Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation

Q: What is the clinical evidence from this study?

Population: Healthy volunteers (n=38). Intervention: Bevacizumab vs. 0.9% sodium chloride (saline). Primary outcome: Absolute forearm blood flow (p=NS).

Alan C. Cameron; Paul Welsh; Karla B Neves; David E. Newby; Rhian M. Touyz; Ninian N. Lang

doi:10.1097/hjh.0000000000002230

August 24, 2019ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam)Open Access

Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation

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Key result

Acute intra-arterial infusion of bevacizumab did not alter resting forearm blood flow, endothelin-1 release, or bradykinin-induced vasodilatation and tissue plasminogen activator release in healthy men.

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Why the study?

VEGF inhibition is linked to hypertension and thrombosis, but whether it directly causes vascular dysfunction via increased ET-1 activity or impaired vasomotor or fibrinolytic function was unknown.

Does intra-arterial bevacizumab alter resting forearm blood flow or bradykinin-induced vasodilatation and fibrinolytic factor release in healthy men?

Structured PICO

Does intra-arterial bevacizumab alter resting forearm blood flow or bradykinin-induced vasodilatation and fibrinolytic factor release in healthy men?

P

Population

38 healthy male volunteers aged 18 to 52 years underwent intra-arterial infusions to assess the acute vascular effects of bevacizumab.

I

Intervention

Intra-arterial infusions of bevacizumab (36-144 μg/dl forearm volume per minute) administered for 15-60 min. In Protocol 2, intra-arterial bradykinin infusion (100 and 1000 pmol/min) was administered in the presence and absence of bevacizumab (144 μg/dl forearm volume per minute), and the presence and absence of endothelin A receptor antagonism with BQ-123 (10 nmol/min).

C

Comparator

Baseline resting state (absence of bevacizumab) and matching placebo (0.9% physiological saline) for the BQ-123 co-infusion.

O

Outcome

Absolute forearm blood flow measured by venous occlusion plethysmography.surrogate

Main Result

p-value: p=NS

Limitations

Conducted in healthy individuals where VEGF levels are not elevated and endothelial function is presumed normal.
No direct evidence that VEGF signaling was indeed inhibited by bevacizumab in the forearm vessels studied.
Did not directly assess the effect of VEGFi upon the activity of other endothelial vasomotor pathways, including NO and EDHF.
Only male participants were included to avoid menstrual cycle-related changes in vascular function.
Only healthy young men were studied to avoid menstrual cycle-related changes and potential teratogenicity.
Did not examine the effect of combined ET-A and ET-B receptor antagonism.
Acute exposure only, which may not reflect chronic VEGFi effects on blood pressure and ET-1 up-regulation.
Did not assess the role of NO synthase inhibition.

Implication

Acute intra-arterial bevacizumab does not impair endothelial function; suggests VEGFi vascular toxicity develops via chronic mechanisms.

Abstract

OBJECTIVE: Although vascular endothelial growth factor inhibition (VEGFi) represents a major therapeutic advance in oncology, it is associated with hypertension and adverse vascular thrombotic events. Our objective was to determine whether VEGFi caused direct vascular dysfunction through increased endothelin-1 (ET-1) activity or impaired endothelial vasomotor or fibrinolytic function. METHODS: Using forearm venous occlusion plethysmography, we measured forearm blood flow during intra-arterial infusions of bevacizumab (36-144 μg/dl forearm volume per minute) administered for 15-60 min in healthy volunteers (n = 6-8). On two separate occasions in 10 healthy volunteers, we further measured forearm blood flow and tissue plasminogen activator (t-PA) release during intra-arterial bradykinin infusion (100 and 1000 pmol/min) in the presence and absence of bevacizumab (144 μg/dl forearm volume per minute), and the presence and absence of endothelin A receptor antagonism with BQ-123 (10 nmol/min). Plasma t-PA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured at baseline and with each dose of bradykinin. RESULTS: Baseline blood flow and plasma ET-1, t-PA and PAI-1 concentrations were unaffected by bevacizumab. Bradykinin caused dose-dependent vasodilatation (P < 0.0001) and t-PA release (P < 0.01) but had no effect on plasma PAI-1 concentrations. Neither bevacizumab nor BQ-123 affected bradykinin-induced vasodilatation and t-PA release. CONCLUSION: Acute exposure to bevacizumab does not directly cause endothelial vasomotor or fibrinolytic dysfunction in healthy young volunteers.

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Cite This Study

Cameron et al. (2019) studied Healthy volunteers (n=38). Bevacizumab vs. 0.9% sodium chloride (saline) was evaluated on Absolute forearm blood flow (p=NS). Acute intra-arterial infusion of bevacizumab did not alter resting forearm blood flow, endothelin-1 release, or bradykinin-induced vasodilatation and tissue plasminogen activator release in healthy men.

synapsesocial.com/papers/6a8985b55c4c6b099dec7385 https://doi.org/10.1097/hjh.0000000000002230

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Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation

Figures

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation

Figures

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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