This K08 mentored physician-scientist award proposal has been designed to facilitate my development into an independent investigator studying calcific aortic valve disease (CAVD). Common in the elderly, and with our aging population, CAVD is expected to affect 4.5 million individuals globally by 2030. CAVD is a progressive disease in which the aortic valves (AV) become increasingly thickened and calcified, ultimately leading to severe AV narrowing, symptoms, left ventricular pressure overload leading to heart failure, and death. Conventional treatment for severe CAVD is transcatheter or surgical AV replacement (AVR). However, as a cardiologist, I have cared for too many patients who were ineligible for these procedures as well as those who suffered from peri-procedural complications such as stroke, and understand the need for preventative therapies. Unfortunately, effective medical therapies preventing the development or progression of CAVD do not currently exist, due to a failure of clinical trials in this arena to address causal risk factors. Recently, multiple human epidemiologic and genetic, as well as in vitro studies, have implicated lipoprotein(a) [Lp(a)], the major lipoprotein carrier of oxidized phospholipids (OxPL) as a risk factor for CAVD. While elevated Lp(a) levels, present in 35% of individuals with CAVD, does not represent a universal risk factor, it identifies patients who are at highest risk for poor outcomes and who may benefit from targeted therapies against Lp(a) and/or OxPL if these are determined to be causal risk factors. The research goals of this proposal are to: 1) test the hypothesis that Lp(a) and its OxPL content cause the development and progression of CAVD in vivo and 2) define the mechanisms by which Lp(a) and OxPL mediate CAVD in vivo. In preliminary work, I have established transgenic mouse models expressing Lp(a) that binds OxPL, mutant Lp(a) lacking OxPL binding, and Lp(a) in combination with a natural antibody that binds and neutralizes OxPL, which are uniquely available only in our laboratory and will be used for this proposal. The K08 will build upon my background as a cardiologist and a basic scientist in lipid metabolism by providing the following training objectives: 1) acquire independent skills in molecular imaging to study AV calcification, a central pathogenic process in progression of CAVD, using mouse models, 2) develop expertise in echocardiographic assessment of AV hemodynamics, used clinically to monitor progression of CAVD, in mice, 3) acquire expertise in proteomic analysis of AVs to understand pathways involved in CAVD, and 4) gain the knowledge and skills needed to be a successful independent investigator through guidance from my multidisciplinary mentorship team including Drs. Sotirios (Sam) Tsimikas, Joseph Witztum, Elena Aikawa, and Kirk Peterson, as well as carefully selected coursework. By the end of this award period, I expect to not only have gained invaluable insight into the mechanisms underlying the progression of AV calcification, but also acquired expertise and preliminary data needed to compete for R01 funding and to translate this knowledge into novel medical therapies for CAVD.
Lipoprotein(a) [Lp(a)], the major lipoprotein carrier of oxidized phospholipids, has consistently been implicated as a risk factor for calcific aortic valve disease through human epidemiological and genetic studies. However, the mechanisms by which Lp(a) and its oxidized phospholipids (OxPL) mediate the development and progression of calcific aortic valve disease in vivo are not known. This proposal will fill these gaps in knowledge through comprehensive analysis of aortic valves, including quantitative molecular imaging of calcification, proteomics, and hemodynamics in transgenic mice expressing Lp(a) that bind OxPL and mutant Lp(a) that do not bind OxPL, which are uniquely available only in our laboratory.
