核子醫學動態造影於心臟灌流及代謝之應用

Abstract

前言 心臟灌流和代謝與心臟功能息息相關。在心臟灌流的部分，靜態心肌灌注造影 (myocardial perfusion imaging) 是一非侵入性的核醫影像工具，臨床廣泛應用於冠狀動脈疾病 (coronary artery disease)之診斷和風險分層評估。但對於心臟多條冠狀動脈血管 (multivessel) 或小血管性 (microvascular) 疾病，因平衡式缺血 (balanced ischemia) 易造成偽陰性的檢查結果。近幾年來因CZT cardiac SPECT的引進，提高動態影像擷取應用於心肌血流定量之可行性。

在成年人的心臟代謝中，大多數的三磷酸腺苷 (adenosine triphosphate) 來自長鏈脂肪酸的氧化 (60-90%)，10-30％來自葡萄糖的氧化作用。在慢性缺血的狀況下，心臟的脂肪酸氧化減少而葡萄糖的攝取增加。許多證據指出，心臟代謝的重塑與心血管疾病的病程與預後息息相關，許多調控心臟代謝的用藥也應運而生。過去的心肌存活評估，是採用靜態葡萄糖正子造影搭配心肌灌流檢查。然而，動態的葡萄糖正子影像擷取可定量心臟葡萄糖使用率，其臨床的價值過去較少有文獻探討此議題。

研究目的 本研究欲透過核醫動態造影量化心肌血流與心肌葡萄糖代謝，並將此影像工具運用到臨床重要的議題上 : 探討心肌血流定量於心臟移植後之血管病變之應用與心肌葡萄糖攝取於高血脂與缺血性心肌病變之角色。

方法與結果 心臟灌流 本研究納入了接受心臟移植手術後的三十八名患者，並進行了 CZT SPECT 及 13N-NH3 PET 動態掃描。前十九名患者使用 99mTc-sestamibi 進行 CZT SPECT，而其餘患者使用 201Tl-chloride。為了探究動態CZT SPECT 定量之心肌血流是否具有中度至重度心臟移植後血管病變之診斷能力，次族群分析包括了在第二項影像掃描後一年內進行血管攝影檢查之患者。

在 201Tl 和 99mTc 兩組之間，患者臨床特徵沒有顯著差異。無論是整體還是3 個冠狀動脈支配之區域，201Tl 和 99mTc CZT SPECT 定量的壓力態之心肌血流和 心肌血流儲備數值均與 13N-NH3 PET 顯示出良好的相關性。在 CZT SPECT 與 PET 之間，除了壓力態的心肌血流 (201Tl : 0.95 versus 99mTc : 0.80, P=0.03)，201Tl 和 99mTc 兩組的 MBF 和 MFR 的相關係數差異不大。201Tl 和 99mTc CZT SPECT 對於檢測 PET MFR < 2.0（201Tl 曲線下面積為 0.92 [0.71–0.99]，99mTc曲線下面積為 0.87 [0.64–0.97]）以及經血管攝影診斷的中度至嚴重 CAV 均有不錯的診斷效力，且 CZT SPECT 的結果與 13N-NH3 PET 相當（CZT 曲線下面積為 0.90 [0.70–0.99]，PET 曲線下面積為 0.86 [0.64–0.97]）。

心臟代謝 這個研究分為兩部分，均使用動態FDG PET進行，且利用Patlak plot分析來定量葡萄糖利用率（metabolic rate of glucose, MRGlu）。在人體研究中，動態FDG PET造影納入缺血性心肌病變患者的心肌存活評估流程中。重大心血管不良事件（Major adverse cardiac event, MACE）被定義為死亡、因急性心肌梗塞、非計畫的冠狀動脈介入治療、心臟裝置植入和心臟衰竭而住院之事件。在動物研究中，使用雄性ApoE-/-小鼠，分為一般飼料與高脂飼料組探討高血脂狀態下，心臟葡萄糖攝取的變化；另，採用高脂飼料餵養的ApoE-/-小鼠，探究鈉-葡萄糖協同轉運蛋白2抑制劑 ( SGLT2 inhibitor ) 治療後對心臟代謝的影響。除了動態FDG PET造影外，小鼠均接受血液和心臟超音波檢查。

在人體研究中，MRGlu值與高脂血症的病史和Statin藥物使用呈負相關。在高脂血症次族群分析中，高MRGlu值（≥ 28.3 µmol/min/100 g）（危險比7.7；95%信賴區間2.4-24.6）是MACE事件發生的獨立預測因子。在動物研究中，ApoE-/-小鼠均出現高脂血症和胰島素抵抗。餵養一般飼料的ApoE-/-小鼠觀察到心臟葡萄糖利用率增強，而餵養高脂飼料的小鼠則觀察到較低的心肌葡萄糖利用率。在心臟超音波的檢查中，心臟結構與收縮功能部分，在對照組和ApoE-/-小鼠之間沒有明顯差異。然而，餵養高脂飼料的ApoE-/-小鼠的等容舒張時間延長。犧牲後，對照組和ApoE-/-小鼠的心臟重與體重的比值間沒有統計學上的顯著差異。經過6週的empagliflozin治療後，餵食高脂飼料的ApoE-/-小鼠在治療後心肌葡萄糖代謝下降。

結論及展望 本研究利用核醫動態造影定量心肌灌流與心肌葡萄糖攝取，分別於心臟移植後血管病變與缺血性心肌病變患者提供有價值的診斷與預後資訊。在心臟移植後的病患，使用動態201Tl和99mTc CZT SPECT定量心肌血流和心肌血流儲備數值，與13N-NH3 PET結果相當，且初步展現對於中重度心臟移植後血管病變不錯的診斷能力。未來可以繼續將此影像應用拓展至其他廣泛瀰漫性心臟小血管病變。

使用動態FDG PET來量化心臟葡萄糖攝取的變化，可作為高脂血症相關心臟代謝疾病的早期警示標誌和缺血性心肌病變的預測因子，未來，可以結合多體學的研究，更深入探討心肌代謝機轉與策定個人化的治療策略，以改善早期心臟代謝不平衡也預防或減少產生重大心血管不良事件的發生。

Introduction Myocardial perfusion and metabolism are closely intertwined with heart function. In the context of cardiac perfusion, static myocardial perfusion imaging is a non-invasive nuclear medicine imaging tool widely used in the diagnosis and risk stratification of coronary artery disease. However, for cases of multi-vessel or microvascular disease in the heart, balanced ischemia can lead to false-negative examination results. In recent years, the introduction of CZT cardiac SPECT has enhanced the feasibility of using dynamic imaging for quantitative assessment of myocardial blood flow. In the adult heart metabolism, the majority of adenosine triphosphate is derived from the oxidation of long-chain fatty acids (60-90%), with 10-30% coming from glucose oxidation. In the context of chronic ischemia, there is a reduction in the oxidation of fatty acids in the heart, while glucose uptake increases. Previous evidence suggest that the remodeling of cardiac metabolism is closely associated with the progression and prognosis of cardiovascular diseases, leading to the development of medications that regulate cardiac metabolism. In the past, static FDG PET was used in myocardial viability assessment, combined with myocardial perfusion examination. However, there is limited literature exploring the clinical value of dynamic FDG PET in quantifying heart glucose utilization.

Research Objectives This study aims to quantify myocardial blood flow and myocardial glucose uptake through nuclear medicine dynamic imaging. It seeks to apply this imaging tool to clinically relevant issues: investigating the application of quantitative myocardial blood flow in cardiac allograft vasculopathy (CAV) and the role of quantitative myocardial glucose uptake in hyperlipidemia and ischemic cardiomyopathy.

Methods and Results Myocardial perfusion This study included 38 patients with prior heart transplants who underwent CZT SPECT and 13N-NH3 PET dynamic scans. The first 19 patients received CZT SPECT with 99mTc-sestamibi, while the remaining patients were administered 201Tl-chloride. To assess the diagnostic accuracy of moderate-to-severe CAV as determined by angiography, patients who had undergone angiographic examinations within one year of their second scan were included in the analysis. Patient characteristics did not significantly differ between the 201Tl and 99mTc tracer groups. Both 201Tl and 99mTc CZT SPECT yielded stress MBF and MFR values that correlated well with 13N-NH3 PET results, both globally and in the three coronary territories. The 201Tl and 99mTc groups showed similar correlation coefficients between CZT SPECT and PET for MBF and MFR, with the exception of stress MBF (201Tl: 0.95 versus 99mTc: 0.80, p=0.03). Both 201Tl and 99mTc CZT SPECT were effective in identifying PET MFR values less than 2.0 (201Tl area under the curve: 0.92 [0.71–0.99], 99mTc area under the curve: 0.87 [0.64–0.97]), as well as angiographically defined moderate-to-severe CAV. CZT SPECT results were comparable to those of 13N-NH3 PET (CZT area under the curve: 0.90 [0.70–0.99], PET area under the curve: 0.86 [0.64–0.97]).

Myocardial metabolism A two-part study was conducted using dynamic 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). The metabolic rate of glucose (MRGlu) was derived using Patlak plot analysis. Dynamic FDG-PET was incorporated into viability assessment for ischemic cardiomyopathy in the human study. Major adverse cardiac events (MACE) were defined as a composite of death, hospitalization for acute myocardial infarction, late coronary intervention, device implantation, and heart failure. Male ApoE-/- mice that were fed a chow or high-fat diet and male wild-type C57BL mice underwent blood examinations and echocardiography in the animal study. The MRGlu values were negatively correlated with a history of hyperlipidemia and statin use in the human study. A high global MRGlu value ( ≥ 28.3 µmol/min/100 g) (hazard ratio 7.7; 95% confidence interval 2.4–24.6) was an independent predictor of MACE in the hyperlipidemia subgroup. The ApoE-/- mice developed hyperlipidemia and insulin resistance. Enhanced myocardial glucose utilization was observed in the ApoE-/- mice that were fed a chow diet, whereas reduced utilization was observed in those that were fed a high-fat diet. Systolic function did not differ significantly between the control and ApoE-/- mice. However, the isovolumetric relaxation time was prolonged in the ApoE-/- mice that were fed a high-fat diet. Besides, APOE KO fed with high fat diet reduced their myocardial glucose metabolism after 6-week empagliflozin treatment.

Conclusion and Perspective This study utilized nuclear medicine dynamic imaging to quantitate myocardial perfusion and myocardial glucose uptake, providing valuable diagnostic and prognostic information for patients with CAV and ischemic cardiomyopathy, respectively. In post-heart transplant patients, the use of dynamic 201Tl and 99mTc CZT SPECT for quantifying myocardial blood flow and myocardial flow reserve values demonstrated results comparable to those of 13N-NH3 PET, showing promising diagnostic capabilities for moderate-to-severe CAV. Future applications of this imaging technique may extend to other extensive diffuse coronary microvascular pathologies. The utilization of dynamic FDG PET to quantify changes in myocardial glucose uptake can serve as an early warning sign for cardiometabolic disorders associated with hyperlipidemia and as a predictive factor for ischemic cardiomyopathy. In the future, combining multi-omics research can further delve into molecular mechanisms and develop personalized treatment strategies to improve early cardiac metabolic imbalances and prevent or reduce the occurrence of adverse cardiovascular events.