Relationship between obstructive sleep apnea severity index and left ventricular function and volume

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1 Reltionship between obstructive sleep pne severity index nd left ventriculr function nd volume Nejt Altints, Ekrem Asln, b Aysen Helvci, Atul Mlhotr b From the 19 Myis University School of Medicine, Deprtment of Pulmonry Medicine, Smsun, b Helth Ministry Okmeydni Trining nd Reserch Hospitl, Deprtment of Internl Medicine Istnbul/Turkey, nd c Hrvrd Medicl School, Brighm nd Women's Hospitl, USA Correspondence: Nejt Altints 19, Myıs University, School of Medicine, Deprtment of Pulmonry nd Sleep Medicine, Smsun/ Turkey T: , F: nejtltints@gmil.com Ann Sudi Med 2012; 32(4): DOI: / BACKGROUND AND OBJECTIVES: Obstructive sleep pne (OSA) cuses incresed crdiovsculr morbidity nd mortlity, including systemic rteril hypertension, coronry hert disese, hert rhythm nd conduction disorders, hert filure nd stroke. In our study, we imed to ssess left ventriculr mss nd myocrdil performnce index (MPI) in OSA ptients. DESIGN AND SETTING: A cross-sectionl study conducted between My 2007 nd August 2009 in tertiry hospitl in Istnbul, Turkey. PATIENTS AND METHODS: Forty subjects without ny crdic or pulmonry disese referred for evlution of OSA hd overnight polysomnogrphy nd echocrdiogrphy. According to the pne-hypopne index (AHI), subjects were clssified into three groups; mild OSA (AHI: 5-14/h; n=7), moderte OSA (AHI: 15-29/h; n=13), nd severe OSA (AHI: 30/h; n=20). The thickness of the interventriculr septum (IVS) nd left ventriculr posterior wll (LVPW) were mesured by M-mode long with left ventriculr mss (LVM) nd LVM index (LVMI). The left ventriculr MPI ws clculted s (isovolumic contrction time + isovolumic relxtion time)/ortic ejection time by Doppler echocrdiogrphy. RESULTS: No differences were observed in ge or body mss index mong the groups, but blood pressures were higher in severe OSA compred with moderte nd mild OSA. In severe OSA, the thickness of the IVS (11.6 [1.7 mm]), LVPW (10.7 [1.7 mm]), LVM (260.9 [50.5 g]), nd LVMI (121.9 [21.1g/m 2 ]) were higher thn in moderte OSA (9.4 [1.3 mm]; 9.9 [1.6]; [35.2]; 94.7 [13.2 g/m 2 ], respectively) nd mild OSA (9.8 [2.4 mm], 8.9 [2.0 mm], [66.2 g], 95.8 [28.6 g/m 2 ], respectively). In severe OSA, MPI (0.8 [0.2]) ws significntly higher thn in mild OSA (0.5 [P<.01]) but not significntly higher thn moderte OSA (0.8 [0.1]). CONCLUSIONS: OSA ptients hve demonstrble crdic bnormlities tht worsen with the severity of pne. The MPI my hve utility in subsequent OSA studies, possibly s surrogte outcome mesure. Obstructive sleep pne (OSA) is serious, underdignosed disese 1,2 ssocited with incresed crdiovsculr morbidity nd mortlity, including systemic hypertension nd pulmonry hypertension, coronry hert disese, hert rhythm nd conduction disorders, nd hert filure nd stroke. 2-6 Given the strong link between OSA nd hypertension, both left ventriculr hypertrophy nd left ventriculr distolic dysfunction (LVDD) re common echocrdiogrphic bnormlities in OSA. 7 Repeted episodes of hypoxemi, hypercpni, nd microrousl plus intrthorcic pressure fluctutions trigger mechnisms such s sympthetic hyperctivity, 8,9 oxidtive stress, 10 systemic inflmmtion, 11 hypercogulbility, 12 nd even endothelil dysfunction. 13 The previling hypothesis is tht these bnormlities combine chroniclly to yield vsculr lesions. The lrge rteries ply crucil role in crdic structure, so incresed rteril stiffness contributes independently to rteril pressure nd to n increse in left ventriculr fterlod, thereby promoting left ventriculr hypertrophy (LVH). 14 Left ventriculr distolic dysfunction precedes left ventriculr systolic impirment nd ccounts for 30% to 40% of overll ptients with left ventriculr fil- 384

2 ure Since systolic nd distolic dysfunctions frequently coexist, combined mesures of left ventriculr performnce might be more reflective of overll crdic dysfunction thn systolic or distolic mesures lone. The Doppler-derived myocrdil performnce index (MPI lso denoted the TEI-Doppler index), n index of combined systolic nd distolic functions, is defined s the sum of isovolumic contrction time nd isovolumic relxtion time (IVRT) divided by the ejection time. Thus, MPI reflects globl LV function s opposed to other mesurements tht reflect minly either LV systolic or distolic function. 18 The MPI is sensitive index of symptomtic hert filure nd predicts future development of hert filure independent of other echocrdiogrphic mesurements. 18 The MPI is noninvsive, quick, nd reproducible technique tht cn be used to evlute left ventriculr globl function. 19 Bsed on the bove findings, we evluted left ventriculr mss (LVM) nd left ventriculr globl function in OSA ptients, including the reltionship between pne-hypopne index (AHI) nd MPI. This im would llow us to test the hypothesis tht OSA hd importnt influences on crdic functions s ssessed by MPI. These dt would llow us to explore the potentil utility of the MPI in future OSA studies, eg, s biomrker or to ssess response to therpy or possibly s robust mrker of disese severity. PATIENTS AND METHODS Forty ptients were referred to the sleep clinic between My 2007 nd August 2009 with symptoms of nocturnl snoring nd/or excessive dytime sleepiness. Ptients who hd known crdic (including ngin or rrhythmi) or lung disese, dibetes mellitus, ngin pectoris, chronic renl nd heptic diseses, nd serum electrolytes imblnces were excluded from the study. The Epworth sleepiness scle 20 ws used to ssess ll prticipnts; ptients with score bove 10/24 (indictive of excessive dytime sleepiness) were recruited into the study. Blood pressure ws mesured ccording to Europen Society of Hypertension-Europen Society of Crdiology guidelines. 21 Hypertension ws defined s blood pressure >140/90 mm Hg. The hert rte (HR) per minute ws mesured in the sitting position nd the body mss index (BMI) of the ptients ws clculted s weight divided by height squred (kg/m 2 ). A 12-led surfce electrocrdiogrm ws tken from every subject to ensure norml sinus rhythm. Overnight-ttended polysomnogrphy ws performed in our sleep lbortory during which we obtined 3-chnnel electroencephlogrm (EEG), n electro-oculogrm, nd submentl electromyogrm using surfce electrodes. The irflow ws mesured by monitoring nsl pressure through nsl cnnule (Ultim Dul Pressure Sensor Brebon Medicl Corportion. Crp. Ontrio, Cnd). The respirtory effort ws mesured by inductnce plethysmogrphy with trnsducers plced on the chest nd bdomen (Respitrce, Ambultory Monitoring, Ardsley, New York, USA). The rteril oxyhemoglobin sturtion (SO 2 ) ws recorded with pulse oximeter (Biox 3740, Ohmed. Boulder, Colordo, United Sttes). All vribles were recorded continuously by computerized dt-cquisition system nd stored electroniclly for lter nlysis (Sndmn, Tyco Helthcre, Knt, Ontrio, Cnd). All-night polysomnogrphic recordings were scored visully ccording to the Rechtschffen nd Kles (R nd K) rules by experienced sleep scorers. 22 Briefly, sleep ws scored s stge 1 to 4 non-rpid eye movement (NREM) or REM. Totl sleep time (TST) ws defined s the durtion of sleep from lights out t the beginning of the study to lights on the following morning. Sleep ltency ws defined s the time from lights out to the first 30-second period of sleep. Sleep efficiency ws defined s the TST expressed s percent of the totl study durtion. Apne ws defined s the bsence of irflow for 10 seconds ssocited with continued respirtory efforts (obstructive), bsence of respirtory efforts (centrl), or fetures of centrl pne followed by obstructive pne (mixed). Hypopne ws defined s 50% reduction in irflow for 10 seconds or mrked reduction in irflow ssocited with 4% oxygen desturtion nd/or rousl from sleep. The number of pnes nd hypopnes per hour of sleep were expressed s AHI. Arousl ws defined s n brupt shift of EEG frequency including lph, thet, nd/or frequencies greter thn 16 Hz (but not spindles), lsting t lest 3 seconds in durtion nd preceded by t lest 10 seconds of stble sleep. Desturtions were ccepted s 4% decrese in oxygen sturtion. Desturtion index (DI) ws defined s the number of oxygen desturtion events per hour of sleep. 23 All echocrdiogrphic mesurements were performed with the subjects in the lterl decubitus position using 2.5 MHz probe. All echocrdiogrphic exmintions were performed by the sme crdiologist who ws blinded to the presence or bsence of OSA. Ventriculr dimeters, volumes, nd functions were mesured ccording to the recommendtions of the Americn Society of Echocrdiogrphy. 24 Bsic mesurements of left ventriculr dimensions in distole nd systole, nd thicknesses of interventriculr septum (IVS), left ventriculr posterior wll (LVPW), nd LVM were mesured by the M-mode technique; LVM 385

3 ws divided by body surfce re to obtin LVM index (LVMI). The left ventriculr ejection frction (LVEF) ws clculted by the Simpson method s (distolic volume systolic volume)/distolic volume. The erly (E) nd tril (A) trnsmitrl mximl flow velocities, the rtio (E/A), nd the decelertion time of E-wve were registered. The IVRT ws mesured by the continuous wve Doppler technique. The velocity of mitrl flow propgtion ws estimted using color Doppler M-mode. The left ventriculr MPI ws clculted s: (isovolumic contrction time + IVRT)/ ortic ejection time. The globl left ventriculr dysfunction ws defined s n MPI 0.50 [0.39 (0.05) norml level]. 25 Dt were presented s men (stndrd devition), nd the Kruskl-Wllis test ws used for group comprisons. The Mnn-Whitney U test ws used when only two groups were compred. A P vlue <.05 ws considered sttisticlly significnt. Tble 1. Bsic chrcteristics of ptients with obstructive sleep pne (OSA) syndrome. Ptients with OSA AHI 5-14/h AHI 15-29/h AHI 30/h P No. of subjects Men ge (yers) 38.3 (6.1) 42.7 (9.1) 48.9 (7.4).01 Mle, n (%) 4 (57.1) 10 (76.9) 17 (85.0) NS Femle, n (%) 3 (42.9) 3 (23.1) 3 (15.0) NS Body mss index (kg/m²) Systolic blood pressure (mm Hg) Distolic blood pressure (mm Hg) Hert rte (pulse/min) Hypertension, n (%) Apne-hypopne index (AHI) (per hour) Desturtion index (per hour) Minimum sturtion of nocturnl rteril oxygen (SO 2 ) (%) 27.5 (5.1) 31.4 (4.6) 31.5 (4.9) (12.7) (17.6) (18.2) (10.0) 78.5 (9.9) 81.4 (8.7) (12.9) 86.4 (9.9) 87.7 (12.0) (14.3) 4 (30.8) 10 (50.0) (2.2) 21.5 (3.8) 50.5 (15.3) (8.4) 22.0 (6.0) 39.7 (18.4) (8.9) 85.3 (4.2) 75.7 (8.3).001 Averge SO 2 (%) 96.1 (1.8) 94.2 (1.9) 91.6 (4.2).001 Sleep durtion (%) 8.6 (11.9) 2.5 (5.0) 18.5 (22.7).002 Dt re presented s n, n (%), or men SD. At SO 2 <90% RESULTS A totl of 31 mles (77.5%) nd 9 femles (22.5%) were included in the study. Ptients were clssified into three subtypes ccording to their AHI scores; mild (AHI 5-14 events/h), moderte (AHI events/h), nd severe (AHI 30 events/h). Twelve percent of ptients were using lcohol nd 42% of ptients were cigrette smokers. Bsic chrcteristics of the ptients with OSA re shown in Tble 1. No significnt differences were observed in their sex, BMI, nd HR mong the OSA ptients (P>.05). However, men of ge, systolic blood pressure, nd distolic blood pressure were higher in severe OSA ptients thn in moderte nd mild OSA ptients. Of the 40 OSA ptients, 15 were hypertensive nd the mjority (50%) were in the severe group. As expected, AHI nd DI were highest in ptients with severe OSA (P<.0001), nd these ptients hd both the lowest verge nd ndir oxygen sturtion (SO 2 ) (P<.0001). The percentge of sleep durtion t <90% SO 2 ws significntly higher in the severe OSA group, while it ws the lowest in the mild OSA group. Bsic echocrdiogrphic mesurements of the left ventricle in ptients with OSA re shown in Tble 2. The left tril dimeter nd left ventriculr end-distolic nd end-systolic dimeters were not sttisticlly different mong groups of OSA ptients in severe OSA ptients. The thickness of IVS, LVPW, LVM, nd LVMI were higher thn both the moderte nd mild OSA ptients. Bsic mesurements in the different OSA groups re shown in Tble 3. The left ventriculr systolic nd distolic functions in ptients with OSA re shown in Tble 4. The left ventriculr systolic function ws not significntly different in the three groups of OSA ptients nd ws within norml limits. While mild OSA ptients hd norml left ventriculr distolic function, moderte nd severe OSA ptients hd LVDD. The left ventriculr MPI ws significntly higher in severe OSA ptients thn in mild OSA ptients (P=.01), but it ws not sttisticlly different between mild nd moderte OSA ptients (P>.05). A positive correltion ws shown between left ventriculr MPI nd AHI reflecting the severity of OSA (P=.001, r = 0.33). The correltion between MPI nd AHI in OSA ptients is shown in Figure 1. DISCUSSION OSA hs importnt influences on crdic functions such s left/right ventriculr dysfunction, crdic rrhythmi, nd pulmonry hypertension. 26 Since these dysfunctions re closely relted with crdic nd systemic complictions, we need reproducible, widely pplicble, nd simple noninvsive method for the 386

4 estimtion of left ventriculr globl function in ptients with OSA. For this purpose, we investigted LVM nd left ventriculr globl function in OSA ptients by MPI including the reltionship between AHI nd MPI. These dt would llow us to explore the potentil utility of the MPI in future OSA studies. Although the mechnism of impirment in myocrdil contrction nd relxtion seen in ptients with OSA is poorly understood, OSA my increse crdic risk due to n imblnce of myocrdil oxygen demnd nd supply s result of hypoxemi, hypercpni, nd incresed sympthetic ctivtion occurring during pne. 27 Diseses, such s hypertension, obesity, nd dibetes mellitus, which often ccompny OSA, lso contribute to the development of LVH. In our study, dibetes mellitus nd coronry rtery disese were excluded nd no significnt differences were observed in BMI between the ptient groups. However, in our study, 15 of 40 OSA ptients were hypertensive, nd the mjority (50%) were in the severe OSA group. Becuse of the compelling evidence of cusl link between OSA nd hypertension, we believe tht it would be inpproprite to exclude hypertensive ptients from these nlyses since the cusl pthwy underlying LVDD from OSA my well involve hypertension. In study by Lvie et l 28 in 2677 people ttending sleep clinic, the reltionship between the severity of OSA significntly contributed to hypertension independent of ll known confounding vribles. Ech pneic event per hour of sleep dded bout 1% to the risk of hving hypertension. Apne nd hypopne cuse temporry elevtions in blood pressure in ssocition with blood oxygen desturtion, rousl, nd sympthetic ctivtion nd my cuse elevted blood pressure during the dytime nd ultimtely sustined hypertension. 29 In our ptients, the percentge of sleep durtion <90% SO 2 ws the highest in the severe OSA group, while it ws the lowest in the mild OSA group. The severe OSA ptients hd more hypoxic durtion in their sleep compred with the moderte nd mild OSA groups. Becuse OSA my cuse hypertension tht my then led to LVH, we do not view the imblnce of blood pressure between groups s confounder, but rther n importnt fctor on the cusl pthwy of interest. In this study, IVS nd LVPW dimeters nd LVM nd LVMI were slightly higher in severe OSA ptients, wheres they were within norml limits in mild nd moderte OSA ptients. Moreover, severe OSA ptients hd slight LVH. Our study did not define the mechnism underlying LVH; however, LVH could be cused by hypertension, intermittent blood pressure surges, nd/or nocturnl hypoxemi. Nod et l 30 re- Tble 2. Echocrdiogrphic mesurements of the left ventricle in ptients with obstructive sleep pne (OSA) syndrome. Ptients with OSA AHI 5-14/h AHI 15-29/h AHI 30/h P No. of subjects Thickness nd dimeters Left trium (19-40 mm) 37.0 (5.1) 36.2 (3.4) 37.5 (4.1).619 Interventriculr septum thickness in distole 9.8 (2.4) 9.4 (1.3) 11.6 (1.7).004 (6-11 mm) Posterior left ventriculr wll thickness in 8.9 (2.0) 9.9 (1.6) 10.7 (1.7).033 distole (37-56 mm) Left ventriculr end-distolic dimeter 46.2 (4.7) 46.7 (6.3) 49.5 (4.2).278 (37-56 mm) Left ventriculr end-systolic dimeter (19-40 mm) 28.7 (4.4) 29.5(4.4) 31.2 (3.4).383 Left ventriculr mss Left ventriculr mss b Left ventriculr mss index b (66.2) (35.2) (50.5) (28.6) 94.6 (13.2) (21.1).020 Dt re presented s men (SD) or n. AHI: Apne-hypopne index Norml vlues; <198 g in femles, <294 g in mles; b <110 g/m 2 in femles, <134 g/m 2 in mles. Tble 3. Sttisticl comprison of the bsic mesurements in the different obstructive sleep pne syndrome groups. Systolic blood pressure Distolic blood pressure Interventriculr septum thickness in distole Posterior left ventriculr wll thickness in distole Left ventriculr mss Left ventriculr mss index Myocrdil performnce index Group 1 Group 2 Group 1 vs 2 vs 3 vs Dt re presented s P vlues obtined using the Mnn-Whitney U test. Group 1: pne-hypopne index (AHI)=5-14, Group 2: AHI=15-29, Group 3: AHI=

5 Tble 4. Left ventriculr functions by echocrdiogrphy in ptients with obstructive sleep pne syndrome. AHI 5-14/h AHI 15-29/h AHI 30/h P N Left ventriculr ejection frction in two dimensions by 67.4 (7.9) 67.6 (4.9) 66.1 (5.6).514 Simpson s method 55-75% Erly mitrl flow velocity (m/sec) 0.8 (0.1) 0.7 (0.2) 0.7 (0.2).601 Atril mitrl flow velocity (m/sec) 0.7 (0.2) 0.6 (0.2) 0.7 (0.2).481 Rtio of erly nd tril mitrl flow 1.2 (0.3) 1.2 (0.4) 1.0 (0.3).369 velocity >1 Mitrl decelertion time, <220 # (m/sec) (46.5) (54.5) (64.0).965 Isovolumic relxtion time, 75.1 (10.2) (19.7) (19.3).002 <100 # (m/sec) Myocrdil performnce index, 0.5 (0.1) 0.8 (0.2) 0.8 (0.2) (0.05) Dt presented s men (SD). AHI: Apne-hypopne index Norml vlues. Figure 1. Correltion between myocrdil performnce index (MPI) nd pnehypopne index (AHI) in obstructive sleep pne syndrome ptients (r=0.33; P<.05). ported echocrdiogrphic evidence of LVH in 50% of ptients with n AHI >20 per hour compred with 21.4% in those with n AHI <20 per hour. In our study, we found tht moderte nd severe OSA ptients hd LVDD nd lso hd globl dysfunction dignosed with incresed MPI, lthough they hd norml LVEF. In contrst, Lbn et l 31 suggested tht OSA my be direct cuse of dytime LV systolic dysfunction. However, severl cross-sectionl studies 32,33 concordnt with our results hve demonstrted tht the dytime LVEF ws norml in ptients with OSA nd did not significntly differ between ptients with OSA nd control subjects. In theory, the discordnce between our study nd Lbn s study my be becuse of our reltively smll smple size or perhps becuse of high risk of technicl filure of echocrdiogrphy in ptients with severe obesity. We would dvocte for future studies using rdionuclide ngiogrphy or crdic mgnetic resonnce in lrge group of OSA ptients. The mechnisms underlying distolic dysfunction in OSA ptients re not cler; however, elevtions in nocturnl blood pressure nd sympthetic nervous system ctivity 34 in OSA subjects crete ventriculr pressure overlod. 35 It could be speculted tht s it occurs in other processes, such s chronic hypertension nd ortic stenosis, incresed pressure overlod t the cellulr level would minly result in decresed levels of srcoplsmic reticulum clcium denosine triphosphotse pump, nd incresed phospholmbn. 36 This process could slow the removl of clcium from the cytosol, which leds to impired ventriculr relxtion. However, the pressure overlod cuses ctivtion of multiple cellulr signls tht crete myocrdil tissue hypertrophy nd interstitil fibrosis, incresing pssive stiffness. 37 Indeed n impired coronry flow reserve would cuse silent ischemi, worsening ventriculr ctive relxtion when left ventriculr distolic pressure begins to rise. Another plusible mechnism to explin the presence of distolic dysfunction is relted to futile inspirtory efforts. 38 These efforts result in exggerted negtive intrthorcic pressure, which leds to n increse in left ventriculr trnsmurl pressure nd hence fterlod without incresing blood pressure. Another consequence of the incresed negtive intrthorcic pressure is the leftwrd shift of the IVS relted to enhnced venous return nd right ventricle dilttion. All of the forementioned effects of the enhnced negtive intrthorcic pressure hve been demonstrted to ffect left ventriculr filling. 35 It is difficult to define how ech of those mechnisms ffects distolic function in single OSA ptient becuse of their complex interctions. However, in the initil stges of the disese, we hypothesize tht mechnicl effects of obstructive events minly crete ventriculr pressure overlod tht by itself might led to slowed ventriculr relxtion. Our study hs strengths, including its novelty, but we cknowledge number of limittions. We hd 388

6 reltively smll smple size nd thus we were likely underpowered for some of our ssessments prticulrly in subgroup nlyses. We lso relize tht number of covrites re present such tht we re unble to distinguish the effects of severe OSA from those of hypoxemi. Although hypertension is quite prevlent mong those with severe OSA, we would rgue tht hypertension my be on the cusl pthwy from OSA to LVH, such tht it my be inpproprite to control for hypertension or to exclude it. Tht is, if we were to select severe OSA ptients without hypertension, we my be choosing those ptients who re somewht resistnt to OSA consequences. Ultimtely, we cknowledge tht control of BMI nd hypertension in future studies s well s controlled interventionl studies will be required to show the isolted effect of AHI on the mesured prmeters nd to drw rigorous conclusions. However, we believe tht our dt represent n importnt ddition to the published studies bsed on their novelty nd the hypotheses tht we hve generted for subsequent reserch. We believe the MPI my hve utility in subsequent OSA reserch, potentilly s surrogte outcome mesure. In conclusion, we found tht the OSA my result in left ventriculr dysfunction. A strong positive correltion ws observed between MPI nd severity of OSA. The MPI is reproducible, widely pplicble, nd simple noninvsive method for the estimtion of left ventriculr globl function in ptients with OSA. Since the ventriculr function provides prognostic informtion in ptients, the results from this study should be further confirmed with severl longitudinl studies. 389

7 REFERENCES 1. Hwng KO, Hmdh AM, Johnson CW, Thoms EJ, Goodrick GK, Bernstm EV. Screening for obstructive sleep pne on the internet: Rndomized tril. Am J Med 2009;122:961.e Kuniyoshi FH, Puslvidysgr S, Singh P, Somers VK. Crdiovsculr consequences of obstructive sleep pne. Indin J Med Res 2010;131: Vnderveken OM, Boudewyns A, Ni Q, Kshyp B, Verbrecken J, De Bcker W, et l. Crdiovsculr implictions in the tretment of obstructive sleep pne. J Crdiovsc Trnsl Res 2011;4: Drger LF, Gent PR, Pedros RP, Nerbss FB, Gonzg CC, Krieger EM, et l. Chrcteristics nd predictors of obstructive sleep pne in ptients with systemic hypertension. Am J Crdiol 2010;105: Di Gurdo A, Profet G, Crisfulli C, Sidoti G, Zmmtro M, Polini I, et l. Obstructive sleep pne in ptients with obesity nd hypertension. Br J Gen Prct 2010;60: Brdley TD, Flors JS. Obstructive sleep pnoe nd its crdiovsculr consequences. Lncet 2009;373: Somers VK, White DP, Amin R, Abrhm WT, Cost F, Culebrs A, et l. Sleep pne nd crdiovsculr disese: An Americn Hert Assocition/ Americn College of Crdiology Foundtion Scientific Sttement from the Americn Hert Assocition Council for High Blood Pressure Reserch Professionl Eduction Committee, Council On Clinicl Crdiology, Stroke Council, nd Council on Crdiovsculr Nursing in collbortion with the Ntionl Hert, Lung, nd Blood Institute Ntionl Center on Sleep Disorders Reserch (Ntionl Institutes of Helth). Circultion 2008;118: Leuenberger U, Jcob E, Sweer L, Wrvdekr N, Zwillich C, Sinowy L. Surges of muscle sympthetic nerve ctivity during obstructive pne re linked to hypoxemi. J Appl Physiol 1995;79: Nrkiewicz K, Somers VK. The sympthetic nervous system nd obstructive sleep pne: Implictions for hypertension. J Hypertens 1997;15: Arnrdottir ES, Mckiewicz M, Gislson T, Teff KL, Pck AI. Moleculr signtures of obstructive sleep pne in dults: A review nd perspective. Sleep 2009;32: Shmsuzzmn AS, Winnicki M, Lnfrnchi P, Wolk R, Kr T, Accurso V, et l. Elevted C- rective protein in ptients with obstructive sleep pne. Circultion 2002;105: Von Knel R, Loredo JS, Ancoli-Isrel S, Mills PJ, Ntrjn L, Dimsdle JE. Assocition between polysomnogrphic mesures of disrupted sleep nd prothrombotic fctors. Chest 2007;131: Nieto FJ, Herrington DM, Redline S, Benjmin EJ, Robbins JA. Sleep pne nd mrkers of vsculr endothelil function in lrge community smple of older dults. Am J Respir Crit Cre Med 2004;169: Romn MJ, Gnu A, Sb PS, Pini R, Pickering TG, Devereux RB. Impct of rteril stiffening on left ventriculr structure. Hypertension 2000;36: Dursunoglu D, Dursunoglu N, Evrengül H, Ozkurt S, Kuru O, Kiliç M, et l. Impct of obstructive sleep pne on left ventriculr mss nd globl function. Eur Respir J 2005;26: Bonow RO, Udelson JE. Left ventriculr distolic dysfunction s cuse of congestive hert filure. Mechnisms nd mngement. Ann Intern Med 1992;117: Fischer M, Bessler A, Hense HW, Hengstenberg C, Muscholl M, Holmer S, et l. Prevlence of left ventriculr distolic dysfunction in the community. Results from Doppler echocrdiogrphic-bsed survey of popultion smple. Eur Hert J 2003;24: Arnlov J, Ingelsson E, Riserus U, Andren B, Lind L. Myocrdil performnce index, Dopplerderived index of globl left ventriculr function, predicts congestive hert filure in elderly men. Eur Hert J 2004;25: Tei C, Nishimur RA, Sewrd JB, Tjik AJ. Noninvsive Doppler-derived myocrdil performnce index: correltion with simultneous mesurements of crdic ctheteriztion mesurements. J Am Soc Echocrdiogr 1997;10: Johns MW. A new method for mesuring dytime sleepiness: The Epworth sleepiness scle. Sleep 1991;14: Mnci G, De Bcker G, Dominiczk A, Cifkov R, Fgrd R, Germno G, et l. Guidelines for the Mngement of Arteril Hypertension: The Tsk Force for the Mngement of Arteril Hypertension of the Europen Society of Hypertension (ESH) nd of the Europen Society of Crdiology (ESC). J Hypertens 2007;25: Rechtschffen A, Kles A. A mnul of stndrdized terminology, techniques nd scoring system for sleep stges of humn subjects. Wshington DC: Public Helth Service, U.S. Government Printing Office; Sleep-relted brething disorders in dults: Recommendtions for syndrome definition nd mesurement techniques in clinicl reserch. The Report of n Americn Acdemy of Sleep Medicine Tsk Force. Sleep 1999;22: Schiller NB, Shh PM, Crwford M, DeMri A, Devereux R, Feigenbum H, et l. Recommendtions for quntittion of the left ventricle by twodimensionl echocrdiogrphy. Americn Society of Echocrdiogrphy Committee on Stndrds. Subcommittee on Quntittion of Two-Dimensionl Echocrdiogrms. J Am Soc Echocrdiogr 1989;2: Tei C, Ling LH, Hodge DO, Biley KR, Oh JK, Rodeheffer RJ, et l. New index of combined systolic nd distolic myocrdil performnce: A simple nd reproducible mesure of crdic function study in normls nd dilted crdiomyopthy. J Crdiol 1995;26: Hedner J, Grote L. The link between sleep pne nd crdiovsculr disese: Time to trget the nonsleepy sleep pneics? Am J Respir Crit Cre Med 2001;163: Leung RS, Brdley TD. Sleep pne nd crdiovsculr disese. Am J Respir Crit Cre Med 2001;164: Lvie P, Herer P, Hoffstein V. Obstructive sleep pne syndrome s risk fctor for hypertension: Popultion study. BMJ 2000;320: Pepprd PE, Young T, Plt M, Sktrud J. Prospective study of the ssocition between sleepdisordered brething nd hypertension. N Engl J Med 2000;342: Nod A, Okd T, Ysum F, Nkshim N, Yokot M. Crdic hypertrophy in obstructive sleep pne syndrome. Chest 1995;107: Lbn JP, Pscl-Seboun S, Bloch E, Orvoën-Frij E, Oppert JM, Huchon G. Left ventriculr systolic dysfunction in ptients with obstructive sleep pne syndrome. Chest 2002;122: Alchntis M, Prdellis G, Pini H, Tourkohoriti G, Jordnoglou J. Left ventriculr function in ptients with obstructive sleep pnoe syndrome before nd fter tretment with nsl continuous positive irwy pressure. Respirtion 2000;67: Lbn JP, Cssuto D, Orvoën-Frij E, Iliou MC, Mundler O, Léger D, et l. Crdiorespirtory consequences of sleep pnoe syndrome in ptients with mssive obesity. Eur Respir J 1998;11: Somers VK, Dyken ME, Clry MP, Abboud FM. Sympthetic neurl mechnisms in obstructive sleep pne. J Clin Invest 1995;96: Brdley TD, Hll MJ, Ando S, Flors JS. Hemodynmic effects of simulted obstructive pnes in humns with nd without hert filure. Chest 2001;119: Ari M, Alpert NR, McLennn DH, Brton P, Perismy M. Altertions in srcoplsmic reticulum gene expression in humn hert filure. A possible mechnism for ltertions in systolic nd distolic properties of the filing myocrdium. Circ Res 1993;72: Gsch WH, Blustein AS, Andris CW, Donhue RP, Avitll B. Myocrdil relxtion. II. Hemodynmic determinnts of rte of left ventriculr isovolumic pressure decline. Am J Physiol 1980;239: Lorell BH, Crbello BA. Left ventriculr hypertrophy: Pthogenesis, detection nd prognosis. Circultion 2000;102: