Sex and Gender in Coronary Microvascular Dysfunction · Sex and Gender in Coronary Microvascular Dysfunction 1. Coronary Microvascular Dysfunction (CMD) 2. Myocardial Infarction with

Sex and Gender in Coronary Microvascular Dysfunction

Coronary Microvascular Dysfunction and Diastolic Heart Failure in Women

International Congress Of Gender MedicineSeptember 22-23, 2015, Berlin/Germany

C. Noel Bairey Merz, M.D., F.A.C.C, F.A.H.AWomen’s Guild Endowed Chair in Women’s Health

Barbra Streisand Women’s Heart CenterPreventive and Rehabilitative Cardiac Center

Cedars-Sinai Heart InstituteLos Angeles, California USA

[email protected]

Presenter Disclosure Information

Women’s Heart Health (Bairey Merz)

DISCLOSURE INFORMATION:The following relationships exist related to this presentation (*paid to CSMC):Grant support*: NHLBI, SWHR, GileadConsulting*: Amgen, PfizerHonorarium*: Gilead, Pri-Med, NAMS, Medscape, Vox MediaStocks: None

3

Sex and Gender in Coronary Microvascular Dysfunction

1. Coronary Microvascular Dysfunction (CMD)

2. Myocardial Infarction with No Obstructive Coronary Angiography (MINOCA)

3. Takusubo Cardiomyopathy (TCM)

Non-obstructive CAD Rates in ACS Trials

*UASource: Anderson Circulation 2007;115:823-826.

%

Chart1

GUSTOGUSTO

TIMI 18TIMI 18

GUSTO*GUSTO*

TIMI IIIa*TIMI IIIa*

CURECURE

FRISC IIFRISC II

RITA 3RITA 3

MuellerMueller

Women

Men

19.5

8.5

17

9

31

14

26

8

14

16

24.5

9.5

28

28

21

11

Sheet1

WomenMen

GUSTO19.58.5

TIMI 18179

GUSTO*3114

TIMI IIIa*268

CURE1416

FRISC II24.59.5

RITA 32828

Mueller2111

Coronary Microvascular Dysfunction Angina

Abnormal SPECT

No obstructive CAD

Abnormal coronary flow reserve and elevated LVEDP

Diffuse atherosclerosisby IVUS

80% women

NCDR estimate 3 million women in the US – a largerproblem than breast cancer.

Circulation. 1999;99:1774

Women with non-obstructive have elevated risk compared to men (Sedlak et al AHJ 2013)

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Coronary Microvascular Dysfunction

Coronary atherosclerosis

Risk Factor ConditionsHypertension, Dylipidemia, Dysglycemia

Sympathetic nervous system activation, endothelial dysfunction, changes in vascular smooth muscle activation, spasm

Inflammatory and pro-oxidative stress

Accelerating FactorsEarly Menopause

Obesity

Subendocardial or Epicardial Ischemia

Takotsubo Cardiomyopathy

Diastolic Dysfunction

Crea, Camici, Bairey Merz EHJ 12/13

Scheme of the potential causes and consequences of coronary microvascular dysfunction

Late Gadolinium Enhancement and Interval Major Adverse Cardiac Events

– WISE CVD

Wei JACC 2015 in press

New LGE was identified at follow-up in 3 (1.7%).One subject with interval MI did not have interval LGE change.

These findings suggest that myocardial injury may be clinically under-diagnosed in this population.

9

Sex and Gender in Coronary Microvascular Dysfunction

1. Coronary Microvascular Dysfunction (CMD)

2. Myocardial Infarction with No Obstructive Coronary Angiography (MINOCA)

3. Takusubo Cardiomyopathy (TCM)

Non-Obstructive CAD –Common in All Forms of ACS

Hochman JS et al. NEJM 1999Berger JS et al. JAMA 2009

STEMI

NSTEMI

UA

p

Estimated Incidence: 40,000-100,000/year in US

Clinical correlates: female sex, younger age, black race

AHA 2014 statistics; Patel MR et al AHJ 2006, Shaw LJ et al Circ 2008, Dwyer JP et al. Int J Cardiol 2008, Chokshi NP et al. Clin Cardiol 2010

What is the Prognosis?

p=0.20

Gehrie et al AHJ 2009

In-hospital outcomes:CRUSADE registry

2% death or MI in-hospital in TIMI IIIA study with non-obstructive CAD2% cardiac death + 2.1% MI over one year in HORIZONS with non-obs CAD10% readmission for unstable angina over one year in TIMI meta-analysis

Diver et al AJC 1994, Planer et al Circ Intervention 2014, Bugiardini R et al Arch Int Med 2006

Chart1

Death or MIDeath or MI

DeathDeath

MIMI

Cardiogenic ShockCardiogenic Shock

HFHF

p=0.16

p=0.16

p=0.92

p=.29

Women

Men

0.019

0.014

0.006

0.007

0.013

0.009

0.01

0.007

0.049

0.036

Sheet1

WomenMen

Death or MI1.9%1.4%

Death0.6%0.7%

MI1.3%0.9%

Cardiogenic Shock1.0%0.7%

HF4.9%3.6%

To resize chart data range, drag lower right corner of range.

Mechanisms – MI with non-obstructive CAD

Plaque ErosionDifferent Underlying Plaque Morphology

Jia H et al, JACC 2013; Farb A et al, Circulation 1996, Guagliumi et al JACC Intv 2014

• More smooth muscle and proteoglycans, no necrotic core, denuded endothelium leading to thrombosis

• Common cause of ACS based on OCT studies• Plaque erosion is more common among younger women in autopsy

studies of sudden death victims

Image adapted from Funk SD et al Int J Vasc Med 2012

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Sex and Gender in Coronary Microvascular Dysfunction

1. Coronary Microvascular Dysfunction (CMD)

2. Myocardial Infarction with No Obstructive Coronary Angiography (MINOCA)

3. Takusubo Cardiomyopathy (TCM)

Stress-induced (“tako-tsubo”) cardiomyopathy

• After psychological stress• Excessive sympathetic stimulation • Apical ballooning of the left ventricle• Recovery in days to weeks• Persistent abnormal CMD after recovery 80-90% women

Teraoka K et al. Circulation. 2005;111:e261-e262

Tako-tsubo = japanese fishing jar

Results

Women higher odds of TTC OR = 8.8

Women >55 compared to Women < 55 OR = 4.8

Conclusion: Takotsubo diagnosed in 0.02% of all hospitalizations, mostly elderly women with history of smoking, etoh abuse, anxiety, and hyperlipidemia.

Sharkey SW et al. J Am Coll Cardiol 2010;55:333-341

Clinical Course and History of Patients With Stress Cardiomyopathy

Mechanisms: CardiotoxicEffects of Catecholamines

Coronary vasoconstriction (α1 stimulation hypoxia and subendocardial injury)

NE-mediated increased Ca2+ release in the sarcoplasma causing myocardial necrosis

Increased inotropy, chronotropy, and afterload increased O2 demand ischemia

Sympathetic nervous system can activate areas of myocardium differentially

Two Speculations (Totally Opposite !!)

Males are biologically better protected against stress Adrenergic innervation is different Adrenergic receptor density on the cardiomyocyte is higher

in men compared to women Autonomic stress response system is different

Males are biologically less resistant than females against stress Males die from LV dysfunction in the acute phase

(Sudden death is more frequent in men) Cardiomyocyte repair after damage is better in women

compared to menStollberger C at al. Int J Cardiol 2011;147:175

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Sex and Gender in Coronary Microvascular Dysfunction

1. Coronary Microvascular Dysfunction (CMD) – most prevalent, under-diagnosed and under-treated with guidelines therapy.

2. Myocardial Infarction with No Obstructive Coronary Angiography (MINOCA) –moderately prevalent, under-treated with guidelines therapy.

3. Takusubo Cardiomyopathy (TCM) – lower prevalence but increasingly recognized - ? Treatment ???

Sex and Gender in Coronary Microvascular Dysfunction�Coronary Microvascular Dysfunction and �Diastolic Heart Failure in Women�International Congress Of Gender Medicine�September 22-23, 2015, Berlin/Germany�Foliennummer 2Sex and Gender in �Coronary Microvascular DysfunctionNon-obstructive CAD Rates in ACS TrialsFoliennummer 5Women with non-obstructive have elevated risk compared to men (Sedlak et al AHJ 2013)Foliennummer 7Late Gadolinium Enhancement and Interval Major Adverse Cardiac Events – WISE CVDSex and Gender in �Coronary Microvascular DysfunctionNon-Obstructive CAD – �Common in All Forms of ACSFoliennummer 11What is the Prognosis?Mechanisms – MI with non-obstructive CADPlaque Erosion�Different Underlying Plaque MorphologySex and Gender in �Coronary Microvascular DysfunctionStress-induced (“tako-tsubo”) cardiomyopathyResultsFoliennummer 18Mechanisms: Cardiotoxic Effects of CatecholaminesTwo Speculations �(Totally Opposite !!)Sex and Gender in �Coronary Microvascular Dysfunction