Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

TCT-669 Very Low Intravenous Contrast Dose (20 cc) Computed Tomographic Angiography Protocol for Pre-Procedural Assessment of the Aortic Annulus Prior to Transcatheter Aortic Valve Replacement: Validation by 3-Dimensional Transesophageal Echocardiography

Von Dr. Fr. Dietric

Strain assessment in patients with aortic regurgitation undergoing transcatheter aortic valve implantation: case series.

BACKGROUND Limited data exist on strain changes after transcatheter aortic valve implantation (TAVI) in patients with aortic regurgitation (AR). CASE SUMMARY Three patients with AR undergoing TAVI showed an initial reduction in global longitudinal strain (GLS), followed by sustained GLS improvement within the first year. DISCUSSION Findings align with those of surgically treated patients with AR. There is a possible superiority of GLS to left ventricular end-diastolic diameter ratio in assessing patients with severe volume overload

Transcatheter Valve Implantation in Failed Surgically Inserted Bioprosthesis Review and Practical Guide to Echocardiographic Imaging in Valve-in-Valve Procedures

AbstractAn increased use of bioprosthetic heart valves has stimulated an interest in possible transcatheter options for bioprosthetic valve failure given the high operative risk. The encouraging results of transcatheter aortic valve implantation in high-risk surgical candidates with native disease have led to the development of the transcatheter valve-in-valve (VIV) procedures for failed bioprostheses. VIV procedures are unique in many ways, and there is an increased need for multimodality imaging in a team-based approach. The echocardiographic approach to VIV procedures has not previously been described. In this review, we summarize key echocardiographic requirements for optimal patient selection, procedural guidance, and immediate post-procedural assessment for VIV procedures

The initial U.S. experience with the Tempo active fixation temporary pacing lead in structural heart interventions

ObjectivesThis multicenter retrospective study of the initial U.S. experience evaluated the safety and efficacy of temporary cardiac pacing with the Tempo® Temporary Pacing Lead.BackgroundDespite increasing use of temporary cardiac pacing with the rapid growth of structural heart procedures, temporary pacing leads have not significantly improved. The Tempo lead is a new temporary pacing lead with a soft tip intended to minimize the risk of perforation and a novel active fixation mechanism designed to enhance lead stability.MethodsData from 269 consecutive structural heart procedures were collected. Outcomes included device safety (absence of clinically significant cardiac perforation, new pericardial effusion, or sustained ventricular arrhythmia) and efficacy (clinically acceptable pacing thresholds with successful pace capture throughout the index procedure). Postprocedure practices and sustained lead performance were also analyzed.ResultsThe Tempo lead was successfully positioned in the right ventricle and achieved pacing in 264 of 269 patients (98.1%). Two patients (0.8%) experienced loss of pace capture. Procedural mean pace capture threshold (PCT) was 0.7 ± 0.8 mA. There were no clinically significant perforations, pericardial effusions, or sustained device‐related arrhythmias. The Tempo lead was left in place postprocedure in 189 patients (71.6%) for mean duration of 43.3 ± 0.7 hr (range 2.5–221.3 hr) with final PCT of 0.84 ± 1.04 mA (n = 80). Of these patients, 84.1% mobilized out of bed with no lead dislodgment.ConclusionThe Tempo lead is safe and effective for temporary cardiac pacing for structural heart procedures, provides stable peri and postprocedural pacing and allows mobilization of patients who require temporary pacing leads.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154941/1/ccd28476.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154941/2/ccd28476_am.pd