Calcium handling in human heart failure--abnormalities and target for therapy.
The fast cycling of calcium between internal stores and the myofilaments with rapid diffusion down steep concentration gradients provides the cellular basis for cardiac contraction and relaxation. In heart failure, the intracellular Ca(2)                                   (+) dynamics are impaired showing reduced systolic peak Ca(2)                                   (+), elevated diastolic Ca(2)                                   (+) levels, and prolonged diastolic Ca(2)                                   (+) decay. The recognition that defects in the function of Ca(2)                                   (+) handling proteins are central to the pathogenesis of heart failure has attracted attention to these proteins as potential targets for therapy. Besides pharmacologic interventions including digitalis, ranolazine, levosimendan and others, cardiac gene therapy holds great promise and the recent clinical studies have proven the feasibility of this therapeutic approach. In this review, the rationale underlying modern therapies that modulate intracellular Ca(2)                                   (+) handling for the treatment of human heart failure are presented and discussed.
Department of Internal Medicine III, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany. hannes.reuter@uk-koeln.de
Hannes
H
Reuter
Robert H G
RH
Schwinger
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D005240:Feasibility Studies; D015316:Genetic Therapy; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009210:Myofibrils / Q000187:drug effects / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000502:physiology; D012508:Sarcolemma / Q000187:drug effects / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000502:physiology; D013599:Systole / Q000187:drug effects / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; C034703:mitochondrial calcium uniporter; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium