abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC São Paulo, SP, Brazil 7vgBDhxSRF8RgtcBktgHqfR 00001 S0066-782X2006000600001 S0066-782X(06)08600601 10.1590/S0066-782X2006000600001 Atualização Alterações cardiovasculares na síndrome da apnéia obstrutiva do sono Cintra Fátima Dumas Poyares Dalva Guilleminault Christian Carvalho Antonio Carlos Tufik Sergio Paola Angelo A. V. de São Paulo Universidade Federal de São Paulo Brazil Stanford University 06 2006 86 6 399 407 08 12 2005 28 12 2005 This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

A síndrome da apnéia obstrutiva do sono (SAHOS) é uma condição prevalente na população, associada a maior risco cardiovascular, freqüentemente não-diagnosticada. O reconhecimento da síndrome requer alto grau de suspeita clínica, especialmente por cardiologistas, e pode ser confirmada por meio da polissonografia. O tratamento da síndrome com o uso de CPAP (pressão positiva na via aérea superior) é altamente eficaz, melhorando o padrão respiratório durante o sono, instituindo o sono reparador e, dessa forma, otimizando a qualidade de vida desses pacientes, além de atenuar ou reverter muitas das complicações cardiovasculares relacionadas a SAHOS. Este artigo aborda a fisiopatologia e os aspectos clínicos das comorbidades cardiovasculares associadas à síndrome.

 26 06 2006

ATUALIZAÇÃO

Alterações cardiovasculares na síndrome da apnéia obstrutiva do sono

Fátima Dumas Cintra; Dalva Poyares; Christian Guilleminault; Antonio Carlos Carvalho; Sergio Tufik; Angelo A. V. de Paola

Universidade Federal de São Paulo e Stanford University - São Paulo, SP - Stanford, CA , USA

Correspondência

RESUMO

A síndrome da apnéia obstrutiva do sono (SAHOS) é uma condição prevalente na população, associada a maior risco cardiovascular, freqüentemente não-diagnosticada. O reconhecimento da síndrome requer alto grau de suspeita clínica, especialmente por cardiologistas, e pode ser confirmada por meio da polissonografia. O tratamento da síndrome com o uso de CPAP (pressão positiva na via aérea superior) é altamente eficaz, melhorando o padrão respiratório durante o sono, instituindo o sono reparador e, dessa forma, otimizando a qualidade de vida desses pacientes, além de atenuar ou reverter muitas das complicações cardiovasculares relacionadas a SAHOS. Este artigo aborda a fisiopatologia e os aspectos clínicos das comorbidades cardiovasculares associadas à síndrome.

INTRODUÇÃO

A doença cardiovascular é uma das principais causas de mortalidade no mundo1. Na cidade de São Paulo, as doenças cardiovasculares associadas à aterosclerose representam a principal causa de óbito semelhante aos países desenvolvidos2,3. Vários estudos4-6 confirmam a importância do tabagismo, níveis elevados de LDL-colesterol, baixos níveis de HDL-colesterol, diabete melito, hipertensão arterial sistêmica, história familiar, obesidade, sedentarismo, obesidade central, síndrome plurimetabólica e ingesta de álcool na gênese da aterosclerose e suas complicações clínicas.

Além desses fatores, têm sido observado recentemente evidências de aumento na taxa de mortalidade cardiovascular em pacientes portadores da síndrome da apnéia/hipopnéia obstrutiva do sono (SAHOS)7. O papel da síndrome como fator de risco cardiovascular merece muita atenção do cardiologista, uma vez que se trata de uma condição freqüentemente não-diagnosticada8.

A SAHOS é caracterizada pela obstrução completa ou parcial recorrente das vias aérea superiores durante o sono, resultando em períodos de apnéia, dessaturação de oxiemoglobina e despertares noturnos freqüentes (figs. 1 e 2) com conseqüente sonolência diurna. Apresenta predileção pelo sexo masculino, e a incidência nos homens e mulheres de meia-idade varia na literatura entre 1% e 5% e 1,2% e 2,5%, respectivamente9-13, podendo aumentar com a idade14. Associa-se freqüentemente a outras doenças cardiovasculares, estimando-se que 40% dos pacientes portadores de hipertensão arterial sistêmica apresentam SAHOS associada, não-diagnosticada e não-tratada15,16.

O quadro 1 mostra algumas definições importantes para interpretação e diagnóstico dessa entidade.

FISIOPATOLOGIA

Maior colapso das vias aéreas superiores durante o sono está associado a maior esforço respiratório e alteração no fluxo nasal e oral, que podem desencadear hipoxemia e hipercapnia20. Esse processo leva a um despertar com restabelecimento da ventilação. A alternância entre os eventos respiratórios anormais e os despertares pode ocorrer várias vezes durante a noite21.

Durante cada episódio de apnéia/hipopnéia obstrutiva a inspiração forçada contra a via aérea ocluída é acompanhada de pressão negativa no espaço pleural. À medida que a apnéia se prolonga, acentuam-se a hipoxemia e a hipercapnia, levando a vasoconstrição pulmonar, com o desenvolvimento de hipertensão pulmonar transitória. Ocorre, por sua vez, estimulação do sistema nervoso simpático, com vasoconstrição sistêmica e hipertensão arterial, e em alguns casos a pressão arterial sistólica pode alcançar níveis noturnos significativamente elevados, mesmo em indivíduos com pressão arterial normal durante a vigília22.

Além disso, o fenômeno de hipoxemia e subseqüente reoxigenação, repetido por inúmeras vezes durante a noite, ocasiona alterações de reperfusão com formação de radicais livres23, e o estresse oxidativo é atualmente considerado um contribuinte importante para as conseqüências cardiovasculares observadas nesse grupo de pacientes24. A associação da SAHOS à obesidade25, o predomínio pelo sexo masculino, e feminino após a menopausa, bem como os efeitos sistêmicos desencadeados com o seu aparecimento sugerem fortemente que a SAHOS é uma doença sistêmica e não uma anormalidade local26,27. Outras evidências importantes que favorecem a interpretação da SAHOS como uma doença sistêmica são as suas correlações com o aumento das citocinas inflamatórias e com a resistência a insulina. As citocinas inflamatórias, como o fator-a de necrose tumoral (TNF- a) e a interleucina 6 (IL-6), estão envolvidas na regulação fisiológica do sono28 e encontram-se anormalmente elevadas em pacientes apnéicos quando comparados com indivíduos normais e com pacientes portadores de obesidade29,30. Entretanto, a correlação entre a SAHOS e a resistência à insulina parece ser independente da obesidade31.

CONSEQÜÊNCIAS CARDIOVASCULARES

As principais conseqüências cardiovasculares são: alterações no sistema nervoso autonômico, hipertensão arterial, arritmias cardíacas, doença arterial coronária, acidente vascular cerebral e insuficiência cardíaca congestiva.

Alterações no sistema nervoso autônomo

As alterações na freqüência cardíaca e pressão arterial, observadas na apnéia obstrutiva durante o sono, são provavelmente secundárias a alterações no sistema nervoso autônomo durante cada evento apneico32, o que foi demonstrado mesmo em pacientes com SAHOS de grau leve33,34. Durante esses eventos observa-se um progressivo aumento na atividade simpática, atingindo o seu pico máximo no término da apnéia, seguido por uma acentuada diminuição durante a recuperação35,36.

Os mecanismos pelos quais a SAHOS determina ativação simpática persistente, ou seja, mesmo durante a vigília, entretanto, ainda não são completamente conhecidos. Existem algumas evidências que enfatizam o papel da hipóxia nesse fenômeno: as concentrações urinárias de norepinefrina são inversamente proporcionais à saturação da oxiemoglobina mínima noturna. Além disso, as mudanças ventilatórias que determinam hipóxia e hipercapnia causam elevação da atividade muscular simpática, que pode persistir por até vinte minutos após a retirada do estímulo37. O seio carotídeo parece desempenhar um papel no processo entre a exposição à hipóxia intermitente noturna e o desenvolvimento da elevação sustentada nos níveis de ativação autonômica, uma vez que a regulação e a sensibilidade barorreflexa estão diminuídas em pacientes com SAHOS, comparados com controles38. Evidências atuais sugerem que o estímulo hipóxico intermitente noturno dos quimioceptores periféricos aumentam o tônus simpático em tais pacientes mesmo em vigília e em condições ideais de suprimento de oxigênio39,40.

Além disso, estudos do sistema nervoso autônomo por meio da variabilidade da freqüência cardíaca mostram que pacientes portadores de SAHOS apresentam um decréscimo no componente de alta freqüência (tônus parassimpático) da variabilidade da freqüência cardíaca e um aumento no componente de baixa freqüência (tônus simpático). Esse padrão anormal parece refletir uma predominância simpática na modulação autonômica da SAHOS41.

Hipertensão

SAHOS é fator de risco independente para hipertensão arterial sistêmica (HAS)42-47. A prevalência da HAS em portadores da SAOS varia de 40% a 90%, e o inverso, a prevalência da SAOS entre portadores de HAS, é de 22% a 62%43. Estudos recentes confirmam essa alta prevalência entre ambas as condições48 e mostram que, em um período de quatro anos, aqueles indivíduos com um índice de apnéia/hipopnéia (IAH) maior que quinze por hora de sono têm um risco três vezes maior (45% de probabilidade) de desenvolver HAS43. Um estudo de 44 pacientes portadores de HAS resistente à medicação mostrou que 83% apresentaram SAHOS49.

Pacientes com SAHOS têm grande variabilidade da pressão arterial (PA) durante a noite, podendo não apresentar o descenso noturno observado em indivíduos normais, levando a um valor médio noturno elevado, mesmo nas situações em que se observam níveis pressóricos normais durante o dia. Esse comportamento da PA pode decorrer dos seguintes fatores: pressão intratorácica negativa com redução do débito cardíaco e ativação diferencial de barorreceptores, hipóxia, hipercapnia, despertar do sono relacionado ao evento respiratório e aumento da atividade simpática50.

O CPAP (contínuos positive airway pressure) tem se mostrado eficaz no tratamento dos pacientes portadores de SAHOS e HAS51,52. Em uma casuística de onze pacientes com HAS refratária, o uso do CPAP reduziu os níveis pressóricos noturnos53. Além disso, em doze pacientes com SAHOS grave, o uso do CPAP reduziu a norepinefrina plasmática e os metabólicos urinários das catecolaminas54.

Até o momento atual, portanto, a SAHOS deve ser considerada no diagnóstico diferencial de causas de hipertensão arterial sistêmica refratária e o uso do CPAP poderia auxiliar na redução das pressões arteriais noturnas e diurnas55,56.

Arritmias cardíacas

A relação entre a SAHOS e as arritmias cardíacas já foi analisada na literatura médica por alguns autores57,58, não havendo consenso nos resultados encontrados e na prevalência das taquiarritmias e das bradiarritmias. Esse fato pode ser em parte explicado pela desconhecida incidência de SAHOS na população geral saudável e pela alta incidência de hipertensão e doenças cardiovasculares em pacientes com SAHOS. Entretanto, sabe-se que o uso do CPAP em pacientes com SAHOS pode diminuir a incidência de arritmias cardíacas, assim como a estimulação cardíaca artificial pode diminuir a gravidade dos distúrbios respiratórios59,60. A figura 3 mostra exemplo de pausa sinusal associada a um evento de apnéia em um paciente portador de SAHOS.

A fibrilação atrial (FA) merece destaque por apresentar maior número de estudos clínicos com os distúrbios respiratórios do sono61-66. A prevalência de FA parece aumentar em pacientes com SAHOS e insuficiência cardíaca congestiva ou revascularização miocárdica recente61,62. Conforme referido anteriormente, a SAHOS ocasiona hipoxemia intermitente, ativação simpática e alterações abruptas na pressão arterial, razões essas possivelmente relacionadas ao desenvolvimento e recorrência de FA. Em um estudo prospectivo62, com pacientes referidos para a cardioversão elétrica de FA/flutter atrial, observaram-se 82% de recorrência nos pacientes com SAHOS sem tratamento ou com tratamento inadequado, e 42% de recorrência nos pacientes tratados. Além disso, no grupo de pacientes não-tratados, a recorrência foi ainda maior entre os que apresentavam maior queda na saturação de oxigênio durante o evento de apnéia. Esses dados sugerem que o tratamento adequado com CPAP pode fazer diminuir a recorrência de FA nos pacientes portadores de SAHOS.

As ectopias ventriculares foram relatadas em até 66% dos pacientes portadores de SAHOS. Entretanto, em um estudo prospectivo com 147 pacientes submetidos a polissonografia com registro simultâneo de Holter, não foi encontrado aumento de arritmias ventriculares67. Os achados discrepantes na literatura médica dificultam o estabelecimento de uma relação direta entre a síndrome e as arritmias ventriculares. Entretanto, quando se analisa a relação entre as ectopias ventriculares e a dessaturação da oxiemoglobina em pacientes com SAHOS68, observa-se que ocorre um aumento acentuado na freqüência de ectopias ventriculares quando a saturação de oxigênio cai abaixo de 60%, e a relação entre eventos apnéicos e arritmias ventriculares parece existir apenas nos pacientes que apresentem importante dessaturação durante a noite.

Pacientes portadores da síndrome apresentam arritmias ventriculares predominantemente durante o sono, diferente dos pacientes com sono normal69, sendo a taquicardia ventricular mais comum em pacientes com SAHOS (0-15%) do que na população geral (0-4%)69. As bradiarritmias são bastante associadas a SAHOS. Guilleminault e cols.70 observaram a ocorrência de pausa sinusal (> 2,5 segundos), bloqueio atrioventricular de segundo grau, e bradicardia sinusal em 11%, 8% e 7%, respectivamente. Koehler e cols.71 analisaram os fatores envolvidos nos bloqueios cardíacos em pacientes com SAHOS, concluindo que na maioria dos casos o bloqueio ocorre durante o estado de sono REM e durante os períodos com queda na saturação de oxigênio em pelo menos 4%.

Apesar dos resultados discordantes na literatura, parece que a queda na saturação de oxigênio durante os episódios de apnéia é um importante fator desencadeador de arritmias cardíacas nos pacientes portadores da síndrome e a sua freqüência associa-se à intensidade da hipóxia.

Doença arterial coronariana

Mesmo com a observação crescente da ocorrência de SAHOS e do concomitante aumento da mortalidade cardiovascular9, a maioria dos estudos apresenta limitações importantes, pelo fato de muitos fatores de risco para SAHOS, como obesidade, sexo masculino, idade, dentre outros, serem os mesmos para hipertensão e doença arterial coronária (DAC). Portanto, definir o risco preciso de DAC atribuído a SAHOS parece ser difícil, mas observações convergentes apontam SAHOS como um importante fator associado a DAC.

Na SAHOS o aumento da atividade nervosa simpática periférica durante o sono persiste, durante a vigília, com o dobro dos valores normais72, podendo contribuir dessa forma para os eventos coronários agudos nas primeiras horas da manhã. Além do envolvimento do sistema nervoso autônomo, a inflamação e a lesão endotelial, observada na SAHOS, poderiam também participar dos mecanismos envolvidos na DAC73.

Em um estudo bem conduzido avaliando o impacto do tratamento da síndrome na evolução cardiovascular em longo prazo (86,5 ± 39 meses) de pacientes com DAC, observou-se que os pacientes adequadamente tratados apresentaram redução significativa no risco de ocorrência de eventos cardiovasculares definidos como morte cardiovascular, síndrome coronária aguda, hospitalização por insuficiência cardíaca, ou necessidade de revascularização miocárdica74.

Alterações noturnas de segmento ST consistentes com isquemia miocárdica são comuns em pacientes com SAHOS e DAC. Mooe e cols.75 avaliaram a ocorrência de isquemia miocárdica noturna e suas relações com as desordens respiratórias do sono. A depressão do segmento ST noturna ocorreu em 31% dos pacientes analisados, e a associação temporal entre os achados eletrocardiográficos e os episódios de apnéia ocorreram em 19% dos casos, sendo mais freqüentes em homens (p < 0,01) e nas desordens respiratórias mais graves.

Acidente vascular cerebral

Entre os indivíduos com acidente vascular cerebral (AVC), a incidência de distúrbio respiratório do sono pode ser maior do que 50%76, com predomínio da forma obstrutiva. Ainda permanece pouco claro, entretanto, se esses eventos detectados após o AVC são conseqüência ou uma condição preexistente ao evento cerebrovascular. Da mesma forma que a doença arterial coronária, a SAHOS e o AVC também apresentam muitos fatores de risco em comum, sendo igualmente difícil provar relação causa-efeito.

Dziewas e cols.77 analisaram a freqüência dos distúrbios respiratórios do sono em grupos de pacientes com primeiro episódio e recorrência de AVC isquêmico. Os pacientes com recorrência apresentaram índice de apnéia/hipopnéia médio maior quando comparados com indivíduos com apenas um episódio (26,6/h versus 15,1/h, p<0,05) e mais freqüentemente apresentavam SAHOS. Na análise multivariada com ajuste para as variáveis clínicas e fatores de risco, a apnéia do sono foi considerada um fator de risco independente para recorrência de AVC, e os autores advogam o uso da polissonografia nesse grupo de pacientes como forma de estratificação de risco.

Provavelmente a SAHOS contribui para a ocorrência de AVC por vários mecanismos: hipertensão arterial sistêmica, aumento da agregação plaquetária, hipercoagulabilidade sangüínea, disfunção endotelial, dentre outros. Além disso, durante a apnéia ocorre um decréscimo no fluxo sangüíneo cerebral secundário à redução no débito cardíaco, que pode predispor indivíduos de risco ao AVC, como os portadores de lesões ateromatosas de circulação carotídea e vertebral. Isso pode ser significantemente mais importante durante o sono REM, estado em que há maior demanda de oxigênio encefálico.

Além disso, a apnéia pode comprometer a cognição, nos pacientes com história de AVC prévio, por determinar aumento da sonolência diurna, prejuízo na concentração e memória78. Por fim, estudos clínicos randomizados avaliando o tratamento da apnéia e evolução neurológica ainda não estão disponíveis.

Insuficiência cardíaca congestiva

Vários estudos também mostraram importante associação entre a insuficiência cardíaca congestiva (ICC) e SAHOS. Javaheri e cols.79 realizaram polissonografia em 81 homens portadores de ICC, identificando a síndrome em 11% dos pacientes. No estudo Sleep Heart Health80, detectou-se que em pacientes apnéicos com IAH > 11/hora o risco para desenvolver ICC foi de 2,38, independentemente de outros fatores de risco estabelecidos, excedendo os encontrados para outras complicações cardiovasculares da SAHOS, como hipertensão, DAC e AVC.

Acredita-se também que a ICC pode colaborar no desenvolvimento da SAHOS por dois motivos: diminuição do tônus muscular das vias aéreas superiores durante a fase de repouso da respiração periódica típica da ICC, e acúmulo de fluidos em partes moles da região cervical, facilitando a tendência ao colapso das vias aéreas superiores.

Estudos com ecocardiografia demonstraram disfunção tanto sistólica81 quanto diastólica82 com aumento do IAH. Possíveis mecanismos incluem efeitos da hipóxia (determinando isquemia e prejuízo da contratilidade), injúria dos miócitos (pelo aumento da concentração das catecolaminas circulantes) e mudança repetitiva nas pressões intratorácicas que acompanham os episódios de apnéia (alterando o relaxamento e o volume sistólico e diastólico final do ventrículo esquerdo)

Finalmente, o diagnóstico dos distúrbios respiratórios do sono em pacientes portadores de ICC pode trazer importantes informações prognosticas e uma opção terapêutica potencial para esse grupo de pacientes83.

Alterações inflamatórias, endoteliais e trombóticas na SAHOS

Foi demonstrada diminuição ou ausência de mecanismos fisiológicos de relaxamento vascular em resposta a substâncias endotélio-dependentes (aumento do vasoconstritor, endotelina e redução da disponibilidade do ácido nítrico e prostaciclinas)84,85. Outra evidência de lesão endotelial foi documentada mediante a produção aumentada de moléculas de adesão, levando a maior ligação de monócitos ao endotélio86. A SAHOS pode também desencadear o estresse oxidativo recorrente87, provavelmente em razão da produção aumentada de espécies oxigênio-reativas por monócitos e granulócitos. Esses achados reforçam resultados prévios de uma produção aumentada de radicais superóxidos por polimorfonucleares em pacientes com SAHOS88 e baixos níveis de óxido nítrico89. A homocisteína também foi descrita como aumentada nessa síndrome90, como resultado de disfunção endotelial combinada com excessiva formação de radicais livres, existindo também relatos de aumento de haptoglobina e proteína amilóide sérica A91,92.

A ligação entre o processo inflamatório e as doenças cardiovasculares tem sido postulada repetidamente93. Pacientes com SAHOS são expostos cronicamente a hipóxia recorrente e a fragmentação do sono, apresentando níveis aumentados de proteína C-reativa e interleucina 6, quando comparados com controles94, existindo também a possibilidade do aumento de proteína C-reativa em tais pacientes por causa da obesidade associada95. Todas essas alterações endoteliais, da coagulação sangüínea e inflamatórias podem contribuir de algum modo para o aumento do risco cardiovascular e aterogênese em pacientes com SAHOS. Por fim, observa-se que o tratamento com CPAP é capaz de melhorar essas alterações, ocorrendo retorno das anormalidades com a suspensão da terapêutica96-103.

Correspondência:

Fátima Dumas Cintra

Av. Marcos Penteado de Ulhoa Rodrigues, 1001

06543-330 – Santana de Parnaíba, SP

E-mail:

fatimacintra@interair.com.br

Recebido em 08/12/05

Aceito em 28/12/05

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Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation. 2003; 107(8):1129-34. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure Circulation. 2003 1129 34 8 107 Yokoe T Minoguchi K Matsuo H Oda N Minoguchi H Yoshino G 95. Guilleminault C, Kirisoglu C, Ohayon MM. C-reactive protein and sleep-disordered breathing. Sleep. 2004; 15; 27(8): 1507-11. C-reactive protein and sleep-disordered breathing Sleep 2004 1507 11 8 15 Guilleminault C Kirisoglu C Ohayon MM 96. Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation. 2000; 21; 102(21): 2607-10. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea Circulation 2000 2607 10 21 21 Kato M Roberts-Thomson P Phillips BG Haynes WG Winnicki M Accurso V 97. Kraiczi H, Caidahl K, Samuelsson A, Peker Y, Hedner J. Impairment of vascular endothelial function and left ventricular filling: association with the severity of apnea-induced hypoxemia during sleep. Chest. 2001; 119(4): 1085-91 Impairment of vascular endothelial function and left ventricular filling: association with the severity of apnea-induced hypoxemia during sleep Chest. 2001 1085 91 4 119 Kraiczi H Caidahl K Samuelsson A Peker Y Hedner J 98. Teramoto S, Kume H, Yamamoto H, Ishii T, Miyashita A, Matsuse T, et al. Effects of oxygen administration on the circulating vascular endothelial growth factor (VEGF) levels in patients with obstructive sleep apnea syndrome. Intern Med. 2003; 42(8): 681-5. Effects of oxygen administration on the circulating vascular endothelial growth factor (VEGF) levels in patients with obstructive sleep apnea syndrome Intern Med. 2003 681 5 8 42 Teramoto S Kume H Yamamoto H Ishii T Miyashita A Matsuse T 99. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease.JAMA. 2003; 290(14): 1906-14. Obstructive sleep apnea: implications for cardiac and vascular disease JAMA. 2003 1906 14 14 290 Shamsuzzaman AS Gersh BJ Somers VK 100. Nieto FJ, Herrington DM, Redline S, Benjamin EJ, Robbins JA. Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. Am J Respir Crit Care Med. 2004; 169(3): 354-60. Sleep apnea and markers of vascular endothelial function in a large community sample of older adults Am J Respir Crit Care Med. 2004 354 60 3 169 Nieto FJ Herrington DM Redline S Benjamin EJ Robbins JA 101. Dyugovskaya L, Lavie P, Lavie L. Phenotypic and functional characterization of blood gammadelta T cells in sleep apnea. Am J Respir Crit Care Med. 2003; 168(2): 242-9. Phenotypic and functional characterization of blood gammadelta T cells in sleep apnea Am J Respir Crit Care Med. 2003 242 9 2 168 Dyugovskaya L Lavie P Lavie L 102. Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med. 2002; 165(1): 67-70. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia Am J Respir Crit Care Med. 2002 67 70 1 165 Schulz R Hummel C Heinemann S Seeger W Grimminger F 103. Von Kanel R, Le DT, Nelesen RA, Mills PJ, Ancoli-Israel S, Dimsdale JE. The hypercoagulable state in sleep apnea is related to comorbid hypertension. J Hypertens. 2001; 19(8): 1445-51. The hypercoagulable state in sleep apnea is related to comorbid hypertension J Hypertens. 2001 1445 51 8 19 Von Kanel R Le DT Nelesen RA Mills PJ Ancoli-Israel S Dimsdale JE Update Cardiovascular comorbidities and obstructive sleep apnea

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a prevalent condition in the general population. It is associated with increased cardiovascular risk and often goes unrecognized. Its diagnose requires a high degree of clinical suspicion, particularly on the part of cardiologists, and it may be confirmed by polysomnography. Continuous positive airway pressure (CPAP) therapy is highly effective, since it improves sleep breathing pattern, promotes restful sleep and thus enhances the quality of life of these patients, in addition to attenuating or reversing many cardiovascular complications related to OSAHS. This paper addresses the pathophysiology and clinical features of cardiovascular comorbidities associated with the syndrome.

UPDATE

Cardiovascular comorbidities and obstructive sleep apnea

Fátima Dumas Cintra; Dalva Poyares; Christian Guilleminault; Antonio Carlos Carvalho; Sergio Tufik; Angelo A. V. de Paola

Universidade Federal de São Paulo e Stanford University - São Paulo, SP, Brazil - Stanford, CA , USA

Mailing Address

ABSTRACT

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a prevalent condition in the general population. It is associated with increased cardiovascular risk and often goes unrecognized. Its diagnose requires a high degree of clinical suspicion, particularly on the part of cardiologists, and it may be confirmed by polysomnography. Continuous positive airway pressure (CPAP) therapy is highly effective, since it improves sleep breathing pattern, promotes restful sleep and thus enhances the quality of life of these patients, in addition to attenuating or reversing many cardiovascular complications related to OSAHS. This paper addresses the pathophysiology and clinical features of cardiovascular comorbidities associated with the syndrome.

INTRODUCTION

Cardiovascular disease is one of the primary causes of mortality worldwide1. In the city of São Paulo, cardiovascular diseases associated with atherosclerosis are the leading cause of death, similar to developed countries2,3. A number of studies4-6 confirm the role of cigarette smoking, high LDL-cholesterol levels, low HDL-cholesterol levels, diabetes mellitus, systemic arterial hypertension, family history, obesity, physical inactivity, central obesity, metabolic syndrome, and alcohol consumption in the genesis of atherosclerosis and its clinical complications.

In addition to these factors, recent evidence shows increased cardiovascular mortality in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS)7. The role of this syndrome as a cardiovascular risk factor deserves the careful attention of the cardiologist, because this condition is often undiagnosed8.

OSAHS is a disorder characterized by recurrent complete or partial upper airway obstruction during sleep, resulting in apneic episodes, oxyhemoglobin desaturation, frequent arousals (figures 1 and 2) and consequent daytime sleepiness. This syndrome is far more common in men. Its incidence in middle-aged men and women in the literature ranges from 1% and 5% and 1.2% and 2.5%, respectively9-13, and may increase with age14. It is often associated with other cardiovascular diseases; moreover, it is estimated that 40% of the patients with systemic hypertension have OSAHS, undiagnosed and untreated15,16.

Chart 1 shows some important definitions for inter-preting and diagnosing this condition.

PATHOPHYSIOLOGY

Increased upper airway collapse during sleep is associated with increased respiratory effort and change in nasal and oral airflow, which may trigger hypoxemia and hypercapnia20. This process results in arousal with resumption of breathing. Abnormal respiratory events and arousals may alternate many times during the night21.

During each episode of obstructive apnea/hypopnea, the inspiratory effort against an occluded airway is accompanied by negative pressure in the pleural space. As apnea persists, hypoxemia and hypercapnia become more marked, leading to pulmonary vasoconstriction and the development of transient pulmonary hypertension. There is however, a stimulation of the sympathetic nervous system, causing systemic vasoconstriction and arterial hypertension; in some cases, systolic blood pressure may reach significantly high nocturnal levels, even in subjects with normal daytime blood pressure

Additionally, the hypoxia and subsequent reoxygenation phenomenon, repeated many times during the night, causes changes in reperfusion, with free radical production23, and oxidative stress is now considered a major contributor to the cardiovascular consequences observed in this group of patients24. Association of OSAHS with obesity25, predominance in male and postmenopausal women, as well as the systemic effects triggered with its onset, strongly suggest that OSAHS is a systemic disease, rather than a local abnormality26,27. Other important evidence favoring the systemic disease hypothesis for OSAHS is its correlation with higher inflammatory cytokine levels and insulin resistance. Inflammatory cytokines, tumor necrosis factor-a (TNF- a), and interleukin-6 (IL-6) are involved in the physiological regulation of sleep28 and are abnormally elevated in apneic patients, when compared to normal and obese subjects29,30. However, the correlation between OSAHS and insulin resistance seems to be independent of obesity31.

CARDIOVASCULAR CONSEQUENCES

The main cardiovascular consequences are changes in autonomic nervous system activity, arterial hypertension, cardiac arrhythmias, coronary artery disease, stroke, and congestive heart failure.

Changes in autonomic nervous system activity

Heart rate and blood pressure changes observed in obstructive sleep apnea are likely to be secondary to autonomic nervous system activation during every apneic event32. This was demonstrated even in patients with mild OSAHS33,34. During these events, a progressive increase in sympathetic activity occurs, reaching its peak at apnea termination, followed by a marked decrease during recovery35,36.

However, the mechanisms by which OSAHS causes persistent sympathetic activation, that is, even during wakefulness, are not entirely clear. Some evidence emphasizes the role of hypoxia in this phenomenon: urinary norepinephrine concentrations are inversely proportional to nadir nocturnal oxyhemoglobin saturation. Furthermore, the ventilatory changes that determine hypoxia and hypercapnia cause an increase in muscle sympathetic nerve activity, which may persist for up to twenty minutes following stimulus withdrawal37. The carotid sinus seems to play a role in the process between exposure to intermittent nocturnal hypoxia and development of sustained elevation in autonomic activation levels, because baroreflex regulation and sensitivity are reduced in patients with OSAHS, compared to controls38. Current evidence suggests that the intermittent nocturnal hypoxic stimulus of peripheral chemoreceptors increases the sympathetic tone in these patients even during wakefulness and optimal oxygen supply39,40.

Moreover, autonomic nervous system studies employing heart rate variability demonstrate that the high-frequency component (parasympathetic tone) of heart rate variability of OSAHS patients declines and the low-frequency component (sympathetic tone) increases. This abnormal pattern seems to reflect sympathetic predominance in the autonomic modulation of OSAHS41.

Hypertension

OSAHS is an independent risk factor for systemic arterial hypertension (SAH)42-47. SAH prevalence in OSAHS patients ranges from 40% to 90%, and the opposite, OSAHS prevalence in SAH patients, ranges from 22% to 62%43. Recent studies corroborate this high prevalence between both conditions48 and show that, in four years, subjects with apnea/hypopnea index (AHI) greater than fifteen per hour of sleep have a five-fold risk (45% likelihood) of developing SAH43. A study with 44 patients with drug-resistant hypertension showed that 83% had OSAHS49.OSAHS patients show great blood pressure (BP) variability during the night, and they may not experience the nocturnal dip observed in normal patients, resulting in higher mean night-time BP values, even when daytime BP is normal. This BP behavior may be due to negative intrathoracic pressure with reduced cardiac output and differential activation of baroreceptors, hypoxia, hypercapnia, breathing-related arousal and increased sympathetic activity50.

Continuous positive airway pressure (CPAP) has proved to be effective in the treatment of patients with OSAHS and SAH51,52. In a series of eleven patients with refractory SAH, CPAP reduced nocturnal blood pressure53. Furthermore, in twelve patients with severe OSAHS, the use of CPAP decreased plasma norepinephrine and urinary catecholamine metabolites54.

Thus far, therefore, OSAHS should be considered in the differential diagnosis of refractory systemic arterial hypertension, and the use of CPAP may help in reducing both daytime and night-time blood pressure55,56.

Cardiac arrhythmias

Some authors have already studied the relationship between OSAHS and cardiac arrhythmias57,58; however, there is no consensus in the medical literature concerning results57,58 and prevalence of tachyarrhythmia and bradyarrhythmia. This may be partly explained by the unknown incidence of OSAHS in the general healthy population and by the high incidence of hypertension and cardiovascular diseases in OSAHS patients. However, it is known that the use of CPAP in OSAHS patients may reduce cardiac arrhythmias, just as artificial cardiac stimulation may attenuate breathing disorders59,60. Figure 3 shows an example of sinus pause associated with apneic event in an OSAHS patient.

Atrial fibrillation (AF) deserves underscoring, because it has been studied in the largest number of clinical trials related to sleep-disordered breathing61-66. Its prevalence seems to increase in patients with OSAHS and congestive heart failure (CHF) or recent myocardial revascularization61,62. As already stated, OSAHS causes intermittent hypoxemia, sympathetic activation, and abrupt changes in blood pressure, which may be related to the development and recurrence of AF. In a prospective study62 of patients referred for electrical cardioversion of atrial fibrillation/atrial flutter, 82% of the untreated or inadequately treated OSAHS patients experienced recurrent AF, compared to 42% of the treated patients. Moreover, in the untreated group, recurrence was even higher among those who showed greater drop in oxygen saturation during the apneic event. These data suggest that appropriate treatment with CPAP may reduce AF recurrence in OSAHS patients.

Ventricular ectopies were reported in up to 66% of OSAHS patients. However, in a prospective study of 147 patients who underwent simultaneous polysomnography and Holter monitoring, no increase in ventricular arrhythmias was found67. In view of discrepant reports in the medical literature, it is difficult to establish a direct relationship between the syndrome and ventricular arrhythmias. Yet, analyzing the relationship between ventricular ectopies and oxyhemoglobin desaturation in patients with OSAHS68, a marked increase is found in ventricular ectopy frequency when oxygen saturation drops below 60%, and the relationship between apneic events and ventricular arrhythmias seems to exist solely in patients with important desaturation during the night.

Patients with this syndrome experience ventricular arrhythmias mainly during sleep, unlike patients with normal sleep68, and ventricular tachycardia is more common in OSAHS patients (0-15%) than in the general population (0-4%)69. Bradyarrhythmias are strongly associated with OSAHS. Guilleminault et al.70 have found sinus pause (> 2.5 seconds), second-degree atrioventricular block, and sinus bradycardia in 11%, 8%, and 7% of the patients, respectively. Koehler et al.71 analyzed factors involved in heart blocks in patients with OSAHS and concluded that most cases occur during REM sleep and periods with oxygen desaturation of at least 4%.

Despite conflicting reports in the literature, oxygen saturation drop during apneic episodes seems to be an important factor triggering cardiac arrhythmias in patients with sleep apnea-hypopnea syndrome, and its frequency is associated with hypoxia severity.

Coronary artery disease

Despite the growing incidence of OSAHS and the concomitant increase in cardiovascular mortality9, most studies face important limitations, because many risk factors, such as obesity, masculine gender and age, among others, are the same as those for hypertension and coronary artery disease (CAD). Therefore, it seems difficult to pinpoint the risk for CAD attributed to OSAHS; however, convergent observations suggest that OSAHS is an important factor associated with CAD.

In OSAHS, the increase in peripheral sympathetic nerve activity during sleep to twice the normal values persists during wakefulness72 and may contribute to acute coronary events in the early morning hours. In addition to autonomic nervous system involvement, both the inflammation and endothelial injury observed in OSAHS are likely to participate in the mechanisms involved in CAD73.

In a well-conducted study evaluating the impact of OSAHS therapy on long-term cardiovascular outcomes (86.5 ± 39 months) in CAD patients, those appropriately treated experienced a significant reduction in cardiovascular event risk, defined as cardiovascular death, acute coronary syndrome, admission for heart failure, or need of myocardial revascularization74.

Nocturnal ST-segment changes consistent with myocardial ischemia are common in patients with OSAHS and CAD. Mooe et al75 evaluated the occurrence of nocturnal myocardial ischemia and its relationship to sleep-related breathing disorders. ST-segment depressions occurred in 31% of the patients studied. Temporal association between electrocardiographic findings and apneic events was found in 19% of the cases, more frequently in men (p < 0.01) and in more severely disordered breathing.

Stroke

Among stroke patients, sleep-disordered breathing incidence, the obstructive form predominantly, may exceed 50%76. It remains quite unclear, however, whether these events detected after stroke are a consequence of the cerebrovascular event or a preexistent condition. As with coronary artery disease, OSAHS and stroke also share many risk factors, and it is equally difficult to prove a cause-effect relationship.

Dziewas et al77 analyzed the frequency of sleep-disordered breathing in groups of patients with first and recurrent ischemic stroke. Patients with recurrent stroke showed higher mean apnea-hypopnea index (AHI) when compared to patients with first-ever stroke (26.6/h vs. 15.1/h, p < 0.05) and most commonly had OSAHS. In the multivariate analysis adjusted for clinical variables and risk factors, sleep apnea was considered an independent risk factor for stroke recurrence, and the authors advocate the use of polysomnography in this group of patients for risk stratification.

OSAHS most probably contributes to recurrent stroke through several mechanisms, such as systemic arterial hypertension, increased platelet aggregation, blood hypercoagulability, and endothelial dysfunction, among others. Moreover, blood flow to the brain declines during apnea, due to reduction in cardiac output, which may predispose risk subjects to stroke, such as those with atheromatous lesions in carotid and vertebral circulations. This may be significantly more important during REM sleep, when brain oxygen demand is higher.

In addition, apnea may impair cognitive function in patients with previous history of stroke, since it causes excessive daytime sleepiness and poor concentration and memory78. Finally, randomized clinical trials examining apnea therapy and neurological outcomes are still lacking.

Congestive heart failure

Several studies also showed an important association between congestive heart failure (CHF) and OSAHS. In the Javaheri et al79 study, 81 men with CHF underwent polysomnography, and 11% were found to have obstructive sleep apnea syndrome. In the Sleep Heart Health study80, apneic patients with an AHI > 11 per hour showed a 2.38 risk of developing CHF, regardless of other established risk factors, exceeding those found for other cardiovascular complications associated with OSAHS, such as hypertension, CAD, and stroke.

It is also believed that CHF contributes to the development of OSAHS for two reasons, namely, decreased upper airway muscle tone during the resting phase of the periodic breathing typical of CHF and fluid accumulation in the soft tissues of the cervical region, contributing to the tendency of upper airway collapse.

Echocardiographic studies showed both systolic81 and diastolic82 dysfunction with increasing AHI. Possible mechanisms include hypoxia effects (determining ischemia and impaired contractility), myocyte injury (due to higher levels of circulating catecholamines), and intrathoracic pressure swings that accompany apneic episodes (changing relaxation and left ventricular end-systolic and end-diastolic volumes).

Finally, the diagnosis of sleep-disordered breathing in CHF patients may provide valuable prognostic information and a potential therapeutic option for this group of patients83.

Inflammatory, endothelial, and thrombotic changes in osahs

Decline or absence of physiological mechanisms involved in vascular relaxation was demonstrated in response to endothelium-dependent substances (increased vasoconstrictor, endothelin, and reduced nitric acid and prostacyclin availability)84,85. Another evidence of endothelial damage was documented by enhanced expression of adhesion molecules, leading to increased adherence of monocytes to endothelial cells86. OSAHS may also trigger recurrent oxidative stress87, probably owing to greater production of oxygen-reactive species by monocytes and granulocytes. These findings reinforce previous results regarding increased production of superoxide radicals from polymorphonuclear neutrophils in patients with OSAHS88 and low levels of nitric oxide89. Plasma homocystein levels were also reported to be elevated in this syndrome90, as a result of endothelial dysfunction combined with excessive production of free radicals. Serium haptoglobin and amyloid A protein were also reported to be higher91,92.

The relationship between inflammatory process and cardiovascular diseases has been repeatedly postulated93. OSAHS patients are chronically exposed to recurrent hypoxia and sleep fragmentation, showing increased C-reactive protein and interleukin-6 levels, when compared to controls94. It is also likely that C-reactive protein levels in these patients are higher because of associated obesity95. All these endothelial, blood clotting, and inflammatory changes may contribute somewhat to higher cardiovascular risk and atherogenesis in OSAHS patients. Finally, CPAP therapy may improve these changes; however, discontinuation of therapy leads to the reappearance of abnormalities96-103.

REFERENCES

Mailing Address:

Fátima Dumas Cintra

Av. Marcos Penteado de Ulhoa Rodrigues, 1001

06543-330 – Santana de Parnaíba, SP - Brazil

E-mail:

fatimacintra@interair.com.br

Received on 12/08/05

Accepted on 12/28/05