Transcatheter repair of aortic leaflet perforation in a patient with prior surgical bicuspid aortic valve repair.

A 47-year-old male underwent surgery for functional bicuspid aortic valve severe regurgitation with a fused right and left coronary cusp. The patient presents nine years after surgical bicuspid aortic valve repair with symptomatic severe aortic regurgitation, diagnosed by TEE and MRI, caused primarily from a perforation located at the base of the surgically fused coronary cusps. The patient had a minimally dilated aortic root that did not yet necessitate surgical intervention. We present a novel percutaneous bicuspid aortic valve perforation repair that potentially decreases the number of surgical operations the patient must undergo during his lifetime.

Predictors and outcomes of recurrent stent thrombosis: results from a multicenter registry.

OBJECTIVES: The aim of this study was to determine the incidence, predictors, and outcomes of recurrent stent thrombosis (rST). BACKGROUND: Patients who had an initial stent thrombosis (ST) develop may be at high risk of rST. METHODS: We analyzed a multicenter California registry of angiographic definite ST at 5 academic hospitals from 2005 to 2013. A detailed review of the angiogram and procedure was performed of patients with and without rST. RESULTS: Among 221 patients with a median follow-up of 3.3 years, definite or probable rST developed in 29, including 19 with angiographic definite rST. The cumulative hazard ratio (HR) of definite or probable rST was 16% at 1 year and 24% at 5 years, whereas the cumulative HR of angiographic definite rST was 11% at 1 year and 20% at 5 years. Despite similar angiographic results, patients who had rST develop had significantly greater peak creatine kinase at the time of initial ST (mean, 2,655 mg/dl vs. 1,654 mg/dl; p = 0.05) than those without rST. The 3-year rate of major adverse cardiovascular events was 50% for patients with rST compared with 22% for patients with a single ST (p = 0.01). After multivariable adjustment, independent predictors of definite/probable rST were age (HR: 1.4; 95 confidence interval [CI]: 1.1 to 1.8 per 10 years), bifurcation ST (HR: 4.4; 95% CI: 1.8 to 10.9), and proximal vessel diameter (HR: 1.8; 95% CI: 1.1 to 3.2 per millimeter). CONCLUSIONS: rST represents an important cause of long-term morbidity and mortality after an initial ST. Bifurcation ST and a larger proximal reference vessel diameter are independently associated with an increased risk of rST.

Electrocardiogram with a twist.

This report presents a 55-year-old man admitted for respiratory failure, who was found to have a brief run of polymorphic ventricular tachycardia (PVT) with normal QT interval. The importance of differentiating PVT caused by torsades de pointes and PVT with normal QT interval is emphasized. This distinction is crucial because of the differing etiologies and management of these arrhythmias.

The thyroid hormone responsive protein (THRP) has a critical role in the embryogenesis of Xenopus laevis.

The human and mouse homologs of the rat thyroid hormone responsive protein (THRP), c-abl-interacting protein 2 (Abi-2), are critically involved in neurological development. The Abi-2 gene is evolutionarily conserved in vertebrates, and is also found in Xenopus laevis and Drosophila melanogaster. The THRP gene is one of the few genes regulated by thyroid hormone in adult animals. Sequence analysis of the 5'-flanking region of the THRP gene identified a putative thyroid hormone response element (TRE) that is conserved between rat and human. To determine whether or not THRP regulates neural growth and development, THRP was constitutively expressed in transgenic X. laevis. Growth of most animals was halted in early neurulation while the few animals that survived the process developed into grossly malformed tadpoles. In contrast, control animals reached late embryonic stage 25. These observations suggest that THRP over-expression in early development is not compatible with completion of early embryogenesis and that a different strategy needs to be employed to investigate THRP function in this model.

The diagnostic accuracy of 64-detector cardiac computed tomography compared with stress nuclear imaging in patients undergoing invasive cardiac catheterization.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of nuclear stress imaging as compared with noninvasive coronary artery imaging using 64-detector row cardiac computed tomography. BACKGROUND: Compared with invasive coronary angiography, multidetector row cardiac computed tomographic angiography (CTA) has shown promise in the accurate detection of coronary stenosis. Myocardial perfusion imaging (MPI) using single photon emission computed tomography is an established method for noninvasively assessing the functional significance of coronary stenosis. This study compared the accuracy of CTA and that of MPI in the detection of relevant lesions of coronary arteries. METHODS: One hundred twenty-two symptomatic patients (77% males) with cardiac catheterization who also underwent MPI and CTA evaluations within 6 months at 2 centers were included. Comparison of CTA for lesions causing greater than 50% and greater than 70% coronary narrowing versus respective lesions on invasive cardiac catheterization (IC) was performed. Similarly, comparison of MPI findings with greater than 50% and greater than 70% lesions on IC was done. RESULTS: The per-patient sensitivity, specificity, and positive and negative predictive values in detecting greater than 50% coronary lesions on IC for CTA were 98.9%, 74.2%, 91.8%, and 95.8%, respectively; and for MPI, 56%, 38.7%, 72.9%, and 23%, respectively. The sensitivity, the specificity, and the positive and negative predictive values in detecting greater than 70% coronary lesions on IC for CTA were 89.7%, 86.4%, 92.1%, and 82.6%, respectively; and for MPI, 57.7%, 43.2%, 64.3%, and 36.5%, respectively. The prevalence of significant coronary artery disease on cardiac catheterization was 74.6% for greater than 50% stenosis and 63.9% for greater than 70% stenosis. CONCLUSIONS: Compared with MPI, CTA provided important information and identified significant lesions in symptomatic intermediate- to high-risk patients. Cost-effective and prospective multicentered studies, currently underway, are needed to further establish the best use of these diagnostic tests in the evaluation of coronary artery disease.

Induction of larval tissue resorption in Xenopus laevis tadpoles by the thyroid hormone receptor agonist GC-1.

A major challenge in understanding nuclear hormone receptor function is to determine how the same ligand can cause very different tissue-specific responses. Tissue specificity may result from the presence of more than one receptor subtype arising from multiple receptor genes or alternative splicing. Recently, high affinity analogs of nuclear receptor ligands have been synthesized that show subtype selectivity. These analogs can greatly facilitate the study of receptor subtype-specific functions in organisms where mutational analysis is problematic or where it is desirable for receptors to be expressed in their normal physiological contexts. We describe here the effects of the synthetic thyroid hormone analog GC-1 on the metamorphosis of the frog Xenopus laevis. The most potent natural thyroid hormone, 3,5,3'-triidothyronine or T3, shows similar binding affinity and transactivation dose-response curves for both thyroid hormone receptor isotypes, designated TRalpha and TRbeta. GC-1, however, binds to and activates TRbeta at least an order of magnitude better than it does TRalpha. GC-1 efficiently induces death and resorption of premetamorphic tadpole tissues such as the gills and the tail, two tissues that strongly induce thyroid hormone receptor beta during metamorphosis. GC-1 has less effect on the growth of adult tissues such as the hindlimbs, which express high TRalpha levels. The effectiveness of GC-1 in inducing tail resorption and tail gene expression correlates with increasing TRbeta levels. These results illustrate the utility of subtype selective ligands as probes of nuclear receptor function in vivo.

The mouse muscle creatine kinase promoter faithfully drives reporter gene expression in transgenic Xenopus laevis.

Developing Xenopus laevis experience two periods of muscle differentiation, once during embryogenesis and again at metamorphosis. During metamorphosis, thyroid hormone induces both muscle growth in the limbs and muscle death in the tail. In mammals, the muscle creatine kinase (MCK) gene is activated during the differentiation from myoblasts to myocytes and has served as both a marker for muscle development and to drive transgene expression in transgenic mice. Transcriptional control elements are generally highly conserved throughout evolution, potentially allowing mouse promoter use in transgenic X. laevis. This paper compares endogenous X. laevis MCK gene expression and the mouse MCK (mMCK) promoter driving a green fluorescent protein reporter in transgenic X. laevis. The mMCK promoter demonstrated strong skeletal muscle-specific transgene expression in both the juvenile tadpole and adult frog. Therefore, our results clearly demonstrate the functional conservation of regulatory sequences in vertebrate muscle gene promoters and illustrate the utility of using X. laevis transgenesis for detailed comparative study of mammalian promoter activity in vivo.

A thyroid hormone antagonist that inhibits thyroid hormone action in vivo.

We have characterized the newly developed thyroid hormone antagonist NH-3 in both cell culture and in vivo model systems. NH-3 binds Xenopus laevis thyroid hormone receptors directly in vitro and induces a conformation distinct from agonist-bound receptors. Transcriptional activation of a thyroid hormone response element-containing reporter gene is strongly inhibited by NH-3 in a dose-dependent manner. In addition, NH-3 prevents X. laevis thyroid hormone receptors from binding to the p160 family of co-activators GRIP-1 and SRC-1 in a two-hybrid assay. To assess the potency of the compound in vivo, we used induced and spontaneous X. laevis tadpole metamorphosis, a thyroid hormone-dependent developmental process. NH-3 inhibits thyroid hormone-induced morphological changes in a dose-dependent manner and inhibits the up-regulation of endogenous thyroid hormone-responsive genes. Spontaneous metamorphosis is efficiently and reversibly arrested by NH-3 with at least the same effectiveness as the thyroid hormone synthesis inhibitor methimazole. Therefore, NH-3 is the first thyroid hormone antagonist to demonstrate potent inhibition of thyroid hormone action in both cell culture- and whole animal-based assays.

Ribozyme suppression of endogenous thyroid hormone receptor activity in Xenopus laevis cells.

Xenopus laevis is an excellent model for thyroid hormone (T3)-regulated gene expression. T3 initiates two drastically different pathways during metamorphosis: death of larval tissues and growth of adult tissues. The role that each T3 receptor (TR) isotype, alpha and beta, plays in metamorphosis is uncertain. The X.laevis tetraploid genome limits experiments to overexpression, misexpression and dominant negative studies. Ribozymes offer an alternative by suppressing gene activity through specific mRNA reduction. It has been suggested that ribozymes will not work in X.laevis because of the organism's intracellular environment and body temperature. In this study, we show that hammerhead ribozymes are active in vitro against transcribed TRbeta message and in vivo against a TRbeta-luciferase fusion protein. We next show that TRbeta-targeted ribozymes can inhibit T3-induced transcription of a reporter gene in cultured X.laevis cells, using T3 response elements from two T3-responsive transcription factor genes. One has early expression kinetics in response to T3 and is proposed to be TRalpha regulated whereas the other has intermediate induction kinetics and thus may be partially TRbeta regulated. Therefore, ribozymes are a potentially valuable tool for overcoming the limitations in this system for examining gene function in X.laevis.