Heart failure is an epidemic which is increasing in prevalence and is associated with
an enormous healthcare burden, accounting for 1-2% of the entire NHS healthcare
budget. Existing treatment options are primarily focussed on preventing or retarding
the progression of disease rather than reversing the disease process. The survival
rate has been stubbornly slow to improve with a 5 year mortality rate of 50%.
Therefore, at present there is an unmet need for novel treatment strategies.
Pluripotent stem cell derived cardiomyocytes (SC-CM) are an exciting and potentially
revolutionary treatment option for repairing the damaged heart. Encouraging
preclinical experiments have reported that it is possible SC-CMs to survive,
electrically couple, and improve contractile function of the host heart, but an increase
in arrhythmia has been observed. It has also been shown that the existing delivery
methods (intracoronary and intramyocardial) used in human clinical trials of bone
marrow mononuclear cells are inadequate to enable long term retention of cells in
the heart and therefore newer strategies are needed. Biomaterials are promising, for
example, engineered heart tissue has been shown in small animal studies to enable
long term cell retention; however, to date the creation of engineered heart tissue
suitable for the first in man clinical trials is lacking.
The aims of this PhD project were to explore the use of biomaterials including
engineered heart tissue and conductive polymers in stem cell grafting experiments.
Firstly, upscaled engineered heart tissue was characterised in-vitro and feasibility
and efficacy tested in a preclinical intermediate model of myocardial infarction. A
rabbit model was chosen and set up for these experiments due to the numerous
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similarities with human myocardium and it being a suitable next step from small
animal models. Cell retention was tested at various time points up to one month and
efficacy was tested using changes in left ventricular function as determined by
echocardiography. Potentially harmful side effects of arrhythmia burden were tested
in-vivo and ex-vivo using telemetry and arrhythmia provocation protocols.The experiments in this PhD described the successful in-vitro characterisation of
upscaled engineered heart tissue and preclinical testing in a rabbit model of
myocardial infarction. The patches were not associated with an increase in
arrhythmia burden and improvements in ventricular function were observed when
compared to infarcted hearts. We were also able to show that conductive polymers
were able to alter the conductive properties of the epicardial surface of the heart and
did not appear pro-arrhythmic in nature.