Christopher Deible

Molecular barriers to biomaterial thrombosis by modification of surface proteins with polyethylene glycol

For cardiovascular biomaterials, thrombosis, thromboembolism and vascular graft occlusion are believed to be precipitated by the adsorption of proteins containing adhesive ligands for platelets. Polyethylene-glycol-diisocyanate(PEG-diisocyanate, 3400 MW) may potentially react with protein amines to form molecular barriers on adsorbed proteins on biomaterials, thereby masking adhesive ligands and preventing acute surface thrombosis. To test this notion, PE, PTFE, and glass microconduits were pre-adsorbed with fibrinogen and treated with PEG-diisocyanate, non-reactive PEG-dihydroxyl, or remained untreated. Following perfusion of 111In-labeled platelets in whole human blood for 1 min (wall shear rate = 312 s(-1)), PEG-diisocyanate treated surfaces experienced 96%(PE), 97%(PTFE) and 94% (glass) less platelet deposition than untreated surfaces. Similar reductions were seen for PEG-diisocyanate versus PEG-dihydroxyl treatment. Low shear perfusions of plasma for one hour prior to blood contact did not reduce the inhibitory effect of PEG-diisocyanate. Platelet adhesion onto collagen coated glass coverslips and platelet deposition onto preclotted Dacron was also reduced by treatment with PEG-diisocyanate (93 and 91%, respectively). Protein-reactive PEG may thus have utility in forming molecular barriers on surface associated proteins to inhibit acute thrombosis on cardiovascular biomaterials.

RV-pulmonary arterial coupling predicts outcome in patients referred for pulmonary hypertension

Objective Prognosis in pulmonary hypertension (PH) is largely determined by RV function. However, uncertainty remains about what metrics of RV function might be most clinically relevant. The purpose of this study was to assess the clinical relevance of metrics of RV functional adaptation to increased afterload. Methods Patients referred for PH underwent right heart catheterisation and RV volumetric assessment within 48 h. A RV maximum pressure (Pmax) was calculated from the RV pressure curve. The adequacy of RV systolic functional adaptation to increased afterload was estimated either by a stroke volume (SV)/end-systolic volume (ESV) ratio, a Pmax/mean pulmonary artery pressure (mPAP) ratio, or by EF (RVEF). Diastolic function of the RV was estimated by a diastolic elastance coefficient β. Survival analysis was via Cox proportional HR, and Kaplan–Meier with the primary outcome of time to death or lung transplant. Results Patients (n=50; age 58±13 yrs) covered a range of mPAP (13–79 mm Hg) with an average RVEF of 39±17% and ESV of 143±89 mL. Average estimates of the ratio of end-systolic ventricular to arterial elastance were 0.79±0.67 (SV/ESV) and 2.3±0.65 (Pmax/mPAP-1). Transplantation-free survival was predicted by right atrial pressure, mPAP, pulmonary vascular resistance, β, SV, ESV, SV/ESV and RVEF, but after controlling for right atrial pressure, mPAP, and SV, SV/ESV was the only independent predictor. Conclusions The adequacy of RV functional adaptation to afterload predicts survival in patients referred for PH. Whether this can simply be evaluated using RV volumetric imaging will require additional confirmation.

Creating molecular barriers to acute platelet deposition on damaged arteries with reactive polyethylene glycol

We report here a novel method for blocking acute platelet deposition at the site of vessel injury by molecularly masking thrombogenic vascular wall proteins with covalently attached polyethylene glycol (PEG). To evaluate this technique, blood containing 111In-labeled platelets was perfused over damaged human placental arteries for 2 min at a wall shear rate of 200 s-1. Denuded vessel segments were incubated for 30, 15, 5, and 1 min with a solution of either reactive PEG-diisocyanate (PEG-ISO) or nonreactive PEG-dihydroxyl (PEG-OH). Vessels treated with PEG-ISO for 1 min exhibited 87 +/- 12% less platelet deposition (p < 0.01) than untreated control vessels, and this reduction did not vary significantly among treatment times, indicating that this reaction occurs rapidly enough to be clinically applicable. To investigate the duration of this thrombotic barrier, denuded pig carotid arteries were treated with reactive PEG-ISO for 1 min, perfused with plasma for 30 min, and then perfused with blood containing radiolabeled platelets. PEG-ISO-treated arteries exhibited 84 +/- 9% less platelet deposition (p < 0.05) than untreated controls. These data demonstrate that damaged arterial surfaces can be rendered resistant to platelet deposition after short contact periods with reactive PEG. Molecular PEG barriers ultimately might find application following vascular procedures to sterically inhibit blood cell interaction with damaged vascular surfaces.

CT of the Pulmonary Veins

Atrial fibrillation (AF) is a common cardiac rhythm disturbance and its incidence is increasing. Radiofrequency catheter ablation (RFCA) is a highly successful therapy for treating AF, and its use is becoming more widespread; however, with its increasing use and evolving technique, known complications are better understood and new complications are emerging. Computed tomography (CT) of the pulmonary veins, or more correctly, the posterior left atrium (LA), has an established role in precisely defining the complex anatomy of the LA and pulmonary veins preablation and has an expanding role in identifying the myriad of possible complications postablation. The purposes of this article are: to review AF and RFCA; to discuss CT evaluation of the LA and pulmonary veins preablation; and to review the complications of RFCA focusing on the role of CT postablation.

Phenotyping the Right Ventricle in Patients with Pulmonary Hypertension

Right ventricular (RV) failure is associated with poor outcomes in pulmonary hypertension (PH). We sought to phenotype the RV in PH patients with compensated and decompensated RV function by quantifying regional and global RV structural and functional changes. Twenty‐two patients (age 51 ± 11, 14 females, mean pulmonary artery (PA) pressure range 13–79 mmHg) underwent right heart catheterization, echocardiography, and ECG‐gated multislice computed tomography of the chest. Patients were divided into three groups: Normal, PH with hemodynamically compensated, and decompensated RV function (PH‐C and PH‐D, respectively). RV wall thickness (WT) was measured at end‐diastole (ED) and end‐systole (ES) in three regions: infundibulum, lateral free wall, and inferior free wall. Globally, RV volumes progressively increased from Normal to PH‐C to PH‐D and RV ejection fraction decreased. Regionally, WT increased and fractional wall thickening (FWT) decreased in a spatially heterogeneous manner. Infundibular wall stress was elevated and FWT was lower regardless of the status of global RV function. In PH, there are significant phenotypic abnormalities in the RV even in the absence of overt hemodynamic RV decompensation. Regional changes in RV structure and function may be early markers of patients at risk for developing RV failure.

Free-Breathing, Motion-Corrected Late Gadolinium Enhancement Is Robust and Extends Risk Stratification to Vulnerable Patients

Background— Routine clinical use of novel free-breathing, motion-corrected, averaged late-gadolinium-enhancement (moco-LGE) cardiovascular MR may have advantages over conventional breath-held LGE (bh-LGE), especially in vulnerable patients. Methods and Results— In 390 consecutive patients, we collected bh-LGE and moco-LGE with identical image matrix parameters. In 41 patients, bh-LGE was abandoned because of image quality issues, including 10 with myocardial infarction. When both were acquired, myocardial infarction detection was similar (McNemar test, P=0.4) with high agreement (&kgr;=0.95). With artifact-free bh-LGE images, pixelwise myocardial infarction measures correlated highly (R 2=0.96) without bias. Moco-LGE was faster, and image quality and diagnostic confidence were higher on blinded review (P<0.001 for all). During a median of 1.2 years, 20 heart failure hospitalizations and 18 deaths occurred. For bh-LGE, but not moco-LGE, inferior image quality and bh-LGE nonacquisition were linked to patient vulnerability confirmed by adverse outcomes (log-rank P<0.001). Moco-LGE significantly stratified risk in the full cohort (log-rank P<0.001), but bh-LGE did not (log-rank P=0.056) because a significant number of vulnerable patients did not receive bh-LGE (because of arrhythmia or inability to hold breath). Conclusions— Myocardial infarction detection and quantification are similar between moco-LGE and bh-LGE when bh-LGE can be acquired well, but bh-LGE quality deteriorates with patient vulnerability. Acquisition time, image quality, diagnostic confidence, and the number of successfully scanned patients are superior with moco-LGE, which extends LGE-based risk stratification to include patients with vulnerability confirmed by outcomes. Moco-LGE may be suitable for routine clinical use.

The aortic root: Comparison of measurements from ECG-gated CT angiography with transthoracic echocardiography

Purpose The purpose of this study was to compare the measurements of the aortic root obtained from electrocardiographically (ECG)-gated computed tomography (CT) angiography (CTA) to the measurements obtained from transthoracic echocardiography (TTE). Materials and Methods This was a retrospective study in a patient population scanned at our institution between December 2005 and January 2007 with retrospectively ECG-gated CTA. ECG-gated CTA was performed with a 64-section helical CT scanner (Light speed, VCT, GE, Milwaukee, WI). Sixty-eight patients; 51 men and 17 women were included in this study. Aortic root diameters were measured by using double oblique reconstruction from axial source images. The TTE measurements of the aortic root were obtained from the reports that were performed within 2 months of CTA. Results The average aortic root diameter measured by TTE was 33±4.1 mm; on CTA it was 36.9±3.8 mm. The median difference between the 2 measurements was 3.9 mm which was significant (P<0.0001). In patients whose aortic root measurements with CTA were normal, the TTE measurements were also normal. However, in the group of patients with dilated aortic roots by CTA, TTE measurements were significantly lower and many were normal. In the group of patients with dilated aortic root by TTE, the CTA measurements of the aortic root were similarly increased. Conclusions Retrospective comparison of TTE and CTA measurements of the aortic root reveal that TTE measurements are substantially lower or even normal in patients found to have dilated aortic root by CTA.

Use of cardiac CT angiography imaging in an epidemiology study - the Methodology of the Multicenter AIDS Cohort Study cardiovascular disease substudy

OBJECTIVE The methodology for use of cardiac CT angiography (CTA) in low risk populations is not well defined. In order to present a reference for future studies, we present CTA methodology that is being used in an epidemiology study- the Multicenter AIDS Cohort Study (MACS). METHODS The Multicenter AIDS Cohort Study (MACS) is an on-going multicenter prospective, observational cohort study. The MACS Cardiovascular Disease substudy plans to enroll 800 men (n= 575 HIV seropositive and n=225 HIV seronegative) age 40-70 years for coronary atherosclerosis imaging using cardiac CTA. The protocol includes heart rate (HR) optimization with beta- blockers; use of proper field of view; scan length limitation; prospective ECG-gating using the lowest beam voltage possible. All scans are evaluated for presence, extent, and composition of coronary atherosclerosis, left atrial volumes, left ventricular volume and mass and non-coronary cardiac pathology. RESULTS The first 498 participants had an average radiation dose of 2.5±1.6 milliSieverts (mSv) for the cardiac CTA study. Overall quality of scans was fair to excellent in 98.6% of studies. There were three significant adverse events-two allergic reactions to contrast and one subcutaneous contrast extravasation. CONCLUSION Cardiac CTA was safe and afforded a low effective radiation exposure to these asymptomatic research participants and provides valuable cardiovascular endpoints for scientific analysis. The cardiac CTA methodology described here may serve as a reference for use in future epidemiology studies aiming to assess coronary atherosclerosis and cardiac anatomy in low risk populations while minimizing radiation exposure.

Polyethylene Glycol Diisocyanate Decreases Platelet Deposition After Balloon Injury of Rabbit Femoral Arteries

AbstractBackground: Platelet deposition after angioplasty remains problematic and may contribute to intimal hyperplasia and restenosis. We proposed that polyethylene glycol diisocyanate (PEG-DISO), a polymer that rapidly forms covalent linkages with amine residues on proteins, could mask thrombogenic vascular wall proteins from platelets, thereby abrogating acute platelet deposition. Methods and Results: To test this hypothesis, we isolated the femoral arteries of 10 New Zealand White rabbits and injured them with 3 passes of a 2F Fogarty catheter which was inserted through a distal arteriotomy. Immediately after balloon injury, 111indium-labeled autologous platelets were infused peripherally and the injured femoral arteries were randomly treated for 1 minute with a PEG-DISO solution in one artery and a control solution of the phosphate buffered saline vehicle in the contralateral artery. Following treatment, reflow was initiated. The vessels were harvested after 1 hour and radioactivity was quantified in a gamma counter. Platelet counts were standardized by weight and expressed as platelets/mg (mean ± SEM). Platelet deposition onto arteries treated with PEG-DISO was (1.2 ± 0.5) × 106 platelets/mg compared to (5.6 ± 4.2) × 106 platelets/mg onto the contralateral control arteries treated with vehicle (P < 0.005). Scanning electron micrographs of the injured vessel segment confirmed qualitatively less platelet deposition on the treated segments than on the control segments. Conclusion: Treatment with PEG-DISO significantly inhibited platelet deposition after vascular injury. These data support the hypothesis that treatment with PEG-DISO masks surface adhesive proteins from platelet receptors in vivo and that the resulting molecular barrier significantly reduces platelet deposition onto the damaged vessel wall for at least one hour. The formation of a molecularly thin barrier to platelet deposition may thus be a novel and effective treatment to abrogate acute intravascular thrombosis and may have value in the treatment of restenosis.

Head CT Scan Overuse in Frequently Admitted Medical Patients

BACKGROUND Patients frequently admitted to medical services undergo extensive computed tomography (CT) imaging. Some of this imaging may be unnecessary, and in particular, head CT scans may be over-used in this patient population. We describe the frequency of abnormal head CT scans in patients with multiple medical hospitalizations. METHODS We retrospectively reviewed all CT scans done in 130 patients with 7 or more admissions to medical services between January 1 and December 31, 2011 within an integrated health care system. We calculated the number of CT scans, anatomic site of imaging, and source of ordering (emergency department, inpatient floor). We scored all head CT scans on a 0-4 scale based on the severity of radiographic findings. Higher scores signified more clinically important findings. RESULTS There were 795 CT scans performed in total, with a mean of 6.7 (± SD 5.8) CT scans per patient. Abdominal/pelvis (39%), chest (30%), and head (22%) CT scans were the most frequently obtained. The mean number of head CT scans performed was 2.9 (SD ± 4.2). Inpatient floors were the major site of CT scan ordering (53.7%). Of 172 head CT scans, only 4% had clinically significant findings (scores of 3 or 4). CONCLUSIONS Patients with frequent medical admissions are medically complex and undergo multiple CT scans in a year. The vast majority of head CT scans lack clinically significant findings and should be ordered less frequently. Interdisciplinary measures should be advocated by hospitalists, emergency departments, and radiologists to decrease unnecessary imaging in this population.