Watchman Device Dislodgement Creating a Left Ventricular Outflow Tract Obstruction Requiring Emergency Cardiopulmonary Bypass.

Left atrial appendage (LAA) occlusion device implantation is becoming a more common alternative for stroke prophylaxis in patients with nonvalvular atrial fibrillation (AF) who are not able to tolerate long-term anticoagulation. Studies suggest the procedure has a 98.5% successful deployment rate (Boersma et al., 2016). We present a case where a rare but known complication involving dislodgement and migration of an implanted Watchman LAA occlusion device led to functional stenosis of the aortic valve creating a left ventricular outflow tract (LVOT) obstruction necessitating emergency cardiopulmonary bypass in the electrophysiology lab to safely retrieve the device.

Post Paddle Boarding Atrial Fibrillation in an Aging Athlete.

Exercise-induced atrial fibrillation has been described in the literature and is a well-known phenomenon. It has been mostly described in long-distance runners. We present a case of a 69-year-old white male who had recurring atrial fibrillation with rapid ventricular response while paddle boarding, but not during other activities such as tennis and cycling. This case highlights the rationale behind different activities provoking atrial fibrillation and the need for multidisciplinary management of this entity including consulting with an electrophysiologist for possible early ablation.

The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors.

The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are multidrug transporters that confer drug resistance to numerous anti-cancer therapeutics in cell culture. These findings initially created great excitement in the medical oncology community, as inhibitors of these transporters held the promise of overcoming clinical multidrug resistance in cancer patients. However, clinical trials of P-gp and ABCG2 inhibitors in combination with cancer chemotherapeutics have not been successful due, in part, to flawed clinical trial designs resulting from an incomplete molecular understanding of the multifactorial basis of multidrug resistance (MDR) in the cancers examined. The field was also stymied by the lack of high-resolution structural information for P-gp and ABCG2 for use in the rational structure-based drug design of inhibitors. Recent advances in structural biology have led to numerous structures of both ABCG2 and P-gp that elucidated more clearly the mechanism of transport and the polyspecific nature of their substrate and inhibitor binding sites. These data should prove useful helpful for developing even more potent and specific inhibitors of both transporters. As such, although possible pharmacokinetic interactions would need to be evaluated, these inhibitors may show greater effectiveness in overcoming ABC-dependent multidrug resistance in combination with chemotherapeutics in carefully selected subsets of cancers. Another perhaps even more compelling use of these inhibitors may be in reversibly inhibiting endogenously expressed P-gp and ABCG2, which serve a protective role at various blood-tissue barriers. Inhibition of these transporters at sanctuary sites such as the brain and gut could lead to increased penetration by chemotherapeutics used to treat brain cancers or other brain disorders and increased oral bioavailability of these agents, respectively.

Rational use of diuretics in acute decompensated heart failure.

Chronic heart failure poses an enormous health care burden to the United States and other developed countries. Acute decompensated heart failure (ADHF) accounts for nearly half of the morbidity and expense of treating this disease. Most patients presenting with ADHF have symptomatic vascular congestion. Diuretics, especially loop diuretics, are the primary pharmacologic intervention used in this population. Despite their widespread use, scant data from randomized clinical trials are available to guide therapeutic choices. In addition, data from several large registries examining weight loss during hospitalization for ADHF suggest that efficacy with diuretic treatment is far from universal. Aggressive diuresis carries a significant risk of electrolyte and volume depletion, with subsequent arrhythmias, hypotension, and worsening renal function. These complications often translate into worse prognosis. Diuretic regimens used to treat ADHF must be individualized based on general knowledge of potency and pharmacokinetic and pharmacodynamic considerations. This article summarizes older and more recent literature to provide a framework for making rational treatment choices in this difficult patient population.

Ruboxistaurin, a protein kinase C beta inhibitor, as an emerging treatment for diabetes microvascular complications.

OBJECTIVE: To review current clinical data regarding the pharmacologic actions of ruboxistaurin (LY333531) mesylate, an inhibitor of protein kinase C (PKC) beta, and its role to potentially reduce the development and/or the progression of diabetic microvascular complications. DATA SOURCES: Primary literature was obtained via a MEDLINE search (1966-August 2004) and through review of pertinent abstracts and presentations at major medical meetings. STUDY SELECTION AND DATA EXTRACTION: Literature relevant to PKC physiology, the pharmacokinetics of ruboxistaurin, and data evaluating the use of ruboxistaurin in treating diabetic microvascular complications in human and relevant animal models was reviewed. DATA SYNTHESIS: PKC is part of a group of intracellular signaling molecules activated in response to various specific hormonal, neuronal, and growth factor stimuli. Hyperglycemia leads to PKC beta 1 and 2 isoform activation, which experimentally has been shown to contribute to the development and progression of diabetic microvascular complications (retinopathy, nephropathy, neuropathy) through various biochemical mechanisms. Animal and/or human studies using ruboxistaurin mesylate, a novel, highly selective inhibitor of PKC beta, have shown delay in the progression and, in some cases, reversal of diabetic retinopathy, nephropathy, and neuropathy. CONCLUSIONS: Ruboxistaurin mesylate, by inhibiting excessive activation of certain PKC isoforms, has the potential to reduce the burden of microvascular complications for patients with diabetes.