Intravascular lesion assessment: Physiology and imaging

Translesional pressure ratios

Translesional physiology is the term given to the intracoronary wire-based pressure or flow measurements obtained proximal (usually aortic pressure from the guide catheter [P _aortic or Pa]) and distal to a stenosis (from a pressure wire or microcatheter [P _distal or Pa]). Translesional pressure measurements are most often used to assess a stenosis for appropriateness of stenting during PCI. Translesional pressure indices include resting or nonhyperemic pressure ratios (NHPR, such as mean distal coronary divided by mean proximal aortic pressure [Pd/Pa] and instantaneous wave-free pressure ratio [iFR]; Fig. 5.4 ) and hyperemic pressure ratios (e.g., fractional flow reserve [FFR] or contrast FFR [cFFR]).

Physiologic lesion assessment is indicated when clinical ischemia is not documented by objective data like electrocardiogram (ECG) changes or ischemic stress testing. Many patients require physiologic assessment because less than half of stable angina CAD patients have documented ischemia by ECG changes or stress testing before undergoing elective procedures. Moreover, unlike nuclear imaging studies, which cannot precisely identify a culprit ischemic vessel, direct translesional pressure measurement can specify which vessel/lesion may be responsible for symptoms in patients with multivessel CAD and hence benefit from PCI. This feature is particularly important for lesions narrowed between 50% to 90% diameter stenosis by visual estimation.

Hyperemic pressure ratios

Pijls and De Bruyne first validated a translesional pressure derived index for determining the physiologic impact of coronary stenoses called the fractional flow reserve (FFR). FFR is defined as the coronary flow across a lesion as a percent of normal flow in the same vessel in the theoretical absence of the lesion.

FFR is measured as the ratio of mean distal coronary pressure divided by the mean proximal aortic pressure (Pd/Pa) during maximal hyperemia. The coronary pressure beyond the stenosis is measured with a 0.014-inch pressure sensor guidewire with a high-fidelity pressure transducer mounted 3 cm from the tip of the wire at the junction of the radiopaque and radiolucent segments. (A microcatheter with an optical pressure sensor can be used as well.) The foundational concept of FFR is the linear coronary pressure-flow relationship during maximal hyperemia; thus the ratios of translesional pressure at maximal hyperemia (i.e., minimal vascular resistance) are equivalent to the ratios of hyperemic flows (poststenotic flow [Qs] divided by normal flow [Qn]). Thus FFR expresses the percentage (Qs/Qn) of a coronary flow across the stenosis and degree of myocardial flow impairment. Table 5.1 lists the calculations for FFR. A full discussion of the FFR method and results can be found elsewhere (see suggested readings).

FFR was developed as a pressure-only method of computing coronary flow reserve of a stenosis independent of the microvascular bed. CFR (maximal flow/basal flow) was thought to reflect the stenosis severity, initially observed in canine models. When CFR was tested in patients undergoing coronary bypass surgery with Doppler flow meters, however, the relationship between angiographic narrowing (% diameter) and CFR was weak. Some patients had impaired CFR because of microvascular disease, and some angiographically severe lesions (e.g., lesion eccentricity) did not reduce CFR at all. Because a normal CFR cannot exclude a stenosis as the cause of a reduced CFR, FFR was developed to be specific for epicardial stenosis narrowing. Table 5.2 shows comparative features of FFR and CFR.

Technique of translesional pressure measurements

See Fig. 5.5 . Pressure across a stenosis can be easily measured using a 0.014-inch pressure sensor wire through a 5 French (5F) or 6F guide catheter. There are several commercially available pressure wire/microcatheter systems. Resting NHPR and/or hyperemic pressure ratios (FFR) are obtained after diagnostic angiography is completed.

The steps to measure translesional pressure at rest and during hyperemia are as follows:

• 1.

  The pressure wire is connected to the system’s pressure analyzer, calibrated, and zeroed to ambient atmosphere on the table, outside the body.

• 2.

  Anticoagulation (intravenous [IV] heparin, usually 70 u/kg) and intracoronary (IC) nitroglycerin (100–200 mcg bolus) are administered.

• 3.

  The wire is advanced through the ‘Y’ connector on the guide to the coronary artery. Before crossing the stenosis, the pressure wire signal and the guide catheter pressure are matched (i.e., equalized, also called normalized ). By early convention, the guidewire transducer was positioned at the end of the guide catheter. In fact, it does not matter exactly where the wire is in relation to the guide catheter or coronary ostium except that at a minimum, the guide pressure should not be damped in the coronary ostium and the guide wire should not be beyond a narrowed left main artery before crossing the target lesion.

• 4.

  The wire is then advanced across the stenosis about 2 cm distal to the coronary lesion (at least 10 artery diameters distal to the lesion).

• 5.

  After waiting for the effect of flushing contrast out of the guide (>1 min), resting NHPR (e.g., Pd/Pa or iFR, or other NHPRs) are measured in duplicate. For FFR, maximal hyperemia is induced with IV adenosine (140 mcg/kg/min) or IC bolus adenosine (50–100 mcg for the right coronary artery [RCA], 100–200 mcg for the left coronary artery [LCA]). Alternative hyperemic agents are rarely used but include nitroprusside (50–100 mcg) or adenosine triphosphate (ATP; 50–100 mcg). FFR is measured at the lowest Pd/Pa ratio after the onset of hyperemia, usually within 2 minutes for IV adenosine and at 15 to 20 seconds after IC adenosine.

• 6.

  FFR is calculated as the ratio of the mean distal guidewire pressure to mean proximal guide catheter pressure (Pd/Pa) during maximal hyperemia. An FFR of less than 0.80 is associated with a hemodynamically significant lesion that benefits from PCI/CABG. NHPR is calculated according to the algorithm selected (Pd/Pa during the diastolic period or fraction thereof).

• 7.

  If a lesion is hemodynamically significant, and PCI is deemed necessary, it can be performed using the pressure wire as the angioplasty guidewire. After the stent implantation, FFR and pressure pullback can be measured along the course of the vessel to assess the adequacy of the intervention and impact of any residual disease or hidden lesions in the target or other vessels.

• 8.

  Finally, at the end of the procedure, check for pressure signal drift. The pressure wire should be pulled back into the guide to confirm equal pressure readings and the lack of pressure signal drift. Signal drift can occur because of changes in the electrical signals from either the wire transducer or the fluid-filled guide catheter pressure transducer. Drift shifts the zero setting of the tracings producing a false reading. On occasion the drift is large, and the last measurements will need to be repeated after re-equalization of pressures in the guide catheter.

Pharmacologic hyperemic agents

Maximal coronary hyperemia is required for accurate FFR. Table 5.3 lists available pharmacologic agents suitable for inducing hyperemia. The most common in use today is adenosine.

Adenosine is the most used hyperemic agent. IV adenosine is weight-based, operator-independent, and the preferred method used for ostial lesion assessment and pressure pullbacks for serial lesions or diffuse disease assessment. By providing a sustained hyperemic stimulus, IV adenosine allows for a slow pullback of the pressure wire, useful to identify the exact location of a pressure drop or the gradual slope of increasing pressure associated with diffuse disease. IV adenosine is often required for the assessment of aorto-ostial narrowings without the guide catheter in place to permit maximal coronary flow without coronary obstruction. Nevertheless, pressures may fluctuate with IV adenosine, such that, at times, no stable period of pressure can be seen. Johnson et al. and Seto et al. reported various fluctuation patterns of pressure changes during IV adenosine infusion ( Fig. 5.6 ). Johnson et al. demonstrated that the lowest Pd/Pa, called a smart minimum, during the adenosine infusion is the FFR value with the highest reproducibility on repeat infusions. The smart minimum FFR is the lowest Pd/Pa without pressure wave artifact that occurs any time after the adenosine effect has begun. Current FFR signal monitors have incorporated software that automatically computes and displays the FFR as the lowest Pd/Pa. The operator and team must continue to view the pressure recordings to ensure that FFR is the smart minimum value and not just “a value” that might be artificial.

IC adenosine is equivalent to IV infusion for determination of FFR. Although IV adenosine has been the standard for FFR for more than three decades and was used successfully to generate the data sets that demonstrated superior FFR-guided outcomes in the FAME (FFR Versus Angiography for Multivessel Evaluation) trial and other studies, recent examinations of hemodynamic variability during IV adenosine have prompted a return to using IC adenosine.

There are many reports of different doses of IC adenosine, ranging from 16 mcg to more than 700 mcg. The optimal doses appear to be 50 to 100 mcg for the RCA and 100 to 200 mcg for the LCA. These doses will eliminate any uncertainty that the operator achieved maximal hyperemia or did not give enough adenosine to get the most accurate FFR. Heart block in more than 10% of patients is observed with RCA IC adenosine in doses greater than 50 mcg. The concentration of IC adenosine should be mixed to provide 10 to 30 mcg/mL. One liter of the adenosine/saline mix can supply the entire lab’s needs for the day. A stopcock and flush syringe connected to the adenosine syringe make delivery of the drug easy ( Fig. 5.7 ).

Submaximal hyperemia and contrast FFR

Radiographic contrast injection causes submaximal coronary hyperemia. Intracoronary contrast media provides an easy and inexpensive tool for predicting FFR. Johnson et al. evaluated cFFR to adenosine FFR and found that approximately an injected bolus contrast volume of 8 mL (give or take 2 mL) per measurement showed less variability for cFFR than resting Pd/Pa and iFR, which had equivalent performance against FFR less than 0.8 (78.5% vs. 79.9% accuracy; p = .78). cFFR improved both metrics (85.8% accuracy and 0.930 area under the curve [AUC]; p < .001 for each) with an optimal binary threshold of 0.83. Leone et al. compared cFFR, Pd/Pa, and FFR ( Fig. 5.8 ). A binary cutoff of 0.83 for cFFR was the best for prediction of FFR and more accurate than resting Pd/Pa (cutoff of 0.92) and iFR (cutoff of 0.90) in predicting FFR, with resting Pd/Pa and iFR providing equivalent diagnostic accuracy. To maximize the accuracy of cFFR, a hybrid approach has been proposed deferring revascularization when cFFR is greater than 0.88 and stenting when cFFR is up to 0.83 ( Fig. 5.9 ). Advantages of cFFR include universal availability with any FFR system, no additional expense, and minimal side effects related to those of contrast media. Because of the short half-life of contrast hyperemia, cFFR is not suitable for pressure pullback curves. cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR and may be useful in clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive.

Pitfalls of translesional pressure measurement

The three most common pitfalls of accurate FFR/NHPR are guide pressure damping, failure to capture the smart minimum Pd/Pa (for FFR), and signal drift. Tables 5.4 and 5.5 list factors that can reduce the accuracy of FFR and NHPR. Fig. 5.10 shows some of the artifacts that may produce false FFR readings.

Guide catheters that produced obstruction with pressure signal damping are at times substituted with catheters having side holes permitting coronary perfusion despite catheter obstruction. These catheters should be avoided because side holes do not eliminate the catheter obstruction but rather create an artificial stenosis through the holes. Removing the guide catheter from the coronary ostium after giving the hyperemic agent will avoid this pitfall.

Nonhyperemic pressure ratios

Procedural cost and time and the need to administer adenosine to achieve maximal hyperemia are thought to have been barriers to the use of FFR. Adenosine-free pressure ratios or NHPRs have been developed as alternatives to FFR and appear to be clinically noninferior to FFR in initial large multicenter trials. All NHPRs use the ratio between distal coronary pressure and aortic pressure. They differ principally in the portion of the diastolic period of the cardiac cycle that is measured. NHPRs are divided into diastolic only (iFR, diastolic pressure ratio [dPR], diastolic hyperemia-free ratio [DFR]) or whole-cycle indices (Pd/Pa, resting full-cycle ratio [RFR]; Fig. 5.11 ). NHPR reproducibility depends on stable resting coronary blood flow. Measurements made close in time to saline flushing, contrast, or nitroglycerin administration may differ because of alteration of resting flow related to residual minimal hyperemia. Other factors and pressure wave artifacts altering reproducibility of NHPRs are the same as those discussed for FFR. Advantages and limitations of hyperemic ratios and NHPRs in the cath lab are summarized in Table 5.6 .

Table 5.6

Advantages and Limitations of Physiologic Assessment in the Catheterization Laboratory

(From Kogame N, Ono M, Kawashima H, et al. The impact of coronary physiology on contemporary clinical decision making. JACC Cardiovasc Interv. 2020;13:1617–1638.)

Wire-Based Physiologic Assessment
Hyperemic Index		NHPR
FFR	iFR	Novel NHPRs (DFR, dPR, RFR)	Pd/Pa
A dvantages
Evidence for outcomes up to 15 yrs (vs. angiography guided PCI, OMT alone) Well validated with noninvasive functional tests in various clinical settings Cost-effectiveness was demonstrated against anglography guided PCI Available with all pressure wires	Evidence for outcomes up to 2 yrs (vs. FFR-guided PCI) Validated with noninvasive functional tests in several clinical settings Well validated with FFR in various clinical settings Hyperemia independent Quicker than FFR Ability with potential to assess serial lesions Coregistration with angiography available	Validated with FFR and iFR in limited clinical settings (retrospective) Hyperemia independent Quicker than FFR	Validated with FFR and IFR in limited clinical settings Hyperemia independent Quicker than FFR Available with all pressure wires
L imitations
Hyperemia required (additional cost and hyperemic agent related side effect) Pressure wire required (additional cost and wire-related complication) Precise acquisition of coronary pressure required Prolonged procedure	Pressure wire required (additional cost and wire-related complication) Precise acquisition of coronary pressure required Proprietary and the software of specific vendor required	No evidence for outcomes Validation data with noninvasive functional tests are limited Pressure wire required (additional cost and wire-related complication) Precise acquisition of coronary pressure required Proprietary and the software of specific vendor required No coregistration with angiography available	No evidence for outcomes Validation data with noninvasive functional tests are limited Pressure wire required (additional cost and wire-related complication) Precise acquisition of coronary pressure required Susceptible to miscalculation from pressure-wire drift No coregistration with angiography available

DFR, Diastolic hyperemia-free ratio; dPR , diastolic pressure ratio; FFR , fractional flow reserve; iFR , instantaneous wave-free pressure ratio ; NHPR , nonhyperemic pressure ratios; OMT , optimal anti-ischemic medications; PCI , percutaneous coronary intervention; RFR , resting full-cycle ratio.

Instantaneous wave-free ratio

For pressures to be linear with coronary flow ratios, FFR must be measured during minimal and stable coronary resistance, usually achieved during adenosine-induced hyperemia. Sen et al. determined from wave intensity analysis that there is a period in diastole in which the reflected pressure waves from the aorta and distal microcirculatory bed are quiescent and called this a “wave-free period” (WFP). The WFP has a fixed resistance and thus the resting Pd/Pa over this interval could be equivalent to FFR ( Fig. 5.12 ). The ratio of Pd/Pa during the wave-free period was called the iFR and was found to correlate with FFR (r = 0.90) with an approximately 80% concordance. After the completion of the two major iFR outcome studies, Define-Flair and iFR Swedeheart (see later), the iFR dichotomous threshold for treatment decisions is 0.89. Overall correspondence between iFR and FFR is approximately 80% to 85%.

Since the introduction of iFR, four other NHPRs have been introduced that are all relatively similar and dependent on the company that manufactured the pressure measuring device. dPR is defined as average Pd/Pa during entire diastole. DFR is defined as average Pd/Pa during Pa less than mean Pa with negative slope. RFR is defined as the lowest filtered mean Pd/Pa during the entire cardiac cycle ( Fig. 5.13 ). Several algorithms exist for calculating dPR, the resting ratio of mean Pd/mean Pa during diastole, with no significant advantage to any calculation. Compared with iFR, dPR is numerically equivalent. One algorithm uses the automatically delineated diastolic period based on the dP/dt curve of the aortic pressure with the flat line of the dP/dt tracing detecting the diastolic WFP. The resting Pd/Pa ratio is available for every translesional pressure measure and is calculated as the ratio of the mean continuous Pd and Pa over the entire cardiac cycle. Numerous studies demonstrated equivalent diagnostic performance of Pd/Pa to iFR noting the higher ischemic threshold of 0.92 for resting Pd/Pa used in most comparative clinical studies. Pd/Pa suffers from the same limitations of other NHPRs in that it has lower reproducibility and higher susceptibility to hemodynamic variability compared with FFR.

Clinical applications of translesional pressure assessment: Specific angiographic subsets

The use of translesional pressure ratios at rest (NHPR) or during hyperemia (cFFR and adenosine FFR) have been studied in a variety of angiographic substrates and clinical presentations. FFR has been available and has more than 25 years of studies, whereas NHPRs are relatively recent with more than 5 years of outcome studies.

The intermediate coronary lesion

For patients with stable ischemic heart disease, the decision to treat or not treat coronary lesions should be based on ischemia from ECG changes, stress testing, or FFR/NHPR. It is a common but erroneous belief that not stenting an angiographically intermediate but hemodynamically insignificant lesions will result in harm to the patient later. This concern is unsupported by many studies ( Table 5.7 ). The exemplar of such studies is the 15-year outcome of the DEFER study, which found that patients having an intermediate lesion (>50% narrowing) with an FFR greater than 0.75 could be safely treated medically with a low event rate over 15-year follow-up, which was no greater than any patient having stable ischemic heart disease treated medically (about 4%/year). In patients with intermediate lesions who were stented despite an FFR greater than 0.75 and in patients with FFR less than 0.75, both groups had significantly higher event rates over the same time. Stenting lesions with FFR greater than 0.75 gives the patient new problems related to the stent procedure acutely or late adverse events (subacute thrombosis, bleeding risk from dual antiplatelet medications). The composite rate of cardiac death and acute myocardial infarction (MI) in the deferred, performed, and reference groups was 3%, 8%, and 16%, respectively ( p = .21 for deferred vs. performed and p = .003 for reference vs. both the deferred and performed groups; Fig. 5.14 ). The percentage of patients free from chest pain on follow-up was not different between the deferred and performed groups. The 5-year risk of cardiac death or MI in patients with a normal FFR is less than 1% per year and not decreased by stenting. Fig. 5.15 is an example of FFR for intermediate lesion assessment.

Table 5.7

Fractional Flow Reserve Studies on Long-Term Outcomes

FFR Outcome Studies	N =	Study Design	Question	Outcome	Journal
DEFER (2007)	325	Prospective MC RCT	Is it safe to defer FFR normal intermediate lesions?	Less MACE in FFR >0.75 when rx’d medically	JACC
FAME (2009)	750	Prospective MC RCT	Does FFR-guided PCI vs. angio-guided for MVD improve outcomes?	Less MACE, lower cost w FFR	NEJM
FAME II (2012)	1220	Prospective MC RCT	Does FFR-guided PCI + OMT vs. OMT alone improve outcomes?	Less MACE w FFR, cost effective	NEJM
FAMOUS-NSTEMI (2014)	350	Prospective MC Randomized (UK)	Does FFR-guided PCI in NSTEMI change angio decisions for revasc? Outcomes?	FFR reclass revasc decision in 22%, Less revasc w FFR	EHJ
DANAMI3-PRIMULTI (2015)	600	Prospective MC Randomized (Denmark)	Dose FFR-guided PCI in MV STEMI vs. IRA only revasc improve outcomes?	Less MACE with FFR	Lancet
Mayo (2013)	7358	Retrospective SC Registry	Does FFR-guided vs. angio-guided PCI improve outcomes in routine practice?	Less MACE with FFR	EHJ
R3F (2014)	1.075	Prospective MC Registry (France)	Does FFR change angio decisions for revasc? Outcomes?	FFR reclass revasc decision in 47%, similar outcomes	Circulation
POST-IT (2015)	918	Prospective MC Registry (Portugal)	Does FFR change angio decisions for revasc? Outcomes?	FFR reclass revasc decision in 44% (follow-up data in press)	In press
Asan registry (2013)		Prospective SC Registry	Does FFR-guided vs. angio-guided PCI improve outcomes in routine practice?	Fewer stents and less MACE with FFR	EJHJ

Angio, Angiography; FFR, fractional flow reserve; MACE, major adverse cardiac event; MC, multicenter; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; revasc, revascularization; rx’d, prescribed; SC, single center.

Instantaneous wave-free ratio

In clinical practice the outcomes of treating intermediate stenosis based on iFR were identified in two large randomized trials, the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization, n = 2492) and iFR SWEDEHEART (Evaluation of iFR vs. FFR in Stable Angina or Acute Coronary Syndrome, n = 2042) studies, and found that iFR-guided PCI was noninferior to FFR-guided PCI for either deferral or treatment of stenoses based on iFR threshold of 0.89 ( Fig. 5.16 ). Although major adverse events were similar, long-term prognostic data for iFR is limited. After iFR SWEDEHEART and DEFINE-FLAIR, the European Society of Cardiology (ESC) guidelines gave a Class I (Level of Evidence: A) recommendation for guiding PCI in both iFR and FFR. Some advantages of iFR over FFR include shorter procedure time, less patient discomfort, and easy pull back, especially for evaluation of serial lesions.