The myofilament force-calcium relationship as a target for positive inotropic therapy in congestive heart failure.
To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through beta-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.
MacGowan
Guy A
GA
Dept of Cardiology, Freeman Hospital and University of Newcastle upon Tyne, Newcastle upon Tyne NE7 7DN, United Kingdom. guy.macgowan@nuth.nhs.uk
D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004734:Energy Metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D006835:Hydrazones / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D011724:Pyridazines / Q000627:therapeutic use*; D000077464:Simendan; D016277:Ventricular Function, Left
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D002118:Calcium