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1615PC Bairey-Merz/Slide #1
Women and Ischemic Heart Disease:Women and Ischemic Heart Disease:A Changing ParadigmA Changing Paradigm
Noel Bairey Merz, M.D., F.A.C.C., F.A.H.A.Medical Director, Women’s Heart Center
and Preventive Cardiac CenterThe Women’s Guild Chair in Women’s Health
Heart InstituteCedars-Sinai Medical Center
1615PC Bairey-Merz/Slide #2
Clinical CV Translational ResearchClinical CV Translational Research
1. A systematic approach to an identified problem
2. T1 (bench bed), T2 (bed clinic), T3 (clinic community)
3. Four key steps –1. Observation2. Mechanisms3. Intervention4. Translation
1615PC Bairey-Merz/Slide #3
Problem: Adverse Mortality Gap Resultingin a New Female Majority for CVD
Current Strategies Not Working Optimally in Women
2
1615PC Bairey-Merz/Slide #4
Clinical Translational ResearchClinical Translational Research
1. Observation
2. Mechanisms
3. Intervention
4. Translation
1615PC Bairey-Merz/Slide #5
Bugiardini and Bairey Merz JAMA 2005;293:477-84
Observation: Women have a two-fold increase in “normal”coronary arteries in the setting of ACS, nonSTE and STE AMI
1615PC Bairey-Merz/Slide #6
Observation:Phenotype -MicrovascularCoronary DiseaseExertional angina
Abnormal SPECT
No obstructive CAD
Abnormal coronary flow reserve and elevated LVEDP
Diffuse atherosclerosisby IVUS
NCDR estimate 3 million women in the US – a largerproblem than breast cancer.
Circulation. 1999;99:1774
3
1615PC Bairey-Merz/Slide #7
Clinical Translational ResearchClinical Translational Research
1. Observation
2. Mechanisms
3. Intervention
4. Translation
1615PC Bairey-Merz/Slide #8
Inflammatory MilieuE2
- Post-Menopause- Hypothalamic Hypoestrogenemic- PCOS
HTN
Obesity
↑ Lipids
Vascular Dysfunction
Positive Remodeling
Progressive Manifestations of Demand Ischemia
Symptomatic Manifestations
Abnormal coronary vasomotionMetabolic Δs, Perfusion
Exposure Time of Mismatch in Myocardial Oxygen Supply / DemandNear Term Prolonged
SubclinicalSubclinicalAtherosclerosisAtherosclerosis
Obstructive Obstructive CADCAD
Progenitor Cell Repair, Microvascular Disease, Fibrosis, Diastolic Dysfxn
NormalNormalArteryArtery-- ↓↓CFRCFR
NormalNormalArteryArtery& CFR& CFR
Autoimmune Diseases
Hypothetical New Understanding of IschemicHeart Disease in Women (Shaw and Bairey Merz)
Shaw et al, JACC 2009
1615PC Bairey-Merz/Slide #9
V3005V3005
4
1615PC Bairey-Merz/Slide #10
Women and Ischemic Heart Disease (Shaw, Bugiardini, Bairey Merz, JACC 2009)
Exposure Time of Mismatch in Myocardial Oxygen Supply / DemandNear Term Prolonged
Rep
etiti
ve /
Prog
ress
ive
Man
ifest
atio
ns o
f Isc
hem
ia
Micro-Infarction/Myocardial Fibrosis
Diastolic Dysfunction
Decreased Segmental Perfusion
Regional Wall Motion
Decreased Subendocardial Perfusion
Systolic Dysfunction
Endothelial and MicrovascularDysfunction
Altered Metabolism/Abnormal ST segment response
1615PC Bairey-Merz/Slide #11
Coronary Reactivity Testing
Post ACHBaseline Post NTG
VasoconstrictionOf LAD
1615PC Bairey-Merz/Slide #12
Pro
port
ion
With
out C
V E
vent
No Dilation (N=67)
Dilation (N=56)
Log-rank p=0.0037
Multivariate p=0.001
Years Of Follow-up0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Mechanisms: Abnormal Coronary Vasomotion To Acetylcholine Independently Predicts Cardiac Events
In Women with No Obstructive CAD
Mechanisms: Abnormal Coronary Vasomotion To Acetylcholine Independently Predicts Cardiac Events
In Women with No Obstructive CAD
VON MERING et al, Circulation 2004;109:722-125
5
1615PC Bairey-Merz/Slide #13
MECHANISM: POLYMORPHISM AT POSITION 573 AT-1R GENE IS ASSOCIATED WITH AN ABNORMAL ENDOTHELIAL FUNCTION, INDEPENDENT OF CAD
-40.00
-30.00
-20.00
-10.00
0.00
10.00
20.00
30.00
TT/TC CC
GENOTYPE
% C
HA
NG
E IN
CO
RO
NA
RY
AR
TE
RY
CR
OS
S S
EC
TIO
NA
L A
RE
A NO CAD
MILD CAD
SIG CAD
n =120, Mean values SE p=0.008, Wilcoxon rank sum TT/TC vs CC
VON MERING, JACC 2001;37:SUPPL A;293A
1615PC Bairey-Merz/Slide #14
Mechanisms: Beta1 Adrenergic Polymorphism* Predicts Adverse Outcome in Women with No Obstructive CAD (n=936)
Pancanowski et al (submitted)
Time to Event (months)
96847260483624120
Cum
ulat
ive
Surv
ival
(%
)
100
90
80
70
60
50
B: Non-obstructive CAD, Gly389 carrier
D: Obstructive CAD, Gly389 carrier
C: Obstructive CAD, Arg389 homozygote
Race-adjusted log-rank A vs. B P=0.015 C vs. D P=0.799
A: Non-obstructive CAD, Arg389 homozygote
*Adrenergic control of myocardial contractility, microvasculature and renin release
1615PC Bairey-Merz/Slide #15
Reduced CFR
NonobstructiveAtheroma
Pro-Atherogenic FactorsHTN, IR,
Inflammation…
Vascular Dysfxn SymptomsAtypical Symptoms
SOBUnusual Fatigue↑ Frequency
Pro-Vasculopathy
Sex-Specific PrecursorsPCOS, Hypoestrogenemia,Menopause
Accelerating FactorsEarly Menopause
Risk Factor Clustering
Hormonal Alterations Coupled with:
Hypothetical Model of Female-Specific Vasculopathic Angina
Subendocardial or Epicardial Ischemia
6
1615PC Bairey-Merz/Slide #16
Diastolic Relaxation Failure Increases Oxygen Diastolic Relaxation Failure Increases Oxygen Consumption and Reduces Oxygen SupplyConsumption and Reduces Oxygen Supply
Sustained contraction of ischemic tissue during diastole:
– Consumes energy, increasing myocardial oxygen consumption
– Causes intramural compression of small vessels, reducing myocardial blood flow and oxygen supply
– (Most blood flow to the heart occurs during diastole)
– Worsens ischemia and angina
1615PC Bairey-Merz/Slide #17Journal of the American College of CardiologyVolume 47, Issue 8 , 18 April 2006, Pages 1630-1638
Mechanisms: Reduced perfusion in patients with normal coronary angiography - MR can measure the subendocardium
51/100 female
1615PC Bairey-Merz/Slide #
Ch
ang
e in
PC
r/A
TP
du
rin
g s
tres
s, p
erce
nt
-50
-40
-30
-20
-10
0
10
20
30
>70% S ten o sisW o m en w ith
C h est P a inb u t n o rm a l A n g io
R efe ren ceP o p u la tio n
p < 0 .025 ,com pared to n o rm a ls
2 sd
Mechanisms: Metabolic PCr/ATP (Magnetic Resonance [MR] 1.5 Tesla) ischemia is prevalent in patients with normal angiography
NEJM 2001
7
1615PC Bairey-Merz/Slide #19
Patient 1
Stress Perfusion Rest Perfusion
RV LV
Papillary muscles
Subendocardial hypoperfusion
Cine –diastolic frame Delayed enhancement
1615PC Bairey-Merz/Slide #20
1615PC Bairey-Merz/Slide #21
Abnormal adenosine stress first pass perfusion demonstrating regional first pass hypoperfusion in the septum and apex in a patient with very recent LAD stent for acute MI. The patient has microvascular obstruction.
8
1615PC Bairey-Merz/Slide #22
Interventional No Reflow: Interventional No Reflow: 21% MI and 2% elective PCI21% MI and 2% elective PCI--stentingstenting
Circulation 2008;117;3152-3156
1615PC Bairey-Merz/Slide #23
Clinical Translational ResearchClinical Translational Research
1. Observation
2. Mechanisms
3. Intervention
4. Translation
1615PC Bairey-Merz/Slide #24
COURAGE Primary EP:COURAGE Primary EP:Survival Free of Death or MISurvival Free of Death or MI
Years0 1 2 3 4 5 6
0.0
0.5
0.6
0.7
0.8
0.9
1.0
PCI + OMT
Optimal Medical Therapy (OMT)
Hazard ratio: 1.0595% CI (0.87-1.27)P = 0.62
7
• Randomization to PCI +
OMT vs. OMT
• Intensive, Guideline-Driven
Medical Therapy & Lifestyle
Intervention In Both Groups
Source: Boden et al. N Engl J Med. 2007; 356:1503-16.
9
1615PC Bairey-Merz/Slide #25
-0.2
0
0.2
0.4
0.6
0.8
1
≤2.0 2.1-2.2 2.3-2.4 2.5-2.6 2.7-2.8 2.9-3.0
Baseline CFR
CF
R C
ha
ng
e
Placebo
ACE-I
Intervention T2: Patients with ischemia and no obstructive CAD randomized to the ACE-I quinipril have improved microvascular coronary function measured by CFR (n=67)
Pepine CJ et al, Circ in press
1615PC Bairey-Merz/Slide #26
Figure 10. Mean Number of Chest Pain or Symptom Episodes in the Prior Month by Eplerenone Vs. Placebo Treatment Group
0
5
10
15
20
25
30
35
40
45
50
Baseline Visit2 Visit3 Visit4
Ches
t Pai
n E
pis
odes
/ M
onth
Placebo
Drug
E-WISE unpublished data
Intervention T2: Patients with ischemia and no obstructive CAD randomized to the aldosterone blocker eplenerone have improved symptoms related to microvascular dysfunction (preliminary data)(n=43).
1615PC Bairey-Merz/Slide #27
-40
-30
-20
-10
0
10
Entry
Exit
placebo1/10 NE/EE
(%)
PCr/ATP MRSRatio p=0.17
comparedto placebo
Intervention: Patients with ischemia and no obstructive CAD randomized to low dose hormone (estrogen-progestin) therapy did not improve ischemia measured by metabolic MR (preliminary data)
Bairey Merz CN et al Am Heart J (in press)
10
1615PC Bairey-Merz/Slide #28
MERLINMERLIN--TIMI 36: Efficacy results TIMI 36: Efficacy results in major subgroupsin major subgroups
Morrow DA et al. JAMA. 2007;297:1775-83.
0.6 0.8 1.41.2 1.6
Favors ranolazine Favors placebo
Gender MenWomen
Age <75 years
≥75 years
Diabetes No DMDM
SubgroupPrimary endpoint
n
TIMI Risk 0-34-7
STD ≥1 mm NoYes
Overall 6560
42692291
5406
1154
43402220
36012959
42552304
Pinteraction
0.12
0.80
0.39
0.16
0.23
Index event UANSTEMI
30673342
0.85
HR (95% CI)
STD = ST-segment depression
1615PC Bairey-Merz/Slide #29
Scan 2 4/14/08
MPRI 1.2
Scan 1 3/3/08
MPRI 2.5
Randomized, cross-over trial of ranolazine 500-1000 po bid vs placebo in women with signs and symptoms of ischemia and no obstructive coronary artery disease: Analysis in progress
1615PC Bairey-Merz/Slide #30
Clinical Translational ResearchClinical Translational Research
1. Observation
2. Mechanisms
3. Intervention
4. Translation
11
1615PC Bairey-Merz/Slide #31
This slide set was adapted from the following 2004-6 ACC/AHA guidelines:
Cardiovascular Disease Prevention in Women 2004
Management of Patients With ST-Elevation Myocardial Infarction
Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction
Preventing Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease
Management of Patients with Chronic Stable Angina
Update for Coronary Artery Bypass Graft Surgery
Evaluation and Management of Chronic Heart Failure in the Adult
The full-text guidelines and executive summaries are also available on the
ACC and AHA websites at www.acc.org and www.americanheart.org
Clinical Practice Guidelines (T3)Clinical Practice Guidelines (T3)
ACC=American College of Cardiology, AHA=American Heart Association
1615PC Bairey-Merz/Slide #32
Impact of AHA Get With The GuidelinesImpact of AHA Get With The Guidelines--CAD CAD Program on Quality of CareProgram on Quality of Care
93
79
64 6757
95
83
6570 70
9787
6573 76
9687
6775 75
9791
6874
82
0102030405060708090
100
Aspirin Beta Blocker ACE Inhibitor Lipid Rx SmokingCessation
Baseline Q1 Q2 Q3 Q4
* ***
* p< 0.05 compared to baseline
* *
***
*
**
GWTG-CAD: 123 US Hospitals n=27,825Labresh, Fonarow et al. Circulation 2003;108:IV-722
**
1615PC Bairey-Merz/Slide #33
GuidelineImplementation andACS and the Sex Survival Gap
Following guidelineimplementation, mortality for womenimproves andthe sex gap narrows(RED)
Persistent sex gap (BLUE)suggests more workStill neededto understand sex-specific pathophysiologyto improve outcomesfor women and men
Novak et al Am J Medicine 2008;121:602.
+
12
1615PC Bairey-Merz/Slide #34
Cardiovascular disease mortality trends for males and females Cardiovascular disease mortality trends for males and females (United States: 1979United States: 1979--2004).2004). Source: NCHS and NHLBI
380
400
420
440
460
480
500
520
79 80 85 90 95 00 04
Years
Dea
ths
in T
ho
usa
nd
s
Males Females
0
Problem: Adverse Mortality Gap Resulting in a New Female CVD MajorityCurrent Strategies Not Working Optimally in Women
NHLBI WISE study And Awareness and Guidelines Campaigns
1615PC Bairey-Merz/Slide #35
Cardiovascular disease mortality trends for males and females Cardiovascular disease mortality trends for males and females (United States: 1979United States: 1979--2004).2004). Source: NCHS and NHLBI
380
400
420
440
460
480
500
520
79 80 85 90 95 00 04
Years
Dea
ths
in T
ho
usa
nd
s
Males Females
0
Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority
Solution: Clinical Translational Research and Guidelines
NHLBI WISE study And Awareness and Guidelines Campaigns
1615PC Bairey-Merz/Slide #36
NOEL BAIREY MERZ, MD SAIBAL KAR, MD
LESLEE SHAW, PhD STEVE NISSEN, MD
CARL J. PEPINE, MD RENU VIRMANI, MD
JULIE JOHNSON, PHARM D, PhD LOUISE THOMSON, MD
WILLIAMS ROGERS, MD DAN BERMAN, MD
VERA BITTNER, MD CHRISANDRA SHUFELT, MD
STEVE REIS, MD POITR SLOMKA, MD
RICARDO AZZIZ, MD EDUARDO MARBAN, MD, PhD
SHERYL F. KELSEY PhD SUPURNA CHOWDHURY PhD
DELIA JOHNSON, PhD RAJ MAKKAR, MD
GERALD POHOST, MD PK SHAH, MD
ARSHED QUYYUMI, MD CALVIN HOBEL, MD
AMIR LERMAN, MD CHANDER AROURA, PhD
BARRY SHARAF, MD GLENN BRAUNSTEIN, MD
GEORGE SOPKO, MD ANITA PHAN, MD
INVESTIGATORS
13
1615PC Bairey-Merz/Slide #37
Ischemic Heart Disease in Women: Ischemic Heart Disease in Women: Changing ParadigmChanging Paradigm
Conclusions and Next StepsConclusions and Next Steps1. Sex differences in ischemic heart disease
mechanisms impact appropriate diagnosis and treatment, contributing to adverse outcomes in women.
2. Microvascular coronary dysfunction can be evaluated using a variety of imaging techniques; CMRI may be an ideal noninvasive modality.
3. Ongoing research is further exploring noninvasive evaluation strategies. Contact us at [email protected] or 310 423 9680 for information or referral.