Endothelial Effects of VEGF Inhibition In Vivo in Man
Condition: Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Observational

Summary: 
      Recent developments in chemotherapy, particularly VEGF-inhibitor (VEGFI) drugs, have markedly
      improved the prognosis of patients with cancer. However, these drugs frequently cause high
      blood pressure (hypertension) which can lead to heart attacks, heart failure and stroke and
      can limit their use for cancer treatment.

      Endothelin-1 is a hormone that causes blood vessels to tighten and may contribute to high
      blood pressure associated with VEGFI drugs. Blocking the effects of endothelin-1 may
      therefore reduce or prevent VEGFI-associated blood pressure changes, although this has never
      been tested in humans.

      Our long-term goal is to assess the protective effects of endothelin-1 blocker drugs in
      patients treated with VEGFI. Before doing so, we must better explore whether VEGFIs cause
      blood vessel narrowing and if endothelin-1 blockers prevent this. We will assess this in
      healthy volunteers using a special technique called 'forearm plethysmography'. We will
      examine the effect of VEGFI on blood flow and also the effect of simultaneous administration
      of endothelin-1 blockers. These will be given at doses that produce local effects in the arm
      without affecting the rest of the body.

      These studies study will show whether endothelin-1 blockers may help treat VEGFI-associated
      hypertension to enable more patients safely to receive vital cancer treatments.
    

Detailed description: 
      Developments in chemotherapy have improved the prognosis for patients with cancer.1,2
      Angiogenesis is essential for tumour growth and metastasis and vascular endothelial growth
      factor (VEGF) is fundamental to this process.3,4 Chemotherapeutic VEGF inhibitor (VEGFI)
      drugs have revolutionised therapy and improved the prognosis and survival of patients with
      previously untreatable malignancies.1,2 Blood pressure elevation is a common complication
      that occurs in up to 80% of patients treated with VEGFI and almost all patients have an
      absolute increase in blood pressure, with 30-60% developing frank hypertension.1,5 Patients
      are at risk of acute hypertensive complications, including stroke, acute coronary syndrome or
      reversible leukoencephalopathy and the development of VEGFI-associated hypertension may
      mandate the premature discontinuation of these important anti-cancer therapies. Those who
      survive their cancer are at risk of developing end-organ damage leading to ischaemic heart
      disease, heart failure, renal failure and stroke.1,5 Indeed, with substantially increased
      cancer survivorship patients often survive long enough to allow cardiovascular morbidity to
      take precedence over their initial cancer diagnosis.

      Mechanisms contributing to the development of VEGFI-associated hypertension may include
      endothelial dysfunction, capillary rarefaction and vascular remodelling.1,5 Endothelin-1
      (ET-1) is a potent endogenous vasoconstrictor and is strongly implicated in the pathogenesis
      of hypertension and endothelial dysfunction. 3,6,7 However, the effects of VEGFI on
      endothelial function and the role of ET-1 in VEGFI-associated hypertension are incompletely
      defined. Indeed, there is a paucity of information on mechanisms contributing to
      VEGFI-induced hypertension and our study will address this key issue.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy volunteer males
      
Biospecimen description: 
      Blood samples without DNA analysis
    
Keywords: VEGF inhibitors; hypertension; endothelial function; thrombosis; venous occlusion plethysmography