Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.

Visually Estimated RESOLVE Score Based on Coronary Computed Tomography to Predict Side Branch Occlusion in Percutaneous Bifurcation Intervention.

PURPOSE: The quantitative RESOLVE (Risk prEdiction of Side branch OccLusion in coronary bifurcation interVEntion) score derived from coronary computed tomography angiography (coronary CTA) was developed as a noninvasive and accurate prediction tool for side branch (SB) occlusion in coronary bifurcation intervention. We aimed to determine the ability of a visually estimated CTA-derived RESOLVE score (V-RESOLVE score) to predict SB occlusion in coronary bifurcation intervention. MATERIALS AND METHODS: The present study included 363 patients with 400 bifurcation lesions. CTA-derived V-RESOLVE score was derived and compared with the quantitative CTA-derived RESOLVE score. The scoring systems were divided into quartiles, and classified as the high-risk and non-high-risk groups. SB occlusion was defined as any decrease in thrombolysis in myocardial infarction flow grade after main vessel stenting. RESULTS: In total, 28 SB occlusions (7%) occurred. The concordance between visual and quantitative CTA analysis showed poor to excellent agreement (weighted κ range: 0.099 to 0.867). The area under the receiver operating curve for the prediction of SB occlusion was significantly higher for the CTA-derived V-RESOLVE score than for quantitative CTA-derived RESOLVE score (0.792 vs. 0.709, P=0.049). The total net reclassification index was 42.7% (P=0.006), and CTA-derived V-RESOLVE score showed similar capability to discriminate between high-risk group (18.6% vs. 13.8%, P=0.384) and non-high-risk group (3.8% vs. 4.9%, P=0.510) as compared with quantitative CTA-derived RESOLVE score. CONCLUSIONS: Visually estimated CTA-derived V-RESOLVE score is an accurate and easy-to-use prediction tool for the stratification of SB occlusion in coronary bifurcation intervention.

Noncalcified plaque burden quantified from coronary computed tomography angiography improves prediction of side branch occlusion after main vessel stenting in bifurcation lesions: results from the CT-PRECISION registry.

OBJECTIVES: To assess the incremental value of quantitative plaque features measured from computed tomography angiography (CTA) for predicting side branch (SB) occlusion in coronary bifurcation intervention. METHODS: We included 340 patients with 377 bifurcation lesions in the post hoc analysis of the CT-PRECISION registry. Each bifurcation was divided into three segments: the proximal main vessel (MV), the distal MV, and the SB. Segments with evidence of coronary plaque were analyzed using semi-automated software allowing for quantitative analysis of coronary plaque morphology and stenosis. Coronary plaque measurements included calcified and noncalcified plaque volumes, and corresponding burdens (respective plaque volumes × 100%/vessel volume), remodeling index, and stenosis. RESULTS: SB occlusion occurred in 28 of 377 bifurcation lesions (7.5%). The presence of visually identified plaque in the SB segment, but not in the proximal and distal MV segments, was the only qualitative parameter that predicted SB occlusion with an area under the curve (AUC) of 0.792. Among quantitative plaque parameters calculated for the SB segment, the addition of noncalcified plaque burden (AUC 0.840, p = 0.003) and low-density plaque burden (AUC 0.836, p = 0.012) yielded significant improvements in predicting SB occlusion. Using receiver operating characteristic curve analysis, optimal cut-offs for noncalcified plaque burden and low-density plaque burden were > 33.6% (86% sensitivity and 78% specificity) and > 0.9% (89% sensitivity and 73% specificity), respectively. CONCLUSIONS: CTA-derived noncalcified plaque burden, when added to the visually identified SB plaque, significantly improves the prediction of SB occlusion in coronary bifurcation intervention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03709836 registered on October 17, 2018.

Comparison of Computed Tomography Angiography Versus Invasive Angiography to Assess Medina Classification in Coronary Bifurcations.

The Medina classification is used to determine the presence of significant stenosis (≥50%) within each of the 3 arterial segments of coronary bifurcation in invasive coronary angiography (ICA). The utility of coronary computed tomography angiography (coronary CTA) for assessment of Medina classification is unknown. We aimed to compare the agreement and reproducibility of Medina classification between ICA and coronary CTA, and evaluate its ability to predict side branch (SB) occlusion following percutaneous coronary intervention (PCI). In total 363 patients with 400 bifurcations were included, and 28 (7%) SB occlusions among 26 patients were noted. Total agreement between CTA and ICA for assessment of Medina class was poor (kappa = 0.189), and discordance between both modalities was noted in 253 (63.3%) lesions. Larger diameter ratio between main vessel and SB in CTA, and larger bifurcation angle in ICA were independently associated with discordant Medina assessment. Whereas the interobserver agreement on Medina classification in CTA was moderate (kappa = 0.557), only fair agreement (kappa = 0.346) was observed for ICA. Finally, Medina class with any proximal involvement of main vessel and SB (1.X.1) on CTA or ICA was the most predictive of SB occlusion following PCI with no significant differences between both modalities (area under the curve 0.686 vs 0.663, p = 0.693, respectively). In conclusion, Medina classification was significantly affected by the imaging modality, and coronary CTA improved reproducibility of Medina classification compared with ICA. Both CTA and ICA-derived Medina class with any involvement of the proximal main vessel and SB was predictive of SB occlusion following PCI.

Accuracy of RESOLVE score derived from coronary computed tomography versus visual angiography to predict side branch occlusion in percutaneous bifurcation intervention.

INTRODUCTION: Visually estimated angiographic V-RESOLVE score was developed as a simple and accurate prediction tool for side branch (SB) occlusion in patients undergoing coronary bifurcation intervention. Data on the use of coronary computed tomography angiography (coronary CTA) for guiding percutaneous coronary intervention in bifurcation lesions is scarce. OBJECTIVES: We aimed to validate the ability of quantitative CTA-derived RESOLVE score for predicting SB occlusion in coronary bifurcation intervention and to compare its predictive value with that of the angiography-based V-RESOLVE score. METHODS: We included 363 patients with 400 bifurcation lesions. Angiographic V-RESOLVE score and CTA-derived RESOLVE score were calculated utilizing the weights from the QCA-based RESOLVE score. The scoring systems were divided into quartiles, and classified as the non-high-risk group and the high-risk group. Accuracy was assessed using areas under the receiver-operator characteristic curve (AUC). SB occlusion was defined as any decrease in Thrombolysis in Myocardial Infarction flow grade (including the absence of flow) in the SB after main vessel stenting. RESULTS: In total, 28 SB occlusions (7%) occurred. CTA-derived RESOLVE and V-RESOLVE scores achieved comparable predictive accuracy (0.709 vs. 0.752, respectively, p = 0.531) for predicting SB occlusion, and the analysis of AUC for each constituent element of the scores did not show any significant difference between CTA and visual angiography. The total net reclassification index was -18.6% (p = 0.194), and there were no significant differences in the rates of SB occlusion in the non-high-risk group (4.9% vs. 3.8%, p = 0.510) and the high-risk group (13.8% vs. 18.6%, p = 0.384) between CTA-derived RESOLVE and V-RESOLVE scores. CONCLUSIONS: The quantitative CTA-derived RESOLVE score is an accurate and reliable alternative to the visually estimated angiographic V-RESOLVE score for prediction of SB occlusion in coronary bifurcation intervention. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03709836.

Mechanisms of Myocardial Infarction in Patients With Nonobstructive Coronary Artery Disease: Results From the Optical Coherence Tomography Study.

OBJECTIVES: This study sought to assess the presence and morphological features of coronary plaques on optical coherence tomography (OCT) as the causes of myocardial infarction with nonobstructive coronary arteries (MINOCA). BACKGROUND: Although coronary atherosclerosis has been postulated as a potential mechanism of MINOCA, the interaction between disrupted coronary plaques and myocardial injury remains unknown. METHODS: In a prospective study, consecutive patients with MI but without significant coronary stenosis (≥50%) at angiography underwent OCT and cardiac magnetic resonance (CMR) with late gadolinium-enhancement (LGE). The infarct-related artery (IRA) was identified by localization of ischemic-type LGE. RESULTS: Thirty-eight MINOCA patients (mean age 62 ± 13 years, 55% female, 39% with ST-segment elevation) were enrolled. Maximal diameter stenosis was 35% by angiography, and 5 patients (13%) had normal angiogram results. Plaque disruption and coronary thrombus were observed in 9 patients (24%) and 7 patients (18%), respectively. Sixteen of 31 patients (52%) undergoing CMR showed LGE. Ischemic-type LGE was present in 7 patients (23%) and was more common in patients with than without plaque disruption (50% vs. 13%, respectively; p = 0.053) and coronary thrombus (67% vs. 12%, respectively; p = 0.014). In the per-lesion analysis, the IRA showed significantly more plaque disruption (40% vs. 6%; p = 0.02), thrombus (50% vs. 4%; p = 0.014), and thin-cap fibroatheroma (70% vs. 30%; p = 0.03) than the non-IRA. CONCLUSIONS: Plaque disruption and thrombus are not uncommon in MI without obstructive coronary stenoses at angiography and may be associated with the presence and location of ischemic-type myocardial injury on CMR. OCT may be valuable in identifying atherosclerotic etiology in individuals with MINOCA. (Optical Coherence Tomography in Patients With Acute Myocardial Infarction and Nonobstructive Coronary Artery Disease [SOFT-MI]; NCT02783963).

Feasibility and safety of augmented-reality glass for computed tomography-assisted percutaneous revascularization of coronary chronic total occlusion: A single center prospective pilot study.

BACKGROUND: Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) may be facilitated by projection of coronary computed tomography angiography (CTA) datasets in the catheterization laboratory. There is no data on the feasibility and safety outcomes of CTA-assisted CTO PCI using a wearable augmented-reality glass. METHODS: A total of 15 patients scheduled for elective antegrade CTO intervention were prospectively enrolled and underwent preprocedural coronary CTA. Three-dimensional and curved multiplanar CT reconstructions were transmitted to a head-mounted hands-free computer worn by interventional cardiologists during CTO PCI to provide additional information on CTO tortuosity and calcification. The results of CTO PCI using a wearable computer were compared with a time-matched prospective angiographic registry of 59 patients undergoing antegrade CTO PCI without a wearable computer. Operators' satisfaction was assessed by a 5-point Likert scale. RESULTS: Mean age was 64 ± 8 years and the mean J-CTO score was 2.1 ± 0.9 in the CTA-assisted group. The voice-activated co-registration and review of CTA images in a wearable computer during CTO PCI were feasible and highly rated by PCI operators (4.7/5 points). There were no major adverse cardiovascular events. Compared with standard CTO PCI, CTA-assisted recanalization of CTO using a wearable computer showed more frequent selection of the first-choice stiff wire (0% vs 40%, p < 0.001) and lower contrast exposure (166 ± 52 vs 134 ± 43 ml, p = 0.03). Overall CTO success rates and safety outcomes remained similar between both groups. CONCLUSIONS: CTA-assisted CTO PCI using an augmented-reality glass is feasible and safe, and might reduce the resources required for the interventional treatment of CTO.

Stent sizing strategies in renal artery stenting: the comparison of conventional invasive renal angiography with renal computed tomographic angiography.

INTRODUCTION: Randomized trials comparing invasive treatment of renal artery stenosis with standard pharmacotherapy did not show substantial benefit from revascularization. One of the potential reasons for that may be suboptimal procedure technique. AIM: To compare renal stent sizing using two modalities: three-dimensional renal computed tomography angiography (CTA) versus conventional angiography. MATERIAL AND METHODS: Forty patients (41 renal arteries), aged 65.1 ±8.5 years, who underwent renal artery stenting with preprocedural CTA performed within 6 months, were retrospectively analyzed. In CTA analysis, reference diameter (CTA-D) and lesion length (CTA_LL) were measured and proposed stent diameter and length were recorded. Similarly, angiographic reference diameter (ANGIO_D) and lesion length (ANGIO_LL) as well as proposed stent dimensions were obtained by visual estimation. RESULTS: The median CTA_D was 0.5 mm larger than the median ANGIO_D (p < 0.001). Also, the proposed stent diameter in CTA evaluation was 0.5 mm larger than that in angiography (p < 0.0001). The median CTA_LL was 1 mm longer than the ANGIO_LL (p = NS), with significant correlation of these variables (r = 0.66, p < 0.0001). The median proposed stent length with CTA was equal to that proposed with angiography. The median diameter of the implanted stent was 0.5 mm smaller than that proposed in CTA (p < 0.0005) and identical to that proposed in angiography. The median length of the actual stent was longer than that proposed in angiography (p = 0.0001). CONCLUSIONS: Renal CTA has potential advantages as a tool adjunctive to angiography in appropriate stent sizing. Careful evaluation of the available CTA scans may be beneficial and should be considered prior to the planned procedure.

CT Angiography for the Detection of Coronary Artery Stenoses in Patients Referred for Cardiac Valve Surgery: Systematic Review and Meta-Analysis.

OBJECTIVES: This study aimed to evaluate the diagnostic accuracy of coronary computed tomography angiography (CTA) for detecting coronary artery stenoses in patients with valvular heart disease undergoing valve surgery. BACKGROUND: Coronary CTA is currently not routinely recommended for detecting coronary artery stenoses before cardiac valve surgery. However, recent improvements in computed tomography technology may enable the identification of the most appropriate candidates for coronary CTA before valve surgery. METHODS: A systematic review was performed of PubMed, EMBASE, and the Cochrane databases for all studies that used ≥16-detector row computed tomography scanning to perform coronary CTA in patients with valvular heart disease scheduled for valve surgery and validated the results against invasive angiography. Summary diagnostic accuracies were calculated by using a bivariate random effects model, and a generalized linear mixed model was applied for heterogeneity analysis. RESULTS: Seventeen studies analyzing 1,107 patients and 12,851 coronary segments were included. Patient-based analysis revealed a pooled sensitivity of 93% (95% confidence interval [CI]: 86 to 97), specificity of 89% (95% CI: 86 to 91), a negative likelihood ratio (LR) of 0.07 (95% CI: 0.04 to 0.16), and a positive LR of 8.44 (95% CI: 6.49 to 10.99) for coronary CTA to identify individuals with stenosis ≥50%. Specificity and positive LR were higher in patients without aortic stenosis (AS) versus those with AS (96% vs. 87% and 21.2 vs. 7.4, respectively), as well as with ≥64 detectors versus <64 detectors (90% vs. 86% and 9.5 vs. 6.9). Heterogeneity analysis revealed a significant impact of AS and the number of detectors on specificity of CTA. CONCLUSIONS: Coronary CTA using currently available technology is a reliable imaging alternative to invasive angiography with excellent sensitivity and negative LR for the detection of significant coronary stenoses in patients undergoing cardiac valve surgery. The specificity of coronary CTA may be decreased against the background of AS (Computed Tomography Angiography for the Detection of Coronary Artery Disease in Patients Referred for Cardiac Valve Surgery: A Meta-Analysis; CRD42015016213).

Automated Quantitative Plaque Analysis for Discrimination of Coronary Chronic Total Occlusion and Subtotal Occlusion in Computed Tomography Angiography.

PURPOSE: The aim of this study was to evaluate the utility of automated plaque analysis in differentiating chronic total occlusion (CTO) from subtotal occlusion (SO) in patients with ambiguous coronary lesions on coronary computed tomography angiography (CTA). MATERIALS AND METHODS: A total of 63 patients with 63 ambiguous coronary lesions on CTA were included. The lesion length (LL), diameter stenosis, plaque volume and composition, remodeling index, and contrast density difference (CDD) (reflecting intraluminal contrast kinetics over the lesion) were assessed using an automatic software tool. All patients underwent invasive coronary angiography. RESULTS: Coronary angiography confirmed 28 CTOs and 35 SOs. CTOs showed significantly longer LL (6.4±12.3 vs. 1.0±2.2 mm, P=0.03) and higher CDD (74%±31% vs. 55%±32%, P=0.02) compared with SO. The optimal thresholds for prediction of CTO for CDD and LL were ≥43% and ≥1 mm, respectively (max. sensitivity: 82% for CDD, max. specificity: 77% for LL). The guidewire manipulation time correlated with LL (r=0.529, P=0.004) and CDD (r=0.435, P=0.021) in lesions attempted by percutaneous coronary intervention. CONCLUSIONS: Automated computed tomography plaque analysis may be applied as a noninvasive tool to differentiate CTO from SO.

First-in-Man Computed Tomography-Guided Percutaneous Revascularization of Coronary Chronic Total Occlusion Using a Wearable Computer: Proof of Concept.

We report a case of successful computed tomography-guided percutaneous revascularization of a chronically occluded right coronary artery using a wearable, hands-free computer with a head-mounted display worn by interventional cardiologists in the catheterization laboratory. The projection of 3-dimensional computed tomographic reconstructions onto the screen of virtual reality glass allowed the operators to clearly visualize the distal coronary vessel, and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. This case provides proof of concept that wearable computers can improve operator comfort and procedure efficiency in interventional cardiology.

Computed tomography angiography for prediction of atrial fibrillation after coronary artery bypass grafting: proof of concept.

BACKGROUND: Postoperative atrial fibrillation (AF) is a serious complication of coronary artery bypass grafting (CABG). There are scant data on the application of coronary computed tomography angiography (CCTA) for prediction of postoperative AF. METHODS: A total of 102 patients (77 male, mean age: 64±10 years) with pre-procedural CCTA undergoing isolated CABG were enrolled. Clinical risk factors were collected. Qualitative and quantitative CCTA analysis of the atria, pulmonary veins (PV), and epicardial adipose tissue (EAT) along the left atrium (LA) was performed to determine the predictors for postoperative AF. The primary endpoint was defined as any in-hospital AF requiring treatment. RESULTS: Postoperative AF occurred in 24% of patients. Patients with AF had higher body mass index (29.7±4.8kg/m(2) vs 27.3±3.9kg/m(2), p=0.013), larger right atrial area (25.4±5.3cm(2) vs 22.3±6.4cm(2), p=0.035), LA systolic volume (114.7±32.8ml vs 96.8±30.4ml, p=0.015), LA EAT volume (5.6±3ml vs 4±2.5ml, p=0.009), and right superior PV ostium area (3.8±1.3cm(2) vs 3±1cm(2), p=0.021) compared to non-AF patients. By multivariable analysis, only LA EAT volume [odds ratio (OR): 1.21, 95% confidence interval (CI): 1.01-1.44, p=0.036] and right superior PV ostium area (OR: 1.63, 95% CI: 1.06-2.50, p=0.026) were independent predictors of AF. The optimal cut-offs for LA EAT volume and right superior PV ostium were >3.4ml and >4.1cm(2), respectively (max. sensitivity: 83%, max. specificity: 86%). CONCLUSIONS: Increased LA EAT and right superior PV ostial size are independently associated with AF after CABG. CCTA might be used as a noninvasive prediction tool for AF in patients undergoing CABG.

Statins impair glucose uptake in human cells.

OBJECTIVE: Considering the increasing number of clinical observations indicating hyperglycemic effects of statins, this study was designed to measure the influence of statins on the uptake of glucose analogs by human cells derived from liver, adipose tissue, and skeletal muscle. DESIGN: Flow cytometry and scintillation counting were used to measure the uptake of fluorescently labeled or tritiated glucose analogs by differentiated visceral preadipocytes, skeletal muscle cells, skeletal muscle myoblasts, and contact-inhibited human hepatocellular carcinoma cells. A bioinformatics approach was used to predict the structure of human glucose transporter 1 (GLUT1) and to identify the presence of putative cholesterol-binding (cholesterol recognition/interaction amino acid consensus (CRAC)) motifs within this transporter. Mutagenesis of CRAC motifs in SLC2A1 gene and limited proteolysis of membrane GLUT1 were used to determine the molecular effects of statins. RESULTS: Statins significantly inhibit the uptake of glucose analogs in all cell types. Similar effects are induced by methyl-ß-cyclodextrin, which removes membrane cholesterol. Statin effects can be rescued by addition of mevalonic acid, or supplementation with exogenous cholesterol. Limited proteolysis of GLUT1 and mutagenesis of CRAC motifs revealed that statins induce conformational changes in GLUTs. CONCLUSIONS: Statins impair glucose uptake by cells involved in regulation of glucose homeostasis by inducing cholesterol-dependent conformational changes in GLUTs. This molecular mechanism might explain hyperglycemic effects of statins observed in clinical trials.

The prevalence and characteristics of intra-atrial right coronary artery anomaly in 9,284 patients referred for coronary computed tomography angiography.

OBJECTIVE: To determine the prevalence, radiologic patterns and clinical characteristics of intra-atrial right coronary artery (IARCA) among adult coronary computed tomography angiography (CCTA) population. METHODS: We included 9,284 consecutive subjects who underwent CCTA at a single high-volume center. The presence of IARCA including the number, length and diameter of IARCA segments with accompanying atherosclerosis and coronary anomalies were evaluated. Additionally, clinical characteristics and midterm follow-up of IARCA patients were recorded. RESULTS: The IARCA prevalence was 0.15% (14/9,284) with 15 intra-atrial segments. The intra-atrial segment length ranged from 14 to 53 mm, and the mean diameter proximal to the entry site was 3.3 ± 0.7 mm. IARCA was more often associated with intramuscular course of the left anterior descending coronary artery (29% vs. 4%, p=0.001) and anomalous origin of the left circumflex artery from the right aortic sinus (14% vs. 0.3%, p=0.001) compared with non-IARCA cases. The majority of IARCA patients were women (86%) presenting with supraventricular arrhythmia (71%). Compared with computed tomographic population without IARCA, IARCA subjects were younger (60 ± 12 vs. 54 ± 14 years, p=0.037) and more often women (51% vs. 86%, p=0.013). At a mean of 20 months follow-up of IARCA patients there were no adverse cardiac events except for supraventricular tachycardia episodes occurring in 36% of subjects. CONCLUSIONS: IARCA occurs rarely and is often associated with additional coronary anomalies. The clinical profile of IARCA patients is most often represented by middle-aged women with supraventricular arrhythmia showing favorable midterm prognosis.

Advanced computed tomographic anatomical and morphometric plaque analysis for prediction of fractional flow reserve in intermediate coronary lesions.

OBJECTIVE: To determine the application of advanced coronary computed tomography angiography (CCTA) plaque analysis for predicting invasive fractional flow reserve (FFR) in intermediate coronary lesions. METHODS: Sixty-one patients with 71 single intermediate coronary lesions (≥ 50-80% stenosis) on CCTA prospectively underwent coronary angiography and FFR. Advanced anatomical and morphometric plaque analysis was performed based on CCTA data set to determine optimal criteria for significant flow impairment. A significant stenosis was defined as FFR ≤ 0.80. RESULTS: FFR averaged 0.85 ± 0.09, and 19 lesions (27%) were functionally significant. FFR correlated with minimum lumen area (MLA) (r=0.456, p<0.001), minimum lumen diameter (MLD) (r=0.326, p=0.006), reference lumen diameter (RLD) (r=0.245, p=0.039), plaque burden (r=-0.313, p=0.008), lumen area stenosis (r=-0.305, p=0.01), lesion length (r=-0.692, p<0.001), and plaque volume (r=-0.668, p<0.001). There was no relationship between FFR and CCTA morphometric plaque parameters. By multivariate analysis the independent predictors of FFR were lesion length (beta=-0.581, p<0.001), MLA (beta=0.360, p=0.041), and RLD (beta=-0.255, p=0.036). The optimal cutoffs for lesion length, MLA, MLD, RLD, and lumen area stenosis were >18.5mm, ≤ 3.0mm(2), ≤ 2.1mm, ≤ 3.2mm, and >69%, respectively (max. sensitivity: 100% for MLA, max. specificity: 79% for lumen area stenosis). CONCLUSIONS: CCTA predictors for FFR support the mathematical relationship between stenosis pressure drop and coronary flow. CCTA could prove to be a useful rule-out test for significant hemodynamic effects of intermediate coronary stenoses.

Advanced 2-dimensional quantitative coronary angiographic analysis for prediction of fractional flow reserve in intermediate coronary stenoses.

PURPOSE: The widespread clinical application of coronary computed tomography angiography (CCTA) has resulted in increased referral patterns of patients with intermediate coronary stenoses to invasive coronary angiography. We evaluated the application of advanced quantitative coronary angiography (A-QCA) for predicting fractional flow reserve (FFR) in intermediate coronary lesions detected on CCTA. MATERIALS AND METHODS: Fifty-six patients with 66 single intermediate coronary lesions (≥ 50% to 80% stenosis) on CCTA prospectively underwent coronary angiography and FFR. A-QCA including calculation of the Poiseuille-based index defined as the ratio of lesion length to the fourth power of the minimal lumen diameter (MLD) was performed. Significant stenosis was defined as FFR ≤ 0.80. RESULTS: The mean FFR was 0.86 ± 0.09, and 18 lesions (27%) were functionally significant. FFR correlated with lesion length (R=-0.303, P=0.013), MLD (R=0.527, P<0.001), diameter stenosis (R=-0.404, P=0.001), minimum lumen area (MLA) (R=0.530, P<0.001), lumen stenosis (R=-0.400, P=0.001), and Poiseuille-based index (R=-0.602, P<0.001). The optimal cutoff values for MLD, MLA, diameter stenosis, and lumen stenosis were ≤ 1.3 mm, ≤ 1.5 mm, >44%, and >69%, respectively (maximum negative predictive value of 94% for MLA, maximum positive predictive value of 58% for diameter stenosis). The Poiseuille-based index was the most accurate (C statistic 0.86, sensitivity 100%, specificity 71%, positive predictive value 56%, and negative predictive value 100%) predictor of FFR ≤ 0.80, but showed the lowest interobserver agreement (intraclass correlation coefficient 0.37). CONCLUSIONS: A-QCA might be used to rule out significant ischemia in intermediate stenoses detected by CCTA. The diagnostic application of the Poiseuille-based angiographic index is precluded by its high interobserver variability.

Statins impair glucose uptake in tumor cells.

Statins, HMG-CoA reductase inhibitors, are used in the prevention and treatment of cardiovascular diseases owing to their lipid-lowering effects. Previous studies revealed that, by modulating membrane cholesterol content, statins could induce conformational changes in cluster of differentiation 20 (CD20) tetraspanin. The aim of the presented study was to investigate the influence of statins on glucose transporter 1 (GLUT1)-mediated glucose uptake in tumor cells. We observed a significant concentration- and time-dependent decrease in glucose analogs' uptake in several tumor cell lines incubated with statins. This effect was reversible with restitution of cholesterol synthesis pathway with mevalonic acid as well as with supplementation of plasma membrane with exogenous cholesterol. Statins did not change overall GLUT1 expression at neither transcriptional nor protein levels. An exploratory clinical trial revealed that statin treatment decreased glucose uptake in peripheral blood leukocytes and lowered (18)F-fluorodeoxyglucose ((18)F-FDG) uptake by tumor masses in a mantle cell lymphoma patient. A bioinformatics analysis was used to predict the structure of human GLUT1 and to identify putative cholesterol-binding motifs in its juxtamembrane fragment. Altogether, the influence of statins on glucose uptake seems to be of clinical significance. By inhibiting (18)F-FDG uptake, statins can negatively affect the sensitivity of positron emission tomography, a diagnostic procedure frequently used in oncology.