Functional consequences of sarcomeric protein abnormalities in failing myocardium.
Sarcomeric protein abnormalities have been recognized for many years in heart failure due to dilated cardiomyopathy (DCM). In contrast, virtually nothing is known about myofilament abnormalities in heart failure occurring in association with diastolic dysfunction. With the exception of sarcomeric protein mutations that cause DCM, the most important mechanism of myofilament dysfunction in DCM is probably altered post-translational modification, in particular the phosphorylation state of troponins I and T and possibly myosin light chain. Other modifications, including oxidation and glycation, may also play a role. Myosin heavy chain isoform switching occurs in human heart failure, but its functional significance is uncertain. Myofilament abnormalities contribute significantly to myocardial dysfunction in DCM, although their relative importance compared with abnormal calcium handling is debated. One consistent functional abnormality in DCM is increased myofilament calcium sensitivity of tension generation, which contributes to slowed or incomplete relaxation. More recently, decreases in the optimal frequency of myofilament work and power generation have been recognized. These changes may contribute to depression of the force-frequency relation in DCM. Altered mechanoenergetics constitute one of the most important manifestations of myofilament dysfunction in heart failure. DCM and hemodynamic overload are associated with more economical and efficient energy utilization by the contractile machinery, which may be protective of the myocardium. This change is strongly associated with depressed myofibrillar ATPase activity. We speculate that the effectiveness of mechanical therapies such as resynchronization may at least in part be related to improved mechanical function without loss of this mechanoenergetic advantage.
LeWinter
Martin M
MM
Cardiology Unit, Department of Medicine, College of Medicine, University of Vermont, Burlington, VT 05401, USA. martin.lewinter@vtmednet.org
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000150:complications; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000209:etiology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology; D006801:Humans; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009210:Myofibrils / Q000201:enzymology; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D012518:Sarcomeres / Q000235:genetics / Q000502:physiology*
D009124:Muscle Proteins; D011494:Protein Kinases; D000251:Adenosine Triphosphatases; D000252:Calcium-Transporting ATPases