Inter-software and inter-scan variability in measurement of epicardial adipose tissue: a three-way comparison of a research-specific, a freeware and a coronary application software platform.

OBJECTIVES: Epicardial adipose tissue (EAT) is a proposed marker of cardiovascular risk; however, clinical application may be limited by variability in post-processing software platforms. We assessed inter-vendor agreement of EAT volume (EATv) and attenuation on both contrast-enhanced (CE) and non-contrast CT (NCT) using a standard coronary CT reporting software (Vitrea), an EAT research-specific software (QFAT) and a freeware imaging software (OsiriX). METHODS: Seventy-six consecutive patients undergoing simultaneous CE and NCT had complete volumetric EAT measurement. Between-software, within-software NCT vs. CE, and inter- and intra-observer agreement were evaluated with analysis by ANOVA (with post hoc adjustment), Bland-Altman with 95% levels of agreement (LoA) and intraclass correlation coefficient (ICC). RESULTS: Mean EATv (freeware 53 ± 31 mL vs. research 93 ± 43 mL vs. coronary 157 ± 64 mL) and attenuation (freeware - 72 ± 25 HU vs. research - 75 ± 3 HU vs. coronary - 61 ± 10 HU) were significantly different between all vendors (ANOVA p < 0.001). EATv was consistently higher in NCT vs. CE for all software packages, with most reproducibility found in research software (bias 26 mL, 95% LoA: 2 to 56 mL), compared to freeware (bias 11 mL 95% LoA: - 46 mL to 69 mL) and coronary software (bias 10 mL 95% LoA: - 127 to 147 mL). Research software had more comparable NCT vs. CE attenuation (- 75 vs. - 72 HU) compared to freeware (- 72 vs. - 57 HU) and coronary (- 61 vs. - 39 HU). Excellent inter-observer agreement was seen with research (ICC 0.98) compared to freeware (ICC 0.73) and coronary software (ICC 0.75) with narrow LoA on Bland-Altman analysis. CONCLUSION: There are significant inter-vendor differences in EAT assessment. Our study suggests that research-specific software has better agreement and reproducibility compared to freeware or coronary software platforms. KEY POINTS: • There are significant differences between EAT volume and attenuation values between software platforms, regardless of scan type. • Non-contrast scans routinely have higher mean EAT volume and attenuation; however, this finding is only consistently seen with research-specific software. • Of the three analyzed packages, research-specific software demonstrates the highest reproducibility, agreement, and reliability for both inter-scan and inter-observer agreement.

Quantitative flow ratio to predict long-term coronary artery bypass graft patency in patients with left main coronary artery disease.

PURPOSE: Fractional flow reserve (FFR) has been demonstrated in some studies to predict long-term coronary artery bypass graft (CABG) patency. Quantitative flow ratio (QFR) is an emerging technology which may predict FFR. In this study, we hypothesised that QFR would predict long-term CABG patency and that QFR would offer superior diagnostic performance to quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS). METHODS: A prospective study was performed on patients with left main coronary artery disease who were undergoing CABG. QFR, QCA and IVUS assessment was performed. Follow-up computed tomography coronary angiography and invasive coronary angiography was undertaken to assess graft patency. RESULTS: A total of 22 patients, comprising of 65 vessels were included in the analysis. At a median follow-up of 3.6 years post CABG (interquartile range, 2.3 to 4.8 years), 12 grafts (18.4%) were occluded. QFR was not statistically significantly higher in occluded grafts (0.81 ± 0.19 vs. 0.69 ± 0.21; P = 0.08). QFR demonstrated a discriminatory power to predict graft occlusion (area under the receiver operating characteristic curve, 0.70; 95% confidence interval [CI], 0.52 to 0.88; P = 0.03). At long-term follow-up, the risk of graft occlusion was higher in vessels with a QFR > 0.80 (58.6% vs. 17.0%; hazard ratio, 3.89; 95% CI, 1.05 to 14.42; P = 0.03 by log-rank test). QCA (minimum lumen diameter, lesion length, diameter stenosis) and IVUS (minimum lumen area, minimum lumen diameter, diameter stenosis) parameters were not predictive of long-term graft patency. CONCLUSIONS: QFR may predict long-term graft patency in patients undergoing CABG.

Comparison of diagnostic performance between quantitative flow ratio, non-hyperemic pressure indices and fractional flow reserve.

BACKGROUND: Quantitative flow ratio (QFR) is an estimate of fractional flow reserve (FFR) and is derived from 3-dimensional quantitative coronary angiography. The DILEMMA score is an angiographic technique developed to predict FFR. Unlike other diastolic indices such as instantaneous wave-free ratio (iFR), diastolic pressure ratio (dPR) and dPR25-75, neither QFR nor DILEMMA score require pressure wires. This study sought to compare the diagnostic performance of QFR, diastolic indices and DILEMMA score to predict FFR. METHODS: Between January 2010 and December 2013, patients who underwent invasive coronary angiography and FFR assessments were retrospectively studied. iFR and dPR were derived from FFR pressure tracings. QFR was computed using commercial software. RESULTS: Eighty-five lesions (25% FFR significant) were included in this study. Median FFR was 0.88 (0.81-0.92). QFR (rs=0.801), iFR (rs=0.710), dPR (rs=0.716), dPR25-75 (rs=0.715) and DILEMMA score (rs=-0.623) significantly correlated with FFR (P<0.001). QFR ≤0.8 had a specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of 95%, 86%, 86% and 95% respectively of predicting significant FFR (P<0.001). Receiver-operating characteristic (ROC) analysis revealed the AUC to predict significant FFR for QFR (0.947), iFR (0.880), dPR (0.883), dPR25-75 (0.880) and DILEMMA score (0.916) were not significantly different. However, QFR was a better predictor of FFR than iFR (0.947 vs. 0.770, P<0.01). CONCLUSIONS: QFR had excellent correlation and accuracy as measured against FFR. When compared to other diastolic indices and DILEMMA score, QFR performed at least as well as the other indices. QFR predicts FFR better than it predicts iFR. QFR is a convenient tool to assess significance of coronary stenosis and a reliable alternative to pressure-wire based indices. Prospective studies are required to investigate the performance and cost-effectiveness of QFR when independently used to guide clinical decision making.

The Natural history of Epicardial Adipose Tissue Volume and Attenuation: A long-term prospective cohort follow-up study.

Epicardial adipose tissue (EAT) is associated with cardiovascular risk. The longitudinal change in EAT volume (EATv) and density (EATd), and potential modulators of these parameters, has not been described. We prospectively recruited 90 patients with non-obstructive coronary atherosclerosis on baseline computed tomography coronary angiography (CTCA) performed for suspected coronary artery disease to undergo a repeat research CTCA. EATv in millilitres (mL) and EATd in Hounsfield units (HU) were analysed and multivariable regression analysis controlling for traditional cardiovascular risk factors (CVRF) performed to assess for any predictors of change. Secondary analysis was performed based on statin therapy. The median duration between CTCA was 4.3years. Mean EATv increased at follow-up (72 ± 33 mL to 89 ± 43 mL, p < 0.001) and mean EATd decreased (baseline -76 ± 6 HU vs. -86 ± 5 HU, p < 0.001). There were no associations between baseline variables of body mass index, age, sex, hypertension, hyperlipidaemia, diabetes or smoking on change in EATv or EATd. No difference in baseline, follow-up or delta EATv or EATd was seen in patients with (60%) or without baseline statin therapy. In this select group of patients, EATv consistently increased and EATd consistently decreased at long-term follow-up and these changes were independent of CVRF, age and statin use. Together with the knowledge of strong associations between EAT and cardiac disease, these findings may suggest that EAT is an independent parameter rather than a surrogate for cardiovascular risk.

End-stage renal failure is associated with impaired coronary microvascular function.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. Studies investigating the disproportionate burden of cardiovascular disease have occurred predominantly in the peripheral vasculature, often used noninvasive imaging modalities, and infrequently recruited patients receiving dialysis. This study sought to evaluate invasive coronary dynamic vascular function in patients with end-stage renal failure (ESRF). PATIENTS AND METHODS: Patients referred for invasive coronary angiography prior to renal transplantation were invited to participate. Control patients were recruited in parallel. Baseline characteristics were obtained. Coronary diameter (via quantitative coronary angiography) and coronary blood flow (via Doppler Flowire) were measured; macrovascular endothelial-dependent and independent effects were evaluated in response to intracoronary acetylcholine infusion (10 and 10 mol/l) and intracoronary glyceryl trinitrate, respectively. Microvascular function was evaluated by response to adenosine and expressed as coronary flow velocity reserve. Mean values were compared. RESULTS: Thirty patients were evaluated: 15 patients with ESRF (mean age 52.1 ± 9, male 73%) and 15 control patients (mean age 53.3 ± 13, male 60%). Comorbidity profile, aside from ESRF, was well matched. Baseline coronary blood flow was similar between groups (101.6 ± 10.3 vs. 103.4 ± 9.1 ml/min, P = 0.71), as was endothelial-dependent response to acetylcholine (159.1 ± 16.9 vs. 171.1 ± 16.8 ml/min, P = 0.41). Endothelial-independent response to glyceryl trinitrate was no different between groups (14.3 ± 3.1 vs. 13.1 ± 2.3%, P = 0.73. A significantly reduced coronary flow velocity reserve was observed in the ESRF cohort compared to controls (2.34 ± 0.4 vs. 3.05 ± 0.3, P = 0.003). CONCLUSION: Patients with ESRF had preserved endothelial-dependent function however compared to controls, demonstrated significantly attenuated microvascular reserve. An impaired response to adenosine may not only represent a component of the pathophysiological milieu in patients with ESRF but may also provide a basis for the suboptimal diagnostic performance of vasodilatory stress in this population.

Association of Volumetric Epicardial Adipose Tissue Quantification and Cardiac Structure and Function.

Background Epicardial adipose tissue ( EAT ) is in immediate apposition to the underlying myocardium and, therefore, has the potential to influence myocardial systolic and diastolic function or myocardial geometry, through paracrine or compressive mechanical effects. We aimed to review the association between volumetric EAT and markers of myocardial function and geometry. Methods and Results PubMed, Medline, and Embase were searched from inception to May 2018. Studies were included only if complete EAT volume or mass was reported and related to a measure of myocardial function and/or geometry. Meta-analysis and meta-regression were used to evaluate the weighted mean difference of EAT in patients with and without diastolic dysfunction. Heterogeneity of data reporting precluded meta-analysis for systolic and geometric associations. In the 22 studies included in the analysis, there was a significant correlation with increasing EAT and presence of diastolic dysfunction and mean e' (average mitral annular tissue Doppler velocity) and E/e' (early inflow / annular velocity ratio) but not E/A (ratio of peak early (E) and late (A) transmitral inflow velocities), independent of adiposity measures. There was a greater EAT in patients with diastolic dysfunction (weighted mean difference, 24.43 mL; 95% confidence interval, 18.5-30.4 mL; P<0.001), and meta-regression confirmed the association of increasing EAT with diastolic dysfunction ( P=0.001). Reported associations of increasing EAT with increasing left ventricular mass and the inverse correlation of EAT with left ventricular ejection fraction were inconsistent, and not independent from other adiposity measures. Conclusions EAT is associated with diastolic function, independent of other influential variables. EAT is an effect modifier for chamber size but not systolic function.

Association of Epicardial Adipose Tissue and High-Risk Plaque Characteristics: A Systematic Review and Meta-Analysis.

BACKGROUND: Epicardial adipose tissue (EAT) is hypothesized to alter atherosclerotic plaque composition, with potential development of high-risk plaque (HRP). EAT can be measured by volumetric assessment (EAT-v) or linear thickness (EAT-t). We performed a systematic review and random-effects meta-analysis to assess the association of EAT with HRP and whether this association is dependent on the measurement method used. METHODS AND RESULTS: Electronic databases were systematically searched up to October 2016. Studies reporting HRP by computed tomography or intracoronary imaging and studies measuring EAT-v or EAT-t were included. Odds ratios were extracted from multivariable models reporting the association of EAT with HRP and described as pooled estimates with 95% confidence intervals (CIs). Analysis was stratified by EAT measurement method. Nine studies (n=3772 patients) were included with 7 measuring EAT-v and 2 measuring EAT-t. Increasing EAT was significantly associated with the presence of HRP (odds ratio: 1.26 [95% CI, 1.11-1.43]; P<0.001). Patients with HRP had higher EAT-v than those without (weighted mean difference: 28.3 mL [95% CI, 18.8-37.8 mL]; P<0.001). EAT-v was associated with HRP (odds ratio: 1.19 [95% CI, 1.06-1.33]; P<0.001); however, EAT-t was not (odds ratio: 3.09 [95% CI, 0.56-17]; P=0.2). Estimates remained significant when adjusted for small-study effect bias (odds ratio: 1.13 [95% CI, 1.03-1.28]; P=0.04). CONCLUSIONS: Increasing EAT is associated with the presence of HRP, and patients with HRP have higher quantified EAT-v. The association of EAT-v with HRP is significant compared with EAT-t; however, a larger scale study is still required, and further evaluation is needed to assess whether EAT may be a potential therapeutic target for novel pharmaceutical agents. CLINICAL TRIAL REGISTRATION: URL: https://www.crd.york.ac.uk/. Unique identifier: CRD42017055473.

Impact of heart rate on diagnostic accuracy of second generation 320-detector computed tomography coronary angiography.

OBJECTIVE: To assess the impact of elevated heart rate (HR) on the diagnostic accuracy and image quality of second-generation 320-detector computed tomography coronary angiography (320-CTCA). METHODS: Consecutive patients with suspected coronary disease referred for invasive coronary angiography (ICA) were prospectively recruited and underwent 320-CTCA. Pre-scan beta-blockers were administered if native HR>80 bpm and post-scan cohorts stratified by traditional (HR ≤60 bpm) and elevated HR (61-80 bpm). A wider phase window was used for the elevated HR group (30-80%). 320-CTCA and ICA were analyzed by independent readers blinded to other data. Significant disease was defined as ≥50% visual stenosis on ICA. Uninterpretable segments by 320-CTCA were considered to be significant on an intention-to-diagnose principle. Image quality was assessed by 5-point Likert score. RESULTS: Of 107 patients studied (1,662 segments), there was no significant difference in sensitivity, specificity, positive and negative predictive value between patients with HR ≤60 bpm (n=55) vs. HR 61-80 bpm (n=52): 97%, 88%, 95%, 94% vs. 100%, 88%, 95%, 100%; Receiver operator characteristic-area under the curve 0.93 vs. 0.94, P=0.82). Overall per-patient diagnostic accuracy was 96% in both groups with no significant difference in interpretable segments (Likert ≥2) or median radiation dose (2.4 mSv vs. 2.7 mSv, P=0.35). Only 4/1,662 (0.2%) segments were uninterpretable by motion artefact in the whole cohort. CONCLUSIONS: In patients with HR >60 and up to 80bpm, second generation 320-CTCA provides comparably adequate diagnostic accuracy to HR ≤60 without significantly impacting upon overall segmental evaluability.

Epicardial adipose tissue and myocardial ischemia assessed by computed tomography perfusion imaging and invasive fractional flow reserve.

BACKGROUND: Epicardial adipose tissue (EAT) is a metabolically active fat depot that is associated with incident coronary artery disease (CAD) and major adverse cardiovascular events. The relationship between EAT and myocardial ischemia remains unclear. This study investigated the relationship between EAT volume and the presence of perfusion defects on myocardial computed tomographic perfusion imaging (CTP) and functional stenoses on invasive fractional flow-reserve (FFR). METHODS: Data were obtained from a previous prospective cross-sectional study in patients with suspected CAD. Patients underwent combined coronary computed tomography angiography (coronary CTA) and CTP followed by invasive coronary angiogram (ICA) and FFR within 14 days. FFR was performed in all major epicardial vessels unless they were angiographically smooth or occluded, with a threshold of <0.8 considered significant. EAT volume was quantified semi-automatically on coronary CTA. RESULTS: There were 38 patients included for analysis, mean age 62.5 ± 10.0 years, 68.4% male. Median EAT volume was 82.8 mL (interquartile range (IQR) 49.3 mL). FFR was interrogated in 73/114 (64%) vessels. There was no difference in EAT volumes in patients with and without CTP defects (84.4 mL, IQR: 35.6 mL vs 81.1 mL, IQR: 53.1 mL, p = 0.7). There was also no difference in EAT volumes in patients with and without FFR-significant vessels (86.5 mL IQR: 36.6 mL vs 79.1 mL IQR: 54.5 mL, p = 0.7) and no difference when analysed by number of CTP positive territories or FFR-significant vessels (p = 0.4 and p = 0.8 respectively). CONCLUSION: This study demonstrated no observable relationship between EAT volume and perfusion defects on myocardial CT perfusion imaging or functional stenosis on invasive FFR.

Imaging of coronary atherosclerosis in various susceptible groups.

Coronary artery disease (CAD) is the leading cause of death and disability worldwide. Atherosclerosis, which is the primary pathophysiologic mechanism for the development of plaque leading to CAD, is a multifactorial process resulting from a complex interplay between genetic susceptibility and various risk factors such as hypertension (HT), dyslipidaemia, diabetes mellitus (DM) and smoking. In addition, influences from other disease states such as chronic kidney disease (CKD), obesity and the metabolic syndrome as well as gender and ethnic diversity also contribute to the disease process. Insights from pathological observations and advances in cellular and molecular biology have helped us understand the process of plaque formation, progression and rupture leading to events. Several intravascular imaging techniques such as intravascular ultrasound (IVUS), Virtual histology IVUS (VH-IVUS) and optical coherence tomography (OCT) allow in vivo assessment of plaque burden, plaque morphology and response to therapy. In addition, non invasive assessment using coronary artery calcium (CAC) score allows risk stratification and plaque burden assessment whilst computed tomography coronary angiography (CTCA) allows evaluation of luminal stenosis, plaque characterisation and quantification. This review aims to summarise the results of invasive and non-invasive imaging studies of coronary atherosclerosis seen in various high-risk populations including DM, metabolic syndrome, obesity, CKD and, gender differences and ethnicity. Understanding the phenotype of plaques in various susceptible groups may allow potential development of personalised therapies.

Chronic Total Occlusion - Percutaneous Coronary Intervention (CTO-PCI) Experience in a Single, Multi-operator Australian Centre: Need for dedicated CTO-PCI programs.

BACKGROUND: Chronic total occlusions (CTOs) represent a unique set of lesions for percutaneous coronary intervention (PCI) because of the complexity of techniques required to treat them. METHODS: We retrospectively reviewed the CTO-PCI experience between January 2010 and December 2012, in a multi-operator single centre, which is one of the largest volume PCI centres in Australia. RESULTS: Eighty-two patients (62.6±11.3 years, 85% males) who had CTO-PCIs were included. The most common site of CTO was the right coronary artery (44%), followed by the left circumflex (30%) and left anterior descending (26%) arteries. Using the Japanese CTO scoring system, 34% of lesions were classified as easy, 37% intermediate, 23% difficult and 6% very difficult. All PCIs were performed by antegrade approach. Selected procedural characteristics included: re-attempt procedure 10%; multiple access sites 21%; more than one guidewire 77%; additional support modality 60%; drug-eluting stents 97%; stent number 1.6±0.8; total stent length 40.1±24.5mm; fluoroscopy time 33±17min; contrast volume 257.2±110.8mL. Overall CTO success rate was 60%. In-hospital adverse outcomes included 1.2% mortality, 9.8% peri-procedural myocardial infarction, 4.9% emergency bypass surgery, 3% cardiac tamponade and 4.9% contrast induced nephropathy. CONCLUSION: We report modest success rates in a single Australian centre experience in a relatively conservative cohort of CTO-PCI prior to the initiation of a dedicated CTO revascularisation program.

Percutaneous Coronary Intervention Enhances Accelerative Wave Intensity in Coronary Arteries.

BACKGROUND: The systolic forward travelling compression wave (sFCW) and diastolic backward travelling decompression waves (dBEW) predominantly accelerate coronary blood flow. The effect of a coronary stenosis on the intensity of these waves in the distal vessel is unknown. We investigated the relationship between established physiological indices of hyperemic coronary flow and the intensity of the two major accelerative coronary waves identified by Coronary Wave Intensity analysis (CWIA). METHODOLOGY / PRINCIPAL FINDINGS: Simultaneous intracoronary pressure and velocity measurement was performed during adenosine induced hyperemia in 17 patients with pressure / Doppler flow wires positioned distal to the target lesion. CWI profiles were generated from this data. Fractional Flow Reserve (FFR) and Coronary Flow Velocity Reserve (CFVR) were calculated concurrently. The intensity of the dBEW was significantly correlated with FFR (R = -0.70, P = 0.003) and CFVR (R = -0.73, P = 0.001). The intensity of the sFCW was also significantly correlated with baseline FFR (R = 0.71, p = 0.002) and CFVR (R = 0.59, P = 0.01). Stenting of the target lesion resulted in a median 178% (interquartile range 55-280%) (P<0.0001) increase in sFCW intensity and a median 117% (interquartile range 27-509%) (P = 0.001) increase in dBEW intensity. The increase in accelerative wave intensity following PCI was proportionate to the baseline FFR and CFVR, such that stenting of lesions associated with the greatest flow limitation (lowest FFR and CFVR) resulted in the largest increases in wave intensity. CONCLUSIONS: Increasing ischemia severity is associated with proportionate reductions in cumulative intensity of both major accelerative coronary waves. Impaired diastolic microvascular decompression may represent a novel, important pathophysiologic mechanism driving the reduction in coronary blood flow in the setting of an epicardial stenosis.

Superior CT coronary angiography image quality at lower radiation exposure with second generation 320-detector row CT in patients with elevated heart rate: a comparison with first generation 320-detector row CT.

BACKGROUND: This study aims to compare the image quality of second generation versus first generation 320-computed tomography coronary angiography (CTCA) in patients with heart rate ≥65 bpm as it has not been specifically reported. METHODS: Consecutive patients who underwent CTCA using second-generation-320-detector-row-CT were prospectively enrolled. A total of 50 patients with elevated (≥65 bpm) heart rate and 50 patients with controlled (<65 bpm) heart rate were included. Age and gender matched patients who were scanned with the first-generation-320-detector-row-CT were retrospectively identified. Image quality in each coronary artery segment was assessed by two blinded CT angiographers using the five-point Likert scale. RESULTS: In the elevated heart rate cohorts, while there was no significant difference in heart rate during scan-acquisition (66 vs. 69 bpm, P=0.308), or body mass index (28.5 vs. 29.6, P=0.464), the second generation scanner was associated with better image quality (3.94±0.6 vs. 3.45±0.8, P=0.001), and with lower radiation (2.8 vs. 4.3 mSv, P=0.009). There was no difference in scan image quality for the controlled heart rate cohorts. CONCLUSIONS: The second generation CT scanner provides better image quality at lower radiation dose in patients with elevated heart rate (≥65 bpm) compared to first generation CT scanner.

An update on stem cell therapies for acute coronary syndrome.

Well into the second decade since its conception, cell transplantation continues to undergo intensive evaluation for the treatment of myocardial infarction. At a mechanistic level, its objectives remain to replace lost cardiac cell mass with new functioning cardiomyocytes and vascular cells, thereby minimizing infarct size and scar formation, and improving clinical outcomes by preventing adverse left ventricular remodeling and recurrent ischemic events. Many different cell types, including pluripotent stem cells and various adult-derived progenitor cells, have been shown to have therapeutic potential in preclinical studies, while early phase human trial experience has provided divergent outcomes and fundamental lessons, emphasizing that there remain key issues to address and challenges to overcome before cell therapy can be applied to wider clinical practice. The purpose of this review is to provide a balanced update on recent seminal developments in this exciting field and look to the next important steps to ensure its forward progression.

Comparison of diagnostic accuracy of combined assessment using adenosine stress computed tomography perfusion + computed tomography angiography with transluminal attenuation gradient + computed tomography angiography against invasive fractional flow reserve.

OBJECTIVES: The goal of this study was to compare the diagnostic accuracy of combined computed tomography perfusion (CTP) + computed tomography angiography (CTA), transluminal attenuation gradient by 320-detector row computed tomography (TAG320) + CTA, and CTP + TAG320 + CTA (multidetector computed tomography-integrated protocol [MDCT-IP]) assessment in predicting significant fractional flow reserve (FFR). BACKGROUND: CTA has limited specificity for predicting functionally significant stenoses. Novel CT techniques, including adenosine stress CTP and TAG320, may improve the diagnostic accuracy of CTA. METHODS: CTA, CTP, and TAG320 were assessed using 320-detector row MDCT. Patients who underwent CTA, CTP, and FFR assessment on invasive coronary angiography were included. CTP was assessed using the visual perfusion assessment. TAG320 was defined as the linear regression coefficient between luminal attenuation and axial distance. A TAG320 cutoff value of -15.1 HU/10 mm as previously described was defined as significant. Functionally significant coronary stenosis was defined as FFR ≤0.8. RESULTS: The cohort included 75 patients (age 64.1 ± 10.8 years, 52 men) and 44 (35%) FFR-significant vessels. In 127 vessels, CTA predicted FFR-significant stenosis with 89% sensitivity and 65% specificity compared with MDCT-IP, which showed 88% sensitivity and 83% specificity. In 97 vessels in which the results of all techniques were available, TAG320 + CTA (area under the curve [AUC] = 0.844) and CTP + CTA (AUC = 0.845) had comparable per-vessel diagnostic accuracy (p = 0.98). The diagnostic accuracy of MDCT-IP (AUC = 0.91) was superior to TAG320 + CTA or CTP + CTA (p = 0.01). CONCLUSIONS: In vessels without significant calcification or artefact, TAG320 + CTA and CTP + CTA provide comparable diagnostic accuracy for functional assessment of coronary artery stenosis. MDCT-IP may provide the best diagnostic accuracy for functional assessment of coronary artery stenosis.

Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction.

BACKGROUND AIMS: Traditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs). METHODS: Three groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 × 10(6) cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2 and 4 weeks after MI. RESULTS: Immediate MSC treatment attenuated early myocardial damage with EF of 35.3 ± 3.1% (dual group, n = 12) and 35.2 ± 2.2% (single group, n = 15) at 1 week after MI compared with 22.1 ± 1.9% in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 ± 3.1% by week 4, which was significantly higher than in the single-therapy group (EF 35.9 ± 1.8%, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium. CONCLUSIONS: Repeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.

Impact of timing and dose of mesenchymal stromal cell therapy in a preclinical model of acute myocardial infarction.

BACKGROUND: Although mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI. METHODS AND RESULTS: Sprague-Dawley rats were used. Allogeneic prospectively isolated MSC ("low" dose 1 × 10(6) or "high" dose 2 × 10(6) cells) were delivered by transepicardial injection immediately after MI ("early-low," "early-high"), or 1 week later ("late-low," "late-high"). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 ± 1.7%, early-low 26.5 ± 3.2%, early-high 7.9 ± 2.6%, late-low 19.6 ± 3.5%, late-high 17.9 ± 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration. CONCLUSIONS: The nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients.