Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort study.

BACKGROUND: Coronary computed tomography angiography (CCTA) is the first line investigation for chest pain, and it is used to guide revascularisation. However, the widespread adoption of CCTA has revealed a large group of individuals without obstructive coronary artery disease (CAD), with unclear prognosis and management. Measurement of coronary inflammation from CCTA using the perivascular fat attenuation index (FAI) Score could enable cardiovascular risk prediction and guide the management of individuals without obstructive CAD. The Oxford Risk Factors And Non-invasive imaging (ORFAN) study aimed to evaluate the risk profile and event rates among patients undergoing CCTA as part of routine clinical care in the UK National Health Service (NHS); to test the hypothesis that coronary arterial inflammation drives cardiac mortality or major adverse cardiac events (MACE) in patients with or without CAD; and to externally validate the performance of the previously trained artificial intelligence (AI)-Risk prognostic algorithm and the related AI-Risk classification system in a UK population. METHODS: This multicentre, longitudinal cohort study included 40 091 consecutive patients undergoing clinically indicated CCTA in eight UK hospitals, who were followed up for MACE (ie, myocardial infarction, new onset heart failure, or cardiac death) for a median of 2·7 years (IQR 1·4-5·3). The prognostic value of FAI Score in the presence and absence of obstructive CAD was evaluated in 3393 consecutive patients from the two hospitals with the longest follow-up (7·7 years [6·4-9·1]). An AI-enhanced cardiac risk prediction algorithm, which integrates FAI Score, coronary plaque metrics, and clinical risk factors, was then evaluated in this population. FINDINGS: In the 2·7 year median follow-up period, patients without obstructive CAD (32 533 [81·1%] of 40 091) accounted for 2857 (66·3%) of the 4307 total MACE and 1118 (63·7%) of the 1754 total cardiac deaths in the whole of Cohort A. Increased FAI Score in all the three coronary arteries had an additive impact on the risk for cardiac mortality (hazard ratio [HR] 29·8 [95% CI 13·9-63·9], p<0·001) or MACE (12·6 [8·5-18·6], p<0·001) comparing three vessels with an FAI Score in the top versus bottom quartile for each artery. FAI Score in any coronary artery predicted cardiac mortality and MACE independently from cardiovascular risk factors and the presence or extent of CAD. The AI-Risk classification was positively associated with cardiac mortality (6·75 [5·17-8·82], p<0·001, for very high risk vs low or medium risk) and MACE (4·68 [3·93-5·57], p<0·001 for very high risk vs low or medium risk). Finally, the AI-Risk model was well calibrated against true events. INTERPRETATION: The FAI Score captures inflammatory risk beyond the current clinical risk stratification and CCTA interpretation, particularly among patients without obstructive CAD. The AI-Risk integrates this information in a prognostic algorithm, which could be used as an alternative to traditional risk factor-based risk calculators. FUNDING: British Heart Foundation, NHS-AI award, Innovate UK, National Institute for Health and Care Research, and the Oxford Biomedical Research Centre.

Arrhythmia and Death Following Percutaneous Revascularization in Ischemic Left Ventricular Dysfunction: Prespecified Analyses From the REVIVED-BCIS2 Trial.

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82-1.30]; P=0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01920048.

Intra-arterial Fractional Flow Reserve Measurements Provide an Objective Assessment of the Functional Significance of Peripheral Arterial Stenoses.

OBJECTIVE: Peripheral arterial stenoses (PAS) are commonly investigated with duplex ultrasound (DUS) and angiography, but these are not functional tests. Fractional flow reserve (FFR), a pressure based index, functionally assesses the ischaemic potential of coronary stenoses, but its utility in PAS is unknown. FFR in the peripheral vasculature in patients with limb ischaemia was investigated. METHODS: Patients scheduled for angioplasty and or stenting of isolated iliac and superficial femoral artery stenoses were recruited. Resting trans-lesional pressure gradient (Pd/Pa) and FFR were measured after adenosine provoked hyperaemia using an intra-arterial 0.014 inch flow and pressure sensing wire (ComboWire XT, Philips). Prior to revascularisation, exercise ABPI (eABPI) and DUS derived peak systolic velocity ratio (PSVR) of the index lesion were determined. Calf muscle oxygenation was measured using blood oxygenation level dependent cardiovascular magnetic resonance prior to and after revascularisation. RESULTS: Forty-one patients (32, 78%, male, mean age 65 ± 11 years) with 61 stenoses (iliac 32; femoral 29) were studied. For lesions < 80% stenosis, resting Pd/Pa was not influenced by the degree of stenosis (p = .074); however, FFR was discriminatory, decreasing as the severity of stenosis increased (p = .019). An FFR of < 0.60 was associated with critical limb threatening ischaemia (area under the curve [AUC] 0.87; 95% CI 0.75 - 0.95), in this study performing better than angiographic % stenosis (0.79; 0.63 - 0.89), eABPI (0.72; 0.57 - 0.83), and PSVR (0.65; 0.51 - 0.78). FFR correlated strongly with calf oxygenation (rho, 0.76; p < .001). A greater increase in FFR signalled resolution of symptoms and signs (ΔFFR 0.25 ± 0.15 vs. 0.13 ± 0.09; p = .009) and a post-angioplasty and stenting FFR of > 0.74 predicted successful revascularisation (combined sensitivity and specificity of 95%; AUC 0.98; 0.91 - 1.00). CONCLUSION: This pilot study demonstrates that FFR can objectively measure the functional significance of PAS that compares favourably with visual and DUS based assessments. Its role as a quality control adjunct that confirms optimal vessel patency after angioplasty and or stenting also merits further investigation.

Coronary Microvascular Dysfunction Is Associated With Myocardial Ischemia and Abnormal Coronary Perfusion During Exercise.

BACKGROUND: Coronary microvascular dysfunction (MVD) is defined by impaired flow augmentation in response to a pharmacological vasodilator in the presence of nonobstructive coronary artery disease. It is unknown whether diminished coronary vasodilator response correlates with abnormal exercise physiology or inducible myocardial ischemia. METHODS: Patients with angina and nonobstructive coronary artery disease had simultaneous coronary pressure and flow velocity measured using a dual sensor-tipped guidewire during rest, supine bicycle exercise, and adenosine-mediated hyperemia. Microvascular resistance (MR) was calculated as coronary pressure divided by flow velocity. Wave intensity analysis quantified the proportion of accelerating wave energy (perfusion efficiency). Global myocardial blood flow and subendocardial:subepicardial perfusion ratio were quantified using 3-Tesla cardiac magnetic resonance imaging during hyperemia and rest; inducible ischemia was defined as hyperemic subendocardial:subepicardial perfusion ratio <1.0. Patients were classified as having MVD if coronary flow reserve <2.5 and controls if coronary flow reserve ≥2.5, with researchers blinded to the classification. RESULTS: Eighty-five patients were enrolled (78% female, 57±10 years), 45 (53%) were classified as having MVD. Of the MVD group, 82% had inducible ischemia compared with 22% of controls (P<0.001); global myocardial perfusion reserve was 2.01±0.41 and 2.68±0.49 (P<0.001). In controls, coronary perfusion efficiency improved from rest to exercise and was unchanged during hyperemia (59±11% vs 65±14% vs 57±18%; P=0.02 and P=0.14). In contrast, perfusion efficiency decreased during both forms of stress in MVD (61±12 vs 44±10 vs 42±11%; both P<0.001). Among patients with a coronary flow reserve <2.5, 62% had functional MVD, with normal minimal MR (hyperemic MR<2.5 mmHg/cm/s), and 38% had structural MVD with elevated hyperemic MR. Resting MR was lower in those with functional MVD (4.2±1.0 mmHg/cm/s) than in those with structural MVD (6.9±1.7 mmHg/cm/s) or controls (7.3±2.2 mmHg/cm/s; both P<0.001). During exercise, the structural group had a higher systolic blood pressure (188±25 mmHg) than did those with functional MVD (161±27 mmHg; P=0.004) and controls (156±30 mmHg; P<0.001). Functional and structural MVD had similar stress myocardial perfusion and exercise perfusion efficiency values. CONCLUSION: In patients with angina and nonobstructive coronary artery disease, diminished coronary flow reserve characterizes a cohort with inducible ischemia and a maladaptive physiological response to exercise. We have identified 2 endotypes of MVD with distinctive systemic vascular responses to exercise; whether endotypes have a different prognosis or require different treatments merits further investigation.

Cardiac Resynchronization Therapy Online: What Patients Find when Searching the World Wide Web.

BACKGROUND: To objectively assess the quality of information available on the World Wide Web on cardiac resynchronization therapy (CRT). Patients frequently search the internet regarding their healthcare issues. It has been shown that patients seeking information can help or hinder their healthcare outcomes depending on the quality of information consulted. On the internet, this information can be produced and published by anyone, resulting in the risk of patients accessing inaccurate and misleading information. METHODS: The search term "Cardiac Resynchronisation Therapy" was entered into the three most popular search engines and the first 50 pages on each were pooled and analyzed, after excluding websites inappropriate for objective review. The "LIDA" instrument (a validated tool for assessing quality of healthcare information websites) was to generate scores on Accessibility, Reliability, and Usability. Readability was assessed using the Flesch Reading Ease Score (FRES). RESULTS: Of the 150 web-links, 41 sites met the eligibility criteria. The sites were assessed using the LIDA instrument and the FRES. A mean total LIDA score for all the websites assessed was 123.5 of a possible 165 (74.8%). The average Accessibility of the sites assessed was 50.1 of 60 (84.3%), on Usability 41.4 of 54 (76.6%), on Reliability 31.5 of 51 (61.7%), and 41.8 on FRES. There was a significant variability among sites and interestingly, there was no correlation between the sites' search engine ranking and their scores. CONCLUSION: This study has illustrated the variable quality of online material on the topic of CRT. Furthermore, there was also no apparent correlation between highly ranked, popular websites and their quality. Healthcare professionals should be encouraged to guide their patients toward the online material that contains reliable information.

Coronary artery disease and outcomes following transcatheter aortic valve implantation.

BACKGROUND: Aortic stenosis is a life-limiting condition for which transcatheter aortic valve implantation (TAVI) is an established therapy. Coronary artery disease (CAD) is frequently found in this patient group and optimal management in these patients remains uncertain. OBJECTIVES: We sought to examine the association of coexistent CAD on mortality and hospital readmission in patients undergoing TAVI. METHODS: In this observational cohort study, we examined patients who underwent TAVI and segregated them by the presence of obstructive epicardial CAD. The primary outcome was 3-year mortality with secondary outcomes being readmission for (1) all-causes, (2) a MACE (Major Adverse Cardiovascular Event) composite endpoint and (3) acute coronary syndrome. Subsidiary outcomes included patient angina and breathlessness scores. RESULTS: 898 patients underwent TAVI, of which 488 (54.3%) had unobstructed coronary arteries and 410 (45.7%) had obstructive CAD. Overall, n=298 (33.2%) patients experienced the primary mortality endpoint with no significant difference when stratified according to CAD (n=160 (32.9%) vs n=136 (33.2%), HR 0.98, CI 0.78 to 1.24). After multivariate analysis, the presence of CAD had no effect on the primary outcome (HR 0.98, CI 0.68 to 1.40). There was no significant difference in readmission for any cause (n=181, 37.1% (CAD) vs n=169, 41.2% (no CAD), p=0.23), including no significant difference on readmission for MACE (n=48, 9.8% (CAD) vs n=45, 11.0% (no CAD), p=0.11). CAD at the time of TAVI also did not alter breathlessness or angina scores before/after TAVI (p>0.05). CONCLUSION: Coexistent CAD had no significant association with mortality, any-cause readmission or symptoms for patients undergoing TAVI in our cohort.

Coronary angioplasty and the internet: what can patients searching online expect to find?

OBJECTIVES: This study set out to assess the quality of online information available on coronary angioplasty. BACKGROUND: Patients searching for healthcare information frequently use the Internet. However the lay reader may not be able to discern the robustness of evidence presented. At present, the overall quality and accuracy of online content regarding coronary angioplasty is unknown. METHODS: The search term "coronary angioplasty" was entered into three popular search engines (Google, Yahoo, and Bing), and the first 50 webpages provided by each search engine pooled. Exclusion criteria consisted of duplicated sites, sites requiring a registration or login, and direct links to documents or videos. The remaining sites were analyzed using the LIDA instrument; a validated method for assessing websites based on accessibility, usability, and readability. Readability was also separately assessed using the Flesch Reading Ease Score (FRES). RESULTS: Of 150 weblinks reviewed, 86 were excluded on the basis of the criteria listed above. The remaining 64 sites achieved mean scores of 50/60 (83%) on accessibility, 40/54 (74%) on usability, 32/51 (62%) on reliability, and 47.5 on FRES. Significant variability was noted among the LIDA scores, with no correlation between LIDA score and search engine ranking. CONCLUSIONS: Although most websites are easy to access, content is frequently out-of-date and fails to be presented in an easily comprehensible format. A minority of websites display factually incorrect information. Clinicians should be wary of patients being misled by erroneous or commercially biased online content, and be able to redirect their patients to more robust, up-to-date sources.

Coronary Jeopardy Score Predicts Ischemic Etiology in Patients With Left Ventricular Systolic Dysfunction.

While cardiovascular magnetic resonance imaging (CMR) is the gold standard diagnostic test for heart failure etiology, it is not universally available. Our aim was to investigate whether quantifying the extent of coronary disease on angiography can predict the presence of an ischemic etiology. We included 176 patients who underwent CMR and coronary angiography for new heart failure with reduced ejection fraction. Based on CMR, 65% had an ischemic etiology and 35% were non-ischemic. A BCIS jeopardy score threshold ≥6 had 76% sensitivity and 97% specificity. In HFrEF, the extent of coronary disease on angiography can be used to rule in or out an ischemic etiology.

How to select patients requiring coronary revascularisation using coronary physiology.

The coronary angiogram is an indicator of flow limiting coronary artery disease but coronary physiology at the time of angiography is vital in assessing the true functional significance of coronary artery disease. With advances in guidewire technology and the greater use of physiology within the catheter laboratory, there is now a slow evolution of physiological indices in being able to reliably assess the functional significance of individual lesions and also the adequacy of revascularization in a growing range of clinical scenarios. As co-registration of physiology with the angiogram and intravascular imaging will become easier, we will find ourselves increasingly in an era of 'Precision PCI'.

Clinical Utility of Novel Fractional Flow Reserve Pullback for Individual Lesion Contribution in Serial Disease.

OBJECTIVES: Fractional flow reserve (FFR) pullback is frequently used to assess serially diseased arteries, but has been shown to be inaccurate due to physiological interaction between individual lesions. We evaluated the clinical utility of a novel solution that improves estimation of true FFR contribution of each stenosis in the presence of serial disease. METHODS: Ten interventional cardiologists were presented with tiered information for 18 elective patients with serial coronary disease and submitted revascularization strategies and assessment of lesion significance. Operators were first shown clinical and angiographic information only (Angio); then, conventional practice FFR (FFRnorm); and finally, pullback with corrected FFR contributions of each stenosis (FFRpred). RESULTS: The treatment strategy agreement between operators was k=0.39, k=0.64, and k=0.77 using Angio, FFRnorm, and FFRpred, respectively (P<.001). Lesion significance uncertainty was 26%, 28%, and 3%, respectively. The number of stents per patient was 1.49 ± 0.57, 1.50 ± 0.57, and 1.3 ± 0.5, respectively (P<.001). In total, percutaneous coronary intervention (PCI) strategy changed in over 50% of cases analyzed, with participants opting for shorter stent length with FFRpred (29.5 ± 15.2 mm) compared with FFRnorm (34.1 ± 14.4 mm; P<.001) and Angio (34.6 ± 14.3; P=.04). This was accompanied by significantly less interobserver variability. CONCLUSION: The ability to quantify the contribution of individual lesions with the novel FFR pullback-based solution significantly increases operator confidence regarding PCI strategy, reduces heterogeneity in practice, and can reduce the planned number of stents and total stent length.

Comparison of fractional flow reserve, instantaneous wave-free ratio and a novel technique for assessing coronary arteries with serial lesions.

AIMS: Physiological indices such as fractional flow reserve (FFR), instantaneous wave-free ratio (iFR) and resting distal coronary to aortic pressure (Pd/Pa) are increasingly used to guide revascularisation. However, reliable assessment of individual stenoses in serial coronary disease remains an unmet need. This study aimed to compare conventional pressure-based indices, a reference Doppler-based resistance index (hyperaemic stenosis resistance [hSR]) and a recently described mathematical correction model to predict the contribution of individual stenoses in serial disease. METHODS AND RESULTS: Resting and hyperaemic pressure wire pullbacks were performed in 54 patients with serial disease. For each stenosis, FFR, iFR, and Pd/Pa were measured by the translesional gradient in each index and the predicted FFR (FFRpred) derived mathematically from hyperaemic pullback data. "True" stenosis significance by each index was assessed following PCI of the accompanying stenosis or measurements made in a large disease-free branch. In 27 patients, Doppler average peak flow velocity (APV) was also measured to calculate hSR (hSR=∆P/APV, where ∆P=translesional pressure gradient). FFR underestimated individual stenosis severity, inversely proportional to cumulative FFR (r=0.5, p<0.001). Mean errors for FFR, iFR and Pd/Pa were 33%, 20% and 24%, respectively, and 14% for FFRpred (p<0.001). Stenosis misclassification rates based on FFR 0.80, iFR 0.89 and Pd/Pa 0.91 thresholds were not significantly different (17%, 24% and 20%, respectively) but were higher than FFRpred (11%, p<0.001). Apparent and true hSR correlated strongly (r=0.87, p<0.001, mean error 0.19±0.3), with only 7% of stenoses misclassified. CONCLUSIONS: Individual stenosis severity is significantly underestimated in the presence of serial disease, using both hyperaemic and resting pressure-based indices. hSR is less prone to error but challenges in optimising Doppler signals limit clinical utility. A mathematical correction model, using data from hyperaemic pressure wire pullback, produces similar accuracy to hSR and is superior to conventional pressure-based indices.

Predicting the Physiological Effect of Revascularization in Serially Diseased Coronary Arteries.

BACKGROUND: Fractional flow reserve (FFR) is commonly used to assess the functional significance of coronary artery disease but is theoretically limited in evaluating individual stenoses in serially diseased vessels. We sought to characterize the accuracy of assessing individual stenoses in serial disease using invasive FFR pullback and the noninvasive equivalent, fractional flow reserve by computed tomography (FFRCT). We subsequently describe and test the accuracy of a novel noninvasive FFRCT-derived percutaneous coronary intervention (PCI) planning tool (FFRCT-P) in predicting the true significance of individual stenoses. METHODS AND RESULTS: Patients with angiographic serial coronary artery disease scheduled for PCI were enrolled and underwent prospective coronary CT angiography with conventional FFRCT-derived post hoc for each vessel and stenosis (FFRCT). Before PCI, the invasive hyperemic pressure-wire pullback was performed to derive the apparent FFR contribution of each stenosis (FFRpullback). The true FFR attributable to individual lesions (FFRtrue) was then measured following PCI of one of the lesions. The predictive accuracy of FFRpullback, FFRCT, and the novel technique (FFRCT-P) was then assessed against FFRtrue. From the 24 patients undergoing the protocol, 19 vessels had post hoc FFRCT and FFRCT-P calculation. When assessing the distal effect of all lesions, FFRCT correlated moderately well with invasive FFR ( R=0.71; P<0.001). For lesion-specific assessment, there was significant underestimation of FFRtrue using FFRpullback (mean discrepancy, 0.06±0.05; P<0.001, representing a 42% error) and conventional trans-lesional FFRCT (0.05±0.06; P<0.001, 37% error). Using FFRCT-P, stenosis underestimation was significantly reduced to a 7% error (0.01±0.05; P<0.001). CONCLUSIONS: FFR pullback and conventional FFRCT significantly underestimate true stenosis contribution in serial coronary artery disease. A novel noninvasive FFRCT-based PCI planner tool more accurately predicts the true FFR contribution of each stenosis in serial coronary artery disease.

Resting Coronary Flow Varies With Normal Cardiac Catheter Laboratory Stimuli.

BACKGROUND: Growing evidence supports physiology-guided revascularization, with Fractional Flow Reserve (FFR) the most commonly used invasive measure of coronary blood flow impairment at the time of diagnostic angiography. Recently, there has been growing interest in stenosis severity indices measured at rest, such as Instantaneous Wave Free Ratio (iFR) and the ratio of distal coronary to aortic pressure at rest (resting Pd/Pa). Their reliability may, theoretically, be more susceptible to changes in microvascular tone and coronary flow. This study aimed to assess variability of resting coronary flow with normal catheter laboratory stimuli. METHODS: Simultaneous intracoronary pressure (Pd) and Doppler Average Peak Flow Velocity (APV) recordings were made at rest and following the verbal warning preceding an intravenous adenosine infusion. RESULTS: 72 patients undergoing elective angiography were recruited (mean age 62 years, 52.7% male) with a wide range of coronary artery disease severity (FFR 0.86 ±â€¯0.09). Average peak flow velocity varied significantly between measurements at rest and just prior to commencement of adenosine, with a mean variation of 10.2% (17.82 ±â€¯9.41 cm/s vs. 19.63 ±â€¯10.44 cm/s, p < 0.001) with an accompanying significant drop in microvascular resistance (6.27 ±â€¯2.73 mm Hg·cm-1·s-1 vs. 5.8 ±â€¯2.92 mm Hg·cm-1·s-1, p < 0.001). These changes occurred without significant change in systemic hemodynamic measures. Whilst there was a trend for an associated change in the resting indices, Pd/Pa and iFR, this was statistically and clinically not significant (0.92 ±â€¯0.08 vs. 0.92 ±â€¯0.08, p = 0.110; and 0.90 ±â€¯0.11 vs. 0.89 ±â€¯0.12, p = 0.073). CONCLUSION: Resting coronary flow and microvascular resistance vary significantly with normal catheter laboratory stimuli, such as simple warnings. The clinical impact of these observed changes on indices of stenosis severity, particularly those measured at rest, needs further assessment within larger cohorts.

Physiology-Guided Management of Serial Coronary Artery Disease: A Review.

Importance: Ischemia-guided revascularization is the cornerstone of contemporary management of coronary artery disease and has evolved from noninvasive functional evaluation to real-time assessment with invasive physiological indices during diagnostic catheterization. However, serial/diffuse disease is common, and revascularization decisions often need to be made about individual lesions within the same vessel. It is unclear whether current physiological techniques, such as fractional flow reserve, can be reliably used to discern the individual contribution of lesions within a serially diseased vessel with erroneous measurements, potentially leading to suboptimal revascularization decisions. This review addresses the application of physiological techniques to serial coronary disease, highlighting challenges and potential solutions. Observations: Physiological indices, such as fractional flow reserve, are well validated and correlated with clinical outcomes; however, the challenging physiology of serial stenoses makes it difficult to apply conventional techniques to identify the physiological significance of individual lesions. The 2 methods are most accurate in assessing serial disease are the manual pullback, with treatment of the greatest pressure gradient, or adopting the use of a large disease-free side branch to isolate the significance of the proximal lesion in the context of serial disease involving the left main coronary artery. In addition, resting indices, such as instantaneous wave-free ratio, have theoretical benefits that may make them more reliable in serial disease, with further data awaited. Conclusions and Relevance: Serial coronary artery disease is common, and physiological assessment is prone to errors. The future, whether it be in improving the interpretation of fractional flow reserve, using resting indices such as instantaneous wave-free ratio, or examining novel flow-based resistance indices, will hopefully improve our management of this common yet unresolved clinical conundrum. In the meantime, revascularisation decisions in this challenging scenario should focus on clinical presentation and physiologic evaluation using a pressure-wire pullback maneuver and left main disease-free side branch where appropriate.

Is heart rate response a reliable marker of adenosine-induced coronary hyperemia?

Introduction Growing evidence supports ischemia-guided management of chest pain, with invasive and non-invasive tests reliant upon achieving adenosine-induced coronary hyperemia (defined as increased blood flow to an organ's perfusion bed). In the non-invasive setting, surrogate markers of hyperemia, such as increases in heart rate, are often used, despite not being formally validated. We tested whether heart rate and other non-invasive indices are reliable markers of coronary hyperemia. Methods The first part involved Doppler flow-based validation of the best pressure-wire markers of hyperemia in 53 patients. Subsequently, using these validated pressure-derived parameters, 265 pressure-wire traces were analysed to determine whether heart rate and other non-invasive parameters correlated with hyperemia. Results In the flow derivation cohort, the best determinant of hyperemia came from having 2 out of 3 of: (1) Ventriculisation of the distal pressure waveform, (2) disappearance of distal dicrotic pressure notch, (3) separation of mean aortic and distal pressures. Within the 244 patients demonstrating hyperemia, non-invasive markers of hyperemia, such as change in heart rate (p = 0.77), blood pressure (p = 0.60) and rate-pressure product (p = 0.86), were poor correlates of coronary hyperemia, with only 37.3% demonstrating a ≥ 10% increase in heart rate that is commonly used to adjudge adenosine-induced hyperemia in the non-invasive setting. Conclusions We demonstrate, by correlation with Doppler-flow data, a validated method of identifying coronary hyperemia within the catheter laboratory using the pressure-wire. We subsequently show that non-invasive parameters, such as heart rate change, are poor predictors of coronary hyperemia during stress imaging protocols that rely upon achieving adenosine-induced hyperemia.

Changes in contractility determine coronary haemodynamics in dyssynchronous left ventricular heart failure, not vice versa.

BACKGROUND: Biventricular pacing has been shown to increase both cardiac contractility and coronary flow acutely but the causal relationship is unclear. We hypothesised that changes in coronary flow are secondary to changes in cardiac contractility. We sought to examine this relationship by modulating coronary flow and cardiac contractility. METHODS: Contractility and lusitropy were altered by varying the location of pacing in 8 patients. Coronary autoregulation was transiently disabled with intracoronary adenosine. Simultaneous coronary flow velocity, coronary pressure and left ventricular pressure data were measured in the different pacing settings with and without hyperaemia and wave intensity analysis performed. RESULTS: Multisite pacing was effective at altering left ventricular contractility and lusitropy (pos. dp/dtmax -13% to +10% and neg. dp/dtmax -15% to +17% compared to baseline). Intracoronary adenosine decreased microvascular resistance (362.5 mm Hg/s/m to 156.7 mm Hg/s/m, p < 0.001) and increased LAD flow velocity (22 cm/s vs 45 cm/s, p < 0.001) but did not acutely change contractility or lusitropy. The magnitude of the dominant accelerating wave, the Backward Expansion Wave, was proportional to the degree of contractility as well as lusitropy (r = 0.47, p < 0.01 and r = -0.50, p < 0.01). Perfusion efficiency (the proportion of accelerating waves) increased at hyperaemia (76% rest vs 81% hyperaemia, p = 0.04). Perfusion efficiency correlated with contractility and lusitropy at rest (r = 0.43 & -0.50 respectively, p = 0.01) and hyperaemia (r = 0.59 & -0.6, p < 0.01). CONCLUSIONS: Acutely increasing coronary flow with adenosine in patients with systolic heart failure does not increase contractility. Changes in coronary flow with biventricular pacing are likely to be a consequence of enhanced cardiac contractility from resynchronization and not vice versa.

Revisiting the Optimal Fractional Flow Reserve and Instantaneous Wave-Free Ratio Thresholds for Predicting the Physiological Significance of Coronary Artery Disease.

BACKGROUND: There has been a gradual upward creep of revascularization thresholds for both fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR), before the clinical outcome trials for both indices. The increase in revascularization that has potentially resulted is at odds with increasing evidence questioning the benefits of revascularizing stable coronary disease. Using an independent invasive reference standard, this study primarily aimed to define optimal thresholds for FFR and iFR and also aimed to compare the performance of iFR, FFR, and resting distal coronary pressure (Pd)/central aortic pressure (Pa). METHODS AND RESULTS: Pd and Pa were measured in 75 patients undergoing coronary angiography±percutaneous coronary intervention with resting Pd/Pa, iFR, and FFR calculated. Doppler average peak flow velocity was simultaneously measured and hyperemic stenosis resistance calculated as hyperemic stenosis resistance=Pa-Pd/average peak flow velocity (using hyperemic stenosis resistance >0.80 mm Hg/cm per second as invasive reference standard). An FFR threshold of 0.75 had an optimum diagnostic accuracy (84%), whereas for iFR this was 0.86 (76%). At these thresholds, the discordance in classification between indices was 11%. The accuracy of contemporary thresholds (FFR, 0.80; iFR, 0.89) was significantly lower (78.7% and 65.3%, respectively) with a 25% rate of discordance. The optimal threshold for Pd/Pa was 0.88 (77.3% accuracy). When comparing indices at optimal thresholds, FFR showed the best diagnostic performance (area under the curve, 0.91 FFR versus 0.79 iFR and 0.77 Pd/Pa, P=0.002). CONCLUSIONS: Contemporary thresholds provide suboptimal diagnostic accuracy compared with an FFR threshold of 0.75 and iFR threshold of 0.86 (cutoffs in derivation studies). Whether more rigorous thresholds would result in selecting populations gaining greater symptom and prognostic benefit needs assessing in future trials of physiology-guided revascularization.

Optimal Application of Fractional Flow Reserve to Assess Serial Coronary Artery Disease: A 3D-Printed Experimental Study With Clinical Validation.

Background Assessing the physiological significance of stenoses with coexistent serial disease is prone to error. We aimed to use 3-dimensional-printing to characterize serial stenosis interplay and to derive and validate a mathematical solution to predict true stenosis significance in serial disease. Methods and Results Fifty-two 3-dimensional-printed serial disease phantoms were physiologically assessed by pressure-wire pullback (Δ FFR app) and compared with phantoms with the stenosis in isolation (Δ FFR true). Mathematical models to minimize error in predicting FFR true, the FFR in the vessel where the stenosis is present in isolation, were subsequently developed using 32 phantoms and validated in another 20 and also a clinical cohort of 30 patients with serial disease. Δ FFR app underestimated Δ FFR true in 88% of phantoms, with underestimation proportional to total FFR . Discrepancy as a proportion of Δ FFR true was 17.1% (absolute difference 0.036±0.048), which improved to 2.9% (0.006±0.023) using our model. In the clinical cohort, discrepancy was 38.5% (0.05±0.04) with 13.3% of stenoses misclassified (using FFR <0.8 threshold). Using mathematical correction, this improved to 15.4% (0.02±0.03), with the proportion of misclassified stenoses falling to 6.7%. Conclusions Individual stenoses are considerably underestimated in serial disease, proportional to total FFR . We have shown within in vitro and clinical cohorts that this error is significantly improved using a mathematical correction model, incorporating routinely available pressure-wire pullback data.

Physiological assessment of left main coronary artery disease.

The left main coronary artery (LMCA) is responsible for supplying the majority of the left ventricular myocardium. Visual estimation of stenosis severity on angiography has major limitations and methods to assess functional significance, such as fractional flow reserve (FFR), have been shown to yield better outcomes; however, to date, major trials examining the use of such physiological indices have excluded LMCA disease. Furthermore, LMCA disease commonly co-exists with downstream disease, which complicates the interpretation of coronary physiological data. This review summarises existing evidence for physio-|logy-guided management of LMCA disease. It will also explore the difficulties posed when functionally assessing LMCA lesions and outline potential solutions. Finally, we aim to provide insight into how novel physiological tools may improve the management of LMCA disease in the future.