Fractional flow reserve: physiological basis, advantages and limitations, and potential gender differences

Abstract

Fractional flow reserve (FFR) is a physiological index of the severity of a stenosis in an epicardial coronary artery, based on the pressure differential across the stenosis. Clinicians are increasingly relying on this method because it is independent of baseline flow, relatively simple, and cost effective. The accurate measurement of FFR is predicated on maximal hyperemia being achieved by pharmacological dilation of the downstream resistance vessels (arterioles). When the stenosis causes FFR to be impaired by > 20%, it is considered to be significant and to justify revascularization. A diminished hyperemic response due to microvascular dysfunction can lead to a false normal FFR value, and a misguided clinical decision. The blunted vasodilation could be the result of defects in the signaling pathways modulated (activated or inhibited) by the drug. This might involve a downregulation or reduced number of vascular receptors, endothelial impairment, or an increased activity of an opposing vasoconstricting mechanism, such as the coronary sympathetic nerves or endothelin. There are data to suggest that microvascular dysfunction is more prevalent in post-menopausal women, perhaps due to reduced estrogen levels. The current review discusses the historical background and physiological basis for FFR, its advantages and limitations, and the phenomenon of microvascular dysfunction and its impact on FFR measurements. The question of whether it is warranted to apply gender-specific guidelines in interpreting FFR measurements is addressed.

Fig. (1)

Current concepts of coronary metabolic control. The concepts are separated for physiological conditions (unchanged level of myocardial oxygenation) and pathological conditions (decreased oxygenation). These pathological conditions include coronary insufficiency. Biochemical reactions and metabolic interactions are indicated by solid arrows and links to effectors by dashed arrows. Pointed ends indicate activation and rounded ends inhibition. PLA_2; phospholipase A_2; AA: arachidonic acid; PG: prostaglandins [12].

Fig. (2)

Tracings demonstrating fractional flow reserve (FFR) as a measure of coronary flow reserve. Shown are coronary blood flow and aortic and coronary pressure tracings from a dog without a coronary stenosis (A) and a severe stenosis (B). A hyperemic response was induced by the coronary vasodilating effect of a contrast injection, indicated by the bar at the bottom of the figure. Without a stenosis (A), the contrast caused a marked increase in coronary blood flow, with little divergence of pressures. However, with a stenosis (B), the contrast increased coronary blood flow modestly with a marked increase in the the aortic-distal coronary pressure gradient. FFR is the ratio of coronary to aortic pressure at maximum hyperemia and reflects the flow reserve [23].

Fig. (3)

The pressure drop across a coronary stenosis (Δ P) is a direct function of coronary flow velocity (v). The steepness of this relationship increases with stenosis severity (from Stenosis A to C). For a given stenosis, the pressure gradient at baseline (square) is determined by resting microvascular resistance and that at maximal hyperemia (circle) is determined primarily by the vasodilator capability of the downstream resistance vessels, although the physical factors described in the text may pose a limitation. The relationship between Δ P and v is defined by the equation at the top of the figure. The first and second terms represent pressure loss caused by viscous friction and expansion losses at the exit of the stenosis, respectively. The coefficients A and B are determined by stenosis geometry and the rheological properties of the blood [48].

Fig. (4)

An increase in minimum microvascular resistance (MR) (as shown for Stenosis C) reduces hyperemic flow, which decreases the pressure gradient across the stenosis, thus increasing fractional flow reserve (FFR). This would be expected to occur with microvascular dysfunction. There is an opposite effect on coronary flow velocity reserve (CFVR). The dashed lines indicate clinically applicable cut-off values [48].

Fig. (5)

Two models of increased coronary resistance with normal epicardial arteries. A. The increased resistance to flow (R₂), which could be either a fixed anatomic or a functional defect, is at the arteriolar level. B. The increased resistance to flow (R₃) is at the intramural prearteriole. P₁ and P₂ = pressures proximal and distal to the abnormal resistance, respectively; R₁ = the normally responsive subepicardial arteriole [80]. Refer to text for a detailed explanation.