Mechanisms of Angiogenesis Inhibitor-Induced Cardiovascular Toxicity

  • Research type

    Research Study

  • Full title

    Markers and Mediators of Angiogenesis Inhibitor-Induced Vascular and Myocardial Toxicity

  • IRAS ID

    250811

  • Contact name

    Ninian N Lang

  • Contact email

    ninian.lang@glasgow.ac.uk

  • Sponsor organisation

    NHS Greater Glasgow and Clyde

  • Duration of Study in the UK

    3 years, 0 months, 1 days

  • Research summary

    Summary of Research
    Survival rates in cancer patients have been improving over the last few decades, particularly since the introduction of newer, more-targeted chemotherapy agents. Vascular Endothelial Growth Factor (VEGF) Signalling Pathway inhibitors (VSPIs) have been used in a wide variety of malignancies. However, since their introduction, it has become clear that these drugs have cardiovascular side effects, notably high blood pressure (hypertension) and can cause impaired pumping of the heart (left ventricular systolic dysfunction [LVSD]).

    These side effects can have a significant impact on patients' physical health as well as leading to the withdrawal of important cancer treatment. The mechanisms by which LVSD develops with these drugs are unclear and have not been well-described to date. The ability of blood vessels to contract and relax may be impaired by VSPIs and this may lead to the development of LVSD.

    The aim of this study is to investigate the effect of VSPIs on large and small blood vessels, as well as left ventricular function. This study will aim to recruit patients diagnosed with cancer who are eligible to receive VSPI treatment at the Beatson West of Scotland Oncology Centre. The CT scans used as part of their usual care for grading cancer, will be used to examine the aorta and heart arteries. Participants will undergo echocardiography and regular blood pressure monitoring. Additionally, the ability of their arteries to enlarge (dilate) and the number of small blood vessels (capillaries) in their fingertips measured with special machines (EndoPat and nailfold capillaroscopy). Blood and urine will be collected. Patients will also be invited to undergo detailed magnetic resonance imaging (MRI) scans of the heart (this is optional).

    With this information, we hope to inform better treatment or prevention of these cardiovascular side effects to ensure patients can receive the best cancer care available.

    Summary of Results
    Vascular endothelial growth factor inhibitors (VEGFI) are effectve cancer drugs but are associated with toxic effects upon the cardiovascular system such as high blood pressure (hypertension) and impaired heart pumping function (left ventricular systolic dysfunction [LVSD]). The timing, frequency and severity of these adverse effects were poorly defined. LVSD may be the result of direct effects of the VEGi drugs on the heart as well as a consequence of high blood pressure but this had not been proven. We therefore set out to address the questions in patients with cancer.

    Patients with cancer due to commence VEGFI were enrolled prospectively (Beatson West of Scotland Cancer Centre, UK). Comprehensive heart and blood vessel assessments were performed at baseline before VEGFI therapy was started and at 4, 12 and 24 weeks of treatment. Cardiac magnetic resonance imaging (CMR) was performed in a subgroup at baseline, 4 and 24 weeks. In addition to our comprehensive echocardiography assessments (heart ultrasound), CMR allowed even better assessment of the effect of these drugs upon the heart, including assessment of small blood vessel function within the heart muscle. Hypertension (high blood pressure) was defined as home BP recordings of at least 135/85 mmHg or new requirement for blood pressure therapy. Cardiotoxicity (heart pump dysfunction) was defined as a drop in left ventricular ejection fraction (LVEF) to a value <50% in line with International CardioOncology Society definitions.
    Results

    Of 97 patients enrolled, 78 attended follow-up and, of these, 53 (68%) were male with a mean age of 63±11 years. Forty (51%) received VEGFI alone and 38 (49%) received VEGFI and immunotherapy. The CMR sub-study enrolled 46 patients.
    Forty-seven patients (60%) developed high blood pressure. Overall, systolic and diastolic BP rose within 1 week from baseline (135 vs 128 mmHg, p<0.001; 82 vs 78 mmHg, respectively) and persisted at 4 weeks but thereafter BP was controlled to values lower than baseline.

    Fifteen patients (19%) developed cardiotoxicity. Overall, echo-assesment of LVEF showed that LVEF had declined at the four week assesment (60% vs 64%, and this persisted throughout follow-up. Of note, BP did not differ between those with and without cardiotoxicity .
    In the CMR sub-study, LVEF was lower after 4 weeks and this persisted at 24 weeks. Blood flow in the small heart blood vessels was also lower at these assessment times.

    In concluision, VEGFI-associated hypertension and cardiotoxicity occur early. VEGFI-associated LVSD appears to persist, despite blood pressure control. VEGFI cardiotoxicity may be a consequence of direct heart tissue and effects upon small arteries in the heart wall. These effects are at least partly independent of high blood pressure. This means that, in order to minimise heart toxicities from these drugs we will need to assess whether specific potential 'heart protective' therapies can be used to prevent or treat these patients to allow optimum safety of anti-cancer therapies.

  • REC name

    South East Scotland REC 01

  • REC reference

    18/SS/0155

  • Date of REC Opinion

    3 Dec 2018

  • REC opinion

    Further Information Favourable Opinion