Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, and Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
Yale Translational Research Imaging Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut; and.
J Nucl Med. 2023 Sep;64(9):1487-1494. doi: 10.2967/jnumed.123.265516. Epub 2023 Jun 15.
Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in mice. mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, F-NaF PET/CT ( = 34, or autoradiography ( = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography ( = 12). The aortic valve signal was quantified as SUV on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. The aortic valve F-NaF signal on PET/CT was significantly higher at 18-24 mo ( < 0.0001) and 10-16 mo ( < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher F-NaF signal than tricuspid aortic valves ( < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson = 0.79, < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV ( < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT ( = 0.55, < 0.001) and autoradiography ( = 0.45, < 0.01). F-NaF PET/CT links valvular calcification to BAV and aging in mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD.
钙化性主动脉瓣疾病 (CAVD) 是一种普遍存在的疾病，其发病率不断上升，且目前尚无已知的医学疗法。 小鼠具有较高的二叶式主动脉瓣 (BAV) 患病率、自发性主动脉瓣钙化和主动脉瓣狭窄 (AS)。 F-NaF PET/CT 可检测人类主动脉瓣钙化过程。然而，其在 CAVD 的临床前模型中的可行性仍有待确定。在这里，我们旨在验证 F-NaF PET/CT 用于跟踪小鼠主动脉瓣钙化，并利用其检查随着年龄增长而发生的钙化以及在 小鼠中与 BAV 和 AS 的相关性。 3-4 月龄、10-16 月龄和 18-24 月龄的 小鼠接受了超声心动图、F-NaF PET/CT（n = 34 或放射性自显影术（n = 45））和组织分析。一部分小鼠同时接受了 PET/CT 和放射性自显影术（n = 12）。主动脉瓣信号在 PET/CT 上被量化为 SUV，在放射性自显影术上被量化为每平方厘米注射剂量的百分比。使用显微镜分析瓣膜组织切片以识别三叶式和二叶式主动脉瓣。 18-24 月龄（<0.0001）和 10-16 月龄（<0.05）时，主动脉瓣的 F-NaF 信号在 PET/CT 上明显高于 3-4 月龄。此外，在 18-24 月龄时，BAV 的 F-NaF 信号高于三叶式主动脉瓣（<0.05）。放射性自显影术证实了这一发现，每个年龄组的 BAV 均具有更高的 F-NaF 摄取率。PET 和放射性自显影术数据之间存在显著相关性（Pearson = 0.79，<0.01），这确立了 PET 定量的准确性。BAV 的钙化速度随年龄增长明显加快（<0.05）。在所有年龄段，BAV 动物的跨主动脉瓣血流速度均明显更高。最后，F-NaF PET/CT 与 autoradiography 之间存在显著相关性（ = 0.55，<0.001）和 autoradiography（ = 0.45，<0.01）。 F-NaF PET/CT 将瓣膜钙化与 小鼠中的 BAV 和衰老联系起来，并表明 AS 可能促进钙化。除了解决瓣膜钙化的病理生物学问题外，F-NaF PET/CT 可能是评估 CAVD 中新兴治疗干预措施的有价值的工具。
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