This picture shows some cardiovascular variables obtained through a method to determine blood flow called pulsed Doppler flowmetry and recorded using a computer-based system (IdeeQ). This technique allows us to make measurements of blood flow in three different vascular beds, while at the same time measuring heart rate and blood pressure, in conscious, freely moving rats. In order to evaluate these changes in the dynamics of the blood flow (haemodynamic), Doppler flow probes need to be surgically placed on the studied vessels. Several parameters will then be recorded using a computer-based system 1,2. Because the experiments are performed in a live rat, this method also permits us to measure haemodynamic changes in different parts of the vascular system, with reflex systems intact; these are often affected by anesthetics.
During my PhD project I will use the pulsed Doppler flowmetry to investigate changes in mesenteric, renal and hindquarters vascular conductance, as well as heart rate and mean arterial pressure, in rats treated with anticancer drugs targeting vascular endothelial growth factor (VEGF) signalling. Moreover, this approach will also provide essential information to clearly define the mechanism of action underlying cardiovascular impairment due to such novel targeted therapies used in cancer treatment. This project will give us more detailed information about the safety pharmacology issues associated with these treatments 3.
- Haywood, J.R., Shaffer, R.A., Fastenow, C., Fink, G.D. & Brody, M.J. Regional blood flow measurement with pulsed Doppler flowmeter in conscious rat. American Journal of Physiology-Heart and Circulatory Physiology 241, H273-H278 (1981).
- Gardiner, S.M., Compton, A.M., Bennett, T. & Hartley, C.J. Can pulsed Doppler technique measure changes in aortic blood flow in conscious rats? American Journal of Physiology-Heart and Circulatory Physiology 259, H448-H456 (1990).
- Poster SPS meeting 2019, Barcelona
The measurement of blood pressure gives us valuable information on the health of a patient’s heart and blood vessels. The blood pressure is recorded as a waveform, a regularly repeating signal over time. Typically, the maximum and minimum value of the waveform are evaluated. In a healthy individual, these values are approximately 120/80 mmHg. In many diseases, the blood pressure is raised.
However, besides this maximum and minimum value, there is considerably more information captured in the recording of a blood pressure, that is often not taken into account. Analysis of the shape of the waveform and variability of this signal may give us additional information on how the heart and blood vessels are affected, particularly after drug treatment. In order to look at subtle changes in these waveform features, a new model was developed, called the attractor reconstruction. This mathematical model converts the blood pressure waveform (on the left-hand side of the flyer) into a 2D image (as shown on the right-hand side). By analysing different features of this 2D image, such as colour or length of the loops, we can extract detailed information on the effects of drugs on the heart and blood vessels. During my project, I will apply this attractor reconstruction on blood pressure waveforms and blood flow waveforms, to see how a number of anticancer drugs affect the cardiovascular system. In this way, I will explore the mechanism and safety of these medicines.
- Nandi, M., & Aston, P. J. (2020). Extracting new information from old waveforms: Symmetric projection attractor reconstruction: Where maths meets medicine. Experimental Physiology, 105(9), 1444–1451. https://doi.org/10.1113/EP087873
- Nandi, M., Venton, J., & Aston, P. J. (2018). A novel method to quantify arterial pulse waveform morphology: Attractor reconstruction for physiologists and clinicians. Physiological Measurement, 39(10). https://doi.org/10.1088/1361-6579/aae46a
This image presents a usual workflow for data analysis by MALDI-MSI. MSI, standing for mass spectrometry imaging, is a label free technique allowing visualization of biomolecules on tissue sections. The image on the flyer shows heart sections obtained from an ischemia mouse model to study peptide distribution differences between ischemic (highlighted in black) and healthy regions. An overlay (right) of a conventional histology image (left) and a MSI image provides a better understanding of the molecular distribution within the tissue.
Segmentation analysis (middle) clustered the peptide spectra into different groups represented by different colors based on their molecular similarity, revealing a specific peptide signature in the ischemic area. This workflow is usually followed by MALDI-MSI guided proteomics for in depth protein identification.
During my PhD-project, I will employ MSI and spatial -omics strategies to study protein and glycan regulation in the field of cardiovascular diseases and toxicology.
Historically, cancer and cardiovascular diseases were seen as separate entities only sharing several common risk factors, e.g. smoking, obesity and genetic background.1 Recent evidence, however, demonstrates that heart failure as a result of a heart attack promotes cancer development in mice.2 In the field of cardio-oncology, the toxic effects of anti-cancer drugs on the heart, eventually leading to heart failure or other cardiovascular adverse events, are being investigated extensively. However, the possibility of heart failure causing or worsening cancer growth is a novel discovery and is leading to the rise of the ‘reversed cardio-oncology’ field.
How does heart failure promote cancer growth? Several studies point towards proteins that are secreted by the damaged heart.2,3 These proteins are secreted by several biological processes with the aim to heal injuries, similar to wound healing. The ‘wound healing’ processes that are favorable in the heart, however, might promote cancer growth. During my PhD I will study the link between heart failure and cancer with a specific focus on endothelium-derived growth factors.
- Avraham, S., Abu-Sharki, S., Shofti, R., Haas, T., Korin, B., Kalfon, R., Friedman, T., Shiran, A., Saliba, W., Shaked, Y., & Aronheim, A. (2020). Early Cardiac Remodeling Promotes Tumor Growth and Metastasis. Circulation, 142(7), 670–683. https://doi.org/10.1161/CIRCULATIONAHA.120.046471
- Meijers, W. C., Maglione, M., Bakker, S. J. L., Oberhuber, R., Kieneker, L. M., De Jong, S., Haubner, B. J., Nagengast, W. B., Lyon, A. R., Van Der Vegt, B., Van Veldhuisen, D. J., Westenbrink, B. D., Van Der Meer, P., Silljé, H. H. W., & De Boer, R. A. (2018). Heart failure stimulates tumor growth by circulating factors. Circulation, 138(7), 678–691. https://doi.org/10.1161/CIRCULATIONAHA.117.030816
- Moslehi, J., Zhang, Q., & Moore, K. J. (2020). Crosstalk between the heart and cancer: Beyond drug toxicity. In Circulation (Vol. 142, Issue 7, pp. 684–687). Lippincott Williams and Wilkins. https://doi.org/10.1161/CIRCULATIONAHA.120.048655
This image shows a size comparison of a regular pen and a pressure volume catheter used for precise analysis of the heart function in mice. This useful but tiny device can be inserted via a blood vessel inside the neck into the left ventricle (left chamber) to determine simultaneously the pressure and volume in the beating heart of a mouse (in vivo experiment). The catheter is connected to a computer allowing real time assessment of each heart beat generating pressure volume loops (PV-loops). PV-loops can be used to assess various parameters that characterize heart function.
Due to the small size of the mice and especially the mice heart, precise assessment of the cardiac function remains challenging. Nowadays, several imaging technologies are used to provide information regarding cardiac function in mice (e.g. ultrasonic or magnetic resonance imaging). However, only PV-loops provide the precise, real time and simultaneous measurement of chamber pressure and volume in mice heart. Also a great advantage of PV-loops is that they have already been well established in humans, thereby enhancing translation of the results to humans.1 During my PhD project I will use PV-loops to study the toxic effects of anti-cancer drugs in mice hearts.2 This gives a better insight into the side effects of anti-cancer drug and helps to develop new strategies to reduce them.
- Townsend, D. W. (2016). Measuring pressure volume loops in the mouse. Journal of Visualized Experiments, 2016(111), 53810. https://doi.org/10.3791/53810
- Poster SPS meeting 2019, Barcelona