Invasive and non-invasive assessment of ischaemia in chronic coronary syndromes: translating pathophysiology to clinical practice

Ozan M Demir, Haseeb Rahman, Tim P van de Hoef, Javier Escaned, Jan J Piek, Sven Plein, Divaka Perera
European Heart Journal, Volume 43, Issue 2, 7 January 2022, Pages 105–117,


Intracoronary physiology testing has emerged as a valuable diagnostic approach in the management of patients with chronic coronary syndrome, circumventing limitations like inferring coronary function from anatomical assessment and low spatial resolution associated with angiography or non-invasive tests. The value of hyperaemic translesional pressure ratios to estimate the functional relevance of coronary stenoses is supported by a wealth of prognostic data. The continuing drive to further simplify this approach led to the development of non-hyperaemic pressure-based indices. Recent attention has focussed on estimating physiology without even measuring coronary pressure. However, the reduction in procedural time and ease of accessibility afforded by these simplifications needs to be counterbalanced against the increasing burden of physiological assumptions, which may impact on the ability to reliably identify an ischaemic substrate, the ultimate goal during catheter laboratory assessment. In that regard, measurement of both coronary pressure and flow enables comprehensive physiological evaluation of both epicardial and microcirculatory components of the vasculature, although widespread adoption has been hampered by perceived technical complexity and, in general, an underappreciation of the role of the microvasculature. In parallel, entirely non-invasive tools have matured, with the utilization of various techniques including computational fluid dynamic and quantitative perfusion analysis. This review article appraises the strengths and limitations for each test in investigating myocardial ischaemia and discusses a comprehensive algorithm that could be used to obtain a diagnosis in all patients with angina scheduled for coronary angiography, including those who are not found to have obstructive epicardial coronary disease.

Graphical Abstract

Illustration of hierarchy of coronary indices and optimal coronary indices by coronary artery disease substrate. CFR, coronary flow reserve; CT, computed tomography; FFR, fractional flow reserve; hMR, hyperaemic microvascular resistance; hSR, hyperaemic stenosis resistance; iFR, instantaneous wave-free ratio; IMR, index of microvascular resistance; NHPR, non-hyperaemic pressure ratio; Pd/Pa, resting distal to aortic pressure ratio; QFR, quantitative flow reserve.


For decades, coronary angiography served as the gold standard in the diagnosis of coronary artery disease (CAD), with a supportive role for non-invasive tests in clinical decision-making. Yet, following a call in the latter part of the 20th century, for greater reliance on physiology and less on anatomy alone, there has been a growing move to functionally characterize the coronary circulation, enabled by a new armamentarium of coronary physiology tools. The demonstration of the clinical and economic benefits of strategies based on functional coronary and myocardial assessment has resulted in an increase in physiology-guided management of patients with CAD, but uptake still lags behind the evidence base. The coronary circulation comprises distinct anatomical and functional compartments, working in concert to match blood supply to highly varying myocardial oxygen requirements. During increased periods of demand, such as exercise, increased aortic pressure, reduced microvascular resistance, and augmentation of the dynamic interaction between the contracting heart and vasculature (cardiac‒coronary coupling) accentuate coronary blood flow to ensure adequate transmural perfusion of the left ventricle. Simultaneous measurement of distal coronary pressure and flow, across a range of physiological conditions, allows comprehensive characterization of the epicardial and microvascular compartments. However, whilst the advent of ultra-thin sensor-tipped guidewires allows these measurements to be carried out in a clinical setting, the measurement of coronary blood flow still remains challenging and often time-consuming. Instead, the observation that the pressure drop across an epicardial artery stenosis is related to blood flow across the stenosis and the fact that pressure is (more or less) linearly related to flow in certain conditions has led to the emergence of techniques to assess stenosis significance based on pressure measurements alone. The most commonly studied catheter laboratory tool is the pressure-derived index, fractional flow reserve (FFR), the use of which is supported by a wealth of prognostic data. Further iterative simplifications of pressure-based epicardial artery assessment have occurred in recent years, first with techniques that have abandoned the need to induce hyperaemia during pressure measurements and more recently, angiographic techniques that obviate the need to measure intracoronary pressure at all. In parallel, entirely non-invasive tools have matured, with the utilization of various techniques including computational fluid dynamic modelling-based computed tomography-derived FFR (CT-FFR) and perfusion imaging, in particular with positron emission tomography (PET) and cardiovascular magnetic resonance (CMR). These methods can complement or, in some patients, be performed instead of invasive physiological measurements. In this review, we cover the physiological principles underlying the regulation of coronary blood flow in health and disease states and explore the potential trade-off between ease and accuracy, as increasing assumptions are applied when moving from comprehensive pressure and flow to the iterative simplifications (Graphical Abstract and Figure 1).

Figure 1

Illustration of inverse relationship between accuracy and ease of use for physiological indices of coronary circulatory evaluation. CT, computed tomography; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; Pd/Pa, resting distal to aortic pressure ratio; QFR, quantitative flow reserve.

Measuring coronary flow in the cardiac catheterization laboratory

Autoregulation is the innate capacity of the coronary circulation to maintain stable flow across a range of perfusion pressures. Seminal canine experiments by Gould demonstrated that in the presence of an epicardial stenosis, resting flow remains constant until relatively severe stenoses, whilst maximal or hyperaemic flow diminishes with less severe coronary obstruction (Figure 2).6 In health, coronary blood flow increases roughly 3- or 4-fold with maximal demand and is expressed as the coronary flow reserve (CFR), the ratio of hyperaemic to resting flow in a vascular bed (Table 1). Whilst a diminished CFR may indicate ischaemia during periods of increased demand, such as exercise, it does not discriminate the location of impairment within the coronary vascular tree, which could be due to an epicardial stenosis, microvascular dysfunction, or both. When used to assess the combined significance of epicardial and microvascular disease, a threshold of 2.0 defines a circulation capable of causing ischaemia. However, for the purpose of selectively measuring functional epicardial stenosis severity, CFR has been largely replaced by indices of relative vascular conductance (i.e. indices that report on the effect of the stenosis compared to a situation in which that stenosis would be non-existing) based on coronary pressure measurements, which are discussed below. Furthermore, the reliability and accuracy of Doppler flow measurements depends on obtaining a stable transducer position within the coronary artery (Figure 3), which is associated with a learning curve and hence the technique is often limited to centres and operators with specific expertise.

Figure 2

The relationship between flow velocity and pressure drop across a diseased coronary segment is unique to its severity and morphology. The figure depicts the curves across three illustrative stenoses of differing grades of severity and shows how this relationship forms the basis of all invasive physiological parameters used in clinical practice. CFR, coronary flow reserve; FFR, fractional flow reserve; hSR, hyperaemic stenosis resistance; NHPR, non-hyperaemic pressure ratio; PH, hyperaemic pressure; PR, resting pressure; VH, hyperaemic velocity; VR, resting velocity.

Figure 3

Guide to performing coronary physiology measurements using pressure, Doppler, and thermodilution wires. ECG, electrocardiogram; FFR, fractional flow reserve; IC, intracoronary; IV, intravenous; NHPR, non-hyperaemic pressure ratio; Pd/Pa, resting distal to aortic pressure ratio.


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Authors: Ozan M Demir, Haseeb Rahman, Tim P van de Hoef, Javier Escaned, Jan J Piek, Sven Plein, Divaka Perera

Publication: Volume 43, Issue 2, Pages 105–117

Publisher: European Heart Journal

Date published: January 7th, 2022


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