Intraobserver Repeatability Assessment of the S390L Firefly WDR Slitlamp in Patients With Dry Eye Disease: Objective, Automated, and Noninvasive Measures.

OBJECTIVES: To assess the intraobserver repeatability of automated, objective, and noninvasive measures obtained with the S390L Firefly WDR slitlamp. METHODS: This cross-sectional study included 50 eyes of patients with dry eye disease with a mean age of 55.06±12.96 years. Three consecutively repeated measures of the following variables were obtained: first noninvasive break-up time (F-NIBUT), average noninvasive break-up time (A-NIBUT), tear meniscus height, tear meniscus area (TMA), nasal ciliary hyperemia (NCIH), temporal ciliary hyperemia (TCIH), nasal conjunctival hyperemia (NCOH), temporal conjunctival hyperemia (TCOH), upper loss area meibomian gland (U-LAMG), lower loss area meibomian gland (L-LAMG), upper meibomian gland dysfunction grade (U-MGD grade), and lower meibomian gland dysfunction grade (L-MGD grade). Intraobserver repeatability was estimated with coefficient of variation (CoV), intrasubject standard deviation (SD) (S w ), and Bland-Altman plots. RESULTS: All variables showed no statistically significant differences in the repeated-measures analysis except for L-MGD grade ( P =0.045). F-NIBUT and A-NIBUT obtained the highest CoV with an average value of 0.48±0.41 [0.02-1.00] and 0.34±0.25 [0.02-1.00], respectively. The remaining variables showed CoVs between 0.04±0.11 [0.00-0.43] and 0.18±0.16 [0.00-0.75]. A-NIBUT, TMA, NCOH, and L-LAMG obtained an S w of 2.78s, 0.21 mm 2 , <0.001, and 4.11%, respectively. Bland-Altman plots showed a high level of agreement between pairs of repeated measures. CONCLUSION: The S390L Firefly WDR slitlamp has moderate intraobserver repeatability for F-NIBUT and A-NIBUT, which suggests that F-NIBUT and A-NIBUT are tests with high variability. The remaining variables show satisfactory intraobserver repeatability.

Contrast-enhanced cine MR sequences in the assessment of myocardial hyperemia in acute myocarditis: can they help? A feasibility study.

The study was designed to assess the accuracy of contrast-enhanced balanced steady-state free precession (cine-SSFP) CMR imaging sequences to exhibit myocardial hyperemia in acute myocarditis, which has for a long time been investigated in some centers using early gadolinium enhancement (EGE) sequence. Contrast-enhanced cine-SSFP (CESSFP) sequences were compared to precontrast cine-SSFP sequences to calculate the early cine-contrast enhancement in 36 consecutive patients with acute myocarditis and 36 controls matched for age and gender. Four-chamber views images were obtained in each subject before and after gadolinium injection. Absolute and relative left ventricular myocardial enhancement of the overall myocardium, then separately of the lateral wall and interventricular septum was analyzed in telediastole. Myocarditis patients displayed higher cine-SSFP absolute enhancement than controls (overall left ventricular myocardium 2.38 ± 0.33 vs 1.84 ± 0.31; lateral wall 2.45 ± 0.35 vs 1.83 ± 0.32; and septum 2.26 ± 0.29 vs 1.82 ± 0.29, p < 0.0001 for all). Less significant differences were observed for the relative enhancement (p < 0.05 for all). Using ROC curves, the optimal threshold value of absolute enhancement to diagnose acute myocarditis was 2.05 (sensitivity: 86%; specificity: 81%). Given the simplicity of use, contrast-enhanced cine-SSFP sequences should be used as an additional diagnostic tool to detect hyperemia in acute myocarditis patients.

Understanding the Basis for Hyperemic and Nonhyperemic Coronary Pressure Assessment.

Despite the now routine integration of invasive physiologic systems into coronary catheter laboratories worldwide, it remains critical that all operators maintain a sound understanding of the fundamental physiologic basis for coronary pressure assessment. More specifically, performing operators should be well informed regarding the basis for hyperemic (ie, fractional flow reserve) and nonhyperemic (ie, instantaneous wave-free ratio and other nonhyperemic pressure ratio) coronary pressure assessment. In this article, we provide readers a comprehensive history charting the inception, development, and validation of hyperemic and nonhyperemic coronary pressure assessment.

Impact of aging on the effects of intracoronary adenosine, peak hyperemia and its duration during fractional flow reserve assessment.

INTRODUCTION: Functional assessment of coronary stenoses is crucial for determining the correct therapeutic strategy. Age-related modifications in cardiovascular function could alter the functional significance of an intermediate coronary lesion. Therefore, the aim of the present study was to investigate the impact of age on fractional flow reserve (FFR) measurements in patients with intermediate coronary artery disease. METHODS: We included patients undergoing coronary angiography at our Division of Cardiology from June 2008 to February 2019 for elective indication or recent acute coronary syndrome and receiving FFR assessment for an intermediate coronary stenosis (angiographic 40-70% stenoses). FFR measurement was performed by pressure-recording guidewire (Prime Wire; Volcano Imaging System Philips Healthcare, San Diego, California, USA), after induction of hyperemia with intracoronary boluses of adenosine (from 60 to 720 µg, with dose doubling at each step). RESULTS: We included in our study 276 patients, undergoing FFR evaluation on 314 lesions, that were divided according to age (< or ≥70 years). Elderly patients displayed a higher cardiovascular risk profile and received more often specific therapy. We found significantly higher FFR values and lower Delta FFR and time to recovery in patients with age ≥70 years old even with high-dose adenosine. Elderly patients showed a trend in lower percentage of positive FFRs, especially with high-dose (P = 0.09). Overall, any FFR ≤ 0.80 was observed in 33.5% of younger patients and 21.1% of patients ≥70 years (P = 0.02). Results were confirmed after correction for baseline differences [adjusted odds ratio (95% confidence interval) = 0.60 (0.33-1.09), P = 0.08]. CONCLUSION: This is one of the first studies investigating the impact of age on the measurement of FFR with high-dose adenosine. Patients with age >70 years old with intermediate CAD are more likely to have higher FFR values and lower duration of hyperemia after adenosine boluses, as compared with younger patients.

Difference in functional assessment of individual stenosis severity in serial coronary lesions between resting and hyperemic pressure-wire pullback: Insights from the GIFT registry.

BACKGROUND: Identifying the individual hemodynamic significance of tandem coronary artery lesions can be complicated by the crosstalk phenomenon which occurs between serial stenoses under hyperemic conditions. Physiological assessments performed under resting conditions are considered to be, theoretically, less affected by the hemodynamic interaction between serial coronary stenoses. The purpose of this study was to assess whether pressure-wire (PW) pullback measurements at rest and during hyperemia provided different information as to which stenosis appeared to be most functionally significant. METHODS: In consecutive patients with angiographically discrete serial lesions, physiological lesion predominance (i.e. proximal or distal) was defined according to the pressure gradient along the vessels on PW-pullback trace. We used instantaneous wave-free ratio (iFR) based assessment as the reference standard and compared fractional flow reserve (FFR) based and hyperemic-iFR based lesion predominance. RESULTS: Eighty-eight vessels (70 patients, mean age 70.3 ± 9.4 years, 80% male) were included in this study. Median iFR, FFR and hyperemic-iFR were 0.85 (interquartile range [IQR]: 0.74 to 0.91), 0.73 (IQR: 0.65 to 0.80) and 0.60 (IQR: 0.49 to 0.71), respectively. When judged against iFR-pullback based physiological assessment, lesion predominance changed in 22.7% (20/88) in FFR and in 20.5% (18/88) in hyperemic-iFR, respectively. There was no statistical difference between FFR and hyperemic-iFR for the impact on these changes (p = 0.77). CONCLUSIONS: In serial coronary lesions, hyperemic PW-pullback disagreed with resting PW-pullback on the lesion-specific identification of ischemia in approximately 20% of cases, either in whole cardiac cycle or in wave-free period.

Assessment of tissue perfusion and vascular function in mice by scanning laser Doppler perfusion imaging.

Post-occlusive reactive hyperemia (PORH) is a key feature of physiological vasomotion to appropriately match the supply/demand ratio of tissues. This adaptive mechanism is severely disturbed in endothelial dysfunction with a reduced flow-mediated dilation (FMD). Reduced PORH and FMD are powerful prognostic risk factors in cardiovascular diseases. While these parameters are frequently determined in human beings, comparable methods applicable to mouse models are sparse. We aimed to evaluate the applicability and accuracy of scanning laser Doppler perfusion imaging (LDPI) to measure PORH in the mouse hindlimb. Changes in mean perfusion in response to vasoactive drugs and PORH (assessed by scanning LDPI) were compared with changes in diameter and blood flow in the femoral artery, as assessed by high-resolution ultrasound. We found that the measured LDPI signal significantly correlated with changes of inflow into the femoral artery. Vasodilation induced by administration of nitroglycerine and acetylcholine increased vessel diameter, blood flow and mean perfusion, while vasoconstriction following administration of epinephrine decreased all three parameters. PORH was induced by temporal occlusion of the femoral artery with an external cuff. During occlusion, mean perfusion decreased to a condition of zero-perfusion and release of the cuff induced an immediate increase in blood flow that was followed by femoral artery dilation driving PORH/perfusion. Surgical removal of the femoral artery decreased mean perfusion to a zero-perfusion level and fully abolished PORH. Importantly, the measurement of the PORH response by scanning LDPI is highly reproducible as determined by repeated measurements and intra/interobserver variation analysis. Last, we found that the PORH response was dependent on nitric oxide synthase and cyclooxygenase and declined with age. Thus, we here provide novel and robust non-invasive methods to serially measure tissue perfusion at baseline and during physiological and pharmacological modulation of vasomotor tone in the hindlimb of mice. The application of these LDPI scanning and ultrasound-based methods may be useful for testing the effects of drugs affecting vasomotor function or future elucidation of mechanisms leading to vasomotor dysfunction in mice in vivo.

Performance of Noninvasive Assessment in the Diagnosis of Right Heart Failure After Left Ventricular Assist Device.

Right heart failure (RHF) after left ventricular assist device (LVAD) is associated with poor outcomes. Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) defines RHF as elevated right atrial pressure (RAP) plus venous congestion. The purpose of this study was to examine the diagnostic performance of the noninvasive Intermacs criteria using RAP as the gold standard. We analyzed 108 patients with LVAD who underwent 341 right heart catheterizations (RHC) between January 1, 2006, and December 31, 2013. Physical exam, echocardiography, and laboratory data at the time of RHC were collected. Conventional two-by-two tables were used and missing data were excluded. The noninvasive Intermacs definition of RHF is 32% sensitive (95% cardiac index (CI), 0.21-0.44) and 97% specific (95% CI, 0.95-0.99) for identifying elevated RAP. Clinical assessment failed to identify two-thirds of LVAD patients with RAP > 16 mm Hg. More than half of patients with elevated RAP did not have venous congestion, which may represent a physiologic opportunity to mitigate the progression of disease before end-organ damage occurs. One-quarter of patients who met the noninvasive definition of RHF did not actually have elevated RAP, potentially exposing patients to unnecessary therapies. In practice, if any component of the Intermacs definition is present or equivocal, our data suggest RHC is warranted to establish the diagnosis.

Hyperemia Analysis Software for Assessment of Conjunctival Hyperemia Severity.

PURPOSE: We developed a hyperemia analysis software, which can quantitatively assess the degree of conjunctival hyperemia, and evaluated the reproducibility and reliability of its percent coverage. In addition, we compared the clinical grading and the percent coverage to examine the applicability of the software analysis. METHODS: We took images of the temporal conjunctiva with slit lamp microscopes. We used our hyperemia analysis software to detect blood vessels in the region of interest using its image processing capabilities and obtained a ratio of the area occupied by blood vessels to the rest of the area. In addition, we used the clinical evaluation criteria of the Japanese guidelines for allergic conjunctival diseases 2017 to clinically grade the hyperemia in each eye. Nine evaluators examined the images and graded the severity of hyperemia into four stages. We looked for a statistical correlation between the results of the hyperemia analysis software and the clinical grading. RESULTS: The percent coverage of the blood vessels in the region of interest calculated by the hyperemia analysis software correlated with the arithmetic average of our clinical grading (r = 0.953; 95% CI, 0.8470340-0.9862136). CONCLUSION: The percent coverage from our hyperemia analysis software reflects the clinical grading score, suggesting that our software can be used to obtain a detailed analysis of conjunctival hyperemia.

Assessment of ocular redness measurements obtained with keratograph 5M and correlation with subjective grading scales.

OBJECTIVE: To examine correlations between ocular redness scores provided by the Keratograph 5M and those determined using two image-based grading scales. METHODS: Observational prospective cross-sectional study. Two hundred and twenty six eyes of two hundred and twenty six participants (175 patients using anti-glaucoma eye drops and 51 subjects untreated). All subjects were scored automatically using the keratograph 5M. These redness scores (RS) were then correlated with the gradings provided by the Efron and McMonnies/Chapman-Davies scale (MC-D) scales (two observers). RESULTS: Excellent reproducibility was observed for both the Efron (weighted K=0.897, 95% CI 0.823-0.904) and MC-D (weighted K=0.783, 95% CI 0.752-0.795) scales. Keratograph RS and the scores obtained with both Efron (Spearman's Rho=0.43, P<0.001) and MC-D (Spearman's Rho=0.48, P<0.001) scales were significantly correlated. RS for the bulbar and limbal - nasal and temporal quadrants also correlated moderately with the two subjective scales. Through Bland Altman analysis, poor agreement was detected between the objective and subjective methods: agreement values for the Efron scale or MC-D scale (matching scorers between observers) versus overall RS showed high biases (-15.58 and -22.05 respectively) and wide limits of agreement (LOA) (-46.169 to 15.005 and -52.534 to 8.19 respectively). Lowest bias was observed between temporal limbal RS and Observer 2 Efron score (-0.04). CONCLUSIONS: Although it emerged as a reliable objective method, the keratograph 5M overestimated the scores compared with the subjective grading scales when used to grade the degree of ocular redness. Therefore, they should not be interchangeable methods.

Contrast Fractional Flow Reserve (cFFR): A pragmatic response to the call for simplification of invasive functional assessment.

AIM: To review the current approaches to simplify functional assessment of coronary stenosis with particular regard for contrast Fractional Flow Reserve (cFFR). METHODS AND RESULTS: Maximal hyperaemia to assess FFR is perceived as time-consuming, costly, unpleasant for the patient and associated with side effects. Resting indexes, like Pd/Pa and iFR, have been proposed to circumvent the use of vasodilators as well as an approach based on the administration of contrast medium to induce coronary vasodilation, the cFFR. Contrast FFR can be obtained quickly, at very low cost in the absence of substantial side effects. Among these alternative indexes, cFFR shows the best correlation with FFR, reduces the use of adenosine even more than a hybrid resting approach but has not yet been tested in a randomized, controlled trial with clinical end-points. CONCLUSION: cFFR represents a cheap, safe and effective alternative to FFR, able to facilitate the dissemination of a functional approach to myocardial revascularization.

Evaluation of Ocular Surface Disease in Patients With Glaucoma: Clinical Parameters, Self-report Assessment, and Keratograph Analysis.

PURPOSE: To assess ocular surface disease (OSD) in glaucoma using clinical parameters, self-report assessment, and keratograph analysis. METHODS: A total of 30 glaucoma patients and 27 subjects with cataracts (control group) were enrolled in the study. Only glaucoma patients who were using at least 1 topical intraocular pressure-lowering medication were included. An ophthalmological examination was performed, including tear break-up time (BUT), assessment of conjunctival hyperemia and keratitis, and completion of the Ocular Surface Disease Index (OSDI) questionnaire. All the patients underwent keratograph analysis including noninvasive BUT, meibography, tear meniscus height, and redness scale. Quality of life was also assessed in all the patients using National Eye Institute Visual Function Questionnaire (NEI VFQ)-25. The comparison of OSD between the 2 groups was assessed. RESULTS: There was a significant difference in OSD: keratitis and conjunctival hyperemia were worse in the glaucoma group (P=0.009 and 0.008, respectively). The glaucoma group had significantly worse scores on the OSDI questionnaire (32.53±20.75 vs. 20.42±18.77; P=0.007). For the keratograph assessment, the glaucoma group had significantly smaller tear meniscus height (0.22±0.08 vs. 0.24±0.04, respectively; P=0.041); worse bulbar redness (2.06±0.67 vs. 1.70±0.45, respectively; P=0.021); higher meibography grades (2.34±1.01 vs. 1.52±0.64, respectively; P=0.001); and worse noninvasive keratograph tear BUT (5.45±4.16 vs. 8.40±5.65, respectively; P=0.023). Patients with glaucoma had a worse quality of life (60.73±18.25 vs. 76.62±8.03, respectively; P=0.039). CONCLUSIONS: Our findings not only confirm the high prevalence of clinical findings of OSD in glaucoma patients but also reveal new objective parameters measured by keratograph analysis.

Preoperative Assessment of Endothelial Function for Prediction of Adverse Events After Cardiovascular Surgery.

BACKGROUND: Cardiovascular surgery is one of the highest risk procedures in the field of surgery. Preoperative assessment of endothelial function has been reported as useful for predicting postoperative adverse events (AEs). The aim of this study was to investigate the relationship between endothelial function assessed by reactive hyperemia index (RHI) and AEs after cardiovascular surgery.Methods and Results:A prospective observational study of 197 patients who underwent cardiovascular surgery was conducted. RHI was measured before the surgery. The primary endpoint was a composite of postoperative death, reoperation, stroke, newly required dialysis, deep sternum infection, and prolonged ventilation within 30 days. The secondary endpoint was new-onset atrial fibrillation (AF) within 30 days. Following cardiovascular surgery, 19 patients (9.6%) had AEs. New-onset AF was documented in 42 (25.9%) of 162 patients without a prior history of AF. In the receiver-operating characteristic curve analysis, RHI significantly predicted AEs (area under the curve [AUC] 0.67, best cutoff value 1.64, P=0.03), whereas RHI did not predict new-onset AF (AUC 0.53, P=0.93). Patients with RHI ≤1.64 had more AEs than those with RHI >1.64 (16.3% vs. 4.5%, P=0.005). Multiple logistic regression analysis showed the number of surgical procedures and RHI ≤1.64 as significant predictors of AEs. CONCLUSIONS: Preoperative endothelial dysfunction assessed by RHI was associated with postoperative AEs in patients with cardiovascular surgery.

Efficacy of pressure parameters obtained during contrast medium-induced submaximal hyperemia in the functional assessment of intermediate coronary stenosis in comparison with instantaneous wave-free ratio.

BACKGROUND: Despite evidence demonstrating the benefits of percutaneous coronary intervention guided by fractional flow reserve (FFR), FFR evaluation has not been widely adopted. We sought to compare the diagnostic performances of instantaneous wave-free ratio (iFR) to a novel contrast medium-induced index in FFR prediction, hypothesizing that the latter parameter would offer superior diagnostic agreement with FFR. METHODS & RESULTS: We studied 132 intermediate stenoses in 97 patients prospectively. iFR was measured first, followed by intracoronary injection of 6 mL contrast medium at 3 mL/s to obtain end-diastolic instantaneous distal coronary pressure/aortic pressure ratio (Pd/Pa) 60 ms before the electrocardiographic R-wave (C-ED-Pd/Pa). Subsequently, conventional hyperemic FFR was measured as a reference standard. Of the 132 lesions, 120 were available for final analysis. The FFR values of 95/120 lesions (79.2%) were between 0.60 and 0.90. C-ED-Pd/Pa values (median 0.79 [interquartile range 0.69-0.87]) were significantly lower than FFR values (0.81 [0.75-0.88], P<0.01), whereas iFR values (0.91 [0.86-0.94], P<0.01) were significantly higher. Correlation coefficients with FFR were 0.78 (standard error of the estimate [SEE] 0.067, P<0.0001) and 0.93 (SEE 0.052, P<0.0001) for iFR and C-ED-Pd/Pa, respectively (P<0.001). The areas under the receiver operating characteristic curves were 0.88 and 0.96 for iFR and C-ED-Pd/Pa, respectively (P<0.01). Diagnostic accuracy was 85.0% and 92.5% for iFR and C-ED-Pd/Pa, respectively (P=0.06). CONCLUSIONS: C-ED-Pd/Pa is a novel, practical, and accurate measure for the physiological assessment of intermediate coronary stenosis compared to iFR.

Assessment of Bulbar Redness with a Newly Developed Keratograph.

PURPOSE: To determine the validity and reliability of the clinical assessment of bulbar redness (BR) using a newly developed corneal topographer. METHODS: This is a cross-sectional diagnostic evaluation study. The BR scores [Oculus Index (OI)] from 30 eyes of 26 patients with different degrees of conjunctival hyperemia were assessed and scored automatically using a new method: a keratograph equipped with scanning and scoring software. The values obtained via this system were correlated with three image-based comparative subjective scales: the Institute for Eye Research (IER), the Efron, and the Validated Bulbar Redness (VBR) grading scales. The IER and Efron scores were interpolated to 0.1 unit, and the VBR scores were interpolated to 1 unit. We also evaluated the repeatability of each method and the level of agreement between the OI score and the scores achieved using the three other image-based methods. RESULTS: There was a significant correlation between the OI score and the scores obtained with the IER (r = 0.921, p < 0.001), Efron (r = 0.958, p < 0.001), and VBR (r = 0.965, p < 0.001) scales. The intraobserver intraclass correlation coefficients were 0.947, 0.874, 0.810, and 0.920 for the OI, IER, Efron, and VBR, respectively, and the intraobserver coefficients of repeatability were 13.924, 16.111, 17.684, and 16.900, respectively. Furthermore, the interobserver intraclass correlation coefficients were 0.889, 0.880, 0.884, and 0.881 for the OI, IER, Efron, and VBR, respectively, and the interobserver coefficients of repeatability were 15.934, 16.366, 22.059, and 21.373, respectively. CONCLUSIONS: The OI is an objective and reliable method for scoring BR. Its reproducibility was the highest of all the four modalities. The keratograph is recommended, therefore, as a suitable alternative for BR assessment.

Quantitative assessment of magnetic resonance derived myocardial perfusion measurements using advanced techniques: microsphere validation in an explanted pig heart system.

BACKGROUND: Cardiovascular Magnetic Resonance (CMR) myocardial perfusion imaging has the potential to evolve into a method allowing full quantification of myocardial blood flow (MBF) in clinical routine. Multiple quantification pathways have been proposed. However at present it remains unclear which algorithm is the most accurate. An isolated perfused, magnetic resonance (MR) compatible pig heart model allows very accurate titration of MBF and in combination with high-resolution assessment of fluorescently-labeled microspheres represents a near optimal platform for validation. We sought to investigate which algorithm is most suited to quantify myocardial perfusion by CMR at 1.5 and 3 Tesla using state of the art CMR perfusion techniques and quantification algorithms. METHODS: First-pass perfusion CMR was performed in an MR compatible blood perfused pig heart model. We acquired perfusion images at physiological flow ("rest"), reduced flow ("ischaemia") and during adenosine-induced hyperaemia ("hyperaemia") as well as during coronary occlusion. Perfusion CMR was performed at 1.5 Tesla (n = 4 animals) and at 3 Tesla (n = 4 animals). Fluorescently-labeled microspheres and externally controlled coronary blood flow served as reference standards for comparison of different quantification strategies, namely Fermi function deconvolution (Fermi), autoregressive moving average modelling (ARMA), exponential basis deconvolution (Exponential) and B-spline basis deconvolution (B-spline). RESULTS: All CMR derived MBF estimates significantly correlated with microsphere results. The best correlation was achieved with Fermi function deconvolution both at 1.5 Tesla (r = 0.93, p < 0.001) and at 3 Tesla (r = 0.9, p < 0.001). Fermi correlated significantly better with the microspheres than all other methods at 3 Tesla (p < 0.002). B-spline performed worse than Fermi and Exponential at 1.5 Tesla and showed the weakest correlation to microspheres (r = 0.74, p < 0.001). All other comparisons were not significant. At 3 Tesla exponential deconvolution performed worst (r = 0.49, p < 0.001). CONCLUSIONS: CMR derived quantitative blood flow estimates correlate with true myocardial blood flow in a controlled animal model. Amongst the different techniques, Fermi function deconvolution was the most accurate technique at both field strengths. Perfusion CMR based on Fermi function deconvolution may therefore emerge as a useful clinical tool providing accurate quantitative blood flow assessment.

Does the instantaneous wave-free ratio approximate the fractional flow reserve?

OBJECTIVES: This study sought to examine the clinical performance of and theoretical basis for the instantaneous wave-free ratio (iFR) approximation to the fractional flow reserve (FFR). BACKGROUND: Recent work has proposed iFR as a vasodilation-free alternative to FFR for making mechanical revascularization decisions. Its fundamental basis is the assumption that diastolic resting myocardial resistance equals mean hyperemic resistance. METHODS: Pressure-only and combined pressure-flow clinical data from several centers were studied both empirically and by using pressure-flow physiology. A Monte Carlo simulation was performed by repeatedly selecting random parameters as if drawing from a cohort of hypothetical patients, using the reported ranges of these physiologic variables. RESULTS: We aggregated observations of 1,129 patients, including 120 with combined pressure-flow data. Separately, we performed 1,000 Monte Carlo simulations. Clinical data showed that iFR was +0.09 higher than FFR on average, with ±0.17 limits of agreement. Diastolic resting resistance was 2.5 ± 1.0 times higher than mean hyperemic resistance in patients. Without invoking wave mechanics, classic pressure-flow physiology explained clinical observations well, with a coefficient of determination of >0.9. Nearly identical scatter of iFR versus FFR was seen between simulation and patient observations, thereby supporting our model. CONCLUSIONS: iFR provides both a biased estimate of FFR, on average, and an uncertain estimate of FFR in individual cases. Diastolic resting myocardial resistance does not equal mean hyperemic resistance, thereby contravening the most basic condition on which iFR depends. Fundamental relationships of coronary pressure and flow explain the iFR approximation without invoking wave mechanics.

Dynamic contrast-enhanced MRI assessment of hyperemic fractional microvascular blood plasma volume in peripheral arterial disease: initial findings.

OBJECTIVES: The aim of the current study was to describe a method that assesses the hyperemic microvascular blood plasma volume of the calf musculature. The reversibly albumin binding contrast agent gadofosveset was used in dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) to assess the microvascular status in patients with peripheral arterial disease (PAD) and healthy controls. In addition, the reproducibility of this method in healthy controls was determined. MATERIALS AND METHODS: Ten PAD patients with intermittent claudication and 10 healthy control subjects were included. Patients underwent contrast-enhanced MR angiography of the peripheral arteries, followed by one DCE MRI examination of the musculature of the calf. Healthy control subjects were examined twice on different days to determine normative values and the interreader and interscan reproducibility of the technique. The MRI protocol comprised dynamic imaging of contrast agent wash-in under reactive hyperemia conditions of the calf musculature. Using pharmacokinetic modeling the hyperemic fractional microvascular blood plasma volume (V(p), unit: %) of the anterior tibial, gastrocnemius and soleus muscles was calculated. RESULTS: V(p) was significantly lower for all muscle groups in PAD patients (4.3±1.6%, 5.0±3.3% and 6.1±3.6% for anterior tibial, gastrocnemius and soleus muscles, respectively) compared to healthy control subjects (9.1±2.0%, 8.9±1.9% and 9.3±2.1%). Differences in V(p) between muscle groups were not significant. The coefficient of variation of V(p) varied from 10-14% and 11-16% at interscan and interreader level, respectively. CONCLUSIONS: Using DCE MRI after contrast-enhanced MR angiography with gadofosveset enables reproducible assessment of hyperemic fractional microvascular blood plasma volume of the calf musculature. V(p) was lower in PAD patients than in healthy controls, which reflects a promising functional (hemodynamic) biomarker for the microvascular impairment of macrovascular lesions.

High-throughput ambulatory assessment of digital reactive hyperemia: concurrent validity with known cardiovascular risk factors and potential confounding.

OBJECTIVES: Reactive hyperemia index (RHI) measurement through digital peripheral arterial tonometry (PAT) is proposed for cardiovascular disease (CVD) risk screening. We evaluated the concurrent validity of RHI, measured in a high-throughput ambulatory setting, with known CVD risk factors and biomarkers. METHODS: PAT was included in the 2007 EADS/Augsburg (Germany) cohort follow-up. CVD risk factors (age, sex, hypertension, hyperlipidemia, diabetes, smoking, physical activity, prevalent coronary heart disease, family history, cholesterol, triglycerides, blood pressure (BP), waist-to-hip ratio (WHR)) and biomarkers (d-dimers, fibrinogen, log(c-reactive protein)) were assessed. The relationship between RHI and CVD risk factors and biomarkers was evaluated using multivariate linear regression, controlling for potential confounders (time of day, time since subject's last meal, baseline heart rate, examiner). RESULTS: Of 926 subjects approached, 710 underwent PAT and 603 (mean age 44.9+/-10 years, 88.7% men) with complete data were included for analysis. RHI was significantly related to being female (beta=0.128, p=0.02), low-density lipoprotein cholesterol (beta=-0.001, p=0.02), systolic BP (beta=0.007, p<0.001), WHR (beta=-1.04, p<0.01), time of day (beta=-0.011, p=0.04) and time since last meal (beta=0.013, p<0.01). CONCLUSIONS: Concurrent validity was partially demonstrated, while the need to control for potential confounding was reinforced. Participation was high and may be higher in less time-constrained settings.

Assessment of critical renal ischemia with real-time infrared imaging.

BACKGROUND: Currently visual and tactile clues such as color, mottling, and tissue turgor are used in the operating room for subjective assessments of organ ischemia. Studies have demonstrated that infrared (IR) imaging is a reliable tool to identify perfusion of brain tumors and kidneys during human surgery. Intraoperative IR imaging has the potential for more objective real-time detection and quantitative assessment of organ viability including early ischemia. We hypothesize, by detecting variations of the IR signal, we can assess the degree to which renal surface temperature reflects underlying renal ischemia. To address this hypothesis, IR imaging-derived temperature fluctuations were evaluated during laparotomy in a porcine model (n = 15). These temperature profiles then underwent spectral (frequency) analysis to assess their relationship to well-described oscillations of the microcirculation. MATERIALS AND METHODS: An IR camera was positioned 30-60 cm above the exposed kidneys. Images (3-5 mum wavelength) were collected (1.0/s) at baseline, during warm renal ischemia, and during reperfusion. Dominant frequency (DF) of the tissue temperature fluctuations were determined by a Fourier transformation (spectral) analysis. RESULTS: IR images immediately showed which segments of the kidney were ischemic. DF at approximately 0.008 Hz that corresponds to blood flow oscillations was observed in thermal profiles. The oscillations were diminished or disappeared after 25 min of warm ischemia and were recovered with reperfusion in a time-dependent fashion. Oscillations were attenuated substantially in ischemic segments, but not in perfused segments of the kidney. CONCLUSIONS: The described oscillations can be measured noninvasively using IR imaging in the operating room, as represented by the DF, and may be an early marker of critical renal ischemia.