Subject selection
This investigation was a prospective single-center study. Twenty-three consecutive patients who had undergone scheduled coronary angiography and coronary flow reserve (CFR) measurement for physiological lesion assessments at Todachuo General Hospital between October 2018 and January 2020 were enrolled. All patients had at least one stenosis in a large epicardial artery that required physiological assessment to determine the intervention indications. The exclusion criteria were a history of coronary artery bypass surgery, extremely tortuous coronary arteries, acute coronary syndrome, occluded coronary arteries, left main disease, coronary ostial stenosis, congestive heart failure, or an absolute contraindication to the use of adenosine triphosphate (ATP). This study was approved by the Institutional Review Board of Todachuo General Hospital (reference number: 0362), and the study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants after a complete explanation of the protocol and potential risks.
Catheterization and measurement of the instantaneous wave-free ratio at rest and during hyperemia
The coronary flow measurements of coronary artery stenosis were performed in the standard manner. Briefly, a digital archive (ComboMap) with a 0.014-inch dual sensor–equipped guidewire (Combowire; Philips-Volcano, San Diego, CA, USA) was used for all physiological measurements. A bolus of intracoronary nitrates (200–300 μg) was administered to all patients before the introduction of the pressure wires. The pressure was calibrated to normal atmospheric pressure before insertion of the wires and was equalized at the tip of the catheter before advancement of the catheter into the distal stenotic lesion.
The Doppler sensor's position was manipulated until an optimal and stable blood velocity signal was obtained distal to the lesion. ATP was then intravenously administered at a rate of 140 μg/kg/min for 3 minutes until steady-state hyperemia was achieved. Aortic pressure (Pa), coronary pressure (Pd), and flow velocity (V) were continuously recorded at rest and throughout the induction of maximum hyperemia. The IC-ECG was recorded during the physiological measurements by connecting the proximal tip of the Combo wire to the unipolar lead terminal of a multichannel electrocardiogram recorder (RMC-4000M Cardio Master with EP amplifier system [JB400G]; Nihon Koden, Tokyo, Japan, or AXIOM Sensis HEMO EP128; Siemens AG, Munich, Germany) using a sterile double-alligator connector. These systems allow simultaneous multichannel recordings of ECGs of limb and chest leads during the IC-ECG recordings. The IC-ECG data were stored digitally for offline analysis.
iFR and ICE-T analysis
The pressure data were directly extracted from the digital archive of the Combo map device console. Using the data from the time of pressure equalization, the time phases of the Pd and flow velocity data were synchronized based on the Pa waveform. To identify variations in the pressure parameters during WFP, the iFR was calculated using the pressure data from three heartbeats included within the automatic iFR calculation data. The iFR was calculated as the Pd/Pa ratio during the WFP (from 25% into diastole until 5 ms before the end of diastole)[8]. The start of diastole was defined at the nadir of the dicrotic notch on the Pa, and the end of diastole as 50 ms before the upstroke in Pa from the subsequent ventricular contraction.
The IC-ECG data were analyzed using the multichannel ECG recorder. ECGs were examined by scaling up the sampling speed by 100 mm/s and the ECG signal amplitude by 10 mm/mV. The following points were traced on the IC-ECG: the beginning of the P-wave, beginning of the QRS complex, end of the T-wave, end of the U-wave, beginning of the subsequent P-wave, and beginning of the subsequent QRS complex. The isoelectric line was considered as the T-P segment preceding the QRS (or QS) complex. If hallmarks of the points were not distinct, then the isoelectric line was determined based on the observation that the electrical potential is small and parallel to the baseline. The time from the Q point to the start and end of the isoelectric line was measured. The IC-ECGs were interpreted by two cardiologists, who arrived at consensus during disagreements.
The start points of the systolic phase in the pressure waveform and the Q point in the IC-ECG were regarded as the same point, and the time-phases were synchronized. The IC-ECG-triggered Pd/Pa ratio (ICE-T) was defined as the average of the Pd/Pa ratio in the period corresponding to the isoelectric line (Figure 1).
Data analysis
The baseline clinical characteristics of the patients, including the number and locations of stenotic lesions, were determined. The iFR and ICE-T values were analyzed offline using MS-Excel (Microsoft Corp., Redmond, WA, USA). The intracoronary resistance (R) was calculated as the Pd value divided by the flow velocity at the same point in time. All indices were determined in a fully automated manner for three consecutive heartbeats and were then averaged. The differences between the minimum and maximum flow velocities during the analysis interval of each index were defined as Δflow velocity (ΔV) (Figure 2). The ΔPd/Pa and ΔR were similarly defined. The mean Pd/Pa, mean V, mean R, ΔPd/Pa, ΔV, and ΔR values of the ICT-T were compared with the iFR at rest and during hyperemia. The periods used for the analysis of the ICT-T were also compared. These comparisons were also performed for the left anterior descending coronary artery (LAD) and non-LAD, respectively.
Statistical analysis
Numerical data were expressed as mean ± SD. Paired t-tests were used for comparisons of the pressure parameters, flow velocity, resistance, and analysis period between the iFR and ICE-T both at rest and during hyperemia. P-values < 0.05 were considered statistically significant. Statistical analyses were performed using SPSS (SPSS 19; IBM Corporation, Armonk, NY, USA).