The therapeutic potential of new insights into myocardial excitation-contraction coupling.
The physiological mechanisms that link myocyte depolarisation and contraction are referred to collectively as excitation-contraction coupling. This important process uses calcium as a second messenger to convert electrical depolarisation of the myocyte sarcolemma into the coordinated contraction of the cell's internal myofilament apparatus. The inotropic properties of the cell are determined by the efficiency of this process and when this efficiency is lost contractile dysfunction and heart failure develop, along with a propensity for arrhythmias. Previous attempts to use positive inotropic drugs in the management of chronic heart failure have been disappointing. Such drugs have been associated with unacceptable side effects and worse morbidity and mortality outcomes, primarily through their non-specific amplification of intracellular cascade pathways that modify the cell's inotropic state. As a result of recent advances in our understanding of how excitation-contraction coupling works in both health and disease it may be possible to design more specifically targeted drug treatment that has the potential to avoid the detrimental effect of currently available drugs while at the same time improving the inotropic properties of the cell.
Scoote
M
M
Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK. mark.scoote@ic.ac.uk
Poole-Wilson
P A
PA
Williams
A J
AJ
D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002118:Calcium / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors; D000252:Calcium-Transporting ATPases / Q000502:physiology; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D015195:Drug Design; D006329:Heart Conduction System / Q000502:physiology; D006333:Heart Failure / Q000628:therapy*; D006801:Humans; D032342:Muscle Cells / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
D000889:Anti-Arrhythmia Agents; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002316:Cardiotonic Agents; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban