수면무호흡증과심혈관계질환 신진호 http://dx.doi.org/10.7599/hmr.2013.33.4.221 pissn 1738-429X eissn 2234-4446 한양대학교의과대학내과학교실 Sleep Apnea Syndrome and the Cardiovascular Diseases Jinho Shin Division of Cardiology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea Sleep apnea syndrome (SAS) has known to be associated with obesity, hypoxemia, sympathetic activation, and hypertension. In addition, SAS is associated with various mechanisms involved in cardiovascular diseases, such as oxidative stress, dyslipidemia, smoking, and psychological stress. In recent prospective observation studies, SAS is known to be a risk factor for cardiovascular diseases, i.e., heart failure, stroke, and coronary artery diseases. The association with heart failure was most evident. In some participants in the longitudinal study applied with continuous positive airway pressure (CPAP) treatment, SAS was not associated with prognosis. With the viewpoints in the current standard of cardiovascular medicine, there seems to be few evidence showing that CPAP treatment could prevent or improve cardiovascular outcome. Detailed review of the limitations of the prospective observational studies suggests that more sophisticated measurement of the clinical outcomes and adjustment of confounding factors will be required in the future studies. And for the clinical application, more evidence of CPAP treatment on the cardiovascular outcomes are mandatory. Key Words: Sleep Apnea Syndromes; Myocardial Infarction; Stroke; Heart Failure; Hypertension Correspondence to: Jinho Shin 우 133-792, 서울시성동구왕십리로 222, 한양대학교병원내과 Department of Internal Medicine, Hanyang University Hospital, 222 Wangsimni-ro, Sungdong-gu, Seoul 133-792, Korea Tel: +82-2-2290-8308 Fax: +82-2-2299-0278 E-mail: jhs2003@hanyang.ac.kr Received 25 August 2013 Revised 16 October 2013 Accepted 24 October 2013 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 서론서기 330년에 Claudius Aelianusensu가저술한 Miscelanea Historica라는서적에서 Pontus의왕 Heraclea Dionysius 는비만하고목에서막힌소리가나며숨쉬기가힘들어서질식하지못하게바늘로찔러서잠을깨워야했다는기술이있다고한다. 1877년에 W. H. Broadbent가처음으로수면무호흡증에대해 Lancet 잡지에보고하였으며 1898 년 Walter A. Wells가상기도협착과수면의관련성에대해서보고하였다. 1956년에 Sidney Burwell이처음으로 The syndrome of Pickwick 를기술하였으며 60년대는수면다원검사 (polysomnography) 가개발되면서수면무호흡증 (sleep apnea syndrome, SAS) 의정의가확립되었고비만이 SAS의필수조건이아니라는점이밝혀졌다. 1970년대에는 Stanford 대학에수면클리닉이 처음으로개설되었다 [1]. 그후 10년간협착부위가후두부가아니라인두부라는점이밝혀졌고 [2], 이에따라 1980년대에는지속적기도양압 (continuous positive airway pressure, CPAP) 치료의효과가입증되었다. 심혈관계질환에대한연구는 2000년대에들어서미네소타대학의 Young 등이수면무호흡증과고혈압과의상관성을보고하면서본격적으로시작되었고최근들어심혈관계질환및심혈관계사망에관한연구로확대되고있다. 총사망률의증가에대해서는널리알려져있으나심혈관계사망률이나심혈관계질환의발생률에대한연구결과에대해서는주의깊은해석이필요하다. 또한수면무호흡증에대한치료효과에대한임상의의관점에서평가가필요한시점이다. 본논문에서는현재까지진행된수면무호흡증관련연구결과중에서심혈관계질환과관련된성과에대해서고찰하고향후발전방향에대해서고찰하고자한다. http://www.e-hmr.org 2013 Hanyang University College of Medicine 221
Jinho Shin Sleep Apnea Syndrome and the Cardiovascular Diseases 본론 1. 수면무호흡증과심혈관계질환에대한연관성의이론적근거 1) 흉강내압변화수면무호흡증상태에서는좌심실의후부하가증가되며 [3], 여성에서 B-type natriuretic peptide (BNP) 의증가와관련되어있다고보고된바있다 [4]. 또한흉강내압이좌심방의용적의급격한변화와관련되어있음이보고되었으며이러한좌심방의변화가심방세동과가설적으로연관될수있다 [5]. 수있다는보고도있다 [14]. 그러나이상에서언급한결과를종합하여유럽고혈압학회및관련학회의 position paper에서는아직도고혈압과 SAS 간의연관관계에는혼란변수가충분히보정되었는지에대해논란이있다고결론지었으며저항성고혈압이나야간혈압이상승하는일부환자에서만 CPAP 치료의의미를부여하였다 [15]. 그중에서야간고혈압에대한치료는아직일반적인치료에포함되지않으므로비록고혈압환자에서 SAS가동반되어있다고하더라도심한저항성고혈압환자가아니라면아직까지고혈압을치료할목적으로 CPAP을권고하는것은이득이없다고본다. 2) 고혈압대규모의단면적연구에서설문조사에의한 SAS와고혈압이연관되어있음이보고되었고 [6], 전향적관찰연구에서혼란변수를보정한후에도고혈압과수면무호흡증이관련되어있음을보고하였다 [7]. 비만과관련하여고혈압에대한 CPAP의치료효과는대사증후군을동반한환자에서보고된바있다 [8]. 그러나비만을보정한연구에서는 CPAP의강압효과가미미하였으며하루 5-6시간이상 CPAP을사용한환자에서수축기혈압 1.89 mmhg만이감소되는다소실망스러운결과도보고되었다 [9]. 심방세동은고혈압, 비만과밀접한관련성이있는부정맥이며뇌졸중의중요한위험인자이다. 그런데수면무호흡증은고혈압비만과관련될뿐만아니라교감신경계항진에따른전기생리학적교란작용에의해심방세동의중요한관련인자로알려져있다 [10]. 무작위임상연구로서 23명의 SAS를동반한고혈압환자에서항고혈압약제인 valsartan과 CPAP의비교를위한교차연구에서 CPAP의 24시간평균혈압에대한강압효과는 2.1 mmhg에불과하였다. 이는 9.1 mmhg의 valsartan의강압효과와대조되는결과로서위약효과를배제하기어려운수준이라할수있다 [11]. 수면무호흡증환자에서고혈압에대한치료효과는저항성고혈압환자에서만 5.6 mmhg를낮추는효과가있었고조절이잘되는고혈압환자에서는효과가없었다는소규모연구결과가있다 [12]. 고혈압의치료약물의임상시험은표준적인임상시험중에서도특히위약효과에영향을많이받는특성이있는데 CPAP의고혈압치료적용에있어서는위약대조군임상시험을진행하는데제한점이있기때문에그효과를과학적으로입증하기어렵다. 고혈압의치료효과에서위약대조군의의의를명확히이해하지못하면자칫 CPAP의효과를과대평가하기쉽다. 실제인체연구에서 CPAP을이용하여위약대조시험을시행한연구가있었는데이연구에서는 subtherapeutic CPAP 을위약대조군으로간주하여항고혈압약제로치료중인환자에서고혈압에대한효과를시험하였다 [13]. 그결과 CPAP의강압효과를입증하지못하였다. 인체의고혈압과는별도로심한 SAS가동반된전단계고혈압이나가면고혈압환자에게 CPAP 치료를시행함으로써고혈압으로진행하는것을예방할 3) 혈압변동성혈압변동성이심혈관계질환에관련되어있을것이라는가설이최근에크게대두되었다. 즉, 혈압변동성과수면무호흡증이연관되어있다는보고가있었으며 [16], 혈압변동성의주요한원인으로지목되고있는혈관경직도에수면무호흡증이관련되어있다는보고가있다 [17]. 4) 야간혈압야간의혈압의높이가심혈관계질환발생과밀접한관련이있다는주장은널리알려져있으며 Young 등의전향적연구에서도고혈압뿐만아니라야간혈압에 SAS가주요한영향을미친다고보고하였다 [18]. 야간혈압에수면장애가미치는영향에대해서는많은가설이있으나메타분석에서 CPAP의효과는정작주간과야간에차이가없다고보고하였다 [19]. 5) 당내인성및비만비만과 SAS의연관성은역사적으로매우밀접한관계가있지만관점에있어서몇번의변화가있었다. 초기의 SAS는전신적인비만과직결되어있다고생각되었으나그이후국소적문제가직접적으로 SAS의원인이된다는점이밝혀졌다 [2]. 그러나당시에는국소적비만의개념이뚜렷하지않아서소위내장비만 (visceral obesity) 과목둘레 (neck circumference) 의관련성은비교적최근에들어서밝혀지게되었다 [20]. 특히인슐린저항성이다양한경로를통해 SAS 를유발할수있다고알려져있으며이러한비만과 SAS 간에양방향상호작용으로인해심혈관계질환을유발할수있다 [21]. 6) 산화스트레스 (oxidative stress) 산화스트레스는비만과 SAS에동시에작용하는매우중요한인자이며 [22], 적어도산화스트레스에대한 CPAP의효과는지속적으로보고되고있다 [23]. 그러나이러한효과가임상적효과로연결될수있을지는아직확신할수없다 [24]. 앤지오텐신 (angiotensin) II는산화스트레스와밀접한관련이있고혈압의높이나변동성과도관련이있어서심혈관계질환의가장중요한인자로인정받고있 222 http://www.e-hmr.org
신진호 수면무호흡증과심혈관계질환 는데 CPAP 또는외과적치료로서 SAS에서호전시킬수있다는보고가있다 [25]. SAS 동물실험모델에서 NADPH oxidase (NOX) 의활성에대한연구가다수보고되어있어서산화스트레스의가설을뒷받침해주고있다. G 단백결합수용체관련신호전달체계에서 angiotensin II가 NADPH oxdase 를매개로 endothelia nitric oxide synthase (enos) 와의 crosstalk를통해산화스트레스조절에관여하는기전은잘알려져있다. 그러나 G 단백결합수용체를경유하는자극과노르에피네프린 (norepinephrine) 수용체자극신호가공통으로경유하고 enos에의해억제되기도하는 rho kinase계의연관성에대해서는아직보고된바가없다. SAS는노르에피네프린, interleukin-6 (IL-6), C-reactive protein (CRP) 등과같은심혈관계에해로운인자와관련되어있다고보고되었다 [21,26]. 7) 고지혈증수면무호흡증환자에서 LDL/HDL 콜레스테롤 (cholesterol) 비율이증가되어있다는보고가있고 [27], CPAP 치료가 LDL 콜레스테롤을낮춘다는보고가있으나 [27], 산화스트레스가 LDL 콜레스테롤에미치는영향과심혈관계질환의관련성을고려해볼때 SAS 와 LDL 콜레스테롤과의관련성에대한연구는드물다고할수있다. 8) 흡연흡연은칼시토닌유전자관련펩티드 (calcitonin gene-related peptide, CGRP) 의활성도를증가시켜인두부협착및 SAS를악화시키는것으로국내연구자에의해보고된바있다 [28]. SAS에서흡연의빈도가높아서심혈관계질환에대한상호작용이있다고알려져있으며 [29], 금연을성공하는데 SAS를조절하는것이도움이된다는보고도있어서 SAS가니코틴중독에영향을줄수있다는가설이있다 [30,31]. 9) 신체활동 (physical activity) 신체활동의감소는그자체가심혈관계질환의주요한위험인자로알려져있다. 또한신체활동은잠재적으로 SAS의개선에관여할수있는요인으로서연구주제로관심을받고있다. 아직은예비적인연구단계에있으나향후연구결과가주목된다 [32]. 10) 정신적스트레스외상후스트레스장애 (posttraumatic stress disorder, PTSD) 가 SAS에관련되어있으며 SAS의치료에있어서 CPAP 치료와선행하여치료함으로써 CPAP 치료에대한충실도 (adherence) 를재고할필요가있음을보고하고있다 [33]. 또한정신적스트레스가심혈관계질환의혼란변수로작용할수있다는보고도있다 [34]. 이상에서본바와같이수면무호흡증은다양한심혈관계위험요인과관련되어있다. 그러나위에서언급된위험인자는수면무호흡 증과의관련성이밝혀지기이전부터심혈관계질환의주요한위험인자로알려져있다. 따라서심혈관계질환과의독립적인관련성을판정하기위해서는반드시이러한기존의심혈관계위험인자에대한충분한통계학적보정이전제되어야한다. 2. 수면무호흡증과심혈관계질환의연관성에대한단면적연구심혈관계질환을갖고있는 1,023명을대상으로한 Shahar 등의연구 (sleep heart study) 에따르면무호흡-저호흡지수 (apnea hypopnea index, AHI) 를기준으로 4분위군을정의하였을때심혈관계질환의유병률이 1사분위군에비해 3사분위군의위험도가 1.28 (1.02-1.61), 4사분위군의위험도가 1.42 (1.13-1.78) 로유의하게높았다. 또한 4사분위군은심부전의위험도 2.38 (1.22-4.62), 뇌졸중의위험도 1.58 (1.02-2.46), 관상동맥질환의위험도 1.27 (0.99-1.62) 로서심혈관계질환에대한관련성은중증수면무호흡증과심부전에서나타남을알수가있다 [35]. 심초음파를이용한심부전연구로는 SAS 환자는좌심실확장기능이약화되어있다는보고가있기도하지만 [36], 비만이심부전의주용한원인이라는점을고려해볼때활동시호흡곤란을기본으로하는심부전의임상증상이비만에의해서도나타날수있음을충분히감안해야한다. Shahar 등의연구는심뇌혈관질환이환자의설문에의존하여정의되었고항고혈압약제의효과에대해서충분히고려하지못하였으므로그결과를해석하는데있어서주의가필요하다. 3. 수면무호흡증과심혈관계질환의전향적연구결과 1) 관찰적연구 65세이상의 SAS의심환자 939명에대해평균 6년여기간을추적관찰한 Marin 등의연구에의하면심혈관계질환의위험도가 2.25 였으며, CPAP 치료군에서는위험도가통계적으로의미가없었다는점을강조함으로써 CPAP의효과를간접적으로주장하였다 [37]. 1,522명에대해 18년간관찰하였고혼란변수를철저히보정한 Young 등의연구에서도심혈관질환의위험도가증가함을보고하였으나생존커브의모양이 10년이전에는차이가없다가 10년이지나면서급격히차이를보이고있으며중증에서만의미있는변화를보였다 [38]. SAS의심환자 1,436명에대한평균 2.9년간관찰결과비만과고혈압의영향을보정한 Shah 등의연구에따르면심혈관계질환의 composite outcome에만영향을주었다 [39]. 결과변수에경피적중재시술또는관상동맥우회로수술여부가포함되어있어서미국적의료환경의사회경제적요인이충분히고려되지않았을가능성이있다. 6,441명에대해총 8년간관찰한 Sleep Heart Health Study (SHHS) 결과중증의남성 (40-70 세 ) 에서만관상동맥질환에대해 1.69 (95% CI: 1.13-2.52) 의위험도가있음을보고하였다. 그러나혼란변수에 http://www.e-hmr.org 223
Jinho Shin Sleep Apnea Syndrome and the Cardiovascular Diseases 콜레스테롤이포함되지않았고같은연구자에의한다른논문에서는심부전발병과관련이있으나관상동맥질환에대해서는논란이있다고보고하였다 [40]. 또다른같은연구진에의한논문에서는남성에서만 4사분위군의뇌졸중위험율이 2.86 (1.1-7.4) 이라고보고하였다 [41]. 이들연구역시뇌졸중을환자설문에의해정의하고있다는점을주목하여야한다. 그밖에도 5,338명을대상으로한 Multi Ethnic Study of Atherosclerosis (MESA) cohort 에서는의사에의해진단된 208명의수면무호흡증환자가 7.5 년간심혈관계사건발생률이 2.16 (1.30-3.58) 로높았다. 그러나수면무호흡증의진단기준이모호하고대상자수가적었다 [42]. 반면 Johansson 등은 331명의 75세이상의고령환자에서 B-type natriuretic peptide (BNP) 를측정하여진단된심부전환자에서 SAS 와사망률은관련성이없다고보고하였다 [43]. 또한 Mehra 등은 104명의급성심근경색증환자에대한관찰연구결과 AHI 30 이상의중증수면무호흡증은 26.0% 였고 72.1% 가폐쇄성이었으나 6개월간의임상경과는수면무호흡증과무관하다고하였다 [44]. 이상에서살펴보았듯이 SAS와심혈관계질환의관련성에있어서일부관련성이있다는연구결과가있기는하지만그러한연구의데이터의신빙성이나심혈관계질환에대한진단상의문제점과이를뒷받침하는보다객관적인지표에의한추가적인입증이이루어져야할필요성이있음을알수있다. 2) 중재적연구 Young 등은전체연구대상의 10% 미만의대상자에서 CPAP이시행된연구에서 CPAP을시행하지않았던환자에서만심혈관계사망률이높다는점을들어서간접적으로 CPAP의효과를시사하였으나이는직접적인증거로서는미흡한결론이다 [38]. SAS의심여성 1,116명을대상으로 72개월간추적관찰한 Campos-Rodriguez 등의연구결과, 중증이면서 CPAP 치료를받지않은여성의사망위험률이 3.5 (1.23-9.98) 로높았음을보고함으로써간접적으로 CPAP의보호효과를주장하고자하였다 [45]. 65세이상의 SAS 의심고령환자 989명을약 6년동안추적관찰한 Martinez-G 등도중증 SAS에서만심혈관계사망위험률이 2.25 였으나 CPAP 치료군에서는위험률이통계적의미가없었다고보고하였다 [46]. 또한 223명의뇌졸중환자에서 166명을대상으로 sleep study를시행하여 CPAP을적용한연구를통해 CPAP을잘시행하지못하는중증도의 AHI 환자의사망위험도가 CPAP을잘시행한환자에비해서 2.69 (1.32-5.61) 로높다고보고하였으나아쉽게도비교군간의 AHI의중증도는보정되지못했다 [47]. 재발성심근경색에대해서도소규모연구에서 CPAP 치료를잘견디지못하는환자의예후가좋지않다는보고가있다 [48]. 현재까지의전향적연구결과에서핵심적인질환은수면무호흡 증과가장밀접한관련성을보여주고있는심부전이라할수있다. 뇌졸중과관상동맥질환에비해심부전에대한수면무호흡증의예 측효과는상대적으로뛰어난것으로보고되기때문이다. 그러나 일반적으로심부전은매우복잡한질환으로서임상연구가매우까 다롭다. 비만은비록통계적으로보정된다고하더라도다양한국소 적비만이중추신경계와연결되어있고호흡곤란증상이나피로감 을흔히호소하기때문에그결과를신뢰하기어렵다. 적어도최근 에심부전진료에적용되고있는 BNP 수치에대한효과가입증되 어야하며대규모의전향적인연구결과가제시되지않는한그효 과에대한임상적판단은유보하여야할것이다 [43,49]. 또한최근각종기구를이용한고혈압조절효과에대한연구결 과의해석과마찬가지로 CPAP 과같은기기를이용한치료는무작 위배정에있어서어려움이있고맹검이불가능하며그순응도를 통제하기가매우어렵기때문에현시점에서임상적증거를주장하 기에는다소부족하다고사료된다. 결론 지금까지의 SAS 의심혈관계질환에대한관련성여부를살펴보 았다. 단면적연구결과와역학적연구결과에서비교적다수의상 관관계를주장하는연구결과가있음에도불구하고전향적연구에 서는 CPAP 의효과가입증되지못했음을알수있다. 이는치료에 의해심혈관계질환의발병률및사망률이현저히개선된연구결 과를보여준비만수술의연구결과와대조를이룬다 [50]. 동물시험 이나단면적연구에서의미가있었던많은가설들이전향적임상 연구에서입증되지못하는경우는허다하다. 따라서 SAS 및 CPAP 치료가심혈관계질환의임상진료에도입되기위해서는반드시향 후전향적인임상연구결과에의해 CPAP 치료의효과가입증되어 야하며지금까지연구결과를볼때전향적연구가임박한시점이 라할수있다. REFERENCES 1. Lavie P. Nothing new under the moon. Historical accounts of sleep apnea syndrome. Arch Intern Med 1984;144:2025-8. 2. Remmers JE, de Groot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44:931-8. 3. Tkacova R, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 1998;98:2269-75. 4. Ljunggren M, Lindahl B, Theorell-Haglow J, Lindberg E. Association between obstructive sleep apnea and elevated levels of type B natriuretic peptide in a community-based sample of women. Sleep 2012;35:1521-7. 5. Orban M, Bruce CJ, Pressman GS, Leinveber P, Romero-Corral A, Korinek J, et al. Dynamic changes of left ventricular performance and left atrial volume induced by the mueller maneuver in healthy young adults 224 http://www.e-hmr.org
신진호 수면무호흡증과심혈관계질환 and implications for obstructive sleep apnea, atrial fibrillation, and heart failure. Am J Cardiol 2008;102:1557-61. 6. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Leiby BE, Vela-Bueno A, et al. Association of hypertension and sleep-disordered breathing. Arch Intern Med 2000;160:2289-95. 7. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-84. 8. Sharma SK, Agrawal S, Damodaran D, Sreenivas V, Kadhiravan T, Lakshmy R, et al. CPAP for the metabolic syndrome in patients with obstructive sleep apnea. N Engl J Med 2011;365:2277-86. 9. Barbe F, Duran-Cantolla J, Capote F, de la Pena M, Chiner E, Masa JF, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;181:718-26. 10. Goyal SK, Sharma A. Atrial fibrillation in obstructive sleep apnea. World J Cardiol 2013;5:157-63. 11. Pepin JL, Tamisier R, Barone-Rochette G, Launois SH, Levy P, Baguet JP. Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010; 182:954-60. 12. Dernaika TA, Kinasewitz GT, Tawk MM. Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. J Clin Sleep Med 2009;5:103-7. 13. Campos-Rodriguez F, Grilo-Reina A, Perez-Ronchel J, Merino-Sanchez M, Gonzalez-Benitez MA, Beltran-Robles M, et al. Effect of continuous positive airway pressure on ambulatory BP in patients with sleep apnea and hypertension: a placebo-controlled trial. Chest 2006;129:1459-67. 14. Drager LF, Pedrosa RP, Diniz PM, Diegues-Silva L, Marcondes B, Couto RB, et al. The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea. Hypertension 2011;57:549-55. 15. Parati G, Lombardi C, Hedner J, Bonsignore MR, Grote L, Tkacova R, et al. Position paper on the management of patients with obstructive sleep apnea and hypertension: joint recommendations by the European Society of Hypertension, by the European Respiratory Society and by the members of European COST (COoperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea. J Hypertens 2012;30: 633-46. 16. Kallianos A, Trakada G, Papaioannou T, Nikolopouloss I, Mitrakou A, Manios E, et al. Glucose and arterial blood pressure variability in obstructive sleep apnea syndrome. Eur Rev Med Pharmacol Sci 2013;17:1932-7. 17. Drager LF, Lorenzi-Filho G. Is CPAP preventing the long-term progression of arterial stiffness in patients with obstructive sleep apnea? Hypertens Res 2010;33:788-9. 18. Hla KM, Young T, Finn L, Peppard PE, Szklo-Coxe M, Stubbs M. Longitudinal association of sleep-disordered breathing and nondipping of nocturnal blood pressure in the Wisconsin Sleep Cohort Study. Sleep 2008; 31:795-800. 19. Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50:417-23. 20. Davies RJ, Stradling JR. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J 1990;3:509-14. 21. Vgontzas AN. Does obesity play a major role in the pathogenesis of sleep apnoea and its associated manifestations via inflammation, visceral adiposity, and insulin resistance? Arch Physiol Biochem 2008;114:211-23. 22. Volna J, Kemlink D, Kalousova M, Vavrova J, Majerova V, Mestek O, et al. Biochemical oxidative stress-related markers in patients with obstructive sleep apnea. Med Sci Monit 2011;17:Cr491-7. 23. de Lima AM, Franco CM, de Castro CM, Bezerra Ade A, Ataide L Jr., Halpern A. Effects of nasal continuous positive airway pressure treatment on oxidative stress and adiponectin levels in obese patients with obstructive sleep apnea. Respiration 2010;79:370-6. 24. Simiakakis M, Kapsimalis F, Chaligiannis E, Loukides S, Sitaras N, Alchanatis M. Lack of effect of sleep apnea on oxidative stress in obstructive sleep apnea syndrome (OSAS) patients. PLoS One 2012;7:e39172. 25. Wang HL, Wang Y, Zhang Y, Chen YD, Wang XC, Liu ZX, et al. Changes in plasma angiotensin II and circadian rhythm of blood pressure in hypertensive patients with sleep apnea syndrome before and after treatment. Chin Med Sci J 2011;26:9-13. 26. Carneiro G, Togeiro SM, Ribeiro-Filho FF, Truksinas E, Ribeiro AB, Zanella MT, et al. Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance. Metab Syndr Relat Disord 2009; 7:537-42. 27. Kawano Y, Tamura A, Kadota J. Association between the severity of obstructive sleep apnea and the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol. Metabolism 2012;61:186-92. 28. Kim KS, Kim JH, Park SY, Won HR, Lee HJ, Yang HS, et al. Smoking induces oropharyngeal narrowing and increases the severity of obstructive sleep apnea syndrome. J Clin Sleep Med 2012;8:367-74. 29. Lavie L, Lavie P. Smoking interacts with sleep apnea to increase cardiovascular risk. Sleep Med 2008;9:247-53. 30. Lin YN, Li QY, Zhang XJ. Interaction between smoking and obstructive sleep apnea: not just participants. Chin Med J (Engl) 2012;125:3150-6. 31. Trenchea M, Deleanu O, Suta M, Arghir OC. Smoking, snoring and obstructive sleep apnea. Pneumologia 2013;62:52-5. 32. Tuomilehto H, Gylling H, Peltonen M, Martikainen T, Sahlman J, Kokkarinen J, et al. Sustained improvement in mild obstructive sleep apnea after a diet- and physical activity-based lifestyle intervention: postinterventional follow-up. Am J Clin Nutr 2010;92:688-96. 33. Collen JF, Lettieri CJ, Hoffman M. The impact of posttraumatic stress disorder on CPAP adherence in patients with obstructive sleep apnea. J Clin Sleep Med 2012;8:667-72. 34. Azevedo Da Silva M, Singh-Manoux A, Shipley MJ, Vahtera J, Brunner EJ, Ferrie JE, et al. Sleep duration and sleep disturbances partly explain the association between depressive symptoms and cardiovascular mortality: the Whitehall II cohort study. J Sleep Res 2013. 35. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163:19-25. 36. Wachter R, Luthje L, Klemmstein D, Luers C, Stahrenberg R, Edelmann F, et al. Impact of obstructive sleep apnoea on diastolic function. Eur Respir J 2013;41:376-83. 37. Marin JM, Carrizo SJ, Vicente E, Agusti AG. 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;365:1046-53. 38. Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Nieto FJ, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-8. 39. Shah NA, Yaggi HK, Concato J, Mohsenin V. Obstructive sleep apnea as a risk factor for coronary events or cardiovascular death. Sleep Breath 2010;14:131-6. 40. Gottlieb DJ, Yenokyan G, Newman AB, O Connor GT, Punjabi NM, Quan http://www.e-hmr.org 225
Jinho Shin Sleep Apnea Syndrome and the Cardiovascular Diseases SF, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352-60. 41. Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O Connor GT, Resnick HE, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010;182:269-77. 42. Yeboah J, Redline S, Johnson C, Tracy R, Ouyang P, Blumenthal RS, et al. Association between sleep apnea, snoring, incident cardiovascular events and all-cause mortality in an adult population: MESA. Atherosclerosis 2011;219:963-8. 43. Johansson P, Alehagen U, Ulander M, Svanborg E, Dahlstrom U, Brostrom A. Sleep disordered breathing in community dwelling elderly: associations with cardiovascular disease, impaired systolic function, and mortality after a six-year follow-up. Sleep Med 2011;12:748-53. 44. Mehra R, Principe-Rodriguez K, Kirchner HL, Strohl KP. Sleep apnea in acute coronary syndrome: high prevalence but low impact on 6-month outcome. Sleep Med 2006;7:521-8. 45. Campos-Rodriguez F, Martinez-Garcia MA, de la Cruz-Moron I, Almeida- Gonzalez C, Catalan-Serra P, Montserrat JM. Cardiovascular mortality in women with obstructive sleep apnea with or without continuous positive airway pressure treatment: a cohort study. Ann Intern Med 2012;156:115-22. 46. Martinez-Garcia MA, Campos-Rodriguez F, Catalan-Serra P, Soler-Cataluna JJ, Almeida-Gonzalez C, De la Cruz Moron I, et al. Cardiovascular mortality in obstructive sleep apnea in the elderly: role of long-term continuous positive airway pressure treatment: a prospective observational study. Am J Respir Crit Care Med 2012;186:909-16. 47. Martinez-Garcia MA, Soler-Cataluna JJ, Ejarque-Martinez L, Soriano Y, Roman-Sanchez P, Illa FB, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5-year follow-up study. Am J Respir Crit Care Med 2009; 180:36-41. 48. Garcia-Rio F, Alonso-Fernandez A, Armada E, Mediano O, Lores V, Rojo B, et al. CPAP effect on recurrent episodes in patients with sleep apnea and myocardial infarction. Int J Cardiol 2013;168:1328-35. 49. Kasai T, Bradley TD. Obstructive sleep apnea and heart failure: pathophysiologic and therapeutic implications. J Am Coll Cardiol 2011;57:119-27. 50. Sjostrom L, Peltonen M, Jacobson P, Sjostrom CD, Karason K, Wedel H, et al. Bariatric surgery and long-term cardiovascular events. Jama 2012; 307:56-65. 226 http://www.e-hmr.org