Sleep apnea and Cardiovascular diseases

D. O. RodensteinService de pneumologie

Cliniques universitaires Saint-LucUniversité catholique de Louvain

Normal Sleep Effects

• Decreases in– Metabolic rate– Sympathetic nervous activity– Blood pressure– Heart Rate

• Increases in– Cardiac vagal tone

Diagnostic study

Obstructive events with thoraco-abdominal paradox

Epidemiology

Epidemiology

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.

Accelération et descéleration cardiaques 55 82

Accelération et descéleration cardiaques 44 100

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

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

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

• 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

Cardiovascular consequences of obstructive sleep apnea

Clinical effects

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

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

Atherosclerosis

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

apneas

Atherosclerosis

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

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.

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

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)

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.

Animal Models

• Intermittent sustained hypoxia

• Intermittent cyclic hypoxia

• Sleep-related obstructive apneas

• Sleep-related auditory arousals

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

Normotensive

Hypertensive

BP

HR

Na

11 consecutive patients with refractory hypertension (hypertension despite 3 different drugs at maximal dosing)

• 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

• In addition, CPAP increases Left Ventricular Ejection Fraction

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

Mechanisms: hormones

Hypertension 2004

ANP

Renin

Angiotensin

Aldosterone

Norepinephrine

Epinephrin

Cytokines

Mechanisms: “metabolism”

Visceral fat

Hyperleptinemia

Insulin resistance

Interleukin-6

Interleukin-1β

Tumor necrosis factor-α

OSAS and cardiovascular disease

Compared with subjects with an AHI ~1, subjects with an AHI >11 have 22% more coronary heart disease, 220% more heart failure, and 55% more stroke, after adjusting for confounding variables.

• Obstructive sleep apnea aggravates the clinical course of coronary artery disease, with higher mortality, more major cardiac events and more restenoses after percutaneous dilation

OSAS and Stroke

In cross-sectional studies, OSAS appears as a possible risk factor for stroke.

New Engl J Med 2005

Longitudinal study. Polysomnography at entry, events on follow-up

New Engl J Med 2005

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• 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.

Chest 2005; 128: 1310-1314

OSAS and cardiovascular mortality

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

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 >6 hours per night (n= 322).

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.

Lancet 2009; 373: 82-93

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

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

Presenting Symptoms

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

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

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

Thank you

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

Intervention studies

Significant decrease in nightime, but not daytime, blood pressure after 3 weeks nCPAP

Acute nocturnal effects of CPAP

Effects of 2 months nocturnal CPAP: decrease in nocturnal and diurnal blood pressure

Mechanisms: arousals

Pepperell et Al, Sleep Med Rev 2002

Mechanisms: sympathetic stimulation

Cheyne Stokes

Cardiovascular consequences of obstructive sleep apnea

Type of effects

• Hemodynamic

• Autonomic

• Chemical

• Inflammatory

• Metabolic