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

 None

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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
6500
4500
2500
1600
Coronary Artery Disease
Stroke
Lung Cancer
Breast Cancer
Colon Cancer
Endometrial Cancer
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.

Increased Mortality in Younger Women by
Vaccarino et al., NEJM 1999;34:217-225

Gupta el al, JACC 2014; 64:337-45

100,0%
90,0%
80,0%
70,0%
60,0%
50,0%
40,0%
30,0%
20,0%
10,0%
0,0%
6.4%
(n=4,565) p<0.0001
3.4%
(n=5,229) p<0.0001
31.9%
(n=71,030) p<0.0001
Women Men
Complications in patients who underwent PCI
Total patients who underwent PCI
68.1%
(n=151,630) p<0.0001
20,0%
18,0%
16,0%
14,0%
12,0%
10,0%
8,0%
6,0%
7.3%
(n=331) p<0.0001
3.8%
(n=200) p<0.0001
4,0%
2,0%
6.4%
(n=4,565) p<0.0001
0,0%
Women Men
Mortality in patients who experienced complications
Complications in patients who underwent PCI
3.4%
(n=5,229) p<0.0001
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
Biological Differences: Greater prevalence of nonobstructive disease, greater prevalence of vascular dysfunction
 coronary microvascular dysfunction
Awareness/Treatment Bias
 Undertreatment of women (primary and secondary prevention)
▪ 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

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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

IDEAL AT RISK
Mosca, Circulation, 2011

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

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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
Daniels, Circ Cardiov Outcomes 2013

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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
Peters et al, Lancet 2014, Dotevall Eur Heart J, 20007,
Barrett-Connor, Global Heart 2013

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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

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540 patients with signs and symptoms of ischemia and
<50% CAD on angiogram (WISE cohort)
Compared to 1000 age and race-matched controls
(WTH)
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

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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
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

 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 30 Circulation 1999;99:1774

Endo-PAT Test Procedure
5 - 10 min 5 min 5 - 10 min
Cuff inflation Occlusion Cuff deflation
Confidential 31

Automatic data analysis
Occluded period
Test arm
Control arm
Reactive hyperemia

Endothelial Dysfunction
Normal
Endothelial Function
Endothelial Dys function
4/15/2020 33

 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

Endothelial dependent
Macrovascular dysfunction
Abnormal vasoreactivity to Acetylcholine
Endothelial
Independent
Abnormal vasoreactivity to
Nitroglycerin
Microvascular dysfunction
Reduced coronary blood flow in response to Acetylcholine
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
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

 High Risk Equivalents: DM, CKD, PVD, COPD, TIA/CVA, Functional Disability

 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

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Liepsic et al, Radiology July 15
2014, epub
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”

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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.
Murthy et al, Circulation 2014; 129:
2518-2527

 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).

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34 yo female no cardiac risk 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
 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.
•
• Only Academic Program in OC focusing on Women’s Heart Care
Specializing :
❤
Coronary Heart Disease
❤
Cardiac Arrhythmia
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Preventive Heart disease and Cardiac Rehab
❤
Heart Failure
❤
Cardiac Imaging
❤
Adult Congenital Heart Disease
❤
Cardiac Research

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:
• 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