Low-dose SPECT/CT for imaging chemotherapy-induced microvascular cardiotoxicity

描述（由申请人提供）：癌症化疗通常会诱导心脏毒性，这可能对癌症患者的总体预后和生存产生重大影响。目前筛查癌症治疗相关心脏毒性的指南主要基于左心室射血分数（EF）的系列评估，EF不是心脏毒性的敏感指标，并且可能仅在太迟的时间点下降以逆转该过程。 除了心脏功能外，微血管系统在心脏毒性中起关键作用。 局部心肌力学存在密切的双向耦合 和微血管灌注。 许多较新的化疗药物可直接导致微血管损伤，这可能先于任何EF下降。由于人口老龄化的增加和新治疗药物的快速引入，预计更多的患者和癌症幸存者将遭受心脏毒性。因此，迫切需要开发新的非侵入性成像技术，可以在EF下降之前早期检测心脏毒性患者的微血管损伤。随着这一迫切的临床需求，我们提出了定量心肌血容量（IMBV）作为一种新的测量微循环功能。99 mTc标记的红细胞（RBC）是临床上可用的用于EF测量的血池示踪剂，并且当示踪剂停留在血管内循环中时，使用单光子发射计算机断层扫描（SPECT）的RBC成像是估计IMBV的自然方法。然而，使用SPECT准确定量IMBV是具有挑战性的，因为99 mTc-RBC在血池中的活性比在心肌中的活性高约5-6倍，主要由于分辨率差和呼吸/心脏运动导致的从血池到心肌的溢出计数可导致显著的IMBV高估。 我们已经开发了各种新的定量低剂量SPECT/CT方法，包括基于CT的部分容积校正和运动校正，并已证明了在大型动物研究中使用SPECT/CT定量IMBV的可行性。 我们假设准确测量IMBV可以提供微循环和血管储备破坏的早期指标，并改善癌症治疗引起的心脏毒性的检测。 在 我们将优化、验证并将这种低剂量（<2 mSv）定量SPECT/CT成像方法转化为大型动物和人体研究。我们将通过四个具体目标进行研究。在目标1中，我们将优化低剂量SPECT/CT成像方法。在目标2中，我们将优化低剂量对比CT数据采集协议。 在目标3中，我们将量化和验证IMBV的系列变化， 建立大动物模型。在目标4中，我们将确定这种SPECT/CT成像方法在患者研究中的可行性。该项目是将这种成像方法转化为大型临床试验和临床实践的垫脚石。

DESCRIPTION (provided by applicant): Cancer chemotherapy often induces cardiotoxicity, which can have a significant impact on the overall prognosis and survival of cancer patients. Current guidelines to screen for cancer therapy-related cardiotoxicity are primarily based on serial assessment of left ventricular ejection fraction (EF), which is not a sensitive index of cardiotoxicity and may only decline at a time point that is too late to reerse the process. In addition to cardiac function, the microvasculature plays a critical rol in cardiotoxicity. There is a close bidirectional coupling of regional myocardial mechanics and microvascular perfusion. Many of the newer chemotherapy agents can directly cause microvascular injury, which may precede any EF drop. Due to an increasing aging population and rapid introduction of new therapy agents, more patients and cancer survivors are expected to suffer from cardiotoxicity. Therefore, there is an urgent need to develop novel non-invasive imaging techniques that might allow early detection of microvascular injury of patients with cardiotoxicity prior to a drop in EF. With this urgent clinical need, we propose to quantify Intramyocardial blood volume (IMBV) as a novel measurement of microcirculation function. 99mTc-labeled red blood cell (RBC) is a clinically available blood pool tracer for EF measurement and RBC imaging using Single Photon Emission Computed Tomography (SPECT) is a natural approach to estimate IMBV as the tracer stays in the intravascular circulation. However, accurate quantification of IMBV using SPECT is challenging, because 99mTc-RBC has ~5-6 fold higher activity in the blood pool than in myocardium, the spill-over counts from blood pool to the myocardium mainly due to poor resolution and respiratory/cardiac motion can cause substantial IMBV overestimation. We have developed various novel quantitative low-dose SPECT/CT methods including CT-based partial volume correction and motion corrections, and have demonstrated the feasibility of quantifying IMBV using SPECT/CT in large animal studies. We hypothesize that accurate measurement of IMBV can provide an early index of disruption of the microcirculation and vascular reserve and improve detection of cancer therapy induced cardiotoxicity. In this proposal, we will optimize, validate, and translate this low-dose (<2 mSv) quantitative SPECT/CT imaging approach into large animal and human studies. We will pursue the study through four Specific Aims. In Aim 1, we will optimize the low-dose SPECT/CT imaging approaches. In Aim 2, we will optimize the low-dose contrast CT data acquisition protocols. In Aim 3, we will quantify and validate the serial changes of IMBV in an established large animal model. In Aim 4, we will establish the feasibility of this SPECT/CT imaging approach in patient studies. This project is a stepping-stone to translate this imaging method to large clinical trials and clinical practice.