Acta Cardiologica

ISSN: 0001-5385 (Print) 0373-7934 (Online) Journal homepage: http://www.tandfonline.com/loi/tacd20

Impact of continuous positive airway pressure therapy on left atrial function in patients with obstructive sleep apnoea: assessment by conventional and two-dimensional speckletracking echocardiography Mustafa Gökhan Vural, Süha Çetin, Hikmet Firat, Ramazan Akdemir, Sadik Ardiç & Ekrem Yeter To cite this article: Mustafa Gökhan Vural, Süha Çetin, Hikmet Firat, Ramazan Akdemir, Sadik Ardiç & Ekrem Yeter (2014) Impact of continuous positive airway pressure therapy on left atrial function in patients with obstructive sleep apnoea: assessment by conventional and twodimensional speckle-tracking echocardiography, Acta Cardiologica, 69:2, 175-184, DOI: 10.1080/ AC.69.2.3017299 To link to this article: https://doi.org/10.1080/AC.69.2.3017299

Published online: 23 May 2017.

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Acta Cardiol 2014; 69(2): 175-184

175

doi: 10.2143/AC.69.2.3017299

Impact of continuous positive airway pressure therapy on left atrial function in patients with obstructive sleep apnoea: assessment by conventional and two-dimensional speckletracking echocardiography Mustafa Gökhan VURAL1, MD; Süha ÇETİN2, MD; Hikmet FIRAT3, MD; Ramazan AKDEMİR4, MD; Sadık ARDIÇ3, MD; Ekrem YETER1, MD 1Dept. of Cardiology, Dışkapı Research and Education Hospital, Ankara, Turkey; 2Dept. of Cardiology, 29 Mayıs Hospital, Ankara, Turkey; 3Dept. of Pulmonary Medicine, Dışkapı Research and Education Hospital, Ankara, Turkey; 4Dept. of Cardiology, Faculty of Medicine, University of Sakarya, Turkey.

Objective The objective of this study was to evaluate left atrial (LA) function in patients with obstructive sleep apnoea (OSA) receiving continuous positive airway pressure therapy (CPAP), incorporating two-dimensional speckle-tracking echocardiography (2D-STE) .

Methods Forty-five control and 117 OSA patients were enrolled in the study. They were categorized into mild, moderate and severe OSA groups according to the apnoea-hypopnoea index (AHI). All patients underwent conventional and 2D-STE. Forty-three patients with AHI greater than 20 were enrolled to receive CPAP therapy for 24 weeks. They underwent echocardiography examination at baseline, after 12 weeks and 24 weeks of CPAP therapy. Results Severe OSA patients have higher total emptying volume index (EVI) and lower total emptying fraction (EFr) (P < 0.05). LA contractile strain and strain rate values of severe OSA were greater than in the other groups (P < 0.05). Left ventricular filling pressure (E/E’) increased with severity of OSA (P < 0.05). The AHI correlated positively with LA-maximal, -pre-contraction, -minimum volume index, contractile strain and strain rate and E/E’ (P < 0.05). AHI correlated negatively with LA reservoir strain and strain rate, conduit strain and strain rate (P < 0.05). In the compliant CPAP group: (i) reduction in the E/E’ ratio (P < 0.05); (ii) reduction in the LA volume indexes (P < 0.05); (iii) reduction in the LA-total EVI, -active EVI and -active EFr (P < 0.05); (iv) increase in the LA-passive emptying volume and -passive emptying fraction (P < 0.05); (v) increase in the LA reservoir strain, -conduit strain and strain rate (P < 0.05) were observed. Conclusion LA volumetric and deformation abnormalities in OSA patients can be reversed as early as 12 weeks into CPAP therapy, with progressive improvement in LA anatomical remodelling over 24 weeks as assessed by conventional and 2D-STE.

Keywords Left atrial deformation – left atrial volume – obstructive sleep apnoea – 2-dimensional strain echocardiography – CPAP therapy.

INTRODUCTION Obstructive sleep apnoea (OSA) is a prevalent disease which is characterized by recurrent upper airway obstruction during sleep which results in apnoea/hypopnoea,

Address for correspondence: Mustafa Gökhan Vural, MD, Dept. of Cardiology, Dışkapı Research and Education Hospital, İrfan Baştuğ Cad. Dışkapı, Ankara, Turkey. E-mail: [email protected] Received 16 October 2013; accepted for publication 21 January 2014.

oxyhaemoglobin desaturation, abnormal nocturnal arousals and daytime sleepiness1. OSA is an important risk factor for cardiovascular morbidity and mortality and associated with stroke, hypertension and death2. Obesity, male gender and aging linked OSA to cardiovascular complications3. Diastolic dysfunction and LA functional and anatomical remodelling is more prevalent in OSA patients compared to the control group and seems to be related to disease severity4,5. Left ventricular diastolic dysfunction might result in LA remodelling in order to maintain proper LV filling pressure. Hypertension, diabetes, left ventricular systolic dysfunction, obesity, aging have been associated with diastolic dysfunction and LA remodelling6,7. On the other hand, LA remodelling is an

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independent predictor of major cardiovascular events8. Impact of long-term CPAP treatment on LA function and structure has been evaluated by using real-time three-dimensional echocardiography and effective CPAP treatment resulted in improved LV diastolic function and LA function but not anatomical remodelling4. The conventional indices of global LA function, such as emptying fraction and volumes, are load-dependent. The assessment of regional function is more difficult, remains highly subjective and is time-consuming. The echocardiographic measurement of myocardial deformations offers a series of regional and global angle- and load-independent parameters that may be useful in the assessment of LA function9. Strain (S) and strain rate (SR) are measures of tissue deformation. Speckle-tracking echocardiography (STE) is a reliable method for the assessment of longitudinal, LA myocardial deformation during the cardiac cycle. Global peak LA longitudinal strain is a strong and independent predictor of cardiovascular events and appears to be superior to conventional parameters of LA analysis10. LA deformation is impaired in patients with hypertension or diabetes despite a normal LA size11. STE may be considered as a promising tool for the early detection of LA strain abnormalities in these patients. LA deformation is impaired in OSA patients and is correlated with disease severity12. Furthermore, improved LA volumetric functions have been demonstrated in OSA patients during CPAP therapy with real-time three-dimensional echocardiography4. We hypothesised that anatomical and functional remodelling that occur in OSA patients could be reversed after effective CPAP treatment. Therefore, we sought to evaluate the LA volume and volumetric function and LA deformation in OSA patients with AHI > 20 before and after 24 weeks of effective CPAP treatment.

METHODS The study cohort consisted of 210 patients recruited from the Sleep Disorders Centre of Diskapi Research and Education Hospital between January 2010 and December 2011, who were referred for clinically indicated sleep study. Data on demographic characteristics, sleep and medical history, and medication use were obtained with the use of a standardized questionnaire before the overnight polysomnogram. The sleep questionnaire included history of snoring and the relationship of snoring with position, choking, witnessed apnoea, sleep fragmentation, nocturia, night sweating, morning tiredness, and headache. The Epworth Sleepiness Scale was used to report subjective daytime sleepiness. Data regarding risk factors for coronary artery disease included a history of hypertension, diabetes mellitus, or hyperlipidaemia reported by the patient on the baseline

medical questionnaire, noted in the file or both. Smoking habits were also documented on the routine baseline questionnaire. The clinical evaluation of patients involved internal medicine, neurologic and psychiatric clinical reviews by physicians. Body mass index (BMI), neck circumference, and craniofacial measurements (overjet, overbite, position of the mandible and maxilla, and soft palate and Mallampatti scores) were obtained. The exclusion criteria were: uncontrolled hypertension or diabetes mellitus (patients with a systolic blood pressure value > 140 mmHg and a diastolic blood pressure value > 90 mmHg and glycated haemoglobine > 6.4%), symptomatic heart failure, overt coronary artery disease or other major chronic medical illnesses which should be treated with regular medication. Patients with sleep disorders other than OSA, such as central sleep apnoea, periodic limb movement syndrome, or narcolepsy were also excluded from the study. Study protocol

As illustrated in figure 1, 210 consecutive patients admitted to our sleep laboratory were enrolled in this prospective study. After excluding the patients with a history of CAD (n = 28), as well as the subjects with inadequate image quality (n = 20), 162 individuals (68 women and 94 men), the final study cohort, were categorized according to the AHI as control subjects (n = 45), mild OSA (n = 22), moderate OSA (n = 27) and severe OSA (n = 68). Twenty-three patients could not complete the study due to special reasons but their data were included in the final analysis. Polysomnography

All participants underwent full-night polysomnography (PSG) using the Compumedics E-series system (Compumedics®, Melbourne, Victoria, Australia). The PSG recordings included 6-channel electroencephalography, 2-channel electrooculography, 2-channel submental electromyography, oxygen saturation by an oximeter finger probe, respiratory movements via chest and abdominal belts, airflow both via nasal pressure sensor and oro-nasal thermistor, electrocardiography, and leg movements via both tibial anterolateral electrodes. Sleep stages and respiratory parameters were scored according to the standard criteria of the American Academy of Sleep Medicine (AASM). Based on the guidelines of the AASM published in 2007, apnoea is defined as a ≥ 90% decrease in airflow persisting for at least 10 seconds relative to the basal amplitude. Hypopnoea is defined as a ≥ 50% decrease in the airflow amplitude relative to the baseline value with an associated ≥ 3% oxygen desaturation or arousal, persisting for at least 10 seconds.

LA function in patients with OSA DISKAPI OSA STUDY January 2010December 2011 (n = 210) History of CAD n = 28 (13%) OSA WITHOUT CAD (n = 182) basal echocardiography Inadequate image quality n = 20 (10%) AHI < 20 n = 71 (43%)

AHI > 20 n = 91 (57%) CPAP randomization

Medical therapy n = 48 (52%) CPAP therapy n = 43 (48%)

12-week echocardiography

24-week echocardiography

Fig. 1 The study design.

Apnoea-hypopnoea index (AHI) was calculated based on the following formula: total number of obstructive apnoeas + hypopnoeas/total sleep time (h). Patients with a sleep recording of < 5 hours and sleep efficiency of < 60% were reevaluated. Patients were divided into four groups according to their  AHI: AHI < 5 representing control subjects (n = 45), 5-15 representing mild OSA (n = 22), AHI 15-30 representing moderate OSA (n =27) and > 30 representing severe OSA (n = 68). Echocardiography

Standard echocardiographic measurements were carried out using a commercially available ultrasound device (ie33, Philips Medical System, Bothell, Washington, USA). Examinations were performed by one experienced cardiologist who was unaware of the groups of individuals. Images were obtained from parasternal and apical windows using 2D, M-mode and Doppler as well as tissue Doppler echocardiography. Left ventricular structures, systolic and diastolic functions were performed according to the guidelines13. LV mass was determined by the Devereux formula14. LA phasic function was assessed by 2D echocardiography by volumetric method which has been well validated15. LA volumes were measured at different time points of the cardiac cycle: maximal LA (LAmax) volume just before opening of the mitral valve; minimal LA (LAmin) volume just at

the closure of the mitral valve; and LA volume preceding atrial contraction (LApreA) at the beginning of the P wave on the electrocardiogram by Simpson’s method using apical four- and two-chamber views and indexed to body surface area. Phasic LA function was calculated as follows: (i) LA reservoir function (LA total emptying volume = Vmax-Vmin and LA total emptying fraction = Vmax-Vmin/Vmax); (ii) LA conduit function (LA passive emptying volume = Vmax-VpreA and LA passive emptying fraction = Vmax-VpreA/Vmax); (iii) LA contractile function (LA active emptying volume = VpreA-Vmin and LA active emptying fraction = VpreA-Vmin/VpreA). LA function was assessed by pulsed wave Doppler measurement of early (E) and late (A) diastolic filling at the tips of the mitral leaflets. Despite being affected by age and loading conditions, peak A wave velocity is often used as an index of LA function assessment16. Tissue Doppler imaging (TDI) allows characterization of intrinsic myocardial wall low velocities and it is relatively load-independent17. The TDI profile of the mitral septal and lateral annulus showed three waves: ventricular systolic velocity (S’), ventricular early diastolic velocity (E’), ventricular late diastolic velocity (A’) during atrial contraction17. The mitral annulus A’ correlated well with LA function in patients with various degrees of LV diastolic dysfunction18. The TDI measurements were obtained at end expiration with an average of three sinus beats and the sample volume was placed on the atrial side of the mitral

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annulus at the basal interatrial septum from the apical four-chamber view. The velocity was set at minimum gain and lower filter settings. Tissue Doppler A’ appeared to be highly predictive of overall cardiac mortality and correlated with exercise capacity in patients with heart failure19. However, TDI A’ assessment provides information on global LA function. It does not allow detailed regional LA functional assessment. Although both Doppler and tissue Doppler techniques are useful for the assessment of LA function, the effects of angle dependency remain a technical challenge. Strain (S) and strain rate (SR) imaging provide data on myocardial deformation by estimating spatial gradients in myocardial velocities20,21. Two-dimensional speckle tracking strain imaging is a novel technique for the assessment of myocardial deformation. This technique utilizes acoustic speckle tracking and is validated against tagged MRI22. For LA 2D STE analysis, images for apical fourand two-chamber views were obtained using conventional, two-dimensional gray scale echocardiography at end expirium and with an ECG recording. All images were obtained at a frame rate of 60-100 frames/s. Three consecutive heart cycles were recorded in digital format for offline analysis using commercially available software QLAB 6.0 (Philips Medical System, Bothell, Washington, USA). To calculate LA-S and -SR the atrial endocardium was first traced manually. The epicardial surface was calculated automatically and after manually reducing the region of interest to the atrial thickness the software automatically divides the atrial wall into six segments. Before acquiring the LA-S and -SR view of apical fourand two-chambers, if STE was not adequate, the region of interest was manually adjusted to include only the atrial wall. Segments in which adequate tracking quality could not be obtained despite manual adjustment were excluded from the analysis, and patients in whom adequate tracking quality was obtained in less than two segments were excluded from the study (20 of 182 patients, 10%). Finally, the LA-S and LA-SR values were averaged for the values obtained for each apical view12. LA reservoir strain and strain rate (S-S and SR-S) during systole was obtained at the time of aortic valve closure and LA contractile strain and strain rate (S-A and SR-A) during late diastole was obtained at the onset of the P wave on the ECG. LA conduit strain during early diastole (S-E) was defined as [(S-S)-(S-A)]. LA conduit strain rate during early diastole (SR-E) was obtained as previously described23. Statistical analysis

The results were presented as mean ± SD for continuous variables or as frequency percentage for categorical variables. Comparison between groups was

performed using the Student’s t test or Mann-Whitney U-statistic test, according to whether variables were normally distributed or not, as tested by the Kolmogorov-Smirnov test. Categorical variables were compared using the χ2 test or the Fisher’s exact test where appropriate. Repeated measures ANOVA was used to compare the results before and after 12 weeks and 24 weeks of CPAP therapy. Post-hoc comparisons were performed with the Bonferroni correction. The correlations between AHI and echocardiographic parameters were evaluated using Pearson correlation coefficients. Linear regression analysis was used to investigate the relationship between two parameters. Univariate and multivariate linear regression analysis was performed to determine independent predictors between absolute reduction of global LA strain and clinical and haemodynamic parameters including age, BMI, systolic blood pressure, heart rate, LV mass, E/E’, minimal O2 saturation and AHI. Statistical analysis was performed using SPSS statistical analysis software (SPSS version 16.0, SPSS Inc., Chicago, IL, USA).

RESULTS Baseline characteristics are summarized in table 1. The groups had similar mean age, BMI, heart rate, systolic and diastolic blood pressures. The prevalence of hypertension and diabetes were slightly higher in OSA patients but this difference did not reach statistical significance. As expected, AHI and minimal O2 saturation were significantly different between all groups. Severe OSA patients had an increased myocardial mass index compared to other groups and E/E’ as well as higher A and lower S’ velocities. A’ velocity was slightly higher in severe OSA patients. Left ventricular echocardiographic measurements of ejection fraction, mitral pulsed Doppler early diastolic velocity (E), mitral annular systolic (S’) and late diastolic (A’) velocities between the four groups were similar. The average mitral annular early diastolic velocity (E’) was significantly reduced in severe OSA patients whereas mitral annular late diastolic velocity tended to be higher in severe OSA patients but this did not reach any statistical significance. There was a significantly higher left ventricular diastolic filling pressure (E/E’) and similar E/A ratio in all OSA groups. The volumetric analysis revealed larger maximum LA volume index in moderate to severe OSA groups and precontraction and minimum LA volume index only in the severe OSA group. The total emptying volume index was higher in the severe OSA group despite a lower total emptying volume fraction. Passive emptying volume index and fraction were lower only in the severe OSA group. Notwithstanding a similar active emptying

LA function in patients with OSA

Table 1 Demographic, clinical, left ventricular systolic and diastolic and sleep study parameters of the study groups Parameters

Control group (n = 45) AHI < 5

Mild OSA (n = 22) AHI 5–15

Moderate OSA (n = 27) AHI 15–30

Severe OSA (n = 68) AHI ≥ 30

48.1 ± 11.8

47.7 ± 11.8

49.4 ± 12.1

49.9 ± 9.5

Clinical parameters Age, years Female, %

21 (46)

11 (40)

28 (41)

BMI, kg/m2

26.7 ± 2.5

27.2 ± 2.3

27.2 ± 2.3

27.6 ± 3.3

SBP, mmHg

130.2 ± 10.1

130.2 ± 13.2

134.4 ± 10.9

135.2 ± 9.9

DBP, mmHg

79.3 ± 9.3

79.7 ± 8.2

83.8 ± 9.8

83.6 ± 11.6

Heart rate, beats/min

73.7 ± 9.2

73.5 ± 8.4

71.7 ± 9.0

74.5 ± 10.1

20 (44)

13 (59)

16 (59)

36 (52)

4 (8)

4 (18)

5 (18)

11 (16) 33 (48)

Hypertension, % Diabetes, %

8 (36)

Dyslipidaemia, %

21 (46)

9 (40)

17 (62)

Smoking, %

23 (51)

11 (50)

13 (48)

36 (52)

5 (11)

5 (22)

8 (29)

19 (27)

4 (8)

2 (9)

5 (18)

7 (10)

17 (37)

9 (40)

11 (40)

28 (41)

2.8 ± 1.0

9.3 ± 3.2

24.9 ± 3.9*¶

57.3 ± 20.4*¶γ

92.2 ± 2.8

92.7 ± 2.8

91.7 ± 3.0

91.9 ± 3.2

Beta blockers, % CCB, % RAAS blockers, % AHI,

Mean O2 saturation, % Min O2 saturation, %

*¶

83.8 ± 5.0

85.1 ± 3.9

79.8 ± 3.5

77.1 ± 6.7*¶

63.9 ± 2.7

63.5 ± 3.1

63.8 ± 2.6

62.7 ± 4.1

9.5 ± 1.1

9.5 ± 1.1

10.0 ± 1.2

10.1 ± 1.1*

LV systolic and diastolic parameters EF, % IVS, mm

PW, mm

8.9 ± 1.0

9.0 ± 1.2

9.2 ± 1.0

9.4 ± 1.0

MI, kg/m2

84.8 ± 4.2

84.1 ± 4.0

86.5 ± 4.4

86.9 ± 6.0*

E, cm/s

75.2 ± 9.8

78.7 ± 16.8

73.9 ± 8.9

71.2 ± 12.2

A, cm/s

75.1 ± 20.9

78.3 ± 21.5

76.9 ± 13.8

86.2 ± 17.8*

S’, cm/s

7.4 ± 2.2

7.8 ± 1.7

6.9 ± 2.4

7.3 ± 2.1

E’, cm/s

11.6 ± 2.5

9.6 ± 2.7*

6.3 ± 2.1*¶

6.1 ± 2.4*¶

A’, cm/s

8.7 ± 2.0

9.2 ± 2.3

9.2 ± 2.5

9.3 ± 1.3

E/A

1.0 ± 0.3

1.0 ± 0.3

1.0 ± 0.3

0.8 ± 0.3

E/E’, cm/s

6.5 ± 2.2

8.4 ± 3.4*

11.9 ± 3.2*¶

12.0 ± 3.8*¶

BMI: body-mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, AHI: apnoea-hypopnoea index, CRP: C-reactive protein, LV: left ventricle, EF: ejection fraction, IVS: interventricular septum, PW: posterior wall, MI: mass index, E: early diastolic inflow, A: late diastolic inflow, S’: systolic annular myocardial velocity, E’: early annular myocardial velocity, A’: late annular myocardial velocity. * P < 0.05 vs. control groups. ¶ P < 0.05 vs. mild OSA. γ P < 0.05 vs. moderate OSA.

volume fraction, active emptying volume tended to be lower in the severe OSA group. The comparison between non-hypertensive OSA patients (n = 52) and hypertensive OSA patients (n = 65) demonstrated a similar LA volume index and volumetric functions. LA reservoir strain and conduit strain values decreased in moderate to severe OSA patients. However, contractile strain increased in severe OSA patients. Furthermore, conduit strain rate decreased in moderate to severe OSA patients and reservoir strain rate as well as contractile strain rate increased only in severe OSA patients. A correlation

analysis was illustrated in table 4. It showed that LA deformations correlated negatively with E/E’, LA volume indexes and AHI and correlated positively with total and passive emptying fractions and minimal O2 saturation. A subset of 28 patients (65% of CPAP randomized patients) who successfully underwent full-night nasal CPAP therapy (5.7 ± 1.2 hours nightly usage) for 24 weeks minimally participated in a repeat echocardiographic study at 12 and 24 weeks. In the CPAP effective treatment group we observed: (i) an increase in early diastolic Doppler velocity (E); (ii) an increase in mitral

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Table 2 Left atrial volumes, phasic functions and strain/strain rate values of the study groups Parameters

Control group (n = 45) AHI < 5

Mild OSA (n = 22) AHI 5-15

Moderate OSA (n = 27) AHI 15-30

Severe OSA (n = 68) AHI ≥ 30

24.3 ± 6.4 15.6 ± 3.5 12.5 ± 3.3

23.5 ± 3.5 16.2 ± 3.1 13.3 ± 3.3

28.1 ± 3.4*¶ 19.0 ± 2.7 15.5 ± 2.0

37.8 ± 7.1*¶γ 31.5 ± 7.5*¶γ 24.9 ± 7.0*¶γ

11.7 ± 3.9 47.5 ± 9.8 8.6 ± 4.0 27.7 ± 10.9 4.0 ± 2.7

10.1 ± 3.1 43.0 ± 11.8 7.3 ± 3.2 24.8 ± 9.5 3.8 ± 2.0

12.6 ± 2.5 44.6 ± 5.8 9.0 ± 2.6 26.5 ± 7.8 4.5 ± 2.7

12.9 ± 4.5¶ 34.4 ± 11.9*¶γ 6.2 ± 3.0*γ 13.4 ± 7.3*¶γ 7.6 ± 4.8*¶γ

19.8 ± 10.3

18.1 ± 6.9

18.1 ± 7.4

21.0 ± 10.6

35.4 ± 4.1 19.9 ± 3.9 15.4 ± 4.4

34.0 ± 2.3 19.6 ± 3.8 14.4 ± 4.6

30.9 ± 5.5* 17.8 ± 3.5* 13.1 ± 4.9

29.3 ± 6.0*¶ 13.0 ± 3.9*¶γ 16.3 ± 6.3γ

1.4 ± 0.3 –1.5 ± 0.3 –1.5 ± 0.5

1.3 ± 0.2 –1.4 ± 0.3 –1.7 ± 0.5

1.3 ± 0.2 –1.1 ± 0.3*¶ –2.2 ± 0.5*

1.1 ± 0.2*¶γ –1.0 ± 0.3*¶ –2.4 ± 0.4*¶

LA volume index (ml/m2) Maximum Pre-contraction, preA Minimum

LA phasic functions Total emptying volume index (ml/m2) Total emptying fraction index (%) Passive emptying volume index (ml/m2) Passive emptying fraction (%) Active emptying volume index (ml/m2) Active emptying fraction (%)

LA strain (%) Reservoir strain, S-S Conduit strain, S-E Contractile strain, S-A

LA strain rate (s-1) Reservoir strain rate, SR-S Conduit strain rate, SR-E Contractile strain rate, SR-A

* ¶ γ

P < 0.05 vs. control group. P < 0.05 vs. mild OSA. P < 0.05 vs. moderate OSA.

Table 3 Left ventricular conventional and tissue Doppler and left atrial volumetric and strain parameters during the course CPAP treatment in compliant patients Parameters

24-week

P value

Baseline

12-week

72.7 ± 12.8 82.1 ± 18.6 7.4 ± 1.3 6.2 ± 1.5 9.4 ± 1.5 12.0 ± 2.5

75.7 ± 14.7 70.0 ± 16.9* 7.0 ± 0.8 7.2 ± 1.5* 8.3 ± 1.2* 10.8 ± 2.6

83.3 ± 8.6*¶ 59.2 ± 15.3*¶ 8.0 ± 1.8¶ 8.6 ± 1.4*¶ 7.2 ± 1.6*¶ 9.8 ± 1.5*

0.002 < 0.001 0.002 < 0.001 < 0.001 0.006

38.3 ± 7.6 32.4 ± 7.5 25.6 ± 7.9 12.6 ± 4.4 33.8 ± 11.9 5.9 ± 2.2 12.2 ± 4.7 6.7 ± 3.6 21.6 ± 11.3

36.6 ± 8.6* 26.7 ± 8.1* 24.5 ± 8.0* 12.0 ± 4.7 33.6 ± 11.9 9.9 ± 4.8* 24.9 ± 10.7* 2.1 ± 0.9* 8.6 ± 4.1*

34.1 ± 7.9*¶ 26.2 ± 8.3* 23.5 ± 8.0* 10.5 ± 5.5* 31.5 ± 16.4 7.8 ± 5.4* 20.4 ± 10.5* 2.7 ± 1.5* 11.0 ± 6.0*

< 0.001 < 0.001 < 0.001 0.004 0.383 < 0.001 < 0.001 < 0.001 < 0.001

29.3 ± 6.4 12.9 ± 3.3 16.1 ± 6.3

30.1 ± 6.2 13.1 ± 3.0 16.8 ± 7.0

31.7 ± 6.5*¶ 15.1 ± 3.6*¶ 16.2 ± 7.3

< 0.001 0.001

1.1 ± 0.2 –1.0 ± 0.3 –1.5 ± 0.5

1.1 ± 0.2 –1.1 ± 0.3* –1.4 ± 0.2

1.0 ± 0.2 –1.1 ± 0.4 –1.4 ± 0.2

Conventional and tissue Doppler E wave, cm/s A wave, cm/s S’ wave, cm/s E’ wave, cm/s A’ wave, cm/s E/E’, cm/s

LA volume index and phasic functions Maximum volume index, ml/m2 Pre contraction index, preA, ml/m2 Minimum volume index, ml/m2 Total emptying volume index, ml/m2 Total emptying fraction, %

Passive emptying volume index, ml/m2 Passive emptying fraction, %

Active emptying volume index, ml/m2 Active emptying fraction, %

Strain, % Reservoir strain, S-S Conduit strain, S-E Contractile strain, S-A

0.417

Strain rate, s–1 Reservoir strain rate, SR-S Conduit strain rate, SR-E Contractile strain rate, SR-A

0.282 0.018 0.350

E wave: early diastolic inflow, A wave: late diastolic inflow, S’: systolic annular myocardial velocity, E’: early annular myocardial velocity, A’: late annular myocardial velocity. * P < 0.05, basal vs. 12 weeks and 24 weeks. ¶ P < 0.05, 12 weeks vs. 24 weeks.

LA function in patients with OSA

Table 4 Correlation between echocardiographic, clinical and polysomnographic parameters in OSA patients (n = 116) Reservoir strain (S-S )

Reservoir strain rate (SR-S )

LV diastolic filling pressure, E/E’

r = –0.244 P = 0.008

0.178 0.054

–0.362 < 0.001

–0.407 < 0.001

–0.112 0.101

–0.407 < 0.001

Maximal LA volume index

r = –0.294 P = 0.001

–0.297 0.001

–0.636 < 0.001

–0.394 < 0.001

0.180 0.052

–0.394 < 0.001

Pre-contraction LA volume index

r = –265 P = 0.004

–0.327 < 0.001

–0.663 < 0.001

–0.347 < 0.001

0.233 0.011

–0.347 < 0.001

Minimal LA volume index

r = –0.240 P = 0.009

–0.349 < 0.001

–0.670 < 0.001

–0.374 < 0.001

0.268 0.003

–0.374 < 0.001

LV mass

r = –0.173 P = 0.063

–0.029 0.756

–0.081 0.388

–0.174 0.061

–0.135 0.147

–0.174 0.061

Active emptying volume index

r = –0.173 P = 0.061

–0.097 0.298

–0.280 0.002

–0.094 0.314

0.027 0.770

–0.094 0.314

Active emptying fraction

r = –0.062 P = 0.507

–0.062 0.506

0.044 0.641

0.044 0.641

–0.107 0.249

–0.107 0.249

Passive emptying volume index

r = –0.005 P = 0.954

0.160 0.086

0.235 0.011

–0.040 0.666

–0.198 0.032

–0.198 0.032

Passive emptying fraction

r = 0.149 P = 0.110

0.256 0.005

0.473 < 0.001

0.139 0.136

–0.214 0.021

0.139 0.136

Total emptying volume index

r = –0.155 P = 0.096

0.041 0.657

–0.058 0.534

–0.113 0.224

–0.132 0.155

–0.113 0.224

Total emptying fraction

r = 0.078 P = 0.402

0.274 0.003

0.447 < 0.001

0.199 0.031

–0.274 0.003

0.199 0.031

Minimal O2 saturation

r = 0.029 P = 0.754

0.409 < 0.001

0.369 < 0.001

0.116 0.206

–0.267 0.004

0.116 0.206

AHI

r = –0.270 P = 0.003

–0.552 < 0.001

–0.710 < 0.001

–0.391 < 0.001

0.266 0.004

–0.391 < 0.001

BMI

r = –0.153 P = 0.100

0.023 0.808

–0.005 0.995

–0.159 0.087

–0.173 0.062

–0.159 0.087

Systolic blood pressure

r = –0.231 P = 0.012

–0.038 0.687

–0.096 0.301

–0.131 0.160

–0.190 0.040

–0.131 0.160

Heart rate

r = –0.239 P = 0.009

–0.005 0.954

–0.172 0.064

–0.213 0.021

–0.137 0.140

–0.213 0.021

annular systolic (S’) and early diastolic (E’) tissue Doppler velocities; (iii) a reduction in late diastolic Doppler velocity (A); (iv) a reduction in late diastolic tissue Doppler velocity (A’) and diastolic filling pressure (E/E’); (v) an increase in passive emptying volume index and passive emptying fraction of LA; (vi) a reduction in both LA volume indexes, active emptying volume index and active emptying fraction of LA; (vii) an increase in reservoir and conduit strains and conduit strain rate. There was no significant difference after 24 weeks in the non-compliant CPAP group. There was no significant difference in LV mass index throughout the 24-week CPAP therapy between baseline and 24-week echo evaluation (85.3 g/ m2 vs. 86.6 g/m2, P > 0.05). Other echocardiographic and clinical variables such as LV ejection fraction, blood pressure and heart rate did not significantly change in the compliant and non-compliant groups, at any time.

Conduit strain (S-E )

Conduit strain rate (SR-E )

Contractile strain (S-A )

Contractile strain rate (SR-A )

DISCUSSION OSA is associated with adverse structural and functional cardiac abnormalities that may lead to increased morbidity and mortality23. In the current study the main findings are: (i) significant reduction in LA deformations and passive LA volumetric functions as well as increase in LA volumes, active volumetric functions and LV diastolic filling pressure in OSA patients; (ii) significant improvement of LA deformation and passive LA volumetric functions as well as reduction in LA volumes, active volumetric functions and LV diastolic filling pressure after 24 weeks of effective CPAP therapy. The improvement of LA deformation seems to be partly associated with the improvement of LV diastolic stiffness and minimal O2 saturation and reduction of AHI after the effective CPAP therapy. We confirmed positive left

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atrial remodelling over 24 weeks using echocardiography in OSA patients receiving CPAP therapy. An improvement in LA functions and volumes were seen as early as 12 weeks into CPAP therapy which continued to improve over 24 weeks of follow-up. Furthermore, significant improvement in LV diastolic function was manifested by an amelioration in the LV filling pressures (reflected by the E/E’) in association with LA function and volume was shown in the CPAP treatment group. Previous studies have demonstrated a reduction of improvement in LA function and volume. Oliveira et al. first evaluated the effects of CPAP therapy on LA volumetric functions and LV diastolic stiffness using three-dimensional echocardiography (3D-Echo) and tissue Doppler echo and found a similar improvement in LA volumetric functions and LV diastolic stiffness4. However, this study demonstrated that 3D-Echo evidence of improved LA remodelling is limited due to a lack of quantitative assessment of the LA deformation. A recent study demonstrated that LA remodelling and dysfunction can be detected in the subclinical stage with evaluation of active and passive functions of the LA using the 2D-STE in OSA patients (n = 58) 12. In our larger study population (n =117), we confirmed these findings using similar methods and further demonstrated an improvement in positive remodelling over 24 weeks. The prevalence of diastolic dysfunction leading to LA enlargement increased with the severity of OSA from 56.8% to 69.7% compared to 44.8% in the non-OSA population24,25. In the previous studies CPAP therapy resulted in an improvement in LV ejection fraction and LV diastolic function24,26. The mechanisms associating OSA and cardiac remodelling are not fully understood. OSA may induce severe intermittent hypoxaemia and carbon dioxide retention during sleep disrupting the normal autonomic and haemodynamic responses to sleep27. Haemodynamic stress occurs at a time of severe hypoxaemia, hypercapnia, and adrenergic activation which proceeds to endothelial dysfunction, systemic inflammation and left atrial enlargement28. Apnoea-hypopnoea events can trigger left ventricular overload, impairing relaxation and leading to LA enlargement and dysfunction in OSA27,29,30. All these factors, along with highly prevalent conditions in OSA such as hypertension and obesity act in synergy to impair diastolic function. LA enlargement is associated with adverse cardiovascular events31. We demonstrated a significant association between LA volume and the disease severity and diastolic impairement. Increased LA afterload which can be evidenced by low early diastolic Doppler (E) and tissue Doppler velocities (E’) results in impaired early LA emptying (LA passive emptying and conduit strain/strain rate). This impaired emptying contributes to larger residual volume before LA contraction (LA pre-contraction volume and contractile

strain/strain rate). The presence of such volumetric changes enhances the importance of atrial contraction (LA active emptying and contractile strain/strain rate) during left ventricular filling especially during exercise. This is demonstrated in our study as increased LA active emptying and higher late diastolic Doppler (A) and tissue Doppler velocities (A’). Increased LA afterload leads to augmentation of the LA volume. Recent studies suggest that the degree of elevated LV filling pressures may not fully explain LA dysfunction and that LA myocardial fibrosis may play a role in LA dysfunction. In OSA patients apoptosis develops due to chronic myocardial cellular damage during sympathetic system activation, oxidative stress, systemic inflammation, endothelial dysfunction32. The severity of LA fibrosis evaluated with magnetic resonance imaging correlates with LA longitudinal strain and strain rate33. The reservoir strain was not protected in our study despite LA enlargement and increased wall tension suggesting a LA tethering effect rather than active deformation. The depressed conduit and reservoir functions in OSA was compensated with the augmentation in the pump function (LA active emptying and contractile strain/strain rate) to provide sufficient LV filling. LA deformation abnormalities were more prominent in severe OSA in our study. This may be due to LA remodelling and accompanying myocardial dysfunction which may be more dependent on apnoea-hypopnoea episodes and more severe oxygen desaturation. In OSA patients (n =117), the weak correlation between LV diastolic dysfunction (E/E’) and LA deformation suggests that the adverse effect of OSA on LA myocardium with LV diastolic dysfunction may not be the only cause of LA dysfunction. Morever, Oliveira et al. showed that OSA severity is an independent predictor of LA functional and structural remodelling when corrected for hypertension, obesity, gender and diabetes30. CPAP therapy is the standard treatment for OSA patients. CPAP therapy reduces the frequency of apnoeic/hypopnoeic events and improves oxygenation during sleep, resulting in diminished sympathetic nervous activation, reduction in LV and LA afterload34. Our study demonstrates an improvement of LA volume and deformation during the CPAP treatment. These results suggest that LA remodelling may be reversed with regular CPAP use, thus potentially lowering the risk of cardiovascular morbidity and mortality in OSA16.

LIMITATIONS The main potential limitation was the presence of confounding cardiovascular risk factors and cardioactive medication in the study population and its influence on

LA function in patients with OSA

myocardial functions. In fact, the aim of the present study was to explore the ultimate effect of CPAP therapy on LA function in an OSA population with its typical cardiovascular risk factors.

CONCLUSIONS In OSA patients, LA enlargement and dysfunction are common and possibly related to the same fibrotic process that affect the fibres of LV and elevated LV filling

pressure. Furthermore, impaired LA longitudinal functions reflected by longitudinal strain and strain rate could be related to fibrosis. Cardiovascular physicians could easily use such non-invasive, quantitative, and technically simple methods to assess the LA alterations. Furthermore, we demonstrated that the LA remodelling in OSA could be at least partially reversed after effective long-term CPAP therapy.

CONFLICT OF INTEREST: none.

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