subjects. J Hypertens. 2007;25: 141–146. 10.1097/HJH.0b013e32801092c1 [DOI] [PubMed] [Google Scholar]
45.Tavil Y, Kanbay A, Sen N, Ulukavak Ciftçi T, Abaci A, Yalçin MR, et al. The relationship between aortic stiffness and cardiac function in patients with obstructive sleep apnea, independently from systemic hypertension. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2007;20: 366–372. 10.1016/j.echo.2006.09.005 [DOI] [PubMed] [Google Scholar]
46.Bratton DJ, Gaisl T, Wons AM, Kohler M. CPAP vs Mandibular Advancement Devices and Blood Pressure in Patients With Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. JAMA. 2015;314: 2280–2293. 10.1001/jama.2015.16303 [DOI] [PubMed] [Google Scholar]
47.Van Ryswyk E, Anderson CS, Barbe F, Loffler KA, Lorenzi-Filho G, Luo Y, et al. Effect of CPAP on Blood Pressure in Obstructive Sleep Apnea with Cardiovascular Disease. Am J Respir Crit Care Med. 2019. 10.1164/rccm.201811-2200LE [DOI] [PubMed] [Google Scholar]
48.Cecelja M, Chowienczyk P. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension. 2009;54: 1328–1336. 10.1161/HYPERTENSIONAHA.109.137653 [DOI] [PubMed] [Google Scholar]
49.Pietri P, Vlachopoulos C, Vyssoulis G, Ioakeimidis N, Stefanadis C. Macro- and microvascular alterations in patients with metabolic syndrome: sugar makes the difference. Hypertens Res Off J Jpn Soc Hypertens. 2014;37: 452–456. 10.1038/hr.2013.148 [DOI] [PubMed] [Google Scholar]
50.Safar ME, Balkau B, Lange C, Protogerou AD, Czernichow S, Blacher J, et al. Hypertension and vascular dynamics in men and women with metabolic syndrome. J Am Coll Cardiol. 2013;61: 12–19. 10.1016/j.jacc.2012.01.088 [DOI] [PubMed] [Google Scholar]
51.Malhotra A, Schwartz AR, Schneider H, Owens RL, DeYoung P, Han MK, et al. Research Priorities in Pathophysiology for Sleep-disordered Breathing in Patients with Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med. 2018;197: 289–299. 10.1164/rccm.201712-2510ST [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med. 2010;182: 325–331. 10.1164/rccm.200912-1869OC [DOI] [PubMed] [Google Scholar]
53.Zamarrón C, García Paz V, Morete E, del Campo Matías F. Association of chronic obstructive pulmonary disease and obstructive sleep apnea consequences. Int J Chron Obstruct Pulmon Dis. 2008;3: 671–682. 10.2147/copd.s4950 [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Stone IS, Barnes NC, Petersen SE. Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease? Heart Br Card Soc. 2012;98: 1055–1062. 10.1136/heartjnl-2012-301759 [DOI] [PubMed] [Google Scholar]
55.Lee HM, Lee J, Lee K, Luo Y, Sin DD, Wong ND. Relation between COPD severity and global cardiovascular risk in US adults. Chest. 2012;142: 1118–1125. 10.1378/chest.11-2421 [DOI] [PubMed] [Google Scholar]
56.McAllister DA, Maclay JD, Mills NL, Mair G, Miller J, Anderson D, et al. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176: 1208–1214. 10.1164/rccm.200707-1080OC [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Weir-McCall JR, Struthers AD, Lipworth BJ, Houston JG. The role of pulmonary arterial stiffness in COPD. Respir Med. 2015;109: 1381–1390. 10.1016/j.rmed.2015.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
58.Vanfleteren LEGW Spruit MA, Groenen MTJ Bruijnzeel PLB, Taib Z Rutten EPA, et al. Arterial stiffness in patients with COPD: the role of systemic inflammation and the effects of pulmonary rehabilitation. Eur Respir J. 2014;43: 1306–1315. 10.1183/09031936.00169313 [DOI] [PubMed] [Google Scholar]
59.Shiina K, Tomiyama H, Takata Y, Yoshida M, Kato K, Nishihata Y, et al. Overlap syndrome: additive effects of COPD on the cardiovascular damages in patients with OSA. Respir Med. 2012;106: 1335–1341. 10.1016/j.rmed.2012.05.006 [DOI] [PubMed] [Google Scholar]
60.Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA, Townsend R, et al. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med. 2014;370: 2265–2275. 10.1056/NEJMoa1306187 [DOI] [PMC free article] [PubMed] [Google Scholar]
61.Vivodtzev I, Tamisier R, Croteau M, Borel J-C, Grangier A, Wuyam B, et al. Ventilatory support or respiratory muscle training as adjuncts to exercise in obese CPAP-treated patients with obstructive sleep apnoea: a randomised controlled trial. Thorax. 2018. 10.1136/thoraxjnl-2017-211152 [DOI] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0236667.r001

Decision Letter 0

Yu Ru Kou

16 Mar 2020

PONE-D-20-05576

Long-term trajectories of arterial stiffness in obese CPAP-treated obstructive sleep apnea

PLOS ONE

Dear Dr Galerneau,

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

Both reviewers raised several concerns that need to be addressed. Also, the reviewer listed a list of comments that require to be revised.

We would appreciate receiving your revised manuscript by Apr 30 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.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

Journal Requirements:

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

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. During your revisions, please clarify the wording in the title and update it in the manuscript file and online submission information. Specifically, we suggest the title to be modified as follows: "Long-term trajectories of arterial stiffness in patients with obesity and obstructive sleep apnea treated with continuous positive airway pressure.

3. Throughout the manuscript, please avoid the use of potentially stigmatising language. For example, please replace 'obese patients' with 'patients with obesity'.

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

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

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

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

5. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 3 in your text; if accepted, production will need this reference to link the reader to the Table.

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I’ve read with interest the manuscript entitled „Long-term trajectories of arterial stiffness in obese CPAP-treated obstructive sleep apnea”. Authors of this study compared arterial stiffness at the time of OSA diagnosis and several years later with CPAP treatment. Authors concluded arterial stiffness progresses despite CPAP treatment. I think the study is well done and the manuscript very well written. I have a few comments/suggestions:

Major:

Why was a second PSG not done during the follow up visit? Or at least the Epworth questionnaire? I think this has to be discussed as a study limitation. We do not know what happened with OSA severity of the treated subjects (it might have been worse over the years in some of the patients with not known CPAP adherence).

Have you compared those patients with known CPAP adherence of at least 4 hours with the rest? What happened with arterial stiffness in just those patients with known CPAP adherence > 4 hours?

Were there any patients with CSA? Please show more PSG parameters.

Minor:

The follow up visit was not the same for all of the patients. What was the reason?

Reviewer #2: General comment

This is an interesting article dealing with an important aspect of sleep apnea morbidity that is not study enough in the litterature

Major Comments

1. In the title, the use of « trajectories » is not appropriate. As written, the goal seems to be to draw the fluctuations of the arterial stiffness over a period. But in this study, there is a comparison of the PWV before and after at least 4 years of CPAP therapy. This term need to be changed into “variations” or “deterioration” for example

2. In the abstract

a. Precise the goal of the study: PWV variation and determinants of increased PWV

b. The methods section is not complete: write a sentence about the analysis done in the study

3. In the analysis, it is interesting and important to know if there is a statistical difference between PWV before and after CPAP therapy.

Minor Comments

Abstract

Line 50: delete “a high”

Line 51: Difficult to understand “and/or current or past smoking”

Introduction

Line 124: As said before, “long term longitudinal trajectories of arterial stiffness”

Line 126: reformulate: “assess the longitudinal changes in PWV”

Methods

Line 144: “full respiratory polysomnography”: restrict it to polysomnography, it already include the respiratory recordings

Line 145: “AHI was calculated from the number of apnea and hypopnea events per hour of sleep” : AHI was calculated “as” not “from”

Line 149 : “Overnight sleep studies were scored according to international guidelines” : precise which ones , references, they differ over years

Line 155: “the ratio of distance to transit time”: it is the ratio of distance “on” not of

Line 175: FEV1/FVC<70%, according to standard definitions : normally you should use FEV1/FVC< lower limit of the normal (LIN), this is the standard definition, according to anthropometric parameters as stipulated by GLI

Line 179-180: “Adherence was defined as a mean CPAP use of at least 4 hours per night.”: generally adherence is evaluated over a period, here was it during the 4-9 years of follow up or only during the last year before the 2nd measurement of PWV?

Line 183 : It is important to be precise about the delay after which the new PWV was measured. 4 to 9 years is too large, even more than the double the 4 years. There may be a difference in PWV according to time (4 and 9 years) in the same patients. Here precise if it was only one measurement of PWV or more after that 4 years of CPAP therapy. This part need to be more precise!!!

Line 193: “univariable analysis”: it is univariate analysis same for multivariable, It is multivariate

Line 195 : Multivariate analysis was compute via which type of regression model?

Line 196: “Age, sex and CPAP treatment were included in the final multivariable model independently of the results of the univariable analysis”: this is called ajustement for age, sex and CPAP treatment

Line 201: “Due to the low number of missing values, a simple imputation method was used to impute missing data: quantitative variables were imputed using the median and qualitative variables were imputed using the most frequent value”: why was there missing values of PWV? This was a prospective study and the primary outcome was PWV, how missing values can be explained only on 107 patients?

Line 203-204: “Statistical analyses were performed with SAS v9.4 software (SAS Institute Inc., Cary, NC, United States)”: this is at the beginning of the section statistical analysis

Line 205: A p-value < 0.05 not “A p-value of < 0.05”

Results

Figure 1:

- Put the n of patients without OSA or with CSA

- As asked before, I don’t understand how 19 patients did not have data on PWV at follow up : Was it a retrospective study?

- Why are you dividing patients at the end into 2 groups according to the CPAP adherence? It is not necessary here to tell us how patients were included in the study. The outcome is changes in PWV not the adherence to CPAP therapy

Line 212: write median (IQR)

Line 214: “Patients commonly exhibited hypertension (58.3% of the population)” rephrase: delete commonly exhibited and of the population

Line 215: remove frequently; in the methods there is no mention about how a patients was characterized as current or former smoker!

Table 1:

- It is not possible to put n (%) in column + Median (IQR) and the same n (%) in lines and at the end “Categorical variables are expressed as a percentage and quantitative variables as the median (25th, 75th percentiles)”. This is repetition!!! . Normally n (%) on the head of the column and median (25th, 75th percentiles) on line for only qualitative variables. And if it is like that, it is not necessary to add as footnotes “Categorical variables are expressed as a percentage and quantitative variables as the median (25th, 75th percentiles)”

- In the bracket of IQR, hyphen not semi column

- Add comma after the name of the variable, eg: Age, (years)- BMI, (Kg/m²)….

- FEV1/ FVC < 70% (%) ; it is n (%)

- It is Fasting “blood”Glucose

- Footnotes: FEV1 is forced expiratory volume during the first second; add SBP, PaCO2, PaO2, SpO2

Line 221:

It is “Determinants of arterial stiffness deterioration” not Determinants deterioration in arterial stiffness

The title of this section don’t fit the results presented. In that part there is a description of Arterial stiffness in the studied population. Please, give another title.

It is after that there the title “Determinants of arterial stiffness deterioration” which will include 2 sections: univariate and multivariate analysis

Line 224: the expression “over the whole period” is not appropriate

Table 2

- Commas after the name of the variable

- Footnotes: remove “a” after as; TLC is not on this table; the expression of median should be uniform over the manuscript, chose between IQR and (25th-75th percentile) even if they express the same thing

Line 230 : remove figure on the title of the section

Figure 2: it is 95% CI not the CI95% and precise the definitions of abbreviations used there somewhere

Line 232: what is the definition of hypertension in the work? is it elevated blood pressure during the investigation or a notion of Hypertension treated or not before? Important to precise it in methods. In that way we will really interpret the results.

Line 234-235: “There was a trend toward a significant association between increase in PWV and COPD (P=0.10)” not well said. The p value is superior from your cut off but this potential associated factor can be included in the final model of multivariate analysis.

Line 240: really good the adjustment

Line 243-244: “The multivariable analysis did not demonstrate a long-term impact of CPAP adherence on PWV evolution”: I am not convinced. CPAP adherence here is evaluated when? Is it the mean or median of CPAP adherence measured each year?

Line 248: To the best of our knowledge instead of to our knowledge; review the expression long term trajectories

Line 251 : dependent of not on

Line 252: “with trends suggesting the influence of type 2 diabetes and COPD comorbidities” : no, not to considered as a major result. The p value is not significant

Line 253: “Neither indices of OSA severity at diagnosis or CPAP adherence” , better to say “Neither indices of OSA severity at diagnosis nor CPAP adherence”

Line 255: “Sleep apnea is known as impacting vascular “ better to say “Sleep apnea is known to impact vascular …

Line 255-261: “our obese OSA population (median age 55 years) showed greater arterial stiffness at baseline, as assessed by PWV, compared to the same age group in the general population”: this assertion have not been verified in your results, you have not compare those groups and had a statistical significant difference. Please rephrase all that

Line 269 : Had been not has been

Line 299-301: no, data shown in this study don’t confirm independent association between COPD and PWV because the P value in multivariate analysis is not significant

The conclusion and perspective section is only talking about perspective. Add a first part that summary your main pertinent results.

Figure 3: same remarks as figure 2

**********

6. 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

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Aug 5;15(8):e0236667. doi: 10.1371/journal.pone.0236667.r002

Author response to Decision Letter 0

6 May 2020

Grenoble, March 26Th

Manuscript number PONE-D-20-05576

Dear Pr Yu Ru Kou,

Please find enclosed the revised version of the manuscript entitled « Long-term trajectories of arterial stiffness in obese CPAP-treated obstructive sleep apnea» by L-M. Galerneau et al., for consideration to be published in Plos One.

Thank you for your e-mail regarding the above manuscript. We are grateful to the reviewers for their time and effort in evaluating our manuscript, and appreciate their constructive comments and criticisms. The following is a point-by-point response to the reviewers’ comments. We provide a revised version with changes marked in red and a clean version.

Yours sincerely,

Dr Louis-Marie Galerneau Pr Jean-Louis Pépin

Answers to reviewer

We thank reviewers for the constructive comments and criticisms.

Comments to the Author

Reviewer #1

I’ve read with interest the manuscript entitled „Long-term trajectories of arterial stiffness in obese CPAP-treated obstructive sleep apnea”. Authors of this study compared arterial stiffness at the time of OSA diagnosis and several years later with CPAP treatment. Authors concluded arterial stiffness progresses despite CPAP treatment. I think the study is well done and the manuscript very well written. I have a few comments/suggestions:

We thank the reviewer for her/his positive appreciation of our work.

Major:

The follow-up long term assessment did not include a PSG as CPAP efficiency was evaluated by the index of residual events downloaded from the CPAP software’s. It is unexpected that the severity of OSA changed dramatically as there was no significant change in BMI (38.5 [35.4 ; 43.1] versus 38.4 [34.3 ; 41.9] for baseline and follow-up respectively; Table 3).

This paragraph has been added in the discussion in the study limitation section.

Or at least the Epworth questionnaire?

We thank the reviewer for this comment. ESS data are available at follow-up and confirm CPAP efficacy. The following line has been added in table 3:

ESS at follow-up: 7 [4; 10]

Have you compared those patients with known CPAP adherence of at least 4 hours with the rest? What happened with arterial stiffness in just those patients with known CPAP adherence > 4 hours?

This issue was already addressed in the submitted version of the paper. The variable CPAP adherence was included in the multivariate analysis (See figure 3) and had no impact on PWV trajectories.

Were there any patients with CSA? Please show more PSG parameters.

Patients with central apnea were excluded. The following sentence has been included in the methods section:

« Patients with central apnea were excluded »

Minor:

The follow up visit was not the same for all of the patients. What was the reason?

The assessments during the follow-up visit were the same for all the patients.

Reviewer #2

General comment

This is an interesting article dealing with an important aspect of sleep apnea morbidity that is not study enough in the literature

We thank the reviewer for her/his positive appreciation of our work.

Major Comments

1. In the title, the use of « trajectories » is not appropriate. As written, the goal seems to be to draw the fluctuations of the arterial stiffness over a period. But in this study, there is a comparison of the PWV before and after at least 4 years of CPAP therapy. This term needs to be changed into “variations” or “deterioration” for example

According to this comment, the title has been replaced by “Long-term variations of arterial stiffness in obese CPAP-treated obstructive sleep apnea”

2. In the abstract

a. Precise the goal of the study: PWV variation and determinants of increased PWV

We have added in the abstract the following sentence: “We aimed to prospectively study long term PWV variations and determinants of PWV deterioration”.

b. The methods section is not complete: write a sentence about the analysis done in the study

To take into account the suggestions of the two reviewers the statistical methods paragraph has been partly rewritten (see below) and we have addressed all the comments:

Statistical Analysis

Statistical analyses were performed with SAS v9.4 software (SAS Institute Inc., Cary, NC, United States). A p-value of < 0.05 was considered as significant. Continuous data are presented as median and interquartile range (IQR) and categorical data as frequency and percentage. A comparison of the main quantitative variables at baseline and at follow-up was performed using a non-parametric Mann-Whitney test. A non-parametric Wilcoxon signed-rank test was used to compare the PWV before and after CPAP use. Due to the non-normality of PWV values, a log-transformation was performed and a log-linear mixed effect model with a patient random effect adjusted for the delay between the two measurements was used to analyze the evolution in arterial stiffness. A univariable univariate analysis between PWV and potentially contributing factors was performed to select variables for the multivariable multivariate model. Variables with a p-value less or equal to 0.20 were retained and introduced into the multivariable multivariate analysis in association with predefined clinically relevant variables. Ajustement for age, sex and CPAP treatment. Due to the log transformation of the PWV, the final estimate presented in the multivariable multivariate analysis corresponded to 100*Beta (where beta was a parameter of the log-linear model and can be directly interpreted as the percent of increase or decrease in the PWV at follow-up). Due to the low number of missing values, a simple imputation method was used to impute missing data: quantitative variables were imputed using the median and qualitative variables were imputed using the most frequent value.

3. In the analysis, it is interesting and important to know if there is a statistical difference between PWV before and after CPAP therapy.

Yes, the difference was significant and the following sentence has been added in the results section:

There was a significant difference of PWV between and after CPAP use (p<0.01).

Minor Comments

Abstract

Line 50: delete “a high” => done

Line 51: Difficult to understand “and/or current or past smoking” => changed

Introduction

Line 124: As said before, “long term longitudinal trajectories of arterial stiffness” => trajectories replaced by variations

Line 126: reformulate: “assess the longitudinal changes in PWV” => longitudinal has been deleted

Methods

Line 144: “full respiratory polysomnography”: restrict it to polysomnography, it already include the respiratory recordings => done

Line 145: “AHI was calculated from the number of apnea and hypopnea events per hour of sleep” : AHI was calculated “as” not “from” => changed

Line 149 : “Overnight sleep studies were scored according to international guidelines” : precise which ones , references, they differ over years => done

Line 155: “the ratio of distance to transit time”: it is the ratio of distance “on” not of => changed

Basically, we agree but FEV1/FVC<70% was one pre-specified inclusion criteria and we cannot change at this stage.

We thank the reviewer for asking for clarification on this. CPAP adherence used for data analysis was corresponding to objective compliance measured in the 3 to 6 months preceding follow-up visit. This sentence has been added in the methods section.

Line 183: It is important to be precise about the delay after which the new PWV was measured. 4 to 9 years is too large, even more than the double the 4 years. There may be a difference in PWV according to time (4 and 9 years) in the same patients. Here precise if it was only one measurement of PWV or more after that 4 years of CPAP therapy. This part need to be more precise!!!

We have taken into account the delay between the two PWV measurements and results were already presented as a mean PWV increase per year (see table 2).

Line 193: “univariable analysis”: it is univariate analysis same for multivariable, It is multivariate => changed

Line 195: Multivariate analysis was compute via which type of regression model?

It was a multivariable log-linear mixed effect model with adjustment on age, sex and CPAP treatment. This has been included in the new statistical analysis section (see above, reviewer 1).

Line 196: “Age, sex and CPAP treatment were included in the final multivariable model independently of the results of the univariable analysis”: this is called adjustment for age, sex and CPAP treatment => changed

There are technical issues for reproducible measurement of PWV in morbidly obese patients. Some data were then not available at follow-up.

Line 203-204: “Statistical analyses were performed with SAS v9.4 software (SAS Institute Inc., Cary, NC, United States)”: this is at the beginning of the section statistical analysis => changed

Line 205: A p-value < 0.05 not “A p-value of < 0.05” => done

Results

Figure 1:

- Put the n of patients without OSA or with CSA

- As asked before, I don’t understand how 19 patients did not have data on PWV at follow up : Was it a retrospective study?

This is a prospective study registered in clinical trials. See response above regarding missing data.

This has been suppressed in the study flow chart.

Line 212: write median (IQR) => done

Line 214: “Patients commonly exhibited hypertension (58.3% of the population)” rephrase: delete commonly exhibited and of the population => done

Table 1:

- In the bracket of IQR, hyphen not semi column => done

- Add comma after the name of the variable, eg: Age, (years)- BMI, (Kg/m²)….=> done

- FEV1/ FVC < 70% (%) ; it is n (%) => corrected

- It is Fasting “blood”Glucose => added

- Footnotes: FEV1 is forced expiratory volume during the first second; add SBP, PaCO2, PaO2, SpO2 => added

Line 221:

It is “Determinants of arterial stiffness deterioration” not Determinants deterioration in arterial stiffness => changed

The title of this section don’t fit the results presented. In that part there is a description of Arterial stiffness in the studied population. Please, give another title. => the title has been changed

It is after that there the title “Determinants of arterial stiffness deterioration” which will include 2 sections: univariate and multivariate analysis => this title has been replaced after

Line 224: the expression “over the whole period” is not appropriate => changed

Table 2

- Commas after the name of the variable => corrected

Line 230 : remove figure on the title of the section => removed

Figure 2: it is 95% CI not the CI95% and precise the definitions of abbreviations used there somewhere => changed

Hypertension was defined as follow:

“Hypertension was defined following the ESC/ESH guidelines ». We have included this sentence in the methods section with the following reference:

Williams LB, Mancia EG, Spiering YHW, Agabiti Rosei EE, Azizi EM, Burnier EM, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. Journal of Hypertension. 2018;36(10):1953-2041.

This has been included in the methods section.

Line 240: really good the adjustment=> thanks

See responses above to the same comments. Thanks.

Line 248: To the best of our knowledge instead of to our knowledge; review the expression long term trajectories => ok

Line 251: dependent of not on => ok

Line 252: “with trends suggesting the influence of type 2 diabetes and COPD comorbidities” : no, not to considered as a major result. The p value is not significant => deleted

Line 253: “Neither indices of OSA severity at diagnosis or CPAP adherence” , better to say “Neither indices of OSA severity at diagnosis nor CPAP adherence” => modified

Line 255: “Sleep apnea is known as impacting vascular “ better to say “Sleep apnea is known to impact vascular … => ok

Line 269 : Had been not has been => ok

Line 299-301: no, data shown in this study don’t confirm independent association between COPD and PWV because the P value in multivariate analysis is not significant => modified

The conclusion and perspective section is only talking about perspective. Add a first part that summary your main pertinent results. => modified

Figure 3: same remarks as figure 2 => modified

PLoS One. doi: 10.1371/journal.pone.0236667.r003

Decision Letter 1

Yu Ru Kou

22 May 2020

PONE-D-20-05576R1

Long-term variations of arterial stiffness in patients with obesity and obstructive sleep apnea treated with continuous positive airway pressure

PLOS ONE

Dear Dr. Galerneau,

One reviewer still had some suggestions. Particularly, he/she did not find one sentence in the revised manuscript that was indicated in your response..

Please submit your revised manuscript by Jul 06 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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.

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). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Yu Ru Kou, 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: Yes

**********

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 would like to thank the authors for revising the manuscript. I think it substantially improved. I have no further comments/questions.

Reviewer #2: Authors have addressed the major part of our recommendations.

But some few corrections need to be done:

Line 153: the reference of AASM need to be in the reference list

Line 178: if “FEV1/FVC<70% was one pre-specified inclusion criteria” you should write it in the section participant as an inclusion criteria. Also, if you write according to standard definitions, we need to have a reference.

Line 180-183: “We thank the reviewer for asking for clarification on this. CPAP adherence used for data analysis was corresponding to objective compliance measured in the 3 to 6 months preceding follow-up visit. This sentence has been added in the methods section.” I am not seeing that sentence in the section on CPAP treatment

Line 243: delete “figure 3” in the title of the section “multivariate analysis” and put it in the text below

Line 311: please, in the conclusion it is not appropriate to write details as “1.34 [0.10; 2.37] m/s” … etc. You can write: “there is an increase in PWV over the study period. Determinants of PWV progression are old age and hypertension”

**********

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: Yes: Virginie Poka-Mayap

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Aug 5;15(8):e0236667. doi: 10.1371/journal.pone.0236667.r004

Author response to Decision Letter 1

8 Jul 2020

All the answers to the questions and the corrections of the reviewers are present in the file "Response to Reviewers".

Line 153: the reference of AASM need to be in the reference list :

The reference has been added in the text

FEV1 / FVC <70% was not an inclusion criteria of our study. We use FEV1 / FVC <70% to define the presence of airflow limitation on pulmonary function test. A reference to FEV1 / FVC <70% defining the airflow limitation has been added in the text.

: Indeed, this sentence did not appear in the method section. The sentence "CPAP adherence used for data analysis was corresponding to objective compliance measured in the 3 to 6 months preceding follow-up visit" was added in the CPAP treatment subsection of the method section.

Line 243: delete “figure 3” in the title of the section “multivariate analysis” and put it in the text below :

Done

Thank you for your comment. The change has been made in the text.

Attachment

Submitted filename: Response to Reviewers 7-7-20.docx

Click here for additional data file.^{(16.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0236667.r005

Decision Letter 2

Yu Ru Kou

13 Jul 2020

Long-term variations of arterial stiffness in patients with obesity and obstructive sleep apnea treated with continuous positive airway pressure

PONE-D-20-05576R2

Dear Dr. Galerneau,

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

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

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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.

Kind regards,

Yu Ru Kou, 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: Yes

**********

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

Reviewer #2: Yes

**********

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

Reviewer #2: Yes

**********

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

Reviewer #2: Yes

**********

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: Yes: Virginie Poka-Mayap

PLoS One. doi: 10.1371/journal.pone.0236667.r006

Acceptance letter

Yu Ru Kou

20 Jul 2020

PONE-D-20-05576R2

Long-term variations of arterial stiffness in patients with obesity and obstructive sleep apnea treated with continuous positive airway pressure

Dear Dr. Galerneau:

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

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

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

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

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Yu Ru Kou

Academic Editor

PLOS ONE

Associated Data

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

Supplementary Materials

S1 Table. Comparison between imputed and non-imputed datasets.

(DOCX)

Click here for additional data file.^{(24.9KB, docx)}

S2 Table. Medication used by patients at the second assessment.

(DOCX)

Click here for additional data file.^{(24.1KB, docx)}

S1 Data

(CSV)

Click here for additional data file.^{(8.1KB, csv)}

S2 Data

(CSV)

Click here for additional data file.^{(6.8KB, csv)}

S3 Data

(CSV)

Click here for additional data file.^{(1.6KB, csv)}

Attachment

Submitted filename: Response to Reviewers 7-7-20.docx

Click here for additional data file.^{(16.1KB, docx)}

Data Availability Statement

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

[pone.0236667.ref001] 1.Pépin JL, Timsit JF, Tamisier R, Borel JC, Lévy P, Jaber S. Prevention and care of respiratory failure in obese patients. Lancet Respir Med. 2016;4: 407–418. 10.1016/S2213-2600(16)00054-0 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref002] 2.Lévy P, Kohler M, McNicholas WT, Barbé F, McEvoy RD, Somers VK, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primer. 2015; 15015 10.1038/nrdp.2015.15 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref003] 3.Murphy AM, Thomas A, Crinion SJ, Kent BD, Tambuwala MM, Fabre A, et al. Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation. Eur Respir J. 2017;49. [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref004] 4.Aron-Wisnewsky J, Clement K, Pépin J-L. Nonalcoholic fatty liver disease and obstructive sleep apnea. Metabolism. 2016;65: 1124–1135. 10.1016/j.metabol.2016.05.004 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref005] 5.Marin JM, Carrizo SJ, Vicente E, Agusti AGN. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365: 1046–1053. 10.1016/S0140-6736(05)71141-7 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref006] 6.McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, et al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med. 2016;375: 919–931. 10.1056/NEJMoa1606599 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref007] 7.Drager LF, McEvoy RD, Barbe F, Lorenzi-Filho G, Redline S, INCOSACT Initiative (International Collaboration of Sleep Apnea Cardiovascular Trialists). Sleep Apnea and Cardiovascular Disease: Lessons From Recent Trials and Need for Team Science. Circulation. 2017;136: 1840–1850. 10.1161/CIRCULATIONAHA.117.029400 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref008] 8.Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55: 1318–1327. 10.1016/j.jacc.2009.10.061 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref009] 9.Mitchell GF, Hwang S-J, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010;121: 505–511. 10.1161/CIRCULATIONAHA.109.886655 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref010] 10.Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertens Dallas Tex 1979. 2001;37: 1236–1241. [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref011] 11.Vlachantoni I-T, Dikaiakou E, Antonopoulos CN, Daskalopoulou SS, Petridou ET. Effects of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea in arterial stiffness: a meta-analysis. Sleep Med Rev. 2013;17: 19–28. 10.1016/j.smrv.2012.01.002 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref012] 12.Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27: 2588–2605. 10.1093/eurheartj/ehl254 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref013] 13.Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30: 445–448. 10.1097/HJH.0b013e32834fa8b0 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref014] 14.Phillips CL, Butlin M, Wong KK, Avolio AP. Is obstructive sleep apnoea causally related to arterial stiffness? A critical review of the experimental evidence. Sleep Med Rev. 2013;17: 7–18. 10.1016/j.smrv.2012.03.002 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref015] 15.Doonan RJ, Scheffler P, Lalli M, Kimoff RJ, Petridou ET, Daskalopoulos ME, et al. Increased arterial stiffness in obstructive sleep apnea: a systematic review. Hypertens Res Off J Jpn Soc Hypertens. 2011;34: 23–32. 10.1038/hr.2010.200 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref016] 16.Chung S, Yoon I-Y, Lee CH, Kim J-W. The association of nocturnal hypoxemia with arterial stiffness and endothelial dysfunction in male patients with obstructive sleep apnea syndrome. Respir Int Rev Thorac Dis. 2010;79: 363–369. [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref017] 17.McEniery CM, Yasmin null, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR, et al. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46: 1753–1760. 10.1016/j.jacc.2005.07.037 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref018] 18.Koivistoinen T, Hutri-Kähönen N, Juonala M, Aatola H, Kööbi T, Lehtimäki T, et al. Metabolic syndrome in childhood and increased arterial stiffness in adulthood: the Cardiovascular Risk In Young Finns Study. Ann Med. 2011;43: 312–319. 10.3109/07853890.2010.549145 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref019] 19.Prenner SB, Chirinos JA. Arterial stiffness in diabetes mellitus. Atherosclerosis. 2015;238: 370–379. 10.1016/j.atherosclerosis.2014.12.023 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref020] 20.Vivodtzev I, Tamisier R, Baguet J-P, Borel JC, Levy P, Pépin J-L. Arterial stiffness in COPD. Chest. 2014;145: 861–875. 10.1378/chest.13-1809 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref021] 21.Lévy P, Bonsignore MR, Eckel J. Sleep, sleep-disordered breathing and metabolic consequences. Eur Respir J. 2009;34: 243–260. 10.1183/09031936.00166808 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref022] 22.Jelic S, Padeletti M, Kawut SM, Higgins C, Canfield SM, Onat D, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation. 2008;117: 2270–2278. 10.1161/CIRCULATIONAHA.107.741512 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref023] 23.Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36: 1953–2041. 10.1097/HJH.0000000000001940 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref024] 24.International Classification of Sleep Disorders 3rd ed. American Academy of Sleep Medicine. 2014. [DOI] [PMC free article] [PubMed]

[pone.0236667.ref025] 25.Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014;146: 1387–1394. 10.1378/chest.14-0970 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref026] 26.Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med. 2012;8: 597–619. 10.5664/jcsm.2172 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref027] 27.Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14: 540–545. 10.1093/sleep/14.6.540 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref028] 28.Berry RB, Brooks R, Gamaldo C, Harding SM, Lloyd RM, Quan SF, et al. AASM Scoring Manual Updates for 2017 (Version 2.4). J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med. 2017;13: 665–666. 10.5664/jcsm.6576 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref029] 29.Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B, Brisac AM, et al. Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies. Hypertension. 1995;26: 485–490. 10.1161/01.hyp.26.3.485 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref030] 30.Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: The GOLD Science Committee Report 2019. Eur Respir J. 2019. [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref031] 31.Société de Pneumologie de Langue Française, Société Française d’Anesthésie Réanimation, Société Française de Cardiologie, Société Française de Médecine du Travail, Société Française d’ORL, Société de Physiologie, et al. [Recommendations for clinical practice. Obstructive sleep apnea hypopnea syndrome in adults]. Rev Mal Respir. 2010;27: 806–833. 10.1016/j.rmr.2010.05.011 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref032] 32.Gay P, Weaver T, Loube D, Iber C, Positive Airway Pressure Task Force, Standards of Practice Committee, et al. Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep. 2006;29: 381–401. 10.1093/sleep/29.3.381 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref033] 33.Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc. 2008;5: 173–178. 10.1513/pats.200708-119MG [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref034] 34.Drager LF, Bortolotto LA, Figueiredo AC, Silva BC, Krieger EM, Lorenzi-Filho G. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007;131: 1379–1386. 10.1378/chest.06-2703 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref035] 35.Pépin J-L, Tamisier R, Baguet J-P, Lévy P. Arterial health is related to obstructive sleep apnea severity and improves with CPAP treatment. Sleep Med Rev. 2013;17: 3–5. 10.1016/j.smrv.2012.11.002 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref036] 36.Reference Values for Arterial Stiffness’ Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: “establishing normal and reference values”. Eur Heart J. 2010;31: 2338–2350. 10.1093/eurheartj/ehq165 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref037] 37.Drager LF, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Chest. 2011;140: 534–542. 10.1378/chest.10-2223 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref038] 38.Drager LF, Bortolotto LA, Maki-Nunes C, Trombetta IC, Alves MJNN, Fraga RF, et al. The incremental role of obstructive sleep apnoea on markers of atherosclerosis in patients with metabolic syndrome. Atherosclerosis. 2010;208: 490–495. 10.1016/j.atherosclerosis.2009.08.016 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref039] 39.Joyeux-Faure M, Tamisier R, Borel J-C, Millasseau S, Galerneau L-M, Destors M, et al. Contribution of obstructive sleep apnoea to arterial stiffness: a meta-analysis using individual patient data. Thorax. 2018. 10.1136/thoraxjnl-2018-211513 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref040] 40.Saito T, Saito T, Sugiyama S, Asai K, Yasutake M, Mizuno K. Effects of long-term treatment for obstructive sleep apnea on pulse wave velocity. Hypertens Res Off J Jpn Soc Hypertens. 2010;33: 844–849. 10.1038/hr.2010.77 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref041] 41.Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31: 1281–1357. 10.1097/01.hjh.0000431740.32696.cc [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref042] 42.Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012;308: 875–881. 10.1001/2012.jama.10503 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref043] 43.Lin X, Chen G, Qi J, Chen X, Zhao J, Lin Q. Effect of continuous positive airway pressure on arterial stiffness in patients with obstructive sleep apnea and hypertension: a meta-analysis. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol—Head Neck Surg. 2016;273: 4081–4088. 10.1007/s00405-016-3914-8 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref044] 44.Tsioufis C, Thomopoulos K, Dimitriadis K, Amfilochiou A, Tousoulis D, Alchanatis M, et al. The incremental effect of obstructive sleep apnoea syndrome on arterial stiffness in newly diagnosed essential hypertensive subjects. J Hypertens. 2007;25: 141–146. 10.1097/HJH.0b013e32801092c1 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref045] 45.Tavil Y, Kanbay A, Sen N, Ulukavak Ciftçi T, Abaci A, Yalçin MR, et al. The relationship between aortic stiffness and cardiac function in patients with obstructive sleep apnea, independently from systemic hypertension. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2007;20: 366–372. 10.1016/j.echo.2006.09.005 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref046] 46.Bratton DJ, Gaisl T, Wons AM, Kohler M. CPAP vs Mandibular Advancement Devices and Blood Pressure in Patients With Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. JAMA. 2015;314: 2280–2293. 10.1001/jama.2015.16303 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref047] 47.Van Ryswyk E, Anderson CS, Barbe F, Loffler KA, Lorenzi-Filho G, Luo Y, et al. Effect of CPAP on Blood Pressure in Obstructive Sleep Apnea with Cardiovascular Disease. Am J Respir Crit Care Med. 2019. 10.1164/rccm.201811-2200LE [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref048] 48.Cecelja M, Chowienczyk P. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension. 2009;54: 1328–1336. 10.1161/HYPERTENSIONAHA.109.137653 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref049] 49.Pietri P, Vlachopoulos C, Vyssoulis G, Ioakeimidis N, Stefanadis C. Macro- and microvascular alterations in patients with metabolic syndrome: sugar makes the difference. Hypertens Res Off J Jpn Soc Hypertens. 2014;37: 452–456. 10.1038/hr.2013.148 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref050] 50.Safar ME, Balkau B, Lange C, Protogerou AD, Czernichow S, Blacher J, et al. Hypertension and vascular dynamics in men and women with metabolic syndrome. J Am Coll Cardiol. 2013;61: 12–19. 10.1016/j.jacc.2012.01.088 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref051] 51.Malhotra A, Schwartz AR, Schneider H, Owens RL, DeYoung P, Han MK, et al. Research Priorities in Pathophysiology for Sleep-disordered Breathing in Patients with Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Research Statement. Am J Respir Crit Care Med. 2018;197: 289–299. 10.1164/rccm.201712-2510ST [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref052] 52.Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med. 2010;182: 325–331. 10.1164/rccm.200912-1869OC [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref053] 53.Zamarrón C, García Paz V, Morete E, del Campo Matías F. Association of chronic obstructive pulmonary disease and obstructive sleep apnea consequences. Int J Chron Obstruct Pulmon Dis. 2008;3: 671–682. 10.2147/copd.s4950 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref054] 54.Stone IS, Barnes NC, Petersen SE. Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease? Heart Br Card Soc. 2012;98: 1055–1062. 10.1136/heartjnl-2012-301759 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref055] 55.Lee HM, Lee J, Lee K, Luo Y, Sin DD, Wong ND. Relation between COPD severity and global cardiovascular risk in US adults. Chest. 2012;142: 1118–1125. 10.1378/chest.11-2421 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref056] 56.McAllister DA, Maclay JD, Mills NL, Mair G, Miller J, Anderson D, et al. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176: 1208–1214. 10.1164/rccm.200707-1080OC [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref057] 57.Weir-McCall JR, Struthers AD, Lipworth BJ, Houston JG. The role of pulmonary arterial stiffness in COPD. Respir Med. 2015;109: 1381–1390. 10.1016/j.rmed.2015.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref058] 58.Vanfleteren LEGW Spruit MA, Groenen MTJ Bruijnzeel PLB, Taib Z Rutten EPA, et al. Arterial stiffness in patients with COPD: the role of systemic inflammation and the effects of pulmonary rehabilitation. Eur Respir J. 2014;43: 1306–1315. 10.1183/09031936.00169313 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref059] 59.Shiina K, Tomiyama H, Takata Y, Yoshida M, Kato K, Nishihata Y, et al. Overlap syndrome: additive effects of COPD on the cardiovascular damages in patients with OSA. Respir Med. 2012;106: 1335–1341. 10.1016/j.rmed.2012.05.006 [DOI] [PubMed] [Google Scholar]

[pone.0236667.ref060] 60.Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA, Townsend R, et al. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med. 2014;370: 2265–2275. 10.1056/NEJMoa1306187 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0236667.ref061] 61.Vivodtzev I, Tamisier R, Croteau M, Borel J-C, Grangier A, Wuyam B, et al. Ventilatory support or respiratory muscle training as adjuncts to exercise in obese CPAP-treated patients with obstructive sleep apnoea: a randomised controlled trial. Thorax. 2018. 10.1136/thoraxjnl-2017-211152 [DOI] [PubMed] [Google Scholar]

PERMALINK

Long-term variations of arterial stiffness in patients with obesity and obstructive sleep apnea treated with continuous positive airway pressure

Louis-Marie Galerneau

Sébastien Bailly

Jean-Christian Borel

Ingrid Jullian-Desayes

Marie Joyeux-Faure

Meriem Benmerad

Marisa R Bonsignore

Renaud Tamisier

Jean-Louis Pépin

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials and methods

Design and study population

Sleep study and sleepiness assessment

Arterial stiffness assessement

Metabolic and inflammatory biomarkers

Respiratory function

CPAP treatment

Follow-up

Statistical analysis

Results

Patient characteristics

Fig 1. Study flow chart.

Table 1. Study population characteristics at baseline.

Follow-up

Table 2. Data at the follow-up PWV assessment.

Table 3. Comparison between baseline and follow-up values.

Determinants of arterial stiffness deterioration

Univariate analysis

Fig 2. Univariate analysis.

Multivariate analysis

Fig 3. Multivariate analysis.

Discussion

Conclusion and perspectives

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Yu Ru Kou

Roles

Author response to Decision Letter 0

Decision Letter 1

Yu Ru Kou

Roles

Author response to Decision Letter 1

Decision Letter 2

Yu Ru Kou

Roles

Acceptance letter

Yu Ru Kou

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases