Download Shaista Malik, MD, PhD, MPH, FACC Associate Professor Cardiac Rehab Program

Shaista Malik, MD, PhD, MPH, FACC
Associate Professor
Medical Director, Preventive Cardiology and
Cardiac Rehab Program
Director, Women’s Heart Disease Program
University of California, Irvine
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Gender differences in clinical presentation,
risk profiles, and outcomes
Guideline/position statements that address
gender differences in prevention and
diagnosis of heart disease
Gaps in literature/future research efforts
At Every Age, More Women Die of Heart Disease Than Breast Cancer
Coronary Artery Disease
Stroke
Lung Cancer
Breast Cancer
Colon Cancer
Endometrial Cancer
6500
Death Rate per 100,000
4500
2500
1600
1200
800
400
0
45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Age (years)
National Center for Health Statistics. 1999:164-167.
by
Increased Mortality in Younger Women
Vaccarino et al., NEJM 1999;34:217-225
Gupta el al, JACC 2014; 64:337-45
100.0%
20.0%
90.0%
18.0%
3.4%
(n=5,229)
p<0.0001
80.0%
16.0%
14.0%
Percent of cases
Percent of cases
70.0%
60.0%
50.0%
40.0%
6.4%
(n=4,565)
p<0.0001
30.0%
7.3%
(n=331)
p<0.0001
12.0%
10.0%
3.8%
(n=200)
p<0.0001
8.0%
6.0%
20.0%
4.0%
68.1%
(n=151,630)
p<0.0001
31.9%
(n=71,030)
p<0.0001
10.0%
0.0%
6.4%
(n=4,565)
p<0.0001
2.0%
3.4%
(n=5,229)
p<0.0001
0.0%
Women
Men
Women
Men
Complications in patients who underwent PCI
Mortality in patients who experienced complications
Total patients who underwent PCI
Complications in patients who underwent PCI
Agarwal M, Kim M, Erande A, Amin A, Patel P, Malik S,
JACC supplement March 2014
Women Have a Two-fold Increase in “Normal” Coronary
Arteries during a Heart Attack: Open Artery Heart Attack
Stable Angina
~50%
~17%
Bugiardini, JAMA 2005;293:477-84
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Risk Factors with greater relative risk in women
 Diabetes, Hypertension, Triglycerides
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Biological Differences: Greater prevalence of nonobstructive disease, greater prevalence of vascular
dysfunction
 coronary microvascular dysfunction
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Awareness/Treatment Bias
 Undertreatment of women (primary and secondary prevention)
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▪
▪
▪
▪
Less cholesterol screening
Fewer lipid-lowering therapies
Less use of heparin, beta-blockers and aspirin during myocardial infarction
Less antiplatelet therapy for secondary prevention
Fewer referrals to cardiac rehabilitation
Fewer implantable cardioverter-defibrillators compared to men with the same
recognized indications
 Lack of evidence based guidance for treatment of CHD in
women
Recognition of risk factors specific to women
(pregnancy related, autoimmune disease)
 Response to lack of risk prediction by FRS, lowering
of score required to be high risk
 Risk categories: Ideal, At risk, High risk
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IDEAL
Mosca, Circulation, 2011
AT RISK
CVD
Mortality
per 100,000
Women
HTN – Hypertension
GDM – Gestational Diabetes
PCOS – Polycystic Ovary Syndrome
Source: Adapted from “CVD Prevention and the Primary Care Partnership”, Deborah Ehrenthal, MD, FACP
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GENDER GAP
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50% higher RR for CHD in
women vs. men with DM (Huxley
et al meta-analysis), even after
adjustment of other RF.
Age gap of 10 years in CVD
presentation between women
and men is completely
attenuated in women with DM
27% higher RR for Stroke in
women vs. men with DM (Peters
et al)
Etiology for this gap could be sex
hormones or lifestyle factors
Huxley et al, BMJ, 2006
Peters et al, Lancet 2014; Malik, Nature Rev Endocrin, 2014
Raloxifene Use for the Heart (RUTH) trial
10,101 post-menopausal women selected for high CHD risk
Negative trail, Raloxifene offered no protection against CHD
3672 with DM without known CHD and 3265 with history of CHD
without known DM
 DM was CHD risk equivalent in women for fatal (not nonfatal) CHD
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Daniels, Circ Cardiov Outcomes 2013
Women have impaired glucose tolerance in OGTT, doesn’t get picked up on
fasting glucose testing
 19% of women, 27% of men with CAD had normal OGTT in the Euro Heart Survey
on diabetes
 A1c maybe a better measure of prevalence of glycemic abnormalities in women
 Anthropometric measures maybe more abnormal in women compared to men
with diabetes, no other differences in co-existing RF between men and women
 Higher adiposity equals higher inflammation
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Peters et al, Lancet 2014, Dotevall Eur Heart J, 20007,
Barrett-Connor, Global Heart 2013
Women's Ischemia
Syndrome Evaluation
(WISE) study
 Women with significant
myocardial ischemia and
“open” arteries
 Tested for function of
the endothelium
 50% of women with
normal angiograms to
have microvascular
coronary dysfunction
(MCD) or small vessel
disease
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WISE Study
Male Pattern
Plaque:
Focal
Female Pattern
Plaque:
Diffuse
Burke et al, Circulation 1998
Khuddus, et al. J Int Cardiology, Dec 2010
Shaw et al, Circ Cardiov Imaging, 2010
Obstructive
Coronary
Disease
More prevalent
in men
Small Vessel Disease
/Microvascular
Coronary
Dysfunction
More prevalent
in women?
Slide courtesy of Noel Bairey-Merz, MD adapted from
New York Times
NY Times
Patients hospitalized for chest
pain or heart attack
Get a diagnostic angiogram
Results of the angiogram lead to
treatment
Increased deaths in those that do
not follow male pattern of heart
disease
Merz C N B Eur Heart J 2011;32:1313-1315
540 patients with signs and symptoms of ischemia and
<50% CAD on angiogram (WISE cohort)
 Compared to 1000 age and race-matched controls
(WTH)
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2.5%/year
Gulati et al., Arch Intern Med 2009;169:843-850
Confers a 2 fold increased risk
Johnson et al., European Heart J 2006;27:1408-1415
Normal
Coronar
y
Arteries
HR 1.52 (1.27-1.83) p<0.001
Jespersen et al., European Heart J 2012;33:734-744
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Symptoms of angina (typical and atypical)
Objective evidence of ischemia by traditional stress
testing
No obstructive CAD by coronary angiogram
Microvascular Coronary Dysfunction (MCD) is believed to
be the high risk subset of Syndrome X patients and
represents true pathology of the small vessels of the heart
Pathophysiologic Definition:
 Disordered function of the smaller (<100-200 um) coronary
resistance vessels
 Functional Definition (coronary flow reserve):
 Increase in coronary blood flow to maximal hyperemic
stimuli (eg, adenosine) < 2.5 fold from baseline
 Coronary flow reserve is the increase in blood flow in
response to metabolic/pharma stimuli
 Abnormal coronary microvascular that is clinically evident as
inappropriate coronary blood flow response
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Primary
 MCD in the absence of obstructive CAD or structural disease
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Secondary
 To obstructive CAD
 To myocardial diseases (anatomical restriction of the
vascular cross-section)
▪ HCM
▪ RCM
▪ LVH (hypertension, aortic stenosis)
 Iatrogenic (distal embolization during PTCA and
vasoconstriction due to recanalization)
Camici P, et al. NEJM 2007;356:830-840
Secondary MCD
Primary MCD
Secondary MCD
Kothawade et al., Curr Prob Cardiol 2011;36:291-318
Shaw et al., JACC 2009;54:1561-75
Diagnosis of MCD/Small Vessel Disease
 Exertional angina or ACS
presentation
 Abnormal stress testing
(nuclear stress test,
Adenosine MRI)
 Endothelial function
testing (EndoPAT-RHI
1.67)
 Abnormal coronary flow
reserve (<2.5, <50%)
 May have diffuse
atherosclerosis by IVUS
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Circulation 1999;99:1774
Endo-PAT Test Procedure
5 - 10 min
Cuff inflation
Confidential
5 min
Occlusion
5 - 10 min
Cuff deflation
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Control arm
Automatic data
analysis
Occluded
period
Test arm
Reactive hyperemia
Endothelial Dysfunction
Normal
Endothelial Function
5/25/2017
Endothelial Dysfunction
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CMRI validated for evaluation of:
 1) subendocardial perfusion 2) myocardial flow reserve
 3) fibrosis and microinfarction 4) assess LV function and mass
Pilz et al. J Cardiovasc Magn Reson 2008;10:8
Panting et al. NEJM 2002;346:1948-53
Measure both pressure and flow
Hasdai et al., Int J Cardiology 1996;53:203-208
>2.5
Endothelial Independent : Adenosine
>50%
Endothelial Dependent : Acetylcholine
Pulse wave doppler to measure blood flow velocity
Coronary blood flow measured by change in diameter of vessle and change in velocity
Macrovascular
dysfunction
Endothelial
dependent
Endothelial
Independent
Microvascular
dysfunction
Abnormal vasoreactivity
to Acetylcholine
Reduced coronary blood flow
in response to Acetylcholine
Abnormal vasoreactivity to
Nitroglycerin
Reduced coronary flow reserve
in response to Adenosine
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Recent clinical trail data show that medical management is safe for those with
stable heart disease
Clinical and prognostic significance of nonobstructive CAD detected by IVUS or
CCTA
Myocardial ischemia is associated with higher mortality in women than in men
Symptoms in women are correlated with coronary vascular dysfunction in the
setting of nonobstructive disease
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In both women and men, the most common
presentation of ischemia is CP
However women have different pattern and
distribution of non-chest related pain symptoms
 Epigastric discomfort with nausea
 Radiation to arms, neck, back
 Dyspnea and fatigue
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More often precipitated by mental or emotional
stress and less frequently by exertion
Significant overlap between men and women
when it comes to symptoms
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Women with stress test abnormalities and
nonobstructive CAD are NO LONGER defined
as having a false-positive test
Test needs to be classified as ABNORMAL
and they are noted to be at elevated risk
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High Risk Equivalents: DM, CKD, PVD, COPD, TIA/CVA, Functional Disability
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Diagnostic Testing Strategy now includes CCTA and Stress MRI
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Prior studies focused on men with
underrepresentation or exclusion of women
Studies of women: WISE, Nurses’ Health
Study, WHI, have not included a male
comparison group
Newer data shows some contradictions
Min et al, JACC 2011; Mieres 2014
Liepsic et al, Radiology July 15
2014, epub
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When matched for age, CAD risk factors, angina typicality, and nonobstructive CAD extent,
women and men experience comparable rates of incident mortality and myocardial infarction.
In multivariable analysis, nonobstructive CAD was associated with similarly increased MACE for
both women (hazard ratio: 1.96 [95% confidence interval [CI: 1.17, 3.28], P = .01) and men (hazard
ratio: 1.77 [95% CI: 1.07, 2.93], P = .03).
“Our data strengthen the WISE conclusions that extent and distribution of epicardial
nonobstructive CAD may not be a significant contributor to sex-based differences in adverse
clinical outcomes”
405 men, 813 women at Mass General referred for suspected CAD
for PET myocardial perfusion imaging
 Coronary flow reserve (CFR) was quantified to assess presence of
CMD, CFR <2 considered abnormal.
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Murthy et al, Circulation 2014; 129:
2518-2527
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Confirms WISE study findings
and extends them to men
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Mental stress–induced myocardial ischemia
(MSIMI) diagnosed as either worsening of WMA
or decrease in EF while doing 1 of 3 mental stress
tasks (mental math, mirror trace, and anger
recall).
Showed that MSIMI is much greater in
prevalence than previously thought.
Of 310 patients in the study only 18 were women,
of these women 57% had MSIMI compared to
41% of men
Men had greater hypertensive response in blood
pressure to stress
Women also had increased platelet aggregation
in reponse to collagen compared to men
(increased aggregation with all agonists but
power limitations).
 34 yo female no cardiac risk
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factors
Severe central chest pressure
with exertion or rest
1 episode of 10/10 pain with
associated symptoms, Tn 4.1
Normal EF, No WMA
Normal Angiogram
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Additional testing: A1c, CRP?
EndoPAT testing
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Additional testing: A1c, CRP?
EndoPAT testing
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Abnormal
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Additional testing: A1c, CRP?
Adenosine MRI
 18% reversible circumferential
subendocardial ischemia, inferolateral wall
Underwent CRT
 Normal coronary arteries
 Abnormal response to adenosine of 1.8
(normal >2.5)
 Abnormal response to Ach of 13% (normal
>50%), with visual vasoconstriction
 Normal response to NTG, no spasm noted
Diagnosis: MCD
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For her chest pain and ischemia
 B-blocker
 add on therapy with Ranolazine if needed
For endothelial dysfunction
 Statin
 ACEI
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Gaps in knowledge
“Paradoxical sex differences” have been noted in which,
compared with men, women have less obstructive
coronary disease, but higher rates of angina and death
Microvascular and endothelial dysfunction has been
postulated to play a significant role in presentation and
pathogenesis of
Personalized approach to women with symptoms
suspicious of heart disease
Abnormal stress test and normal angiogram= abnormal
test
Test for microvascular dysfunction (stress MRI, CRT in cath
lab, endothelial function tests)
UC Irvine’s Women’s Heart practice is a unique,
integrative program dedicated to comprehensive clinical
service, innovative research, and outstanding education
for clinicians and patients alike, with the common goal of
diagnosing and treating women’s heart disease.
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Only Academic Program in OC focusing on Women’s Heart Care
Specializing :
❤Coronary Heart Disease
❤Cardiac Arrhythmia
❤Preventive Heart disease and Cardiac Rehab
❤Heart Failure
❤Cardiac Imaging
❤Adult Congenital Heart Disease
❤Cardiac Research
UC Irvine:
OurProgram
Women’s
UCIHeal:
Women’s
Heart
Heart Program Clinical Services
We are the one academic-based women’s heart
practice in Orange County with the largest number of
physicians and researchers dedicated to women’s
heart health.
Members include:
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Shaista Malik MD PhD—preventive cardiology and
cardiac rehab
Jin Kyung Kim MD PhD—role of hormones and
heart disease and Echo
Dawn Lombardo DO—heart failure program and
Echo
Jeannette Lin MD—adult congenital heart disease
Afshan Hameed MD—high risk pregnancy and
heart disease
Pranav M. Patel, MD—interventional cardiology
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55 y/o female with HTN and dyslipidemia, has
had CP, pressure like sensation, not related to
physical exertion. Had TMST two years ago
at outside facility with no ischemic changes.
She presents to preventive program for
weight loss
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34 y/o female with h/o migrane and TIA
presents to clinic c/o CP radiating to her jaw.
CP is not exertional and is worse at night.
Stress echo was negative
Pt continued to have CP, EndoPAT test
ordered.
Abnormal EndoPAT, Adenosine MRI ordered