FFR Versus iFR in Assessment of Hemodynamic Lesion Significance Using Gene Polymorphisms and Lesion Morphology Assessed by OCT (FiGARO Trial)

BACKGROUND AND RATIONALE FOR THE STUDY Coronary artery disease (CAD) is the most frequent causes of death and disability in developed countries. The main diagnostic method for detection of CAD is a coronary angiography (CAG. However, the correlation between CAG and proven hemodynamic significance in borderline stenosis (40-70% of lumen narrowing) is only about 50%. The main method for detection of flow-limiting lesions is fractional flow reserve (FFR). FFR is calculated as distal pressure (Pd) divided by proximal pressure (Pa). The cut-off for hemodynamic significance is 0.8 and less. The use of FFR for lesion assessment has a level of recommendation of I A in European guidelines for coronary interventions from 2014. The FAME trail revealed that routine usage of FFR measurement decreased the costs of coronary interventions over two years. The reasons are smaller quantity of implanted stents and decreased number of procedures for in stent restenosis as a direct result of the lower incidence of initial stent implantation. FAME-2 trial has shown lower incidence of urgent revascularization in patients with FFR less than 0,8 treated by coronary intervention compared to those treated conservatively. This study was preliminary halted before reaching mortality endpoint for safety reasons.

Critical condition for proper FFR measurement is maximal vasodilatation. Since we do not have marker for this condition based on pressure measurement only we can only presume that it was reached by adenosine administration. There are a lot of limitations for this assumption. Foremost, technique for proper intravenous and intracoronary adenosine administration must follow strict rules and therefore can be done incorrectly and leads to wrong result in same cases. Furthermore, impaired endothelial function leads to lower response to adenosine administration. This situation can leads to false negative FFR result. The patients with CAD have frequently significant endothelial dysfunction causing lower response to vasodilatation stimuli. Endothelial dysfunction will be analyzed by a system named EndoPAT (Itamar Medical, Israel) that measures ischemia induced vasodilatation on fingers. The hypothesis that has never been tested is how polymorphism in genes for enzymes playing an important role in proper endothelial function (HO-1, hemoxygenase-1 and ENOS, endothelial NO synthase) can influences adenosine-induced vasodilatation and subsequently FFR measurement. These polymorphisms are not infrequent in population with CAD (they can be found in 40-50% in such patients).

Another possible limitation for FFR measurement is type of blood flow in coronary arteries. In presence of coronary stenosis, plaque roughness or sharp angle of a lumen the type of flow can be changed from laminar to turbulent. This type of flow is even accelerated during hyperemia induced by adenosine administration. It leads to lose of energy and exaggerates pressure drop behind stenosis that - for this reason- may not be proportional to stenosis severity. This situation can theoretically causes false positive FFR measurement. To answer this question the investigators will analyze the endothelial shear stress (ESS) that can distinguish laminar and turbulent flow and morphological indices (plaque surface, plaque eccentricity, lumen volume and lumen shape) by optical coherence tomography (OCT).

The new index able to identify physiologically significant stenosis has been recently described. It is instantaneous wave-free ratio (iFR). This technique uses a pressure gradient as well, but -unlike to FFR- iFR compares pressures (proximal and distal to stenosis) only in a specific phase of diastole (so called "wave free period"), where microvascular resistance is naturally low and stable .

The cut off point for iFR is 0.9. The correlation between FFR and iFR is between 80% and 90% in all lesions. However, the correlation between FFR and iFR close to their cut-off point is only 50%-60%. It is substantial caveat, because to estimate hemodynamic significance of borderline lesions is the main indication for these techniques. Discrepancies between FFR and iFR can be very confusing a discouraging for lesion hemodynamic assessment.