Between July 2016 and October 2019, 8 patients (all males) with end-stage ICM were enrolled in our prospective phase I single-center clinical trial. Patient characteristics and comorbidities are summarized in Table 1. All procedural steps were logistically feasible, and all patients received the cell therapy within 12 hours of BM aspiration and less than 1 hour after CD133 + stem cell purification, as per the study protocol.
Table 1
Baseline characteristics of the study population.
Pre-operative patient characteristics | |
Age | 62 ± 2.4 |
Male sex | 8 (100%) |
Mean LVEF (%) | 42 ± 0.04 |
Hypertension | 7 (88%) |
History of diabetes | 7 (88%) |
History of hyperlipidemia | 4 (50%) |
History of peripheral arterial disease | 1 (13%) |
Arrhythmias | 1 (13%) |
Previous Bypass surgery | 6 (75%) |
Previous myocardial infarction | 7 (88%) |
Previous Coronary intervention | 5 (63%) |
Previous stroke | 1 (13%) |
Previous implanted cardioverter defibrillators | 4 (50%) |
The inclusion and exclusion criteria for the study cohort are outlined in Supplemental Table 1. All patients underwent a baseline evaluation of their functional status and cardiac function using the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12, Seattle Angina Questionnaire (SAQ), and the New York Heart Association heart failure symptoms score. Cardiac function was assessed using a transthoracic echocardiogram. Myocardial ischemia was confirmed at baseline using myocardial single-photon emission computerized tomography (SPECT) imaging. Follow-up evaluations for clinical and functional status, echocardiography, and myocardial perfusion were performed at 6- and 12-months post-procedure. Statistical analyses: Throughout the manuscript, data are expressed as mean ± standard error of the means (SEM). Differences were analyzed using the unpaired Student t-test or analysis of variance (one-way ANOVA) as appropriate. A value of P < 0.05 was considered significant. Statistical analyses were performed using the Prism 9 package (GraphPad, La Jolla, CA) and SPSS version 25 (SPSS, IBM Corp, Armonk, NY).
Technique:
On the day of the procedure, patients underwent bone marrow aspiration and CD133 + cells were processed and separated using the clinical-grade closed CliniMACS system (Miltenyi Biotech, Germany)7. TMLR was performed using a Heart Laser CO2 Transmyocardial Revascularization System (Novadaq Technologies Inc., BC, Canada) through a lateral thoracotomy followed by transmyocardial transplantation of purified CD133 + cells (mean number of transplanted cells 12.5 x106 cells). Cell viability was greater than 85% and cell purity was greater than 75%. The number of TMLR channels and the territories of the heart where the TMLR and CD 133 + injections were performed are summarized in Table 2.. These territories were selected based on the presence of ischemia and viable myocardium on the pre-procedural nuclear stress test. CD133 + cells were injected in the immediate proximity of the TMLR channels using a 25G needle. We obtained serial cardiac enzymes and a 48-hour echocardiogram during the postoperative period. The primary endpoint was procedural feasibility and safety defined as peri-procedural myocardial infarction, infection, arrhythmia, or cardiogenic shock. Secondary exploratory endpoints included 6- and 12-month changes in left ventricular function and myocardial ischemia. Secondary clinical endpoints included major adverse cardiac or cerebrovascular events, or hospitalization for adverse cardiac events at 6- and 12- months. The study protocol was approved by the Institutional Review Board at the University of Kentucky and was performed under an investigational new drug (IND) approval from the FDA. The study was registered in clinicaltrials.gov under the number: NCT03043742. All patients gave written and informed consent to participate in the trial.
Table 2
Details of combined TMLR and CD 133 + injection.
Patient # | TMLR channels (n) | Site of TMLR (relation to LV) | Number of CD 133 + injections |
1 | 14 | Anterolateral and posterior wall | 28 |
2 | 12 | Inferior wall | 12 |
3 | 10 | Inferior wall | 10 |
4 | 13 | Anterolateral and posterior | 13 |
5 | 15 | Anterolateral and posterior wall | 15 |
6 | 15 | Anterolateral and posterior wall | 15 |
7 | 13 | Anterior and inferior wall | 13 |
8 | 15 | Anterolateral wall | 13 |