Biased Agonism at the Angiotensin Receptor

Article, see p 1056 Dilated cardiomyopathy (DCM) is a myocardial disease characterized by ventricular dilation and reduced pumping power. Numerous factors, including infections, congenital defects, genetic mutations, and exposure to chemotherapeutic agents or alcohol, can damage the myocardium and predispose the heart to DCM. Familial DCM accounts for 20% to 50% of all cases, with mutations affecting genes encoding cytoskeletal proteins (eg, titin, troponin, α-tropomyosin) or proteins required for contraction (eg, phospholamban).1 DCM is 1 of the leading causes of chronic heart failure (CHF). Conventional treatments for DCM and CHF have much in common. Mainstays include medications that block the renin-angiotensin and sympathetic nervous systems. Use of ACE inhibitors, angiotensin receptor blockers, and β-blockers in CHF is associated with reduction in both mortality and morbidity. Blocking the respective G protein-coupled receptors (GPCRs) protects the myocardium from further damage because exaggerated activation of these neurohormonal stimuli is maladaptive, leading to cardiomyocyte death, ventricular remodeling, and further deterioration of cardiac function. On the contrary, the use of inotropic agents in the treatment of heart failure has experienced ups and downs over the past 200 years. For >100 years, cardiac glycosides (digitalis) were the only effective therapy for CHF. Inotropes, including sympathomimetics, phosphodiesterase inhibitors, and calcium sensitizers developed in the late 20th century, improve short-term cardiac performance but in some cases increase mortality in the long run.2 Their use is restricted to acute decompensation in CHF. Despite these challenges, the quest for safe therapeutic agents to improve contractile performance of the failing heart has not ceased.3 In this issue of Circulation , Ryba and colleagues4 report the effect of long-term administration of TRV067, a novel ligand of the angiotensin II type 1 receptor (AT1R), on the structure and function of failing hearts in a genetic mouse model …