Authored by Ilan A Yaeger*
Abstract
Current single-artery FFR-oriented coronary stenosis severity assessment methods (resting Pd/Pa, wave-free iFR and hyperemic FFR) are used successfully in single vessel disease (SVD) cases. In such cases the stenotic artery is in an independent stand-alone position with a proximal intracoronary aortic driving pressure. The treatment decision criteria of each method (FFR threshold value and FFR ‘grey range’) apply to FFR of the artery (denoted FFRtrue) which is the remnant fraction left in the stenotic artery of the calculated virtual blood flow of the very same artery prior to the onset of stenosis. As FFRtrue can be expressed in terms of the total stenotic resistance Rs of the artery and the microvascular resistance Rmv associated with the artery, FFRtrue can be also justifiably regarded as an ad-hoc intrinsic property of the stenotic artery. It doesn’t change unless the artery undergoes revascularization, turning its FFRtrue to nearly 1.00. The general scenario however encountered in the PCI practice is one in which a stenotic artery interconnects with other stenotic arteries and it is no longer in an independent stand-alone position since inter-arterial stenosisstenosis interactions take place. Due to this substantial change of circumstances, treatment decision criteria no longer apply to FFRtrue of an artery, rather to its actual FFR (denoted FFRreal).
The multi-artery FFR method is not intended to constitute a substitute for any of the current FFR-oriented methods. As single-artery FFRoriented methods cannot resolve complex scenarios of interacting stenotic coronary arteries, in this article the novel multi-artery FFR method extends these methods to the multi-artery domain with no need to alter their associated experimental techniques nor their treatment decision criteria. Reduction of the mathematics to minimal number of simple formulas in this article enables the PCI practitioner to apply the formulas to measured intracoronary pressures in real time.
Keywords: Multi-artery fractional flow reserve; Fractional flow reserve; Percutaneous coronary intervention; Revascularization; Percutaneous transluminal coronary angioplasty
Abbreviations: FFR: Fractional Flow Reserve; PCI: Percutaneous Coronary Intervention; iFR: Instantaneous Wave-Free Ratio; CABG: Coronary Artery Bypass Graft; ISR: In-Stent Restenosis; DES: Drug-Eluting Stent; ST: Stent Thrombosis; MACE: Major Adverse Coronary Event; MVD: Multi- Vessel Disease; SVD: Single Vessel Disease
1. Introduction
1.1. Single-artery FFR-oriented methods
Upon encountering a coronary stenosis, the percutaneous coronary intervention (PCI) practitioner is faced with a familiar dilemma: Revascularization or Conservative Medical Treatment? An unjustified revascularization can expose the patient unnecessarily to risks. The risks of a coronary artery bypass graft (CABG) operation are well known. Stenting however has its own risks. Though in-stent restenosis (ISR) has been substantially diminished by using drug-eluting stents (DES), it has not been eradicated. Within a period of a year or two, in cases of simple lesions and without particular risk factors, the ISR rate is usually less than 5% [1]. In cases of complex lesions and additional risk factors however, double digit rates are not uncommon [2]. The sudden incidence of stent thrombosis (ST) is around 1% [3]. By the traditional PCI method, in each of the two extreme cases, the very low and the very high stenosis severity ranges, the decision from which the patient can benefit is obvious from visual inspection and can be readily made. It is in the intermediate stenosis severity range (30%-70% diameter stenosis) where visual stenosis severity assessment can be difficult due to the absence of a well-defined quantitative criterion. The PCI terrain was consequently ripe for the appearance of some FFR-oriented methods.
At the time of its inception, the hyperemic FFR method has conceptually revolutionized the field of coronary stenosis severity assessment [4]. In contrast to the traditional and essentially qualitative angiographic approach, the FFR method focused on a quantitative measure of the functional performance of the stenotic artery in a pharmacologically induced state of hyperemia. In this method the hyperemia state is mandatory, and the resulting microvascular resistance is minimal and stable while maximal dilatation of the coronary artery and of its associated microvasculature takes place. The hyperemic FFR index of a stenotic coronary artery is the currently available remnant fraction of the (calculated) original maximal blood flow through the artery in its virtual stenosis-free state, namely
FFR=Qs/Qo (1)
Qs - blood flow through artery in stenotic state
Qo - blood flow through artery in a virtual stenosis-free state
As the hyperemic pressure and blood flow are in a linearity relationship, the FFR index is obtained experimentally from measurements of intracoronary pressures. If a single stenotic artery is exposed to the aortic pressure, and the venous pressure is assumed to be nearly zero, its hyperemic FFR index (denoted FFRtrue) is equal numerically to the ratio of the mean distal pressure Pd and the mean proximal aortic pressure Pa [4], namely
FFRtrue = Pd/Pa (2)
FFRtrue of a single stenotic artery can be also expressed in terms of the total stenotic resistance Rs of the artery and its associated microvascular resistance Rmv:
FFRtrue = 1/(1 + Rs/Rmv) (3)
In an experimental statistical study FFR-guided decision for treatment of stenotic coronary arteries proved to be superior to angiography-guided approach when the number of major adverse coronary events (MACE) over a period of several years was taken into consideration [4]. It was also found experimentally that for a single stenotic artery a condition of FFRtrue<0.75 implies a mandatory revascularization of the stenotic artery whereas 0.85 indicates that treating the single artery just by medication is enough. If the FFRtrue index is in the ‘grey range’ of treatment decision uncertainty, 0.75≤ FFRtrue ≤0.85, additional clinical factors related to the patient under consideration should be considered in order to reach the correct treatment decision [5]. Patients feel uncomfortable during the state of hyperemia associated with the hyperemic FFR method. In order to get around this negative aspect and other downsides of this method, the instant wave-free ratio (iFR) method in which no state of hyperemia is required was introduced in 2012 [6]. The familiar resting Pd/ Pa method in which the ratio distal to aortic pressure at rest is averaged over the full cardiac cycle (for several consecutive cycles) also shows results comparable to these of the hyperemic FFR and free wave iFR methods [7].
Despite the establishment of the superiority of the hyperemic FFR method over angiographic stenosis severity assessment in the FAME study [8], there is a grave downside associated with the 3 FFR-oriented methods - they do not take into account inter-arterial interactions as can be seen in the FAME study itself. The cases treated in that study were formally multi vessel disease (MVD) cases involving 2 or 3 major coronary arteries LAD, LCx and RCA. However, an inspection of the conditions of the FAME study reveals that cases of diseased LMCA were excluded from the study, leaving each of LAD and LCx arteries directly exposed to the aortic pressure. This fact rendered all 3 arteries independent of each other since the proximal pressure in each one was the full aortic pressure, and each was consequently treated in that study as an independent single vessel disease (SVD) case. The inevitable conclusion is that the basic hyperemic FFR method cannot yield a rigorous resolution of complex MVD cases. In recent years attempts have been made to study the effect of downstream stenoses on LMCA employing the hyperemic single-artery FFR method but since this method does not take into account inter-arterial interactions, those attempts provided only general quantitative results rather than rigorous resolution of stenotic coronary configurations involving LMCA on an individual case basis [9,10].
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