Thank you for the introduction, and thank you for inviting me to present on invasive testing for microvascular disease. These are my disclosures, and these are the objectives. So coronary microvascular dysfunction can be defined as impaired vasodilation or increased vasoconstriction. The endothelium plays an important role in modulating smooth muscle function by releasing vasodilating substances including nitric oxide in response to exercise or other stimuli including acetylcholine. In the presence of atherosclerosis or cardiovascular disease risk factors, the endothelium becomes dysfunctional and there may be blunted coronary vasodilation or increased vasoconstriction. Impaired vasodilation may also be endothelial independent as functional abnormalities of the smooth muscle cells can be impaired, reflected by impaired vasodilation in response to adenosine or dipyridamole. Over the last 10 years, there has been significant advancement in the evaluation of patients with suspected ischemia and no obstructive coronary arteries. We can measure coronary flow reserve or CFR, which reflects function over the entire macro circulation and micro circulation. In the absence of significant macrovascular coronary disease, we can use CFR to understand micro circulatory function. We can also measure index of microvascular resistance or IMR, which assesses coronary microvascular dysfunction independent of epicardial stenosis. In the cath lab, we can measure coronary flow reserve using a Doppler wire or by using the thermodilution method. Both of these methods involve administration of adenosine to achieve hyperemia. Doppler CFR is the ratio of the hyperemic average peak coronary flow velocity to rest average peak coronary flow velocity. Certain conditions can elevate resting coronary flow, such as elevated blood pressure, heart rate, and high resting flow is also more often seen in women and obese individuals. The thermodilution method in orange involves a pressure temperature sensor guide wire and saline bolus to measure CFR and IMR. In this method, we record the mean distal coronary pressure at hyperemia and the mean transit time for saline to pass between the proximal and distal sensors at rest and at hyperemia as you can see using these formulas. The Coronary Vasomotion Disorders International Study Group published clinical criteria for suspecting microvascular angina as outlined here. Coronary microvascular dysfunction can be diagnosed in the setting of no obstructive coronary disease when there is impaired CFR using invasive or non-invasive modalities less than 2 or 2.5, coronary microvascular spasm during acetylcholine provocative testing, abnormal IMR greater than 25, or coronary slow flow phenomenon. Even traditional stress tests have poor sensitivity to diagnose coronary microvascular dysfunction. Invasive or non-invasive tests that measure coronary flow reserve and other coronary vasomotion disorders such as coronary endothelial dysfunction and vasospasm are often recommended in the evaluation of patients with suspected inoca. The 2021 ACCA Shaker Guideline for the Evaluation and Diagnosis of Chest Pain included this clinical decision pathway for inoca, informing us about diagnosing coronary microvascular dysfunction and vasospasm. Stress PET or stress CMR with evaluation of myocardial flow reserve are recommended as class 2A for patients with stable angina and suspected inoca. Invasive coronary function testing may be considered as class 2A recommendation for more comprehensive diagnosis of CMD and coronary vasospasm, and this testing is reimbursable by insurance. Invasive testing may be preferred for patients with persistent angina despite empiric treatment or after non-invasive testing, patients with history of inoca, or patients with history of cardiac arrest due to coronary vasospasm. But ultimately, test choice should be guided by local availability and expertise. Invasive testing of CFR or IMR has yielded similar prevalence of coronary microvascular dysfunction as compared to non-invasive testing of CFR. As you can see from this meta-analysis of 37 studies of patients with no obstructive coronary disease, blue represents the prevalence in studies reporting non-invasive methods, while red represents invasive methods. Indothelial prevalence was 41%. There are several different protocols for invasive coronary function testing. In the Women's Ischemia Syndrome Evaluation, or WISE, we interrogate endothelial-independent and endothelial-dependent pathways of coronary microvascular and macrovascular function using incremental doses of intracoronary adenosine, acetylcholine, and nitroglycerin. The thresholds that we chose for abnormal CFR, coronary blood flow change, and coronary artery diameter response are shown in this table. Epicardial spasm is defined as a greater than 90% constriction in the presence of chest pain and ischemic ECG changes in response to acetylcholine, while microvascular spasm is diagnosed when there is chest pain and ischemic ECG changes, but less than 90% constriction to acetylcholine. Invasive coronary function testing has given us insight on the prevalence and heterogeneity of CMD. In this Mayo Clinic study, a large cohort of over 1,000 patients with no obstructive CED, about two-thirds were female, underwent invasive coronary function testing for measurement of CFR and CBF. They found a high prevalence of coronary microvascular dysfunction, 64%, with abnormalities related to endothelial-dependent CMD, endothelial-independent CMD, or both. The Y study found that both CFR and change in CBF, or coronary blood flow, are independent prognostic markers of major adverse cardiovascular events and death in women with INOCA. Epicardial vasoconstriction to acetylcholine predicted angina hospitalizations. Studies of thermodilution CFR and IMR in INOCA patients have also shown heterogeneity. In this study of 230 patients undergoing testing with normal FFR and no obstructive coronary disease, you can see that there are patients with concordant or discordant CFR and IMR results. This plot on the left shows CFR on the y-axis and IMR on the x-axis. Those with normal CFR and IMR are in blue, so concordant. Abnormal CFR and IMR in red, also concordant. And discordant CFR and IMR are in orange and gray. The patients with discordant CFR and IMR appear to be due to differences in resting flow. But the major takeaway is that those with abnormally high IMR and low CFR, represented in red, had the worst clinical outcomes, as shown in this figure on the right, while the other three groups had similar low incidence of adverse outcomes. Invasive coronary function testings have also taught us that spasm is highly prevalent in patients with suspected INOCA when we look for it, 49 percent. Epicardial spasm was overall present in 40 percent and microvascular spasm in 24 percent in this meta-analysis. Fortunately, among vasospasm patients generally treated with calcium channel blockers and nitrates, cardiac mortality is low. In this study of over 700 men and women who underwent invasive acetylcholine provocation, epicardial vasospasm was associated with increased hazard of myocardial infarction and repeated angiography, while microvascular spasm was associated with recurrent angina hospitalizations. Not only does invasive testing provide diagnostic and prognostic information, it can improve patient-reported outcomes. The CORMICA trial randomized 151 patients in the U.K. to undergo invasive coronary function testing-guided care or traditional angiography-guided care. For the patients undergoing the intervention, anti-anginals were stratified based on whether tests showed microvascular dysfunction and or vasospasm. This approach was shown to improve angina control and quality of life in patients with no obstructive CAD at six months and at one year. The European expert consensus document on inoca thus recommends such a stratified approach. Anti-anginal medications are recommended based on the suspected or proven mechanism of their anginal symptoms, such as whether they have microvascular dysfunction on the left and or vasospasm on the right. However, we need studies to determine which diagnostic and treatment strategies ultimately reduce long-term outcomes in patients with inoca.

invasive testing

microvascular disease

coronary microvascular dysfunction

coronary flow reserve

index of microvascular resistance