A reversible state of heart dysfunction treatable by RAS inhibition

Heart failure is a progressive condition characterised by cardiomyocyte loss and cardiac fibroblast proliferation leading to cardiac hypertrophy and impaired heart function. Cardiac hypertrophy is commonly associated with high blood pressure in response to altered renin-angiotensin system (RAS) activity. However, there is evidence that RAS activity has a role in the early stages of heart failure that is independent of its influence on blood pressure. To investigate this, Justin F. X. Ainscough's group used a conditional mouse model in which a human angiotensin II type-I receptor transgene (HART) was expressed in fully matured cardiomyocytes. Persistent HART activity in young mice causes heart dysfunction without cardiac hypertrophy. This dysfunction correlates with increased expression of pro-angiogenic markers in cardiomyocytes and elicits a compensatory response in non-myocyte cells, which show downregulation of pro-angiogenic genes and inflammatory markers. Noteworthy, this stage is reversible by downregulation of HART expression. Further activation of the receptors, instead, leads to a secondary stage characterised by cardiomyocyte death and activation of fibroblast and inflammatory cells, which leads to further deterioration of heart function. This study therefore identifies an early stage of heart dysfunction associated with increased RAS activity, potentially treatable with RAS inhibitors to prevent heart failure development. Page 783