Michael R Zile1, Catalin F Baicu2, John S Ikonomidis2, Robert E Stroud2, Paul J Nietert2, Amy D Bradshaw2, Rebecca Slater2, Bradley M Palmer2, Peter Van Buren2, Markus Meyer2, Margaret M Redfield2, David A Bull2, Henk L Granzier2, Martin M LeWinter2. 1. 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. 2. 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.).
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. METHODS AND 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.
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. METHODS AND 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.
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