Safety and outcomes analysis: transcatheter implantation of autologous angiogenic cell precursors for the treatment of cardiomyopathy

Abstract

Background Stem cell transplantation is an emerging therapy for severe cardiomyopathy, proffering stem cell recruitment, anti-apoptosis, and proangiogenic capabilities. Angiogenic cell precursors (ACP-01) are autologous, lineage-specific, cells derived from a multipotent progenitor cell population, with strong potential to effectively engraft, form blood vessels, and support tissue survival and regeneration. Methods This IRB approved outcome analysis reports upon 74 consecutive patients who failed medical management for severe cardiomyopathy, and were selected to undergo transcatheter intramyocardial or intracoronary implantation of ACP-01. Serious adverse events (SAEs) were reported. Cell analysis was conducted for each treatment. The left ventricular ejection fraction (LVEF) was measured by multi-gated acquisition scan (MUGA) or echocardiogram at 4 months ± 1.9 months and 12 months ± 5.5 months. Patients reported quality of life statements at 6 months (± 5.6 months). Results Fifty-four of 74 patients met requirements for inclusion (48 males and five females; age 68.1 ± 11.3 years). The mean treatment cell number of 57 × 106 ACP-01 included 7.7 × 106 CD34 + and 21 × 106 CD31 + cells with 97.6% viability. SAEs included one death (previously unrecognized silent MI), ventricular tachycardia (n = 2) requiring cardioversion, and respiratory infection (n = 2). LVEF in the ischemic subgroup (n = 41) improved by 4.7% ± 9.7 from pre-procedure to the first follow-up (4 months ± 1.9 months) (p < 0.004) and by 7.2% ± 10.9 at final follow-up (n = 25) at average 12 months (p < 0.004). The non-ischemic dilated cardiomyopathy subgroup (n = 8) improved by 7.5% ± 6.0 at the first follow-up (p < 0.017) and by 12.2% ± 6.4 at final follow-up (p < 0.003, n = 6). Overall improvement in LVEF from pre-procedure to post-procedure was significant (Fisher’s exact test p < 0.004). LVEF improvement was most marked in the patients with the most severe cardiomyopathy (LVEF < 20%) improving from a mean 14.6% ± 3.4% pre-procedurally to 28.4% ± 8% at final follow-up. Quality of life statements reflected improvement in 33/50 (66%), no change in 14/50 (28%), and worse in 3/50 (6%). Conclusion Transcatheter implantation of ACP-01 for cardiomyopathy is safe and improves LVEF in the setting of ischemic and non-ischemic cardiomyopathy. The results warrant further investigation in a prospective, blinded, and controlled clinical study. Trial Registration: IRB from Genetic Alliance #APC01-001, approval date July 25, 2022. Condensed Abstract Cardiomyopathy is common and associated with high mortality. Stem cell transplantation is an emerging therapy. Angiogenic cell precursors (ACP-01) are lineage-specific endothelial progenitors, with strong potential for migration, engraftment, angiogenesis, and support of tissue survival and regeneration. A retrospective outcomes analysis of 53 patients with ischemic and non-ischemic dilated cardiomyopathy undergoing transcatheter implantation of ACP-01 demonstrated improvements in the left ventricular ejection fraction of 7.2% ± 10.9 (p < 0.004) and 12.2% ± 6.4, respectively, at 12 months (± 5) follow-up. Quality of life statements reflected improvement in 33/50 (66%) patients.

Angiogenic Precursor Cell Treatment of Critical Limb Ischemia Decreases Ulcer Size, Amputation and Death Rate: Re-Examination of phase II ACP NO-CLI Trial Data

“…Second, ACP-01 exert a potent paracrine eff ect, Secreting Vascul ar Endothelial Growth Factor (VEGF) and angiogenin, directly promoting angiogenesis and the generation of new capillaries through proliferation and luminogenesis [26]. Potent levels of VEGF and angiogenin are secreted by ACP-01 [8]. Third, ACP-01 increase expression of Interl eukin 8 (CXCL 8) which enhances angiogenesis through the Ras-MAPK/PI3K activation and the AP-1/NF-kB axis ( [8].…”

“…Potent levels of VEGF and angiogenin are secreted by ACP-01 [8]. Third, ACP-01 increase expression of Interl eukin 8 (CXCL 8) which enhances angiogenesis through the Ras-MAPK/PI3K activation and the AP-1/NF-kB axis ( [8]. Fourth, elevated CXCL8 mobilize an additional reservoir of endothelial cell progenitors, such as peripheral CD34 + precursor cells, which amplify the angiogenic response [27,28].…”

“…Sixth, ACP-01, via upregulation of CXCL8 and its downstream activation of Nuclear Factor Kappa B, exert a pro-angiogenesis infl uence and prosurvival infl uence by transcription of anti-apoptotic factors [32][33][34][35]. Seventh, the expression of CXCL8 [8] modulates the infl ammatory process via downstream recruitment of monocytes and secretion of matrix metalloproteinases to eff ect degradation of extracellular matrix and facilitation of phagocytosis, and preferential selection of the M2 phenotype, with the consequence of decreased tissue scarring. The M2 "alternatively activated" macrophage releases antiinfl ammatory mediators, protecting and promoting repair and homeostatic functions [36][37][38][39].…”

“…A previous phase II, open-label, randomized clinical trial of 20 PAD/ CLI patients treated with ACP-01 found a signifi cant improvement in hemodynamic parameters, pain, walking ability, wound healing rate and lowering of major amputations [9]. In addition, the safety and effi cacy of ACP-01 was demonstrated in patients with severe ischemic cardiomyopathy and non-ischemic dilated cardiomyopathy [8]. More recently, a the randomized, blinded, multi-center, Phase II trial of patients with severe CLI for whom there were no surgical options (NO-CLI), compared intramuscular injections of autologous (ACP-01) with placebo, and showed no signifi cant diff erences between the treated and control groups at 12 months [Bhuiyan, et al, submitted].…”

“…Autologous Angiogenic Cell Precursors (ACP-01) are autologous hematopoietic stem cell derivatives, transdiff erentiated from the Synergetic Cell Precursor (SCP). ACP-01 secrete an array of angiogenic factors and cytokines that foster angiogenesis, recruitment of systemic stem cells, engraftment and support of tissue survival and regeneration [7,8]. A previous phase II, open-label, randomized clinical trial of 20 PAD/ CLI patients treated with ACP-01 found a signifi cant improvement in hemodynamic parameters, pain, walking ability, wound healing rate and lowering of major amputations [9].…”