Hypertension Due to Antiangiogenic Cancer Therapy With VEGF Inhibitors: Is Autonomic Nervous System Toxicity Another Possible Mechanism?

Abstract

We read with interest the review article by Small et al., on the subject of vascular endothelial growth factor (VEGF) inhibitor-induced hypertension. This is an important, emerging cross-disciplinary area and the review was timely. In their article, the authors outline several potential mechanisms for VEGF inhibitor-induced hypertension, including downregulation of nitric oxide species, decreases in prostacyclin signalling, increases in generation of endothelin, and bioavailability of reactive oxygen species, rarefaction, renal dysfunction, and volume overload.1Small H.Y. Montezano A.C. Rios F.J. et al.Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome.Can J Cardiol. 2014; 30: 534-543Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar We wish to highlight another potential mechanism by which VEGF inhibitors might contribute to hypertension. Animal models have suggested autonomic nervous system (ANS) toxicity as a potential mechanism for VEGF inhibitor induced-hypertension. VEGF has been shown in in vitro studies to play a role in neurogenesis.2Storkebaum E. Lambrechts D. Carmeliet P. VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection.Bioessays. 2004; 26: 943-954Crossref PubMed Scopus (438) Google Scholar, 3Storkebaum E. Ruiz de Almodovar C. Meens M. et al.Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery.Circulation. 2010; 122: 273-281Crossref PubMed Scopus (33) Google Scholar Studies in mouse models have shown that interfering with VEGF function leads to defects in the regulation of arterial resistance, which has been linked to dysfunction of the neuroeffector junction. We are conducting a prospective pilot study to investigate the effects of the VEGF inhibitor bevacizumab on ANS function. We enrolled a cohort of patients without cardiovascular comorbidities who received bevacizumab for the treatment of colon cancer. Patients had a baseline electrocardiogram (ECG) and echocardiogram. A 10-minute high-resolution ECG was recorded before, during, and immediately after the first dose of the drug and analyzed for heart rate variability (HRV)—a marker of ANS function. Blood for measurement of plasma catecholamines, aldosterone, and renin was drawn immediately before and after the drug infusion. Patients returned at 3 and 6 months for a repeat 10-minute ECG recording. Paired t tests and repeated measures analysis of variance were used to compare baseline HRV recordings with those recorded after 3- and 6-month courses of the drug. To date, 10 patients have been enrolled and 7 have survived to the 6-month follow-up. There were no significant changes in HRV parameters during the acute period, but patients did experience a significant decrease in plasma aldosterone levels (145.1 vs 85.9 pmol/L; P = 0.016).4McIntyre W.F. Seaborn G.E. Hammad N. et al.Acute detrimental effects of the anti-cancer agent bevacizumab on heart rate variability.Can J Cardiol. 2013; 29: S332-S333Abstract Full Text Full Text PDF Google Scholar Changes in HRV indexes at 6 months are reported in Table 1.Table 1Heart rate variability changes in 7 patients over a 6-month course of bevacizumab treatmentHeart rate variabilityBaseline (Mean ± SD)6-Month (Mean ± SD)DifferencePSDNN, ms31 ± 1327 ± 11−3.60.19RMSSD, ms29 ± 1326 ± 13−3.10.5Sample entropy1.31 ± 0.31.59 ± 0.50.280.141LF, norm0.52 ± 0.20.53 ± 0.20.010.8HF (norm)0.48 ± 0.20.47 ± 0.2−0.010.8LF/HF1.40 ± 0.91.91 ± 2.10.510.429P values in bold indicate a statistical trend.HF, high frequency; LF, low frequency; RMSSD, root mean square of successive difference; SDNN, standard deviation of N-N intervals. Open table in a new tab P values in bold indicate a statistical trend. HF, high frequency; LF, low frequency; RMSSD, root mean square of successive difference; SDNN, standard deviation of N-N intervals. A 6-month course of bevacizumab for the treatment of metastatic colon cancer produced trends toward changes in standard deviation of N-N intervals and sample entropy over the same period. These findings further support the hypothesis that exposure to this drug might have an effect on the ANS. A larger patient series and longer follow-up are planned to further characterize the effects of bevacizumab on the ANS.