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Ischemia and Myocardial Infarction with Non-obstructive CAD Noel Bairey Merz MD, Janet Wei MD, Chrissandra Shufelt MD, Margo Minissian ACNP-BC, Saibal Kar MD, Bruce Samuels MD, Babak Azarbal MD, Tim Henry MD Women’s Heart Center Cedars Sinai Heart Institute Los Angeles

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Ischemia and Myocardial Infarction with

Non-obstructive CAD

Noel Bairey Merz MD, Janet Wei MD,

Chrissandra Shufelt MD, Margo Minissian ACNP-BC,

Saibal Kar MD, Bruce Samuels MD, Babak Azarbal MD, Tim Henry MD

Women’s Heart Center

Cedars Sinai Heart Institute

Los Angeles

Presenter Disclosure

Information Bairey Merz DISCLOSURE INFORMATION

The following relationships exist related to this

presentation (*paid to Cedars-Sinai Medical Center):

Grant support*: NHLBI, FAMRI, Gilead, Louis B Mayer

Foundation, Erika J. Glazer Women’s Heart Research

Initiative, NIH-CTSI, California Institute of Precision

Medicine (CIAPM), Abbott Diagnostics

Consulting*: Medscape, Gilead, NIH, Sanofi Vascular

Honorarium*: Practice Point, Pri-Med

Stocks: None

Mechanisms of Myocardial Infarction: Atherosclerotic and Non-atherosclerotic

Prevalence and Prognosis

Pathophysiology

Diagnosis

Treatment

Next Steps

Bugiardini and Bairey Merz JAMA 2005;293:477-84

MI with no obstructive CAD (MINOCA): Women have a two-fold

increase in “normal” coronary arteries in the setting of ACS,

NSTEMI and STEMI

Prevalence of Coronary Vascular Dysfunction

Reis AHJ 2001; Pepine JACC 2008; Hasdai D et al. Mayo Clin Proc. 1998; EHJ 2016

• Approximately 50% of patients with: • persistent chest pain • non-obstructive coronary artery disease

have physiologic evidence of coronary vascular dysfunction.

● Takotsubo cardiomyopathy (TCM) And spontaneous coronary artery dissection (SCAD) have 10-15% Recurrence, and frequently have persistent chest pain.

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 CAD

2% cardiac death + 2.1% MI over one year in HORIZONS with non-obs CAD

10% 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. Slide courtesy of H Reynolds

Mechanisms of Myocardial Infarction: Atherosclerotic and Non-atherosclerotic

Prevalence and Prognosis ⎯ 10% MINOCA

⎯ Adverse prognosis

Pathophysiology

Diagnosis

Treatment

Next Steps

Mechanisms – MI with non-obstructive CAD

Slide courtesy of H Reynolds MD

How frequent is plaque disruption in MI with non-obstructive CAD?

• Prospective cohort studies

– 50 women, IVUS of 2 vessels, ~2 days 38%

– 68 men and women, IVUS, <24 hours 37%

– Only clinical correlate of plaque rupture/ ulceration in both studies: % angiographic stenosis

– No angiographically normal patients with plaque disruption in these small studies

• For comparison, plaque rupture in 49% of STEMI cases (OCT ~2 hours, OCTAVIA)

Reynolds et al Circ 2011, Ouldzein H et al Ann Cardiol Angeiol 2012 Guagliumi et al JACC Interventions 2014 Slide courtesy of H Reynolds MD

1615PC Bairey-Merz/Slide # 10

1615PC Bairey-Merz/Slide # 11

Morphology of Intramyocardial Emboli in Epicardial

Plaque Thrombosis Women vs. men:

– Any emboli: 73% vs. 37%, p<.001

– Mean emboli: 12 ± 3 vs. 4 ± 1, p=.02

Acute myocardial necrosis:

– Any emboli: 88% vs. 39%, p<.001

– Mean emboli: 18 ± 5, 4 ± 1, p<.001

CD61

Fibrin II

EM

Burke and Virmani R et al,

In press

Mechanisms of Myocardial Infarction: Atherosclerotic and Non-atherosclerotic

Prevalence

Pathophysiology ⎯Plaque rupture/erosion and embolization ⎯Coronary macro and microvascular spasm ⎯Takotsubo cardiomyopathy ⎯Myocarditis ⎯SCAD

Diagnosis

Treatment Next steps needed

Atherosclerotic At least 50-60%

Non-atherosclerotic

Coronary Microvascular Dysfunction

Coronary atherosclerosis

Risk Factor Conditions Hypertension, Dylipidemia, Dysglycemia

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

Inflammatory and pro-oxidative stress

Accelerating Factors Early Menopause

Obesity

Subendocardial or Epicardial Ischemia

Takotsubo Cardiomyopathy

PlaqueRupture/Erosion

Crea, Camici, Bairey Merz EHJ 12/13

Scheme of the potential causes and consequences of coronary

microvascular dysfunction-related MINOCA

Invasive Testing 2006

Indications For Invasive Coronary Reactivity Testing

Evidence of ischemia (INOCA or MINOCA)

+

No obstructive CAD

+

Persistent chest pain

Chest pain refractory to medical

management

Preference for definitive diagnosis

We cite a 1/600 (IVUS)-1,000 (CRT) SAE; Wei JACC Intervention 2012

IVUS side-by-side with Angio

Bedside Controller

at your fingertips

Plug and Play digital

imaging

Catheterization Laboratory Set Up

Cath Lab with

facilities to perform

Quantitative

Coronary

Angiography

Doppler Flow Wire

for measurement of

coronary blood

velocity (IMR OK)

Coronary Reactivity Testing - Interpretation

Microvascular Dysfunction

Macrovascular Dysfunction

Non-Endothelial Dependent

CFR in response to adenosine ≤ 2.5

Change in coronary artery diameter in

response to nitroglycerin < 20%

Endothelial Dependent

Change in CBF in response to

acetylcholine < 50%

Change in coronary artery diameter in

response to acetylcholine < 0%

Coronary Spasm Chest Pain + EKG changes

+/- Change in coronary artery diameter in response to acetylcholine <90%

CBF: CSA of coronary artery x average peak velocity /2

Coronary Reactivity Testing – Reporting Findings

1. Nonobstructive coronary artery atherosclerosis.

2. Elevated LVEDP (23 mmHg).

3. No evidence of heightened cardiac nociception.

4. Elevated resting average peak velocity (29 cm/sec), suggesting abnormal resting coronary vasomotor tone.

5. Diffuse coronary vasospasm to high dose acetylcholine.

Microvascular Dysfunction

Macrovascular Dysfunction

Non-Endothelial Dependent

CFR 3.9

(Abnl ≤ 2.5)

NTG +18%

(Abnl < 20%)

Endothelial Dependent

CBF change -4.5% (Abnl < 50%)

ACH +67% (Abnl < 0%)

Pursue non-invasive stress testing for objective evidence of ischemia

Is patient able to exercise?

Is baseline EKG ok to pursue ETT

If yes, start with ETT:

Elicit symptoms

Detection of Ischemic EKG changes

METS and functional capacity

Arrhythmias

Hypertensive response to exercise

If ETT inconclusive and/or persistent symptoms

• Add an imaging test – Stress Echo (diastolic function, hypertrophy,

pulmonary hypertension, valvular problems, WMA)

– Stress SPECT (rarely)

– PET-CT with Coronary Flow Reserve (added benefit of CAC)

– Adenosine Stress Cardiac Magnetic Resonance Imaging (added benefit of scar imaging and best for tissue characterization)

Noninvasive Testing 2008

CMRI LGE IMAGING: Troponin Leaks are not False Positives!

Bakir JACC 2014:63:A391 and Wei et al Circulation manuscript (in press)

TOP) 56 year-old woman with diabetes, hyperlipidemia, hypertension, persistent angina and

history of NSTEMI. LGE demonstrated distal anterior subendocardial scar (6g) without

significant change at one year follow-up. Coronary reactivity testing revealed LAD

atherosclerosis and microvascular endothelial dysfunction.

BOTTOM) 26 year old woman with recurrent MIs (recent ramus artery spasm) and

miscarriages. LGE revealed regions of mid-myocardial scar (11g) in inferior, basal septal,

basal lateral and basal anterior wall. She had interval MI but no significant change in scar size.

Wei JACC 2015 65:A399 and Circulation manuscript (in press)

Mechanisms of Myocardial Infarction: Atherosclerotic and Non-atherosclerotic

Prevalence

Pathophysiology

Diagnosis ⎯Advanced imaging with:

• OCT/IVUS • CMRI-LGE

• CTA

Treatment

Next Steps

Treatment • ACC/AHA guidelines do not specifically discuss

secondary prevention for MINOCA patients

• ESC guidelines indicate dual antiplatelet therapy + statin (targeting atherosclerotic plaque rupture CMD capillary obliteration mechanisms)

• Is this appropriate for:

– Takotsubo (ACE may reduce recurrence)?

– Epicardial vasospasm (CCB reduces recurrence)?

– SCAD (FMD associated media hemorrhage)?

– Myocarditis?

Potential Treatment Targets for Angina and No

Obstructive CAD

• Coronary Endothelial Dysfunction - ACE-I, Statins, L-arginine supplementation, Aerobic Exercise, Enhanced External Counterpulsation (EECP)

• Abnormal Non-endothelial Dysfunction (reduced CFR)- Beta-blockers/ alpha-beta blockers; nitrates, ?PDE5-I

• Coronary Smooth Muscle Dysfunction - Calcium Channel Blockers; Rho-kinase inhibitors (not available), nicorandil (not available)

• Anti-Anginal - Anti-Ischemic – Ranolazine, ?Aminophylline

• Abnormal Cardiac Nociception - Low Dose Tricyclic Medication, Spinal Cord Stimulation (TENS unit), Cognitive Behavioral Therapy

• Atherosclerosis – Aspirin, Statin

• Elevated LVEDP – ACE-I, aldosterone antagonist (eplerenone)

Mehta PK and Bairey Merz CN. Braunwald’s The Heart 9th Edition 2011.

Low use of meds and elevated 1 year MI rate following angiographic non-obstructive CAD

}

Mechanisms of Myocardial Infarction: Atherosclerotic and Non-atherosclerotic

Prevalence

Pathophysiology

Diagnosis

Treatment ⎯Empiric atherosclerotic-IHD Rx is

reasonable (ASA/DAPT, statin, ACE/ARB, BB)

⎯Evidence to advise guidelines needed

Next Steps

HARP Study – PI Janet Wei/N Bairey Merz MD Can the prevalence of plaque disruption in MI with non-obstructive CAD be higher than 45%?

• 3-vessel imaging

• OCT (optical coherence tomography) improves detection of disrupted plaque

– Plaque rupture

– Plaque erosion

– Calcified nodule

– Dissection

Slide courtesy of H Reynolds MD

Figure 3

Microvascular Dysfunction

LV Remodeling Diastolic and Systolic Dysfunction

Myocardial Ischemia

Genetic and Environmental Factors

Myocardial Fibrosis and Scar MINOCA HFpEF

Arrhythmias Sudden Death

Arteriolar Remodelling

WISE-HFpEF Study – PI CN Bairey Merz MD - Proposed cascade of events in coronary microvascular dysfunction-related MINOCA, INOCA, and HFpEF

Crea, Camici, Bairey Merz EHJ 12/13

Ischemia and Myocardial Infarction with Non-obstructive CAD

MINOCA occurs dominantly in women and is not a false positive MI!

Differential can include plaque rupture, plaque erosion, epicardial or microvascular spasm, Takotsubo, spontaneous coronary dissection (SCAD), myocarditis

Additional diagnostics should be used (OCT/IVUS, CMRI, CTA)

A majority involve atherosclerosis

Current US guidelines do not address MINOCA

ESC guidelines - DAPT and high intensity statin

Next step MINOCA research needed for evidence-based guidelines