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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
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 # 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
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)
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.
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