Author + information
- Mikaela L. McKenney-Drake, PhD,
- Paul R. Territo, PhD,
- Ali Salavati, MD, MPH,
- Sina Houshmand, MD,
- Scott Persohn, BA,
- Yun Liang, PhD,
- Mouhamad Alloosh, MD,
- Sharon M. Moe, MD,
- Connie M. Weaver, PhD,
- Abass Alavi, MD, PhD (Hon) and
- Michael Sturek, PhD∗ ()
- ↵∗Van Nuys Medical Science Building, 635 Barnhill Drive, MS 385, Indianapolis, Indiana 46202
Studies to date have focused on 18F-sodium fluoride (18F-NaF) uptake in advanced lesions of coronary artery disease (CAD) patients (1). However, others suggest that 18F-NaF soft-tissue uptake imaged by positron-emission tomography (PET) may occur in coronary arteries before the advanced stages of CAD characterized by structural coronary artery calcification (CAC) resolvable by computed tomography (CT) (2).
Although CAC is recognized as a result of passive disease progression, we are now beginning to understand that it may be an active process due to smooth muscle phenotype dedifferentiation and osteogenesis. Aikawa et al. (3) demonstrated in mice an association between osteogenic activity and inflammation in early atherosclerosis before the stage of calcium detectable by the gold standard CT.
Using the Ossabaw miniature swine model of metabolic syndrome (MetS) and CAD (4), we assessed 18F-NaF PET/CT imaging to detect CAC activity in the early neointimal thickening stages of CAD. Lean and MetS groups underwent 18F-NaF PET/CT imaging and intravascular ultrasound (IVUS). To measure tracer uptake directly in the left anterior descending artery (LAD) and right coronary artery (RCA), contrast-enhanced CT images were reformatted along the vessel’s linear axis and coregistered with PET images. MetS pigs revealed almost a 2-fold increase in 18F-NaF uptake in the arteries compared with lean pigs (p < 0.05) (Figure 1A).
Although in MetS Ossabaw swine fed an excess-calorie atherogenic diet for ∼10+ months, mature complex atherosclerotic lesions containing overt IVUS-resolvable calcium crystals will naturally develop (4), these particular pigs were studied after only 6 months on the diet to assess 18F-NaF uptake in earlier stage CAD. The most widely used quantitative analysis of CAD by IVUS imaging (i.e., percentage of plaque burden) clearly confirmed CAD development (MetS: 25 ± 1% LAD, 20 ± 1% RCA vs. lean: 1 ± 1% LAD, 0.2 ± 0% RCA) (p < 0.05). To more accurately assess early CAD in the absence of clinically significant plaque burden, we quantified neointima as the percentage of arterial wall coverage (MetS: 51 ± 6% LAD, 57 ± 9% RCA vs. lean: 3 ± 1% LAD, 12 ± 3% RCA) (p < 0.05). We have extensively used the IVUS percentage of wall coverage technique (4) when characterizing CAD in pigs in the earliest stages of disease progression (i.e., type I, II, and III lesions) (5). The von Kossa histological stain of the RCA (Figure 1B) revealed sparse macroaggregates of hydroxyapatite in only 36% of MetS pigs, which did not significantly correlate with 18F-NaF uptake. These data suggest that histological assessment is less sensitive than 18F-NaF PET/CT.
Our major finding is the positive association between neointimal wall coverage and 18F-NaF uptake in the arteries (Figures 1C and 1D). We illustrate the potential for early detection of CAD and molecular CAC activity by noninvasive 18F-NaF PET/CT imaging before the development of advanced atherosclerotic lesions that are resolvable by conventional CT, histology, and IVUS imaging. Our in vivo detection of coronary calcification in neointimal thickening occurs several stages earlier than previously reported.
Please note: Dr. Weaver serves on the advisory board of Pharmavite, LLC, National Osteoporosis Foundation, International Life Sciences Institute, and Showalter; and has received grants from NIH, Dairy Research Institute, Dairy Australia, Nestle, Tate & Lyle, Fonterra, Kraft, and Pharmavite. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Aikawa E.,
- Nahrendorf M.,
- Figueiredo J.L.,
- et al.
- Stary H.C.