Of Phospholamban, Mice, and Humans With Heart Failure

espite recent advances in the medical treatment of chronic heart failure, 1 this clinical syndrome remains progressive.For example, in recently completed clinical trials demonstrating a reduction in mortality by medical therapy with ␤-blockade 2,3 or spironolactone, 4 the survival curves of the active treatment groups retained a downward slope, such that at 20 to 24 months after randomization, only 80% to 85% of subjects with mild to moderate 2,3 and 70% of subjects with advanced 4 heart failure remained alive.The progressive nature of heart failure is due to the inexorable worsening of the underlying disease processes, myocardial dysfunction, and remodeling.5,6 What are the critical factors responsible for progressive contractile dysfunction and remodeling of the failing heart?Data from clinical studies implicate both the adrenergic and reninangiotensin-aldosterone systems, because treatment with ␤-blocking agents and renin-angiotensin-aldosterone system inhibitors attenuate the dysfunction/remodeling processes.6 Other signaling pathways are also involved, as shown by studies in animal models 7 and the failure of inhibiting both the adrenergic and renin-angiotensin-aldosterone systems to completely prevent progression in dysfunction, remodeling, and mortality.