Sleep Breath DOI 10.1007/s11325-015-1175-1


Right ventricular geometry and mechanics in patients with obstructive sleep apnea living at high altitude Tolga Sinan Güvenç 1 & Nergiz Hüseyinoğlu 2 & Serkan Özben 3 & Şeref Kul 4 & Rengin Çetin 5 & Kaya Özen 2 & Coşkun Doğan 6 & Bahattin Balci 2

Received: 25 November 2014 / Revised: 5 February 2015 / Accepted: 31 March 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Purpose Repetitive obstruction of larynx during sleep can lead to daytime pulmonary hypertension and alterations in right ventricular morphology and function in a small fraction of obstructive sleep apnea syndrome (OSAS) patients. Environmental effects, particularly high altitude, can modify the effects of OSAS on pulmonary circulation, since altituderelated hypoxia is related with pulmonary vasoconstriction. This potential interaction, however, was not investigated in previous studies. Methods A total of 41 newly diagnosed OSAS patients were included in this study after pre-enrolment screening. Two-dimensional, three-dimensional, and Doppler echocardiographic data were collected after polysomnographic verification of OSAS. Three-dimensional echocardiograms were analyzed to calculate right ventricular volumes, volume indices, and ejection fraction. Results Systolic pulmonary artery pressure (38.35±8.60 vs. 30.94±6.47 mmHg; p=0.002), pulmonary acceleration time (118.36±16.36 vs. 103.13±18.42 ms; p=0.001), right ventricle (RV) end-diastolic volume index (48.15±11.48 vs. 41.48± 6.45 ml; p=0.009), and RV end-systolic volume index (26.50

* Tolga Sinan Güvenç [email protected] 1

Umraniye Training and Research Hospital, Istanbul, Turkey


Kafkas University School of Medicine, Kars, Turkey


Bakirkoy Research and Training Hospital for Psychiatry, Neurology, and Neurosurgery, Istanbul, Turkey


Bezmialem Vakıf University, Istanbul, Turkey


Kars State Hospital, Kars, Turkey


Kartal Lutfi Kırdar Research and Training Hospital, Istanbul, Turkey

±8.11 vs. 22.15±3.85; p=0.01) were significantly higher in OSAS patients, with similar RVejection fraction (EF) between groups. No significant differences were noted in other twodimensional, Doppler or speckle-tracking strain, measurements. Both RVEF and pulmonary acceleration time were predictors of disease severity. Conclusions A greater degree of RV structural remodeling and higher systolic pulmonary pressure were observed in OSAS patients living at high altitude compared to healthy highlanders. The reversibility of these alterations with treatment remains to be studied. Keywords Obstructive sleep apnea . Pulmonary hypertension . Right ventricle . High altitude . Three-dimensional echocardiography

Introduction Obstructive sleep apnea syndrome (OSAS), which is characterized by episodic cessation of respiration during sleep due to obstruction of the respiratory tract, is associated with abnormalities in pulmonary circulation, including transient increases in pulmonary arterial pressure (PAP) during episodes of apnea and an abnormal response of pulmonary circulation to hypoxic stimuli, leading to permanent daytime pulmonary hypertension in a small fraction of patients [1–3]. As an extension of these abnormalities in pulmonary circulation, a myriad of alterations in right ventricular (RV) morphology and function were defined in OSAS patients, ranging from hypertrophy of RV to diastolic and systolic dysfunction [4–6]. Although the precise cause of abnormalities in pulmonary circulation and right ventricle remains unknown, it is acknowledged that episodic or daytime hypoxia and abnormal

Sleep Breath

pulmonary vascular response to hypoxia in some OSAS patients are responsible for these abnormalities [3, 7, 8]. High-altitude (HA) environments are characterized with reduced partial oxygen fraction of inspired air, hypoxemia, increased pulmonary vascular resistance and right ventricular adaptation to changes in PAP [9]. Previous observations in obese individuals and in those with coexistent obesity and OSAS had shown that the combination of these conditions and high altitude promotes the development of pulmonary hypertension, even at moderate (i.e., between 1,500 and 3, 500 m) altitudes [8, 10]. However, structural and functional information regarding the right heart were not provided in these studies. Two-dimensional (2D) echocardiography, which is usually employed in OSAS studies to evaluate RV performance, is valuable in assessing structural remodeling and systolic or diastolic dysfunction in everyday practice, but neither RV diastolic or systolic volumes nor ejection fraction (EF) can be reliably calculated [11]. In contrast, three-dimensional (3D) echocardiography allows a more thorough assessment of RV volumes, with a good correlation with cardiac magnetic resonance (MR) and a low interobserver and intraobserver variability [11–13]. In this study, we aimed to investigate PAP and structural and functional changes of the right heart in OSAS patients living at moderately high altitude, as assessed with two- and three-dimensional echocardiography and deformation imaging.

Materials and methods Patient enrolment For the present study, patients who admitted to institutional neurology or pulmonology departments and who were diagnosed as OSAS after clinical and polysomnographic assessment were prospectively enrolled after screening procedures. Patients who were under 18 years old—those who had previously been diagnosed as OSAS and had received treatment, those with known chronic lung disorders including chronic obstructive pulmonary disorder and interstitial lung diseases, those with known diagnosis of pulmonary hypertension, those with known history of congestive heart failure (including those with heart failure with preserved ejection fraction), all types of cardiomyopathies, those with known pericardial diseases, previous myocardial infarction, a history of revascularization or presence of critical coronary stenosis in at least one major coronary artery, congenital heart diseases that could induce pulmonary hypertension (PH), more than mild valvular regurgitation or aortic stenosis, any mitral, pulmonary, or tricuspid stenosis, renal or liver failure, and patients using medications that are known to affect pulmonary circulation—were

excluded. Control group was formed from age- and gendermatched healthy individuals without a history of cardiac or pulmonary diseases including OSAS. To exclude any de novo cardiac or pulmonary conditions, a screening phase was used prior to enrolment (detailed below). Subjects with systemic conditions, such as hypertension or diabetes, were not excluded unless they had other criteria for exclusion. To avoid any confounders that could arise from altitude-related factors, the following additional entry criteria were applied to both patients and controls: (i) all subjects were required to be born at the study location (Kars, 1,768 m above sea level), (ii) none of the subjects should have lived at sea level or at a higher altitude for a prolonged period of time (6 months or more), and (iii) no trips to a different altitude should be made within 6 months. Screening procedures for OSAS patients and healthy controls included a complete physical examination by a cardiologist (KÖ), pulmonary diseases specialist (CD), and a neurologist (SÖ), and the subjects were referred to additional tests if a different diagnosis was suspected. Specifically, all healthy volunteers were referred to polysomnographic analysis if one or more of the cardinal features of OSAS were recognized by one of these physicians: loud snoring and snorts during sleep, abnormal respiratory patterns during sleep (apnea, hypopnea, and arousals related to respiratory efforts) which could be selfreported or reported by a family member, and signs/symptoms related to disturbed sleep (sleepiness, poor concentration, narcolepsy, snoring, resuscitative snorts). Volunteers with an abnormal polysomnographic test were excluded from the study. A screening two-dimensional echocardiographic examination was performed by a cardiologist experienced in echocardiography (TSG) to all subjects prior to enrolment. Subjects with an ejection fraction less than 55 % as measured with biplane Simpson’s method, more than grade I diastolic dysfunction (mitral E/averaged E′ ratio of more than 13 or a mitral E/A ratio>1 with additional evidence for grade II or more diastolic dysfunction, or unexplained severe left atrial dilatation defined as a left atrial volume index>40 ml/m2), valve diseases fulfilling exclusion criteria (as defined before), left ventricular septal and/or posterior wall thickness≥1.5 cm, and those with congenital heart disease discovered during screening echocardiography were excluded at this stage. In addition, subjects with insufficient image quality for two- or three-dimensional echocardiographic image acquisition were excluded. During physical examination, demographic and anthropometric information, as well as past medical history, were recorded. Body mass index (BMI) was calculated by dividing weight of the subject to the square of subject’s height. Body surface area (BSA) was calculated according to Mosteller’s formula. After screening, a total of 41 OSAS patients and 26 healthy controls were included in this present study (Fig. 1). Prior to enrolment in the study, all subjects were informed about the procedures and a written informed consent statement was

Sleep Breath Fig. 1 The flow diagram of the study, showing screening procedures and the total number of subjects included/excluded at each stage. A full list of inclusion/ exclusion criteria can be found in the text. Dx diagnosis, OSAS obstructive sleep apnea syndrome, PH pulmonary hypertension

Preliminary Evaluation - 60 consecutive OSAS patients diagnosed with polysomnography - 30 healthy volunteers

Remaining Screening Phase

- 52 OSAS patients

- Evaluation by pulmonary diseases specialist, cardiologist, neurologist

-28 healthy volunteers

Inclusion/Exclusion Criteria + >18 y, Dx of OSAS, living at high altitude -Significant left-sided heart pathology, significant valvopathy, other diseases that may cause PH, rhythm other than sinus

- Screening echocardiography - Additional tests if needed

Study Population - 41 OSAS patients - 26 healthy volunteers

- Acquisition of two- and threedimensional echocardiograms and offline interpretation - Statistical analysis and calculation of observer variability

End of Study

obtained. This study was carried out in compliance with Helsinki Declaration and institutional ethics committee (Kafkas University Ethics Committee) approved the study before initiation. Polysomnography Polysomnographic recordings for a full-night were obtained with Embla® N7000 (Medcare, Iceland) platform. During these test: electroencephalography (EEG), electrocardiography (ECG), electrooculogram (EOG), submental and anterior tibialis muscle electromyography (EMG), nasal pressure, oronasal airflow with thermal sensor, snoring, oxygen saturation with a finger oxymeter, and respiratory effort by thoracic and abdominal inductance plethysmography were measured and recorded. Sleep-disordered breathing events were scored manually by a neurologist experienced in polysomnography (NH) in compliance with American Academy of Sleep Medicine criteria [14]. Obstructive apnea was defined as a drop in the peak oronasal thermal sensor excursion by ≥90 % from baseline for at least 10 s and hypopnea was defined as at least a 50 % drop in airflow for at least 10 s despite respiratory efforts and at least a 3 % drop in oxyhemoglobin saturation. Apnea–hypopnea index (AHI) was defined as the total number of partial obstructions (hypopnea) and complete cessations (apnea) of breathing occurring per hour of sleep. OSAS was diagnosed if patients had an AHI of more than or equal to 5. Patients with an AHI between 5 and 15 were regarded as having mild, between 15 and 30 were graded as moderate, while those with an AHI more than or equal to 30 were accepted as severe OSAS [15].

Echocardiographic examination All echocardiographic procedures, including pre-enrolment screening and image acquisition for the study, were carried out using a GE Vivid 7 platform (GE Healthcare, Piscataway, NJ, USA) equipped with a 1.5–4.0 MHz matrixarray probe for two-dimensional imaging and a 1.5–3.6 MHz four-dimensional (4D) sector array probe for threedimensional imaging. Both image acquisition and measurements were conducted by the same cardiologist (TSG) blinded to the clinical data of subjects. All obtained images were sent to a workspace for offline measurements. Image quality was accepted as adequate if cardiac chambers could be visualized from standard imaging planes, with a special importance given to full visualization of right ventricular free wall from apical four-chamber view. All two-dimensional and Doppler imaging parameters were recorded according to American Society of Echocardiography recommendations [16]. For all Doppler measurements and tricuspid annular plane systolic excursion (TAPSE) calculation, three cycles were recorded and an average of three cycles was obtained. Longitudinal strain and strain rate of right ventricular free (lateral) wall were measured from apical four-chamber view using speckle-tracking technology. Longitudinal strain was preferred as the indicator of right ventricular regional contractility since apicobasal contraction is the main direction of RV shortening. From the stored images, endocardial borders were drawn semiautomatically. All measurements and recordings were performed with Echopac-PC software (GE Healthcare, Piscataway, NJ, USA) capable of semiautomated speckletracking and strain calculations. Average strain and strain rate

Sleep Breath

measurements for each segment were obtained from the final data, and mean right ventricular free-wall strain was calculated as the arithmetic mean of the three segments. Three-dimensional images of the right ventricle were recorded from apical four-chamber view. Four cycles were recorded when the subject was holding his/her breath, which were combined automatically to form one full-volume image of heart. For each subject, two complete datasets were obtained and recorded for postprocessing. The dataset with higher image quality was preferred for volumetric calculations. For semiautomatic endocardial border tracking and RV volume calculations, 4D RV quantification software (Tomtec Imaging Systems GmBH, Unterschleissheim, Germany) was used. Final end-diastolic (RVEDV) and end-systolic (RVESV) volumes, as well as RV stroke volume and ejection fraction, were obtained from software-generated cast of RV (Fig. 2). Statistical analysis All statistical analyses were performed with SPSS 17.0 for Windows software (IBM Inc., USA) in a compatible computer. Continuous variables were expressed as mean±SD, while categorical variables were reported as percentages. One-way Kolmogorov–Smirnov test was conducted to test normal distribution within groups. For parameters with a normal distribution, Student’s t test was used for comparison, while nonparametric tests (Kruskal–Wallis for three or more groups and Mann–Whitney U test for two groups) were used to compare

Fig. 2 An example for the calculation of right ventricular end-diastolic and end-systolic volumes utilizing three-dimensional echocardiography. This right ventricular cast is produced by semiautomatic delineation of right ventricular endocardial contours in end-diastolic frames from three different planes (short axis, four chambers, and oblique), allowing the software to complete the rest of the borders in all other frames. The right ventricle is seen from the lateral wall, showing inflow, body and infundibular parts

groups when the parameter was not distributed normally. Nonparametric tests were also preferred for subgroup analyses due to a low number of subjects in the moderate OSAS group. For comparisons involving categorical variables, Chi-square test or Fisher’s exact test were used depending on the expected cell count. Univariate relationships between AHI and clinical echocardiographic variables were investigated using Pearson’s correlation test. Echocardiographic variables with a linear correlation (tested with Pearson correlation and scatter plot graphics, with r≥0.25 and p

Right ventricular geometry and mechanics in patients with obstructive sleep apnea living at high altitude.

Repetitive obstruction of larynx during sleep can lead to daytime pulmonary hypertension and alterations in right ventricular morphology and function ...
482KB Sizes 0 Downloads 7 Views