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Pittsburgh Mind Body CenterSummer Institute
Sleep and Cardiovascular Disease
Relationships, Mechanisms
Charles Atwood, MDUPMC Sleep Medicine Center
Sleep Core, PMBC II
Healthcare Industry Relationships
• Grants– VA and NIH– Respironics, Resmed, Medcare, Guidant
• Consulting – Respironics, Resmed, Boerhinger-Ingelheim, Jazz
Pharmaceutical, GRQ Consultants (health policy)
• Speakers bureau– Boerhinger-Ingelheim, Jazz
Goals and Objectives
• Short overview of sleep
• Interaction between sleep and CV system
• Brief overview of sleep apnea
• Mind-body medicine, sleep, sleep apnea and CV disease: current understanding and future directions
Health Relationships
HEALTH
Exercise Nutrition
Sleep
Definition of Sleep
A complex collection of physiological and behavioral processes that are organized around behaviors such as quiet recumbency with closed eyes
-Carskadon
Function(s) of Sleep
• Ecological - survival advantage for sleeping animals• Improves quality of wakefulness
– Better alertness, mood, cognition
• Role in learning – “sleeping on it” improves learning • Neural effects - role in maintaining neural plasticity• Resensitize NT receptors (norepi, serotonin)• Energy conservation, recharging brain, housekeeping
hypothesis• Metabolic, immunity, inflammation regulation• Longevity
Basic Characteristics of Sleep
• Conserved through phylogeny– Argues for fundamental importance
• Internal rhythmicity – Self-regulating and sustaining
• Homeostastic drive – Sleep drive proportional to time since last sleep
• Circadian drives– Internal ~24 hour clock interacts with homeostatic
drive
Homeostatic vs. Circadian Sleep Drive
Homeostatic mechanisms (S) interact with Circadian factors (C) to
determine sleep propensity across the day
Changes in Sleep with Aging
STAGE 1 SLEEP
Note: slow, rolling eye- movementsmixed frequency EEG
STAGE 2 SLEEP
K complex Sleep spindle
STAGE 3 AND 4
Note slow (delta) waves in EEG and EOG channels
EEG
EEG
EOG
EOG
STAGE REM
Small amplitude, desynchronized (replacement of higher amplitude “synchronous EEG waves with lower amplitude, higher frequency waves) waves Rapid eye movements (phasic REM) and periods of minimal (tonic) eye movement Skeletal muscle inhibition
Sleep HypnogramSLEEP STAGES ACROSS THE NIGHT
Sleep – Wake is but one of many
circadian rhythms
Dijk & Lockley, J Appl. Physiol, 02
Sleep and the Cardiovascular system
waking
sleeping
•Stress•Circadian factors•Exercise•Diet•Illness
•Stress•Circadian effects•Sleep stages•Illness
Characteristics of the CV System during Sleep
NonREM sleep Decreased HR Decreased BP Decr baroceptor
sensitivity Decreased SNS
tone
REM sleep Increased HR Increased BP Variable baroceptor
sensitivity Increased SNS tone
Somers, V. K. et al. N Engl J Med 1993;328:303-307
Sympathetic Nerve Activity by Stage of Sleep
Somers et al, NEJM, 1993
SNS Activation in Different Sleep Stages and Events
Somers, NEJM, 1993
Overview of Sleep Apnea
Epidemiological Studies of OSA
• Wisconsin Cohort Study– On going study of OSA and CV disease in
middle-aged WI state workers– Established accepted prevalence of OSA
• Men: 25% with OSA, 4% with OSA on PSG• Women: 9% with OSA, 2% with OSA syndrome
• Pennsylvania Study– Confirmed above with larger, broader
sample; different methods
Epidemiology of OSA and CV Disease
• Sleep Heart Health Study– Collaborative study of existing CV cohort
studies (Framingham, Wisconsin study, CVS, ARIC, etc)
– Home based polysomnograms added to usual battery of tests
Prevalence of Sleep Apnea
Age in years
OS
A P
rev
ale
nce
0.3
0.25
0.2
0.15
0.1
0.05
0.3
0.25
0.2
0.15
0.1
0.05
035 45 55 65 75 85
AJRCCM 2002 165:1217–1239
Plateau
Why Sleep Apnea Isn’t Going Away…..
Pathogenesis of OSA
Genetic factors Obesity influence
Small pharyngeal airway
Airway Closure
Sleep effectVentilatory control factors
Upper Airway Sites Contributing to OSA
White, DPAJRCCM 2005
Anatomic Determinants of Airway Closure
Evidence of a Role for Ventilatory Control Mechanisms in Obstructive Sleep Apnea
Onal and Lopata, ARRD, 1982
Sleep-Sensitive Neuromodulators
Sleep Phasic Respiratory Input
Superior Laryngeal Nerve
White, DPAJRCCM 2005
Balance of Pressures in Upper Airway Physiology
Small airway size Upper airway resistance Neg inspiratory pressure Extra lumenal tissue pressure Greater collapsibility Smaller mandible
Favors collapse
Pharyngeal dilator muscles Larger airway size Larger mandible Less collapsibility Higher lung volume
Favors patency
Comparison of Obstructive and Central Sleep Apnea
Obstructive– Common (5%)– Male predominance
(approximately 2:1)– Snoring, sleepiness
common– Assoc with aging,
obesity, male gender
Central– Less common – Gender differences
less clear– Snoring, sleepiness
less prominent– Assoc with advanced
heart, brain disease
Most Common Clinical Features
• Loud snoring– Most common complaint– 40% of men, 20% of women report habitual
snoring– Associated with considerable social and
marital hazard– 70-90% of OSA patients snore; in one
study only 6% of OSA did not snore**Viner et al, Ann Int Med, 1991
Most Common Clinical Features
• Nocturnal choking/gasping– Bed partners may recognize this more
commonly than the patient– Differential diagnosis includes:
• Nocturnal panic disorder• Paroxysmal nocturnal dyspnea• GERD/Reflux
Most Common Clinical Features
• Daytime Sleepiness– Differential includes
• insufficient sleep• medical and psych disorders• Meds• sleep disorders
– Subjective measurement with Epworth score– Objective measurement with sleep latency
testing (daytime sleep study)
0
5
10
15
20
25
30
0 10 20 30 40 50 60 70 80 90 100
Ep
wo
rth
Sle
epin
ess
Sca
le
Apnea – Hypopnea Index
The Relationship of Self Reported Sleepiness to Sleep Apnea
n = 4653
Non-Sleepy Sleep Apnea
Sleepy Sleep Apnea
Representative Signals
Normal Breathing
Hypopnea
Oximetry
Heart Rate
Nasal Airflow
Effort
30 sec
Oximetry
Heart Rate
Nasal Airflow
Effort
30 sec
Representative Signals
30 sec
OSA
CSA / CSR
Oximetry
Heart Rate
Nasal Airflow
Effort
Oximetry
Heart Rate
Nasal Airflow
Effort
30 sec
Sleep Apnea is Associated with Significant Co-morbidities
Cardiovascular Complications
MetabolicComplications
Neuro-cognitiveComplications
Concentration and Neurocognitive Deficits in OSA
SLEEP APNEAMakes you sleepyMakes stupidMakes you crash cars
Sources of Data for Understanding OSA and CV
Disease
• Epidemiologic studies – about 20, from 5 continents
• Clinical Studies – hundreds, and growing
• Intervention Studies – handful, but growing
Mechanisms of OSA Contributing to Risk of CV Disease
Shamsuzzaman, et al, JAMA, 2003
0
0.5
1
1.5
2
2.5
I 2 3 4
CAD
CHF
CVA
Sleep Disordered Breathing and CV Disease: Cross-sectional Results of the SHHS
OddsRatio
Quartile of AHI (IQ range 1.3-11)
Shahar et al., AJRCCM 2001;163:19-25
CAD, p=0.08CHF, p=0.008CVA, p=0.06
severity
Incident Hypertension within 4 years according to Apnea-Hypopnea Index
0
0.5
1
1.5
2
2.5
3
0 .1-4.9/hr 5.0-14.9/hr
N =709
Adjusted for baseline hypertension, age, sex, BMI, waist and neck circumference, alcohol and cigarette use.
NEJM 2000 342: 1378 - 1384
A/H Index> 15 hr
AdjOR
Cu
mu
lati
ve
In
cid
en
ce
of
Fa
tal
CV
Ev
en
ts
Cu
mu
lati
ve
In
cid
en
ce
of
No
n-f
ata
l C
V E
ve
nts
AIM: Observational study to compare incidence of fatal and non-fatal cardiovascular events in simple snorers, patients with untreated OSA,patients treated with CPAP, and healthy men recruited from the general population.Design: Prospective observational cohort. 264 healthy men, 377 simple snorers, 403 with untreated mild-moderate OSA (AHI 5-30), 235 with untreated severe OSA (AHI > 30), and 372 with OSA and treated with CPAP
Lancet 2005 365: 1046–53
MonthsMonths
.
Conclusion: In men, severe OSA significantly increases the risk of fatal and non-fatalcardiovascular events. CPAP treatment reduces this risk.
Long-term cardiovascular outcomes in men with OSA
Clinical Studies in OSA
• Studies of SNS and BP
• Studies of endothelial function and correlates of OSA
• Correlating OSA with time of death
Shamsuzzaman et al. JAMA 2003;290:1906-1914
Neural and Circulatory Changes in Obstructive Sleep Apnea
2
2.5
3
3.5
4
4.5
5
Baseline %FMD
<1.5
1.5-4.9
5.0-14.9
15.0-29.9
>29.9
Endothelial Function in OSA
Adapted from Nieto et al, AJRCCM 2004;169:354-60
DiameterOf Brachial Artery, mm
Condition
P = 0.003
P = 0.028
Quintile of AHI severity
(flow mediateddilatation)
Comparison of Relative Risk of Death from CV Disease in OSA vs. General
Population Over 24 hours
Gami et al, NEJM 2005, 352:1206-1214
ROS
Xanthine Oxidase Mitochondrial Dysfunction Homocysteine
Activation of Transcription Factors
Monocyte Activation
Lymphcyte Activation
Endothelial cell Activation
Adhesion Molecule Expression
Monocyte Lymphocyte / Endothelial Adhesion
Endothelial Dysfunction
Vascular Disease
Intermittent Hypoxia
Sleep Med Rev2003 7:35-51
Intervention Studies in OSA
• Best evidence is for OSA and BP and CPAP as an intervention
• Pepperell et al
• Recent meta-analysis of intervention trials of CPAP in OSA and effect of BP
Effect of Positive Airway Pressure on Upper Airway Patency
Randomized, Placebo-Controlled Trial of CPAP on BP Control in OSA Pepperell et al, Lancet 2001;359:204-10
118 subjects with OSAPlacebo: sham CPAPDuration of study: 4 weeksMatched for ODI, ESS, BMIEqual CPAP adherence in groups
B
Tx
Haentjens, P. et al. Arch Intern Med 2007;167:757-764
Meta-analysis: CPAP effect on BP in OSA
Haentjens, P. et al. Arch Intern Med 2007;167:757-764
Meta-analysis for the net change in 24-hour ambulatory mean blood pressure
Mind-Body Science and Sleep Possible Areas of Overlapping Interest
• Stress – CV disease link• Depression – CV disease link• Behavioral factors,hypertension and sleep
parameters• Role of exercise, fitness and diet in sleep
quality• Stress and sleep quality: effects on health
Blood Pressure and Sleep:Dipping vs. Non-dipping
• BP dipping during sleep is normal• Non-dipping is associated with
– Worsened outcomes in CHF– OSA– Poorer renal function– Incident stroke
• Relationship to other variables?– Socio-economic status– Race– OSA
Dipping Status and SESStepnowsky et al, Psychosomatic Medicine, 2004;66:651-4
78 subjects Evenly distributed racially
and by gender 24 hr ambulatory BP
monitoring Home based full PSG Hollingshead SES measure
– education, occupation; Lower score, higher SES
Dipping ratio calculated Night BP/Day BP
White Male
N= 28Age 38.8 ± 1.7
Black Male
N= 19Age 40.8 ± 1.7
White FemaleN= 14
Age 23.6 ± 1.8
Black FemaleN= 17
Age 39.1 ± 1.4
WM WF BM BF
MAPPM/
AM
77.6 /
91.0
75.1/
85.1
86.5/
95.7
82.2/
90.9
AHI 10.1 6.5 7.8 9.6
Social Index
44.3 ± 2.6
33.2 ± 3.6
44.3 ± 2.5
39.7 ± 3.6
Dip Ratio
0.86 ±0.01
0.84 ±0.02
0.91 ±0.02
0.90 ±0.02
SES, Sleep Apnea and BP DippingStepnowsky et al, Psychosomatic Medicine, 2004
SES Accounts for a Significant Amount of Variance in Dipping Status
from Stepnowsky et al., Psychosomatic Medicine, 2004
Proposed Model Integrating Sleep Disordered Breathing, Psychological Stress and Nocturnal Physiology as Predictors of CVD Risk Factors
Heart SCORESleep SCORE
Sleep Disordered Breathing
Nocturnal Physiology• Non SDB sleep Characteristics• Urinary catecholamines• Autonomic function• BP dipping status
Psychological stress• Acute & chronic life events• Ambient stress
Established CV Risk Factors• Cholesterol• Hyperglycemia• Blood Pressure • Smoking Cardiovascular
Morbidity & Mortality• Coronary calcification• Brachial artery size• Endothelial dysfunction• MI• Stroke • Death
Emerging CV Risk Factors• Inflammation• Metabolic Syndrome• Renal Insufficiency
Summary/Conclusions
• Sleep related factors are important; awareness among mind-body investigators is growing
• OSA is the best studied aspect of sleep in relation to CV disease
• Most research in OSA and CV disease has been epidemiological and clinical – little mechanisms research has been performed
• Once mechanisms are better understood, more sophisticated interventions can be developed
QUESTIONS?
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