PhD project title: Obesity and Cardiac Arrhythmias – Does Obesity Affect the Responses to Anti-Arrhythmic Drugs?
Background: Atrial fibrillation (AF) is prevalent in 4% of the general population and on the rise due to ageing population and lifestyle factors (1). For every unit increase in body mass index, there is a parallel 3-3.5% increase in AF risk (2). There is clear evidence that obesity itself drives cardiac tissue remodelling, via alterations in ion channel expression, fatty tissue deposition and fibrosis (3). Our pilot data indeed demonstrates that obesity alters atrial electrical function in high fat diet fed mice (Fig 1, panel A). Patients with AF receive one of a number of anti-arrhythmic drugs (AADs) in order to return to sinus rhythm. However, 5-year recurrence of AF is high, over 60- 80% (4, 5) Recent clinical trial suggests that obesity can negatively affect the response to a standard cardiovascular drug spironolactone (6). Mechanisms driving the altered response are unclear.
Aims: In this project we will utilise our obesity animal models, patient data (acquired during ablation) and cellular models to examine whether and how obesity alters cardiac electrophysiology and antiarrhythmic drug responses.
Experimental Methods and Research Plan: The project will provide training opportunities in state-of-the-art methodologies and be implemented in several stages, providing a number of intermediate goals and allowing for several independent deliverables, see Gannt chart in Figure 1D.
Proposal is divided into three programmes of study:
Programme 1 - Adipocyte-Cardiomyocyte co-culture: Here we will use our expertise in cardiac cell co-culture(7) (Figure 1C) and optical mapping (8)(Figure 1B) to determine the effects of adipocytes on AADs responses (including beta blockers, sodium channel blockers, calcium channel blockers and potassium channel blockers). Initially, the student will determine optimal adipocyte-cardiomyocyte co-culture conditions and voltage/calcium dye loading, using optical mapping. Human pluripotent stem cell derived atrial cardiomyocytes (hPSC-CM) developed using established methodology are commonly used in our laboratory(9). Cardiomyocytes-adipocyte co-cultures will be plated at incremental ratios (1:1 to 1:10), loaded with voltage (fluovolt) sensitive dyes and electrical handling will be assessed by our state-of-the-art optical mapping setup and our high-throughput software ElectroMap (8) (see Figure 1C for electrophysiology parameters to be studied).
Programme 2 - Mouse model of obesity: We previously demonstrated that high fat diet alters atrial electrophysiology (Figure 1B), leading to pro-arhythmic changes. Here we will examine whether AADs responses are altered in obese hearts. Obesity in mice will be induced by an “all American diet” (high fat, high protein chow and 15% fructose water). Effects of AADs on atrial electrophysiology will be examined in vivo and in vitro, using ECG measured in vivo and in isolated atria assessed using optical mapping(8).
Programme 3 - Patient electrophysiology data: We will utilise human cardiac mapping data, collected routinely in AF ablation clinics from our collaborators at Birmingham, Oxford, Hamburg and Leicester to examine whether obesity alters AADs responses. Anatomical and electrophysiological data will be extracted from electroanatomical mapping systems (e.g. CARTO®, KODEX-EPD®) using our already developed data parsers. Low voltage areas, local activation time, conduction velocity, heterogeneity and fractionation will be measured from normal, overweight, and obese patients. We will investigate how these parameters are altered by AAD treatment, and whether these responses are altered by obesity. Further to these ‘traditional’ analyses, we will employ artificial intelligence approaches to develop classification and prediction models to examine the interaction between obesity and AADs, and the chance of recurrence following ablation procedures.
Expected outcomes and impact:
Our translational approach will robustly characterise the effects of cardiomyocyte- adipocytes coupling on electrical activity in hPSC-CM lines and shed light on the effects of obesity on responses to standard anti-arrhythmic drugs.
- Chugh, S. S., Havmoeller, R., Narayanan, K., Singh, D., Rienstra, M., Benjamin, E. J., Gillum, R. F., Kim, Y. H., McAnulty, J. H., Jr., Zheng, Z. J., Forouzanfar, M. H., Naghavi, M., Mensah, G. A., Ezzati, M., and Murray, C. J. (2014) Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 129, 837-847
Wang, T. J., Parise, H., Levy, D., D'Agostino, R. B., Sr., Wolf, P. A., Vasan, R. S., and Benjamin, E. J. (2004) Obesity and the risk of new-onset atrial fibrillation. Jama 292, 2471-2477
Nalliah, C. J., Bell, J. R., Raaijmakers, A. J. A., Waddell, H. M., Wells, S. P., Bernasochi, G. B., Montgomery, M. K., Binny, S., Watts, T., Joshi, S. B., Lui, E., Sim, C. B., Larobina, M., O'Keefe, M., Goldblatt, J., Royse, A., Lee, G., Porrello, E. R., Watt, M. J., Kistler, P. M., Sanders, P., Delbridge, L. M. D., and Kalman, J. M. (2020) Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality. J Am Coll Cardiol 76, 1197-1211
Raitt, M. H., Volgman, A. S., Zoble, R. G., Charbonneau, L., Padder, F. A., O'Hara, G. E., Kerr, D., and Investigators, A. (2006) Prediction of the recurrence of atrial fibrillation after cardioversion in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 151, 390-396
Valembois, L., Audureau, E., Takeda, A., Jarzebowski, W., Belmin, J., and Lafuente- Lafuente, C. (2019) Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 9, CD005049
Elkholey, K., Papadimitriou, L., Butler, J., Thadani, U., and Stavrakis, S. (2021) Effect of Obesity on Response to Spironolactone in Patients With Heart Failure With Preserved Ejection Fraction. Am J Cardiol 146, 36-47
Ackers-Johnson, M., Li, P. Y., Holmes, A. P., O'Brien, S. M., Pavlovic, D., and Foo, R. S. (2016) A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Nonmyocytes From the Adult Mouse Heart. Circ Res 119, 909-920
O'Shea, C., Holmes, A. P., Yu, T. Y., Winter, J., Wells, S. P., Correia, J., Boukens, B. J., De Groot, J. R., Chu, G. S., Li, X., Ng, G. A., Kirchhof, P., Fabritz, L., Rajpoot, K., and Pavlovic, D. (2019) ElectroMap: High-throughput open-source software for analysis and mapping of cardiac electrophysiology. Sci Rep 9, 1389
Holmes, A. P., Saxena, P., Kabir, S. N., O'Shea, C., Kuhlmann, S. M., Gupta, S., Fobian, D., Apicella, C., O'Reilly, M., Syeda, F., Reyat, J. S., Smith, G. L., Workman, A. J., Pavlovic, D., Fabritz, L., and Kirchhof, P. (2021) Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone. Heart Rhythm 18, 1212-1220
BBSRC Strategic Research Priority: Understanding the Rules of Life: Stem Cells & Systems Biology & Integrated Understanding of Health: Diet and Health & Pharmaceuticals
Techniques that will be undertaken during the project:
- Stem cell differentiation,
- Cardiac optical mapping,
- in vivo animal physiology,
- Algorithm development (MatLab),
- Artificial intelligence led data analysis.
Contact: Dr Davor Pavlovic, University of Birmingham