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Coronary physiological parameters at a crossroads

1. International Centre for Circulatory Heath, Imperial College London, London, United Kingdom; 2. Academic Medical Center, Amsterdam, the Netherlands

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Coronary angiography remains the gold standard in the diagnosis of coronary artery disease in the cardiac catheterisation laboratory. However, the limitations of angiography for assessing epicardial stenosis severity led, in the 1990s, to the introduction of sensor-equipped guidewires that measure coronary pressure and flow selectively distal to a lesion11. Serruys PW, Di Mario C, Meneveau N, de Jaegere P, Strikwerda S, de Feyter PJ, Emanuelsson H. Intracoronary pressure and flow velocity with sensor-tip guidewires: a new methodologic approach for assessment of coronary hemodynamics before and after coronary interventions. Am J Cardiol. 1993;71:41D-53D. . The most frequently used parameter is fractional flow reserve (FFR), defined as the ratio of the pressure distal to a lesion relative to the aortic pressure that assumes minimal influence of the microvascular resistance during hyperaemic conditions22. Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B, Gould KL. 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. . An alternative is the assessment of coronary flow reserve (CFR), defined as the ratio of the distal hyperaemic flow relative to baseline flow33. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol. 1974;33:87-94. . CFR is considered to be less lesion-specific when compared to FFR as it is determined by the resistance of both the epicardial lesion and the distal microvasculature44. Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, Higano ST, Lim MJ, Meuwissen M, Piek JJ, Pijls NH, Siebes M, Spaan JA; American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. 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. .

The use of combined pressure flow measurements using a single wire (ComboWire®; Philips Volcano, Thornton, CO, USA) allows the calculation of the hyperaemic microvascular resistance index (hMVR)55. Di Mario C, de Feyter PJ, Slager CJ, de Jaegere P, Roelandt JR, Serruys PW. Intracoronary blood flow velocity and transstenotic pressure gradient using sensor-tip pressure and Doppler guidewires: a new technology for the assessment of stenosis severity in the catheterization laboratory. Cathet Cardiovasc Diagn. 1993;28:311-9. ,66. Di Mario C, Krams R, Gil R, Serruys PW. Slope of the instantaneous hyperemic diastolic coronary flow velocity-pressure relation. A new index for assessment of the physiological significance of coronary stenosis in humans. Circulation. 1994;90:1215-24. . This allows two important observations to be made. The first is that there is a large variation in hMVR between patients in contrast to the assumption underlying the FFR concept77. van de Hoef TP, Nolte F, EchavarrÍa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart. 2014;100:951-9. . Secondly, variation in hMVR significantly determines the pressure gradient across a lesion77. van de Hoef TP, Nolte F, EchavarrÍa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart. 2014;100:951-9. . This is a fundamental observation, as it demonstrates that even the highest dose of adenosine infusion cannot increase blood flow to the severely diseased microcirculation. Thus, when evaluating the same stenosis when blood flow is low, the pressure gradient is low, whereas when blood flow is high the pressure gradient is high. Together, these findings suggest that the validation studies in healthy animals in FFR22. Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B, Gould KL. 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. are overly simplistic, and cannot be translated directly to humans88. van de Hoef TP, Siebes M, Spaan JA, Piek JJ. Fundamentals in clinical coronary physiology: why coronary flow is more important than coronary pressure. Eur Heart J. 2015;36:3312-9a. .

FFR and CFR discordance

The distal pressure-flow measurements using wires equipped with both pressure and flow sensors show that every epicardial stenosis can be characterised according to its pressure-flow curve (Figure 1). The steepness of the curve indicates the severity of the lesion. However, the magnitude of the pressure gradient is dependent on the magnitude of maximal flow velocity. This behaviour of the coronary circulation according to pressure-flow relationship is relevant for the interpretation of FFR-CFR discordance99. Echavarria-Pinto M, Escaned J, Macías E, Medina M, Gonzalo N, Petraco R, Sen S, Jimenez-Quevedo P, Hernandez R, Mila R, Ibañez B, Nuñez-Gil IJ, Fernández C, Alfonso F, Bañuelos C, García E, Davies J, Fernández-Ortiz A, Macaya C. Disturbed coronary hemodynamics in vessels with intermediate stenoses evaluated with fractional flow reserve: a combined analysis of epicardial and microcirculatory involvement in ischemic heart disease. Circulation. 2013;128:2557-66. ,1010. Echavarría-Pinto M, van de Hoef TP, van Lavieren MA, Nijjer S, Ibañez B, Pocock S, Quirós A, Davies J, Meuwissen M, Serruys PW, Macaya C, Piek JJ, Escaned J. Combining Baseline Distal-to-Aortic Pressure Ratio and Fractional Flow Reserve in the Assessment of Coronary Stenosis Severity. JACC Cardiovasc Interv. 2015;8:1681-91. . A low hMVR may result in the combination of a normal CFR but abnormal FFR, whereas a high hMVR may result in the combination of a normal FFR but abnormal CFR, even though the curve remains the same1111. Petraco R, van de Hoef TP, Nijjer S, Sen S, van Lavieren MA, Foale RA, Meuwissen M, Broyd C, Echavarria-Pinto M, Foin N, Malik IS, Mikhail GW, Hughes AD, Francis DP, Mayet J, Di Mario C, Escaned J, Piek JJ, Davies JE. 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. . This phenomenon explains the discordance between FFR and CFR that occurs in 30-40% of the patients with intermediate lesions99. Echavarria-Pinto M, Escaned J, Macías E, Medina M, Gonzalo N, Petraco R, Sen S, Jimenez-Quevedo P, Hernandez R, Mila R, Ibañez B, Nuñez-Gil IJ, Fernández C, Alfonso F, Bañuelos C, García E, Davies J, Fernández-Ortiz A, Macaya C. Disturbed coronary hemodynamics in vessels with intermediate stenoses evaluated with fractional flow reserve: a combined analysis of epicardial and microcirculatory involvement in ischemic heart disease. Circulation. 2013;128:2557-66. ,1212. Petraco R, Park JJ, Sen S, Nijjer SS, Malik IS, Echavarría-Pinto M, Asrress KN, Nam CW, Macías E, Foale RA, Sethi A, Mikhail GW, Kaprielian R, Baker CS, Lefroy D, Bellamy M, Al-Bustami M, Khan MA, Gonzalo N, Hughes AD, Francis DP, Mayet J, Di Mario C, Redwood S, Escaned J, Koo BK, Davies JE. Hybrid iFR-FFR decision-making strategy: implications for enhancing universal adoption of physiology-guided coronary revascularisation. EuroIntervention. 2013;8:1157-65. . Critically, discordance is driven by the flow velocity, which is determined by the degree of microcirculatory resistance.

01_Davies117e.eps

Figure 1. The transstenotic pressure gradient is determined by anatomical stenosis severity, hyperaemic microvascular resistance and coronary flow velocity characteristics.

The report in this issue of EuroIntervention from Young-Woo Seo et al1313. Seo KW, Lim HS, Yoon MH, Tahk SJ, Choi SY, Choi BJ, Yang HM, Shin JH, Hwang GS, Park JS, Jin XJ. The impact of microvascular resistance on the discordance between anatomical and functional evaluations of intermediate coronary disease. EuroIntervention. 2017;13:185-92. confirms earlier findings between FFR and hMVR77. van de Hoef TP, Nolte F, EchavarrÍa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart. 2014;100:951-9. .

In contrast to earlier angiographic studies, they used intravascular ultrasound for more accurate lesion assessment (minimal lumen area [MLA]) in combination with pressure-Doppler flow assessment. They also demonstrated a large variability in hMVR and its association with FFR whereby a low hMVR leads to a lower FFR and a high hMVR leads to a higher FFR. By dividing MLA and hMRV into tertiles they elegantly demonstrate the interactions between FFR, MLA and hMVR (Figure4 in Seo et al1313. Seo KW, Lim HS, Yoon MH, Tahk SJ, Choi SY, Choi BJ, Yang HM, Shin JH, Hwang GS, Park JS, Jin XJ. The impact of microvascular resistance on the discordance between anatomical and functional evaluations of intermediate coronary disease. EuroIntervention. 2017;13:185-92. ). For any lesion assessed by MLA, there is a clear positive association between FFR and hMVR, in particular in the range of intermediate lesions (MLA 2.1-2.9 mm²) where it is most relevant for clinical decision making. This analysis provides further evidence that FFR is susceptible to the health and status of the vasodilatory response of the coronary microcirculation99. Echavarria-Pinto M, Escaned J, Macías E, Medina M, Gonzalo N, Petraco R, Sen S, Jimenez-Quevedo P, Hernandez R, Mila R, Ibañez B, Nuñez-Gil IJ, Fernández C, Alfonso F, Bañuelos C, García E, Davies J, Fernández-Ortiz A, Macaya C. Disturbed coronary hemodynamics in vessels with intermediate stenoses evaluated with fractional flow reserve: a combined analysis of epicardial and microcirculatory involvement in ischemic heart disease. Circulation. 2013;128:2557-66. ,1010. Echavarría-Pinto M, van de Hoef TP, van Lavieren MA, Nijjer S, Ibañez B, Pocock S, Quirós A, Davies J, Meuwissen M, Serruys PW, Macaya C, Piek JJ, Escaned J. Combining Baseline Distal-to-Aortic Pressure Ratio and Fractional Flow Reserve in the Assessment of Coronary Stenosis Severity. JACC Cardiovasc Interv. 2015;8:1681-91. .

The diagnostic triangle

This clinical decision making of coronary intervention should ideally be based upon an appropriate interpretation of the patients’ complaints, the results of non-invasive diagnostic testing as well as the result of intracoronary haemodynamic measurements for guidance of interventions. This diagnostic triangle should be the basis for our clinical decision making during cardiac catheterisation. In daily clinical practice, there is frequently a paucity of documentation of myocardial ischaemia prior to cardiac catheterisation. In the present report, it is notable that there is no information of non-invasive stress tests in the diagnostic workup of this well-equipped intervention centre. In the absence of non-invasive stress tests, an operator depends upon the interpretation of the complaints of the patients and the results of intracoronary diagnostic techniques to guide ad hoc coronary interventions. This approach requires an intimate knowledge of the limitations and pitfalls of the diagnostic techniques applied. The FAME trials1414. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’ t Veer M, Klauss V, Manoharan G, Engstrøm T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213-24. ,1515. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N, Möbius-Winkler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engström T, Oldroyd KG, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Jüni P, Fearon WF; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367:991-1001. reported the potential of FFR, leading to a class I indication, level of evidence A for clinical decision making in stenosis assessment. However, the results of FAME 2 also showed that 60% of the patients with lesions and an FFR <0.80, allocated to optimal medical therapy, did not require a PCI during a two-year follow-up period1515. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N, Möbius-Winkler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engström T, Oldroyd KG, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Jüni P, Fearon WF; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367:991-1001. , probably because of inclusion of non-flow-limiting lesions (low resistance and high flow) that did not induce myocardial ischaemia and thus exhibited a good long-term prognosis1616. van de Hoef TP, van Lavieren MA, Damman P, Delewi R, Piek MA, Chamuleau SA, Voskuil M, Henriques JP, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv. 2014;7:301-11. . In this respect, it is important to note that the patient, and not the diagnostic technique, should always be considered as the gold standard.

Clinical implications

What do the results of the present study mean for our daily clinical practice? Next to FFR, the instantaneous wave-free ratio (iFR) has been introduced as a tool to measure the transstenotic pressure ratio during the wave-free period in diastole1717. Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, Tarkin J, Petraco R, Broyd C, Jabbour R, Sethi A, Baker CS, Bellamy M, Al-Bustami M, Hackett D, Khan M, Lefroy D, Parker KH, Hughes AD, Francis DP, Di Mario C, Mayet J, Davies JE. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol. 2012;59:1392-402. . It is an attractive alternative to FFR because it does not require hyperaemia. The development of iFR has recently led to the reporting of two large, randomised, prospective multicentre clinical trials –DEFINE-FLAIR1818. Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, Bhindi R, Lehman SJ, Walters D, Sapontis J, Janssens L, Vrints CJ, Khashaba A, Laine M, Van Belle E, Krackhardt F, Bojara W, Going O, Härle T, Indolfi C, Niccoli G, Ribichini F, Tanaka N, Yokoi H, Takashima H, Kikuta Y, Erglis A, Vinhas H, Canas Silva P, Baptista SB, Alghamdi A, Hellig F, Koo BK, Nam CW, Shin ES, Doh JH, Brugaletta S, Alegria-Barrero E, Meuwissen M, Piek JJ, van Royen N, Sezer M, Di Mario C, Gerber RT, Malik IS, Sharp AS, Talwar S, Tang K, Samady H, Altman J, Seto AH, Singh J, Jeremias A, Matsuo H, Kharbanda RK, Patel MR, Serruys P, Escaned J. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J Med. 2017;376:1824-34. , and iFR SWEDEHEART1919. Götberg M, Christiansen EH, Gudmundsdottir IJ, Sandhall L, Danielewicz M, Jakobsen L, Olsson SE, Öhagen P, Olsson H, Omerovic E, Calais F, Lindroos P, Maeng M, Tödt T, Venetsanos D, James SK, Kåregren A, Nilsson M, Carlsson J, Hauer D, Jensen J, Karlsson AC, Panayi G, Erlinge D, Fröbert O; iFR-SWEDEHEART Investigators. Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI. N Engl J Med. 2017;376:1813-23. . Both of these studies demonstrated in ~4,500 patients that iFR was non-inferior to revascularisation guided by FFR with respect to major adverse cardiac events (MACE) at one year1818. Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, Bhindi R, Lehman SJ, Walters D, Sapontis J, Janssens L, Vrints CJ, Khashaba A, Laine M, Van Belle E, Krackhardt F, Bojara W, Going O, Härle T, Indolfi C, Niccoli G, Ribichini F, Tanaka N, Yokoi H, Takashima H, Kikuta Y, Erglis A, Vinhas H, Canas Silva P, Baptista SB, Alghamdi A, Hellig F, Koo BK, Nam CW, Shin ES, Doh JH, Brugaletta S, Alegria-Barrero E, Meuwissen M, Piek JJ, van Royen N, Sezer M, Di Mario C, Gerber RT, Malik IS, Sharp AS, Talwar S, Tang K, Samady H, Altman J, Seto AH, Singh J, Jeremias A, Matsuo H, Kharbanda RK, Patel MR, Serruys P, Escaned J. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J Med. 2017;376:1824-34. ,1919. Götberg M, Christiansen EH, Gudmundsdottir IJ, Sandhall L, Danielewicz M, Jakobsen L, Olsson SE, Öhagen P, Olsson H, Omerovic E, Calais F, Lindroos P, Maeng M, Tödt T, Venetsanos D, James SK, Kåregren A, Nilsson M, Carlsson J, Hauer D, Jensen J, Karlsson AC, Panayi G, Erlinge D, Fröbert O; iFR-SWEDEHEART Investigators. Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI. N Engl J Med. 2017;376:1813-23. . Furthermore, a markedly lower incidence of patient discomfort and unpleasant side effects was reported in the iFR arm, as well as a significant 10% saving in procedural time.

Today, FFR and iFR are the most frequently used intracoronary haemodynamic parameters, based on evidence, availability and simplicity. However, unlike FFR, a number of key physiological properties of iFR limit it from being confounded by inter-patient variations in microvascular function, hMVR or hyperaemic flow velocity. Firstly, iFR is measured under basal conditions, thereby avoiding the need for a hyperaemic stimulus that is itself variable between patients. Secondly, resting coronary flow remains stable at ~20 cm/s across almost the entire range of stenosis severities, up to ~90% stenosis, where even resting flow profiles are impaired33. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol. 1974;33:87-94. ,2020. Nijjer SS, de Waard GA , Sen S, van de Hoef TP, Petraco R, Echavarría-Pinto M, van Lavieren MA, Meuwissen M, Danad I, Knaapen P, Escaned J, Piek JJ, Davies JE, van Royen N. Coronary pressure and flow relationships in humans: phasic analysis of normal and pathological vessels and the implications for stenosis assessment: a report from the Iberian-Dutch-English (IDEAL) collaborators. Eur Heart J. 2016;37:2069-80. .

In an analogy to the FFR-CFR comparison, a normal iFR may result in an abnormal FFR when hMVR is low and, similarly, an abnormal iFR may result in a normal FFR when hMVR is high. As is illustrated in the present report, the use of FFR in this diagnostic workup is debatable, as an abnormal FFR (<0.80) may coincide with a low hMVR, resulting in a normal coronary flow reserve (>2.0) and a normal iFR. Such a lesion is, by definition, non-flow-limiting, and coronary revascularisation in this setting may not be beneficial to the patient. This rationale suggests that measurement of flow may be an important factor in improving the accuracy of the FFR measures which are altered by microvascular disease88. van de Hoef TP, Siebes M, Spaan JA, Piek JJ. Fundamentals in clinical coronary physiology: why coronary flow is more important than coronary pressure. Eur Heart J. 2015;36:3312-9a. . However, only modest gains in flow-based technology have occurred over the past 15 years, largely attributable to the simplicity and relative robustness of coronary pressure measurements in clinical practice and patient outcome data demonstrating beneficial effects of coronary pressure-based revascularisation decision making. In order for true coronary flow-based clinical decision making to evolve, it is important to develop flow-based technologies further in order to: i) make these measurements applicable in daily clinical practice; and ii) regain interest from clinicians to apply them in their daily practice. Regarding the latter, studies such as those from Young-Woo Seo presented in this issue of the journal play an important role, since they remind us of the complexity of ischaemic heart disease and the great potential of multimodality physiological assessment to optimise diagnosis.

Conflict of interest statement

J. Davies is co-developer of IP which is licensed to Volcano Philips by Imperial College London. He receives consultancy and research funding from Philips Volcano. C. Cook is on the speaker’s bureau for Philips Volcano. J. Piek is a consultant for Philips Volcano and Abbott Vascular.

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References

  • 1. Serruys PW, Di Mario C, Meneveau N, de Jaegere P, Strikwerda S, de Feyter PJ, Emanuelsson H. Intracoronary pressure and flow velocity with sensor-tip guidewires: a new methodologic approach for assessment of coronary hemodynamics before and after coronary interventions. Am J Cardiol. 1993;71:41D-53D.
  • 2. Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B, Gould KL. 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.
  • 3. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol. 1974;33:87-94.
  • 4. Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, Higano ST, Lim MJ, Meuwissen M, Piek JJ, Pijls NH, Siebes M, Spaan JA; American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. 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.
  • 5. Di Mario C, de Feyter PJ, Slager CJ, de Jaegere P, Roelandt JR, Serruys PW. Intracoronary blood flow velocity and transstenotic pressure gradient using sensor-tip pressure and Doppler guidewires: a new technology for the assessment of stenosis severity in the catheterization laboratory. Cathet Cardiovasc Diagn. 1993;28:311-9.
  • 6. Di Mario C, Krams R, Gil R, Serruys PW. Slope of the instantaneous hyperemic diastolic coronary flow velocity-pressure relation. A new index for assessment of the physiological significance of coronary stenosis in humans. Circulation. 1994;90:1215-24.
  • 7. van de Hoef TP, Nolte F, EchavarrÍa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart. 2014;100:951-9.
  • 8. van de Hoef TP, Siebes M, Spaan JA, Piek JJ. Fundamentals in clinical coronary physiology: why coronary flow is more important than coronary pressure. Eur Heart J. 2015;36:3312-9a.
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  • 10. Echavarría-Pinto M, van de Hoef TP, van Lavieren MA, Nijjer S, Ibañez B, Pocock S, Quirós A, Davies J, Meuwissen M, Serruys PW, Macaya C, Piek JJ, Escaned J. Combining Baseline Distal-to-Aortic Pressure Ratio and Fractional Flow Reserve in the Assessment of Coronary Stenosis Severity. JACC Cardiovasc Interv. 2015;8:1681-91.
  • 11. Petraco R, van de Hoef TP, Nijjer S, Sen S, van Lavieren MA, Foale RA, Meuwissen M, Broyd C, Echavarria-Pinto M, Foin N, Malik IS, Mikhail GW, Hughes AD, Francis DP, Mayet J, Di Mario C, Escaned J, Piek JJ, Davies JE. 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.
  • 12. Petraco R, Park JJ, Sen S, Nijjer SS, Malik IS, Echavarría-Pinto M, Asrress KN, Nam CW, Macías E, Foale RA, Sethi A, Mikhail GW, Kaprielian R, Baker CS, Lefroy D, Bellamy M, Al-Bustami M, Khan MA, Gonzalo N, Hughes AD, Francis DP, Mayet J, Di Mario C, Redwood S, Escaned J, Koo BK, Davies JE. Hybrid iFR-FFR decision-making strategy: implications for enhancing universal adoption of physiology-guided coronary revascularisation. EuroIntervention. 2013;8:1157-65.
  • 13. Seo KW, Lim HS, Yoon MH, Tahk SJ, Choi SY, Choi BJ, Yang HM, Shin JH, Hwang GS, Park JS, Jin XJ. The impact of microvascular resistance on the discordance between anatomical and functional evaluations of intermediate coronary disease. EuroIntervention. 2017;13:185-92.
  • 14. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’ t Veer M, Klauss V, Manoharan G, Engstrøm T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213-24.
  • 15. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N, Möbius-Winkler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engström T, Oldroyd KG, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Jüni P, Fearon WF; FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367:991-1001.
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