Invasive coronary physiology in patients with angina and non-obstructive coronary artery disease: a consensus document from the coronary microvascular dysfunction workstream of the British Heart Foundation/National Institute for Health Research Partnership

Introduction

Stable ischaemic heart disease comprises a broad range of coronary pathophysiology associated with a spectrum of prognostic outcomes and potential therapies.1 The aim of diagnostic testing is to elucidate whether there is an ischaemic mechanism causing anginal chest symptoms and to determine the optimal therapies for individual patients. We now know that a large proportion of patients with angina, or indeed demonstrable myocardial ischaemia, have non-obstructed coronary arteries (ANOCA or INOCA). ANOCA is an umbrella term, which comprises different pathophysiological disease entities. These include coronary microvascular disease (CMD), coronary endothelial dysfunction and epicardial coronary vasospasm, each with distinct prognostic outlooks and guideline-directed therapies. The presence of coronary vascular abnormalities corresponds with myocardial ischaemia and abnormal coronary perfusion during exercise, as well as greater morbidity and mortality, and represents a modifiable therapeutic target, which should therefore be proactively identified. Over the past decade, there has been a rapid growth in the evidence base supporting routine physiological assessment to guide management of patients with ANOCA, with a recent strengthening to IIA recommendation in the current ESC guidelines. In patients who are referred for angiography and found to have functionally non-obstructive disease, the catheter laboratory visit represents an ideal opportunity to resolve diagnostic ambiguity, improve patient outcomes and optimise resource utilisation.

The UK CMD workstream is an initiative supported by the NIHR-BHF Cardiovascular Partnership, which aims to standardise and harmonise coronary vascular physiology assessment in the UK enabling research involving data collected during standard care and in clinical research studies. The partnership aims to promote clinical research collaborations through international networks. This document sets out the core assessments that need to be performed to identify the presence of coronary vascular abnormalities in patients presenting to the cardiac catheterisation laboratories.

Coronary vascular physiology assessment in patients with ANOCA

Coronary vascular assessment can be performed readily and safely and provides accurate and reproducible evaluation of microvascular function. Fractional flow reserve (FFR) quantifies the functional significance of epicardial coronary artery stenoses, but does not allow additional physiological assessment of patients with ANOCA. The main parameter used to distinguish normal from abnormal coronary microvascular function is the coronary flow reserve (CFR). CFR is the ratio of hyperaemic to baseline coronary blood flow (CBF) and reflects the ability to augment myocardial blood supply in response to increased demand, determined by the extent to which microvascular resistance can be dynamically decreased. CMD can be secondary to architectural changes within the microcirculation, such as vascular smooth muscle hypertrophy and capillary rarefaction, or vasomotor dysfunction, such as endothelial and/or vascular smooth muscle dysfunction. An inability to adequately augment CBF is characteristic of CMD and is associated with increased likelihood of myocardial ischaemia and adverse cardiovascular outcomes. While absolute CBF (mL/min) is difficult to measure in a clinical setting, it can currently be estimated by one of the two techniques: Doppler to measure coronary flow velocity or Thermodilution to measure the mean transit time of room temperature saline, each requiring the use of different sensor-tipped, ultra-thin, intracoronary (IC) guidewires. CBF is estimated at rest and in response to pharmacological stressors, like adenosine (to test endothelium-independent function) and acetylcholine (ACh; to test endothelium-mediated vasodilatation).

In the absence of obstructive epicardial coronary artery disease (CAD), an impaired CFR (defined as <2.5) confirms the diagnosis of endothelium-independent CMD, while an impaired acetylcholine flow reserve (AChFR) (defined as ≤1.5) confirms the diagnosis of coronary endothelial dysfunction. The Coronary Vasomotion Disorders International Study Group (COVADIS) states that CMD can be diagnosed at a CFR threshold of 2.0 or 2.5.12 A recent study has demonstrated that patients with CFR 2.0–2.5 are physiologically indistinguishable from those with CFR <2.0.10 This study found the optimal dichotomous CFR threshold for predicting global myocardial ischaemia to be 2.5 (sensitivity 95%, specificity 65%; area under the curve=0.80, p<0.001). Importantly, myocardial perfusion and exercise physiology parameters of patients with CFR 2.0–2.5 resembled those of patients with CFR <2.0. Therefore, CFR <2.5 is an accurate surrogate of (substrate for) myocardial ischaemia, with a high sensitivity and reasonable specificity.

The combined use of adenosine and ACh provides the highest accuracy when confirming or excluding the presence of an ischaemic substrate in patients with ANOCA. This has significant implications on patient management and resource utilisation. The CorMicA study has demonstrated that stratifying treatment in patients with ANOCA based on coronary vascular physiology assessment yields superior outcomes to empirical therapy, supporting the role of coronary physiology testing in this patient cohort.

Patient selection

Patient selection is critical to ensure optimal resource utilisation and to offer maximal benefit to the appropriate patient cohort. For these reasons, invasive coronary vascular physiology assessment should be reserved for patients with a high pre-test probability of coronary vascular dysfunction, i.e. patients with cardiovascular risk factors, typical symptoms of angina despite optimal medical therapy ±evidence of ischaemia on stress imaging, in the absence of obstructive epicardial CAD.

Protocol

Patients with symptoms suggestive of myocardial ischaemia who are referred for coronary angiography and found to have unobstructed coronary arteries (confirmed with pressure-based indices as appropriate, namely FFR>0.80 or non-hyperaemic pressure ratio >0.89) should proceed to estimation of coronary flow by using thermodilution or Doppler-based techniques. CFR calculated by the two techniques are both reliable in identifying myocardial ischaemia validated against positron emission tomography imaging.

Vascular access

We recommend using the radial artery as the preferred route of access, given the overwhelming safety data associated with this strategy. Intra-arterial nitrates may be used to prevent the occurrence of radial artery spasm; these have a short half-life and are unlikely to affect the integrity of results obtained.

Target coronary artery

We recommend using the left anterior descending (LAD) artery as the target coronary artery for assessment. The LAD subtends a large percentage of the myocardium, and much of the evidence base on CFR in ANOCA is derived from measurements made in the LAD. If the LAD artery cannot be used for technical reasons, then we recommend using the left circumflex artery, followed by the right coronary artery (RCA). Operators may also wish to assess a specific coronary artery if there is objective evidence of localised ischaemia or vasospasm elsewhere.

To avoid catheter or wire thrombosis, intravenous or intra-arterial heparin (70–100 U/kg) should be administered to achieve therapeutic anticoagulation (activated clotting time 250 s) before coronary instrumentation.

Doppler-based technique (ComboWire, Philips Volcano, California)

Following intubation of the target vessel, the ComboWire (fitted with pressure and Doppler sensors) is advanced until the pressure sensor is between the guide catheter and the ostium of the coronary artery in question. The introducer needle should be withdrawn, the catheter flushed with saline and the ComboWire pressure equalised to the catheter signal. The ComboWire should then be manipulated into the mid-to-distal LAD (at least 5 cm from the ostium) and fine rotational movements applied to obtain optimal and stable Doppler traces using the density of the signal on the visual display of the console as well as the phasic auditory signal. Optimal readings occur when the Doppler probe is aligned co-axially with vessel. When using a wire with offset sensors, it is desirable to manipulate the wire so that the tip is in a retroflex (or looped) orientation, which allows a more stable signal and ensures that the pressure and Doppler sensors are in the same location within the artery.

Once an optimal Doppler signal is obtained, the catheter laboratory team should optimise the signal to noise ratio by varying the instantaneous peak velocity threshold and/or the display threshold. On most consoles, the flow velocity scales will be set to auto adjust, although manual setting of the velocity scale can allow further optimisation (especially in instances of 50 Hz electrical interference) in the hands of experienced teams.

Endothelium-independent function assessment (CFR)

IC nitrate should be administered before any readings are taken. We suggest using lower doses of short-acting glyceryl trinitrate (GTN) (≤200 µg). The half-life of GTN is approximately 2 min, which makes it an appealing choice in case ACh assessment is planned later. The short half-life of GTN should prevent false negative outcomes during the subsequent ACh assessment. Once steady state is achieved, the baseline coronary pressure and flow measurements can be taken.

Once stable pressure and flow signals are achieved, the baseline average peak velocity (APV) should be documented. Hyperaemia should now be induced either by intravenous administration of adenosine at a dose of 140 µg/kg/min or by IC bolus of adenosine (use maximum dose tolerated in relation to the occurrence of atrioventricular block, usually 60–120 µg in the left coronary artery (LCA) and 30–60 µg in the RCA). Hyperaemia is confirmed when the APV increases, as the microvascular resistance drops significantly, and the steady-state APV is taken to be the hyperaemic APV. Other markers of hyperaemia include systemic symptoms related to IV adenosine, ventricularisation of the distal coronary pressure waveform, disappearance of the distal dicrotic pressure notch and separation of mean aortic and distal pressures. The CFR should be calculated once maximal hyperaemia is confirmed, and good quality flow signals are achieved by adjusting scales and tracking (figure 1). CFR <2.5 is suggestive of CMD.

Figure 1
Coronary vascular physiology assessment, using Doppler wire, demonstrating normal epicardial coronary artery (FFR=0.84) and endothelium-independent coronary microvascular (CFR=3.1) physiology. The aortic (red) and distal coronary (yellow) pressures are used to calculate Pd/Pa and FFR. The Doppler flow signals are used to derive the instantaneous peak velocity (IPV) and averaged peak velocity (APV), which are used as a surrogate for coronary blood flow. The pressure and flow traces are both ECG-gated. CFR=APV-P/APV-B; hMR=Pd/APV-P; hSR=(Pa-Pd)/APV. APV-B, basal averaged peak velocity; APV-P, hyperaemic averaged peak velocity; CFR, coronary flow reserve; FFR, fractional flow reserve; HMR, hyperaemic microvascular resistance; HSR, hyperaemic stenosis resistance.