Ischemia with Nonobstructive Coronary Arteries (INOCA)

• Patients with angina with evidence of myocardial ischemia from non-invasive testing (e.g. PET and other stress test modalities), but have no flow-limiting/obstructive coronary artery disease. ¹
  • 
• Endotypes:
  • Vasospastic Angina
  • Microvascular Dysfunction
  • TODO

![[Ischemia with Nonobstructive Coronary Arteries INOCA-1748817002120.webp]] Figure source: ²

Endotypes of INOCA

Endotype	Features	Diagnosis
Microvascular Dysfunction	Structural and/or functional abnormalities in the microvascular system A limitation in the vasodilatory ability and absolute conductance ability of the microvascular system Associated with risk factors of cardiovascular disease, ventricular hypertrophy, or cardiomyopathies	Based on invasive physiologic assessment: - FFR >0.80 or NHPR >0.89 - CFR < 2.0-2.5 - IMR >25U or HMR >2.5 mm Hg/cm/s
Epicardial Vasospastic Angina	Hyper-reactive response of the epicardial coronary artery segment to vasoconstrictive stimuli	Based on provocation test using ergonovine or acetylcholine: - Ischemic Sx during test - Transient total/subtotal coronary artery occlusion - Ischemic ECG ∆ in ≥ 2 contiguous leads
Microvascular Vasospastic Angina	Spasm of vascular smooth muscle cells in prearteriolar vessels and arterioles	Based on provocation test using acetylcholine: - Ischemic Sx during test - Absence of total/subtotal coronary artery occlusion - Ischemic ECG ∆ in ≥ 2 contiguous leads
Masked diffuse disease	Coronary angiography can underestimate diffuse coronary atherosclerosis. Invasive physiologic assessment and/or intravascular coronary imaging can reveal hidden coronary atherosclerosis.	Based on invasive physiologic assessment: - FFR ≤0.80 or NHPR ≤0.89 with gradual step-up during pull back tracing Based on intravascular imaging studies

CFR = coronary flow reserve; ECG = electrocardiogram; FFR = fractional flow reserve; HMR = hyperemic microvascular resistance; IMR = index of microcirculatory resistance; INOCA = ischemia with nonobstructive coronary artery disease; NHPR = nonhyperemic pressure ratio.

Source: Figure 2 of ³

Figure source: Figure 1 of ⁴

• Sequence of evaluation:
  • Step 1: Exclude flow-limiting/obstructive epicardial CAD
  • Step 2: Physiologic testing to assess for coronary microvascular disease
  • Step 3: Provocative testing to assess for epicardial and/or microvascular vasospastic angina
  • 

Chest Pain

Figure source: Figure 14 of ⁵

Physiologic Testing

• Comprehensive physiologic assessment using a pressure sensor guidewire is needed to discriminate myocardial ischemia caused by epicardial coronary artery lesions and coronary microvascular disease ¹
  • Physiologic testing cannot provide information on vasospastic angina ¹
• Metrics
  • Fractional Flow Reserve (FFR) or non-hyperemic pressure ratio (NHPR) is a standard invasive method to define ischemia-causing epicardial coronary artery lesions.¹
    • FFR ≤0.80 and NHPR ≤0.89 indicate flow-limiting or ischemia-causing epicardial coronary artery stenosis
  • Index of Microvascular Resistance (IMR)

Physiologic Index	Definition	Cutoff Value	Features
FFR	Ratio of distal coronary pressure to aortic pressure during hyperemia	≤0.80	Reflecting disease burden of epicardial coronary artery
NHPR	Ratio of distal coronary pressure to aortic pressure during the resting state	≤0.89	Reflecting disease burden of epicardial coronary artery Several NHPRs: instantaneous wave-free ratio, resting full cycle ratio, and diastolic pressure ratio.
CFR	Ratio of hyperemic coronary flow and resting coronary flow	<2.0-2.5	Reflecting both epicardial coronary artery disease and microvascular dysfunction
IMR	Distal coronary artery pressure multiplied by hyperemic mean transit time	>25 U	Microvascular-specific index
HMR	Ratio of maximal coronary flow velocity to distal coronary artery pressure during hyperemia	>2.5 mm Hg/cm/s	Microvascular-specific index

Caption: Invasive physiologic indexes are helpful in identifying the presence of myocardial ischemia and discriminating the mechanisms of myocardial ischemia. Fractional flow reserve (FFR) or nonhyperemic pressure ratio (NHPR) reflects the degree of flow limitation caused by epicardial coronary artery lesions, and the index of microcirculatory resistance (IMR) or hyperemic microvascular resistance (HMR) represents the status of the microcirculatory system. Coronary flow reserve (CFR) is influenced by both macrovascular and microvascular disease status.¹

Provocative Testing

• 📝 A patient can have BOTH, i.e. concomitant epicardial and microvascular vasospastic angina
  • coexistence confirmed in cases with microvascular vasospasm occurring with a lower dose of acetylcholine than epicardial artery spasm
• Microvascular vasospastic angina can be diagnosed with acetylcholine infusion during coronary angiography using a lower dose of acetylcholine compared with that of epicardial coronary spasm.
• When angina and ischemic electrocardiographic changes (ST-segment depression or elevation ≥0.1 mV) in at least 2 contiguous leads occur after acetylcholine infusion without significant epicardial coronary artery constriction (<90%), the presence of microvascular spasm can be diagnosed
• Complications include refractory spasm by provocation test or fatal arrhythmia

Management

Source: Figure 5 of ³

• Lifestyle modification
• Risk factor management, including hypertension, HLD, smoking, and diabetes
  • Optimal BP 💊 depends on INOCA endotype
• Anti-Anginal Therapy
  • Calcium Channel Blockers (CCBs) should be considered 1st-line in patients with evidence of either epicardial or microvascular spasm following acetylcholine testing

Management of Microvascular Angina

Table source: Table 3 of ³

Treatment	Mechanism of effect
BBs (Nebivolol 2.5–10 mg daily)	- ↓ Myocardial oxygen consumption - Antioxidant properties
CCBs (Amlodipine 10 mg daily)	- Vascular smooth muscle relaxation - ↓ Myocardial oxygen consumption
Ranolazine (375–750 mg twice daily or 500 mg–1 g twice daily in the USA)	- Improves microvascular perfusion reserve index in patients with MVA and reduced CFR
Trimetazidine (35 mg twice daily)	- Increases cell tolerance to ischaemia by maintaining cellular homeostasis
ACE inhibitors (Ramipril 2.5 - 10mg), ARBs	- Improve CFR - ↓ Workload - May improve small vessel remodelling

Management of Vasospastic Angina

See Management of Vasospastic Angina

Footnotes

1. Hwang, D., Park, S.-H., & Koo, B.-K. (2023). Ischemia With Nonobstructive Coronary Artery Disease. JACC: Asia, 3(2), 169–184. https://doi.org/10.1016/j.jacasi.2023.01.004 ↩ ↩² ↩³ ↩⁴ ↩⁵

2. Hokimoto S, Kaikita K, Yasuda S, Tsujita K, Ishihara M, Matoba T, Matsuzawa Y, Mitsutake Y, Mitani Y, Murohara T, Noda T, Node K, Noguchi T, Suzuki H, Takahashi J, Tanabe Y, Tanaka A, Tanaka N, Teragawa H, Yasu T, Yoshimura M, Asaumi Y, Godo S, Ikenaga H, Imanaka T, Ishibashi K, Ishii M, Ishihara T, Matsuura Y, Miura H, Nakano Y, Ogawa T, Shiroto T, Soejima H, Takagi R, Tanaka A, Tanaka A, Taruya A, Tsuda E, Wakabayashi K, Yokoi K, Minamino T, Nakagawa Y, Sueda S, Shimokawa H, Ogawa H; Japanese Circulation Society and Japanese Association of Cardiovascular Intervention and Therapeutics and Japanese College of Cardiology Joint Working Group. JCS/CVIT/JCC 2023 Guideline Focused Update on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction. Circ J. 2023 May 25;87(6):879-936. doi: 10.1253/circj.CJ-22-0779. Epub 2023 Apr 6. PMID: 36908169. ↩

3. Kunadian, V., Chieffo, A., Camici, P. G., Berry, C., Escaned, J., Maas, A. H. E. M., Prescott, E., Karam, N., Appelman, Y., Fraccaro, C., Louise Buchanan, G., Manzo-Silberman, S., Al-Lamee, R., Regar, E., Lansky, A., Abbott, J. D., Badimon, L., Duncker, D. J., Mehran, R., … Baumbach, A. (2020). An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. European Heart Journal, 41(37), 3504–3520. https://doi.org/10.1093/eurheartj/ehaa503 ↩ ↩² ↩³

4. Camici, P. G., d’Amati, G., & Rimoldi, O. (2014). Coronary microvascular dysfunction: mechanisms and functional assessment. Nature Reviews Cardiology, 12(1), 48–62. https://doi.org/10.1038/nrcardio.2014.160 ↩

5. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain. Journal of the American College of Cardiology. 2021;78(22):e187-e285. doi:10.1016/j.jacc.2021.07.053 ↩