Fractional Flow Reserve or Coronary Flow Reserve for the Assessment of Myocardial Perfusion: Implications of FFR as an Imperfect Reference Standard for Myocardial Ischemia

Purpose of Review: Accumulating evidence exists for the value of coronary physiology for clinical decision-making in ischemic heart disease (IHD). The most frequently used pressure-derived index to assess stenosis severity, the fractional flow reserve (FFR), has long been considered the gold standard for this purpose, despite the fact that the FFR assesses solely epicardial stenosis severity and aims to estimate coronary flow impairment in the coronary circulation. The coronary flow reserve (CFR) directly assesses coronary blood flow in the coronary circulation, including both the epicardial coronary artery and the coronary microvasculature, but is nowadays less established than FFR. It is now recognized that both tools may provide insight into the pathophysiological substrate of ischemic heart disease, and that particularly combined FFR and CFR measurements provide a comprehensive insight into the multilevel involvement of IHD. This review discusses the diagnostic and prognostic characteristics, as well as future implications of combined assessment of FFR and CFR pressure and flow measurements as parameters for inducible ischemia. Recent Findings: FFR and CFR disagree in up to 40% of all cases, giving rise to fundamental questions regarding the role of FFR in contemporary ischemic heart disease management, and implying a renewed approach in clinical management of these patients using combined coronary pressure and flow measurement to allow appropriate identification of patients at risk for cardiovascular events. Summary: This review emphasizes the value of comprehensive coronary physiology measurements in assessing the pathophysiological substrate of IHD, and the importance of acknowledging the broad spectrum of epicardial and microcirculatory involvement in IHD. Increasing interest and large clinical trials are expected to further strengthen the potential of advanced coronary physiology in interventional cardiology, consequently inducing reconsideration of current clinical guidelines

Assessing the haemodynamic impact of coronary artery stenoses: Intracoronary flow versus pressure measurements

Fractional flow reserve (FFR)-guided percutaneous coronary intervention results in better long-term clinical outcomes compared with coronary angiography alone in intermediate stenoses in stable coronary artery disease (CAD). Coronary physiology measurements have emerged for clinical decision making in interventional cardiology, but the focus lies mainly on epicardial vessels rather than the impact of these stenoses on the myocardial microcirculation. The latter can be quantified by measuring the coronary flow reserve (CFR), a combined pressure and flow index with a strong ability to predict clinical outcomes in CAD. However, combined pressure-flow measurements show 30-40 % discordance despite similar diagnostic accuracy between FFR and CFR, which is explained by the effect of microvascular resistance on both indices. Both epicardial and microcirculatory involvement has been acknowledged in ischaemic heart disease, but clinical implementation remains difficult as it requires individual proficiency. The recent introduced pressure-only index instantaneous wave-free ratio, a resting adenosine-free stenosis assessment, led to a revival of interest in coronary physiology measurements. This review focuses on elaborating the coronary physiological parameters and potential of combined pressure-flow measurements in daily clinical practice

Pressure-derived estimations of coronary flow reserve are inferior to flow-derived coronary flow reserve as diagnostic and risk stratification tools

Background: Pressure-derived coronary flow reserve (CFRpres) and pressure-bounded CFR (CFRpb) enable simple estimation of CFR from routine pressure measurements, but have been inadequately validated. We sought to compare CFRpres and CFRpb against flow-derived CFR (CFRflow) in terms of diagnostic accuracy, as well as regarding their comparative prognostic relevance. Methods: We evaluated 453 intermediate coronary lesions with intracoronary pressure and flow measurements. CFR was defined as hyperemic flow/baseline flow. The lower bound (CFRpres) and upper bound of CFRpb were defined as √[(ΔPhyperemia) / (ΔPrest)] and [(ΔPhyperemia) / (ΔPrest)], respectively. Long-term follow-up (median: 11.8-years) was performed in 153 lesions deferred from treatment to document the occurrence of major adverse cardiac events (MACE) defined as a composite of cardiac death, myocardial infarction and target vessel revascularization. CFR < 2.0 was considered abnormal. Results: CFRpb was normal or abnormal in 56.7% of stenoses, and indeterminate in 43.3% of stenoses. There was a poor diagnostic agreement between CFRpres and CFRpb with CFRflow (overall agreement: 45.5% and 71.6% of vessels, respectively). There was equivalent risk for long-term MACE for lesions with abnormal versus normal CFRpres (Breslow p = 0.562), whereas vessels with abnormal CFRflow were significantly associated with increased long-term MACE (Breslow p < 0.001). For vessels where CFRpb was abnormal or normal, there was equivalent risk for long-term MACE for vessels with abnormal versus normal CFRpb (Breslow p = 0.194), whereas vessels with abnormal CFRflow were associated with increased MACE rates over time (Breslow p < 0.001). Conclusions: Pressure-derived estimations of CFR poorly agree with flow-derived measurements of CFR, which may explain the inferior association with long-term MACE as compared to flow-derived CFR

Objective Identification of Intermediate Lesions Inducing Myocardial Ischemia Using Sequential Intracoronary Pressure and Flow Measurements

Background Although ischemic heart disease has a complex and multilevel origin, the diagnostic approach is mainly focused on focal obstructive disease as assessed by pressure-derived indexes. The prognostic relevance of coronary flow over coronary pressure has been suggested and implies that identification of relevant perfusion abnormalities by invasive physiology techniques is critical for the correct identification of patients who benefit from coronary revascularization. The purpose of this study was to evaluate the diagnostic potential of a sequential approach using pressure-derived indexes instantaneous wave-free ratio (iFR), fractional flow reserve (FFR), and coronary flow reserve (CFR) measurements to determine the number of intermediate lesions associated with flow abnormalities after initial pressure measurements. Methods and Results A total of 366 intermediate lesions were assessed with simultaneous intracoronary pressure and flow velocity measurements. Contemporary clinical iFR, FFR, and CFR cut points for myocardial ischemia were applied. A total of 118 (32%) lesions were FFR+ and 136 (37%) lesions were iFR+. Subsequent CFR assessment resulted for FFR in a total of 91 (25%) FFR+/CFR+ and for iFR a total of 111 (30%) iFR+/CFR+ lesions. An iFR, FFR, and invasive flow velocity assessment approach would have yielded 20% of lesions (74 of 366) as ischemic. Conclusions Ultimately, 20% of intermediate lesions are associated with flow abnormalities after applying a pressure and flow velocity sequential approach. If iFR is borderline, FFR has limited additional value, in contrast with CFR. These results emphasize the use of coronary physiology in assessing stenosis severity but may also further question the contemporary reputation of a pressure-based approach as a gold standard for the detection of myocardial ischemia in ischemic heart disease

Principles and pitfalls in coronary vasomotor function testing

BACKGROUND: Coronary vasomotor dysfunction can be diagnosed in a large proportion of patients with angina in the presence of non-obstructive coronary artery disease (ANOCA) using comprehensive protocols for coronary vasomotor function testing (CFT). Although consensus on diagnostic criteria for endotypes of coronary vasomotor dysfunction has been published, consensus on a standardised study testing protocol is lacking. AIMS: In this review we provide an overview of the variations in CFT used and discuss the practical principles and pitfalls of CFT. METHODS: For the purposes of this review, we assessed study protocols that evaluate coronary vasomotor response as reported in the literature. We compared these protocols regarding a number of procedural aspects and chose six examples to highlight the differences and uniqueness. RESULTS: Currently, numerous protocols co-exist and vary in vascular domains tested, the manner in which to test these domains (e.g., preprocedural discontinuation of medication, provocative agent, solution, infusion time, and target artery) and techniques used for measurements (e.g., Doppler vs thermodilution technique). CONCLUSIONS: This lack of consensus on a uniform functional testing protocol hampers both a broader clinical acceptance of the concepts of coronary vasomotor dysfunction, and the widespread adoption of such testing protocols in current clinical practice. Furthermore, the endotype of coronary vasomotor dysfunction might differ among the few specialised centres that perform CFT as a result of the use of different protocols

Time course of coronary flow capacity impairment in ST-segment elevation myocardial infarction

BACKGROUND: Microvascular dysfunction in the setting of ST-elevated myocardial infarction (STEMI) plays an important role in long-term poor clinical outcome. Coronary flow reserve (CFR) is a well-established physiological parameter to interrogate the coronary microcirculation. Together with hyperaemic average peak flow velocity, CFR constitutes the coronary flow capacity (CFC), a validated risk stratification tool in ischaemic heart disease with significant prognostic value. This mechanistic study aims to elucidate the time course of the microcirculation as reflected by alterations in microcirculatory physiological parameters in the acute phase and during follow-up in STEMI patients. METHODS: We assessed CFR and CFC in the culprit and non-culprit vessel in consecutive STEMI patients at baseline (n = 98) and after one-week (n = 64) and six-month follow-up (n = 65). RESULTS: A significant trend for culprit CFC in infarct size as determined by peak troponin T (p = 0.004), time to reperfusion (p = 0.038), the incidence of final Thrombolysis In Myocardial Infarction 3 flow (p = 0.019) and systolic retrograde flow (p = 0.043) was observed. Non-culprit CFC linear contrast analysis revealed a significant trend in C-reactive protein (p = 0.027), peak troponin T (p < 0.001) and heart rate (p = 0.049). CFC improved both in the culprit and the non-culprit vessel at one-week (both p < 0.001) and six-month follow-up (p = 0.0013 and p < 0.001) compared with baseline. CONCLUSION: This study demonstrates the importance of microcirculatory disturbances in the setting of STEMI, which is relevant for the interpretation of intracoronary diagnostic techniques which are influenced by both culprit and non-culprit vascular territories. Assessment of non-culprit vessel CFC in the setting of STEMI might improve risk stratification of these patients following coronary reperfusion of the culprit vessel

Quantification of Myocardial Mass Subtended by a Coronary Stenosis Using Intracoronary Physiology

BACKGROUND: In patients with stable coronary artery disease, the amount of myocardium subtended by coronary stenoses constitutes a major determinant of prognosis, as well as of the benefit of coronary revascularization. We devised a novel method to estimate partial myocardial mass (PMM; ie, the amount of myocardium subtended by a stenosis) during physiological stenosis interrogation. Subsequently, we validated the index against equivalent PMM values derived from applying the Voronoi algorithm on coronary computed tomography angiography. METHODS: Based on the myocardial metabolic demand and blood supply, PMM was calculated as follows: PMM (g)=APV×D2×π/(1.24×10-3×HR×sBP+1.6), where APV indicates average peak blood flow velocity; D, vessel diameter; HR, heart rate; and sBP, systolic blood pressure. We calculated PMM to 43 coronary vessels (32 patients) interrogated with pressure and Doppler guidewires, and compared it with computed tomography-based PMM. RESULTS: Median PMM was 15.8 g (Q1, Q3: 11.7, 28.4 g) for physiology-based PMM, and 17.0 g (Q1, Q3: 12.5, 25.9 g) for computed tomography-based PMM (P=0.84). Spearman rank correlation coefficient was 0.916 (P<0.001), and Passing-Bablok analysis revealed absence of both constant and proportional differences (coefficient A: -0.9; 95% CI, -4.5 to 0.9; and coefficient B, 1.00; 95% CI, 0.91 to 1.25]. Bland-Altman analysis documented a mean bias of 0.5 g (limit of agreement: -9.1 to 10.2 g). CONCLUSIONS: Physiology-based calculation of PMM in the catheterization laboratory is feasible and can be accurately performed as part of functional stenosis assessment

Coronary Flow Capacity to Identify Stenosis Associated With Coronary Flow Improvement After Revascularization: A Combined Analysis From DEFINE FLOW and IDEAL

Background Coronary flow capacity (CFC), which is a categorical assessment based on the combination of hyperemic coronary flow and coronary flow reserve (CFR), has been introduced as a comprehensive assessment of the coronary circulation to overcome the limitations of CFR alone. The aim of this study was to quantify coronary flow changes after percutaneous coronary intervention in relation to the classification of CFC and the current physiological cutoff values of fractional flow reserve, instantaneous wave-free ratio, and CFR. Methods and Results Using the combined data set from DEFINE FLOW (Distal Evaluation of Functional Performance With Intravascular Sensors to Assess the Narrowing Effect -Combined Pressure and Doppler FLOW Velocity Measurements) and IDEAL (Iberian-Dutch-English), a total of 133 vessels that underwent intracoronary Doppler flow measurement before and after percutaneous coronary intervention were analyzed. CFC classified prerevascularization lesions as normal (14), mildly reduced (40), moderately reduced (31), and severely reduced (48). Lesions with larger impairment of CFC showed greater increase in coronary flow and vice versa (median percent increase in coronary flow by revascularization: 4.2%, 25.9%, 50.1%, and 145.5%, respectively; P50% increase in coronary flow after percutaneous coronary intervention. Receiver operating characteristic curve analysis demonstrated that only CFC has a superior predictive efficacy to CFR (P<0.05). Multivariate analysis revealed lesions with ischemic CFC to be the independent predictor of a significant coronary flow increase after percutaneous coronary intervention (odds ratio, 10.7; 95% CI, 4.6-24.8; P<0.001). Conclusions CFC showed significant improvement of identification of lesions that benefit from revascularization compared with CFR with respect to coronary flow increase. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02328820

Impact of core laboratory assessment on treatment decisions and clinical outcomes using combined fractional flow reserve and coronary flow reserve measurements – DEFINE-FLOW core laboratory sub-study

Objective: The role of combined FFR/CFR measurements in decision-making on coronary revascularization remains unclear. DEFINE-FLOW prospectively assessed the relationship of FFR/CFR agreement with 2-year major adverse cardiac event (MACE) and target vessel failure (TVF) rates, and uniquely included core-laboratory analysis of all pressure and flow tracings. We aimed to document the impact of core-laboratory analysis on lesion classification, and the relationship between core-laboratory fractional flow reserve (FFR) and coronary flow reserve (CFR) values with clinical outcomes and angina burden during follow-up. Methods: In 398 vessels (348 patients) considered for intervention, ≥1 coronary pressure/flow tracing was approved by the core-laboratory. Revascularization was performed only when both FFR(≤0.80) and CFR(<2.0) were abnormal, all others were treated medically. Results: MACE was lowest for concordant normal FFR/CFR, but was not significantly different compared with either discordant group (low FFR/normal CFR: HR:1.63; 95%CI:0.61–4.40; P = 0.33; normal FFR/low CFR: HR:1.81; 95%CI:0.66–4.98; P = 0.25). Moreover, MACE did not differ between discordant groups treated medically and the concordant abnormal group undergoing revascularization (normal FFR/low CFR: HR:0.63; 95%CI:0.23–1.73;P = 0.37; normal FFR/low CFR: HR:0.70; 95%CI:0.22–2.21;P = 0.54). Similar findings applied to TVF. Conclusions: Patients with concordantly normal FFR/CFR have very low 2-year MACE and TVF rates. Throughout follow-up, there were no differences in event rates between patients in whom revascularization was deferred due to preserved CFR despite reduced FFR, and those in whom PCI was performed due to concordantly low FFR and CFR. These findings question the need for routine revascularization in vessels showing low FFR but preserved CFR. Clinical trial registration: http://ClinicalTrials.go