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?