Prognostic value of microvascular resistance and its association to fractional flow reserve:a DEFINE-FLOW substudy

OBJECTIVE: This study aimed to evaluate the prognostic value of hyperemic microvascular resistance (HMR) and its relationship with hyperemic stenosis resistance (HSR) index and fractional flow reserve (FFR) in stable coronary artery disease. METHODS: This is a substudy of the DEFINE-FLOW cohort (NCT02328820), which evaluated the prognosis of lesions (n=456) after combined FFR and coronary flow reserve (CFR) assessment in a prospective, non-blinded, non-randomised, multicentre study in 12 centres in Europe and Japan. Participants (n=430) were evaluated by wire-based measurement of coronary pressure, flow and vascular resistance (ComboWire XT, Phillips Volcano, San Diego, California, USA). RESULTS: Mean FFR and CFR were 0.82±0.10 and 2.2±0.6, respectively. When divided according to FFR and CFR thresholds (above and below 0.80 and 2.0, respectively), HMR was highest in lesions with FFR>0.80 and CFR<2.0 (n=99) compared with lesions with FFR≤0.80 and CFR≥2.0 (n=68) (2.92±1.2 vs 1.91±0.64 mm Hg/cm/s, p<0.001). The FFR value was proportional to the ratio between HMR and the HMR+HSR (total resistance), 95% limits of agreement (−0.032; 0.019), bias (−0.003±0.02) and correlation (r(2)=0.98, p<0.0001). Cox regression model using HMR as continuous parameter for target vessel failure showed an HR of 1.51, 95% CI (0.9 to 2.4), p=0.10. CONCLUSIONS: Increased HMR was not associated with a higher rate of adverse clinical events, in this population of mainly stable patients. FFR can be equally well expressed as HMR/HMR+HSR, thereby providing an alternative conceptual formulation linking epicardial severity with microvascular resistance. TRIAL REGISTRATION NUMBER: NCT02328820

Characterization of quantitative flow ratio and fractional flow reserve discordance using doppler flow and clinical follow-up

The physiological mechanisms of quantitative flow ratio and fractional flow reserve disagreement are not fully understood. We aimed to characterize the coronary flow and resistance profile of intermediate stenosed epicardial coronary arteries with concordant and discordant FFR and QFR. Post-hoc analysis of the DEFINE-FLOW study. Anatomical and Doppler-derived physiological parameters were compared for lesions with FFR+QFR− (n = 18) vs. FFR+QFR+ (n = 43) and for FFR−QFR+ (n = 34) vs. FFR−QFR− (n = 139). The association of QFR results with the two-year rate of target vessel failure was assessed in the proportion of vessels (n = 195) that did not undergo revascularization. Coronary flow reserve was higher [2.3 (IQR: 2.1–2.7) vs. 1.9 (IQR: 1.5–2.4)], hyperemic microvascular resistance lower [1.72 (IQR: 1.48–2.31) vs. 2.26 (IQR: 1.79–2.87)] and anatomical lesion severity less severe [% diameter stenosis 45.5 (IQR: 41.5–52.5) vs. 58.5 (IQR: 53.1–64.0)] for FFR+QFR− lesions compared with FFR+QFR+ lesions. In comparison of FFR−QFR+ vs. FFR-QFR- lesions, lesion severity was more severe [% diameter stenosis 55.2 (IQR: 51.7–61.3) vs. 43.4 (IQR: 35.0–50.6)] while coronary flow reserve [2.2 (IQR: 1.9–2.9) vs. 2.2 (IQR: 1.9–2.6)] and hyperemic microvascular resistance [2.34 (IQR: 1.85–2.81) vs. 2.57 (IQR: 2.01–3.22)] did not differ. The agreement and diagnostic performance of FFR using hyperemic stenosis resistance (> 0.80) as reference standard was higher compared with QFR and coronary flow reserve. Disagreement between FFR and QFR is partly explained by physiological and anatomical factors. Clinical Trials Registration https://www.clinicaltrials.gov; Unique identifier: NCT01813435. Graphical abstract: Changes in central physiological and anatomical parameters according to FFR and QFR match/mismatch quadrants

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

ASSESSMENT OF RENAL SYMPATHETIC CONTROL USING INVASIVE PRESSURE AND FLOW VELOCITY MEASUREMENTS IN HUMANS

OBJECTIVE: Renal sympathetic innervation is important in the control of renal and systemic hemodynamics and a target for pharmacological and catheter-based therapies. The effect of a physiological sympathetic stimulus using static handgrip exercise on renal hemodynamics and intraglomerular pressure in humans is unknown. DESIGN AND METHOD: We recorded renal arterial pressure and flow velocity in patients with a clinical indication for coronary or peripheral angiography using a sensor-equipped guidewire during baseline, handgrip, resting, and hyperemia following intrarenal dopamine (30 ug/kg). Changes in perfusion pressure were expressed as delta mean arterial pressure, changes in flow velocity as percentage with respect to baseline. Intraglomerular pressure was estimated using a Windkessel model. RESULTS: We included 18 patients with median age 57 years (range 27-85), 61% male in the final analysis. An overview of the hemodynamic responses is given in Figure 1. During static handgrip mean renal arterial pressure increased by 15.2 mmHg (range 4.2-53.0), while flow decreased by 11.2%, but with large variation between individuals (range -13.4-49.8%). Intraglomerular pressure increased with 4.2 mmHg (range -3.9-22.1). Flow velocity under resting conditions remained stable with median 100.6% (range 82.3-114.6) compared to baseline. During hyperemia, maximal flow was 180% (range 111-281), while intraglomerular pressure decreased to 33.0 mmHg [IQR 26.7-39.8]. Changes in renal pressure and flow during handgrip exercise were correlated (rho = -0.68; p = 0.002). CONCLUSIONS: We show that there are significant variations in the response to sympathetic stimulation following static handgrip exercise using invasive renal arterial measurements. These results demonstrate that intra-arterial renal hemodynamic measurements can be used to determine the renal effect of systemic sympathetic stimulus and allows identification of patients with higher and lower sympathetic control of renal perfusion. This may be useful in determining the response to therapeutic interventions aimed at altering renal sympathetic control

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

Distal Evaluation of Functional performance with Intravascular sensors to assess the Narrowing Effect—combined pressure and Doppler FLOW velocity measurements (DEFINE-FLOW) trial: Rationale and trial design

Background: It remains uncertain if invasive coronary physiology beyond fractional flow reserve (FFR) can refine lesion selection for revascularization or provide additional prognostic value. Coronary flow reserve (CFR) equals the ratio of hyperemic to baseline flow velocity and has a wealth of invasive and noninvasive data supporting its validity. Because of fundamental physiologic relationships, binary classification of FFR and CFR disagrees in approximately 30%-40% of cases. Optimal management of these discordant cases requires further study. Aim: The aim of the study was to determine the prognostic value of combined FFR and CFR measurements to predict the 24-month rate of major adverse cardiac events. Secondary end points include repeatability of FFR and CFR, angina burden, and the percentage of successful FFR/CFR measurements which will not be excluded by the core laboratory. Methods: This prospective, nonblinded, nonrandomized, and multicenter study enrolled 455 subjects from 12 sites in Europe and Japan. Patients underwent physiologic lesion assessment using the 0.014” Philips Volcano ComboWire XT that provides simultaneous pressure and Doppler velocity sensors. Intermediate coronary lesions received only medical treatment unless both FFR (≤0.8) and CFR ( 0.80 and CFR ≥ 2.0. Enrollment has been completed, and final follow-up will occur in November 2019

Characterization of quantitative flow ratio and fractional flow reserve discordance using doppler flow and clinical follow-up

Abstract: The physiological mechanisms of quantitative flow ratio and fractional flow reserve disagreement are not fully understood. We aimed to characterize the coronary flow and resistance profile of intermediate stenosed epicardial coronary arteries with concordant and discordant FFR and QFR. Post-hoc analysis of the DEFINE-FLOW study. Anatomical and Doppler-derived physiological parameters were compared for lesions with FFR+QFR− (n = 18) vs. FFR+QFR+ (n = 43) and for FFR−QFR+ (n = 34) vs. FFR−QFR− (n = 139). The association of QFR results with the two-year rate of target vessel failure was assessed in the proportion of vessels (n = 195) that did not undergo revascularization. Coronary flow reserve was higher [2.3 (IQR: 2.1–2.7) vs. 1.9 (IQR: 1.5–2.4)], hyperemic microvascular resistance lower [1.72 (IQR: 1.48–2.31) vs. 2.26 (IQR: 1.79–2.87)] and anatomical lesion severity less severe [% diameter stenosis 45.5 (IQR: 41.5–52.5) vs. 58.5 (IQR: 53.1–64.0)] for FFR+QFR− lesions compared with FFR+QFR+ lesions. In comparison of FFR−QFR+ vs. FFR-QFR- lesions, lesion severity was more severe [% diameter stenosis 55.2 (IQR: 51.7–61.3) vs. 43.4 (IQR: 35.0–50.6)] while coronary flow reserve [2.2 (IQR: 1.9–2.9) vs. 2.2 (IQR: 1.9–2.6)] and hyperemic microvascular resistance [2.34 (IQR: 1.85–2.81) vs. 2.57 (IQR: 2.01–3.22)] did not differ. The agreement and diagnostic performance of FFR using hyperemic stenosis resistance (> 0.80) as reference standard was higher compared with QFR and coronary flow reserve. Disagreement between FFR and QFR is partly explained by physiological and anatomical factors. Clinical Trials Registrationhttps://www.clinicaltrials.gov; Unique identifier: NCT01813435. Graphical abstract: Changes in central physiological and anatomical parameters according to FFR and QFR match/mismatch quadrants.[Figure not available: see fulltext.

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