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Background: Absolute hyperaemic coronary blood flow (Q, in mL/min) and resistance (R, in Wood units [WU]) can be measured invasively by continuous thermodilution. Aims: The aim of this study was to assess normal reference values of Q and R. Methods: In 177 arteries (69 patients: 25 controls, i.e., without identifiable coronary atherosclerosis; 44 patients with mild, non-obstructive atherosclerosis), thermodilution-derived hyperaemic Q and total, epicardial, and microvascular absolute resistances (R tot, R epi, and R micro) were measured. In 20 controls and 29 patients, measurements were obtained in all three major coronary arteries, thus allowing calculations of Q and R for the whole heart. In 15 controls (41 vessels) and 25 patients (71 vessels), vessel-specific myocardial mass was derived from coronary computed tomography angiography. Results: Whole heart hyperaemic Q tended to be higher in controls compared to patients (668±185 vs 582±138 mL/min, p=0.068). In the left anterior descending coronary artery (LAD), hyperaemic Q was significantly higher (293±102 mL/min versus 228±71 mL/min, p=0.004) in controls than in patients. This was driven mainly by a difference in R epi (43±23 vs 83±41 WU, p=0.048), without significant differences in R micro. After adjustment for vessel-specific myocardial mass, hyperaemic Q was similar in the three vascular territories (5.9±1.9, 4.9±1.7, and 5.3±2.1 mL/min/g, p=0.44, in the LAD, left circumflex and right coronary artery, respectively). Conclusions: The present report provides reference values of absolute coronary hyperaemic Q and R. Q was homogeneously distributed in the three major myocardial territories but the large ranges of observed hyperaemic values of flow and of microvascular resistance preclude their clinical use for inter-patient comparison.

BACKGROUND: It is already known that high coronary microvascular resistance (Rμ) is linked to altered left ventricular stiffness and might be an early indicator of heart failure with preserved ejection fraction (HFpEF). Left atrial dysfunction, on the other hand, varies according to the grade of left ventricular diastolic dysfunction. This is the first study to use the latest development for invasive assessment of Rμ and to combine it with echocardiographic assessment of left atrial strain during reservoir phase (LASr) by speckle tracking in relation to left ventricular (LV) diastolic function.METHODS AND RESULTS: An invasive angiogram was performed in 97 patients because of suspected ANOCA. All patients underwent comprehensive echocardiography, yet image quality was poor in 15 patients leaving 82 patients to include in the final analysis. In order to compare Rμ with LASr values, patients were divided into 4 groups based upon normal values of Rμ as defined by Fournier et al. The mean LASr was plotted against the four resistance groups. The LASr was 48.6% in the lowest resistance group, and 40.1%, 36.3% and 30.1% in the low intermediate, high intermediate and high resistance group respectively. These differences were significant compared to the lowest resistance group (p < 0.05). Although higher Rμ groups showed more diastolic dysfunction, LASr was already decreased irrespective of the severity of diastolic dysfunction.CONCLUSION: This study shows a relationship between increased Rμ and reduced LASr, that seems to precede conventional measures of left ventricular diastolic dysfunction. This suggests that microvascular dysfunction might be an early indicator for the development of impaired LA function.

Background: It would be ideal for a non-hyperaemic index to predict fractional flow reserve (FFR) more accurately, given FFR's extensive validation in a multitude of clinical settings. Aims: The aim of this study was to derive a novel non-hyperaemic algorithm based on deep learning and to validate it in an internal validation cohort against FFR. Methods: The ARTIST study is a post hoc analysis of three previously published studies. In a derivation cohort (random 80% sample of the total cohort) a deep neural network was trained (deep learning) with paired examples of resting coronary pressure curves and their FFR values. The resulting algorithm was validated against unseen resting pressure curves from a random 20% sample of the total cohort. The primary endpoint was diagnostic accuracy of the deep learning-derived algorithms against binary FFR ≤0.8. To reduce the variance in the precision, we used a fivefold cross-validation procedure. Results: A total of 1,666 patients with 1,718 coronary lesions and 2,928 coronary pressure tracings were included. The diagnostic accuracy of our convolutional neural network (CNN) and recurrent neural networks (RNN) against binary FFR ≤0.80 was 79.6±1.9% and 77.6±2.3%, respectively. There was no statistically significant difference between the accuracy of our neural networks to predict binary FFR and the most accurate non-hyperaemic pressure ratio (NHPR). Conclusions: Compared to standard derivation of resting pressure ratios, we did not find a significant improvement in FFR prediction when resting data are analysed using artificial intelligence approaches. Our findings strongly suggest that a larger class of hidden information within resting pressure traces is not the main cause of the known disagreement between resting indices and FFR. Therefore, if clinicians want to use FFR for clinical decision making, hyperaemia induction should remain the standard practice.

¿QUÉ SE SABE DE LA RESERVA FRACCIONAL DE FLUJO TRAS UN IMPLANTE DE STENT? La presentación del concepto de reserva fraccional de flujo (RFF) a mediados de la década de 1990 trasladó la fisiología coronaria de la ciencia experimental al uso rutinario en la sala de hemodinámica1-3. Además de contribuir a comprender mejor mecanismos fisiológicos básicos tales como la autorregulación, la vasodilatación compensatoria y la reserva del flujo coronario presentados 20 años antes por Gould et al.4, no cabe duda de que la RFF ha cambiado nuestra interpretación de los angiogramas coronarios y ha tenido una enorme influencia tanto en el proceso de toma de decisiones como en los resultados de los pacientes3,5,6. Esto ha llevado a adoptar la RFF como único índice fisiológico con una indicación de uso clase I A en las ...

WHAT DO WE KNOW ABOUT FRACTIONAL FLOW RESERVE AFTER STENTING? The introduction of the concept of fractional flow reserve (FFR) in the mid 90s moved coronary physiology from experimental science to routine use at the cath lab.1-3 Added to the better understanding of basic physiological mechanisms such as self-regulation and compensatory vasodilation and the coronary flow reserve introduced 20 years earlier by Gould et al.,4 FFR has undeniably changed our interpretation of coronary angiograms and had a major influence on the clinical decision-making process, and patient outcomes.3,5,6 This has resulted in the unique adoption of FFR as the only physiological index with a class I A indication for use in the clinical practice guidelines produced by the most important cardiologic societies worldwide.7,8 FFR has taught us that coronary angiography and the anatomic images we can acquire at the cath lab only...

ObjectiveThe prognostic importance of a coronary stenosis depends on its functional severity and its depending myocardial mass. Functional severity can be assessed by fractional flow reserve (FFR), estimated non-invasively by a specific validated CT algorithm (FFRCT). Calculation of myocardial mass at risk by that same set of CT data (CTmass), however, has not been prospectively validated so far. The aim of the present study was to compare relative territorial-based CTmass assessment with relative flow distribution, which is closely linked to true myocardial mass.MethodsIn this exploratory study, 35 patients with (near) normal coronary arteries underwent CT scanning for computed flow-based CTmass assessment and underwent invasive myocardial perfusion measurement in all 3 major coronary arteries by continuous thermodilution. Next, the mass and flows were calculated as relative percentages of total mass and perfusion.ResultsThe mean difference between CTmass per territory and invasively measured myocardial perfusion, both expressed as percentage of total mass and perfusion, was 5.3±6.2% for the left anterior descending territory, −2.0±7.4% for the left circumflex territory and −3.2±3.4% for the right coronary artery territory. The intraclass correlation between the two techniques was 0.90.ConclusionsOur study shows a close relationship between the relative mass of the perfusion territory calculated by the specific CT algorithm and invasively measured myocardial perfusion. As such, these data support the use of CTmass to estimate territorial myocardium-at-risk in proximal coronary arteries.

Objectives: This study aimed to prospectively investigate intra-aortic balloon pump counterpulsation (IABP) support in large myocardial infarction complicated by persistent ischemia after primary percutaneous coronary intervention (PCI). Background: Use of IABP is suggested to be effective by increasing diastolic aortic pressure, thereby improving coronary blood flow. This can only be expected with exhausted coronary autoregulation, typical in acute myocardial infarction complicated by persistent ischemia. In this situation, augmented diastolic pressure is expected to increase myocardial oxygenation. Methods: One hundred patients with large STEMI complicated by persistent ischemia after primary PCI were randomized to treatment with or without IABP therapy on top of standard care. IABP support was initiated following primary PCI, immediately after inclusion. Primary end point was all-cause mortality, need for (additional) mechanical hemodynamic support, or readmission for heart failure within 6 months. Results: Mean age was 63 ± 10 years, 76% were male. Mean systolic and diastolic blood pressure were 120 ± 25 mmHg and 73 ± 17 mmHg. Mean heart rate was 75 ± 18 mmHg. Before PCI, mean summed ST-deviation was 21 ± 8 mm with only minimal ST-resolution after PCI. One patient in the IABP group reached the primary end point versus four patients in the control group (2% vs. 8%; p = 0.16). After primary PCI, resolution of ST-deviation was significantly more pronounced in the IABP group (73 ± 17%) compared to the control group (56 ± 26%; p < 0.01). Conclusions: In this pilot study, in patients with large STEMI and persistent ischemia after primary PCI, use of IABP showed a nonsignificant decrease in mortality, necessity for (additional) mechanical hemodynamic support or readmission for heart failure at 6 months, and resulted in more rapid ST-resolution.

BACKGROUND: Patients with three-vessel coronary artery disease have been found to have better outcomes with coronary-artery bypass grafting (CABG) than with percutaneous coronary intervention (PCI), but studies in which PCI is guided by measurement of fractional flow reserve (FFR) have been lacking.METHODS: In this multicenter, international, noninferiority trial, patients with three-vessel coronary artery disease were randomly assigned to undergo CABG or FFR-guided PCI with current-generation zotarolimus-eluting stents. The primary end point was the occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization. Noninferiority of FFR-guided PCI to CABG was prespecified as an upper boundary of less than 1.65 for the 95% confidence interval of the hazard ratio. Secondary end points included a composite of death, myocardial infarction, or stroke; safety was also assessed.RESULTS: A total of 1500 patients underwent randomization at 48 centers. Patients assigned to undergo PCI received a mean (±SD) of 3.7±1.9 stents, and those assigned to undergo CABG received 3.4±1.0 distal anastomoses. The 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG (hazard ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.2), findings that were not consistent with noninferiority of FFR-guided PCI (P = 0.35 for noninferiority). The incidence of death, myocardial infarction, or stroke was 7.3% in the FFR-guided PCI group and 5.2% in the CABG group (hazard ratio, 1.4; 95% CI, 0.9 to 2.1). The incidences of major bleeding, arrhythmia, and acute kidney injury were higher in the CABG group than in the FFR-guided PCI group.CONCLUSIONS: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year. (Funded by Medtronic and Abbott Vascular; FAME 3 ClinicalTrials.gov number, NCT02100722.).

In ST-elevation myocardial infarction (STEMI), early restoration of blood flow, preferably by primary percutaneous coronary intervention (PPCI), is paramount to limit infarct size (IS) and improve long-term outcomes 1. However, reperfusion by itself may also cause damage to the myocardium and increase IS. This has been termed myocardial reperfusion injury 2. In animal models of acute myocardial infarction, it has been demonstrated that hypothermia decreases IS 3. In contrast, human studies applying systemic cooling methods have not yet been able to confirm this protective effect. Recently, we developed a new method to provide selective intracoronary hypothermia during PPCI 4. The EUROpean Intracoronary Cooling Evaluation in patients with ST-elevation myocardial infarction (EURO-ICE) trial will assess the efficacy of this method. Methods STUDY OBJECTIVES The primary objective of the EURO-ICE trial is to evaluate the effect of selective intracoronary hypothermia (SIH) on IS.

Aims Pressure loss versus transvalvular flow analysis challenges physiologic models of current aortic valve stenosis. New conceptual frameworks are needed to explain these real-world observations. Methods and results A patient-specific, 3D-printed, silicon model of a stenotic valve was placed inside an in-vitro haemodynamic model of the circulatory system. Instantaneous pressure and flow in the aorta and left ventricle were simulated according to measured patient specific parameters. Thereafter, a realistic transcatheter aortic valve was implanted (TAVI) in the model. Simulated post-TAVI mean pressure gradients resembled patient observations (3.7 ± 0.7 mmHg vs 6.7 ± 2.3 mmHg), but pre-TAVI measurements underestimated the pressure gradient (35.1 ± 0.6 mmHg vs 45.3 ± 1.5 mmHg). Conclusion Patient-specific 3D-printed stenotic aortic valve models could simulate baseline haemodynamics. A TAVI procedure was successfully performed on the 3D silicone rubber valve in a physiologic in-vitro model. Pre-TAVI haemodynamics in the model underestimated in-patient mean pressure gradient, whereas post TAVI pressure gradient was predicted correctly with the TAVI valve inside the 3D printed model. This study shows that these types of models could be used to study AS hemodynamics with the TAVI valve inside the 3D printed model. Improvements in the 3D-printed model, like addition of calcification and fine-tuning of the haemodynamic model, could further enhance accuracy of the simulation.

Importance Whether the improvement in myocardial perfusion provided by percutaneous coronary intervention (PCI) is associated with symptomatic relief or improved outcomes has not been well investigated. Objective To investigate the prognostic value of the improvement in fractional flow reserve (FFR) after PCI (ΔFFR) on patients’ symptoms and 2-year outcomes. Design, Setting, and Participants This study is a post hoc analysis of data from patients undergoing FFR-guided PCI in the randomized clinical trials Fractional Flow Reserve vs Angiography for Multivessel Evaluation (FAME) 1 (NCT00267774; 2009) and FAME 2 (NCT01132495; 2012), with inclusion of 2 years of follow-up data. The FAME 1 trial included patients with multivessel coronary artery disease from 20 medical centers in Europe and the United States. The FAME 2 trial included patients with stable coronary artery disease involving up to 3 vessels from 28 sites in Europe and North America. Lesions from the group in the FAME 1 trial from whom FFR was measured and the group in the FAME 2 trial who received FFR-guided PCI plus medical therapy were analyzed. Data analysis occurred from May 2017 to May 2018. Interventions Measure of post-PCI FFR. Main Outcomes and Measures Vessel-oriented clinical events at 2 years, a composite of cardiac death, target vessel-associated myocardial infarction, and target vessel revascularization. Results This analysis included 639 patients from whom pre-PCI and post-PCI FFR values were available. Of their 837 lesions, 277 were classified into the lowest tertile (ΔFFR≤0.18), 282 into the middle tertile (0.19≤ΔFFR≤0.31), and 278 into the highest tertile (ΔFFR>0.31). Vessel-oriented clinical events were significantly more frequent in the lowest tertile (n = 25 of 277 [9.1%]) compared with the highest tertile (n = 13 of 278 [4.7%]; hazard ratio, 2.01 [95% CI, 1.03-3.92]; P = .04). In addition, a significant association was observed between ΔFFR and symptomatic relief (odds ratio, 1.33 [95% CI, 1.02-1.74]; P = .02). Conclusions and Relevance In this analysis of 2 randomized clinical trials, the larger the improvement in FFR, the larger the symptomatic relief and the lower the event rate. This suggests that measuring FFR before and after PCI provides clinically useful information.

Primary percutaneous coronary intervention (PPCI) has dramatically changed the outcome of patients with ST-elevation myocardial infarction (STEMI). However, despite improvements in interventional technology, registry data show little recent change in the prognosis of patients who survive STEMI, with a significant incidence of cardiogenic shock, heart failure, and cardiac death. Despite a technically successful PPCI procedure, a variable proportion of patients experience suboptimal myocardial reperfusion. Large infarct size and coronary microvascular injury, as the consequence of ischaemia–reperfusion injury and distal embolization of atherothrombotic debris, account for suboptimal long-term prognosis of STEMI patients. In order to address this unmet therapeutic need, a broad-range of device-based treatments has been developed. These device-based therapies can be categorized according to the pathophysiological pathways they target: (i) techniques to prevent distal atherothrombotic embolization, (ii) techniques to prevent or mitigate ischaemia/reperfusion injury, and (iii) techniques to enhance coronary microvascular function/integrity. This review is an overview of these novel technologies with a focus on their pathophysiological background, procedural details, available evidence, and with a critical perspective about their potential future implementation in the clinical care of STEMI patients.

Background Global fractional flow reserve (FFR) (ie, the sum of the FFR values in the 3 major coronary arteries) is a physiologic correlate of global atherosclerotic burden. The objective of the present study was to investigate the value of global FFR in predicting long‐term clinical outcome of patients with stable coronary artery disease but no ischemia‐inducing stenosis. Methods and Results We studied major adverse cardiovascular events (MACEs: all‐cause death, myocardial infarction, and any revascularization) after 5 years in 1122 patients without significant stenosis (all FFR >0.80; n=275) or with at least 1 significant stenosis successfully treated by percutaneous coronary intervention (ie, post–percutaneous coronary intervention FFR >0.80; n=847). The patients were stratified into low, mid, or high tertiles of global FFR (≤2.80, 2.80–2.88, and ≥2.88). Patients in the lowest tertile of global FFR showed the highest 5‐year MACE rate compared with those in the mid or high tertile of global FFR (27.5% versus 22.0% and 20.9%, respectively; log‐rank P =0.040). The higher 5‐year MACE rate was mainly driven by a higher rate of revascularization in the low global FFR group (16.4% versus 11.3% and 11.8%, respectively; log‐rank P =0.038). In a multivariable model, an increase in global FFR of 0.1 unit was associated with a significant reduction in the rates of MACE (hazard ratio [HR], 0.988; 95% CI, 0.977–0.998; P =0.023), myocardial infarction (HR, 0.982; 95% CI, 0.966–0.998; P =0.032), and revascularization (HR, 0.985; 95% CI, 0.972–0.999; P =0.040). Conclusions Even in the absence of ischemia‐producing stenoses, patients with a low global FFR, physiologic correlate of global atherosclerotic burden, present a higher risk of MACE at 5‐year follow‐up.

Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Na&iuml, ve Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome.

Highlights • Transcatheter aortic valve implantation (TAVI) outcome is comparable to surgery. • How TAVI patients fare compared to the general population is not fully understood. • Relative survival was used to compare TAVI patients to the Dutch population. • Survival after TAVI is for patients >80 years similar to the general population. • Quality of life is comparable to that of the general population after TAVI., Background Little is known about survival and quality of life (QoL) of patients treated by transcatheter aortic valve implantation (TAVI) compared to the age- and sex-matched general population. In this study we compared subgroups of the National Heart Registration TAVI cohort to the Dutch age- and sex-matched population at the level of survival and QoL. Methods and results From the Netherlands Heart Registration (NHR) the TAVI cohort (5489 patients, period 2013–2017) was extracted. These data were compared to the national Dutch population data collected from the national statistics office, Statistics Netherlands (CBS). Subgroups were defined according to sex and age (80). For QoL analyses the age subgroups 75 were used. Long term survival was significantly higher in the general population compared to the TAVI population. Elderly TAVI patients (>80 years) had the same survival as the age-matched general population (46vs43% at 5 years, respectively). Survival in women was better than in men in both the general population and the TAVI cohort. Patients treated by TAVI, aged 65 years and older had a comparable QoL to that of the general population. Conclusions This study shows that TAVI patients aged 80 years and older have a similar long-term survival as an age-matched general population. However, because of lower survival in under 80 TAVI patients, the overall long term survival of all TAVI patients is worse than that of the general population in the Netherlands. This study also suggests that QoL after TAVI treatment is comparable to QoL in the general population.

How did a percutaneous coronary intervention/coronary artery bypass grafting randomised trial generate the anatomic syntax score?

Background This study aimed to investigate longitudinal physiological changes in the recanalized coronary chronic total occlusion (CTO) vessel and its dependent myocardium after successful percutaneous coronary intervention ( PCI ). Methods and Results In this pilot study, 25 patients scheduled for elective CTO PCI with viable myocardium and angiographically visible collaterals were included. Absolute coronary blood flow and absolute microvascular resistance were measured invasively using continuous thermodilution. Measurements were performed immediately after successful CTO PCI and at short‐term follow‐up. In a subgroup of patients, physiological measurements were performed at the predominant donor vessel before CTO PCI , immediately afterwards, and at follow‐up. Absolute coronary blood flow in the recanalized CTO artery increased from 148±53 mL /min immediately after PCI to 221±77 mL /min at follow‐up ( P CTO artery, decreased from 545±255 Wood units immediately after the procedure to 387±128 Wood units at follow‐up ( P =0.014). There were no significant changes in the absolute coronary blood flow and resistance in the predominant donor between baseline and follow‐up. Positive remodeling of the distal CTO vessel with an increase in lumen diameter was observed. Conclusions After successful CTO PCI , blood flow in the recanalized artery and microvascular function of the dependent myocardium are not immediately normal but recover over time.

AIMS: Randomised controlled trials have reported instantaneous wave-free ratio (iFR) to be non-inferior to fractional flow reserve (FFR) for major adverse cardiovascular events at one year; however, iFR is limited by sensitive landmarking of the pressure waveform, and the assumption that maximal flow and minimal resistance occur during a fixed period of diastole. We sought to validate the resting full-cycle ratio (RFR), a novel non-hyperaemic index of coronary stenosis severity based on unbiased identification of the lowest distal coronary pressure to aortic pressure ratio (Pd/Pa), independent of the ECG, landmark identification, and timing within the cardiac cycle.METHODS AND RESULTS: VALIDATE-RFR was a retrospective study designed to derive and validate the RFR. The primary endpoint was the agreement between RFR and iFR. RFR was retrospectively determined in 651 waveforms in which iFR was measured using a proprietary Philips/Volcano wire. RFR was highly correlated to iFR (R2=0.99, pCONCLUSIONS: RFR is diagnostically equivalent to iFR but unbiased in its ability to detect the lowest Pd/Pa during the full cardiac cycle, potentially unmasking physiologically significant coronary stenoses that would be missed by assessment dedicated to specific segments of the cardiac cycle.

Background: Among patients with documented stable coronary artery disease and in whom no revascularization was performed, we compared the respective values of angiographic diameter stenosis (DS) and fractional flow reserve (FFR) in predicting natural history. Methods: The present analysis included the 607 patients from the FAME 2 trial (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2) in whom no revascularization was performed. FFR varied from 0.20 to 1.00 (average 0.74±0.16), and DS (by quantitative coronary analysis) varied from 8% to 98% (average 53±15). The primary end point, defined as vessel-oriented clinical end point (VOCE) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent, and not urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: positive concordance (FFR≤0.80; DS≥50%), negative concordance (FFR>0.80; DS0.80; DS≥50%). Results: The rate of VOCE was highest in the positive concordance group (log rank: X 2 =80.96; P =0.001) and lowest in the negative concordance group. The rate of VOCE was higher in the positive mismatch group than in the negative mismatch group (hazard ratio, 0.38; 95% confidence interval, 0.21–0.67; P =0.001). There was no significant difference in VOCE between the positive concordance and positive mismatch groups (FFR≤0.80; hazard ratio, 0.77; 95% confidence interval, 0.57–1.09; P =0.149) and no significant difference in rate of VOCE between the negative mismatch and negative concordance groups (FFR>0.80; hazard ratio, 1.89; 95% confidence interval, 0.96–3.74; P =0.067). Conclusions: In patients with stable coronary disease, physiology (FFR) is a more important determinant of the natural history of coronary stenoses than anatomy (DS). Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT01132495.

In recent years, novel ultrasound functional imaging (UFI) techniques have been introduced to assess cardiac function by measuring, e.g. cardiac output (CO) and/or myocardial strain. Verification and reproducibility assessment in a realistic setting remain major issues. Simulations and phantoms are often unrealistic, whereas in vivo measurements often lack crucial hemodynamic parameters or ground truth data, or suffer from the large physiological and clinical variation between patients when attempting clinical validation. Controlled validation in certain pathologies is cumbersome and often requires the use of lab animals.In this study, an isolated beating pig heart setup was adapted and used for performance assessment of UFI techniques such as volume assessment and ultrasound strain imaging. The potential of performing verification and reproducibility studies was demonstrated. For proof-of-principle, validation of UFI in pathological hearts was examined.Ex vivo porcine hearts (n = 6, slaughterhouse waste) were resuscitated and attached to a mock circulatory system. Radio frequency ultrasound data of the left ventricle were acquired in five short axis views and one long axis view. Based on these slices, the CO was measured, where verification was performed using flow sensor measurements in the aorta. Strain imaging was performed providing radial, circumferential and longitudinal strain to assess reproducibility and inter-subject variability under steady conditions. Finally, strains in healthy hearts were compared to a heart with an implanted left ventricular assist device, simulating a failing, supported heart.Good agreement between ultrasound and flow sensor based CO measurements was found. Strains were highly reproducible (intraclass correlation coefficients >0.8). Differences were found due to biological variation and condition of the hearts. Strain magnitude and patterns in the assisted heart were available for different pump action, revealing large changes compared to the normal condition. The setup provides a valuable benchmarking platform for UFI techniques. Future studies will include work on different pathologies and other means of measurement verification.

Aims Fractional flow reserve (FFR) has proven to its prognostic and therapeutic value. However, the additive prognostic value of coronary flow reserve (CFR) remains unclear. This study sought to investigate the clinical utility of combined FFR and CFR measurements to predict outcomes. Methods and results Using the prospective, multicentre Interventional Cardiology Research Incooperation Society–FFR registry, a total of 2088 lesions from 1837 patients were included in this substudy. Based on baseline and hyperaemic pressure gradients, we computed physiologic limits of CFR [the so called pressure-bounded (pb) CFR] and classified lesions as low (0.80 [adjusted hazard ratio (aHR): 2.15, 95% confidence interval (CI): 1.19–3.89; P = 0.011. In contrast, the incidence of MACE did not differ between patients with pb-CFR 0.99). Conclusions In this large, prospective registry of over 2000 coronary lesions, FFR was strongly associated with clinical outcomes. In contrast, a significant association between pb-CFR and clinical events could not be determined and adding knowledge of pb-CFR did not improve prognostication over FFR alone.

Objectives: The objective was to evaluate the safety, feasibility, and accuracy of the jailed-pressure wire technique using a durable optical fiber-based pressure wire with high-pressure dilatation using a non-compliant balloon after main vessel stenting. Background: Fractional flow reserve (FFR) information can help interventionists determine whether they should treat a jailed-side branch (SB). However, re-crossing a pressure wire into a jailed-SB is sometimes technically difficult. Methods: Fifty-one consecutive lesions from 48 patients who underwent the jailed-pressure wire technique were retrospectively investigated. The primary endpoint was complication rate and secondary endpoints included success rate of FFR measurement, incidence of wire disruption, and final drift rate. The usability of FFR for percutaneous coronary intervention of coronary bifurcation lesion was also evaluated. Results: Median age of the patients was 69 years and 80.4% were men. The most frequent underlying disease was stable angina (70.6%) and 68.6% were type B2 lesions. Our main findings were: the procedure was performed successfully in all cases without any complications or wire disruption, FFR could be measured without significant final drift in 95.9% of cases, and FFR measurements helped interventionists determine whether to perform a final kissing balloon dilatation in 49.0% cases. Conclusions: The jailed-pressure wire technique using a durable optical fiber-based pressure wire with high-pressure post-dilatation maneuver was safe, feasible, and accurate.

International variability in infarct size following acute anterior ST-elevation myocardial infarction without shock treated with primary percutaneous coronary intervention (PCI) has been little studied. Patients enrolled in the Counterpulsation to Reduce Infarct Size pre‐PCI for Acute Myocardial Infarction international randomized trial were analyzed according to their region of enrollment: United States (US) (n = 60), Europe/Australia (EU/AU) (n = 104), or India (n = 123). Cardiac magnetic resonance imaging was performed 3–5 days after PCI to assess infarct size, expressed as percentage of left ventricular mass, and analyzed by an imaging core laboratory. The relation between infarct size and region was modelled using multivariable linear regression adjusting for time from symptom onset to first hospital contact, myocardial infarction severity, and baseline characteristics. Infarct size was 36.4% of left ventricular mass in US patients (95% confidence interval [CI] 31.5 to 41.4), 36.5% (95% CI 32.6 to 40.4) in EU/AU patients, and 44.7% (95% CI 41.1 to 48.2) in patients from India (p = 0.01). In multiplicity-adjusted regression analysis, mean infarct size in patients from India was higher than in US patients (mean difference of 8.3%; 95% CI 0.7 to 15.8; p = 0.03), and EU/AU patients (mean difference of 8.2%; 95% CI 1.6 to 14.8; p = 0.01). There was no significance difference in infarct size between patients from the EU/AU and the US (mean difference of 0.1%; 95% CI −7.5 to 7.4; p = 0.99). ln conclusion, in patients with anterior ST-elevation myocardial infarction without cardiogenic shock treated with primary PCI, infarct size was larger in India compared to the United States and EU/AU, even after adjustment for performance metrics, including time to treatment, and other potential confounders. Future studies are needed to better elucidate this discrepancy.

Asymptomatic (“silent”) ischemia is considered a factor of poor prognosis, especially after myocardial infarction (MI) [(1)][1]. Yet, in patients with stable coronary disease, the prognostic value of asymptomatic ischemia and the effect of revascularization are less well established. In the

Aims Continuous thermodilution is a novel technique to quantify absolute coronary flow and microvascular resistance (MVR). Notably, intracoronary infusion of saline elicits maximal hyperaemia, obviating the need for adenosine. The primary aim of this study was to validate continuous thermodilution in humans by comparing invasive measurements to [15O]H2O positron emission tomography (PET). As a secondary goal, absolute flow and MVR were compared between invasive measurements obtained with and without adenosine. Methods and results Twenty-five patients underwent coronary computed tomography angiography (CCTA), [15O]H2O PET, and invasive assessment. Absolute coronary flow and MVR were measured in the left anterior descending and left circumflex artery using a dedicated infusion catheter and a temperature/pressure sensor-tipped guidewire. Invasive measurements were performed with and without adenosine. In order to compare invasive flow measurements with PET perfusion, subtending myocardial mass of the investigated vessels was derived from CCTA using the Voronoi algorithm. Invasive and non-invasive measurements of adenosine-induced hyperaemic flow and MVR showed strong correlation (r = 0.91; P Conclusions Continuous thermodilution is an accurate method to measure absolute coronary flow and MVR, which is evidenced by strong agreement with [15O]H2O PET derived flow and resistance. Absolute flow and MVR correlate highly between invasive measurements obtained with and without adenosine, which confirms that intracoronary infusion of room temperature saline elicits steady-state maximal hyperaemia.

OBJECTIVES: To identify clinical, angiographic and hemodynamic predictors of discordance between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR). BACKGROUND: The iFR was found to be non-inferior to the gold-standard FFR for guiding coronary revascularization, although it is discordant with FFR in 20% of cases. A better understanding of the causes of discordance may enhance application of these indices. METHODS: Both FFR and iFR were measured in the prospective multicenter CONTRAST study. Clinical, angiographic and hemodynamic variables were compared between patients with concordant values of FFR and iFR (cutoff \textless/=0.80 and \textless/=0.89, respectively). RESULTS: Out of the 587 patients included, in 466 patients (79.4%) FFR and iFR agreed: both negative, n = 244 (41.6%), or positive, n = 222 (37.8%). Compared with FFR, iFR was negative discordant (FFR+/iFR-) in 69 (11.8%) patients and positive discordant (FFR-/iFR+) in 52 (8.9%) patients. On multivariate regression, stenosis location (left main or proximal left anterior descending) (OR: 3.30[1.68;6.47]), more severe stenosis (OR: 1.77[1.35;2.30]), younger age (OR: 0.93[0.90;0.97]), and slower heart rate (OR: 0.59[0.42;0.75]) were predictors of a negative discordant iFR. Absence of a beta-blocker (OR: 0.41[0.22;0.78]), older age (OR: 1.04[1.00;1.07]), and less severe stenosis (OR: 0.69[0.53;0.89]) were predictors of a positive discordant iFR. CONCLUSIONS: During iFR acquisition, stenosis location, stenosis degree, heart rate, age and use of beta blockers influence concordance with FFR and should be taken into account when interpreting iFR.

Aim Variations in treatment are the result of differences in demographic and clinical factors (e.g. anatomy), but physician and hospital factors may also contribute to treatment variation. The choice of treatment is considered important since it could lead to differences in long-term outcomes. This study explores the associations with stent choice: i.e. drug-eluting stent (DES) versus bare-metal stents (BMS) for Dutch patients diagnosed with stable or unstable coronary artery disease (CAD). Methods & results Associations with treatment decisions were based on a prospective cohort of 692 patients with stable or unstable CAD. Of those patients, 442 patients were treated with BMS or DES. Multiple logistic regression analyses were performed to identify variables associated with stent choice. Bivariate analyses showed that NYHA class, number of diseased vessels, previous percutaneous coronary intervention, smoking, diabetes, and the treating hospital were associated with stent type. After correcting for other associations the treating hospital remained significantly associated with stent type in the stable CAD population. Conclusions This study showed that several factors were associated with stent choice. While patients generally appear to receive the most optimal stent given their clinical characteristics, stent choice seems partially determined by the treating hospital, which may lead to differences in longterm outcomes.

Aims: Echocardiography and tomographic imaging have documented dynamic changes in aortic stenosis (AS) geometry and severity during both the cardiac cycle and stress-induced increases in cardiac output. However, corresponding pressure gradient vs. flow relationships have not been described. Methods and results: We recruited 16 routine transcatheter aortic valve implantations (TAVI's) for graded dobutamine infusions both before and after implantation; 0.014″ pressure wires in the aorta and left ventricle (LV) continuously measured the transvalvular pressure gradient (ΔP) while a pulmonary artery catheter regularly assessed cardiac output by thermodilution. Before TAVI, ΔP did not display a consistent relationship with transvalvular flow (Q). Neither linear resistor (median R2 0.16) nor quadratic orifice (median R2

Background— The principle of continuous thermodilution can be used to calculate absolute coronary blood flow and microvascular resistance (R). The aim of the study is to explore the safety, feasibility, and reproducibility of coronary blood flow and R measurements as measured by continuous thermodilution in humans. Methods and Results— Absolute coronary flow and R can be calculated by thermodilution by infusing saline at room temperature through a dedicated monorail catheter. The temperature of saline as it enters the vessel, the temperature of blood and saline mixed in the distal part of the vessel, and the distal coronary pressure were measured by a pressure/temperature sensor-tipped guidewire. The feasibility and safety of the method were tested in 135 patients who were referred for coronary angiography. No significant adverse events were observed; in 11 (8.1%) patients, bradycardia and concomitant atrioventricular block appeared transiently and were reversed immediately on interruption of the infusion. The reproducibility of measurements was tested in a subgroup of 80 patients (129 arteries). Duplicate measurements had a strong correlation both for coronary blood flow (ρ=0.841, P P P P Conclusions— Absolute coronary blood flow (in L/min) and R (in mm Hg/L/min or Wood units) can be safely and reproducibly measured with continuous thermodilution. This approach constitutes a new opportunity for the study of the coronary microcirculation.

Background: Whether the benefit in quality of life (QOL) after percutaneous coronary intervention depends on the severity of the stenosis as determined by fractional flow reserve (FFR) remains unknown. This study sought to investigate the relationship between FFR values and improvement in QOL. Methods: From the FAME 1 and 2 trials (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), we identified 706 stable patients with coronary artery disease who had at least 1 lesion with an FFR≤0.80 that was treated with percutaneous coronary intervention and 185 patients with coronary artery disease who had no lesion with an FFR≤0.80 and were treated medically who served as a reference group. QOL was assessed by the European Quality of Life–5 Dimensions index at baseline, 1 month, and 1 year. We assessed the relationship between QOL improvement (defined as the change in European Quality of Life–5 Dimensions index from baseline) and FFR as a continuous value and according to abnormal FFR tertile. Results: QOL improved significantly after percutaneous coronary intervention in each abnormal FFR tertile, whereas it did not change in the reference group. The lowest abnormal FFR subgroup had the greatest improvement in QOL at 1 month ( P P =0.002 for 1 month and 0.049 for 1 year), greater delta FFR ( P =0.021 for 1 month and 0.025 for 1 year), and higher angina class ( P =0.001 for 1 month and Conclusions: Among patients with stable coronary artery disease, FFR and angina severity predict QOL improvement after percutaneous coronary intervention. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00267774 and NCT01132495.

Background Guidelines recommend coronary artery bypass graft (CABG) surgery over percutaneous coronary intervention (PCI) for the treatment of 3-vessel coronary artery disease (3-VD). The inferior results of PCI demonstrated by previous large randomized trials comparing PCI and CABG might be explained by the use of suboptimal stent technology and by the lack of fractional flow reserve (FFR) guidance of PCI. Trial design The objective of this investigator-initiated, multicenter, randomized clinical trial is to investigate whether FFR-guided PCI with new-generation stents is noninferior to CABG in patients with 3-VD, not including the left main coronary artery. Eligible patients must have ≥50% coronary stenoses in all 3 major epicardial vessels or major side branches. Patients with a nondominant right coronary artery may be included only if the left anterior descending artery and left circumflex have ≥50% stenoses. Consecutive patients who meet all of the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 fashion to either CABG or FFR-guided PCI. Coronary artery bypass graft will be performed based on the angiogram as per clinical routine. Patients assigned to FFR-guided PCI will have FFR measured in each diseased vessel and only undergo stenting if the FFR is ≤0.80. The primary end point of the study is a composite of major adverse cardiac and cerebrovascular events, including death, myocardial infarction, repeat coronary revascularization, and stroke at 1 year. Key secondary end point will be a composite of death, myocardial infarction, and stroke at 3-year follow-up. Other secondary end points include the individual adverse events, cost-effectiveness, and quality of life at 2-year, 3-year, with up to 5-year follow-up. Conclusion The FAME 3 study will compare in a multicenter, randomized fashion FFR-guided PCI with contemporary drug-eluting stents to CABG in patients with 3-VD.

Objectives\ud \ud This study classified and quantified the variation in fractional flow reserve (FFR) due to fluctuations in systemic and coronary hemodynamics during intravenous adenosine infusion.\ud \ud Background\ud \ud Although FFR has become a key invasive tool to guide treatment, questions remain regarding its repeatability and stability during intravenous adenosine infusion because of systemic effects that can alter driving pressure and heart rate.\ud \ud Methods\ud \ud We reanalyzed data from the VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice) study, which enrolled consecutive patients who were infused with intravenous adenosine at 140 μg/kg/min and measured FFR twice. Raw phasic pressure tracings from the aorta (Pa) and distal coronary artery (Pd) were transformed into moving averages of Pd/Pa. Visual analysis grouped Pd/Pa curves into patterns of similar response. Quantitative analysis of the Pd/Pa curves identified the “smart minimum” FFR using a novel algorithm, which was compared with human core laboratory analysis.\ud \ud Results\ud \ud A total of 190 complete pairs came from 206 patients after exclusions. Visual analysis revealed 3 Pd/Pa patterns: “classic” (sigmoid) in 57%, “humped” (sigmoid with superimposed bumps of varying height) in 39%, and “unusual” (no pattern) in 4%. The Pd/Pa pattern repeated itself in 67% of patient pairs. Despite variability of Pd/Pa during the hyperemic period, the “smart minimum” FFR demonstrated excellent repeatability (bias −0.001, SD 0.018, paired p = 0.93, r2 = 98.2%, coefficient of variation = 2.5%). Our algorithm produced FFR values not significantly different from human core laboratory analysis (paired p = 0.43 vs. VERIFY; p = 0.34 vs. RESOLVE).\ud \ud Conclusions\ud \ud Intravenous adenosine produced 3 general patterns of Pd/Pa response, with associated variability in aortic and coronary pressure and heart rate during the hyperemic period. Nevertheless, FFR – when chosen appropriately – proved to be a highly reproducible value. Therefore, operators can confidently select the “smart minimum” FFR for patient care. Our results suggest that this selection process can be automated, yet comparable to human core laboratory analysis.

Background: Recently, 2 randomized controlled trials showed that the instantaneous wave-free ratio (iFR), a resting coronary physiological index, is noninferior to fractional flow reserve for guiding revascularization. The resting distal to aortic coronary pressure (Pd/Pa) measured at rest is another adenosine-free index widely available in the cardiac catheterization laboratory; however, little is known about the agreement of Pd/Pa using iFR as a reference standard. Objectives: The goal of this study was to investigate the agreement of Pd/Pa with iFR. Methods: A total of 763 patients were prospectively enrolled from 12 institutions. iFR and Pd/Pa were measured under resting conditions. Using iFR ≤0.89 as a reference standard, the agreement of Pd/Pa and its best cutoff value were assessed. Results: According to the independent core laboratory analysis, iFR and Pd/Pa were analyzable in 627 and 733 patients (82.2% vs. 96.1%; p < 0.001), respectively. The median iFR and Pd/Pa were 0.90 (interquartile range: 0.85 to 0.94) and 0.92 (interquartile range: 0.88 to 0.95), and the 2 indices were highly correlated (R2 = 0.93; p < 0.001; iFR = 1.31 * Pd/Pa –0.31). According to the receiver-operating characteristic curve analysis, Pd/Pa showed excellent agreement (area under the curve: 0.98; 95% confidence interval: 0.97 to 0.99; p < 0.001) with a best cutoff value of Pd/Pa ≤0.91. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 93.0%, 91.4%, 94.4%, 93.3%, and 92.7%, respectively. These results were similar in patients with acute coronary syndrome and stable angina. Conclusions: Pd/Pa was analyzable in a significantly higher number of patients than iFR. Pd/Pa showed excellent agreement with iFR, suggesting that it could be applied clinically in a similar fashion. (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology? [CONTRAST]; NCT02184117)

We thank Dr Uretsky et al for suggesting to check for potential differences in baseline characteristics and—more importantly—in outcome between patients with and patients without post-percutaneous coronary intervention fractional flow reserve (post-PCI FFR) measurements.1 It is indeed likely that procedural characteristics, not captured by the case record form, may have influenced the operator to decide to perform or not to perform the final FFR measurements. Checking for these differences in outcome might increase the generalizability of the conclusions. We will therefore perform this analysis in …

Background— The predictive value of fractional flow reserve (FFR) measured immediately after percutaneous coronary intervention (PCI) with drug-eluting stent placement has not been prospectively investigated. We investigated the potential of post-PCI FFR measurements to predict clinical outcome in patients from FAME 1 and 2 trials (Fractional Flow Reserve or Angiography for Multivessel Evaluation). Methods and Results— All patients of FAME 1 and FAME 2 who had post-PCI FFR measurement were included. The primary outcome was vessel-oriented composite end point at 2 years, defined as vessel-related cardiovascular death, vessel-related spontaneous myocardial infarction, and ischemia-driven target vessel revascularization. Eight hundred thirty-eight vessels in 639 patients were analyzed. Baseline FFR values did not differ between vessels with versus without vessel-oriented composite end point (0.66±0.11 versus 0.63±0.14, respectively; P =0.207). Post-PCI FFR was significantly lower in vessels with vessel-oriented composite end point (0.88±0.06 versus 0.90±0.06, respectively; P =0.019). Comparing the 2-year outcome of lower and upper tertiles of post-PCI FFR significant difference was found favoring upper tertile in terms of overall vessel-oriented composite end point (9.2% versus 3.8%, respectively; hazard ratio, 1.46; 95% confidence interval, 1.02–2.08; P =0.037) and target vessel revascularization (7.0% versus 2.4%, respectively; hazard ratio, 1.59; 95% confidence interval, 1.03–2.46; P =0.037). When adjusted to sex, hypertension, diabetes mellitus, target vessel, serial stenosis, and baseline percentage diameter stenosis, a strong trend was preserved in terms of target vessel revascularization (harzard ratio, 1.55; 95% confidence interval, 0.97–2.46; P =0.066), favoring the upper tertile. Post-PCI FFR of 0.92 was found to have the highest diagnostic accuracy; however, the positive likelihood ratio remained low ( Conclusions— A higher post-PCI FFR value is associated with a better vessel-related outcome. However, its predictive value is too low to advocate its use as a surrogate clinical end point.

Background— During thermodilution-based assessment of volumetric coronary blood flow, we observed that intracoronary infusion of saline increased coronary flow. This study aims to quantify the extent and unravel the mechanisms of saline-induced hyperemia. Methods and Results— Thirty-three patients were studied; in 24 patients, intracoronary Doppler flow velocity measurements were performed at rest, after intracoronary adenosine, and during increasing infusion rates of saline at room temperature through a dedicated catheter with 4 lateral side holes. In 9 patients, global longitudinal strain and flow propagation velocity were assessed by transthoracic echocardiography during a prolonged intracoronary saline infusion. Taking adenosine-induced maximal hyperemia as reference, intracoronary infusion of saline at rates of 5, 10, 15, and 20 mL/min induced 6%, 46%, 111%, and 112% of maximal hyperemia, respectively. There was a close agreement of maximal saline- and adenosine-induced coronary flow reserve (intraclass correlation coefficient, 0.922; P P =0.021). Conclusions— Intracoronary infusion of saline at room temperature through a dedicated catheter for coronary thermodilution induces steady-state maximal hyperemia at a flow rate ≥15 mL/min. These findings open new possibilities to measure maximal absolute coronary blood flow and minimal microcirculatory resistance.

BackgroundWe need new biomarkers that can predict cardiovascular disease to improve both diagnosis and therapeutic strategies. The CIRCULATING CELLS study was designed to study the role of several cellular mediators of atherosclerosis as biomarkers of coronary artery disease (CAD). An objective and reproducible method for the quantification of CAD extension is required to establish relationships with these potential biomarkers. We sought to analyse the correlation of the SYNTAX score with known CAD risk factors to test it as a valid marker of CAD extension.Methods and resultsA subgroup of 279 patients (67.4% males) were included in our analysis. Main exclusion criteria were a history of previous percutaneous coronary intervention or surgical revascularisation that prevent an accurate assessment of the SS. Diabetes mellitus, smoking, renal insufficiency, body mass index and a history of CAD and myocardial infarction were all positively and strongly associated with a higher SYNTAX score after adjustment for the non-modifiable biological factors (age and sex). In the multivariate model, age and male sex, along with smoking and renal insufficiency, remain statistical significantly associated with the SYNTAX score.ConclusionIn a selected cohort of revascularisation-naive patients with CAD undergoing coronary angiography, non-modifiable cardiovascular risk factors such as advanced age, male sex, as well as smoking and renal failure were independently associated with CAD complexity assessed by the SYNTAX score. The SYNTAX score may be a valid marker of CAD extension to establish relationships with potential novel biomarkers of coronary atherosclerosis.Keywords: Coronary artery disease, Coronary angiography, Risk assessment, Risk factors

Background Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcomes compared with an angiography-guided strategy in patients with multivessel coronary artery disease (CAD). However, the effect of age on FFR has not been well-studied. We aimed to evaluate the impact of age on the favorable results of routine FFR-guided PCI for multivessel CAD.Methods We compared 1 year outcomes between FFR-guided PCI and angiography-guided PCI in the 512 patients enrolled in the FAME study < 65 years old compared to the 493 patients ≥ 65 years old. We also evaluated the effect of age on the FFR result of varying degrees of visually estimated coronary stenosis.Results The 1-year rate of death, myocardial infarction or repeat revascularization in the angiography-guided group tended to be higher than in the FFR-guided group for both those patients < 65 (17.2% vs. 12.0%, P = 0.098) and those ≥ 65 years old (19.7% vs. 14.3%, P = 0.111) with no significant interaction based on age (P = 0.920). Older patients had higher FFR in vessels with 50% to 70% stenosis (0.83 ± 0.11 vs. 0.80 ± 0.13, P = 0.028) and in vessels with 71% to 90% stenosis (0.69 ± 0.15 vs. 0.65 ± 0.16, P = 0.002). The proportion of functionally significant lesions (FFR ≤ 0.80) in vessels with 71% to 90% stenosis was significantly lower in elderly compared to younger patients (75.3% vs. 84.1%, P = 0.013).Conclusions FFR-guided PCI is beneficial regardless of age, however, older patients have fewer functionally significant lesions, despite a similar angiographic appearance.

Purpose: The international multicentre FAME Study (n=1,005) demonstrated significant health benefits for patients undergoing multivessel percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) measurement compared with angiography guidance alone (ANGIO). We determined the cost-effectiveness and the public health/budget impact for Australia. Methods: We performed a prospective economic evaluation comparing FFR vs. ANGIO in patients with multivessel disease based on original patient-level FAME data. We used Australian utilities (EQ-5D) and costs to calculate quality-adjusted life years (QALYs) and incremental cost-effectiveness adopting the societal perspective. The public health and budget impact from the payer's perspective was based on Australian PCI registries. Uncertainty was explored using deterministic sensitivity analyses and the bootstrap method (n=5,000 samples). Results: The cost-effectiveness analysis showed that FFR was cost-saving and reduces costs by 1,776 AUD per patient during one year. Over a two-year time horizon, the public health impact ranged from 7.8 to 73.9 QALYs gained and the budget impact from 1.8 to 14.5 million AUD total cost savings. Sensitivity analyses demonstrated that FFR was cost-saving over a wide range of assumptions. Conclusions: FFR-guided PCI in patients with multivessel coronary disease substantially reduces cardiac events, improves QALYs and is cost-saving in the Australian health care system.

Currently, there is little doubt that interpretation of coronary artery disease and decision making with respect to revascularization based on visualassessmentoftheangiogramisafundamentally flawedapproach. The importance of additional functional testing to assess the hemodynamic severity of a coronary stenosis is undisputable. Over the decades, a number of physiologic indices have emerged to assess the functional significance of coronary artery disease. Of these, fractional flow reserve (FFR) is most commonly used. There is incontrovertible proof now that stenting of ischemic stenoses as indicated by a FFR ≤0.80 generally improvesoutcome, whereasstentingofnon-ischemicstenosisasindicated by a FFR N0.80 offers nobenefit compared to medical treatment and can mostly be avoided [1–6]. To assess the true strength or quality of anything in the world around us—whether in science, engineering, or biology—testing under conditionsof stress is mandatory. In analogy,therefore, the windtunnel for physiologic testing of coronary arteries is maximum hyperemia. Accurate assessment of FFR can be done only during maximum hyperemic conditions. An interesting analysis of a rather new hyperemic drug, regadenoson, is published in the current issue of Cardiovascular Revascularization Medicine (CRM) [7].

Biomarkers for primary or secondary risk prediction of cardiovascular disease (CVD) are urgently needed to improve individual treatment and clinical trial design. The vast majority of biomarker discovery studies has concentrated on plasma/serum as an easily accessible source. Although numerous markers have been identified, their added predictive value on top of traditional risk factors has been limited, as the biological specimen does not specifically reflect expression profiles related with CVD progression and because the signal is often diluted by marker release from other organs. In contrast to serum markers, circulating cells serve as indicators of the actual disease state due to their active role in the pathogenesis of CVD and are responsible for the majority of secreted biomarkers. Therefore, the CIRCULATING CELLS study was initiated, focusing on the cellular effectors of atherosclerosis in the circulation. In total, 714 patients with coronary artery disease (CAD) symptoms were included. Blood cell fractions (monocytes, T-lymphocytes, platelets, granulocytes, PBMC) of all individual patients were isolated and stored for analysis. Concomitantly, extensive flow cytometric characterization of these populations was performed. From each patient, a detailed clinical profile together with extensive questionnaires about medical history and life style was obtained. Various high-throughput -omics approaches (protein, mRNA, miRNA) are currently being undertaken. Data will be integrated with advanced bioinformatics for discovery and validation of secondary risk markers for adverse events. Overall, the CIRCULATING CELLS study grants the interesting possibility that it will both identify novel biomarkers and provide useful insights into the pathophysiology of CAD in patients.

Background— Several studies have shown that fractional flow reserve (FFR) measurement can aid in the assessment of left main coronary stenosis. However, the impact of downstream epicardial stenosis on left main FFR assessment with the pressure wire in the nonstenosed downstream vessel remains unknown. Methods and Results— Variable stenoses were created in the left main coronary arteries and downstream epicardial vessels in 6 anaesthetized male sheep using balloon catheters. A total of 220 pairs of FFR assessments of the left main stenosis were obtained, before and after creation of a stenosis in a downstream epicardial vessel, by having a pressure-sensor wire in the other nonstenosed downstream vessel. The apparent left main FFR in the presence of downstream stenosis (FFR app ) was significantly higher compared with the true FFR in the absence of downstream stenosis (FFR true ; 0.80±0.05 versus 0.76±0.05; estimate of the mean difference, 0.035; P true and FFR app correlated with composite FFR of the left main plus stenosed artery ( r =−0.31; P app >0.80, 9% were associated with an FFR true of Conclusions— A clinically relevant effect on the FFR assessment of left main disease with the pressure wire in a nonstenosed downstream vessel occurs only when the stenosis in the other vessel is proximal and very severe.

Stent boost (SB) imaging is an enhancement of the radiologic edge of the stent by digital management of regular X-ray images. The purpose of the present study was to validate SB imaging by comparison with the anatomical standard using intravascular ultrasound (IVUS). We investigated SB and IVUS after stent implantation in 68 arteries in 60 patients. Based on those findings, we added high-pressure dilatation in four patients and another stent implantation in four patients. We defined the SB criteria for adequate stent deployment as: complete stent expansion, stent minimum diameter ≥70% of reference diameter, and stent minimum diameter ≥2.0 mm; and IVUS criteria for adequate stent deployment as: minimal stent area ≥5.0 mm2. If the reference vessel was 2. IVUS findings indicated inadequate stent deployment in 21/72 observations (29%). Seven SB images showed inadequate stent expansion. SB predicted inadequate findings of IVUS with 100% specificity, 33% sensitivity, and 81% agreement. Although the sensitivity of SB image for adequate stent deployment is low, the specificity is sufficiently high for it to be the first-line for monitoring just after stent implantation in centers where IVUS is not used routinely.

Objectives This work compares the diagnostic performance of adenosine-free coronary pressure wire indices based on lesion location. Background Several adenosine-free coronary pressure wire indices have been proposed to assess the functional significance of coronary artery lesions; however, there is a theoretical concern that lesion location and the mass of perfused myocardium may affect diagnostic performance. Methods A total of 763 patients were prospectively enrolled from 12 institutions. Fractional flow reserve (FFR) and contrast-based FFR (cFFR) were obtained during adenosine-induced maximal hyperemia and contrast-induced submaximal hyperemia respectively, whereas the instantaneous wave-free ratio (iFR) and distal pressure/aortic pressure (Pd/Pa) were obtained at rest. Using an FFR of ≤0.80 as a reference standard, the diagnostic accuracy of each index was compared based on lesion location (left main or proximal left anterior descending artery [LM/pLAD] compared with other lesion locations). Results The median FFR, cFFR, iFR, and Pd/Pa were 0.81 (interquartile range [IQR]: 0.74 to 0.87), 0.86 (IQR: 0.79 to 0.91), 0.90 (IQR: 0.85 to 0.94), and 0.92 (IQR: 0.88 to 0.95), respectively. The cFFR, iFR, and Pd/Pa were less accurate in LM/pLAD compared with other lesion locations (cFFR: 80.3% vs. 87.8%; iFR: 73.3% vs. 81.8%; Pd/Pa: 71.4% vs. 81.1%, respectively). By receiver-operating characteristics curve analysis, cFFR provided better diagnostic accuracy than resting indices regardless of lesion location (p ≤0.0001 vs. iFR and Pd/Pa for both groups). Conclusions The cFFR, iFR, and Pd/Pa are less accurate in LM/pLAD compared with other lesion locations, likely related to the larger amount of myocardium supplied by LM/pLAD. Nevertheless, cFFR provides the best diagnostic accuracy among the adenosine-free indices, regardless of lesion location.