Myocardial stiffness in patients with heart failure and a preserved ejection fraction contributions of collagen and titin

Michael R. Zile, Catalin F. Baicu, John S. Ikonomidis, Robert E. Stroud, Paul J. Nietert, Amy D. Bradshaw, Rebecca Slater, Bradley M. Palmer, Peter Van Buren, Markus Meyer, Margaret M. Redfield, David A. Bull, Hendrikus "Henk" Granzier, Martin M. LeWinter

Research output: Contribution to journalArticle

219 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1247-1259
Number of pages13
JournalCirculation
Volume131
Issue number14
DOIs
StatePublished - 2015

Fingerprint

Connectin
Collagen
Heart Failure
Hypertension
Phosphorylation
Biomarkers
Fibrillar Collagens
Blood Pressure
Inflammation
Biopsy
Tissue Inhibitor of Metalloproteinase-1
Brain Natriuretic Peptide
Cardiac Myocytes
Coronary Artery Bypass
Biochemistry
C-Reactive Protein
Extracellular Matrix
Histology
Diabetes Mellitus
Protein Isoforms

Keywords

  • Collagen
  • Diastole
  • Heart failure
  • Hypertension
  • Hypertrophy

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Zile, M. R., Baicu, C. F., Ikonomidis, J. S., Stroud, R. E., Nietert, P. J., Bradshaw, A. D., ... LeWinter, M. M. (2015). Myocardial stiffness in patients with heart failure and a preserved ejection fraction contributions of collagen and titin. Circulation, 131(14), 1247-1259. https://doi.org/10.1161/CIRCULATIONAHA.114.013215

Myocardial stiffness in patients with heart failure and a preserved ejection fraction contributions of collagen and titin. / Zile, Michael R.; Baicu, Catalin F.; Ikonomidis, John S.; Stroud, Robert E.; Nietert, Paul J.; Bradshaw, Amy D.; Slater, Rebecca; Palmer, Bradley M.; Van Buren, Peter; Meyer, Markus; Redfield, Margaret M.; Bull, David A.; Granzier, Hendrikus "Henk"; LeWinter, Martin M.

In: Circulation, Vol. 131, No. 14, 2015, p. 1247-1259.

Research output: Contribution to journalArticle

Zile, MR, Baicu, CF, Ikonomidis, JS, Stroud, RE, Nietert, PJ, Bradshaw, AD, Slater, R, Palmer, BM, Van Buren, P, Meyer, M, Redfield, MM, Bull, DA, Granzier, HH & LeWinter, MM 2015, 'Myocardial stiffness in patients with heart failure and a preserved ejection fraction contributions of collagen and titin', Circulation, vol. 131, no. 14, pp. 1247-1259. https://doi.org/10.1161/CIRCULATIONAHA.114.013215
Zile, Michael R. ; Baicu, Catalin F. ; Ikonomidis, John S. ; Stroud, Robert E. ; Nietert, Paul J. ; Bradshaw, Amy D. ; Slater, Rebecca ; Palmer, Bradley M. ; Van Buren, Peter ; Meyer, Markus ; Redfield, Margaret M. ; Bull, David A. ; Granzier, Hendrikus "Henk" ; LeWinter, Martin M. / Myocardial stiffness in patients with heart failure and a preserved ejection fraction contributions of collagen and titin. In: Circulation. 2015 ; Vol. 131, No. 14. pp. 1247-1259.
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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.",
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AU - Baicu, Catalin F.

AU - Ikonomidis, John S.

AU - Stroud, Robert E.

AU - Nietert, Paul J.

AU - Bradshaw, Amy D.

AU - Slater, Rebecca

AU - Palmer, Bradley M.

AU - Van Buren, Peter

AU - Meyer, Markus

AU - Redfield, Margaret M.

AU - Bull, David A.

AU - Granzier, Hendrikus "Henk"

AU - LeWinter, Martin M.

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N2 - 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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KW - Collagen

KW - Diastole

KW - Heart failure

KW - Hypertension

KW - Hypertrophy

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