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Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease. • The angiograms of the 200 participants randomised in the ORBITA trial were visually assessed, twice, by 25 cardiologists • The cardiologists predicted the FFR and iFR visually, just using the angiogram • The visual FFR and iFR provided significant additional information in predicting placebo-controlled ischaemia improvement with stenting • In this analysis, expert group consensus visual assessment provided as much additional information as invasively measured FFR and iFR [ABSTRACT FROM AUTHOR]

While there is a discordance between fractional flow reserve (FFR) and non-hyperemic pressure ratios (NHPRs) in some cases, the mechanisms underlying these discordances have not yet been fully clarified. We examined whether vascular damage as assessed by measurement of the brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness, or ankle brachial pressure index (ABI), a marker of atherosclerotic arterial stenosis, might be associated with their discordances. FFR and NHPRs were measured in 283 consecutive patients (69 ± 10 years old). Based on previously established cut-off values of the two markers (i.e. +/− = FFR ≤/> 0.80 or =NHPRs ≤/> 0.89), the study participants were divided into four groups (the + and - signs denoting "predictive of significant stenosis" and "not predictive of significant stenosis," respectively): the FFR+/NHPRs+ group (n = 124), FFR-/NHPRs+ group (n = 16), FFR+/NHPRs- group(n = 65), and FFR-/NHPRs- group (n = 78). The baPWV and ABI were also measured in all the participants, and values of <2000 cm/s and ≥1.00 of the baPWV and ABI, respectively, were considered as representing relatively less advanced atherosclerotic systemic vascular damage. The prevalence of subjects with ABI ≥1.00 was higher in the FFR+/NHPRs- group than in the FFR-/NHPRs- group (p < 0.05). When the study subjects were divided into 2 groups, namely, the FFR+/NHPRs- group and the combined group, the prevalence of ABI ≥1.00 and that of baPWV <2000 cm/s were higher in the FFR+/NHPRs- group as compared with those in the combined group (p < 0.05). The results of binary logistic regression analysis demonstrated that ABI ≥1.00 was associated with a significant odds ratio (2.34, p < 0.05) for the FFR+/NHPRs- discordance. The FFR+/NHPRs- discordance appears to be observed in patients with relatively less advanced atherosclerotic systemic vascular damage. Thus, ABI ≥1.00 may be a marker of the presence of the FFR+/NHPRs- discordance. ABI, ankle brachial pressure index; DBP, diastolic blood pressure; EF, ejection fraction; FFR, fractional flow reserve; NHPRs, non-hyperemic pressure ratios. [Display omitted] • Fractional flow reserve positive discordance was observed in 65/283 subjects. • This discordance had least systemic vascular damage. • Ankle brachial pressure index ≥1.00 predicts this discordance. [ABSTRACT FROM AUTHOR]

Background and Objectives: The revascularization strategy for percutaneous coronary intervention (PCI) in patients with multivessel (MV) acute coronary syndrome (ACS) remains controversial. Certain gaps in the evidence are related to the optimal timing of non-culprit lesion revascularization and the utility of instantaneous wave-free ratio (iFR) in the management of MV ACS intervention. The major benefits of iFR utilization in MV ACS patients in one-stage complete revascularization are: (1) the possibility to virtually plan the PCI, both the location and the extension of the necessary stenting to achieve the prespecified final hemodynamic result; (2) the opportunity to validate the final hemodynamic result of the PCI, both in culprit artery and all non-culprit arteries and (3) the value of obliviating the uncomfortable, costly, time consuming and sometimes deleterious effects from Adenosine, as there is no requirement for administration. Thus, iFR use fosters the achievement of physiologically appropriate complete revascularization in MV ACS patients during acute hospitalization. Materials and Methods: This pilot study was aimed to test the feasibility of a randomized trial research protocol as well as to assess patient safety signals of co-registration iFR-guided one-stage complete revascularization compared with that of standard staged angiography-guided PCI in de novo patients with MV ACS. This was a single-center, prospective, randomized, open-label clinical trial consecutively screening patients with ACS for MV disease. The intervention strategy of interest was iFR-guided physiologically complete one-stage revascularization, in which the virtual PCI planning of non-culprit lesions and the intervention itself were performed in one stage directly following treatment of the culprit lesion and other critical stenosis of more than ninety percent. Seventeen patients were recruited and completed the 3-month follow-up. Results: Index PCI duration was significantly longer while the volume of contrast media delivered in index PCI was significantly greater in the iFR-guided group than in the angiography-guided group (119.4 ± 40.7 vs. 47 ± 15.5 min, p = 0.004; and 360 ± 97.9 vs. 192.5 ± 52.8 mL, p = 0.003). There were no significant differences in PCI-related major adverse cardiovascular events (MACE) between the groups during acute hospitalization and at 3-months follow-up. One-stage iFR-guided PCI requires fewer PCI attempts until complete revascularization than does angiography-guided staged PCI. Conclusions: Complete revascularization with the routine use of the virtual planning tool in one-stage iFR-guided PCI is a feasible practical strategy in an everyday Cath lab environment following the protocol designed for the study. No statistically significant safety signals were documented in the number of PCI related MACE during the 3-month follow-up. [ABSTRACT FROM AUTHOR]

BackgroundInstantaneous wave free ratio (iFR) does not require adenosine, but has a relatively wide intermediate range where functional assessment remains inconclusive. In this pilot study, we sought to enhance iFR through with the use of intracoronary (IC) saline (iFRs) and contrast media (iFRc) and determine whether these techniques correlated well with fractional flow reserve (FFR).MethodsPatients with coronary artery stenosis (CAS) associated with an iFR in the intermediate zone (≥0.86 and ≤0.93) were prospectively assessed with resting distal coronary pressure/aorta pressure (Pd/Pa), iFR, iFRs, iFRc and FFR.ResultsA total of 40 coronary lesions were studied (40 patients). Pearson correlation coefficients for FFR and iFR, FFR and iFRs, FFR and iFRc were respectively: 0.57 (P=0.0002), 0.80 (P

Background and Objectives: The revascularization strategy for percutaneous coronary intervention (PCI) in patients with multivessel (MV) acute coronary syndrome (ACS) remains controversial. Certain gaps in the evidence are related to the optimal timing of non-culprit lesion revascularization and the utility of instantaneous wave-free ratio (iFR) in the management of MV ACS intervention. The major benefits of iFR utilization in MV ACS patients in one-stage complete revascularization are: (1) the possibility to virtually plan the PCI, both the location and the extension of the necessary stenting to achieve the prespecified final hemodynamic result; (2) the opportunity to validate the final hemodynamic result of the PCI, both in culprit artery and all non-culprit arteries and (3) the value of obliviating the uncomfortable, costly, time consuming and sometimes deleterious effects from Adenosine, as there is no requirement for administration. Thus, iFR use fosters the achievement of physiologically appropriate complete revascularization in MV ACS patients during acute hospitalization. Materials and Methods: This pilot study was aimed to test the feasibility of a randomized trial research protocol as well as to assess patient safety signals of co-registration iFR-guided one-stage complete revascularization compared with that of standard staged angiography-guided PCI in de novo patients with MV ACS. This was a single-center, prospective, randomized, open-label clinical trial consecutively screening patients with ACS for MV disease. The intervention strategy of interest was iFR-guided physiologically complete one-stage revascularization, in which the virtual PCI planning of non-culprit lesions and the intervention itself were performed in one stage directly following treatment of the culprit lesion and other critical stenosis of more than ninety percent. Seventeen patients were recruited and completed the 3-month follow-up. Results: Index PCI duration was significantly longer while the volume of contrast media delivered in index PCI was significantly greater in the iFR-guided group than in the angiography-guided group (119.4 ± 40.7 vs. 47 ± 15.5 min, p = 0.004; and 360 ± 97.9 vs. 192.5 ± 52.8 mL, p = 0.003). There were no significant differences in PCI-related major adverse cardiovascular events (MACE) between the groups during acute hospitalization and at 3-months follow-up. One-stage iFR-guided PCI requires fewer PCI attempts until complete revascularization than does angiography-guided staged PCI. Conclusions: Complete revascularization with the routine use of the virtual planning tool in one-stage iFR-guided PCI is a feasible practical strategy in an everyday Cath lab environment following the protocol designed for the study. No statistically significant safety signals were documented in the number of PCI related MACE during the 3-month follow-up.

Introduction: Contrast medium Pd/Pa ratio (cFFR) was introduced as an alternative to fractional flow reserve (FFR). Aim: To assess the accuracy of cFFR in predicting of FFR, quantitative flow ratio (QFR) and instantaneous wave-free ratio (iFR). Material and methods: Resting Pd/Pa, cFFR, FFR, QFR, and iFR were measured in 110 intermediate coronary lesions. cFFR was obtained after intracoronary injection of contrast medium. FFR was measured after the intravenous administration of adenosine. QFR was derived from fixed empiric hyperemic flow velocity based on coronary angiography. iFR was calculated by measuring the resting pressure gradient across a coronary lesion during diastole. Results: Forty-four patients with 110 intermediate coronary lesions were enrolled. Mean baseline Pd/Pa was 0.93 ±0.05. Mean cFFR value was similar to FFR value (0.83 ±0.09 vs. 0.81 ±0.09; p = 0.13) and QFR (0.81 ±0.1; p = 0.69) and iFR (0.90 ±0.07; p = 0.1). A total of 46 vessels (41.8%) had FFR ≤ 0.80, 50 (45.5%) vessels had cFFR ≤ 0.83, 44 (40.0%) vessels had QFR ≤ 0.80, and 38 (34.5%) vessels had iFR ≤ 0.89. An excellent agreement between cFFR and resting Pd/Pa, FFR, QFR, and iFR was confirmed (intraclass correlation coefficients of 0.83, 0.99, 0.98, and 0.88, respectively). The optimal cutoff value of cFFR was 0.83 for prediction of FFR ≤ 0.80 with sensitivity, specificity, and accuracy of 96.9%, 97.8%, and 97.3%, respectively. 100% sensitivity was observed for a cutoff value of 0.82 and 100% specificity for a cutoff value of 0.84; AUC = 0.998 (0.995-1.00); p < 0.001. Conclusions: Contrast medium Pd/Pa ratio seems to be accurate in predicting the functional significance of borderline coronary lesions assessed with FFR, iFR, and QFR. [ABSTRACT FROM AUTHOR]

Currently there is lack of data regarding the use of optical coherence tomography (OCT) to depict the hemodynamic relevance of coronary stenoses in diabetic patients. We sought to assess the diagnostic accuracy of OCT-derived morphologic assessment in identifying hemodynamically significant coronary lesions as determined by both, the resting instantaneous wave-free ratio (iFR) and the hyperemic fractional flow reserve (FFR) in diabetic patients. Diabetic patients presenting with at least one intermediate coronary lesion were prospectively and consecutively enrolled. All lesions were systematically assessed by iFR, FFR and OCT. A total of 41 intermediate lesions were analysed. Mean iFR and FFR values were 0.90 ± 0.04 and 0.81 ± 0.06, respectively (intra-class correlation coefficient 0.49; 95% CI 0.22-0.79). A moderate correlation between iFR and OCT derived minimal lumen diameter (MLD, r = 0.49) and minimal lumen area (MLA, r = 0.50) was found. Conversely, there was a poor correlation between FFR and OCT-derived MLD (r = 0.34) and MLA (r = 0.32). The diagnostic efficiency of MLA and MLD to identify iFR significant stenoses showed an AUC of 0.82 (95% CI 0.69-0.95) for MLD and 0.83 (95% CI 0.71-0.96) for MLA. A worse diagnostic efficiency was found when FFR was used as the reference with an AUC of 0.71 (95% CI 0.54-0.87) for MLD and 0.70 (95% CI 0.53-0.87). OCT-derived MLA and MLD were the strongest independent anatomic predictors of abnormal iFR and FFR values. In diabetic patients, OCT-derived MLA and MLD showed a moderate diagnostic efficiency in identifying functionally significant coronary stenoses by FFR or iFR. In diabetics, anatomic OCT measurements better predicted resting than FFR-determined physiologically significant lesions. [ABSTRACT FROM AUTHOR]

Objectives The authors investigated 2-year clinical outcomes according to fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) values in deferred lesions. Background Invasive physiological indices such as FFR or iFR are used in clinical practice to select ischemia-causing stenosis and to guide the treatment strategy for patients with coronary artery disease. Methods From the 3V FFR-FRIENDS (3-Vessel Fractional Flow Reserve for the Assessment of Total Stenosis Burden and Its Clinical Impact in Patients With Coronary Artery Disease) study, 821 deferred lesions (n = 374) with both FFR and iFR available were included in this study. The primary outcome was major adverse cardiac events (MACE) (a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization) at 2 years. The lesions were classified according to FFR and iFR cutpoints into concordant normal (Group 1: FFR >0.80 and iFR >0.89), high FFR and low iFR (Group 2: FFR >0.80 and iFR ≤0.89), low FFR and high iFR (Group 3: FFR ≤0.80 and iFR >0.89), and concordant abnormal (Group 4: FFR ≤0.80 and iFR ≤0.89). Results Deferred lesions with low FFR (≤0.80) or low iFR (≤0.89) showed significantly higher rates of 2-year MACE, compared with high FFR (>0.80) or high iFR (>0.89), respectively (7.2% in low FFR vs. 2.4% in high FFR; p < 0.001; 8.1% in low iFR vs. 2.4% in high iFR; p < 0.001). Both FFR and iFR showed significant association with occurrence of MACE as continuous values (hazard ratio [HR] of FFR: 0.570, 95% confidence interval [CI]: 0.337 to 0.963; p < 0.001; HR of iFR: 0.350, 95% CI: 0.217 to 0.567; p < 0.001). When comparing the discriminant ability between FFR and iFR, the c-index was comparable between FFR and iFR (c-index 0.677 vs. 0.685; p = 0.857). Among 4 groups classified according to FFR and iFR levels, only Group 4 with concordant abnormal results showed significantly higher risk of MACE, compared with group 1 (HR: 7.708, 95% CI: 2.621 to 22.667; p < 0.001). Conclusions Both FFR and iFR showed significant association with future risk of MACE in deferred lesions. The discordant results between FFR and iFR were not associated with the increased risk of MACE. The risk of MACE was significantly increased only in lesions with abnormal results of both FFR and iFR. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although invasive physiological assessment for coronary stenosis has become a standard practice to guide treatment strategy, coronary circulatory response and changes in invasive physiological indexes, according to different anatomic and hemodynamic lesion severity, have not been fully demonstrated in patients with coronary artery disease. METHODS: One hundred fifteen patients with left anterior descending artery stenosis who underwent both 13N-ammonia positron emission tomography and invasive physiological measurement were analyzed. Myocardial blood flow (MBF) measured with positron emission tomography and invasively measured coronary pressures were used to calculate microvascular resistance and stenosis resistance. RESULTS: With progressive worsening of angiographic stenosis severity, both resting and hyperemic transstenotic pressure gradient and stenosis resistance increased (P<0.001 for all) and hyperemic MBF (P<0.001) and resting microvascular resistance (P=0.012) decreased. Resting MBF (P=0.383) and hyperemic microvascular resistance (P=0.431) were not changed and maintained stable. Both fractional flow reserve and instantaneous wave-free ratio decreased as angiographic stenosis severity, stenosis resistance, and transstenotic pressure gradient increased and hyperemic MBF decreased (all P<0.001). When the presence of myocardial ischemia was defined by both low hyperemic MBF and low coronary flow reserve, the diagnostic accuracy of fractional flow reserve and instantaneous wave-free ratio did not differ, regardless of cutoff values of hyperemic MBF and coronary flow reserve. CONCLUSIONS: This study demonstrated how the coronary circulation changes in response to increasing coronary stenosis severity using 13N-ammonium positron emission tomography-derived MBF and invasively measured pressure data. Currently used resting and hyperemic pressure-derived invasive physiological indexes have similar patterns of relationships to the different anatomic and hemodynamic lesion severities. [ABSTRACT FROM AUTHOR]

Background The invasive physiologic index such as fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) is used in clinical practice to identify ischemia-causing stenosis and to guide treatment strategy. We investigated clinical and angiographic characteristics of lesions with discrepancy between FFR and iFR. Methods From the 3V FFR-FRIENDS study, 975 vessels (393 patients) with available pre-intervention FFR and iFR were included in this study. The vessels were classified according to FFR and iFR into: concordant normal (Group 1 [ n = 724]: FFR > 0.80 and iFR ≥ 0.90); high FFR and low iFR (Group 2 [ n = 33]: FFR > 0.80 and iFR < 0.90); low FFR and high iFR (Group 3 [ n = 82]: FFR ≤ 0.80 and iFR ≥ 0.90); and concordant abnormal (Group 4 [ n = 136]: FFR ≤ 0.80 and iFR < 0.90). Results Angiographic stenosis severity assessed by percent diameter stenosis, minimum lumen diameter and lesion length was increased from Group 1 to Group 4 (all p < 0.001). SYNTAX score increased and FFR decreased proportionally from Group 1 to Group 4 (all p < 0.001). In multivariable GEE model, female, diabetes mellitus, smaller reference vessel diameter, and higher %DS were significantly associated with low iFR among high FFR groups (Group 2 discordance). Conversely, males, absence of diabetes mellitus and lower %DS were significantly associated with high iFR among low FFR groups (Group 3 discordance). Conclusions Four groups classified according to FFR and iFR were different in clinical and angiographic characteristics, SYNTAX score, and predictors of discordance. The lesions with discordant FFR and iFR may need to be interpreted as a different clinical entity. [ABSTRACT FROM AUTHOR]

Background: Determining the functional significance of each individual coronary lesion in patients with serial coronary stenoses is challenging. It has been proposed that nonhyperemic pressure ratios, such as the instantaneous wave free ratio (iFR) and the ratio of resting distal to proximal coronary pressure (Pd/Pa) are more accurate than fractional flow reserve (FFR) because autoregulation should maintain stable resting coronary flow and avoid hemodynamic interdependence (cross-talk) that occurs during hyperemia. This study aimed to measure the degree of hemodynamic interdependence of iFR, resting Pd/Pa, and FFR in a porcine model of serial coronary stenosis. Methods: In 6 anesthetized female swine, 381 serial coronary stenoses were created in the left anterior descending artery using 2 balloon catheters. The degree of hemodynamic interdependence was calculated by measuring the absolute changes in iFR, resting Pd/Pa, and FFR across the fixed stenosis as the severity of the other stenosis varied. Results: The hemodynamic interdependence of iFR, resting Pd/Pa, and FFR was 0.039+/-0.048, 0.021+/-0.026, and 0.034+/-0.034, respectively (all P PP<0.001).> Conclusions: When assessing serial coronary stenoses, nonhyperemic pressure ratios are affected by hemodynamic interdependence. When the functional significance of serial coronary stenoses is severe, the effect is similar to that which is seen with FFR. * The fractional flow reserve of a proximal stenosis is influenced by the presence of a distal stenosis and vice versa in coronary seral lesions. * It has been proposed that coronary autoregulation maintains stable resting coronary blood flow, ensuring that serial coronary stenosis do not hemodynamically interact under resting conditions. * The nonhyperemic pressure ratios (eg, instantaneous wave free ratio and the ratio of resting distal to proximal coronary pressure) are not immune to hemodynamic interdependence in serial coronary stenoses. * The degree of hemodynamic interdependence of instantaneous wave free ratio and the ratio of resting distal to proximal coronary pressure depends on the functional severity of the serial coronary stenoses, being lower in less severe stenoses, but clinically significant in more severe stenoses. [ABSTRACT FROM AUTHOR]

Background: Although invasive physiological assessment for coronary stenosis has become a standard practice to guide treatment strategy, coronary circulatory response and changes in invasive physiological indexes, according to different anatomic and hemodynamic lesion severity, have not been fully demonstrated in patients with coronary artery disease., Methods: One hundred fifteen patients with left anterior descending artery stenosis who underwent both 13 N-ammonia positron emission tomography and invasive physiological measurement were analyzed. Myocardial blood flow (MBF) measured with positron emission tomography and invasively measured coronary pressures were used to calculate microvascular resistance and stenosis resistance., Results: With progressive worsening of angiographic stenosis severity, both resting and hyperemic transstenotic pressure gradient and stenosis resistance increased ( P <0.001 for all) and hyperemic MBF ( P <0.001) and resting microvascular resistance ( P =0.012) decreased. Resting MBF ( P =0.383) and hyperemic microvascular resistance ( P =0.431) were not changed and maintained stable. Both fractional flow reserve and instantaneous wave-free ratio decreased as angiographic stenosis severity, stenosis resistance, and transstenotic pressure gradient increased and hyperemic MBF decreased (all P <0.001). When the presence of myocardial ischemia was defined by both low hyperemic MBF and low coronary flow reserve, the diagnostic accuracy of fractional flow reserve and instantaneous wave-free ratio did not differ, regardless of cutoff values of hyperemic MBF and coronary flow reserve., Conclusions: This study demonstrated how the coronary circulation changes in response to increasing coronary stenosis severity using 13 N-ammonium positron emission tomography-derived MBF and invasively measured pressure data. Currently used resting and hyperemic pressure-derived invasive physiological indexes have similar patterns of relationships to the different anatomic and hemodynamic lesion severities., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01366404., (© 2017 American Heart Association, Inc.)

Physiologic assessment using fractional flow reserve (FFR) to guide percutaneous coronary interventions (PCI) has been demonstrated to improve clinical outcomes, compared to angiography-guided PCI. Recently, resting indices such as resting Pd/Pa, "instantaneous wave-free ratio", and contrast medium induced FFR have been evaluated for the assessment of the functional consequences of coronary lesions. Herein, we review and discuss the use of FFR and other indices for the functional assessment of coronary lesions. This review will cover theoretical aspects, as well as practical points and common pitfalls related to coronary physiological assessment. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Fractional flow reserve (FFR) requires the use of maximal hyperaemia as described in the original preclinical and clinical validation studies and subsequent practice changing randomized controlled trials. A perception that the need for hyperaemia (usually induced with adenosine) was one of the obstacles to more widespread adoption of FFR has led to interest in the use of resting non-hyperaemic indices to assess the functional significance of coronary stenoses. We examine the current evidence base and conclude that resting indices agree with FFR in only 80 % of lesions when a binary cut-off is employed but closer to 90 % when hybrid strategies utilising both resting indices and FFR are utilised. It seems counter intuitive to sacrifice diagnostic accuracy when in most patients and healthcare systems the induction of hyperaemia with adenosine is safe and emminently affordable., Competing Interests: Disclosure: Dr Hennigan has previously received speaker fees from Volcano Corporation. Dr Robertson has no conflicts of interest to declare. Professor Berry has undertaken consultancy work and given lectures based on institutional contracts between his employer, the University of Glasgow and St Jude Medical. St Jude Medical has also provided support for research with pressure wires. Prof Oldroyd has received speaker fees and institutional grant support from St Jude Medical and speakers fees from Volcano.