Catheter-Based Therapies: Current Practices and Considerations

In just over a decade, there have been paradigm shifts globally in the catheter-based therapies available for the management of patients with severe aortic stenosis. The use of transcatheter aortic valve replacement (TAVR) has been a crucial turning point in the field of cardiology as it granted an option for a minimally invasive method to replace a valve for patients who may or may not be suitable for cardiac surgery. In this chapter, we discuss the current practices and considerations as well as the ongoing evolution of catheter-based approaches for TAVR. The predominant focus of the chapter will be on aortic valve device modifications, prototypes of valves, device delivery systems, and the various techniques. However, discussions on indications/contraindications, proper work-up, preparation, equipment and personnel, complications, and post-procedural management & surveillance will also be reviewed

Cryptococcus neoformans presenting as a large pulmonary cavitary lesion in an immunocompetent female

Pulmonary cryptococcus is a rare but fatal fungal infection historically associated with Human Immunodeficiency Virus (HIV) and immunosuppression, yet increasingly also being recognized in immunocompetent patients as a result of antiretroviral therapy and improved HIV control reducing HIV-associated cryptococcus in advanced countries. Appropriate management may be delayed if left unrecognized. We present the case of an immunocompetent middle-aged female with nonspecific respiratory symptoms who was found to have a large cavitary lung mass resulting in external compression of the pulmonary vein, ultimately leading to a diagnosis of pulmonary Cryptococcus neoformans. By presenting this case, we hope to elucidate the challenges in diagnosing and managing this fatal disease in timely fashion

Acquired Cardiac Dextroposition

Despite tremendous advancements in electrocardiography machine algorithms, accurately diagnosing dextrocardia, pseudodextrocardia, and limb lead reversal remains a serious challenge. We present the case of a patient with acquired cardiac dextroposition, or “pseudodextrocardia,” in which the electrocardiography machine algorithm incorrectly interpreted the finding as “dextrocardia vs limb lead reversal.” (Level of Difficulty: Advanced.

Severe Acute Cor Pulmonale With Impending Shock

The S1Q3T3 sign associated with cor pulmonale was first described by Sylvester McGinn and Paul White in 1935. It has since become an overlooked and relatively nonspecific finding associated with pulmonary embolism. We present this case to elucidate the importance for clinicians to promptly identify this electrocardiographic triad

To intervene or not to intervene: A case of symptomatic neurocysticercosis complicated by ventriculitis

Although well described in the current literature, Neurocysticercosis [NCC] remains an enigma when confronted by practitioners. This is in part due to the haphazard nature of the parasitic infection on the central nervous system [CNS]. These include single or multiple anatomic sites of infection, stage of parasitosis, and the resultant inflammatory response. As a result, NCC can present with a complex constellation of symptomatic presentations, making therapeutic regiments highly individualized. Despite intervention, other impediments may arise post-therapy due to the nature of the infection. We present a case of rapidly progressive symptomatic NCC that initially was successfully treated, however would eventually succumb to complications of ventriculitis

Severe aortic insufficiency‐induced cardiogenic shock treated with left atrial VA‐ECMO and emergent valve‐in‐valve TAVR

Abstract Conventional venoarterial extracorporeal membrane oxygenation (VA‐ECMO) places a functional afterload burden on the left ventricle. In the setting of acute severe aortic insufficiency‐induced cardiogenic shock, the utility of VA‐ECMO in combination with a failing valve may result in catastrophic haemodynamic consequences. This challenge is compounded when the culprit is a failing surgical bioprosthetic valve. We present a case of severe rapid‐onset bioprosthetic aortic insufficiency‐induced cardiogenic shock successfully resuscitated with left atrial VA‐ECMO promptly followed by emergent percutaneous valve‐in‐valve transaortic valve replacement. We discuss the logistics, implications, and associated haemodynamic manifestations in utilizing this strategy for such disease processes

Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP), decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231) breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR) in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM) of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC) protein levels, although other protein levels were unaffected. This study demonstrates for the first time that mitochondrial thiol modification inhibits metabolism via inhibition of both aconitase and GAC in a breast cancer cell model

A Novel Class of Mitochondria-Targeted Soft Electrophiles Modifies Mitochondrial Proteins and Inhibits Mitochondrial Metabolism in Breast Cancer Cells through Redox Mechanisms

<div><p>Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics have failed. Ideally, these agents would have relatively low toxicity against normal cells, and will specifically inhibit the growth and proliferation of cancer cells. Our group and others have previously demonstrated that breast cancer cells exhibit increased mitochondrial oxygen consumption compared with non-tumorigenic breast epithelial cells. This suggests that it may be possible to deliver redox active compounds to the mitochondria to selectively inhibit cancer cell metabolism. To demonstrate proof-of-principle, a series of mitochondria-targeted soft electrophiles (MTSEs) has been designed which selectively accumulate within the mitochondria of highly energetic breast cancer cells and modify mitochondrial proteins. A prototype MTSE, IBTP, significantly inhibits mitochondrial oxidative phosphorylation, resulting in decreased breast cancer cell proliferation, cell attachment, and migration <i>in vitro</i>. These results suggest MTSEs may represent a novel class of anti-cancer agents that prevent cancer cell growth by modification of specific mitochondrial proteins.</p></div

Bioenergetic parameters in MB231 cells.

<p><b>Panels A-F:</b> Bioenergetic parameters were calculated from the OCR traces in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120460#pone.0120460.g005" target="_blank">Fig. 5</a>, panels A-C. Values are mean ± SE obtained from 10–15 wells in two separate experiments; *<i>p</i><0.05 compared to BTPP; #<i>p</i><0.05 compared to vehicle.</p

Effect of IBTP treatment on mitochondrial respiration of MB231 cells.

<p><b>Panel A:</b> Cells plated on XF24 plates were treated with the indicated concentrations of IBTP or BTPP for 4h in 0.5% FBS-containing medium. After treatment, the medium was removed and replaced with XF assay medium (DMEM, containing 5mM glucose, 0.5% FBS, 5mM HEPES without bicarbonate) and equilibrated 1h before OCR measurement. <b>Panel B:</b> Cells plated on 6-well plates were treated with the indicated concentrations of IBTP or BTPP for 4h. After the incubation, the cells were harvested immediately by trypsinization. The harvested cells were replated in XF24 plates and allowed adhere for an additional 20h in complete medium containing 10% FBS (total 24h). The medium was removed and replaced with assay medium and equilibrated 1h before OCR measurement. <b>Panel C</b>: After 4h of IBTP or BTPP treatment, the medium was replaced with complete medium containing 10% FBS, and incubated for 48h. The cells were harvested after 48h, replated in XF24 plates and allowed adhere for an additional 20h in complete medium. The medium was replaced with assay media and incubated 1h before measurement of OCR (total duration 72h).</p