Altered hetero- and homeometric autoregulation in the terminally failing human heart

Objective and methods: To further investigate length-dependent force generation in human heart, nonfailing (donor hearts, NF) and terminally failing (heart transplants, dilated cardiomyopathy, DCM) left ventricular myocardiurn was studied under various preload (4-40 mN/mm(2)) or length conditions. In addition, morphological studies (van Giesson Trichrome staining, electron microscopy) were performed. Results: In NF, a biphasic increase in force of contraction (FOC) was observed after elevating the preload (4-40 mN/mm(2)): there was an immediate fast increase (FOCf), followed by a slow increase over several minutes (FOCs), which was paralleled by an increase in the systolic fura-2 transient. In DCM, FOCf, FOCs, and the systolic fura-2 transient were blunted and diastolic tension was increased at increasing muscle length. Only in NF, a stretched induced increase in diastolic fura-2 ratio was observed. In DCM, no obvious interstitial fibrosis and no difference in basement membrane structure and attachment were observed. Conclusions: Since FOCf has been attributed to the Frank-Starling mechanism, whereas FOCs represents a length-dependent increase in the intracellular Ca (2+)-transient, the impaired length-dependent force generation in failing myocardium results from a dysregulation of both myofibrillar Ca2+-sensitivity as well as the intracellular Ca2+_ homeostasis. Interstitial fibrosis may have only minor impact on force generation in human end-stage heart failure. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.