Adam D. Staruch

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-β-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.

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.

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.

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.

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.

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 mm2, >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.

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.