"Don't flog the heart!" - development of specific drug therapies for heart failure

Understanding the cellular and molecular biology of heart failure is essential to developing targeted and effective treatment. Investigators are divided in their belief regarding the primary abnormality and whether it lies in dysregulation of neurohormonal signalling; nitric oxide synthesis and oxidative stress; cellular energy supply; or cellular ions. Our research demonstrates that these independently studied pathways are, in fact, closely interrelated. The Na+-K+ pump is critical in the determination of intracellular sodium levels, which are elevated in heart failure. Drug therapies have been developed targeting the neurohormonal abnormalities seen in the clinical syndrome of heart failure. We have examined the effect of many of these medications on the activity of the Na+-K+ pump and observed a perfect correlation between the ability of the treatment to stimulate the pump and its clinical outcome. This is illustrated by the stimulation of the pump by inhibition of the renin- angiotensin signalling pathway, and by aldosterone antagonists. We have also examined the role of reactive oxygen species as mediators of angiotensin and adrenergic regulation of the pump, demonstrating that intracellular pathways activated by Beta(1)/Beta(2)-adrenoceptors and the angiotensin II type 1 receptor converge, with both activating NAD(P)H oxidase and inhibiting the Na+-K+ pump via oxidative stress. In contrast, targeted stimulation of the Beta(3)-receptor resulted in nitric oxide-dependent pump stimulation in vitro, and improvements in left ventricular function in a large-animal heart failure model. Further characterisation of the intricate pathways involved in the hormonal regulation of the myocyte and its response to heart failure may aid in specific targeting of therapy.