Key result
Adenoviral overexpression of VEGF-B186 significantly increased the risk of sudden cardiac death in pigs compared to other gene transfers (HR 500.5) by inducing sympathetic nerve growth.
Why the study?
VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but high doses of VEGF-B unexpectedly promoted ventricular arrhythmias.
Does VEGF-B overexpression increase sympathetic nerve growth and susceptibility to ventricular arrhythmias in preclinical models?
Does VEGF-B overexpression increase sympathetic nerve growth and susceptibility to ventricular arrhythmias in preclinical models?
Hazard Ratio: 500.5 (95% CI 46.4–5396.7)
p-value: p=<0.0001
High-dose VEGF-B gene therapy induces sympathetic nerve sprouting in the myocardium, unexpectedly increasing the risk of ventricular arrhythmias and sudden cardiac death.
High-dose VEGF-B may promote ventricular arrhythmias via nerve proliferation; leaves open safe dosing for proangiogenic gene therapy in ischemic heart disease.
VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but, unexpectedly, we found that high doses of VEGF-B promote ventricular arrhythmias (VAs). VEGF-B knockout, alpha myosin heavy-chain promoter (αMHC)-VEGF-B transgenic mice, and pigs transduced intramyocardially with adenoviral (Ad)VEGF- B186 were studied. Immunostaining showed a 2-fold increase in the number of nerves per field (76 vs. 39 in controls, p < 0.001) and an abnormal nerve distribution in the hypertrophic hearts of 11- to 20-month-old αMHC-VEGF-B mice. AdVEGF-B186 gene transfer (GT) led to local sprouting of nerve endings in pig myocardium (141 vs. 78 nerves per field in controls, p < 0.05). During dobutamine stress, 60% of the αMHC-VEGF-B hypertrophic mice had arrhythmias as compared to 7% in controls, and 20% of the AdVEGF-B186-transduced pigs and 100% of the combination of AdVEGF-B186- and AdsVEGFR-1-transduced pigs displayed VAs and even ventricular fibrillation. AdVEGF-B186 GT significantly increased the risk of sudden cardiac death in pigs when compared to any other GT with different VEGFs (hazard ratio, 500.5; 95% confidence interval [CI] 46.4-5,396.7; p < 0.0001). In gene expression analysis, VEGF-B induced the upregulation of Nr4a2, ATF6, and MANF in cardiomyocytes, molecules previously linked to nerve growth and differentiation. Thus, high AdVEGF-B186 overexpression induced nerve growth in the adult heart via a VEGFR-1 signaling-independent mechanism, leading to an increased risk of VA and sudden cardiac death.
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Lähteenvuo et al. (2020) studied Cardiac arrhythmias and myocardial ischemia (n=334). AdVEGF-B186 gene transfer vs. AdLacZ control or other gene transfers was evaluated on Sudden cardiac death (HR 500.5, 95% CI 46.4-5396.7, p=<0.0001). Adenoviral overexpression of VEGF-B186 significantly increased the risk of sudden cardiac death in pigs compared to other gene transfers (HR 500.5) by inducing sympathetic nerve growth.
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