Sleep apnea as a risk factor for cardiovascular disease

Sleep apnea as a risk factor for cardiovascular disease Malcolm Kohler Chair Respiratory Medicine, Clinical Director, Department of Pulmonology, University Hospital Zurich

Incidence of fatal cardiovascular events (%) CV Cardiovascular events in OSA events in OSA Controls Snorers Mild OSA without CPAP OSA without CPAP OSA with CPAP No CPAP P=0.0008 CPAP Months Prospective, controlled cohort study (372 patients with CPAP, 235 without CPAP) Marin et al. Lancet 2005

Patienten without recurrent event (%) Cerebral events in OSA 100 CPAP adherent patients 90 80 P=0.03 70 CPAP non-adherent patients 60 0 3 6 9 12 15 18 Time (months) Prospective, non-randomised interventional study, 51 patients with stroke and OSA, 18 months follow-up Martinez-Garcia et al. Chest 2005

Aneurysma Expansion (mm/year) Abdominal aortic aneurysm & OSA ODI categories Cohort study, 127 patients with abdominal aortic aneurysm Mason et al. AJRCCM 2011

Cummulative incidence (%) CV Cardiovascular events in OSA events in OSA Incidence of hypertension or cardiovascular events Years Years RCT (357 patients with CPAP vs 366 without CPAP) Barbe et al. JAMA 2012

CV events in OSA David after a holiday in the USA

Mechanisms of vascular damage in OSA Kohler & Stradling. Nat Rev Cardiol 2010

Sympathetic activity, acute blood pressure rises Increased sympathetic nervous system activity during apnoea Somers et al. J Clin Invest 1995

Acute blood pressure rises Blood pressure rises with every arousal = repetitive mechanical stress on arterial wall Systolic blood pressure (mmhg) 250 200 150 100 50 0 10 minutes Camen & Kohler, 2012

Blood pressure variability and CV risk Decile (SD SBP) Decile (SD SBP) UK-TIA trial, ASCOT-BPLA Rothwell et al. Lancet 2010

Sympathetic activity Placebo-CPAP CPAP RCT, N=102, 4 weeks CPAP vs Placebo-CPAP Kohler et al. ERJ 2008

Sustained blood pressure increase in OSA Placebo CPAP Reduction of diastolic BP of 3.3 mmhg with CPAP Mean arterial pressure (mmhg) CPAP Time (Hours) Randomised, controlled study, N=118, 4 weeks of CPAP vs Placebo CPAP Pepperell et al. Lancet 2002

Increased blood pressure and heart rate 80 P<0.001 Heart rate (1/min) 70 60 Reduction of diastolic BP of 6.9 mmhg with CPAP Diastolic blood pressure (mmhg) 50 90 85 80 P<0.01 0 2 4 6 8 10 12 14 Days RCT, n=41, CPAP vs CPAP withdrawal Kohler et al. AJRCCM 2011

How does this BP reduction compare? The effect of CPAP compares to a risk reduction for stroke and myocardial infarction of 34% and 21%, respectively! MacMahon et al. Lancet 1990

Flow-mediated dilatation (%) Endothelial dysfunction Baseline Post Ischaemia 8 P=0.002 P<0.001 6 4 2 0 Baseline 7 Days 14 Days RCT, n=41, CPAP vs CPAP withdrawal Kohler et al. AJRCCM 2011

Aortic stiffness in OSA ΔP/PP x 100 = Augmentation index (%) Placebo-CPAP CPAP RCT, N=72 OSAS patients, 4 weeks of CPAP vs Placebo-CPAP Kohler et al. ERJ 2008

OSA and abdominal aortic atherosclerosis Kylintireas et al. Atherosclerosis 2012

Aneurysma expansion (mm/year) OSA and abdominal aortic aneurysms Oxygen desaturation index categories Effect corrected for blood pressure, other CV risk factors and medication Mason et al. AJRCCM 2011

Intermittent hypoxia and blood pressure Baseline (air) Intermittent hypoxia Recovery (air) Blood pressure (mmhg) Δ = 4 mmhg RCT, 10 healthy males, air vs intermittent hypoxia for 4 days Foster et al. J Physiol 2009

Intermittent hypoxia and blood pressure 12 healthy subjects, intermittent hypoxia for 14 days Tamisier et al. ERJ 2011

Effect of oxygen on blood pressure in OSA RCT, CPAP vs lifestyle vs oxygen at night for 12 weeks Gottlieb et al. New Engl J Med 2014

Oxidative stress & endothelial dysfunction OSA patients before therapy OSA patients after therapy Endothel. fct. marker Oxidative stress marker Uncontrolled interventional study, 32 OSA patients, 4 weeks of CPAP Jelic et al. Circulation 2008

8-Isoprostane (pg/ml) NOx (μg/ml) Oxidative stress & endothelial dysfunction Oxidative stress marker Endothelial function marker Baseline Sham-CPAP CPAP Baseline Sham-CPAP CPAP RCT (cross-over), 31 patients with OSA, 12 weeks of CPAP or Placebo-CPAP. Alonso-Fernandez et al. Thorax 2009

Inflammation? OSA systemic inflammation Placebo-CPAP CPAP RCT, N=100, OSA patients with comorbidities, 4 weeks of CPAP vs Placebo-CPAP Kohler et al. Thorax 2009

Inflammation? Metabolic alterations? OSA systemic inflammation Deterioration following CPAP withdrawal (%) 80 60 40 20 0 P=0.01 P<0.01 P=0.03 P<0.01 P=0.93 P=0.58 P=0.08 P=0.84 P=0.66-20 NE FMD HR BP LDL HOMA CRP IL-6 TNF RCT, 41 OSA patients, CPAP vs CPAP withdrawal for 2 weeks Kohler & Stradling, J Physiol 2012

Intrathoracic pressure swings Intrathoracic pressure change increases aortic diameter 0 Intrathoracic pressure (mmhg) -40 20 Aortic diameter (mm) 16 Animal model, obstructed airways (simulated obstructive apnoea) Peters et al. JAP 1988

Intrathoracic pressure swings Proximal ascending aorta (mm) 29 * 28 27 26 25 Baseline Threshold Mueller Apnoea Experimentally simulated obstructive hypopnoea/apnoea, 20 healthy subjects Stoewhas et al. Chest 2011

Intrathoracic pressure swings Experimentally simulated obstructive hypopnoea/apnoea, 10 patients with suspected CAD Clarenbach et al. J Appl Physiol 2013

Intrathoracic pressure swings Clarenbach et al. J Appl Physiol 2013

Marfan s syndrome and OSA r=0.50, p=0.0003 Kohler et al. Thorax 2009

Aortic events in patients with Marfan s & OSA Non OSA P=0.012 OSA Cohort study, 44 patients with Marfan s syndrome Kohler et al. Respiration 2013

Take home message CV events in OSA Most of the vascular consequences of OSA seem to be due to increased sympathetic nervous system activity. This may be the result of both recurrent arousals and oxidative stress. There is good evidence from RCTs proving a causal relationship between OSA, vascular dysfunction and hypertension. OSA-induced hypertension ought to translate into increased morbidity and mortality, but this remains to be proven in RCTs. Whether intrathoracic pressure swings cause cardiovascular disease remains to be proven in controlled trials.

Take home message CV events in OSA Most of the vascular consequences of OSA seem to be due to increased sympathetic nervous system activity. This may be the result of both recurrent arousals and oxidative stress. There is good evidence from RCTs proving a causal relationship between OSA, vascular dysfunction and hypertension. OSA-induced hypertension ought to translate into increased morbidity and mortality, but this remains to be proven in RCTs. Whether intrathoracic pressure swings cause cardiovascular disease remains to be proven in controlled trials. There is still no data from RCTs proving a causal relationship between OSA and cardiovascular events!