Brent D. Wilson

Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells.

Elevated blood levels of homocysteine represent an independent risk factor for premature arterial vascular disease and thrombosis. We investigated whether homocysteine could induce tissue factor (TF) procoagulant activity in cultured human endothelial cells. Homocysteine increased cellular TF activity in a time- and concentration-dependent manner. Low concentrations of homocysteine (0.1 to 0.6 mmol/L), similar to those found in the blood of patients with homocystinuria, enhanced TF activity by 25% to 100%. Other sulfur-containing amino acids (cystine, homocystine, cysteine, and methionine) induced less TF activity than did homocysteine; however, beta-mercaptoethanol and dithiothreitol were more effective than homocysteine in increasing TF activity. Preincubation of homocysteine with a sulfhydryl inhibitor such as N-ethylmaleimide prevented homocysteine induction of TF activity. A quantitative polymerase chain reaction method indicated that homocysteine increased TF mRNA in endothelial cells. These results indicate that an atherogenic amino acid, homocysteine, can initiate coagulation by the TF pathway through a mechanism involving the free thiol group of the amino acid and by TF gene transcription. These data support the hypothesis that perturbation of vascular coagulant mechanisms may contribute to the thrombotic tendency seen in patients with homocystinuria.

Atrial Fibrillation Ablation Outcome Is Predicted by Left Atrial Remodeling on MRI

Background—Although catheter ablation therapy for atrial fibrillation (AF) is becoming more common, results vary widely, and patient selection criteria remain poorly defined. We hypothesized that late gadolinium enhancement MRI (LGE-MRI) can identify left atrial (LA) wall structural remodeling (SRM) and stratify patients who are likely or not to benefit from ablation therapy. Methods and Results—LGE-MRI was performed on 426 consecutive patients with AF without contraindications to MRI before undergoing their first ablation procedure and on 21 non-AF control subjects. Patients were categorized by SRM stage (I–IV) based on the percentage of LA wall enhancement for correlation with procedure outcomes. Histological validation of SRM was performed comparing LGE-MRI with surgical biopsy. A total of 386 patients (91%) with adequate LGE-MRI scans were included in the study. After ablation, 123 patients (31.9%) experienced recurrent atrial arrhythmias during the 1-year follow-up. Recurrent arrhythmias (failed ablations) occurred at higher SRM stages with 28 of 133 (21.0%) in stage I, 40 of 140 (29.3%) in stage II, 24 of 71 (33.8%) in stage III, and 30 of 42 (71.4%) in stage IV. In multivariate analysis, ablation outcome was best predicted by advanced SRM stage (hazard ratio, 4.89; P<0.0001) and diabetes mellitus (hazard ratio, 1.64; P=0.036), whereas increased LA volume and persistent AF were not significant predictors. LA wall enhancement was significantly greater in patients with AF versus non-AF controls (16.6±11.2% versus 3.1±1.9%; P<0.0001). Histological evidence of remodeling from surgical biopsy specimens correlated with SRM on LGE-MRI. Conclusions—Atrial SRM is identified on LGE-MRI, and extensive LGE (≥30% LA wall enhancement) predicts poor response to catheter ablation therapy for AF.

Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation.

Increasing evidence suggests that the formation of oxidized low‐density lipoprotein (Ox‐LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox‐LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox‐LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 μg/ml of Ox‐LDL increasing tissue factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox‐LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox‐LDL, protein C activation was reduced ~ 80% by incubating cultured endothelial cells with Ox‐LDL. The effect of Ox‐LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.—Weis, J. R.; Pitas, R. E.; Wilson, B. D.; Rodgers, G. M. Oxidized low‐density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation. FASEB J. 5: 2459–2465; 1991.

THE ROLE OF AGOUTI-RELATED PROTEIN IN REGULATING BODY WEIGHT

Defects in signaling by leptin, a hormone produced primarily by adipose tissue that informs the brain of the bodys energy reserves, result in obesity in mice and humans. However, the majority of obese humans do not have abnormalities in leptin or its receptor but instead exhibit leptin resistance that could result from defects in downstream mediators of leptin action. Recently, two potential downstream mediators, agouti-related protein (Agrp) and its receptor, the melanocortin-4 receptor (Mc4r), have been identified. Agrp and Mc4r are excellent candidates for human disorders of body weight regulation and represent promising targets for pharmacological intervention in the treatment of these disorders.

Association of atrial fibrosis quantified using LGE-MRI with atrial appendage thrombus and spontaneous contrast on transesophageal echocardiography in patients with atrial fibrillation

Transesophageal echocardiography (TEE) is used to evaluate for left atrial appendage (LAA) thrombi prior to restoration of sinus rhythm in atrial fibrillation (AF). We examined the relationship of atrial fibrosis quantified using late gadolinium enhancement MRI (LGE‐MRI) with TEE findings.

Molecular Pharmacology of Agouti Protein in Vitro and in Vivo

ABSTRACT: Agouti protein and Agouti‐related protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from α‐MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxy‐terminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby α‐MSH and Agouti protein function as independent ligands that inhibit each others binding and transduce opposite signals through a single receptor.

Novel Approach for Endothelializing Vascular Devices: Understanding and Exploiting Elastin–Endothelial Interactions

Elastin is an essential component of arteries which provides structural integrity and instructs smooth muscle cells to adopt a quiescent state. Despite interaction of endothelial cells with elastin in the internal elastic lamina, the potential for exploiting this interaction therapeutically has not been explored in detail. In this study, we show that tropoelastin (a precursor of elastin) stimulates endothelial cell migration and adhesion more than smooth muscle cells. The biological activity of tropoelastin on endothelial cells is contained in the VGVAPG domain and in the carboxy-terminal 17-amino acids. We show that the effects of the carboxy-terminal 17 amino acids, but not those of VGVAPG, are mediated by integrin αVβ3. We demonstrate that tropoelastin covalently linked to stainless steel disks promotes adhesion of endothelial progenitor cells and endothelial cells to the metal surfaces. The adherent cells on the tropoelastin-coated metal surfaces form monolayers that can withstand and respond to arterial shear stress. Because of the unique effects of tropoelastin on endothelial and smooth muscle cells, coating intravascular devices with tropoelastin may stimulate their endothelialization, inhibit smooth muscle hyperplasia, and improve device performance.

Evaluation of highly accelerated real-time cardiac cine MRI in tachycardia.

Electrocardiogram (ECG)‐gated breath‐hold cine MRI is considered to be the gold standard test for the assessment of cardiac function. However, it may fail in patients with arrhythmia, impaired breath‐hold capacity and poor ECG gating. Although ungated real‐time cine MRI may mitigate these problems, commercially available real‐time cine MRI pulse sequences using parallel imaging typically yield relatively poor spatiotemporal resolution because of their low image acquisition efficiency. As an extension of our previous work, the purpose of this study was to evaluate the diagnostic quality and accuracy of eight‐fold‐accelerated real‐time cine MRI with compressed sensing (CS) for the quantification of cardiac function in tachycardia, where it is challenging for real‐time cine MRI to provide sufficient spatiotemporal resolution. We evaluated the performances of eight‐fold‐accelerated cine MRI with CS, three‐fold‐accelerated real‐time cine MRI with temporal generalized autocalibrating partially parallel acquisitions (TGRAPPA) and ECG‐gated breath‐hold cine MRI in 21 large animals with tachycardia (mean heart rate, 104 beats per minute) at 3T. For each cine MRI method, two expert readers evaluated the diagnostic quality in four categories (image quality, temporal fidelity of wall motion, artifacts and apparent noise) using a Likert scale (1–5, worst to best). One reader evaluated the left ventricular functional parameters. The diagnostic quality scores were significantly different between the three cine pulse sequences, except for the artifact level between CS and TGRAPPA real‐time cine MRI. Both ECG‐gated breath‐hold cine MRI and eight‐fold accelerated real‐time cine MRI yielded all four scores of ≥ 3.0 (acceptable), whereas three‐fold‐accelerated real‐time cine MRI yielded all scores below 3.0, except for artifact (3.0). The left ventricular ejection fraction (LVEF) measurements agreed better between ECG‐gated cine MRI and eight‐fold‐accelerated real‐time cine MRI (mean difference, –1.6%) than between ECG‐gated cine MRI and three‐fold‐accelerated real‐time cine MRI (mean difference, –5.7%). Eight‐fold‐accelerated real‐time cine MRI with CS yields acceptable diagnostic quality and relatively accurate LVEF measurements in the challenging setting of tachycardia. Copyright

Noninvasive Diagnosis of Chemotherapy Related Cardiotoxicity

Chemotherapeutic agents reduce mortality and can prevent morbidity in a wide range of malignancies. These agents are, however, associated with toxicities of their own, and the treating physician must remain ever vigilant against the risk outgrowing the benefit of therapy. Thus, pre-treatment evaluation and monitoring for toxicity during and following administration is a fundamental tenet of oncologic practice. Among the most insidious and deadly toxicities of anti-tumor agents is cardiac toxicity, which in some cases may be irreversible. Early detection of cardiotoxicity allows the treating oncologist to redirect therapy or dose modify, taking into account the cost of a reduction in therapy against the potential of further injury to the patient. In these instances, the role of the cardiologist is to assist and advise the oncologist by providing diagnostic and prognostic information regarding developing cardiotoxicity. This review discusses noninvasive diagnostic options to identify and characterize cardiotoxicity and their use in prognosis and guiding therapy. We also review established protocols for cardiac safety monitoring in the treatment of malignancy.

Increased risk of death due to heart disease after radiotherapy for esophageal cancer

OBJECTIVE To evaluate the risk of heart disease related death (HDRD) following radiation therapy (RT) for esophageal cancer (EC). METHODS Using the Surveillance, Epidemiology, and End Results (SEER) database, two cohorts of patients with EC were created: (I) patients who received RT with their initial therapy; and (II) those who did not. Heart disease specific survival (HDSS) was analyzed using Kaplan-Meier methods. Cox proportional-hazards regression methods were used for univariate and multivariate analyses. RESULTS We identified 40,778 patients with EC. A total of 26,377 patients received RT and 14,401 did not. HDSS analysis revealed increased risk of HDRD in those receiving RT (P<0.05), with an absolute risk of HDRD of 2.8%, 5.3% and 9.4% at 5-, 10- and 20-year, respectively. Log rank test of HDSS revealed the risk of HDRD became significant at 8 months (P<0.05). The following were associated with HDRD: RT, age, race, stage at presentation, time period of diagnosis, and known comorbid condition keeping one from esophagectomy. On multivariate analysis, RT remained predictive of HDRD [hazard ratio (HR) 1.46, P<0.05]. When considering only candidates for definitive therapy, RT remained predictive of HDRD on univariate (HR 1.53, P<0.0001) and multivariate (HR 1.62, P<0.0001) analyses. CONCLUSIONS The use of RT leads to increased risk of HDRD that is detectable as early as eight months from diagnosis. More research is needed to define optimal dose volume parameters to prevent cardiac death. Consideration should be given to this risk in relation to prognosis and the expected benefits of RT.