Comparison of Longitudinal Skeletal Thigh Muscle Findings With Magnetic Resonance Imaging in Patients With Peripheral Artery Disease With-Versus-Without Diabetes Mellitus.

The aim of this secondary analysis of ELIMIT (The Effect of Lipid Modification on Peripheral Artery Disease after Endovascular Intervention Trial) was to determine longitudinal changes over 24 months in skeletal thigh muscle volumes and individual muscle compartments in patients with peripheral artery disease (PAD) with and without diabetes. A total of 48 patients with available magnetic resonance imaging of the distal superficial femoral artery at baseline and 2 years were included in this analysis. Muscle volumes and superficial femoral artery wall, lumen, and total vessel volumes were quantified. Intrareader reproducibility of muscle tracings was assessed with the intraclass correlation coefficient using a 2-way model. Baseline characteristics were similar between patients with PAD with and without diabetes, except for smoking history (p = 0.049), cholesterol levels (p <0.050), and calf walking pain (p = 0.049). Interobserver reproducibility of the muscle volume tracings was excellent for all muscle groups (all intraclass correlation coefficients >0.86, confidence interval 0.69 to 0.94). Total muscle and total leg volumes increased significantly between baseline and 24 months among patients with PAD without diabetes (31 ± 6.4 cm3 vs 32 ± 7.0 cm3, p <0.001; 18 ± 4.4 cm3 vs 19 ± 4.8 cm3, p = 0.045), whereas there was no change in patients with PAD and diabetes. Total muscle volume was inversely associated with age and body mass index in patients with PAD both with and without diabetes (p <0.05). In conclusion, magnetic resonance imaging-quantified thigh muscle volumes are highly reproducible and may be of interest in assessing PAD patients with and without diabetes.

Regional Replacement and Diffuse Interstitial Fibrosis in Aortic Regurgitation: Prognostic Implications From Cardiac Magnetic Resonance.

OBJECTIVES: This study used cardiac magnetic resonance (CMR) to assess left ventricular (LV) remodeling in chronic aortic regurgitation (AR) to identify both forms of myocardial fibrosis and examine its association with clinical outcomes. BACKGROUND: Chronic AR leads to LV remodeling, which is associated with 2 forms of myocardial fibrosis: regional replacement fibrosis that is directly imaged by late gadolinium enhancement (LGE) CMR; and diffuse interstitial fibrosis, which can be inferred by T1 mapping techniques. METHODS: Patients with chronic AR who were undergoing contrast CMR with T1 mapping for valve assessment from 2011 to 2018 were enrolled. Patients with a confounding etiology of myocardial fibrosis were excluded. In addition to quantification of AR severity and LV volumetrics, LGE and T1 mapping pre- and post-contrast were performed to measure extracellular volume (ECV) and indexed ECV (iECV). Patients were followed up longitudinally to assess for the composite event of death and the need for aortic valve replacement. RESULTS: A total of 177 patients with isolated chronic AR were included (66% males, median age 58 years [IQR: 47.0-68.0 years]) with a median follow up of 2.5 years (IQR: 1.07-3.56 years). The iECV significantly increased with AR severity (P < 0.001), whereas ECV and replacement fibrosis did not (P = NS). On multivariate analysis, iECV remained associated with the composite event (P = 0.01). On Kaplan-Meier analysis stratified by AR regurgitant fraction (RF) and iECV, patients with AR RF severity ≥30% and iECV ≥24 mL/m2 demonstrated the highest event rate. CONCLUSIONS: Among CMR biomarkers of fibrosis, iECV was more closely associated than replacement fibrosis or ECV with survival free of aortic valve replacement.

Extracellular Volume in Primary Mitral Regurgitation.

OBJECTIVES: This study used cardiovascular magnetic resonance (CMR) to evaluate whether elevated extracellular volume (ECV) was associated with mitral valve prolapse (MVP) or if elevated ECV was a consequence of remodeling independent of primary mitral regurgitation (MR) etiology. BACKGROUND: Replacement fibrosis in primary MR is more prevalent in MVP; however, data on ECV as a surrogate for diffuse interstitial fibrosis in primary MR are limited. METHODS: Patients with chronic primary MR underwent comprehensive CMR phenotyping and were stratified into an MVP cohort (>2 mm leaflet displacement on a 3-chamber cine CMR) and a non-MVP cohort. Factors associated with ECV and replacement fibrosis were assessed. The association of ECV and symptoms related to MR and clinical events (mitral surgery and cardiovascular death) was ascertained. RESULTS: A total of 424 patients with primary MR (229 with MVP and 195 non-MVP) were enrolled. Replacement fibrosis was more prevalent in the MVP cohort (34.1% vs. 6.7%; p < 0.001), with bi-leaflet MVP having the strongest association with replacement fibrosis (odds ratio: 10.5; p < 0.001). ECV increased with MR severity in a similar fashion for both MVP and non-MVP cohorts and was associated with MR severity but not MVP on multivariable analysis. Elevated ECV was independently associated with symptoms related to MR and clinical events. CONCLUSIONS: Although replacement fibrosis was more prevalent in MVP, diffuse interstitial fibrosis as inferred by ECV was associated with MR severity, regardless of primary MR etiology. ECV was independently associated with symptoms related to MR and clinical events. (DeBakey Cardiovascular Magnetic Resonance Study [DEBAKEY-CMR]; NCT04281823).

Impact of Cardiac Cycle on Thoracic Aortic Geometry-Morphometric Analysis of Ecg Gated Computed Tomography.

BACKGROUND: Understanding morphological changes of ascending aorta, aortic arch and descending aorta with cardiac and respiratory motion is critical for planning of endovascular repair of thoracic aorta. The aim of this study was to determine the impact of the cardiac cycle on thoracic aortic geometry. METHODS: In this retrospective study, electrocardiogram-gated cardiac computed tomography from 116 patients who were evaluated for transcatheter aortic valve replacement were reviewed. A protocol for measurements of maximal diameters and lengths of the thoracic aorta and supra-aortic vessels was established. Measurements were made in multiplanar views perpendicular to the semiautomatically created centerline on both systolic and diastolic phases. RESULTS: Mean age was 77 ± 11 years of our study cohort. Mean systolic and diastolic diameter were 31.6 ± 0.42 and 30.1 ± 4.4 mm at the sinotubular junction (STJ), 35.6 ± 4.8 and 34.8 ± 4.7 mm in the ascending aorta, 29.1 ± 3.3 and 28.5 ± 3.3 mm in the aortic arch (distal left common carotid artery), and 26.7 ± 5.4 and 25.8 ± 5.4 mm in the descending aorta. Mean diameter change was 1.5 ± 0.9 mm at the STJ, 0.8 ± 0.9 mm in the ascending aorta, 0.6 ± 0.8 mm in the aortic arch, and 0.9 ± 1.2 mm in the descending aorta. Mean arterial strain was 5.0 ± 3.2% at the level of the STJ, 2.4 ± 2.7% in the ascending aorta, 2.0 ± 2.9% in the aortic arch, and 3.9 ± 5.7% in the descending aorta. CONCLUSIONS: Our results demonstrated that small but significant circumferential and longitudinal strain was present at every aortic level. These findings may have implications for endovascular thoracic aortic repair and may provide reference values for future comparison.

Four-dimensional flow cardiovascular magnetic resonance in aortic dissection: Assessment in an ex vivo model and preliminary clinical experience.

OBJECTIVE: Four-dimensional flow cardiovascular magnetic resonance may improve assessment of hemodynamics in patients with aortic dissection. The purpose of this study was to evaluate the feasibility and accuracy of 4-dimensional flow cardiovascular magnetic resonance assessment of true and false lumens flow. METHODS: Thirteen ex vivo porcine aortic dissection models were mounted to a flow loop. Four-dimensional flow cardiovascular magnetic resonance and 2-dimensional phase-contrast cardiovascular magnetic resonance measurements were performed, assessed for intraobserver and interobserver variability, and compared with a reference standard of sonotransducer flow volume measurements. Intraobserver and interobserver variability of 4-dimensional flow cardiovascular magnetic resonance were also assessed in 14 patients with aortic dissection and compared with 2-dimensional phase-contrast cardiovascular magnetic resonance. RESULTS: In the ex vivo model, the intraobserver and interobserver measurements had Lin's correlation coefficients of 0.98 and 0.96 and mean differences of 0.17 (±3.65) mL/beat and -0.59 (±5.33) mL/beat, respectively; 4-dimensional and sonotransducer measurements had a Lin's concordance correlation coefficient of 0.95 with a mean difference of 0.35 (±4.92) mL/beat, respectively. In patients with aortic dissection, the intraobserver and interobserver measurements had Lin's concordance correlation coefficients of 0.98 and 0.97 and mean differences of -0.95 (±8.24) mL/beat and 0.62 (±10.05) mL/beat, respectively; 4-dimensional and 2-dimensional flow had a Lin's concordance correlation coefficient of 0.91 with a mean difference of -9.27 (±17.79) mL/beat because of consistently higher flow measured with 4-dimensional flow cardiovascular magnetic resonance in the ascending aorta. CONCLUSIONS: Four-dimensional flow cardiovascular magnetic resonance is feasible in patients with aortic dissection and can reliably assess flow in the true and false lumens of the aorta. This promotes potential future work on functional assessment of aortic dissection hemodynamics.

Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis.

INTRODUCTION: There is conflicting evidence about the impact of gender on outcomes after coronary artery bypass grafting (CABG). METHODS: We performed a multivariate logistic regression and propensity score matched analyses in 13,115 patients (75% men) who underwent CABG between January 1, 1995 and December 31, 2009. The primary outcome was in-hospital mortality. Secondary outcomes included post-operative respiratory failure, stroke, myocardial infarction, sternal and leg wound infections, atrial fibrillation (AF), renal failure, need for postoperative intra-aortic balloon pump (IABP) support, and length of hospital stay. RESULTS: A higher proportion of women (184; 5.6%) suffered in-hospital death compared to men (264; 2.7%), p<0.0001. After propensity score matching (n=3600 total, 1800 in each group), female gender was an independent predictor of mortality after isolated CABG (odds ratio [OR]=1.84; 95% confidence interval [CI] 1.22-2.78). Women also experienced a higher incidence of postoperative complications including stroke (3.8% vs. 2.3%, OR 1.37; 95% CI 1.08-1.73) and leg wound infection (3.4% vs. 1.7%, OR 1.75; 95% CI 1.36-2.54) on multivariate regression analyses. However, these differences were not significant after propensity score matching. We also observed a lower risk of post-operative AF (21.2% vs. 22.1%, OR 0.78; 95% CI 0.70-0.86) in women that remained significant after propensity matching (O.R. 0.76; 95% C.I. 0.65-0.90). Length of hospital stay was longer in women compared with men (11.9 ± 9.0 vs. 10.4 ± 9.2 days, p<0.0001). CONCLUSIONS: Female gender is an independent predictor of increased mortality and a lower incidence of post-operative AF after isolated CABG.

Preclinical strategy to reduce clinical hepatotoxicity using in vitro bioactivation data for >200 compounds.

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Carotid arterial wall characteristics are associated with incident ischemic stroke but not coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Ultrasound measurements of arterial stiffness are associated with atherosclerosis risk factors, but limited data exist on their association with incident cardiovascular events. We evaluated the association of carotid ultrasound-derived arterial stiffness measures with incident coronary heart disease (CHD) and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Carotid arterial strain and compliance, distensibility and stiffness indices, pressure-strain, and Young elastic moduli were measured in 10 407 individuals using ultrasound. Hazard ratios for incident CHD (myocardial infarction, fatal CHD, coronary revascularization) and stroke in minimally adjusted (age, sex, center, race) and fully adjusted models (minimally adjusted model+diabetes, height, weight, total cholesterol, high-density lipoprotein cholesterol, tobacco use, systolic blood pressure, antihypertensive medication use, and carotid intima-media thickness) were calculated. RESULTS: The mean age was 55.3 years. Over a mean follow-up of 13.8 years, 1267 incident CHD and 383 ischemic stroke events occurred. After full adjustment for risk factors and carotid intima-media thickness, all arterial stiffness parameters (carotid arterial strain hazard ratio [HR], 1.14 [95% CI, 1.02-1.28]; arterial distensibility HR, 1.19 [1.02-1.39]; stiffness indices HR, 1.14 [1.04-1.25]; pressure-strain HR, 1.17 [1.06-1.28]; Young elastic moduli HR, 1.13 [1.03-1.24]), except arterial compliance (HR, 1.02 [0.90-1.16], were significantly associated with incident stroke but not with CHD. CONCLUSIONS: After adjusting for cardiovascular risk factors, ultrasound measures of carotid arterial stiffness are associated with incident ischemic stroke but not incident CHD events despite that the 2 outcomes sharing similar risk factors. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00005131.

Isolated coronary artery bypass grafting in obese individuals: a propensity matched analysis of outcomes.

BACKGROUND: There is conflicting data regarding the impact of obesity on morbidity and mortality in patients undergoing isolated coronary artery bypass grafting (CABG). METHODS AND RESULTS: Retrospective cohort analysis of patients who underwent CABG from January 1, 1995, through July 31, 2010 was performed. Patients were classified as obese or non-obese (body mass index ≥ 30.0 kg/m(2) and <30.0 kg/m(2), respectively). The primary outcome was in-hospital mortality. Secondary outcomes included postoperative respiratory failure, postoperative stroke, postoperative myocardial infarction, sternal and leg wound infections, postoperative atrial fibrillation, postoperative ventricular tachycardia, postoperative renal failure and length of hospital stay. Propensity-matched stepwise multivariable logistic regression was performed. Of 13,115 patients, 4,619 (35.2%) were obese. In the propensity-matched logistic regression models (n = 8,442), obesity was not associated with postoperative mortality (odds ratio = 1.13, 95% confidence interval 0.86-1.48). However, obesity was associated with postoperative respiratory failure, postoperative renal insufficiency, sternal wound infection, and leg wound infection. Obesity was also associated with a decreased risk of postoperative bleeding and re-operation from bleeding. CONCLUSIONS: Obesity was associated with an increased risk of postoperative respiratory failure, postoperative renal failure, and surgical site infections. However, obesity was not associated with in-hospital mortality in patients undergoing CABG.