Sleep apnea and Cardiovascular diseases

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Sleep apnea and Cardiovascular diseases

• D. O. Rodenstein
• Service de pneumologie
• Cliniques universitaires Saint-Luc
• Université catholique de Louvain

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Normal Sleep Effects

• Decreases in
• Metabolic rate
• Sympathetic nervous activity
• Blood pressure
• Heart Rate
• Increases in
• Cardiac vagal tone

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Diagnostic study
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Obstructive events with thoraco-abdominal paradox
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Epidemiology
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Epidemiology
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There is a high prevalence of obstructive sleep
apneas/hypopnea, in both men and women. Many
subjects in the general population have more than
20 apneas/hypopneas per hour of sleep.
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Accelération et descéleration cardiaques 55 ? 82
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Accelération et descéleration cardiaques 44 ? 100
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Possible mechanisms linking Sleep Apnea to
Cardiovascular consequences

• Episodic Repetitive Hypercapnic Hypoxia
• Repetitive Reoxygenation
• Free Oxygen Radicals
• Repetitive arousals
• Sympathetic surges
• Inhibition of lung expansion
• Inhibition of parasympathetic tone

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Possible mechanisms linking Sleep Apnea to
Cardiovascular consequences

• Increase in Neural Sympathetic Traffic
• Peripheral vasoconstriction
• Increase negative intrathoracic pressure
• Increase left ventricular afterload
• Increased thoracic blood pooling and right
  ventricular preload
• Hypoxia related pulmonary vasoconstriction
• Increase in right ventricular afterload
• Paradoxical leftward shift of the
  interventricular septum
• Decrease in stroke volume

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• Intermittent hypoxia related to the production of
• Oxygen-Free-Radicals
• Tumor necrosis factor a
• Interleukin 8
• Interleukin 6
• C Reactive Protein

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• Decrease endothelium dependent vasodilation
• Decrease endothelial nitric oxide (eNOS)
• Increased oxidated lipoproteins
• Increase in adhesion molecules
• Vascular smooth muscle proliferation
• Platelet aggregation and activation
• Increase in Fibrinogen and decrease in PAI1
  (Plasminogen Activator Inhibitor type-1) activity

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Cardiovascular consequences of obstructive sleep
apneaClinical effects

• Hypertension
• Atherosclerosis
• Coronary artery disease
• Heart failure
• Arrhythmias
• Stroke
• Sudden death
• Glucose intolerance

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Arrhythmias

• Arrhythmias in general seem not to be more
  prevalent in OSA, but recurrent atrial
  fibrillation is probably twice as frequent in OSA
  compared to non OSA patients

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Atherosclerosis

• Increase markers of early atherosclerosis
• Carotid Intima-Media Thickness
• Decreased arterial compliance
• Silent Brain Infarction
• Decrease in cerebral blood flow during apneas

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Atherosclerosis

• In animals, association of exposure to chronic
  intermittent hypoxia and a rich cholesterol diet
  lead to atherosclerosis, whereas neither of both
  alone does

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Hypertension

• Epidemiological studies have shown that
  approximately 40 of patients with sleep apnea
  have hypertension, and that about 40 of patients
  with hypertension have sleep apnea. Actual
  figures vary, depending on the definitions and
  thresholds for sleep apnea and hypertension.

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Sleep Apnea and Hypertension A
Population-based Study Khin Mae Hla Terry B.
Young Tom Bidwell Mari Palta James B. Skatrud
and Jerome Dempsey
Ann Int Med 1994
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Confounders

• Hypertension, as sleep apnea, rarely comes alone.
  Therefore, before implying causality from
  association, possible confounders need to be
  considered.
• These include gender, age, alcohol consumption,
  smoking, obesity (in general, or in particuler as
  for instance neck circumference)

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Odds ratio for hypertension at 4 year follow-up
according to baseline apnea-hypopnea index in 704
subjects from the Wisconsin Sleep Cohort. 184
subjects were followed-up for 8 years. Data were
adjusted for baseline hypertension, body mass
index, neck and waist circumference, age, gender,
alcohol consumption and smoking habits.
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Animal Models

• Intermittent sustained hypoxia
• Intermittent cyclic hypoxia
• Sleep-related obstructive apneas
• Sleep-related auditory arousals

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A drop in mean blood pressure of 10 mmHg would
reduce coronary heart disease risk by 37 and
stroke risk by 56. Subtherapeutic CPAP reduced
AHÍ by 50 but did not influence blood pressure
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Normotensive
BP HR Na
Hypertensive
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11 consecutive patients with refractory
hypertension (hypertension despite 3 different
drugs at maximal dosing)
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• Treatment with CPAP lowers blood pressure in
  patients with OSA. This effect is modest but
  consistent, and is more evident in patient with
  more severe hypertension

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• In addition, CPAP increases Left Ventricular
  Ejection Fraction

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Hypertension Conclusions

• Sleep apnea is an independent cause of systemic
  hypertension, beyond the effects of obesity,
  gender, age etc
• Patients with sleep apnea have 30 to 300 more
  risk of hypertension
• Treatment of sleep apnea may contribute to the
  treatment or control of hypertension, decreasing
  mean blood pressure by about 10 mmHg

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Mechanisms hormones
ANP Renin Angiotensin Aldosterone Norepinephrine E
pinephrin Cytokines
Hypertension 2004
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Mechanisms metabolism
Visceral fat Hyperleptinemia Insulin
resistance Interleukin-6 Interleukin-1ß Tumor
necrosis factor-a
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OSAS and cardiovascular disease
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Compared with subjects with an AHI 1, subjects
with an AHI gt11 have 22 more coronary heart
disease, 220 more heart failure, and 55 more
stroke, after adjusting for confounding
variables.
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• Obstructive sleep apnea aggravates the clinical
  course of coronary artery disease, with higher
  mortality, more major cardiac events and more
  restenoses after percutaneous dilation

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OSAS and Stroke
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In cross-sectional studies, OSAS appears as a
possible risk factor for stroke.
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New Engl J Med 2005
Longitudinal study. Polysomnography at entry,
events on follow-up
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New Engl J Med 2005
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Chest 2005 128 1310-1314

• 218 patients with sleep apnea and 218 normal
  subjects matched for age, gender, neighborhood
  and family physician were compared for health
  care costs for the 2 years prior to diagnosis.
• Patients mean annual individual costs (948 US)
  were significantly higher than costs for controls
  (571 US). Excess costs were due to more
  admissions, more consultations and more
  prescribed medications.
• The main prescribed pharmacological groups were
  cardiovascular and alimentary tract and
  metabolism.

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OSAS and cardiovascular mortality
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In this prospective study, severe OSAS increases
the risk of fatal and non-fatal cardiovascular
events in the 10 years following the initial
diagnosis. Effective treatment with nCPAP in
compliant patients eliminates this increased risk
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4 years follow-up of patients with severe OSAS
treated with nCPAP according to compliance to
tretment less than 1 hour per night (n 85), 1
to 6 hours per night (n 342) and gt6 hours per
night (n 322).
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Untreated (or very poorly treated) patients with
severe OSAS have a reduced survival after 4 years
follow-up, compared to similar patients
moderately or very compliant to nCPAP therapy
(85.5 vs 91.3 vs 96.4). The main cause of
death was cardiovascular. Compliance to nCPAP,
hypertension, age and FEV1 independently
predicted survival.
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Lancet 2009 373 82-93
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Conclusions

• Obstructive sleep apnea is
• A prevalent disease
• Linked to obesity
• Causally related to hypertension
• Increasing risks for
• Heart failure
• Stroke
• Cardiovascular related mortality
• Reversible under CPAP treatment

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Conclusions

• Obstructive sleep apnea is NOT a cardiovascular
  disease
• It is a respiratory sleep-related disease
• The events that follow breathing cessation lead
  to cardiovascular consequences, among others, but
  the primary event is the sleep-related collapse
  of the pharynx in the face of persistent
  ineffective breathing efforts

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Presenting Symptoms

• Related to sleep
• Unrefreshing sleep
• Unrestorative sleep
• Disturbing snoring
• Breathing pauses
• Restless sleep
• Nocturia
• Nocturnal sweating
• Gasping sounds
• Wake-up suffocating

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Presenting Symptoms

• Related to wakefulness
• Tiredness
• Lack of energy
• Sleepiness
• Memory impairment
• Anxiety and Irritability
• Depression
• Lack (or loss) of interest
• Sexual Dysfunction (Erectile Dysfunction, loss of
  sexual desire)
• Headaches

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Conclusions

• Even if the patient is referred just for
  refractory hypertension, the treatment of
  obstructive sleep apnea will correct a large
  series of consequences
• Neurologic
• Cognitive
• Behavioral
• Cardiovascular

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Thank you
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In the cross-sectional Sleep Heart Health Study,
sleep apnea significantly increases the risk for
coronary heart disease, heart failure, stroke,
and combined cardiovascular disease,
independently from confounding factors
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Intervention studies
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Significant decrease in nightime, but not
daytime, blood pressure after 3 weeks nCPAP
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Acute nocturnal effects of CPAP
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Effects of 2 months nocturnal CPAP decrease in
nocturnal and diurnal blood pressure
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Mechanisms arousals
Pepperell et Al, Sleep Med Rev 2002
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Mechanisms sympathetic stimulation
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Cheyne Stokes
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Cardiovascular consequences of obstructive sleep
apneaType of effects

• Hemodynamic
• Autonomic
• Chemical
• Inflammatory
• Metabolic