How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease: Lessons from the British Heart Foundation CorMicA Trial

Ischaemic heart disease persists as the leading global cause of death and lost life years in adults. Angina is a common clinical presentation of ischaemic heart disease related to a supply:demand mismatch of myocardial blood flow, typically provoked by exertion or stress. Invasive coronary angiography is the reference test for angina and identifies obstructive coronary artery disease (CAD) as a cause for symptoms. In Europe and the US, approximately 4 million elective coronary angiograms are performed each year. However, up to half of all angina patients undergoing elective coronary angiography with symptoms and/or signs of ischaemia have no obstructive epicardial coronary artery disease (INOCA). This large, heterogeneous group includes patients with microvascular angina (MVA), vasospastic angina (VSA) or both conditions together. The burden of these conditions on physical and mental wellbeing can be profound; they are associated with morbidity and a reduction in quality of life. Patients with these conditions commonly attend primary and secondary care, driving up health resource utilisation.

We propose that optimal clinical management starts with the correct diagnosis; hence we begin by summarising the rationale and protocol for invasive tests of coronary function in INOCA patients. We discuss drivers of myocardial ischaemia and reappraise existing consensus guideline-based management in light of the CORonary MICrovascular Angina (CorMicA) study, the first randomised controlled trial of invasive coronary function testing linked to stratified medical therapy in angina. This review aims to educate and empower the invasive cardiologist to perform vasoreactivity testing and to provide them with an understanding of the positive impact of personalised medicine for individual angina patients. We conclude pointing to future directions in care and the benefits of improved diagnosis linked to translational clinical research to develop targeted disease-modifying therapy.

Background and Aetiology of Angina Without Obstructive Coronary Disease

INOCA is a recently proposed ‘umbrella’ term conveying the importance of stable coronary syndromes beyond obstructive CAD (Figure 1). INOCA aligns with the sibling term MINOCA, which stands for myocardial infarction with no obstructive CAD. MINOCA is a similarly diverse syndrome with distinct underlying causes.

Figure 1: Ischaemia with No Obstructive Coronary Artery Disease: A Coronary Syndrome
The traditional paradigm where angina is ubiquitously associated with obstructive epicardial disease overlooks the importance other determinants of myocardial ischaemia. These three groups of factors combine to determine the physiological myocardial perfusion gradient. CAD = coronary artery disease; INOCA = ischaemia but no obstructive coronary artery disease; SEVR = subendocardial viability ratio.

Depending on the patient population studied and the techniques used, between one-third and two-thirds of angina patients with a negative angiogram have an underlying disorder of coronary vascular function. Importantly, the two most common causes of INOCA (MVA and VSA) are not excluded by a negative non-invasive CT coronary angiogram or invasive coronary angiogram. For affected patients, symptom burden, morbidity and health resource utilisation can be considerable.

As cardiologists, we often adopt a ‘stenosis-centric’ approach. However, as clinicians we must appreciate the complexity and individual contributors to ischaemia in patients without obstructive epicardial disease (Figure 1). Systemic factors, including heart rate, blood pressure (and their product) and myocardial supply:demand ratio (Buckberg index), are important. Coronary factors are well recognised, but certain nuances are overlooked. For example, Gould and Johnson recently used their quantitative myocardial perfusion database of over 5,900 patients to show that occult coronary diffuse obstructive coronary disease or flush ostial stenosis may be overlooked on angiography and mislabelled as microvascular angina with suboptimal treatment. Other coronary factors that can cause ischaemia and propensity to acute coronary syndromes include structural microvascular dysfunction, endothelial impairment, myocardial bridging and/or epicardial vasospasm.

The final group of factors that can drive INOCA is cardiac, including left ventricular hypertrophy or restrictive cardiomyopathy where subendocardial ischaemia results from challenges with arteriolar vessels penetrating deeper into the myocardial tissue with shorter diastole and enhanced systolic myocardial vessel constriction. Heart failure (with reduced or preserved ejection fraction) can lead to elevated left-ventricular end diastolic pressures that reduce the physiological myocardial perfusion gradient.

Valvular heart disease, e.g. aortic stenosis or left ventricular outflow tract obstruction, is a well-recognised cause of INOCA, although controversy exists over whether symptoms in mechanical outflow tract obstruction (aortic stenosis) relate to microvascular dysfunction, supply:demand factors or both. Most experts support haemodynamic factors as the main cause of ischaemia here, especially since symptoms and coronary flow reserve improve immediately after valve replacement.

Non-invasive Functional Testing

Non-invasive tests provide indirect assessments of myocardial resistance by assessing perfusion during exercise or pharmacological stress, typically using systemic adenosine. Nevertheless, perfusion assessment lacks the sensitivity to diagnose the relative contributions of epicardial and microvascular disease to myocardial blood flow reduction. In addition, some patients with a propensity to vasospastic chest pain syndromes may have normal findings from pharmacological and exercise stress testing. This review focuses on the invasive diagnosis and related management of angina subjects without obstructive disease; the non-invasive workup is covered elsewhere.

Diagnosis and Rationale for Invasive Testing

In the cardiac catheterisation laboratory, coronary vascular function may be assessed ad hoc during the patient’s index coronary angiogram. This often involves an interventional diagnostic procedure (IDP) where a guidewire-based assessment of coronary blood flow is performed at rest and during interrogation with pharmacological probes, typically adenosine and acetylcholine.

The rationale for an IDP is three-fold. First, these patients often present with typical angina for invasive coronary angiography, which offers an opportunity for the cardiologist to provide patients with an accurate diagnosis and explanation for their symptoms. Second, discrimination of MVA, VSA and non-cardiac chest pain permits distinct treatment outlined in consensus practice guidelines. Third, evidence of coronary vascular dysfunction carries prognostic insights for patients and their clinicians. However, in contemporary standard practice, additional invasive tests on patients with unobstructed coronary arteries are very rarely performed.

The IDP consists of two steps: assessment of coronary circulation vasorelaxation using invasive coronary physiology at rest and with hyperaemia; and second, assessment of the propensity of the coronary circulation to excessive vasoconstriction using intra-arterial acetylcholine (microvascular and/or epicardial vasospasm) (Table 1). We typically prefer the left anterior descending coronary artery as the target vessel because it subtends the largest myocardial mass. While regional microvascular dysfunction is well recognised, interrogation of multiple vessels increases the procedural duration such that the benefits of testing may be outweighed by the risks.