IAmA cardiovascular disease researcher exploring what happens to the cardiac muscle during heart failure. Ask me anything!
Hi Reddit! I’m Sian Harding, Professor of Cardiac Pharmacology at Imperial College London. My research focuses on what happens to the cardiac muscle during heart failure.
What is heart failure?
Heart failure in humans is a syndrome characterised by fatigue, breathlessness and water retention. It happens after recovery from an initial cardiac injury and affects more than 500,0000 people in the UK alone, accounting for up to 40% of all deaths worldwide.
Cardiac injury is often due to heart attack but can also be a consequence of genetic defects, infection or chemotherapy. It has a poor prognosis, with mortality similar to some of the worst cancers. Suffering from heart failure means to be at high risk of shorter life expectancy and generally reduced quality of life.
The cardiac muscle cell, or cardiomyocyte, is the building block of the heart. Deterioration of myocyte function during the development of heart failure is a process that is distinct from the original injury to the heart and may be the result of the body's attempt to produce maximum work from a damaged muscle. Characterisation of the functional alterations to the myocyte, and the molecular processes underlying them, has led to ideas for specific treatments for the failing heart.
About my research
My research at the National Heart & Lung Institute is centred on the cardiomyocyte and its role in heart failure. Starting with simply understanding what happens in heart failure and the effects on myocardial function, to developing models and systems around that.
We use several different animal species (mice, rabbits, rats) to either mimic the heart failure syndrome as a whole, for example by tying off part of the heart muscle under anaesthesia, or to imitate just part of it such as the high catecholamine levels.
My research group was also among the first to do work on isolated human cardiomyocytes. Our understanding from this work leads to involvement in gene therapy trials and more recently in using pluripotent stem cells to produce genotype-specific cardiomyocytes.
This allows the possibility of gene editing and creating engineered heart tissue. It can be a really powerful tool for looking at larger scale characteristics like arrhythmia.
About animal research
Research involving animals forms an important element of our work but is not undertaken lightly. My commitment towards the Reduction, Refinement and Replacement principles is evident from my pioneering work with human myocardial tissue. However, to fully mimic and understand what happens to the cardiac muscle during heart failure, some use of animal model is still critical for our research.
We have also recently been using cardiomyocytes made from human induced pluripotent stem cells. These are an exciting new replacement method, as they can be used for making strips of tissue (Engineered Heart Tissue) and mutations can be introduced either by making the cells directly from affected patients or by gene editing. We are also using the Engineered Heart Tissue in our cardiac damage models on the way to a cardiac patch therapy for heart failure.
My commitment to animal welfare is reflected in my role as Chair of the Animal Welfare and Ethical Review Body (AWERB) which reviews Imperial researchers’ animal research to guarantee the combination of best science with the highest standards of animal welfare (http://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/regulation/)
Reference for this research:
- Davies CH, Davia K, Bennett JG, Pepper JR, Poole-Wilson PA, Harding SE. Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation. 1995;92:2540-9.
- Schobesberger S, Wright P, Tokar S, Bhargava A, Mansfield C, Glukhov AV, et al. T-tubule remodelling disturbs localized beta2-adrenergic signalling in rat ventricular myocytes during the progression of heart failure. Cardiovasc Res. 2017;113(7):770-82.
- Harding SE, Brown LA, del Monte F, O'Gara P, Wynne DG, Poole-Wilson PA. Parallel Changes in the b-Adrenoceptor/Adenylyl Cyclase System between the Failing Human Heart and the Noradrenaline-treated Guinea-pig. In: Nagano M, Takeda N, Dhalla NS, editors. The Cardiomyopathic Heart: Raven Press; 1993.
- Hellen N, Pinto RC, Vauchez K, Whiting G, Wheeler JX, Harding SE. Proteomic Analysis Reveals Temporal Changes in Protein Expression in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes In Vitro. Stem Cells Dev. 2019;%20. doi:10.
- Smith JGW, Owen T, Bhagwan JR, Mosqueira D, Scott E, Mannhardt I, et al. Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits. Stem Cell Reports. 2018;11(5):1226-43.
Animal research at Imperial College London: https://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/
Animal research report 2016/17: http://www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/annual-report/
UPDATE [12.45PM ET / 5.45PM GMT]: Thanks very much for your great questions everyone. I’m heading off for now but will be checking back in tomorrow, so please do submit any more questions you may have.
And a big thanks to r/IAmA for hosting this AMA!