Assessment of Vascular Dysfunction in Patients Without Obstructive Coronary Artery Disease

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care.

I schemic heart disease is a leading global cause of premature disability (1) and death (2). The classic cause of ischemic heart disease is coronary atherosclerosis, but disorders of coronary vasomotion are increasingly recognized (3)(4)(5). Approximately whether epicardial or microvascular, can also cause myocardial ischemia in patients with obstructive coronary artery disease (CAD) (3)(4)(5).
Coronary vasomotion disorders cause a relative supply-demand mismatch of myocardial blood flow and nutrients relative to their requirements, inducing myocardial ischemia that may be transient, recurrent, and/or chronic. Ischemia with no obstructive CAD (INOCA) is typically a chronic health problem (7,8).
Vasospasm may also be a primary cause of myocardial infarction (MI) with no obstructive coronary disease and type 2 MI. Although rarely used in daily practice, adjunctive tests of coronary function are supported by emerging clinical trial evidence, and European Society of Cardiology guidelines now support their use (9,11,13,22). Coronary functional disorders also occur among patients with obstructive CAD (3), but current diagnostic testing is limited with an upstream

HIGHLIGHTS
Patients with symptoms of INOCA can have treatable coronary vasomotion disorders.
Epicardial and microvascular vasospasm may cause MI with no obstructive CAD and type 2 MI.
Invasive physiological testing (functional coronary angiography) helps exclude, diagnose, and treat these conditions.
Stratified medicine can transform the management and well-being of these patients.

Invasive Coronary Assessment in INOCA
Two patients with similar baseline angiograms and clinical presentations without obstructive epicardial coronary artery disease (CAD). Each patient undergoes the an interventional diagnostic procedure (IDP), which reveals a distinct diagnosis. Therapies for microvascular and vasospastic angina are distinct and should be guided by the IDP results. The yellow figure shows a typical case of vasospastic angina with preserved microvascular function. The patient was previously on a beta-blocker, and this was substituted for by a calcium-channel blocker with smoking cessation counseling. The blue figure depicts a patient with proven microvascular dysfunction but no severe vasospasm. There were abnormalities in both microcirculatory resistance (index of microcirculatory resistance [IMR]) and coronary vasodilator reserve (coronary flow reserve [CFR]). The patient had a diagnosis of microvascular angina and cessation of long-acting nitrate medication with up-titration of a beta-blocker.
The patient underwent cardiac rehabilitation classes to assist in weight loss and identify relevant life-style factors implicated in the condition. Note that some operators may prefer to perform vasoreactivity testing before instrumenting the artery for guidewire based invasive CFR and microvascular resistance measurement.

Syndromes of Coronary Vascular Dysfunction
A U G U S T 2 4 , 2 0  The noninvasive management of symptomatic patients has evolved in recent years. In Europe, practice guidelines for the management of symptomatic  Fulton (reproduced with permission from Fulton [30]). This image offers an unsurpassed illustration of the coronary microcirculation, contrasting starkly with the lack of microcirculatory information on the invasive coronary angiogram (30). (B) This schematic illustrates compartmentalized physiological assessment according to the probes acetylcholine and adenosine. The metrics fractional flow reserve and nonhyperemic pressure ratios are predominantly tests of epicardial coronary obstruction to blood flow, whereas index of microcirculatory resistance and hyperemic microcirculatory resistance are more specific to the microcirculatory function. Finally, coronary flow reserve is a metric that can be influenced by any combination of epicardial or microvascular disease or changes in resting flow. There are evolving data from many large prospective studies on the independent prognostic impact of Set-up Acetylcholine may be pre-ordered, according to local arrangements. Obtain informed consent. Undertake team briefing on indication and protocol. Administer heparin 5,000 IU (as per local standard care procedures). Use radial artery access; avoid administration of vasodilator drugs, as they may confound measurement of coronary vascular function. Administer short-acting intra-arterial GTN (avoid verapamil/GDN). Use a 5-F guide catheter to reduce spasm in small radial arteries.

Coronary angiography Projection
Choose an imaging projection that reveals the long axis of the target vessel (i.e., no foreshortening), with minimal vessel overlap.
TIMI frame count Ensure that cine acquisition is sufficiently long to assess for myocardial blush of contrast media.
Diagnostic guidewire A single target coronary artery may be sufficient for diagnosis and decision making; in general, select the left anterior descending coronary artery. If normal results are obtained and clinical suspicion remains high, consider undertaking the IDP in a second coronary artery. Advance the guidewire into the distal third of the target coronary artery.

ComboWire Doppler
Consider using a buddy wire to safely advance the ComboWire.
Coronary reactivity testing Avoid a vasodilator cocktail in radial procedures.
Retain the buddy wire in situ to facilitate direct intracoronary testing. A dedicated intracoronary catheter is generally not necessary (and may increase the risks of the procedure); injection of acetylcholine is done through the guiding catheter into the lumen of the left main coronary artery. Prior to starting the infusion of acetylcholine, initially flush the lumen of the guide with w2 ml of the infusate (depending on the French size of the catheter used) to replace the flushing saline in the shaft of the catheter. Once the acetylcholine solution has reached the tip of the catheter, further injection is done more slowly and steadily over 20 s. The catheter is then slowly refilled with saline, remembering that this procedure will lead to extrusion of acetylcholine at the tip of the catheter for at least as long until all the acetylcholine solution is replaced by saline. If infusing into a "dominant" coronary artery, consider "half dose" of the acetylcholine to limit bradycardia.
In cases with normal coronary function or "negative" test responses, if clinical suspicion persists, a dose of 200 mg may be infused into the left coronary artery, increasing sensitivity without impairment of specificity. Use isosorbide dinitrate, which has short-acting effects, unlike GTN.
Ford et al.

FIGURE 2 Cardiac Catheterization Laboratory Interventional Diagnostic Procedure Protocol
Proposed step-by-step approach to guidewire-based assessment of coronary vascular function using thermodilution or Doppler and then vasoreactivity testing using acetylcholine (Ach). This simple approach focuses on thermodilution, which is straightforward to include during daily practice. Note that some operators may prefer to perform vasoreactivity testing first without the guidewire, allowing Ach challenge prior to any short-acting nitrate administration. HMR ¼ hyperemia microvascular resistance; IC ¼ intracardiac; LVEDP ¼ left ventricular enddiastolic pressure; LV gram ¼ left ventriculogram; NHPR ¼ nonhyperemic pressure ratio; seg ¼ segment; TT ¼ transit time (for bolus of normal saline); other abbreviations as in Figure 1. TREATMENT. Historically, there was no randomized evidence that a diagnostic strategy linked to therapy improves patient well-being. The CorMicA (Coronary Microvascular Angina) trial was undertaken to address this evidence gap (11,38). Patients with INOCA were randomized 1:1 to the intervention group (stratified medical therapy, interventional or functional diagnostic procedure disclosed) or the control group (standard care, IDP performed, results not disclosed). The diagnosis of a clinical endotype (MVA, VSA, both, or none) was linked to guideline-based management (10). After disclosure of the IDP result, more than one-half of treating clinicians changed the initial diagnosis and treatment on the basis of    The IDP is a combinatory technique involving direct invasive measurements of coronary vascular function initially with a diagnostic guidewire, then acetylcholine reactivity testing (Tables 1 and 2, Figure 1).