Global left ventricular AdVEGF-B186R127S gene transfer impairs the contractility reserve in the tachypacing-induced porcine model of nonischemic HFrEF

Abstract Background Gene therapy is a promising new approach for treating cardiac diseases. Vascular endothelial growth factor B (VEGF-B) has evoked hope as a potential transgene in ischemic heart disease and heart failure (HF) due to its ability to promote cell survival, cardio-specific angiogenesis, and cardiac function improvement in animal models (1,2). VEGF-B186R127S, a VEGF-receptor 1-specific isoform of VEGF-B was synthesized to avoid arrhythmogenic side effects of other isoforms of VEGF-B 2. Recently, we have published a new method of cardiac gene transfer (GT), allowing global left ventricular (LV) transduction via retrograde injections of coronary veins (3). Purpose This study aimed to test the effects of global adenovirus-mediated (Ad) VEGF-B186R127S GT on cardiac function in a nonischemic HFrEF pig model. Methods HFrEF was induced in pigs by rapid ventricular pacing of four weeks; the first week was paced at 170 bpm and the following three weeks at 200 bpm. For the following four weeks, the pacing rate was set at 150 bpm, aiming not to exacerbate HF but to delay the recovery. After three weeks of rapid pacing, GT was performed via retrograde injections of three main LV veins, as described previously (3). 2E12 vp of AdVEGF-B186R127S (n=15) or AdLacZ (n=13) was administered. The GT timing was designed to produce maximal transgene expression at the 4-week timepoint, at which point the HF stage was at its worst. Echocardiography, treadmill exercise stress test (EST), and LV pressure measurements during rest and dobutamine-induced stress were performed at the baseline, immediately after the rapid pacing phase (4-week timepoint), at 6-week timepoint, and immediately before sacrifice (8-week timepoint). Additionally, echocardiography was performed immediately before GT (3 weeks timepoint). Eight animals from both groups also underwent the EST at 3-week timepoint. Results AdVEGF-B186R127S-treated pigs showed significantly lower systolic dp/dt during stress (2353 ± 183 vs 2888 ± 164 p=0.0008) and lower myocardial contractile reserve (0.932 ± 0.172 vs 1.193 ± 0.136, p=0.04) at 4-week timepoint. At later timepoints, the differences between the groups returned to non-significance. Results of other measurements of systolic and diastolic cardiac function and exercise stress test showed congruently transient weakening in the VEGF-B186R127S group compared to the LacZ group in 4-week timepoint; however, remaining non-significant. Conclusions Ad-mediated transgene expression ceases after approximately 2 weeks from GT. Since the negative effect of VEGF-B186R127S was visible only a week after GT but not at later time points, we conclude that active VEGF-B186R127S transgene expression weakens cardiac function in nonischemic HFrEF. Further studies are needed about VEGF-B effects in other HF types.The catheterization setup of the GT Study timeline and results