This is a competing K24 renewal application for the important project, """"""""Cardiac Performance by Quantitative Echocardiography."""""""" The candidate's productivity in peer-reviewed publications, success in extramural funding, and vigorous mentoring activities in patient-oriented research have been a direct result of this award. The candidate been recently been promoted to tenured Professor of Medicine and has mentored 7 trainees in clinical research resulting in 12 peer-reviewed publications with the trainee as 1st author and the candidate as senior author; 8 others are submitted or in preparation. All trainees successfully obtained competitive support with the candidate as mentor, including a peer-reviewed Fellowship Award and Outcomes Grant from the American Society of Echocardiography. All have or will be going on to full-time academic faculty positions. This renewal will continue and intensify these activities. Project 1 tests the key hypotheses that novel load-independent echocardiographic left ventricular (LV) functional measures can identify heart failure (HF) patients on assist device (LVAD) who have LV recovery, and that mvocardial inflammation and expression of TNF-alpha are markers for reversible LV dysfunction. Our exciting preliminary data on 36 LVAD patients demonstrate identification of LV recovery and successful LVAD removal in 10. This proposal will test our novel imaging approach of preload-adjusted maximal power, in comparison to a routine clinical assessment that includes exercise oxygen consumption and right heart catheterization. We will also correlate LV recovery with markers of myocardial inflammation and TNF-alpha expression to add mechanistic insight. Project 2 focuses on cardiac resynchronization therapy (CRT) that benefits many HF patients, but 25-35% are still non-responders using QRS criteria. Project 2 tests the key hypotheses: 1) that novel imaging markers of mechanical dyssynchrony can reliably predict patient response to CRT and 2) that imaging-guided LV lead placement at the site of latest mechanical activation will result in a more favorable clinical outcome than routine LV lead placement. Our novel approaches include tissue Doppler and speckle tracking to assess longitudinal and radial mechanics. Our data on 42 patients predict acute response to CRT (up to 95% sensitivity and 100% specificity), however, predicting long-term outcome is unclear. We have also shown that LV lead placement concordant with site of latest mechanical activation results in greater improvements than routine lead positioning. This proposal will test the predictive value of our imaging dyssynchrony markers in 320 CRT patients and includes a randomized trial of image-guided LV lead position vs. routine care. Primary outcome variables (Packer composite HF score, 6 min. walk test, and ejection fraction) will be assessed at 6 mo. and 1 year. These studies will provide valuable insight to the correct utilization of these extensive therapies and provide abundant opportunities for mentoring of trainees.
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