Figure 3.
VEGF-B186 Overexpression Increases Susceptibility to Ventricular Arrhythmias
(A) αMHC-VEGF-B mice (n = 10) were more susceptible to arrhythmias during dobutamine stress. 60% of animals displayed arrhythmias 10 min after i.p. dobutamine injection (p < 0.05), suggesting that these mice were more sensitive to sympathetic stimulation. (B) Arrhythmias were also observed after Ad overexpression of VEGF-B186. ECGs were recorded on day 6 after GT. Ventricular extrasystoles and non-sustained VTs were observed in only one AdLacZ control after acute myocardial infarction, one AdVEGF-B186-transduced normoxic pig, and one AdVEGF-B186+AdsVEGFR-1-transduced normoxic pigs. In contrast, all of the ischemic AdVEGF-B186+AdsVEGFR-1 pigs (n = 6) displayed VAs 6 days after GT (p < 0.05). To better characterize these arrhythmias, a subset of animals received an implantable cardiac rhythm monitor on day 0, and data were collected at the time of death or at the time of sacrifice on day 6. (C) A representative example of sinus rhythm (SR) and the onset of ventricular tachycardia (VT) observed after AdVEGF-B186+sVEGFR-1 GT. Two AdVEGF-B186+sVEGFR-1-transduced animals and one AdVEGF-B186+AdsNrp-1-transduced animal died of VF. (D) In one of the animals, the whole chain of events was documented, demonstrating VT and induction of ventricular fibrillation (VF) leading to sudden cardiac death. AdVEGF-B186 gene transfer increased the probability of sudden cardiac death after acute myocardial infarction. (E) A retrospective analysis of myocardial ischemia operations and Ad GT performed on pigs in our laboratory (n = 334) revealed that AdVEGF-B186 GT (alone or in combination with AdsVEGFR-1) increased the incidence of sudden cardiac death. Only 7 animals died 24 h to 6 days after GT; 5 of these animals had received AdVEGF-B186 GT, 1 had received AdVEGF-B186+sVEGFR-1 GT, and 1 was unrelated to this study. A statistically significant difference between the survival of AdVEGF-B186 and that of another GT group was observed when analyzed with the log-rank test (hazard ratio, 0.001998; 95% CI = 0.0001853–0.02153, p < 0.0001).