Tests thymosin β4 in a porcine model of chronic myocardial ischemia under both normocholesterolemia and hypercholesterolemia—addressing the clinical reality that most patients have cardiovascular risk factors. TB4 improved endothelial function, collateral vessel formation, capillarization, and cardiac contractility in both conditions, with hypercholesterolemia partially attenuating some endpoints. Demonstrates TB4 efficacy in a large-animal model with metabolic comorbidity—a critical translational step bridging rodent data to the clinical patient population.
Abstract
Translations of new therapeutic options for cardiovascular disease from animal studies into a clinical setting have been hampered, in part by an improper reflection of a relevant patient population in animal models. In this study, we investigated the impact of thymosin β4 (Tβ4), which promotes collateralization and capillarization, during hypercholesterolemia, a known risk factor of coronary artery disease. Initial in vitro results highlighted an improved endothelial cell function upon Tβ4 treatment under control conditions and during hypercholesterolemic stress (scratch area [pixels]: oxidized low-density lipoprotein [oxLDL], 191,924 ± 7,717; and oxLDL + Tβ4, 105,621 ± 11,245). To mimic the common risk factor of hypercholesterolemia in vivo, pigs on regular (NC) or high-fat (HC) diet underwent chronic myocardial ischemia followed by recombinant adeno-associated virus (rAAV)-mediated transduction of Tβ4 or LacZ as a control. We show that Tβ4 overexpression improves capillarization and collateralization (collaterals: NC + rAAV.LacZ, 2.1 ± 0.5; NC + rAAV.Tβ4, 6.7 ± 0.5; HC + rAAV.LacZ, 3.0 ± 0.3; and HC + rAAV.Tβ4, 6.0 ± 0.4), ultimately leading to an improved myocardial function in both diet groups (ejection fraction [EF] at day 56 [%]: NC + rAAV.LacZ, 26 ± 1.1; NC + rAAV.Tβ4, 45 ± 1.5; HC + rAAV.LacZ, 26 ± 2.5; and HC + rAAV.Tβ4, 41 ± 2.6). These results demonstrate the potency of Tβ4 in a patient-relevant large animal model of chronic myocardial ischemia.