Beyond Coronary Artery Disease: Assessing the Microcirculation

Abstract

Ischemic heart disease (IHD) affects more than 20 million adults in the United States. Although classically attributed to atherosclerosis of the epicardial coronary arteries, nearly half of patients with stable angina and ischemic heart disease who undergo invasive coronary angiography do not have obstructive epicardial coronary artery disease. Ischemia with non-obstructive coronary arteries, or INOCA, is frequently caused by microvascular angina with underlying coronary microvascular dysfunction (CMD). Guidelines and consensus statements now recommend comprehensive assessment of coronary physiology to identify CMD in these patients, and recent advances in the invasive evaluation of the microcirculation has led to specific, quantitative, and reproducible measures of coronary microcirculatory function. Greater understanding the pathophysiology, diagnosis, and treatment of CMD holds promise to improve clinical outcomes of patients with ischemic heart disease.

Background

Ischemic heart disease (IHD) affects more than 20 million adults in the United States and is a leading cause of death.¹ Stable ischemic heart disease is associated with angina, decreased exercise tolerance, and adverse health-related quality of life. Although angina is classically attributed to atherosclerosis of the epicardial coronary arteries, recent evidence suggests that nearly half of patients who undergo invasive coronary angiography for the evaluation of angina do not have obstructive coronary disease.^2,3 This perplexing clinical scenario, first described in 1967 and later termed cardiac Syndrome X, is now referred to as ischemia with non-obstructive coronary arteries, or INOCA.⁴ Underlying mechanisms of INOCA include microvascular angina with coronary microvascular dysfunction (CMD), epicardial coronary spasm, and non-cardiac chest pain.^5,6 Recent American and European clinical practice guidelines recognize the impact of INOCA and recommend functional assessment of the coronary microcirculation to determine mechanisms of ischemia and guide pharmacological therapy.^7-9 The objective of this review is to (a) outline the anatomy of the coronary circulation and the pathophysiology of CMD, (b) describe current approaches to assess the coronary microcirculation in the cardiac catheterization laboratory, and (c) examine the clinical implications of CMD in INOCA and other cardiovascular disorders.

Anatomy and Physiology of the Coronary Microcirculation

Anatomy

From the epicardial vessels to the myocardium, the coronary circulation can be divided into three distinct “compartments” (Figure 1). Blood enters the coronary circulation via the major epicardial coronary arteries, vessels 500 μm to 5mm in size that course predominantly along the surface of the myocardium and can be easily visualized by coronary angiography. Epicardial coronary arteries have been the focus of coronary interventions for more than half a century. Despite their important role as proximal conduit vessels, the epicardial coronaries only directly supply 5-10% of the myocardium. In normal physiologic conditions, epicardial coronary arteries offer little resistance to blood flow due to their relatively large diameters. Nitric oxide-mediated vasodilation of the epicardial coronaries accommodates increased blood flow in times of high metabolic demand. Atherosclerotic plaques in the epicardial coronaries can lead to dramatic increases in resistance to flow.¹⁰ The epicardial coronary arteries branch and taper into a vast network of arterioles to supply the myocardium.

Figure 1. Anatomy of the compartments of the coronary circulation.

CAD = Coronary artery disease; NO = Nitric oxide

Extra-myocardial pre-arteriolar vessels, which range in diameter from 100 to 500 μm, form the intermediate compartment of the coronary circulation. These pre-arteriolar vessels run in parallel, leading to physiologic drops in pressures.¹¹ Proximal pre-arterioles in this compartment are most sensitive to changes in intravascular flow, whereas distal vessels are sensitive to changes in pressure. Vasoconstriction and vasodilation of the pre-arterioles maintains constant arteriolar pressures.¹² This compartment may be responsible for CMD in patients with INOCA.

The third and final compartment of the coronary circulation consists of innumerable intramural arterioles <100μm in diameter. These vessels directly supply low-pressure myocardial capillary beds that serve as the site for nutrient and gas exchange. Arterioles in the coronary circulation have a high resting tone and dilate in response to local metabolites produced by the surrounding myocardium, including adenosine, nitric oxide, and prostaglandins.¹¹ Thus, arterioles are responsible for the metabolic regulation of myocardial blood flow.

In normal circumstances, the three compartments of the coronary circulation work in concert to regulate myocardial blood flow in response to metabolic demands. Once maximal myocardial oxygen extraction (~75%) has been reached, additional metabolic demands must be met with increases in myocardial blood flow.¹³ Increases in heart rate and contractility can augment cardiac output, and vasodilatory metabolites from the myocardium decrease microcirculatory arteriolar resistance to enhance coronary blood flow (CBF).¹³ Thus, the microcirculation plays a pivotal role to ensure coronary perfusion matches myocardial oxygen demand.

Pathobiology of Coronary Microvascular Disease

Coronary microvascular disease has been broadly classified as microvascular dysfunction (a) in the absence of obstructive CAD or myocardial diseases, (b) in the presence of myocardial disease, (c) in the presence of obstructive CAD, or (d) from an iatrogenic cause.¹⁴ A variety of mechanisms can contribute to structural or functional abnormalities of the microcirculation.^15,16 In patients without obstructive atherosclerosis or myocardial diseases, the pathogenesis of microvascular disease may include arteriolar remodeling and fibrosis, intimal proliferation, smooth muscle hypertrophy, or vessel rarefaction. Small vessel atherosclerosis, platelet activation and plugging,¹⁷ or microembolization of thrombotic material in the setting of epicardial atherosclerotic disease may also contribute.¹⁸ In the setting of myocardial disease, such as left ventricular hypertrophy, increased intramyocardial, left ventricular diastolic, and coronary venous pressures may also lead to increased resistance to microcirculatory flow.¹⁹

In addition to structural disorders of the microcirculation, functional abnormalities associated with impairment to the normal responses to neurohormonal and metabolic signaling can lead to impaired microcirculatory flow. This may include attenuated responses to or decreased synthesis of vasodilators such as nitric oxide.^20,21 Coronary microvascular spasm, with episodic increases in microvascular resistance and provocation of myocardial ischemia can also occur.²²

Although the exact pathophysiology of CMD is uncertain, risk factors include older age, hypertension, dyslipidemia, diabetes mellitus, cigarette smoking, and chronic inflammatory disorders, including systemic lupus erythematosus and rheumatoid arthritis.^23-28 Additional investigation is needed to identify modifiable risk factors to prevent development of microcirculatory disease.

Assessing the Microcirculation in the Catheterization Laboratory

Unlike the epicardial coronary arteries, coronary microcirculation cannot be directly visualized. Thus, assessments are largely based on parameters of microcirculatory flow. Coronary flow reserve, or CFR, the original integrated measure of coronary epicardial flow and microvascular function, is defined as the ratio of hyperemic CBF to CBF at rest. Normal coronary arteries can augment blood flow >4-fold at maximal hyperemia, while a CFR <2 to <2.5 in the absence of epicardial coronary disease is abnormal and reflects microvascular dysfunction (Table 1).^5,6

Table 1.

Invasively derived measures to assess coronary microvascular dysfunction

Technique	Measurement Method	Normal Value	Comments
Coronary Flow Reserve (CFR)	Doppler or Thermodilution	> 2.0 - 2.5	Requires hyperemia Not specific for microvascular disease Affected by resting hemodynamics and coronary epicardial stenosis Predicts long term MACE
Index of Microcirculatory Resistance (IMR)	Thermodilution (Bolus dose)	< 25	Requires hyperemia Specific to the coronary microcirculation Less variable than CFR despite change in hemodynamics Requires correction (Yong) in the presence of significant epicardial stenosis Predicts long term death and heart failure readmissions in patients with STEMI May predict graft dysfunction early after orthotopic heart transplant
Hyperemic microvascular resistance (hMR)	Doppler	≤ 2	Specific to the coronary microcirculation Technical challenges of optimal Doppler signal acquisition
Resistive reserve ratio (RRR)	Doppler or Thermodilution	< 1.7-3.5	Superior to CFR for prognosis
Minimal microvascular resistance (mMR)	Doppler	Not Defined	Measured during wave-free period window of diastole and does not require hyperemia Limited data on prognostic value
Rmicro	Thermodilution (Continuous Infusion)	< 500 Woods units	Strong agreement with PET-derived coronary flow Saline infusion induces hyperemia Accuracy in obstructive coronary artery disease is not well defined Equipment not available in the United States
Microvascular Resistance Reserve (MRR)	Thermodilution (Continuous Infusion)	Not Defined	Novel index Specific to microvasculature; corrected for epicardial conductance Independent of autoregulation and myocardial mass Requires Validation

Invasive evaluation of CFR can be performed in the catheterization laboratory using thermodilution or Doppler-based assessment of CBF. The intracoronary Doppler guidewire, first developed in the late 1980s, contains a piezoelectric ultrasound transducer mounted at the tip to measure CBF velocity.²⁹ The current generation of wire (FloWire or ComboWire XT, Phillips Volcano) can measure the average peak velocity (APV) of CBF at a specific location using a commercially available console with dedicated software (ComboMap, Philips, Volcano). Coronary APV is typically measured at rest, and then again after induction of hyperemia with the administration of a non-endothelial dependent vasodilator such as adenosine. Doppler-derived CFR is typically simplified as the ratio of the hyperemic APV to the APV measured at rest. To estimate CBF, the vessel diameter (D) at the site of APV measurement can be determined using quantitative coronary angiography, and flow can then be calculated by the formula: CBF = 0.5 x APV x (D2 π)/4.²⁹ In response to an infusion of acetylcholine, an endothelial-dependent vasodilator, CBF typically increases substantially. Augmentation of CBF by <50% in the presence of acetylcholine is abnormal and, in the absence of significant epicardial coronary constriction, indicates that endothelial dependent microvascular dysfunction may be present.^30,31

In contrast to Doppler-based measures that measure coronary velocity at a single location, coronary thermodilution techniques assesses flow based on temperature changes across the entire vessel. This technique requires 3mL bolus injections of room temperature saline through the guide catheter, with a distal thermistor on a coronary pressure-wire recording temperatures in the coronary artery (PressureWire X, Abbott Vascular). The shaft of this wire acts as a proximal thermistor. The speed of change of the distal temperature (relative to the proximal temperature) is used to calculate the mean transit time (T_mn), which is inversely proportional to coronary flow according to the principles of indicator dilution theory.

Doppler and thermodilution approaches to measurement of coronary flow each have limitations. Doppler-derived measures of coronary flow velocity assume that flow at the transducer is parallel, laminar, and parabolic, and may not remain constant at different wire positions.³² Indeed, animal and human studies have demonstrated significant variability in Doppler wire measurements,³³ and Doppler measurements tend to be technically more challenging, require more time for data acquisition, and have a steeper learning curve.^34,35 Although coronary thermodilution is somewhat easier to obtain, it can be significantly impacted by changes in guide catheter position during administration of saline boluses. In an early porcine model, thermodilution-derived CFR correlated better with absolute flow measured by an external coronary flow probe than did the Doppler wire-derived CFR.³⁶ However, in a study of 98 vessels in 40 consecutive patients, Doppler-derived CFR correlated more closely with PET-derived CFR than thermodilution-derived CFR.³⁷ Ultimately, both techniques are considered to be valid in the assessment of the coronary microcirculation (Table 1).

Unfortunately, CFR is not specific to microcirculation and is affected by epicardial coronary stenosis and resting hemodynamics. In the absence of obstructive epicardial disease, a reduced CFR can reflect increased microcirculatory resistance to flow, an abnormal response to the standard vasodilatory stimulus, or increased resting coronary flow prior to vasodilator administration. Among patients with INOCA, high resting flow is more common in women, younger patients, and patients with fewer cardiovascular risk factors, and may represent a distinct pathology.³⁸

Microvascular resistance indices offer an alternative method to interrogate the microcirculation.³⁹ The index of microcirculatory resistance (IMR), first reported in 2003, is a thermodilution-based measure that reflects the minimal achievable resistance of the microcirculation with endothelial-independent vasodilators (Table 1).³² IMR is based on Ohm's law, which states that the potential difference across an ideal conductor is proportional to the current through the conductor (Voltage = Current x Resistance). Applying this to coronary physiology, the microcirculation acts as a conductor, the voltage is analogous to the difference in pressure across the microvasculature (mean distal coronary pressure [P_d] – coronary venous pressure [P_v]), and current is myocardial flow (1/T_mn). Since coronary venous pressure (P_v) is usually negligible, IMR may be calculated by the formula: IMR = P_d x T_mn. A normal value of IMR has been reported to be <25,^40-42 with higher values reported in the RCA, perhaps due to longer vessel length and larger diameters accounting for a somewhat prolonged T_mn.⁴²

Still, there are some situations in which IMR must be interpreted with caution. In the presence of a significant coronary stenosis, collateral flow to the vessel of interest may increase the coronary wedge pressure (Pw). Thus, coronary thermodilution may underestimate flow and IMR may overestimate resistance.⁴³ To account for collateral flow, the following formula has been proposed: IMR = Pa x T_mn x ([P_d -P_w]/[P_a - P_w]).⁴³ Since coronary wedge pressures are not routinely measured, a correction factor for IMR has been derived and validated from experimental data with coronary wedge pressures (P_w) measured during proximal vessel balloon occlusions.^44,45 Corrected IMR can be calculated using Yong’s modification (corrected IMR = Pa × T_mn × [(1.35 × Pd/Pa) − 0.32]) during hyperemia.

There are a number of benefits to IMR, which remains stable in the presence of increasing epicardial stenosis,⁴³ is relatively independent of resting hemodynamics.⁴⁶ Variability in IMR is lower than that of CFR, despite changes in heart rate, blood pressure and contractility.⁴⁶ Finally, IMR is highly reproducible measure over time, with low interobserver variability despite manual injection of saline boluses.^47,48

Microcirculatory resistance can also be determined using a guidewire with a Doppler ultrasound transducer and simultaneous distal coronary pressure monitoring. The Doppler-derived hyperemic microvascular resistance (hMR) is analogous to IMR and is defined as the ratio of mean distal pressure to the Doppler-derived APV (Table 1).⁴⁹ An hMR ≥2 is generally considered to be abnormal. In patients with INOCA, HMR >1.9 predicted recurrent chest pain in one study, although in another, a threshold of ≥2.5 provided the highest sensitivity and specificity to detect CMR-determined microvascular disease or abnormal invasive CFR.^34,50 A related measure, the minimal microvascular resistance (mMR), was proposed as the ratio of hyperemic distal coronary pressure and hyperemic APV measured during wave-free period window of diastole, when microvascular resistance is at its lowest.⁵¹ Although conceptually attractive, mMR requires further study.

The resistive reserve ratio (RRR), another recently developed microcirculatory parameter, is calculated as the ratio of baseline microvascular resistance to hyperemic microvascular resistance, with higher values indicating greater vasodilatory capacity of the microcirculation (Table 1).^52,53 Thresholds for abnormal RRR are not well established, but have been proposed between <1.7 – 3.5 in various populations and with both Doppler and Thermodilution derived resistance measures.^54-56 In a study of 1,692 patients with INOCA, Doppler-derived RRR < 2.62 was associated with mortality and was superior to CFR to predict long-term survival.⁵⁷ Low RRR was also associated with long-term outcomes in cohorts with acute MI and CAD undergoing revascularization.^55,56

Continuous thermodilution is another emerging technique to assess the microcirculation.⁵⁸ Temperature changes associated with intracoronary saline infusion, administered at a known rate through a dedicated monorail infusion catheter, can be measured in the distal coronary with a thermistor on a pressure-sensing coronary wire to calculate absolute coronary flow (Q). Absolute coronary flow can be derived as Q = 1.08 x T_i/T x Q_i, where T_i is the temperature of saline as it exits the catheter, T is the temperature of the blood in the distal coronary during the steady-state infusion, and Q_i is the saline infusion rate (in mL/min).^59,60 Based on Ohms law, absolute microvascular resistance (R=P_d/Q), measured in Woods units (WU), can be obtained. Slow coronary infusions of saline (typically 8-10 mL/min) are used to assess baseline resistance at rest, while hyperemia is induced at higher saline infusion rates (15-25 mL/min).⁶¹ Continuous thermodilution Q has strong agreement with PET-derived coronary flow,⁶² absolute resistance >500 WU is the optimal threshold to identify patients with an IMR ≥25, ⁶³ and both absolute flow and resistance are associated with angina.⁶⁴

Based on absolute flow from continuous thermodilution measures, the Microvascular Resistance Reserve (MRR) has been proposed as an index specific for the microvasculature, independent of autoregulation and myocardial mass, and corrected for epicardial conductance. MRR can be defined as the ratio of the pure microvascular resistance at rest, as it would exist in the absence of epicardial disease affecting microcirculatory autoregulation, to the minimal microvascular resistance measured during hyperemia. Although the derivation of the formula for MRR is beyond the scope of this review, in practice, MRR can be calculated as the CFR divided by fractional flow reserve (FFR), corrected for coronary driving pressures as follows: MRR = (CFR / FFR) x (P_{a at rest} / P_{a at hyperemia}).⁶⁵ This conceptually elegant and promising new measure of microcirculatory function requires additional validation.

Practical Approach to Invasive Microcirculatory Assessment

Prior to testing, patients should be advised to abstain from caffeine intake to ensure appropriate responses to hyperemic agents. When combined with acetylcholine or ergonovine reactivity testing, patients should also withhold long-acting nitrates, calcium channel blockers, and beta blockers for 48 hours prior to testing. Coronary angiography should be performed to assess for epicardial coronary stenosis and myocardial bridges. Coronary microvascular testing should be performed using a guiding catheter (preferably ≥6 French) that is stably engaged in the coronary ostium, after administration of intracoronary nitroglycerin and systemic anticoagulation.

To measure thermodilution-based CFR and IMR, a 0.014” coronary pressure–temperature sensor guidewire (Pressure Wire, Abbott Vascular) should be introduced into the guide, and residual contrast media flushed with saline. Pressure waveforms should be equalized with the pressure sensor at the tip of the guide catheter. Next, the temperature and pressure sensor should be advanced to the distal two thirds of the LAD, approximately 8 to 10 centimeters into the circumflex and placed in a large obtuse marginal branch or dominant distal vessel, or in the distal RCA prior to the bifurcation of the posterior descending artery. A 3-way stopcock and a 3-mL syringe should be connected to the manifold. Next, 3mL boluses of room-temperature saline should be briskly injected through the guide catheter to determine T_mn at rest. Measurements are performed in triplicate. If there is >30% variability between the measurements, the T_mn value that deviates most significantly from the mean value should be replaced. Once assessment of baseline flow has been completed, hyperemia is induced with intravenous adenosine (140 mcg/kg/min), or with a bolus of intracoronary papaverine (10–20 mg). Once maximal hyperemia has been achieved, typically ~2 minutes after initiation of intravenous adenosine, 3mL boluses of room temperature saline should again be briskly injected through the guide. CFR can be calculated as the ratio of T_mn at rest to T_mn at hyperemia; IMR is the product of T_mn and P_d at hyperemia. Non-hyperemic pressure ratios and fractional flow reserve (FFR) should also be assessed to determine significance of any angiographically intermediate epicardial lesions. RRR can be calculated as the ratio of baseline to hyperemic microvascular resistance (T_{mn at rest} x P_{d at rest})/IMR.

Doppler-based measurements of CFR and hMR follow a similar sequence. After intracoronary nitroglycerin, a 0.014” coronary guidewire with a pressure sensor and Doppler crystal (ComboWire XT, Philips Volcano) should be positioned parallel to the vessel, away from the vessel wall, and manipulated to obtain a stable maximal Doppler flow signal. APV is measured at rest and again with maximal hyperemia, as previously described. The CFR is calculated as the ratio of hyperemic APV to resting APV. The hMR is calculated as the hyperemic P_d divided by the hyperemic APV. To assess endothelial dependent microvascular function, CBF at rest and during acetylcholine infusions can be estimated from Doppler-derived APV and luminal dimensions from quantitative coronary angiography.

Clinical Implications of Microcirculatory Disease

Microvascular Disease in INOCA

Nearly 50% of patients who present with chest pain have angiographically normal or non-obstructive epicardial coronary arteries (<50% stenosis) by angiography.^2,3,66 A comprehensive approach to the diagnosis of INOCA, including testing for microvascular disease, can improve the care of these patients (Figure 2). In the Coronary Microvascular Angina (CorMicA) trial, 151 patients underwent blinded assessment of coronary microvascular function and provocative testing for coronary artery spasm; participants were randomly assigned to disclosure of the results or usual care.⁶ Overall, microvascular angina was identified in 52% of patients, coronary spasm was identified in 20%, and mixed microvascular and spasm diagnosis was present in 17%, with no discernable etiology identified in the remaining 11%.⁶⁷ Although non-cardiac chest pain was presumed in 60-65% of participants prior to randomization, the results of testing improved diagnostic certainty, reduced the number of patients inappropriately diagnosed with non-cardiac chest pain, and impacted therapy in the overwhelming majority of patients in the intervention group. Although similar at baseline, patients assigned to disclosure of coronary functional testing had significantly better Angina Summary Scores and quality of life at 6 months and 1 year compared to the control group.^6,68 This trial provides compelling data in support of invasive microvascular testing to guide therapy and improve symptoms in INOCA (Figure 2). Additional studies to evaluate the clinical benefit of microvascular testing without coronary spasm testing are currently underway (iCorMICA NCT04674449).

Figure 2. Diagnostic pathway for the invasive assessment of patients with INOCA.

*Assessed with Doppler APV and coronary diameter via quantitative coronary angiography to determine coronary blood flow at rest and with ACh.

INOCA = ischemia with non-obstructive coronary arteries; PET = positron emission tomography; CMR= cardiovascular magnetic resonance; CFR = coronary flow reserve; IMR = index for microvascular resistance; CMD = coronary microvascular disease; ECG = electrocardiogram; CAD = coronary artery disease; CFVR = coronary flow velocity reserve; FFR = fractional flow reserve; Ach = acetylcholine.

Although outcomes are more favorable than patients with obstructive disease, INOCA is associated with excess major adverse cardiovascular events compared with reference populations without ischemic heart disease.⁶⁹ Data from Women’s Ischemia Syndrome Evaluation (WISE) registry indicate that CFR <2.3 is associated with increased risks of MACE in patients with INOCA.^31,70 In an multicenter international study of INOCA patients with microvascular angina, the annual incidence of the composite of MACE was 7.7%.⁷¹ In a study-level metanalysis, CMD was associated with 5-fold greater odds for major adverse cardiovascular events compared to patients without CMD.⁷² Thus, novel therapies to reduce the risk of MACE in patients with microvascular disease are urgently needed.

Impact of CMD in MI and PCI

In patients with acute myocardial infarction (MI), distal embolization of thrombotic material can lead to the “no-reflow phenomenon”, characterized by myocardial tissue hypoperfusion in the presence of a patent epicardial coronary artery. No-reflow, mediated by microvascular disease, is a strong predictor for adverse outcomes post-MI.⁷³ Quantitative assessment of the coronary microcirculation provides additional insights into MI severity and outcomes. In patients with ST segment elevation MI (STEMI), IMR post-PCI correlates with myocardial injury, echocardiographic wall motion abnormalities,⁷⁴ myocardial viability by PET,⁷⁵ and myocardial salvage by cardiac magnetic resonance (CMR).⁴⁸ Although IMR correlates with microvascular obstruction by CMR imaging overall,⁷⁶ discordances between the two measures are reported in up to a third of cases.⁷⁷ Still, in a cohort of 253 patients undergoing primary PCI for STEMI with a median follow up of 2.8 years, elevated IMR ≥40 immediately after revascularization was associated with an two-fold excess hazard of long-term death or rehospitalization for heart failure, and a four-fold excess hazard of mortality.⁷⁸ The Doppler-derived resistance index, hMR, has also been associated with outcomes after STEMI.³⁵ Similarly in patients who presented with NSTEMI and underwent PCI, post-PCI elevated IMR >27 was an independent predictor of MACE over a median follow-up of 21 months.⁷⁹

Even in stable patients undergoing PCI, a high baseline IMR is an independent risk factor for periprocedural MI. Among patients undergoing PCI of simple LAD lesions, pre-PCI IMR ≥27, was independently associated with a 23-fold increase in the risk of periprocedural MI.⁸⁰ Furthermore, in a cohort of 572 patients undergoing successful PCI for stable ischemic heart disease, post-PCI IMR was independently associated with major adverse cardiovascular events at follow up.⁸¹

Conclusion

The coronary microcirculation represents the next frontier in the diagnosis and treatment of coronary artery disease. Recognition of the importance of coronary physiology has expanded our understanding of ischemic heart disease and European and American societal guidelines now recommend comprehensive assessment of microvascular function in patients with INOCA.^7,8 Recent advances in invasive techniques and technologies to quantify microcirculatory CBF and resistance are vital to the comprehensive evaluation of coronary artery disease. Additional studies are needed to determine optimal therapies for patients with coronary microcirculatory disease in various cardiac disease states.

Key Points:

• Coronary microvascular dysfunction (CMD) is an important cause of ischemia with non-obstructive coronary arteries (INOCA).

• The pathophysiology of CMD is not well established.

• Coronary flow reserve (CFR), the index of microcirculatory resistance (IMR), hMR, and RRR are invasively measured indices to evaluate the microcirculation.

• CMD is associated with clinical outcomes in patients with INOCA and obstructive CAD.