Pressure- and 3D-derived coronary Flow Reserve with Hydrostatic Pressure Correction - A Validation by Intracoronary Doppler Measurements

Purpose : To develop a method of coronary flow reserve (CFR) calculation derived from three-dimensional (3D) coronary angiographic parameters and intracoronary pressure data during fractional flow reserve (FFR) measurement. Methods : Altogether 19 coronary arteries of 16 native and 3 stented vessels were reconstructed in 3D. The measured distal intracoronary pressures were corrected to the hydrostatic pressure based on the height differences between the levels of the vessel orifice and the sensor position. Classical fluid dynamic equations were applied to calculate the flow during the resting state and vasodilatation on the basis of morphological data and intracoronary pressure values. 3D-derived coronary flow reserve (CFR p-3D ) was defined as the ratio between the calculated hyperemic and the resting flow and was compared to the CFR values simultaneously measured by the Doppler sensor (CFR Doppler ).


Introduction
According to the current European guideline on coronary revascularization, pressure wire-derived fractional flow reserve (FFR) measurement is recommended for the functional assessment of lesion severity in patients with 40-90% diameter stenosis and without prior evidence of ischemia [1]. A more recent guideline suggests the consideration of a guidewire-based coronary flow reserve CFR measurement in patients with persistent symptoms but with preserved FFR [2] based on earlier publications [3][4][5]. The combination of FFR and CFR evaluation may identify the potential components of ischemia originating from the decreased conductance of the epicardial vessels and the increased resistance of the microvasculature [6][7][8][9].
As a temperature sensor, the pressure-wire sensor makes it possible to calculate thermodilution, however, this method comes with several limitations, as already detailed in early validation studies [10][11][12]. On the other hand, the direct measurement of coronary flow velocity by a Doppler sensor is considered technically difficult to perform; consequently, it is not routinely used in clinical practice.
The resistance of the microvasculature (Rμ) is defined as the ratio of the distal coronary pressure divided by the distal coronary flow rate. During bolus thermodilution measurements, the resistive reserve ratio was calculated as the index expressing the ratio between hyperemic and basal microcirculation [13]. Lately, the term microvascular resistance reserve (MRR) was suggested for the same index during continuous thermodilution technique [14] and Doppler measurements [15].
MMR is calculated as the ratio of Rμ at rest and Rμ during hyperemia.
In our study, we aimed at developing a clinically applicable method for calculating specific CFR and MRR values (CFRp-3D and MRRp-3D) during FFR measurement, using simple hemodynamic calculations that combine intracoronary pressure data and 3D anatomical parameters (Figure 1).
The results of our calculations were compared to data obtained using invasive Doppler wire measurement, as a gold standard of flow assessment.
It has recently been underlined that pressure differences are systematically detectable between the different segments of the coronary arteries in the supine position [16][17][18]. We also investigated how the correction of distal pressure for hydrostatic pressure offset affects the pressure-derived flow determination.

Patient inclusion criteria
Patients, who underwent clinically indicated invasive physiological investigations, were selected for this study, with a single stenosis of intermediate severity (40-80% based on visual assessment) in a main branch of the epicardial coronary artery system. Cases with good quality hyperemic and resting pressure and Doppler traces were included for the evaluations. Only traces without pressure drift (<1 mmHg) confirmed by the pullback of the pressure sensor at the end of the procedure were considered. Patients with an acute coronary syndrome, left main stenosis, ostial stenosis, earlier bypass surgery or diffuse coronary artery disease were excluded. The study has been approved by the local ethics committee of the University of Debrecen and has therefore been performed in concordance with the Declaration of Helsinki.

Invasive coronary angiography and simultaneous pressure and flow measurement by ComboWire
After administering 5000 international units (IU) of intravenous, unfractionated heparin (UFH) and intracoronary glyceryl trinitrate (GTN), diagnostic angiographic cine-recordings were acquired from standard projections, using a digital X-ray equipment (Axiom Artis, Siemens). Diagnostic angiographic images were recorded at 15 frames per second. Low-or iso-osmolar contrast material (CM) (iopamidol [Scanlux] or iodixanol [Visipaque]) was injected in 5 mL fractions with a speed of 3 mL/sec using a dedicated contrast pump (ACIST CVi™, ACIST Medical Systems). If the operator detected a 40-80% diameter stenosis by visual assessment, complete physiological measurements were performed via a 6F guiding catheter, using a ComboWire equipped with both pressure and Doppler sensors (Philips Volcano, San Diego, CA, USA).
After the pressures were equalized with the sensor positioned at the level of the catheter tip, it was advanced through the coronary artery stenosis, and measurements were performed approximately 2 cm distal to the lesion. Following the basal pressure and flow measurements, 150-200 µg intracoronary adenosine was administered, and the pressure and Doppler traces were recorded. One representative measurement is presented in Figure 2.

Three-dimensional quantitative coronary artery reconstruction and hemodynamic calculations
Offline 3D angiographic reconstruction was performed from two selected angiograms of good quality, with an at least 25 • difference in angle, using dedicated software (QAngio XA Research Edition 1.0, Medis Specials bv, Leiden). The reconstructed vessel segment was marked from the coronary orifice to the location of the wire sensors. Numerous geometric measures describing the lesion (average cross-sectional diameters and vessel segment lengths), as well as the proximally and distally connecting vessel segments were automatically obtained by the software. These values with intracoronary pressure at the proximal and distal positions during the resting and vasodilation states were combined for hemodynamic calculations. The method and its validation are described in our previous papers in detail [19,20].

Calculation of the MRRp-3D
The resistance of the microvascular system is the ratio of the distal coronary pressure (Pd) divided by distal coronary flow (Q) during resting condition and hyperemia. The ratio of the resting and hyperemic resistance gives us the microvascular resistance reserve (MRR):

Correction of the distal coronary pressure for hydrostatic pressure
In supine position, the measured pressure difference between the catheter tip and the pressure sensor distal to the lesion originates from two components, namely the pressure loss caused by the flow through the stenosis, and the difference between the hydrostatic pressure at the catheter tip at the coronary orifice and the level of the distal intracoronary sensor (Figure 3).
The latter component can be referred as hydrostatic offset (∆Phyrostatic pressure), and can modify the without and with hydrostatic pressure correction. Sensitivity and specificity of CFRp-3D without and with hydrostatic pressure correction were calculated using the standard method.

Results
We performed simultaneous intracoronary pressure and Doppler measurement by ComboWire in 20 patients screened in the study. In 3 cases the Doppler signal quality was insufficient for the calculation, in 1 further case more than 2 mmHg drift was detected at the end of the investigation and the attempt for repeat measurement was also failed. Therefore, sixteen 16 patients (14 males, 2 females) with single, intermediate epicardial coronary stenosis were involved in the study. In 3 cases, measurements were performed both before and after stent implantation.
Patient characteristics are presented in Table 1. The results of 3D reconstruction and the measured physiological data are summarized for each interrogated vessel in Table 2.

Correlation and agreement between the results of the CFRDoppler measurements and calculated
CFRp-3D values without and with the correction for hydrostatic offset When including morphological data from 3D coronary angiography in the hemodynamic calculation and correcting the values for hydrostatic pressure, a strong correlation was found between the individual CFRp-3D values and the CFRDoppler measurements (r=0.89, p<0.0001). A weak, but still significant correlation was demonstrated even without the correction of hydrostatic error (r=0.57, p=0.01) Figure 4 A-B. The difference between the two correlations was found to be significant (p=0.02).
The Bland-Altman analysis showed the mean differences between the Doppler-measured and the In contrast with our method where the distal flow is rendered to the tapered vessel size [19], their in vitro and in vivo models, did not account for flow to side branches, resulting in underestimation of the volumetric flow [29]. This underestimation could lead to unlikely low resting and hyperemic calculated flow values in major coronary branches, as was pointed out in the editorial responding to their paper [30]. It is very obvious that in their in vivo study the hydrostatic pressure error had caused at least partly the very week correlation to the Doppler results.
The direction of the effect of the hydrostatic offset depends on the orientation of the sensor in the distal position relative to the coronary orifice.
If one interrogates distal LAD with the sensor, the hydrostatic pressure is lower in supine position, which results in higher pressure ratios after hydrostatic offset correction. In contrast, LCx takes a downward course, which leads to higher hydrostatic pressure at the level of the sensor, and consequently the pressure values are lower compared to the measured one following correction.
The height correction of RCA measurements can result a slight increase of the distal pressure value, as the distal sensor in the distal RCA is at a lower level compared to the orifice (Figure 6 A and   B) [18]. Thus, a slight increase in the corrected pressure ratios can be observed (Figure 6 A and   B).
In our opinion, the correction of distal pressure for hydrostatic pressure is essential when determining pressure-derived CFR. A minor hydrostatic pressure may have a significant influence on the measured pressure gradient, especially in resting state. Figure 6C, where the correction resulted in significant differences between the calculated CFRp-3D and the uncorrected values, most prominently in the range of higher CFR values.

This phenomenon is demonstrated in
The weCFRp-3D values calculated after the correction for hydrostatic pressure and those derived from native pressure values were compared with the Doppler flow measurements. A strong correlation was demonstrated between the individual CFRp-3D and the CFRDoppler values when the correction for hydrostatic pressure was made, while only week correlation was found without hydrostatic pressure correction.
Importantly, the elimination of hydrostatic pressure offset increased the specificity of our method from 46.1% to 92.3%, while the sensitivity of both calculations remained 100% against the "gold standard" Doppler measurement.

Limitations of the study
The main limitation of our pilot study of CFRp-3D calculations is represented by the small sample size. However, the archived and statistically highly significant results look promising.
We are aware that our simple model considers only Hagen-Poiseuille-type friction losses and highly simplified Borda-Carnot type separation losses. For this reason, the calculation of the flow rate is also not expected to be always accurate, but because the CFR is by definition a ratio-type parameter, the CFRp-3D may be accurate enough for clinical applications [20]. The simplified haemodynamic model used for the calculation of the CFRp-3D is able to consider only one stenosis, with a normal proximal and distal segments. Consequently, our flow calculation method in the present form may not be adequate for assessing the hemodynamic relevance of sequential stenoses.
In cases with a very low resting pressure gradient, any small error during the measurement could potentially cause a great deviation in the results, as these values are represented in the denominator during the calculations. However, most of the cases with intermediate coronary lesions showed not less than a 1-2 mmHg resting pressure gradient, which allowed the appropriate calculation of the CFRp-3D.

Conclusions
In this study, we proposed a method of combined determination of FFR and CFR without the need for Doppler wire or thermodilution procedure. In our opinion, the CFRp-3D is applicable for any coronary angiography with the clinically indicated invasive measurement of the FFR, when the target vessel is suitable for 3D reconstruction. The flow calculation does not require significantly more time this way. We have created an online calculation tool (http://coronart.unideb.hu/) available, which enables a more comprehensive assessment of coronary physiology than FFR measurement alone. As a result, the consequences of an epicardial stenosis can be assessed simultaneously with the state of the microvasculature, thereby supporting the clinical decision for selecting the most appropriate therapy. In our opinion, large-scale studies are warranted to investigate the clinical relevance of the pressure-flow relation determined by our technique [31].

Ethics approval
The study was conducted in accordance with the Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Funding
The University of Debrecen supported this work in the framework of a proof-of-concept project (PoC 007).

Figure 2. Results of simultaneous pressure and flow measurements by the ComboWire
In this case the average proximal (aortic) and distal pressures were detected to be 95 mmHg and 88 mmHg, respectively. At maximal hyperemia (P), the average peak velocity (APV-P) increased to 29 cm/s parallel with the increase in the pressure drop (the proximal and distal pressures were 89 mmHg and 79 mmHg, respectively). The measured FFR was 0.89, while the CFR 2.9 (Case 10).

Figure 3. The height difference between the LAD orifice and the sensor position
After 3D reconstruction, the height difference between the orifice and the pressure wire sensor was transformed to mmHg getting hydrostatic pressure (red) (Case 10). This value (5.58 mmHg) influences the gradient between the aortic pressure at the tip of the catheter and the pressure detected by the sensor of the pressure wire, and it has a great impact on the results of the CFR calculation.