Project Summary/Abstract:
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.
