obstructive sleep apnea and cardiovascular risk barbe.pdfobstructive sleep apnea and cardiovascular...

Obstructive Sleep Apnea and

cardiovascular risk

Ferran Barbé, MD

Institut de Recerca Biomedica. IRBLleida

CIBERES. Instituto de Salud Carlos III.

Madrid.

Obstructive Sleep Apnea (OSA)


• Affects 10% of population

• Excessive daytime sleepiness; poor quality of life and road accidents.

• Increased morbi-mortality mainly due to cardiovascular causes.


Sánchez-de-la-Torre, M. The Lancet Respiratory Medicine 2012

OSA and cardiovascular consequences Sanchez de la Torre et al Lancet Respir Med 2013

CPAP (Continuos Positive Airway Pressure)

• Chronic treatment

• More than 4 h/day to be effective (CV risk)


AHI Reference

0 1 2 3 4 5 6 7 8 9 10

3.30

5.20

> 30 Marin. Lancet 2005

> 36 Yaggi. NEJM 2005

> 30 Young. Sleep 2008

OR (95% IC)

2.87

1.46 > 30 Punjabi PLOS 2009

Odd Ratio for death in OSA

OSA and mortality Punjabi et al Plos Med 2010

N = 6441

Follow up: 8.2 yrs

1047 participants

died

OSA and long-term mortality

Marin JM

Lancet 2005

MEN

1651

Men 49.8 (8.1)

years

Martinez-Garcia MA

AJRCCM 2013

ELDERLY

936

Elderly

71.2 (4.4) years

Rodriguez-Campos F

Ann Intern Med 2011

WOMEN

1116

Women 57.5 (12.1)

years

Meta-analysis of OSA and serious CVE Loke et al. Circ Cardiovasc Qual Outcomes 2012

STROKE

Meta-analysis of OSA and serious CVE Loke et al. Circ Cardiovasc Qual Outcomes 2012

Odds ratio for stroke Loke et al Circ Cardiovasc Qual Outcomes 2012

STROKE

CPAP 46%

Efficacy of CPAP on 5ys survival in stroke O. Parra et alt. J Sleep Res 2014

Meta-analysis of OSA and serious CVE Loke et al Circ Cardiovasc Qual Outcomes 2012

CHD

CV DEATH

Meta-analysis of OSA and serious CVE Loke et al Circ Cardiovasc Qual Outcomes 2012

“OSA appears to be associated with

stroke, but the relationship with isquemic

heart disease and cardiovascular mortality

needs further research.”

Meta-analysis of OSA and CV mortality Loke et al Circ Cardiovasc Qual Outcomes 2012

Effect of Continuous Positive Airway

Pressure on the Incidence of

Hypertension and Cardiovascular

Events in Nonsleepy Patients With

OSA

Incidence of hypertension and CVE in OSA Barbé et al JAMA 2012

17

DESIGN: Randomized prospective controlled study

POPULATION: Patients with AHI > 20 and Epworth scale < 10

MEASUREMENTS: Blood pressure measurement

CVE

EVALUATIONS: Basal, 3, 6, 12, 24, 36, 48 month

Incidence of Hypertension and CVE in OSA Barbé et al JAMA 2012

18

CPAP

n= 357

Conservative

n= 366

Age (yrs) 52 ± 11 52 ± 11

Male 88% 84%

AHI (h-1) 42 ± 30 35 ± 23*

BMI (K.m-2) 31 ± 5 31 ± 5

Epworth 6.5 ± 2 6.5 ± 2

SBP (mmHg) 132 ± 17 131 ± 17

DPB (mmHg) 80 ± 11 80 ± 11

Compliance (h) 4.2 ± 2 -


CPAP 46%

p = 0.2


CPAP 46%

p = 0.2 p = 0.04


CV = 18 (n= 3,166)

CV = 27 (n= 8,397)

CV = 6 (n= 624)

CV = 2 (n= 920))

CV = 2 (n= 110))

CV = 1 (n= 50)

CV = 2 (n= 2500)

CV = 1 (n= 50)

CV = 1 (n= 150)

OSA and ongoing RCT´s CV studies = 61 (n = 18,705)

CPAP use and change in BP Martinez-Garcia et al. JAMA 2013

-30

-20

-10

01

02

0

ch

an

ge

s in 2

4h m

ea

n B

P (

mm

Hg

)

0 2 4 6 8CPAP use (hours/day)

r = 0.3

p = 0.006

-30

-20

-10

01

02

0

ch

an

ge

s in 2

4h m

ea

n B

P (

mm

Hg

)

0 2 4 6 8CPAP use (hours/day)

r = 0.3

p = 0.006

CPAP use and change in BP Martinez-Garcia et al. JAMA 2013

Non-responders

(n=18)

Responders p-value

(n=20)

Change in mean blood pressure after

CPAP treatment (pre- minus post-CPAP), mmHg -0.25 [-5;2.5] 11 (7.5;14.1) NA

Sex, male, n(%) 18 (100) 20 (100) 1

Age, years 60 [52;66] 54 [50.8;63] 0.14

BMI, kg·m-2 32 [30.1;34] 32.1 [30.7;37.6] 0.39

Neck perimeter, cm 42.5 [42;43.8] 44 [42.0;46] 0.49

Apnea-hypopnea index, event/h 34.5 [22.2;47.8] 48.5 [31.5;59] 0.12

TSat90 6 [1.5;11.2] 7 [2.00;27] 0.17

Epworth sleep scale score 9 [6.5;12] 8 [5.00;9] 0.26

CPAP mean use, h/day 5.5 [4.5;6] 5.5 [4.88;6.5] 0.87

24-h mean blood pressure, mmHg 113 [107;114] 118 [111;122] 0.057

SBP, mmHg 142 [136;150] 147 [138;152] 0.41

DBP, mmHg 82.5 [74.2;85.8] 88.5 [82.5;94] 0.026

Nocturnal blood pressure pattern, n(%) 0.76

Dipper 4 (22.2) 7 (35)

Non-dipper 9 (50) 9 (45)

Riser 5 (27.8) 4 (20)

Precision medicine in RH and OSA Sanchez de la Torre et al. JACC 2015

MicroARNs (miRNAs):

Small genetic sequences that regulate gene expression.

Related with manifestation of phenotypes and diseases.

Precision medicine in RH and OSA Sanchez de la Torre et al JACC 2015

miRNA PCR array

• Rationale: Determination of miRNA expression in OSA patients with RH could lead to specific profiles and be related to response to CPAP treatment.

Differentially expressed miRNAs Cardiovascular disease

hsa-miR-144-3p Differentiation/Development (Up-Regulated)

hsa-miR-100-5p Cardiomyopathy (Up-regulated)

hsa-miR-486-5p Cardiac Hypertrophy (Down-Regulated)


hsa-miR-7-5p Cardiomyopathy (Down-regulated)

hsa-miR-378a-3p Cardiomyopathy (Down-regulated) and Differentiation/Development (Up-Regulated)

hsa-miR-92a-3p Cardiomyopathy (Up-regulated)

Differentially expressed miRNAs Cardiovascular disease

hsa-miR-144-3p Differentiation/Development (Up-Regulated)

hsa-miR-100-5p Cardiomyopathy (Up-regulated)



hsa-miR-7-5p Cardiomyopathy (Down-regulated)

hsa-miR-378a-3p Cardiomyopathy (Down-regulated) and Differentiation/Development (Up-Regulated)

hsa-miR-92a-3p Cardiomyopathy (Up-regulated)

3 miRNAs with the highest associations with a

favorable BP response to CPAP


Training set (n=24). AUC=0.85 Validation set (n=14). AUC= 0.92


HIPARCO-Score

HIPARCO-

Score

% favorable BP

responders to CPAP

(observed)

% favorable BP

response to

CPAP

(predicted)

0 0% 6%

1 50% 21%

2 50% 46%

3 67% 75%

4 67% 80%

5 100% 90%

6 100% 98%

Take home messages

Is OSA associated with increased CV mortality?

Probably YES

Does CPAP reduce CV mortality ? ? Is OSA asociated with ischemic heart disease?

Probably NO

Is OSA asociated with stroke?

Probably YES

Does CPAP reduce the incidence of CV

disease? Probably YES

In patients with RH and OSA, can you predict

blood pressure response to CPAP treatment? YES

Ferran Barbé

Manuel Sánchez-de-la-Torre

Alicia Sánchez

Anabel Castro

Asunción Seminario

Cecilia Turino

Estefania Galera

Fernando Santamaría

Joan Escobar

Joan Valls

Jordi de Batle

Luis Fer. Casas

Lydia Pascual

Marina Canales

Marina Flores

Mireia Dalmases

Manel Vilà

Maricel Arbonés

Spanish Sleep and Breathing Network

Initial exclusion criteria: -Secondary RH -Aged<18 -Pregnancy -Severe hypersomnia -Previous CPAP treatment -Renal failure (creat>1.5 mg/dl) -CVE in the month prior

CPAP and resistant hypertension Martinez-Garcia et al. JAMA 2013

# 82 %


CPAP

n= 98

Conservative

n= 96

Age (yrs) 58 ± 10 58 ± 10

Male 72% 65%

AHI (h-1) 41 ± 19 40 ±19

BMI (K.m-2) 35 ± 5 34 ± 6

Epworth 9 ± 4 9 ± 4

SBP (mmHg) 145 ± 12 144 ± 13

DPB (mmHg) 83 ± 11 83 ± 10

Compliance (h) 5 ± 2 -


Intention-to-treat Per protocol (CPAP use ≥ 4h)

-10

-8

-6

-4

-2

0

BP changes

(mmHg)

SBP DBP MeanBP SBP DBP MeanBP

Control group CPAP group

mmHg -3.1 -3.2 -3.1 -4.9 -4.1 -4.4

*No changes in BMI or antAHT drugs in the follow-up

p (values) 0.09 0.005 0.016 0.01 0.001 0.001

Title: Method for predicting response to Continuous Positive Air Pressure

treatment

Application number: EP14382533.9 (European Patent Office) (December

2014)

Precision Medicine in Patients with Resistant Hypertension and

Obstructive Sleep Apnea: Blood Pressure Response to CPAP

Treatment.


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