PMC9426776_01
Timeline of symptoms and treatment and the clinical trial flowchart of the human induced pluripotent stem (iPS) cell-derived cardiomyocyte (hiPSC-CM) patches. (A) The date in parentheses indicates the number of days since the first attack. The patient underwent anti-heart failure medications (maximum dosages), such as beta-blockers, ACE inhibitors, and diuretics, before transplantation. In the first 3 months after transplantation, the patient received immunosuppressant drugs, including steroids, tacrolimus hydrate, and mycophenolic acid (mofetil); thereafter, these drugs were discontinued. Notably, no medications were introduced/stopped post transplantation. (B) The clinical trial flowchart of hiPSC-CM patches. Clinical-grade iPS cells were established and procured from CiRA (Kyoto University). The hiPSC-CM patches were manufactured in the cell processing center in Osaka University Hospital using the MCB cells generated in the Center for Gene and Cell Processing of Takara Bio Inc. (Kusatsu, Japan). The following quality inspections were performed during the manufacturing process: QC1: Quality check of the MCB. The detailed procedure of the generation of MCB is described elsewhere. QC2: viability, purity of cardiomyocytes, sterility, mycoplasma testing, and endotoxin testing (Supplementary Table 1). CAG, coronary angiography; RCA, right coronary artery; LCX, left circumflex coronary artery branch; LAD, left anterior descending coronary artery; PCI, percutaneous coronary intervention; LMT, left main coronary trunk; AV, atrioventricular node branch; ACS, acute coronary syndrome; IABP, intra-aortic balloon pumping; PCPS, percutaneous cardiopulmonary support; and ACE, angiotensin-converting enzyme; iPS, induced pluripotent stem; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; MCB, master cell bank.
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A 51-year-old male patient was repeatedly admitted to the hospital owing to severe heart failure due to ischemic cardiomyopathy (Figure 1A). Although catecholamine treatment and circulatory support could eventually be withdrawn on day 21 after the second attack (Figure 1A), the heart failure persisted (New York Heart Association [NYHA] classification = III). Trials, https://jrct.niph.go.jp/en-latest-detail/jRCT2053190081, Figure 1B) using allogeneic iPSC-CM patches was approved by the institutional review boards of Osaka University (#199006-A) and the Ministry of Health, Labor, and Welfare, Japan (#2019-143).
Transplantation of hiPSC-CM and cardiac moving pattern before and after surgery. (A) First transplantation of hiPSC-CM patches onto the heart surface of a patient with severe cardiomyopathy. Left: hiPSC-CM patch was transplanted into the epicardium of the anterior and lateral walls of the LV through the fourth intercostal space under IABP support. Right: Three patches were transplanted into the epicardium of the LV anterior and lateral walls. (B) The moving pattern observed via four-dimensional CT. Colors were set so that red indicated a good dynamic area; the darker the color, the lower the movement. The images show the moving pattern in chronological order of the heart at pre-implantation (pre), 6 months, and 1 year after implantation. The dotted line in the bottom figure shows the area where the patches were attached. hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; LV, left ventricle; IABP, intra-aortic balloon pumping; CT, computed tomography.
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We prepared three allogeneic iPSC-CM patches (3.3 x 107 cells/patch) that were successfully transplanted into the epicardium of the LV anterior and lateral walls (Figure 2A) through the fourth intercostal space under IABP support; no other surgical procedures, including coronary artery bypass grafting, were performed. During the first 3 months after transplantation, the patient received immunosuppressant drugs, including prednisolone, tacrolimus, and mycophenolate mofetil; thereafter, these drugs were discontinued (Supplementary Figure 2). This analysis revealed that the moving distance, especially in the transplantation area, improved significantly at 6 months and 1 year after transplantation (Figure 2B and Supplemental Movies), indicating that the myocardium under the transplanted sheets greatly benefited from the angiogenesis mediated by cytokine-paracrine effects.
Changes in end-systolic wall stress. (A) Bull's-eye grid showing the changes in end-systolic wall stress before and 6 months after surgery, calculated by computed tomography. Red and orange highlight the areas of reduction in wall stress by over 20 and 10-20%, respectively. Light blue highlights the remaining areas. (B) Change in the global (left) and regional (transplanted area, right) end-systolic wall stress 6 months after transplantation.
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The LV global wall stress, especially that in the LV anterior and lateral walls that received the allogeneic iPSC-CM patches, was reduced after surgery (Figure 3), suggesting the possible attenuation of cardiac fibrosis and the prolongation of survival. Consistent with the potential tumorigenic safety reported in the preclinical study, the FDG-PET analysis revealed no tumorigenesis after transplantation (Supplementary Figure 3).
13N-ammonia PET images of myocardial blood flow at rest and during stress after hiPSC-CM sheet implantation. (A) Color-coded polar maps with superimposed 17-segment bull's-eye grids with blood flow quantitated under stress and at rest, as well as flow reserve values, are shown in each segment (upper figures). Myocardial blood flow images (short axis) are shown in the lower figures. Red arrows indicate preserved myocardial flow reserves in the anteroseptal to lateral segments. The areas surrounded by the dotted line in the flow reserve figure show a: anteroseptal, b: anterior, and c: anterolateral regions, and the average values of the two area parts were calculated. (B) Change in myocardial blood flow. Myocardial blood flow in the segmental regions LAD, Cx, and RCA at rest and under stress. (C) Change in myocardial flow reserve. Myocardial flow reserve in the whole and each segmental region at 6 months and 1 year after hiPSC-CM patch transplantation. 13N-ammonia PET, 13N-ammonia positron emission tomography; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; LAD, left anterior descending coronary artery; Cx, circumflex coronary artery; RCA, Right coronary artery.
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According to the 13N-ammonia PET images (Figure 4A), the MBF at rest was left anterior descending (LAD) 0.85, circumflex coronary artery (Cx) 0.69, and right coronary artery (RCA) 0.66 ml/g/min at 6 months after transplantation (Figure 4B). However, 1 year after transplantation, the MBF at rest showed a slight decline (LAD 0.65; Cx 0.54; RCA 0.50 ml/g/min) (Figure 4B). MBF under stress was LAD 1.80, Cx 1.58, and RCA 1.49 ml/g/min at 6 months after transplantation but improved 1 year after transplantation (LAD 3.19; Cx 2.93; RCA 3.17 ml/g/min) (Figure 4B). Moreover, from 6 months to 1 year after transplantation, the coronary flow reserves in the whole myocardium greatly improved from 2.16 to 5.30, and the coronary flow reserves in all segmental regions of LV were also dramatically ameliorated (6 months vs. 1 year: LAD 2.12 vs. 4.90; Cx 2.27 vs. 5.40; RCA 2.21 vs. 6.47) (Figure 4C).