Cardiovascular and systemic microvascular-effects of anti-vascular endothelial growth factor therapy for cancer

J. Todd Belcik, Qi Yue, Beat A. Kaufmann, Aris Xie, Sherry Bullens, Terry Morgan, Susan Bagby, Ganesh Kolumam, Joe Kowalski, Jon A. Oyer, Stuart Bunting, Jonathan Lindner

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)618-625
Number of pages8
JournalJournal of the American College of Cardiology
Volume60
Issue number7
DOIs
StatePublished - Aug 14 2012

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Vascular Endothelial Growth Factor A
Ventricular Remodeling
Neoplasms
Ramipril
Heart Ventricles
Therapeutics
Hypertension
Blood Volume
Angiotensin II
Blood Vessels
Skeletal Muscle Ventricle
Hemodynamics
Blood Pressure
Kidney
Ventricular Function
Elastic Modulus
Peptidyl-Dipeptidase A
Stroke Volume
Echocardiography
Myocardium

Keywords

  • contrast echocardiography
  • VEGF
  • ventricular hypertrophy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Cardiovascular and systemic microvascular-effects of anti-vascular endothelial growth factor therapy for cancer. / Belcik, J. Todd; Yue, Qi; Kaufmann, Beat A.; Xie, Aris; Bullens, Sherry; Morgan, Terry; Bagby, Susan; Kolumam, Ganesh; Kowalski, Joe; Oyer, Jon A.; Bunting, Stuart; Lindner, Jonathan.

In: Journal of the American College of Cardiology, Vol. 60, No. 7, 14.08.2012, p. 618-625.

Research output: Contribution to journalArticle

Belcik, J. Todd ; Yue, Qi ; Kaufmann, Beat A. ; Xie, Aris ; Bullens, Sherry ; Morgan, Terry ; Bagby, Susan ; Kolumam, Ganesh ; Kowalski, Joe ; Oyer, Jon A. ; Bunting, Stuart ; Lindner, Jonathan. / Cardiovascular and systemic microvascular-effects of anti-vascular endothelial growth factor therapy for cancer. In: Journal of the American College of Cardiology. 2012 ; Vol. 60, No. 7. pp. 618-625.
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T1 - Cardiovascular and systemic microvascular-effects of anti-vascular endothelial growth factor therapy for cancer

AU - Belcik, J. Todd

AU - Yue, Qi

AU - Kaufmann, Beat A.

AU - Xie, Aris

AU - Bullens, Sherry

AU - Morgan, Terry

AU - Bagby, Susan

AU - Kolumam, Ganesh

AU - Kowalski, Joe

AU - Oyer, Jon A.

AU - Bunting, Stuart

AU - Lindner, Jonathan

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KW - contrast echocardiography

KW - VEGF

KW - ventricular hypertrophy

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