Altered hetero- and homeometric autoregulation in the terminally failing human heart.
OBJECTIVE
To further investigate length-dependent force generation in human heart, nonfailing (donor hearts, NF) and terminally failing (heart transplants, dilated cardiomyopathy, DCM) left ventricular myocardium was studied under various preload (4-40 mN/mm2) 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/mm2): 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 Ca2+-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.
Brixius
Klara
K
Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, Joseph-Stelzmann-Str. 9, 50924 Cologne (Lindenthal), Germany.
Reuter
Hannes
H
Bloch
Wilhelm
W
Schwinger
Robert H G
RH
D000328:Adult; D020013:Calcium Signaling / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000503:physiopathology*; D016022:Case-Control Studies; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007537:Isometric Contraction / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000473:pathology; D046509:Tissue Culture Techniques; D016474:Weight-Bearing / Q000502:physiology