title: α-B Crystallin Reverses High Diastolic Stiffness of Failing Human Cardiomyocytes.
abstract: BACKGROUND
  Cardiomyocytes with a less distensible titin and interstitial collagen contribute to the high diastolic stiffness of failing myocardium. Their relative contributions and mechanisms underlying loss of titin distensibility were assessed in failing human hearts.
  
  
  RESULTS
  Left ventricular tissue was procured in patients with aortic stenosis (AS, n=9) and dilated cardiomyopathy (DCM, n=6). Explanted donor hearts (n=8) served as controls. Stretches were performed in myocardial strips, and an extraction protocol differentiated between passive tension (Fpassive) attributable to cardiomyocytes or to collagen. Fpassive-cardiomyocytes was higher in AS and DCM at shorter muscle lengths, whereas Fpassive-collagen was higher in AS at longer muscle lengths and in DCM at shorter and longer muscle lengths. Cardiomyocytes were stretched to investigate titin distensibility. Cardiomyocytes were incubated with alkaline phosphatase, subsequently reassessed after a period of prestretch and finally treated with the heat shock protein α-B crystallin. Alkaline phosphatase shifted the Fpassive-sarcomere length relation upward only in donor. Prestretch shifted the Fpassive-sarcomere length relation further upward in donor and upward in AS and DCM. α-B crystallin shifted the Fpassive-sarcomere length relation downward to baseline in donor and to lower than baseline in AS and DCM. In failing myocardium, confocal laser microscopy revealed α-B crystallin in subsarcolemmal aggresomes.
  
  
  CONCLUSIONS
  High cardiomyocyte stiffness contributed to stiffness of failing human myocardium because of reduced titin distensibility. The latter resulted from an absent stiffness-lowering effect of baseline phosphorylation and from titin aggregation. High cardiomyocyte stiffness was corrected by α-B crystallin probably through relief of titin aggregation.
authors.affiliation: From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (C.F., J.K., R.M., N.H., W.J.P.); and Department of Cardiovascular Physiology, Ruhr University Bochum, Germany (N.H.).
authors.forename: Constantijn
authors.initials: C
authors.lastname: Franssen
authors.affiliation: From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (C.F., J.K., R.M., N.H., W.J.P.); and Department of Cardiovascular Physiology, Ruhr University Bochum, Germany (N.H.).
authors.forename: Jeroen
authors.initials: J
authors.lastname: Kole
authors.affiliation: From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (C.F., J.K., R.M., N.H., W.J.P.); and Department of Cardiovascular Physiology, Ruhr University Bochum, Germany (N.H.).
authors.forename: René
authors.initials: R
authors.lastname: Musters
authors.affiliation: From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (C.F., J.K., R.M., N.H., W.J.P.); and Department of Cardiovascular Physiology, Ruhr University Bochum, Germany (N.H.).
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.affiliation: From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (C.F., J.K., R.M., N.H., W.J.P.); and Department of Cardiovascular Physiology, Ruhr University Bochum, Germany (N.H.). wj.paulus@vumc.nl.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000494:pharmacology; D001024:Aortic Valve Stenosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001696:Biomechanical Phenomena; D002311:Cardiomyopathy, Dilated / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism; D064211:Connectin / Q000378:metabolism; D003971:Diastole / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D066329:Protein Aggregates; D038203:alpha-Crystallin B Chain / Q000494:pharmacology*
chemical_list: D064211:Connectin; D066329:Protein Aggregates; C577285:TTN protein, human; D038203:alpha-Crystallin B Chain; D003094:Collagen; D000469:Alkaline Phosphatase
keywords: aortic valve stenosis; collagen; diastole; extracellular matrix; heat shock proteins