Functional coronary angiography for the assessment of the epicardial vessels and the microcirculation

Introduction

More than half a century after revolutionising clinical practice, coronary angiography remains the cornerstone for the evaluation and treatment of coronary artery disease (CAD). Notwithstanding its relevance as a diagnostic tool, coronary angiography is fraught with major limitations as a method to ascertain the functional relevance of coronary stenoses, particularly in lesions of intermediate angiographic severity.

Attempts to bridge the gap between the angiographic morphology and functional relevance of coronary stenoses were led in the 1970s by Lance Gould and other investigators. These authors used stenosis geometry data, objectively assessed with the then newly developed quantitative coronary angiography (QCA) methods, and incorporated these data into fluid dynamic equations used to predict translesional pressure loss over a range of flow values and resistances, ultimately founding the basis for the development of coronary physiology assessment.

However, the transition of this angiographic tool from the realm of research into clinical practice was hindered, on the one hand, by the lack of correlation with ischaemic and clinical outcomes and, on the other, by the development of intracoronary physiology, particularly fractional flow reserve (FFR), which initiated the era of catheter guidewires for evaluation of ischaemia.

The additive benefit of FFR in clinical decision-making regarding revascularisation in patients with coronary stenoses has been clearly demonstrated in numerous dedicated randomised clinical trials. Nevertheless, although this ultimately led to FFR being incorporated into international clinical practice guidelines over the following decade, coronary physiological interrogation remained largely underused in cardiac catheterisation laboratories.

Explanations for the low penetrance in clinical practice are twofold: inertial (i.e., the operator’s apprehension about angiographic data and/or mistrust in coronary physiology) and technical (perceived complexity of adenosine infusion, procedural time and costs). The realisation that the adoption of invasive physiology was somewhat hampered by the requirement for vasodilatory drugs and coronary instrumentation has sparked two new developments in the last decade: 1) the introduction of non-hyperaemic indices, greatly simplifying the procedure by not mandating pharmacological hyperaemia induction; and, more recently, 2) the development of functional angiographic systems that can provide physiological information without either pressure guidewires or hyperaemic drugs (Figure 1).

In this review, we revisit the physiological principles and technical aspects of the different modalities of wireless functional coronary angiography (FCA), focusing on invasive coronary angiography (ICA) and coronary computed tomography angiography (CCTA). We will also evaluate the existing evidence and discuss the clinical applicability of wireless FCA in specific clinical scenarios. Finally, we provide our vision for future prospects and how FCA will change current clinical practice.

Figure 1. Timeline of the evolution of non-invasive coronary physiology and the respective landmark studies. CAAS vFFR: vessel fractional flow reserve; caFFR: computational pressure-flow dynamics derived FFR; FFR: fractional flow reserve; FFR_angio: angiography-derived FFR; FFR_CT: computed tomography-derived FFR; QFR: quantitative flow ratio; vFFR: virtual fractional flow reserve

Key principles of functional coronary imaging

Basic concepts and caveats of invasive coronary physiology

To fully understand the developments made in FCA, it is important to revisit some key concepts of coronary physiology.

FFR is the most widely used pressure-derived index of functional coronary stenosis severity; it expresses the percentage reduction in myocardial blood supply attributable to the interrogated stenosis. A translesional pressure ratio of 0.75 obtained during maximal hyperaemia indicates an impairment in myocardial blood supply of 25%, compared to the supply in the hypothetical absence of that same stenosis.

The cornerstone of FFR, which enables the use of pressure as a surrogate of flow, is the linearity of the pressure/flow relationship during hyperaemia. Under hyperaemic conditions, the fall in coronary pressure caused by a stenosis is proportional to the fall in maximal blood supply to the myocardium.

In the epicardial coronary arteries, flow is driven by the myocardial perfusion pressure (MPP) and is equivalent to the difference between the aortic pressure (P_a) and the central venous pressure (P_v). Whenever there is an epicardial stenosis, the MPP is equivalent to the difference between the poststenotic distal pressure (P_d) and the P_v . Therefore, FFR can be estimated from pressure measurements as follows: P_d − P_v/P_a − P_v or ≈P_d/P_a, as the effect of central venous pressure is usually negligible. Uniquely, FFR has a constant value of 1.0 in every normal coronary artery and is not influenced by variations in blood pressure, myocardial contractility, or heart rate.

The pressure loss across a coronary stenosis (ΔP) is dependent upon the severity of the narrowing and also on the magnitude of flow (Q) that goes through it. Pressure loss across a stenosis is due to: 1) viscous friction (f) and 2) flow separation due to acceleration through the stenosis (t), which leads to blood swirling and reverse currents. The expression ΔP = fQ² + tQ² explains why there is a quadratic increment in pressure loss through a stenosis with an increase in coronary flow.

Assessing functional stenosis relevance from coronary angiograms

To derive patient-specific estimations of blood flow and pressure in coronary arteries from coronary angiography, three fundamental steps must be followed: 1) selection of a fluid equation solver (computational fluid dynamics or simplified fluid dynamics equations), 2) reconstruction of a three-dimensional (3D) model of the coronary arteries, and 3) definition of boundary conditions (Figure 2).

Figure 2. Steps for obtaining a functional coronary imaging index. 1) Standard invasive coronary angiography or computed tomography angiography data are obtained. A quantitative 3-dimensional anatomical model is generated. 2) A physiological model of the coronary microcirculation is obtained from patient-specific data following specific principles: the resting coronary flow is proportional to the subtended myocardial mass; the microvascular resistance is inversely correlated with vessel size; the microvascular resistance is reduced during maximal hyperaemia. 3) Physical laws of fluid dynamics are applied to compute coronary blood flow, solving the Navier-Stokes equations or simplified equations. 4) The chosen functional index is calculated throughout the coronary artery. FFR_CT: computed tomography-derived fractional flow reserve; QFR: quantitative flow ratio; vFFR: virtual fractional flow reserve.

Solving fluid equations

Most image-based FFR techniques utilise computational fluid dynamics (CFD), a generic term used for all the mathematical engineering that is required to describe and analyse fluid flow. Through computational processing, the governing equations of fluid dynamics, i.e., Navier-Stokes equations, can be solved for the unknown coronary pressure and blood velocity that vary in position and time. Blood density and viscosity are usually assumed when solving these equations, as blood, despite its complex rheological properties, can be managed as a Newtonian fluid with constant viscosity, particularly in large arteries.

In order to reduce the computational power and time required to complete a full CFD analysis, and thus make it feasible for online vessel assessment in the catheterisation laboratory, a simplified version of CFD, using simpler mathematical coefficients, is frequently used in commercially available systems. These approaches benefit from using actual blood flow velocity by using TIMI (Thrombolysis in Myocardial Infarction) frame count and aortic pressure values, which are directly accessible for online study, instead of standardised values.

Coronary geometric models

A 3D reconstruction of the vessel lumen, which is used by most FCA systems, can be extracted from computed tomography (CT) images or from orthogonal invasive angiographic projections. Most systems integrate into the calculated metadata embedded in the DICOM image format, containing information on relevant parameters such as table/image intensifier height and frame rates. The obtained geometric model can then be divided into smaller entities, i.e., finite elements, forming the blocks of a virtual mesh, over which the equational unknowns are calculated. It is important to keep in mind that friction losses causing flow limitation may be due to microhaemorrheological disturbances caused by diffuse disease. Capturing the haemodynamic effect of minute but extensive vessel irregularities with imaging techniques relies on a very accurate reconstruction of the arterial lumen, which may not be possible because of limits in angiographic resolution.

Boundary flow conditions

The haemodynamics of epicardial vessels are strongly influenced by phenomena such as the cardiac cycle, intrinsic microvascular resistance, and extravascular compression. Boundary conditions are the mathematical limits (inlet and outlet) upon which haemodynamic models are applied to the entrance and exit of the reconstructed vessel segments, to simulate the influence of such factors. Although the inlet boundary is usually easily obtainable (through directly measuring aortic pressures or by proving a population average model) the same is not true for the outlet boundary, which includes terms such as microcirculatory resistance and central venous pressure. Preset conditions are frequently assumed, although, as previously discussed, the actual values of aortic pressure and flow velocity can be incorporated into the calculations to provide a more realistic estimate of boundary conditions.