Integrating Physiology into the DNA of Coronary Revascularisation – A Historical Perspective, Contemporary Review and Blueprint for the Future of Coronary Physiology

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare:

For permissions and non-commercial reprint enquiries, please visit to start a request.

For author reprints, please email
Average (ratings)
No ratings
Your rating


The clinical and economic benefits of physiologically guided revascularisation have been demonstrated, yet its clinical adoption remains unacceptably low. Recently, new indices of stenosis severity have been introduced that aim to improve adoption by circumventing the limitations of existing indices. The most validated of these new indices is the instantaneous wave-free ratio (iFR). This review will describe the physiological basis of this index, how it avoids the problems of existing indices such as fractional flow reserve (FFR) and the clinical validation studies of iFR to date. We will then describe a novel use of iFR, which has the potential to transform the use of physiology in the catheter lab and finally integrate physiology into the DNA of coronary revascularisation

Disclosure:Justin Davies is a Consultant to Volcano Corporation and Medtronic. Justin Davies and Imperial College own intellectual property regarding instantaneous wave-free ratio (iFR), which is licensed by the Imperial College to Volcano Corporation. Imperial College London is coordinating the Functional Lesion Assessment of Intermediate Stenoses to guide Revascularisation (FLAIR) study, which is supported by an unrestricted grant from Volcano Corporation. All the authors have had travel expenses to conferences supported by industry, including Volcano Corporation, St Jude Medical, Medtronic, Pfizer and AstraZeneca.



Correspondence Details:Sayan Sen, International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, 59–61 North Wharf Road, London W2 1LA UK. E:

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

The use of physiology to guide revascularisation in patients with coronary disease has been demonstrated to improve clinical outcomes and reduce costs.1,2 Despite this, its adoption into clinical practice is very low,3 moreover, when it is employed it is used simplistically – only to determine if the vessel is ischaemic or not.

Recently, several new indices of stenosis severity have been introduced that aim to improve adoption by addressing some of the major limitations of the existing clinical standard – fractional flow reserve (FFR).4,5 The most validated of these indices is the instantaneous wave-free ratio (iFR).4 This review will highlight the clinical problem in terms of hyperaemia-based indices, the physiological background of iFR, overview its validation studies and discuss the potential of ongoing clinical outcome studies.

Finally, the unique potential of hyperaemia-free indices will be discussed; to determine if they can fundamentally transform the use of physiology from a tool that can only ascertain
if revascularisation is required into a tool that can also guide how the revascularisation procedure should be performed.

The Clinical Problem

The main physiological foundation of FFR is that it can only make inferences about the haemodynamic significance of a stenosis under conditions of maximal hyperaemia.6,7 Superficial interpretation of this presumption has led some to believe that the haemodynamic significance of a stenosis can only be assessed during maximal hyperaemia.8–10

This has significant clinical and physiological implications that have directly impacted the adoption of FFR and simultaneously hindered the development of novel indices.7

Clinically, hyperaemic agents such as adenosine cannot be administered to all patients, almost always cause patient discomfort and their administration adds significant time to the procedure. Even in the most practiced hands, in institutions that routinely perform physiological measurements, an FFR assessment has been shown to add at least 10 minutes to the diagnostic procedure.11

Scientifically, the overly simplistic assumption that a single dose of adenosine can achieve maximal hyperaemia in every single patient regardless of myocardial territory and co-morbidity is now coming under increasing scientific scrutiny. A plethora of factors can influence the degree of hyperaemia achievable, including the dose of hyperaemic agent, its route of administration, left ventricular end diastolic pressure, right atrial pressure, age, gender, concomitant medication, diet and even the sleep pattern of the patient.12–20

Physiologically, it is increasingly evident that maximal hyperaemia is impossible to achieve in the catheter lab and given the sheer number

Figure 1: The iFR is Identified in Real-time Permitting Beat-bybeat Calculation of iFR

Article image

Figure 2: Studies Comparing iFR to FFR using Imperial-derived Algorithm (Green) or Investigator-derived Algorithms (Blue)

Article image

of variables affecting hyperaemia isolating the patients in which hyperaemia has been insufficient is equally impossible.21–23

This is particularly true of pressure-derived hyperaemic indices, such as FFR, which by definition do not measure flow and are therefore most vulnerable to this limitation.

This uncertainty has led clinicians to administer ever-increasing doses of adenosine and even adding other drugs to try and reassure themselves that ‘maximal hyperaemia’ is achieved. However, this only serves to create confusion because the FFR treatment threshold of 0.8 had not been validated against ischaemia at higher doses of adenosine making interpretation of the FFR value challenging and importantly not supported by outcome data. All these factors contribute to the poor ‘usability’ of FFR in the clinical domain – reflected in single figure adoption rates for FFR across most of the world despite a wealth of evidence being established for over 20 years.3

Can the Lessons of the Past Help us Find a Solution?

In recognition of the above limitations of FFR, hyperaemia-free indices have been introduced.4,5 These indices aim to circumvent the myriad limitations created by the need for administrating a hyperaemic agent in the hope of facilitated adoption by making procedures quicker, cheaper, safer and independent of the variability of attaining maximal hyperaemia. The most validated hyperaemia free index is iFR.4

iFR is not dependent on maximal hyperaemia and therefore shifts the paradigm away from maximal hyperaemia for the assessment of stenosis severity. This is based on a wealth of physiological data over the last 30 years that has clearly demonstrated that maximal hyperaemia is not required if stenosis assessment is made during a specific phase of the cardiac cycle.24–26

In a seminal experiment by Gould in 1978 it was demonstrated that the haemodynamic significance of stenoses could in fact be determined under basal conditions.24 Using combined pressure and flow velocity analysis he identified a phase in the cardiac cycle during which stenoses could reliably be differentiated into mild, moderate and severe. Using meticulous manual post hoc analysis of pressure and flow data he clearly demonstrated that the optimal period of the cardiac cycle to assess a stenosis was when intra-coronary haemodynamics are free of the confounding effects of the contracting and relaxing myocardium. This period within diastole has been studied in detail in several studies over the last 30 years and all indices derived over this period have been demonstrated to be at least as accurate as FFR and most importantly not reliant on maximal hyperaemia.26,27 Despite the clear physiological advantages of these indices over FFR, their clinical use was hindered by the need for simultaneous flow velocity measurements (which are challenging and time consuming to perform) and post hoc manual analysis of the pressure and flow traces; preventing real-time stenosis assessment.

Recently, using combined pressure and flow assessment in humans wave intensity analysis identified a period within diastole when intra-coronary haemodynamics are also free of all wave activity, which is caused by relaxation and contraction of the myocardium.4 More importantly, using sophisticated computational algorithms this period can now be isolated in real-time on a beat-to-beat basis using the pressure waveform alone; making clinical use of this period feasible in daily clinical practice. It is during this period that iFR is calculated4 (see Figure 1).

Given the well-documented physiology of this period of the cardiac cycle and its unique suitability for stenosis assessment it is not surprising that iFR has been found to be able to determine the haemodynamic significance of stenoses. Furthermore because iFR can be measured within seconds, does not require hyperaemic agents and uses existing pressure wire technology its potential to improve adoption of physiology to realise the clinical and economic benefits of physiologically guided revascularisation is clear.28

Figure 3: Comparison of iFR and FFR to an Independent Measure of Stenosis Severity in Five Studies Including Over 500 Lesions

Article image

Integrating Physiology into the DNA

Article image

iFR Validation Studies to Date

The classification match of iFR to FFR has been studied in over 3,500 vessels, this series of studies has definitively identified a treatment threshold of <0.9 for iFR.4,29–36

The agreement of iFR to FFR in the above studies has consistently been found to be approximately 80 % depending on the distribution of stenoses in the study population (see Figure 2). Interpretation of this statistic should take account of the fact that the classification match of two FFR measurements across the same lesion is not 100 % but 85 %.37,38 A finding suggested by the DEFER study39,40 but recently confirmed using modern pressure wire technology.41
Such classification agreement between two FFR measurements across the same lesion is not surprising given the biological variability of any physiological measurement especially if that measurement

Figure 5: How Resting Flow and Hyperaemic Flow Vary with Stenosis Severity and the Impact on Tandem Lesion Assessment

Article image

is reliant on the heterogeneous and unpredictable effects of a hyperaemic agent.42

While FFR is viewed as a clinical standard for ischaemia it is widely accepted that there is no true gold standard test for ischaemia.43 Therefore, when two indices such as iFR and FFR agree so closely how do we interpret the significance of stenoses when iFR and FFR disagree? Several studies have attempted to look at this (see Figure 3).23,36,42–45 Each has taken iFR and FFR and compared with another index of stenosis severity. The salient findings of this body of research in over 500 stenoses are clear:

  1. When iFR and FFR disagree – FFR is not necessarily correct.
  2. Hyperaemia does not improve diagnostic accuracy.

The Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve (JUSTIFY-CFR) was the largest of these studies to systematically assess how iFR and FFR agree with underlying flow. It demonstrated that when iFR and FFR disagree that iFR was

Figure 6: iFR-pullback Provides an Adenosine-free Measure of Serial Stenosis Severity

Article image

Figure 7: Co-registration of Physiology and Anatomy

Article image

more indicative of the underlying flow characteristics of the vessel.44 Furthermore in the clinically relevant 0.6–0.9 FFR range, in which most of our patients fall, iFR was significantly more accurate than FFR.

Some have highlighted concerns with regards to the doses of hyperaemic agent, choice of reference test and therefore the validity of these studies. The meticulous validation of FFR during its development serves as template for the validation of new indices. It should be noted that FFR was validated against the same reference tests during its development,
using doses of adenosine and routes of administration identical to the studies now comparing iFR with FFR. Should we discount these pivotal FFR studies too? If so, what should be done with the guidelines and scientific recommendations supporting FFR that were based upon these?

The above studies clearly challenge the dogma that hyperaemia is necessary for stenosis assessment but also point to major potential differences between iFR and FFR that may make iFR more clinically useful than FFR.

Indeed the ability of iFR to be independent from the response of the microcirculation to a hyperaemic agent suggests that, it may also have a role in conditions that have traditionally been considered unsuitable for FFR assessment. The assessment of disease in the acute coronary syndrome population, vessels with tandem lesions, patients with renal failure, diabetes and hypertension are all vulnerable to a variable response of the microcirculation to hyperaemic stimuli – a limitation circumvented with resting indices. The role of iFR and FFR in these populations will be further elucidated in the Functional Lesion Assessment of Intermediate Stenoses to guide Revascularisation (DEFINE-FLAIR) and iFR SWEDEHEART studies.

Randomised Clinical Outcome Studies Designed to Address the Clinically Important Questions

In reality the adoption of any new index will be based on large randomised clinical trials with hard outcome end-points. But for clinicians to be able to translate the results of these studies to the patients they treat the trials must include patients in which physiological assessment is routinely made in clinical practice.

Prior to the Adenosine Vasodilator Independent Stenosis Evaluation (ADVISE) registry FFR had never been systematically studied in clinically relevant patient populations.44 The mean FFR values in the Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention (FAME) and FAME II studies were 0.71 and 0.64, respectively; significantly lower than mean FFR values in contemporary studies that have included intermediate lesions.24,44 This suggests that the FAME populations are significantly different from the patients we assess in clinical practice today.

To address this, iFR clinical outcome studies have been designed to centre on clinically relevant patient populations. Their inclusion and exclusion criteria are aimed at truly capturing the patients in whom physiology is performed in clinical practice. As a result, regardless of iFR, DEFINE-FLAIR (NCT02053038, see Figure 4) and iFR SWEDEHEART (NCT02166736) will provide the first and largest prospective real-world randomised controlled trial database for FFR in clinically relevant patient populations.

In addition there are several other unique aspects of these studies that will have direct clinical impact:

  1. They will provide the largest prospective evaluation of physiology to guide revascularisation in non-culprit vessels in acute coronary syndrome patients.
  2. They will provide the largest prospective evaluation of post-percutaneous coronary intervention (PCI) physiology assessment to predict clinical outcomes.
  3. They will provide the largest prospective evaluation of physiology to guide multi-vessel revascularisation. Combined, these studies will include at least three times the number of patients in FAME I and FAME II combined.
  4. FLAIR includes over 40 centres in over 18 countries and will therefore provide the first and largest prospective comparison of physiology outcomes between different global geographical regions.
  5. These studies will also provide a contemporary insight into the outcomes of the major clinical patient subsets of diabetes, renal failure and hypertension.

DEFINE-FLAIR and iFR SWEDEHEART will therefore provide a definitive prospective assessment of the role of both iFR and FFR in clinical practice and address some of the major uncertainties hitherto unaddressed in this field.

Regardless of the current debate upon the physiology of basal versus hyperaemia indices the data from these studies will definitively answer if hyperaemia is still required to safely assess stenosis severity and guide revascularisation. Given the simplicity and reduced uncertainty of iFR assessment they therefore have the potential to dramatically increase the adoption of physiology, finally permitting realisation of the clear health and cost benefits of such an approach.

Integrating Physiology into the DNA of Revascularisation – A Blueprint for the Future

To date, FFR has generally been used in a binary fashion to inform the clinician if the vessel should be treated or not. The physiology of resting haemodynamics means that it is possible for indices such as iFR to provide a further dimension to the role of physiology
in the catheter lab by not only guiding when to treat but also where to treat. This is particularly useful in the increasingly prevalent subset of patients with diffuse coronary disease and tandem stenosis. In these patients iFR has the potential to reduce the prevalence of abnormal physiology post-PCI by ensuring that
the correct lesion is targeted.

The reliance of FFR on maximal hyperaemia has prevented it from being used to isolate individual stenosis severity in vessels with tandem lesions.45,46 This is because when trying to assess the significance of a proximal stenosis the distal stenosis will blunt hyperaemic flow across the proximal lesion, therefore placement of the pressure sensor in between the two stenoses will under-estimate the severity of the proximal lesion. When the distal lesion is treated, hyperaemic flow is much higher and the FFR of the proximal vessel significantly different (see Figure 5).

Baseline indices, by contrast, are uniquely suited to the isolation of a specific stenosis in the context of tandem lesions. This is due to the fact that baseline flow is maintained constant until stenosis grades of greater than 85 %.47 As a result, iFR is able to isolate specific stenosis severity within a vessel with multiple lesions (see Figure 6). When the distal lesion is treated, in contrast to hyperaemic flow, baseline flow does not significantly change and
therefore the pressure drop across the proximal stenosis and iFR remains similar48 (see Figure 5).

This ability to predict post-PCI iFR provides the potential to extend the role of physiology in interventional cardiology. Rather than simply informing us that a vessel is ischaemic, real-time hyperaemia-free point-to-point calculation of iFR along the entire vessel combined with co-registration with imaging will permit the possibility of virtual PCI. The clinician will therefore be able to determine (i) if a stent is required (ii) where the stent should be placed and (iii) the length of the stent to get the best haemodynamic result within a matter of seconds and remove the need for multiple hyperaemic pullback runs (see Figure 7).

Such an approach can be expected to significantly reduce stent length, procedural time and costs while simultaneously improving adoption in a patient population that is currently poorly served by FFR.


The routine use of physiology to guide revascularisation is unacceptably low. To improve adoption iFR has been introduced. This index is based on established physiology, can be measured within seconds, does not require hyperaemic agents and uses existing pressure wire technology. Importantly, it has the potential to extend the role of physiology by permitting accurate assessment of vessels with diffuse disease or tandem lesions. The unique characteristics of iFR physiology combined with modern imaging opens the potential of virtual PCI: for the first time allowing physiology to tell us not only if we need a stent but where and therefore how to stent to get the best outcomes for our patients.


  1. Tonino PAL, De Bruyne B, Pijls NHJ, et al., Fractional flow reserve versus angiography for guiding percutaneous coronary intervention, N Engl J Med, 2009;360:213–24.
    Crossref | PubMed
  2. De Bruyne B, Fearon WF, Pijls NHJ, et al. Fractional flow reserve-guided PCI for stable coronary artery disease,
    N Engl J Med, 2014;371:1208–17.
    Crossref | PubMed
  3. Kleiman NS, Bringing it all together: integration of physiology with anatomy during cardiac catheterization, J Am Coll Cardiol, 2011;58:1219–21.
    Crossref | PubMed
  4. Sen S, Escaned J, Malik IS, et al., Development and validation of a new adenosine-independent index of stenosis severity from coronary wave–intensity analysis, J Am Coll Cardiol, 2012;59:1392–402.
    Crossref | PubMed
  5. Van de Hoef TP, Petraco R, van Lavieren MA, et al., Diagnostic accuracy of basal stenosis resistance index (BSR) is higher than that of instantaneous wave-free ratio (iFR): validation of basal stenosis resistance index in an independent cohort of simultaneous pressure and flow measurements, J Am Coll Cardiol, 2013;62:B193.
  6. Pijls NH, van Son JA, Kirkeeide RL, et al., Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty, Circulation, 1993;87:1354–67.
    Crossref | PubMed
  7. Pijls NHJ, Tonino PAL, The crux of maximum hyperemia: the last remaining barrier for routine use of fractional flow reserve, JACC Cardiovasc Interv, 2011;4:1093–5.
    Crossref | PubMed
  8. Pijls NHJ, Van’t Veer M, Oldroyd KG, et al., Instantaneous wave-free ratio or fractional flow reserve without HyperemiaNovelty or nonsense?, J Am Coll Cardiol, 2012;59:1916–7.
    Crossref | PubMed
  9. Rudzinski W, Waller AH, Kaluski E, Instantaneous wave-free ratio and fractional flow reserve: close, but not close enough!, J Am Coll Cardiol, 2012;59:1915–6; author reply 1917–8.
    Crossref | PubMed
  10. Finet G, Rioufol G, A new adenosine-independent index of stenosis severity: why would one assess a coronary stenosis differently?, J Am Coll Cardiol, 2012;59:1915; author reply 1917–8.
    Crossref | PubMed
  11. Ntalianis A, Trana C, Muller O, et al., Effective radiation dose, time, and contrast medium to measure fractional flow reserve, JACC Cardiovasc Interv, 2010;3:821–7.
    Crossref | PubMed
  12. Sun LJ, Wang GS, Cui M, et al., Factors influencing the functional significance in intermediate coronary stenosis,
    J Geriatr Cardiol, 2015;12:107-12.
  13. Matsumoto H, Nakatsuma K, Shimada T, et al., Effect of caffeine on intravenous adenosine-induced hyperemia in fractional flow reserve measurement, J Invasive Cardiol, 2014;26:580–5.
  14. Echavarría-Pinto M, Gonzalo N, Ibañez B, et al., Low coronary microcirculatory resistance associated with profound hypotension during intravenous adenosine infusion: implications for the functional assessment of coronary stenoses, Circ Cardiovasc Interv, 2014;7:35–42.
    Crossref | PubMed
  15. Seto AH, Tehrani DM, Bharmal MI, Kern MJ, Variations of coronary hemodynamic responses to intravenous adenosine infusion: implications for fractional flow reserve measurements, Catheter Cardiovasc Interv, 2014;84:416–25.
    Crossref | PubMed
  16. Tarkin JM, Nijjer S, Sen S, et al., Hemodynamic response to intravenous adenosine and its effect on fractional flow reserve assessment: results of the Adenosine for the Functional Evaluation of Coronary Stenosis Severity (AFFECTS) study, Circ Cardiovasc Interv, 2013;6:654–61.
    Crossref | PubMed
  17. Leonardi RA, Townsend JC, Patel CA,et al., Left ventricular end-diastolic pressure affects measurement of fractional flow reserve, Cardiovasc Revasc Med, 2013;14:218–22.
    Crossref | PubMed
  18. Butt M, Khair OA, Dwivedi G, et al., Myocardial perfusion by myocardial contrast echocardiography and endothelial dysfunction in obstructive sleep apnea, Hypertension, 2011;58:417–24.
    Crossref | PubMed
  19. Olsen RH, Pedersen LR, Jürs A, et al., A randomised trial comparing the effect of exercise training and weight loss on microvascular function in coronary artery disease, Int J Cardiol, 2015;185:229–35.
    Crossref | PubMed
  20. Layland J, Wilson AM, Whitbourn RJ, et al., Impact of right atrial pressure on decision-making using fractional flow reserve (FFR) in elective percutaneous intervention, Int J Cardiol, 2013;167:951–3.
    Crossref | PubMed
  21. Barbato E, Sarno G, Berza CT, et al., Impact of alpha- and beta-adrenergic receptor blockers on fractional flow reserve and index of microvascular resistance, J Cardiovasc Transl Res, 2014;7:803–9.
    Crossref | PubMed
  22. De Luca G, Venegoni L, Iorio S, et al., Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve, JACC Cardiovasc Interv, 2011;4:1079–84.
    Crossref | PubMed
  23. Sen S, Asrress KN, Nijjer S, et al., Diagnostic classification of the instantaneous wave-free ratio is equivalent to fractional flow reserve and is not improved with adenosine administration: Results of CLARIFY (Classification Accuracy of Pressure-Only Ratios Against Indices Using Flow Study), J Am Coll Cardiol, 2013;61:1409–20.
    Crossref | PubMed
  24. Gould KL, Pressure-flow characteristics of coronary stenoses in unsedated dogs at rest and during coronary vasodilation, Circ Res, 1978;43:242–53.
    Crossref | PubMed
  25. Marques KMJ, Spruijt HJ, Boer C, et al., The diastolic flow-pressure gradient relation in coronary stenoses in humans,
    J Am Coll Cardiol, 2002;39:1630–6.
    Crossref | PubMed
  26. Marques KMJ, van Eenige MJ, Spruijt HJ, et al., The diastolic flow velocity-pressure gradient relation and dpv50 to assess the hemodynamic significance of coronary stenoses, Am J Physiol Heart Circ Physiol, 2006;291:H2630–5
    Crossref | PubMed
  27. Kern MJ, An adenosine-independent index of stenosis severity from coronary wave-intensity analysis: a new paradigm in coronary physiology for the cath lab?, J Am Coll Cardiol, 2012;59:1403–5.
    Crossref | PubMed
  28. Petraco R, Escaned J, Sen S, et al. Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry, EuroIntervention, 2013;9:91–101.
    Crossref | PubMed
  29. Park JJ, Petraco R, Nam CW, et al., Clinical validation of the resting pressure parameters in the assessment of functionally significant coronary stenosis; results of an independent, blinded comparison with fractional flow reserve, Int J Cardiol, 2013;168:4070–5.
    Crossref | PubMed
  30. Escaned J, ADVISE II: Late breaking clinical trial, TCT Oral Present, 2013.
  31. Indolfi C, Mongiardo A, Spaccarotella C, et al., The instantaneous wave-free ratio (iFR) for evaluation of non-culprit lesions in patients with acute coronary syndrome and multivessel disease, Int J Cardiol, 2015;178:46–54.
    Crossref | PubMed
  32. Petraco R, Al-Lamee R, Gotberg M, et al. Real-time use of instantaneous wave-free ratio: Results of the ADVISE in-practice: An international, multicenter evaluation of instantaneous wave-free ratio in clinical practice, Am Heart J, 2014;168:739–48.
    Crossref | PubMed
  33. Jeremias A, Maehara A, Genereux P, et al., Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa With fractional flow reserve: The RESOLVE Study, J Am Coll Cardiol, 2014;63:1253–61.
    Crossref | PubMed
  34. Van de Hoef TP, Meuwissen M, Escaned J, et al., Head-to-head comparison of basal stenosis resistance index, instantaneous wave-free ratio, and fractional flow reserve: diagnostic accuracy for stenosis-specific myocardial ischaemia, EuroIntervention, 2014 [Epub ahead of print].
  35. Johnson NP, Kirkeeide RL, Asrress KN, et al., Does the instantaneous wave-free ratio approximate the fractional flow reserve?, J Am Coll Cardiol, 2013;61:1428–35.
    Crossref | PubMed
  36. Petraco R, Escaned J, Sen S, et al., How high can “accuracy” be for iFR (or IVUS, or SPECT, or OCT...) if using fractional flow reserve as the gold standard?, EuroIntervention, 2013;9:770–2
  37. Petraco R, Sen S, Nijjer S, et al., Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions, JACC Cardiovasc Interv, 2013;6:222–5
    Crossref | PubMed
  38. Bech GJW, Bruyne BD, Pijls NHJ, et al., Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis a randomized trial, Circulation, 2001;103:2928–34.
    Crossref | PubMed
  39. Kern MJ, Lerman A, Bech JW, et al., Physiological assessment of coronary artery disease in the cardiac catheterization laboratory a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, Circulation, 2006;114:1321–41.
    Crossref | PubMed
  40. Gaur S, Bezerra HG, Lassen JF, et al., Fractional flow reserve derived from coronary CT angiography: variation of repeated analyses, J Cardiovasc Comput Tomogr, 2014;8:307–14.
    Crossref | PubMed
  41. Seto AH, Tehrani DM, Bharmal MI, Kern MJ, Variations of coronary hemodynamic responses to intravenous adenosine infusion: implications for fractional flow reserve measurements, Catheter Cardiovasc Interv, 2014;84:416–25.
    Crossref | PubMed
  42. Pijls NH, De Bruyne B, Peels K, et al., Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses, N Engl J Med, 1996;334:1703–8.
    Crossref | PubMed
  43. De Waard G, Danad I, da Cunha RP, et al., Hyperemic FFR and baseline iFR have an equivalent diagnostic accuracy when compared to myocardial blood flow quantified by H215O PET perfusion imaging, J Am Coll Cardiol, 2014;63:A1692.
  44. Petraco R, van de Hoef TP, Nijjer S, et al., Baseline instantaneous wave-free ratio as a pressure-only estimation of underlying coronary flow reserve: results of the JUSTIFY-CFR Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve), Circ Cardiovasc Interv, 2014;7:492–502.
    Crossref | PubMed
  45. Sen S, Nijjer S, Petraco R, Malik IS, Francis DP, Davies J, Instantaneous wave-free ratio: numerically different, but diagnostically superior to FFR? Is lower always better?, J Am Coll Cardiol, 2013;62:566.
    Crossref | PubMed
  46. Bruyne BD, Pijls NHJ, Heyndrickx GR, et al., Pressure-derived fractional flow reserve to assess serial epicardial stenoses theoretical basis and animal validation, Circulation, 2000;101:1840–7.
    Crossref | PubMed
  47. Kim H-L, Koo BK, Nam CW, et al., Clinical and physiological outcomes of fractional flow reserve-guided percutaneous coronary intervention in patients with serial stenoses within one coronary artery, JACC Cardiovasc Interv, 2012;5:1013–8.
    Crossref | PubMed
  48. Gould KL, Lipscomb K, Calvert C, Compensatory changes of the distal coronary vascular bed during progressive coronary constriction, Circulation, 1975;51:1085–94.
    Crossref | PubMed
  49. Nijjer SS, Sen S, Petraco R, et al., Pre-angioplasty instantaneous wave-free ratio (iFR) pullback provides virtual intervention and predicts hemodynamic outcome for serial lesions and diffuse coronary artery disease, JACC Cardiovasc Interv, 2014 [Epub before print].
    Crossref | PubMed