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

低剂量 SPECT/CT 对化疗引起的微血管心脏毒性进行成像

• 批准号: 9049541
• 负责人: Chi Liu
• 金额: $ 76.27万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049541
• 关键词: Animal Model; Animals; Biopsy; Blood; Blood Circulation; Blood Vessels; Blood Volume; Cancer Patient; Cancer Survivor; Canis familiaris; Cardiac; Cardiotoxicity; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Clinical assessments; Coupling; Data; Detection; Dose; Doxorubicin; Drops; EFRAC; Early Diagnosis; Erythrocytes; Functional disorder; Future; Goals; Guidelines; Health; Heart; Human; Hybrids; Image; Imaging Techniques; Injection of therapeutic agent; Injury; Iodine; Kidney; Label; Left Ventricular Ejection Fraction; Measurement; Measures; Mechanics; Mediating; Methods; Microcirculation; Microscopic; Motion; Myocardial; Myocardium; Neuregulins; Pathway interactions; Patients; Perfusion; Play; Process; Protocols documentation; Radiation; Radiolabeled; Recruitment Activity; Reproducibility; Resolution; Rest; Role; Sample Size; Scanning; Screening for cancer; Signal Pathway; Slice; Speed; Stress; Testing; Thick; Time; Toxic effect; Tracer; Translating; Trastuzumab; Variant; Ventricular; X-Ray Computed Tomography; aging population; angiogenesis; animal imaging; base; cancer therapy; cellular imaging; chemotherapeutic agent; chemotherapy; clinical practice; clinically relevant; data acquisition; design; heart motion; imaging modality; improved; in vivo; indexing; low-dose spiral CT; non-invasive imaging; novel; novel therapeutics; outcome forecast; radiotracer; reconstruction; respiratory; single photon emission computed tomography

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.

描述（由申请人提供）：癌症化疗通常会诱导心脏毒性，这可能会对癌症患者的整体预后和存活产生重大影响。筛查与癌症治疗相关的心脏毒性的当前指南主要基于对左心室射血分数（EF）的序列评估，这不是心脏毒性的敏感指数，并且只能在为时已晚的时间点下降。 除心脏功能外，微脉管系统在心脏毒性方面也具有关键的ROL。 区域心肌力学有紧密的双向耦合 和微血管灌注。 许多较新的化学疗法剂可能直接引起微血管损伤，这可能在任何EF下降之前。由于人口老龄化和新疗法的快速引入，预计更多的患者和癌症幸存者将患有心脏毒性。因此，迫切需要开发新型的非侵入性成像技术，这些技术可能会在EF下降之前及早发现心脏毒性患者的微血管损伤。在这种紧急的临床需求下，我们建议将心膜内血容量（IMBV）量化为微循环功能的新测量。 99MTC标记的红细胞（RBC）是一种临床上可用的血池示踪剂，用于EF测量，使用单光子发射计算机断层扫描（SPOCT）是一种自然方法，可以估算IMBV，因为示踪剂留在血管内循环中。但是，使用SPECT对IMBV进行准确的定量是具有挑战性的，因为99MTC-RBC在血液库中的活性高约5-6倍，而在心肌中的活性高约5-6倍，因此从血液库到心肌的溢出计数主要是由于分辨率差和呼吸/心脏运动可能导致大量IMBV高估。 我们已经开发了各种新型的定量低剂量SPECT/CT方法，包括基于CT的部分体积校正和运动校正，并证明了在大型动物研究中使用SPECT/CT量化IMBV的可行性。 我们假设准确的IMBV测量可以提供微循环和血管储备中断的早期指数，并改善癌症治疗诱导的心脏毒性的检测。 在 该建议将优化，验证和转化为大型动物和人类研究的低剂量（<2 msv）定量SPECT/CT成像方法。我们将通过四个具体目标来进行研究。在AIM 1中，我们将优化低剂量SPECT/CT成像方法。在AIM 2中，我们将优化低剂量对比度CT数据采集协议。 在AIM 3中，我们将量化和验证IMBV的串行变化 建立了大型动物模型。在AIM 4中，我们将在患者研究中确定这种SPECT/CT成像方法的可行性。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。