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Background: Coronary blood flow in humans is known to be predominantly diastolic. Small studies in animals and humans suggest that this is less pronounced or even reversed in the right coronary artery (RCA)., Aims: This study aimed to characterise the phasic patterns of coronary flow in the left versus right coronary arteries of patients undergoing invasive physiological assessment., Methods: We analysed data from the Iberian-Dutch-English Collaborators (IDEAL) study. A total of 482 simultaneous pressure and flow measurements from 301 patients were included in our analysis., Results: On average, coronary flow was higher in diastole both at rest and during hyperaemia in both the RCA and LCA (mean diastolic-to-systolic velocity ratio [DSVR] was, respectively, 1.85±0.70, 1.76±0.58, 1.53±0.34 and 1.58±0.43 for LCA rest , LCA hyp , RCA rest and RCA hyp , p<0.001 for between-vessel comparisons). Although the type of RCA dominance affected the DSVR magnitude (RCA dom =1.55±0.35, RCA co-dom =1.40±0.27, RCA non-dom =1.35; standard deviation not reported as n=3), systolic flow was very rarely predominant (DSVR was greater than or equal to 1.00 in 472/482 cases [97.9%] overall), with equal prevalence in the LCA. Stenosis severity or microvascular dysfunction had a negligible impact on DSVR in both the RCA and LCA (DSVR x hyperaemic stenosis resistance R 2 =0.018, p=0.03 and DSVR x coronary flow reserve R 2 <0.001, p=0.98)., Conclusions: In patients with coronary artery disease undergoing physiological assessment, diastolic flow predominance is seen in both left and right coronary arteries. Clinical interpretation of coronary physiological data should therefore not differ between the left and the right coronary systems.

Aims: We evaluated the occurrence and physiology of respiration-related beat-to-beat variations in resting Pd/Pa and FFR during intravenous adenosine administration, and its impact on clinical decision-making., Methods and Results: Coronary pressure tracings in rest and at plateau hyperemia were analyzed in a total of 39 stenosis from 37 patients, and respiratory rate was calculated with ECG-derived respiration (EDR) in 26 stenoses from 26 patients. Beat-to-beat variations in FFR occurred in a cyclical fashion and were strongly correlated with respiratory rate (R 2  = 0.757, p < 0.001). There was no correlation between respiratory rate and variations in resting Pd/Pa. When single-beat averages were used to calculate FFR, mean ΔFFR was 0.04 ± 0.02. With averaging of FFR over three or five cardiac cycles, mean ΔFFR decreased to 0.02 ± 0.02, and 0.01 ± 0.01, respectively. Using a FFR ≤ 0.80 threshold, stenosis classification changed in 20.5% (8/39), 12.8% (5/39) and 5.1% (2/39) for single-beat, three-beat and five-beat averaged FFR. The impact of respiration was more pronounced in patients with pulmonary disease (ΔFFR 0.05 ± 0.02 vs 0.03 ± 0.02, p = 0.021)., Conclusion: Beat-to-beat variations in FFR during plateau hyperemia related to respiration are common, of clinically relevant magnitude, and frequently lead FFR to cross treatment thresholds. A five-beat averaged FFR, overcomes clinically relevant impact of FFR variation., (© 2021 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

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., (© The European Society of Cardiology 2020.)

Background: Microvascular dysfunction in the setting of ST-segment myocardial infarction (STEMI) is thought to be related to stress-related metabolic changes, including acute glucose intolerance. The aim of this study was to assess the relationship between admission glucose levels and microvascular function in non-diabetic STEMI patients., Methods: 92 consecutive patients with a first anterior-wall STEMI treated with primary percutaneous coronary intervention (PPCI) were enrolled. Blood glucose levels were determined immediately prior to PPCI. After successful PPCI, at 1‑week and 6‑month follow-up, Doppler flow was measured in culprit and reference coronary arteries to calculate coronary flow velocity reserve (CFVR), baseline (BMR) and hyperaemic (HMR) microvascular resistance., Results: The median admission glucose was 8.3 (7.2-9.6) mmol/l respectively 149.4 mg/dl [129.6-172.8] and was significantly associated with peak troponin T (standardised beta coefficient [std beta] = 0.281; p = 0.043). Multivariate analysis revealed that increasing glucose levels were significantly associated with a decrease in reference vessel CFVR (std beta = -0.313; p = 0.002), dictated by an increase in rest average peak velocity (APV) (std beta = 0.216; p = 0.033), due to a decreasing BMR (std beta = -0.225; p = 0.038) in the acute setting after PPCI. These associations disappeared at follow-up. These associations were not found for the infarct-related artery., Conclusion: Elevated admission glucose levels are associated with impaired microvascular function assessed directly after PPCI in first anterior-wall STEMI. This influence of glucose levels is an acute phenomenon and contributes to microvascular dysfunction through alterations in resting flow and baseline microvascular resistance.

Objectives: This study developed a neural network to perform automated pressure waveform analysis and allow real-time accurate identification of damping., Background: Damping of aortic pressure during coronary angiography must be identified to avoid serious complications and make accurate coronary physiology measurements. There are currently no automated methods to do this, and so identification of damping requires constant monitoring, which is prone to human error., Methods: The neural network was trained and tested versus core laboratory expert opinions derived from 2 separate datasets. A total of 5,709 aortic pressure waveforms of individual heart beats were extracted and classified. The study developed a recurrent convolutional neural network to classify beats as either normal, showing damping, or artifactual. Accuracies were reported using the opinions of 2 independent core laboratories., Results: The neural network was 99.4% accurate (95% confidence interval: 98.8% to 99.6%) at classifying beats from the testing dataset when judged against the opinions of the internal core laboratory. It was 98.7% accurate (95% confidence interval: 98.0% to 99.2%) when judged against the opinions of an external core laboratory not involved in neural network training. The neural network was 100% sensitive, with no beats classified as damped misclassified, with a specificity of 99.8%. The positive predictive and negative predictive values were 98.1% and 99.5%. The 2 core laboratories agreed more closely with the neural network than with each other., Conclusions: Arterial waveform analysis using neural networks allows rapid and accurate identification of damping. This demonstrates how machine learning can assist with patient safety and the quality control of procedures., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pressure-derived coronary flow reserve (CFR pres ) and pressure-bounded CFR (CFR pb ) enable simple estimation of CFR from routine pressure measurements, but have been inadequately validated. We sought to compare CFR pres and CFR pb against flow-derived CFR (CFR flow ) 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 (CFR pres ) and upper bound of CFR pb were defined as √[(ΔP hyperemia ) / (ΔP rest )] and [(ΔP hyperemia ) / (ΔP rest )], 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: CFR pb was normal or abnormal in 56.7% of stenoses, and indeterminate in 43.3% of stenoses. There was a poor diagnostic agreement between CFR pres and CFR pb with CFR flow (overall agreement: 45.5% and 71.6% of vessels, respectively). There was equivalent risk for long-term MACE for lesions with abnormal versus normal CFR pres (Breslow p = 0.562), whereas vessels with abnormal CFR flow were significantly associated with increased long-term MACE (Breslow p < 0.001). For vessels where CFR pb was abnormal or normal, there was equivalent risk for long-term MACE for vessels with abnormal versus normal CFR pb (Breslow p = 0.194), whereas vessels with abnormal CFR flow 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Coronary artery spasm may be the underlying mechanism in up to 10% of cases of acute coronary syndrome (ACS) and sudden cardiac death. Asian individuals exhibit a 3-times greater incidence of spasm than Caucasians; this is likely due to different types of mechanisms. Consequently, solid data is limited about the long-term prognosis in Caucasian patients presenting with ACS and/or out-of-hospital cardiac arrest (OHCA) caused by coronary spasm., Methods: Between 2002 and 2015, thirty Caucasian patients with coronary artery spasm presenting with ACS (N = 29) and/or OHCA (N = 11) were enrolled in this prospective registry. Follow-up, consisting of regular outpatient visits, was conducted with a mean follow-up period of 7.5 ± 3.3 years. Outcomes included presence of stable angina pectoris, recurrence of ACS, occurrence of implantable cardioverter defibrillator (ICD) shocks and death., Results: The majority of patients (60%) remained asymptomatic during the entire follow-up period. At the end of the follow-up period only 3 patients still experienced stable angina (10%). Only 2 patients (7%) had a recurrent cardiac event, in which the ICD provided appropriate shock therapy. Half of the patients treated with stenting (N = 6), required re-interventions., Conclusion: Coronary spasm with ACS and/or OHCA in a Caucasian patient cohort has a relatively benign prognosis in the majority of patients in long-term follow-up, if treated appropriately with medical therapy. Both the role of ICD in OHCA secondary to coronary spasm, and the efficacy of stenting to treat vasospastic angina, warrant further study in large-sized prospective clinical trials.

Aims: It is unclear whether microvascular dysfunction following ST-elevation myocardial infarction (STEMI) is prognostic for long-term left ventricular function (LVF), and whether recovery of the microvasculature status is associated with LVF improvement. The aim of this study was to assess whether microvascular dysfunction in the infarct-related artery (IRA), as assessed by coronary flow reserve (CFR) within one week after PPCI, was associated with LVF at both four months and two years., Methods and Results: In 62 patients, CFR and hyperaemic microvascular resistance index (HMRI) in the IRA were assessed by intracoronary Doppler flow measurements within one week and at four months. CMR was performed at the same time points and also at two years. CFR at baseline was associated with left ventricular ejection fraction (LVEF) at four months (β=4.66, SE=2.10; p=0.03) and at two-year follow-up (β=5.84, SE=2.45; p=0.02). HMRI was not associated with LVF. In large infarcts, absolute improvement of CFR in the first four months was associated with LVEF improvement (β=5.09, SE=1.86, p=0.01)., Conclusions: Microvascular dysfunction, assessed by CFR, in the subacute phase of STEMI is prognostic for LVEF at four months and two years. This underlines the pivotal role of microvascular dysfunction following STEMI.

Background: Coronary microcirculatory dysfunction portends a poor cardiovascular outcome. Invasive assessment of microcirculatory dysfunction by coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) is affected by coronary artery disease (CAD). In this study we propose minimal microvascular resistance (mMR) as a new measure of microcirculatory dysfunction and aim to determine whether mMR is influenced by CAD., Methods and Results: We obtained 482 simultaneous measurements of intracoronary Doppler flow velocity and pressure. The mMR is defined as the ratio between distal coronary pressure and flow velocity during the hyperemic wave-free period. Measurements were divided into 2 cohorts. Cohort 1 was a paired analysis involving 81 pairs with a vessel with and without CAD to investigate whether HMR, CFR, and mMR are modulated by CAD. CFR was lower, and HMR was higher, in vessels with CAD than in vessels without CAD: 2.12±0.79 versus 2.56±0.63 mm Hg·cm -1 ·s, P<0.001, and 2.61±1.22 versus 2.31±0.89 mm Hg·cm -1 ·s, P=0.04, respectively. mMR was equal in vessels with and without CAD: 1.54±0.77 versus 1.53±0.57 mm Hg·cm -1 ·s, P=0.90. Differences for CFR occurred when FFR was 0.60 to 0.80 or ≤0.60 but not when FFR ≥0.80. For HMR, the difference occurred only when FFR ≤0.60. For mMR, no difference was observed in any FFR stratum. Cohort 2 was used for validation and showed significant relationships for CFR and HMR with FFR: Pearson r=0.488, P<0.001 and -0.159, P=0.03, respectively; mMR had no association with FFR: Pearson r=0.055; P=0.32., Conclusions: mMR is a novel index to assess microcirculatory dysfunction and is not modified by the presence of obstructive CAD., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Our understanding of human coronary physiological behaviour is derived from animal models. We sought to describe physiological behaviour across a large collection of invasive pressure and flow velocity measurements, to provide a better understanding of the relationships between these physiological parameters and to evaluate the rationale for resting stenosis assessment., Methods and Results: Five hundred and sixty-seven simultaneous intracoronary pressure and flow velocity assessments from 301 patients were analysed for coronary flow velocity, trans-stenotic pressure gradient (TG), and microvascular resistance (MVR). Measurements were made during baseline and hyperaemic conditions. The whole cardiac cycle and the diastolic wave-free period were assessed. Stenoses were assessed according to fractional flow reserve (FFR) and quantitative coronary angiography DS%. With progressive worsening of stenoses, from unobstructed angiographic normal vessels to those with FFR ≤ 0.50, hyperaemic flow falls significantly from 45 to 19 cm/s, Ptrend < 0.001 in a curvilinear pattern. Resting flow was unaffected by stenosis severity and was consistent across all strata of stenosis (Ptrend > 0.05 for all). Trans-stenotic pressure gradient rose with stenosis severity for both rest and hyperaemic measures (Ptrend < 0.001 for both). Microvascular resistance declines with stenosis severity under resting conditions (Ptrend < 0.001), but was unchanged at hyperaemia (2.3 ± 1.1 mmHg/cm/s; Ptrend = 0.19)., Conclusions: With progressive stenosis severity, TG rises. However, while hyperaemic flow falls significantly, resting coronary flow is maintained by compensatory reduction of MVR, demonstrating coronary auto-regulation. These data support the translation of coronary physiological concepts derived from animals to patients with coronary artery disease and furthermore, suggest that resting pressure indices can be used to detect the haemodynamic significance of coronary artery stenoses., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Vasodilator-free basal stenosis resistance (BSR) equals fractional flow reserve (FFR) accuracy for ischaemia-inducing stenoses. Nonetheless, basal haemodynamic variability may impair BSR accuracy compared with hyperaemic stenosis resistance (HSR). We evaluated the influence of basal haemodynamic variability, as encountered in practice, on BSR accuracy versus HSR when derived from simultaneous pressure and flow velocity measurements, and determined its diagnostic performance for HSR-defined significant stenoses., Methods and Results: Simultaneous coronary pressure and flow velocity were obtained in 131 stenoses. The impact of basal haemodynamic conditions on BSR was evaluated by means of their relationship with the relative difference between BSR and HSR. Diagnostic performance of BSR, FFR, iFR, and resting Pd/Pa was assessed by comparing the area under the curve (AUC), using HSR as reference standard. The relative difference between BSR and HSR was not associated with basal heart rate, aortic pressure or rate pressure product. Among all stenoses, as well as within the 0.6-0.9 FFR range, BSR AUC was significantly greater than resting Pd/Pa and iFR AUC; all other AUCs were equivalent., Conclusions: With simultaneous pressure and flow velocity measurements, basal conditions do not systematically limit BSR accuracy compared with HSR. Consequently, diagnostic performance of BSR is equivalent to FFR, and closely approximates HSR.

Aims: We sought to compare the diagnostic accuracy of basal stenosis resistance index (BSR), instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) for stenosis-specific myocardial ischaemia identified by means of a combined reference standard of myocardial perfusion scintigraphy and the hyperaemic stenosis resistance index., Methods and Results: BSR and FFR were determined for 299 coronary stenoses, iFR was determined for 85 coronary stenoses (iFR cohort). The discriminative value for stenosis-specific myocardial ischaemia was compared by means of the area under the receiver operating characteristic (ROC) curves (AUC). Classification agreement with the reference standard was determined according to ROC curve-derived ischaemic cut-off values, as well as according to clinical cut-off values, equivalent to the 0.80 FFR cut-off. Across all stenoses, the discriminative value of BSR and FFR was equivalent (AUC: 0.90 and 0.91, respectively, p=0.46). In the iFR cohort, the discriminative value was equivalent for BSR, iFR, and FFR (AUC: 0.88, 0.84, and 0.88, respectively; p≥0.20 for all). At both ischaemic as well as clinical cut-off values, classification agreement with the reference standard was equivalent for BSR and FFR across all stenoses, as well as for BSR, iFR, and FFR in the iFR cohort., Conclusions: BSR, iFR, and FFR have equivalent diagnostic accuracy for the detection of ischaemia-generating coronary stenoses.

Objectives: The purpose of this study is to evaluate whether coronary flow capacity (CFC) improves discrimination of patients at risk for major adverse cardiac events (MACE) compared with coronary flow reserve (CFR) alone, and to study the diagnostic and prognostic implications of CFC in relation to contemporary diagnostic tests for ischemic heart disease (IHD), including fractional flow reserve (FFR)., Background: Although IHD results from a combination of focal obstructive, diffuse, and microcirculatory involvement of the coronary circulation, its diagnosis remains focused on focal obstructive causes. CFC comprehensively documents flow impairment in IHD, regardless of its origin, by interpreting CFR in relation to maximal flow (hyperemic average peak flow velocity [hAPV]), and overcomes the limitations of using CFR alone. This is governed by the understanding that ischemia occurs in vascular beds with substantially reduced hAPV and CFR, whereas ischemia is unlikely when hAPV or CFR is high., Methods: Intracoronary pressure and flow were measured in 299 vessels (228 patients), where revascularization was deferred in 154. Vessels were stratified as having normal, mildly reduced, moderately reduced, or severely reduced CFC using CFR thresholds derived from published data and corresponding hAPV percentiles. The occurrence of MACE after deferral of revascularization was recorded during 11.9 years of follow-up (quartile 1: 10.0 years, quartile 3: 13.4 years)., Results: Combining CFR and hAPV improved the prediction of MACE over CFR alone (p = 0.01). After stratification in CFC, MACE rates throughout follow-up were strongly associated with advancing impairment of CFC (p = 0.002). After multivariate adjustment, mildly and moderately reduced CFC were associated with a 2.1-fold (95% confidence interval: 1.1 to 4.0; p = 0.017), and 7.1-fold (95% confidence interval: 2.9 to 17.1; p < 0.001) increase in MACE hazard, respectively, compared with normal CFC. Severely reduced CFC was identified by FFR ≤0.80 in 90% of cases, although ≥40% of vessels with normal or mildly reduced CFC still had an FFR ≤0.80., Conclusions: CFC provides a cross-modality platform for the diagnosis and risk-stratification of IHD and enriches the interpretation of contemporary diagnostic tests in IHD., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to understand the physiological basis of baseline distal-to-aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR) agreement and discordance, using coronary flow reserve (CFR), stenosis resistance, and microcirculatory resistance measurements, and form there, to investigate the potential value of combining Pd/Pa with FFR in the diagnostic rationale., Background: Pd/Pa is always available before FFR assessment, and emerging data supports the notion that baseline indices can determine the ischemic potential of coronary stenosis in selected subsets., Methods: A total of 467 stenosed vessels from 363 patients were investigated with pressure and flow sensors during baseline and hyperemia: 168 vessels (135 patients) with thermodilution-derived flow, and 299 vessels (228 patients) with Doppler-derived flow., Results: Pd/Pa correlated more strongly with CFR than FFR (ρ difference = 0.129; p for ρ comparison <0.001). Although Pd/Pa and FFR were closely correlated (ρ = 0.798; 95% confidence interval: 0.767 to 0.828), categorical discordance was observed in 19.3% of total vessels. Such discordance was associated with the patients' clinical profile and was characterized by contrastive changes in stenosis resistance, microcirculatory resistance, and the underlying CFR. Notably, all stenosis with Pd/Pa ≤0.83 (n = 74, 15.8%) progressed to FFR ≤0.80, and although no Pd/Pa cutoff was able to exclude the development of FFR ≤0.80 in the high end of values, only 15 (10.1%) vessels with Pd/Pa ≥0.96 (n = 149, 31.9%) developed FFR ≤0.80, from which none had definite ischemia, as defined by CFR ≤1.74., Conclusions: Combining baseline Pd/Pa with FFR seems to provide a more comprehensive physiological examination of stenosed coronary arteries and a closer pressure-based appraisal of the flow reserve of the downstream myocardial bed., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Percutaneous coronary intervention (PCI) aims to increase coronary blood flow by relieving epicardial obstruction. However, no study has objectively confirmed this and assessed changes in flow over different phases of the cardiac cycle. We quantified the change in resting and hyperemic flow velocity after PCI in stenoses defined physiologically by fractional flow reserve and other parameters., Methods and Results: Seventy-five stenoses (67 patients) underwent paired flow velocity assessment before and after PCI. Flow velocity was measured over the whole cardiac cycle and the wave-free period. Mean fractional flow reserve was 0.68±0.02. Pre-PCI, hyperemic flow velocity is diminished in stenoses classed as physiologically significant compared with those classed nonsignificant (P<0.001). In significant stenoses, flow velocity over the resting wave-free period and hyperemic flow velocity did not differ statistically. After PCI, resting flow velocity over the wave-free period increased little (5.6±1.6 cm/s) and significantly less than hyperemic flow velocity (21.2±3 cm/s; P<0.01). The greatest increase in hyperemic flow velocity was observed when treating stenoses below physiological cut points; treating stenoses with fractional flow reserve ≤0.80 gained Δ28.5±3.8 cm/s, whereas those fractional flow reserve >0.80 had a significantly smaller gain (Δ4.6±2.3 cm/s; P<0.001). The change in pressure-only physiological indices demonstrated a curvilinear relationship to the change in hyperemic flow velocity but was flat for resting flow velocity., Conclusions: Pre-PCI physiology is strongly associated with post-PCI increase in hyperemic coronary flow velocity. Hyperemic flow velocity increases 6-fold more when stenoses classed as physiologically significant undergo PCI than when nonsignificant stenoses are treated. Resting flow velocity measured over the wave-free period changes at least 4-fold less than hyperemic flow velocity after PCI., (© 2015 American Heart Association, Inc.)

Background: Coronary flow reserve has extensive validation as a prognostic marker in coronary disease. Although pressure-only fractional flow reserve (FFR) improves outcomes compared with angiography when guiding percutaneous coronary intervention, it disagrees with coronary flow reserve classification 30% of the time. We evaluated whether baseline instantaneous wave-free ratio (iFR) could provide an improved pressure-only estimation of underlying coronary flow reserve., Methods and Results: Invasive pressure and flow velocity were measured in 216 stenoses from 186 patients with coronary disease. The diagnostic relationship between pressure-only indices (iFR and FFR) and coronary flow velocity reserve (CFVR) was compared using correlation coefficient and the area under the receiver operating characteristic curve. iFR showed a stronger correlation with underlying CFVR (iFR-CFVR, ρ=0.68 versus FFR-CFVR, ρ=0.50; P<0.001). iFR also agreed more closely with CFVR in stenosis classification (iFR area under the receiver operating characteristic curve, 0.82 versus FFR area under the receiver operating characteristic curve, 0.72; P<0.001, for a CFVR of 2). The closer relationship between iFR and CFVR was found for different CFVR cutoffs and was particularly marked in the 0.6 to 0.9 FFR range. Hyperemic FFR flow was similar to baseline iFR flow in functionally significant lesions (FFR ≤0.75; mean FFR flow, 25.8±13.7 cm/s versus mean iFR flow, 21.5±11.7 cm/s; P=0.13). FFR flow was higher than iFR flow in nonsignificant stenoses (FFR >0.75; mean FFR flow, 42.3±22.8 cm/s versus mean iFR flow, 26.1±15.5 cm/s; P<0.001)., Conclusions: When compared with FFR, iFR shows stronger correlation and better agreement with CFVR. These results provide physiological evidence that iFR could potentially be used as a functional index of disease severity, independently from its agreement with FFR., (© 2014 American Heart Association, Inc.)

Myocardial tissue perfusion remains compromised in 30-40% of patients with ST-segment elevation myocardial infarction (STEMI) despite restored epicardial patency after primary percutaneous coronary intervention (pPCI). This phenomenon is attributed to microvascular dysfunction secondary to numerous pathophysiological mechanisms, including distal embolisation of plaque and thrombus material. Its association with larger post-infarction myocardial necrosis, impaired left ventricular recovery, and worse clinical outcome illustrates the pertinence of a comprehensive armamentarium for the diagnosis, protection and treatment of microvascular dysfunction in STEMI patients. Current strategies to protect the microvasculature during pPCI are based on the assumption that distal embolisation of thrombotic and atheromatous debris is the main mechanism precipitating impaired myocardial tissue perfusion. However, recent findings suggest that this assumption is only true for the border zone of the ischaemic myocardium, whereas the infarct core consists of intramyocardial haemorrhage secondary to microvascular destruction, rather than obstruction. This observation has pertinent implications for contemporary and future adjuvant treatment strategies in STEMI patients. In this review, we provide an overview of the currently available armamentarium to assess the microvasculature, review contemporary strategies in pPCI to protect the myocardium, and discuss novel insights into microvascular pathophysiology that may help guide our focus from the coronary arteries to the microvasculature.

Background: Fractional flow reserve (FFR) aims to identify the extent of epicardial disease, but may be obscured by involvement of the coronary microvasculature. We documented the impact of hyperaemic stenosis resistance (HSR) and hyperaemic microvascular resistance (HMR) on FFR, and its relationship with myocardial ischaemia in patients with stable coronary artery disease., Methods and Results: We evaluated 255 coronary arteries with stenoses of intermediate severity by means of intracoronary pressure and flow measurements to determine FFR, HSR and HMR. Myocardial perfusion scintigraphy (MPS) was performed to identify inducible myocardial ischaemia. In 178 patients, HMR was additionally determined in a reference coronary artery. Target vessel HMR was stratified according to reference vessel HMR tertiles. The diagnostic OR for inducible ischaemia on MPS of a positive compared with a negative FFR was significantly higher only in the presence of a high HMR (at the 0.75 and 0.80 FFR cut-off). Among stenoses with a positive FFR, the prevalence of ischaemia was significantly higher when HMR was high despite equivalent FFR across the HMR groups. This was paralleled by a concomitant significant increase in HSR with increasing HMR across groups. The relation between FFR and HSR (r(2)=0.54, p<0.001) was modulated by the magnitude of HMR, and improved substantially after adjustment for HMR (adjusted-r(2)=0.73, p<0.001), where, for epicardial disease of equivalent severity, FFR increased with increasing HMR., Conclusions: Identification of epicardial disease severity by FFR is partly obscured by the microvascular resistance, which illustrates the necessity of combined pressure and flow measurements in daily practice., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Discordance between fractional flow reserve (FFR) and coronary flow velocity reserve (CFVR) may reflect important coronary pathophysiology but usually remains unnoticed in clinical practice. We evaluated the physiological basis and clinical outcome associated with FFR/CFVR discordance., Methods and Results: We studied 157 intermediate coronary stenoses in 157 patients, evaluated by FFR and CFVR between April 1997 and September 2006 in which revascularization was deferred. Long-term follow-up was performed to document the occurrence of major adverse cardiac events: cardiac death, myocardial infarction, or target vessel revascularization. Discordance between FFR and CFVR occurred in 31% and 37% of stenoses at the 0.75, and 0.80 FFR cut-off value, respectively, and was characterized by microvascular resistances during basal and hyperemic conditions. Follow-up duration amounted to 11.7 years (Q1-Q3, 9.9-13.3 years). Compared with concordant normal results of FFR and CFVR, a normal FFR with an abnormal CFVR was associated with significantly increased major adverse cardiac events rate throughout 10 years of follow-up, regardless of the FFR cut-off applied. In contrast, an abnormal FFR with a normal CFVR was associated with equivalent clinical outcome compared with concordant normal results: ≤ 3 years when FFR <0.75 was depicted abnormal and throughout 10 years of follow-up when FFR ≤ 0.80 was depicted abnormal., Conclusions: Discordance of CFVR with FFR originates from the involvement of the coronary microvasculature. Importantly, the risk for major adverse cardiac events associated with FFR/CFVR discordance is mainly attributable to stenoses where CFVR is abnormal. This emphasizes the requirement of intracoronary flow assessment in addition to coronary pressure for optimal risk stratification in stable coronary artery disease., (© 2014 American Heart Association, Inc.)

Opinion Statement: Fractional flow reserve (FFR)-guided coronary revascularization is associated with an unequivocal clinical benefit compared with angiographic guidance. However, the well-documented clinical merit of FFR-guided revascularization has resulted in several misunderstandings as to its diagnostic characteristics. Moreover, it has led to the use of FFR as a gold-standard reference test for the identification of stenosis-related inducible myocardial ischemia. Frequently overlooked is the fact that FFR was originally validated against noninvasive stress-testing to document its ability to identify ischemia-generating stenoses, as well as its optimal cut-off value to do so, which illustrates the paradox of using FFR as a gold-standard reference for this purpose. The diagnostic characteristics of FFR are more complex than is widely understood, and its conceptual validity is based on multiple assumptions that are not considered in clinical practice. In contrast, the validity of FFR as a clinical tool is based on empirical evidence derived from multiple large-scale randomized controlled trials. It is, therefore, of great importance to understand the fundamental physiological basis of FFR, and to be aware of the underlying assumptions and their implications, for appropriate application and interpretation of FFR on an individual basis. This review aims to elucidate the assumptions that underlie the concept of FFR, to provide insight into their consequences for daily practice, and to highlight the practical methodology that is critical for its interpretation in clinical practice.