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

描述(申请人提供)：癌症化疗通常会引起心脏毒性，这可能会对癌症患者的整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对左心室射血分数(EF)的连续评估，EF不是心脏毒性的敏感指标，可能只会在为时已晚而无法逆转这一过程的时间点下降。除了心脏功能外，微血管在心脏毒性中也起着关键作用。局部心肌力学存在紧密的双向耦合。 和微血管灌流。许多较新的化疗药物可直接导致微血管损伤，这可能先于EF下降。由于人口老龄化和新治疗药物的迅速推出，预计会有更多的患者和癌症幸存者遭受心脏毒性。因此，迫切需要开发新的非侵入性成像技术，以便在EF下降之前及早发现心脏毒性患者的微血管损伤。在这种迫切的临床需求下，我们建议量化心肌内血容量(IMBV)作为一种新的微循环功能测量方法。99mTc标记的红细胞(RBC)是一种临床上可用的用于EF测量的血池示踪剂，而利用单光子发射计算机断层扫描(SPECT)进行RBC成像是一种自然的方法，因为示踪剂停留在血管内循环中。然而，使用SPECT准确定量IMBV是具有挑战性的，因为99mTC-RBC在血池中的活性是在心肌中的~5-6倍，从血池到心肌的溢出计数主要是由于分辨率差和呼吸/心脏运动导致的，可能会导致IMBV的严重高估。我们开发了各种新的定量低剂量SPECT/CT方法，包括基于CT的部分体积校正和运动校正，并在大型动物研究中证明了使用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中断的早期指标，并提高对癌症治疗所致心脏毒性的检测。在……里面 在这项提议中，我们将优化、验证这种低剂量(2 MSv)定量SPECT/CT成像方法，并将其应用于大型动物和人体研究。我们将通过四个具体目标进行这项研究。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度CT数据采集方案。在目标3中，我们将量化和验证IMBV在一个 建立了大动物模型。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规模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.