Is Obstructive Sleep Apnoea a Risk Factor for Thoracic Aortic Aneurysm Expansion? A Prospective Cohort Study.
Condition: Aortic Aneurysm; Obstructive Sleep Apnea
MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Thoracic
Study type: Observational

Summary: 
      The objective of this prospective cohort study in patients with a known thoracic aortic
      aneurysm is to test the hypothesis that yearly aneurysm progression rate is higher in
      patients with obstructive sleep apnoea (OSA) compared to patients without OSA, and that the
      need for aortic operation or proven or presumed death from aortic rupture or dissection
      happens more often in patients with thoracic aortic aneurysm and OSA compared to patients
      without OSA.
    

Detailed description: 
      Thoracic aortic aneurysm An aortic aneurysm is defined as a localised dilatation of the
      aorta, which includes all three layers of the vessel, intima, media and adventitia. The
      incidence of thoracic aortic aneurysm is estimated to be six to ten cases per 100,000 patient
      years, most commonly occurring in the sixth and seventh decade of life. Thoracic aortic
      aneurysms are two to four times more commonly found in males than in females. Sixty percent
      of thoracic aortic aneurysms involve the ascending aorta, 40% the descending aorta, and 10%
      involve the thoraco-abdominal aorta. The pathogenesis and natural history as well as the
      therapy of thoracic aortic aneurysms differ for each of these segments.

      Thoracic aneurysms of the ascending aorta are considered to result from cystic degeneration
      of the media layer, a process associated with weakening of the aortic wall. Cystic medial
      degeneration occurs with aging, but seems to be increased in some families and with arterial
      hypertension. Other risk factors which have been suggested to be associated primarily with
      thoracic aneurysm formation of the descending aorta are the same as those for atherosclerosis
      (e.g. hypertension, smoking and hypercholesterolemia). Whether atherosclerosis itself is a
      prerequisite for aortic aneurysm development is a matter of debate. A multifactorial,
      non-atherosclerotic cause such as a defect in vascular structural proteins and breakdown of
      extracellular matrix proteins in combination with increased mechanical stress has been
      postulated as the most likely mechanism for thoracic aneurysm formation.

      Transthoracic echocardiography, computed tomography or MR angiography are recommended for
      serial re-evaluation of a thoracic aortic aneurysm.

      Natural history data on thoracic aortic aneurysms is scarce; however, aneurysm diameter has
      been shown to increase by 1 to 10 mm per year. The rate of expansion is related to the
      diameter of the aneurysm with larger aneurysms expanding faster; the findings of an early
      cohort study on the natural course of thoracic aortic aneurysms found a yearly expansion of
      7.9mm in aneurysms >50mm, compared to 1.7mm in aneurysms ≤50mm.

      In several series of patients, aneurysm rupture occurred in 32% to 68% of medically treated
      patients. The most important identified risk factor for rupture seems to be the size of the
      aneurysm; the yearly rate of dissection or rupture ranges from 2%, to 3%, to 7%, for thoracic
      aortic aneurysms less than 50 mm, 50-59 mm, and ≥60 mm in diameter, respectively. Expansion
      rate per year, male gender, hypertension, systemic steroid therapy and inflammation are other
      factors associated with increased risk of aneurysm rupture.

      Asymptomatic patients with a thoracic aortic aneurysm are usually managed medically with
      blood pressure control using a beta blocker and serial evaluation of aneurysmal size
      progression. Surgery is reserved for symptomatic patients, and for asymptomatic patients with
      rapid aneurysm expansion (usually defined as >10mm per year), or an aneurysm diameter >50 to
      60mm, depending on the affected aortic segment, body size and other clinical factors.
      However, thoracic aneurysm repair is associated with high morbidity and mortality rates
      between 3% and 12% in more recent retrospective series. In cases of emergency surgery for
      thoraco-abdominal aneurysm the 30 day mortality has even been reported to be as high as 40%.

      Therefore, any modifiable factors influencing the onset of a thoracic aneurysm and its
      progressive expansion are of major interest, hopefully leading to new therapeutic strategies
      to improve morbidity and mortality.

      Obstructive sleep apnoea (OSA) is characterised by a repetitive collapse of the pharynx
      during sleep, which results in apnoea or hypopnoea associated with oxygen desaturations and
      arousals from sleep, often many hundred times per night. OSA, defined as apnoea-hypopnoea
      index (AHI) of 5/h or higher, is a common but underdiagnosed sleep-related breathing disorder
      affecting up to 25% of the middle-aged male population twenty years ago, that now is
      substantially increased due to higher prevalence of obesity. It is estimated that 80-90% of
      moderate to severe OSA are not diagnosed. The gold-standard diagnostic test for OSA is
      in-laboratory polysomnography. Alternatively, OSA can be diagnosed with high sensitivity and
      specificity - in subjects with high probability for OSA based on clinical symptoms - by
      in-hospital respiratory polygraphy or portable monitor devices at home (cardiorespiratory
      sleep study). The usual and most effective treatment for OSA is continuous positive airway
      pressure (CPAP) therapy. A device delivers a continuous level of positive airway pressure
      with fixed or auto-titrating pressure keeping airway patency and thereby preventing apnoeas
      and hypopnoeas.

      Preliminary data from observational and non-randomised studies indicate an association
      between OSA and cardiovascular events. There is also evidence that severe symptomatic sleep
      apnoea is associated with hypertension, stroke and myocardial infarction. The proposed
      mechanisms underpinning the association between OSA and vascular dysfunction leading to
      cardio- and cerebrovascular disease are increasingly large intrathoracic pressure changes
      leading to mechanical stress on the heart and large artery walls, arousal-induced reflex
      sympathetic activation with resultant repetitive blood pressure rises, sometimes to over
      200mmHg, and intermittent hypoxia leading to increased oxidative stress and sympathetic
      activity. The rises in blood pressure induce extensive shear stresses on blood vessel walls -
      forces that are thought to cause vascular wall damage.

      Recent findings from observational studies suggest a possible link between OSA, thoracic
      aortic dilatation and aortic events in patients with Marfan's syndrome. Marfan's syndrome is
      an inherited disorder of the connective tissue and aortic root dilatation with subsequent
      rupture is the commonest life-threatening manifestation. In a cross-sectional study including
      patients with Marfan's syndrome, the severity of OSA was positively correlated with the
      diameter of the aortic root. In a recent prospective Marfan cohort study, the rate of aortic
      events (defined as operation because of rapid progressive aortic dilatation, and death
      because of aortic rupture) was compared between patients with and without OSA. Aortic-event
      free survival was significantly shorter in patients with Marfan's syndrome and OSA compared
      to patients without OSA, suggesting that OSA may be an important risk factor for aortic
      events in Marfan's syndrome.

      The underlying mechanisms through which OSA may promote aortic dilatation are not clear. OSA
      has been shown to be associated with increased diurnal blood pressure as well as with large
      and recurrent surges in blood pressure during apnoeic events, which is the main identified
      risk factor for aortic dilatation and dissection. In addition, obstructive apnoeas are
      associated with repeated inspiratory effort against the collapsed upper airway causing
      recurrent large negative intrathoracic pressures (sometimes as low as -80 mmHg) and thereby
      producing outward radial forces on intrathoracic structures including the aorta. This
      hypothesis is supported by the findings of Peters et al. who reported increased aortic
      diameters during obstructive apnoeas in an animal model. In healthy humans, experimentally
      simulated obstructive apnoea/hypopnoea has also been shown to lead to an acute increase in
      proximal aortic diameter and transmural pressures.

      In a recently published cohort study of patients with abdominal aortic aneurysms, it was
      shown that severe OSA may be associated with an accelerated expansion of abdominal aortic
      aneurysms. Because there is only limited cross-sectional and inconclusive data on the
      possible association between OSA and thoracic aortic aneurysm from non-Marfan study
      populations a prospective large cohort study of patients with thoracic aortic aneurysms is
      needed to investigate whether OSA is associated with faster progression of aortic dilatation,
      and aortic events, in a high risk population. Should OSA appear to be a factor associated
      with an increased risk for rapid aortic dilatation and aortic events, then a randomised
      controlled trial in those with OSA would be appropriate, looking at the effect of continuous
      positive airway pressure (the definitive treatment for OSA) on thoracic aortic dilatation.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Diagnosis of thoracic aortic aneurysm defined by the following parameters

          -  Women: at the level of the sinus of valsalva >39mm, or ascending aorta >42mm.

          -  Men: at the level of the sinus of valsalva >44mm, or ascending aorta >46mm.
      
Keywords: aortic aneurysm; obstructive sleep apnea