TY - JOUR
T1 - Cardiovascular and systemic microvascular-effects of anti-vascular endothelial growth factor therapy for cancer
AU - Belcik, J. Todd
AU - Qi, Yue
AU - Kaufmann, Beat A.
AU - Xie, Aris
AU - Bullens, Sherry
AU - Morgan, Terry K.
AU - Bagby, Susan P.
AU - Kolumam, Ganesh
AU - Kowalski, Joe
AU - Oyer, Jon A.
AU - Bunting, Stuart
AU - Lindner, Jonathan R.
N1 - Funding Information:
This study was supported in part by a grant from Genentech Inc. Dr. Kaufmann is supported by a research grant from the Lichtenstein Foundation . Dr. Morgan is supported by the Office of Research on Women's Health and the National Institute of Child Health and Human Development, Oregon BIRCWH HD043488-08 . Dr. Lindner is supported by grants R01-HL-078610 , R01-DK-063508 , and RC1-HL-100659 from the National Institutes of Health . All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
PY - 2012/8/14
Y1 - 2012/8/14
N2 - Objectives: This study sought to evaluate the contribution of microvascular functional rarefaction and changes in vascular mechanical properties to the development of hypertension and secondary ventricular remodeling that occurs with anti-vascular endothelial growth factor (VEGF) therapy. Background: Hypertension is a common side effect of VEGF inhibitors used in cancer medicine. Methods: Mice were treated for 5 weeks with an anti-murine VEGF-A monoclonal antibody, antibody plus ramipril, or sham treatment. Microvascular blood flow (MBF) and blood volume (MBV) were quantified by contrast-enhanced ultrasound in skeletal muscle, left ventricle (LV), and kidney. Echocardiography and invasive hemodynamics were used to assess ventricular function, dimensions and vascular mechanical properties. Results: Ambulatory blood pressure increased gradually over the first 3 weeks of anti-VEGF therapy. Compared with controls, anti-VEGF-treated mice had similar aortic elastic modulus and histological appearance, but a marked increase in arterial elastance, indicating increased afterload, and elevated plasma angiotensin II. Increased afterload in treated mice led to concentric LV remodeling and reduced stroke volume without impaired LV contractility determined by LV peak change in pressure over time (dp/dt) and the end-systolic dimension-pressure relation. Anti-VEGF therapy did not alter MBF or MBV in skeletal muscle, myocardium, or kidney; but did produce cortical mesangial glomerulosclerosis. Ramipril therapy almost entirely prevented the adverse hemodynamic effects, increased afterload, and LV remodeling in anti-VEGF-treated mice. Conclusions: Neither reduced functional microvascular density nor major alterations in arterial mechanical properties are primary causes of hypertension during anti-VEGF therapy. Inhibition of VEGF leads to an afterload mismatch state, increased angiotensin II, and LV remodeling, which are all ameliorated by angiotensin-converting enzyme inhibition.
AB - Objectives: This study sought to evaluate the contribution of microvascular functional rarefaction and changes in vascular mechanical properties to the development of hypertension and secondary ventricular remodeling that occurs with anti-vascular endothelial growth factor (VEGF) therapy. Background: Hypertension is a common side effect of VEGF inhibitors used in cancer medicine. Methods: Mice were treated for 5 weeks with an anti-murine VEGF-A monoclonal antibody, antibody plus ramipril, or sham treatment. Microvascular blood flow (MBF) and blood volume (MBV) were quantified by contrast-enhanced ultrasound in skeletal muscle, left ventricle (LV), and kidney. Echocardiography and invasive hemodynamics were used to assess ventricular function, dimensions and vascular mechanical properties. Results: Ambulatory blood pressure increased gradually over the first 3 weeks of anti-VEGF therapy. Compared with controls, anti-VEGF-treated mice had similar aortic elastic modulus and histological appearance, but a marked increase in arterial elastance, indicating increased afterload, and elevated plasma angiotensin II. Increased afterload in treated mice led to concentric LV remodeling and reduced stroke volume without impaired LV contractility determined by LV peak change in pressure over time (dp/dt) and the end-systolic dimension-pressure relation. Anti-VEGF therapy did not alter MBF or MBV in skeletal muscle, myocardium, or kidney; but did produce cortical mesangial glomerulosclerosis. Ramipril therapy almost entirely prevented the adverse hemodynamic effects, increased afterload, and LV remodeling in anti-VEGF-treated mice. Conclusions: Neither reduced functional microvascular density nor major alterations in arterial mechanical properties are primary causes of hypertension during anti-VEGF therapy. Inhibition of VEGF leads to an afterload mismatch state, increased angiotensin II, and LV remodeling, which are all ameliorated by angiotensin-converting enzyme inhibition.
KW - VEGF
KW - contrast echocardiography
KW - ventricular hypertrophy
UR - http://www.scopus.com/inward/record.url?scp=84864697674&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864697674&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2012.02.053
DO - 10.1016/j.jacc.2012.02.053
M3 - Article
C2 - 22703929
AN - SCOPUS:84864697674
SN - 0735-1097
VL - 60
SP - 618
EP - 625
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 7
ER -