Janet Wei, MD, FACCBarbara Streisand Women’s Heart CenterBiomedical Imaging Research Institute

Ischemia with No Obstructive Coronary Artery Disease: 2019 Update

Disclosures

•No conflicts

2

3

Objectives

•Recognize the prevalence and prognosis of ischemia with no obstructive coronary artery disease (INOCA).

• Identify mechanisms contributing to INOCA and myocardial infarction with no obstructive coronary artery disease (MINOCA).

•Review current diagnostic and management strategies for women with INOCA/MINOCA.

Prevalence of Non-Obstructive CAD

13.5

13.9

5.0

4.2

7.6

6.8

27.1

30.5

10.2

9.1

8.8

10.2

MetaAnalysisn=19,777

GUSTOIIb

MetaAnalysisn=14,466

GUSTOIIb

MetaAnalysisn=102,004

GUSTOIIb

%withnon-obstructiveCAD

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

STEMI

NSTEMI

UA

p<0.02forallcomparisons

4

• Estimated 54,000-187,000 cases/year in US• Up to 5% one-year death rate

EHJ2016;AHAstatistics2016;PasupathyetalCirculation.2015;131:861-870 5

MI with No Obstructive CAD (MINOCA)

•No angiographic obstructive CAD (≥50% in major epicardial vessel)

6Fourth Universal Definition of Myocardial Infarction, J Am Coll Cardiol, 2018.

STEMI Patients with MINOCA

•STEMI patients with MINOCA are at even higher risk of in-hospital death than other MINOCA patients–Odds ratio for death 6.0 in women, 4.2 in men with ST elevation–Higher than in STEMI with obstructive CAD (2.6 women, 2.3 men)

• ACTION registry, N=322,523

7Smilowitz N et al, Circ Cardiovasc Qual Outcomes. 2017; 10:e003443

Chest Pain without Obstructive CAD

Marinescu MA et al. JACC Cardiovascular Imaging 2015. 8

Normal Coronary Macro- and Microcirculation

Taqueti VR, Di Carli MF. J Am Coll Cardiol. 2018;72(21):2625-41. 9

Pathogenic Mechanisms

Camici PG, Crea F. N Engl J Med. 2007;356:830-40. 10

Women’s Ischemia Syndrome Evaluation (WISE)

•Persistent symptoms of angina (typical and atypical)

•No obstructive CAD by angiography

Bairey Merz et al. JACC 2006;47(suppl 3):S21-9.Camici et al. J Nucl Med 2010; 50:1076-1087.

11

Vascular Dysfunction is Common in INOCA

Non-endothelial-dependent CMDCoronary Flow Reserve (CFR) ≤ 2.5 to adenosine

138/293 (47%)

Endothelial-dependent CMD∆ Coronary Blood Flow (CBF) ≤ 50% to acetylcholine

112/220 (51%)

Endothelial-dependent macrovascular dysfunction<5% increase in diameter in response to acetylcholine

127/220 (58%)

Macrovascular smooth muscle dysfunction<20% increase in diameter to nitroglycerin

136/225 (60%)

Women’s Ischemia Syndrome Evaluation (WISE)

Wei J et al. JACC Interventions 2012;5(6):646-53 12

High Prevalence of Coronary Microvascular Dysfunction (CMD) in Both Sexes

Sara JD et al. JACC Interventions. 2015;8:1445–53Murthy V et al. Circulation 2014;129:2518-2527

Invasive DiagnosisMayo Clinic: 1,439 patients

- Mean age 51.9 years- 34.9% male

- CMD (CFR≤2.5,CBF≤50%)

Men: 60% with CMDWomen: 66% with CMD

13

Noninvasive Diagnosis (PET)Brigham & Women’s: 1218 patients

- Mean age 61.9 years- 33.3% male

- CMD (CFR <2)

Men: 51% with CMDWomen: 54% with CMD

Epicardial Vasospasm

IC Acetylcholine IC Nitroglycerine

Ong P et al. J Am Coll Cardiol. 2012;59:655–62

45% with epicardial spasm in ACOVA (35/124 pts with exertional angina & no obstructive CAD)

14

Mieres JH, et al. Circulation. 2014;130:350-379.

Women With Suspected Ischemic Heart Disease

15

16

Negative Stress Test Does Not Rule Out INOCA

Cassar A et al. Circ Cardiovasc Interv. 2009;2(3): 237–244

How to diagnose INOCA?

Non-Invasive–Cardiac stress MRI –Cardiac PET with CFR–Doppler Echo with CFR

Invasive–Coronary Reactivity Testing during angiography

17

Stress Cardiac MRI - Semiquantitative

Stress Perfusion mid-ventricle

Rest Perfusion mid-ventricle

MPRI <1.84 predicts ≥1 CRT abnormality (sensitivity 73%,specificity 74%)

Thomson LE, Wei J et al. Circ Cardiovasc Imaging. 2015;8(4):e002481. 18

Myocardial Perfusion Reserve IndexMPRI = (upslope tissue/upslope LV) stress

(upslope tissue/upslope LV) rest

StressPerfusion RestPerfusion

MyocardialSI

MyocardialSI

Time(msec) Time(msec)

Myocardial Blood Flow Quantification by PET

19Blankstein R, 2019

Indications For Invasive Coronary Testing

Evidence of ischemia+

No obstructive CAD+

Persistent chest pain

Chest pain refractory to medical management

Preference for definitive diagnosis

20WeiJetal.JACCInterventions.2012;5(6):646-53;Reriani Metal.CoronaryArteryDisease.2015;27(3):213-20;OngPetal.Circulation.2014;129(17):1723-30

WISE and Mayo Clinic safety data: <0.6-0.7% serious adverse event (coronary dissection, MI)

Coronary Reactivity Testing

AbnormalCoronaryFlowReserveto

Adenosine

Vasoconstrictionduringlow-doseAcetylcholine

CFR1.8

Weietal.JACCCardiovasc Interv.2012;5:646–653 21

Microvascular Dysfunction

MacrovascularDysfunction

Non-Endothelial Dependent

CFR <2.5 to Adenosine

Coronary dilation <20% to Nitroglycerin

Endothelial Dependent

∆CBF <50% to Acetylcholine

Coronary dilation≤0% to Acetylcholine

Coronary Spasm Chest Pain + ECG changes + significant constriction to Acetylcholine

Bairey Merz CN et al. Circulation. 2017;135(11):1075-1092

Coronary Reactivity Testing Pathways

22

CFR Predicts Adverse CV Outcomes

Pepine CJ et al. JACC. 2010; Taqueti VR et al. Eur Heart J. 2018. 23

HeartFailurewithPreservedEjectionFraction(HFpEF)Hospitalization

Underdiagnosis of MI in Women with INOCA

•MRI late gadolinium enhancementà scar

•Among 340 women with suspected INOCA, scar prevalence was 8%, with an annual 1% new scar incidence.

•One-third of women with scar did not have prior diagnosis of MI à ?undertreated

24Wei J et al. Circulation 2018;137(8):874-876

Coronary Endothelial Dysfunction

ACE-I, statins, L-arginine, aerobic exercise, EECP

Abnormal Coronary Flow Reserve

Beta-blockers/alpha-beta blockers, ACE-I

Abnormal Smooth Muscle/ Vasospasm

Calcium channel blockers, Nitrates

Anti-Anginal/Anti-IschemicRanolazine, Ivabradine,

Xanthine derivatives, Nicorandil

Abnormal Cardiac NociceptionLow dose tricyclic, spinal cord

stimulation, stellate ganglion block, cognitive behavioral therapy

Mehta PK, Wei J, Bairey Merz CN. Chronic Coronary Artery Disease, A Companion to Braunwald’s Heart Disease, 2018.

INOCA Therapy

25

NO OUTCOMES DATA

Women’sIschemiaTrialtoReduceEventsinNon-ObstructiveCAD

CSMCSitePI:ChrisandraShufeltMD,MSFundingbyDepartmentofDefense

https://warriorwomenstrial.com/

•WARRIOR is a prospective, randomized, blinded study evaluating intensive medical treatment (IMT) vs. usual care in symptomatic women with INOCA

•We are recruiting women who have:–have signs and symptoms of suspected ischemia–non-obstructive CAD defined as <50% diameter narrowing of a major epicardial vessel (by catheterization or coronary CTA)

WARRIOR Trial

1No UAP, ACS, MI, etc. 2Symptoms = Angina or angina equivalent. 5Exclude women with Hx of non compliance, HIV, HepC, etc.eGFR <30, liver disease, etc. 6Intensive Medical Therapy= Potent statin (+ ACE-I (or ARB)7Usual Care= Usual clinical care

INTENSIVE MEDICAL Strategy (IMT)6

N=2211

Clinically Stable1 Women withSymptoms2 of Ischemia

Nonobstructive CAD4 byInvasive Coronary Angio or CCTA Women with

Exclusions5

RANDOMIZEN=4,422

Primary Care GUIDELINE MEDICAL Strategy (UC)7

N=2211

Average Follow-up 3 Years Primary Outcome: First occurrence of Death, MI, Stroke, or

Hospitalization for HF or Angina

StudyDesign

How should we treat MINOCA?

• Incomplete understanding of mechanisms in MINOCA leads to:– Variable use of secondary prevention measures by clinicians– Uncertainty about which post-MI treatment guideline recommendations should apply

29

MINOCA: Variety of Underlying Etiologies

30

MINOCA: Variety of Underlying Etiologies

31

Thrombophilia Screening in Patients with MINOCA

32Pasupathy et al Circulation. 2015; 131: 861-870

More Research is Needed

• Mechanistic studies to date have been small and single-center• We need to:

• Define prevalence and outcomes of specific etiologies• Understand the role of thrombosis• Determine the best diagnostic strategy• Select medications to be used, best target population for future studies

Summary

1) INOCA is common in women and associated with adverse prognosis.2) Noninvasive and invasive diagnosis of coronary vasomotor

dysfunction pathways provides prognostic information and may influence therapeutic strategies.

3) Further research is needed to understand mechanisms leading to INOCA and MINOCA, to guide therapy to reduce outcomes.

34