title: Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.
abstract: BACKGROUND
  The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin.
  
  
  RESULTS
  Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intraoperative left ventricular epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes mellitus), hypertension (HTN) without (-) HFpEF (n=31), and HTN with (+) HFpEF (n=22). One or more of the following studies were performed on the biopsies: passive stiffness measurements to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay), collagen assays (biochemistry or histology), or titin isoform and phosphorylation assays. In comparison with controls, patients with HTN(-)HFpEF had no change in left ventricular end-diastolic pressure, myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers of inflammation (C-reactive protein, soluble ST2, tissue inhibitor of metalloproteinase 1). In comparison with both control and HTN(-)HFpEF, patients with HTN(+)HFpEF had increased left ventricular end-diastolic pressure, left atrial volume, N-terminal propeptide of brain natriuretic peptide, total, collagen-dependent, and titin-dependent stiffness, insoluble collagen, increased titin phosphorylation on PEVK S11878(S26), reduced phosphorylation on N2B S4185(S469), and increased biomarkers of inflammation.
  
  
  CONCLUSIONS
  Hypertension in the absence of HFpEF did not alter passive myocardial stiffness. Patients with HTN(+)HFpEF had a significant increase in passive myocardial stiffness; collagen-dependent and titin-dependent stiffness were increased. These data suggest that the development of HFpEF depends on changes in both collagen and titin homeostasis.
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.). zilem@musc.edu.
authors: Michael R
authors: MR
authors: Zile
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Catalin F
authors: CF
authors: Baicu
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: John S
authors: JS
authors: Ikonomidis
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Robert E
authors: RE
authors: Stroud
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Paul J
authors: PJ
authors: Nietert
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Amy D
authors: AD
authors: Bradshaw
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Rebecca
authors: R
authors: Slater
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Bradley M
authors: BM
authors: Palmer
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Peter
authors: P
authors: Van Buren
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Markus
authors: M
authors: Meyer
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Margaret M
authors: MM
authors: Redfield
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: David A
authors: DA
authors: Bull
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Henk L
authors: HL
authors: Granzier
authors: From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson (R.S., H.L.G.); Cardiology Unit, Department of Medicine, University of Vermont, Burlington (B.M.P., P.V.B., M.M., M.M.L.W.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (B.M.P., P.V.B., M.M.L.W.); Division of Cardiology, Mayo Clinic, Rochester, MN (M.M.R.); and Division of Cardiothoracic Surgery, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City (D.A.B.).
authors: Martin M
authors: MM
authors: LeWinter
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D003094:Collagen / Q000032:analysis / Q000502:physiology*; D003187:Compliance; D064211:Connectin / Q000032:analysis / Q000502:physiology*; D048909:Diabetes Complications / Q000378:metabolism / Q000473:pathology; D003971:Diastole; D004548:Elasticity; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D006352:Heart Ventricles; D006801:Humans; D006973:Hypertension / Q000150:complications; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000032:analysis; D011499:Protein Processing, Post-Translational; D013318:Stroke Volume
chemical_list: D015415:Biomarkers; D064211:Connectin; D020033:Protein Isoforms; C577285:TTN protein, human; D003094:Collagen
keywords: collagen; diastole; heart failure; hypertension; hypertrophy
references: Circ Res. 2004 Oct 1;95(7):708-16
references: 15345656
references: Anal Biochem. 1985 Oct;150(1):86-90
references: 4083486
references: J Biol Chem. 1987 Jan 15;262(2):772-7
references: 3100520
references: Anal Biochem. 1992 Jun;203(2):187-90
references: 1384382
references: JAMA. 1996 May 22-29;275(20):1557-62
references: 8622246
references: Circulation. 2005 Feb 15;111(6):774-81
references: 15699264
references: J Am Soc Echocardiogr. 2005 Dec;18(12):1440-63
references: 16376782
references: Heart Fail Rev. 2005 Sep;10(3):211-23
references: 16416044
references: Cardiovasc Res. 2006 Mar 1;69(4):876-87
references: 16376870
references: Circulation. 2006 Apr 25;113(16):1966-73
references: 16618817
references: N Engl J Med. 2006 Jul 20;355(3):251-9
references: 16855265
references: Circ Heart Fail. 2011 Jan;4(1):27-35
references: 21068341
references: J Am Coll Cardiol. 2011 Feb 22;57(8):977-85
references: 21329845
references: J Mol Cell Cardiol. 2011 Apr;50(4):731-9
references: 21255582
references: JAMA. 2011 Aug 24;306(8):856-63
references: 21862747
references: Circulation. 2011 Sep 6;124(10):1151-9
references: 21844073
references: Circ J. 2011;75(11):2605-13
references: 21821961
references: Circulation. 2011 Dec 6;124(23):2491-501
references: 22064591
references: Circulation. 2011 Dec 20;124(25):2882-91
references: 22144574
references: Am J Physiol Heart Circ Physiol. 2012 Apr 1;302(7):H1429-37
references: 22287584
references: Circulation. 2012 Aug 14;126(7):830-9
references: 22806632
references: Am J Physiol Heart Circ Physiol. 2012 Nov 1;303(9):H1128-34
references: 22942178
references: J Mol Cell Cardiol. 2013 Jan;54:90-7
references: 23220127
references: Cardiovasc Res. 2013 Mar 1;97(3):464-71
references: 23213108
references: Circ Res. 2013 Feb 15;112(4):664-74
references: 23283722
references: Circulation. 2013 Feb 26;127(8):938-44
references: 23439446
references: Circ Heart Fail. 2013 Mar;6(2):184-92
references: 23258572
references: JAMA. 2013 Mar 27;309(12):1268-77
references: 23478662
references: Eur Heart J. 2013 May;34(19):1424-31
references: 23470495
references: Circulation. 2013 Jul 2;128(1):5-8
references: 23709670
references: Circulation. 2013 Jul 2;128(1):19-28
references: 23709671
references: J Cardiovasc Transl Res. 2013 Aug;6(4):501-15
references: 23716130
references: J Am Coll Cardiol. 2013 Jul 23;62(4):263-71
references: 23684677
references: Cardiovasc Res. 2013 Sep 1;99(4):648-56
references: 23764881
references: Circ Res. 2013 Aug 30;113(6):725-38
references: 23989715
references: Circ Heart Fail. 2013 Nov;6(6):1239-49
references: 24014826
references: Circ Heart Fail. 2014 Jan;7(1):104-15
references: 24249049
references: Circ Res. 2014 Mar 14;114(6):1052-68
references: 24625729
references: N Engl J Med. 2014 Apr 10;370(15):1383-92
references: 24716680
references: Pflugers Arch. 2014 Jun;466(6):1037-53
references: 24663384
references: J Am Coll Cardiol. 2014 Jul 1;63(25 Pt A):2817-27
references: 24768876
references: Circ Heart Fail. 2012 Nov;5(6):803-11
references: 23014131
references: J Mol Cell Cardiol. 2000 Dec;32(12):2151-62
references: 11112991
references: Circulation. 2001 Aug 14;104(7):779-82
references: 11502702
references: Circ Res. 2002 Jun 14;90(11):1181-8
references: 12065321
references: Circulation. 2002 Sep 10;106(11):1333-41
references: 12221049
references: Circulation. 2002 Dec 10;106(24):3068-72
references: 12473553
references: Electrophoresis. 2003 Jun;24(11):1695-702
references: 12783444
references: Lancet. 2003 Sep 6;362(9386):777-81
references: 13678871
references: Circ Res. 2004 Feb 20;94(3):284-95
references: 14976139
references: Nat Med. 2004 Mar;10(3):248-54
references: 14966518
references: N Engl J Med. 2004 May 6;350(19):1953-9
references: 15128895
references: Circulation. 2004 Jul 13;110(2):155-62
references: 15238456
references: N Engl J Med. 2006 Jul 20;355(3):260-9
references: 16855266
references: Circulation. 2006 Aug 1;114(5):397-403
references: 16864724
references: Eur Heart J. 2006 Oct;27(19):2338-45
references: 16963472
references: J Mol Cell Cardiol. 2007 Jan;42(1):186-95
references: 17069849
references: Eur Heart J. 2007 Oct;28(20):2539-50
references: 17428822
references: Circulation. 2008 Jan 1;117(1):43-51
references: 18071071
references: Eur J Heart Fail. 2008 Feb;10(2):149-56
references: 18279770
references: Circulation. 2008 Sep 30;118(14):1433-41
references: 18794390
references: N Engl J Med. 2008 Dec 4;359(23):2456-67
references: 19001508
references: Circ Res. 2009 Jan 2;104(1):87-94
references: 19023132
references: Circ Res. 2009 Jan 2;104(1):12-4
references: 19118283
references: J Muscle Res Cell Motil. 2008;29(6-8):189-201
references: 19140019
references: Pharmacol Rep. 2009 Jan-Feb;61(1):139-45
references: 19307702
references: Circ Res. 2009 Mar 27;104(6):780-6
references: 19179657
references: J Am Coll Cardiol. 2009 Jun 9;53(23):2150-8
references: 19497441
references: Circulation. 2009 Jun 23;119(24):3070-7
references: 19506115
references: Circulation. 2010 Feb 16;121(6):768-74
references: 20124120
references: J Mol Cell Cardiol. 2010 May;48(5):972-8
references: 20026128
references: Histochem Cell Biol. 2010 Jul;134(1):23-30
references: 20490536
references: J Card Fail. 2010 Jun;16(6):e1-194
references: 20610207
references: J Am Coll Cardiol. 2010 Jul 20;56(4):278-87
references: 20633819