A Tale of Collagen AND Titin: Myocardial Stiffness in HFPEF

Journal Wrap | Patients with hypertension (HTN) with heart failure and preserved ejection fraction (HFpEF) had a significant increase in passive myocardial stiffness with an increase in both collagen- and titin-dependent stiffness, according to a recent study published in Circulation.

The study analyzed 70 patients recruited to undergo intraoperative left ventricular (LV) myocardial biopsy from amongst those scheduled for coronary artery bypass grafting at multiple centers. Patients were divided into three groups: reference (n = 17, no HTN or diabetes), HTN without HFpEF (n = 31), and HTN with HFpEF (n = 22). All participants underwent an echocardiogram, determination of plasma biomarkers, and an intraoperative LV epicardial anterior wall biopsy. A differential extraction protocol was used to determine total, collagen-dependent, and titin-dependent stiffness. Collagen volume fraction (CVF) was measured using light microscopy; titin isoform analysis was performed, and titin phosphorylation levels were quantified. Four classes of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) and N-terminal propeptide of the brain natriuretic peptide (NT-proBNP) were measured.

While study investigators noted no significant differences in collagen- and titin-dependent tension between control and HTN without HFpEF patients, both collagen- and titin-dependent tension was significantly increased in HTN with HFpEF patients (with an increase of 220% in collagen-dependent stiffness and 92% in titin-dependent stiffness). Compared with control and HTN without HFpEF groups, there was a significant increase in insoluble and total collagen and CVF in the HTN with HFpEF group. Compared with both control and HTN without HFpEF groups, patients with HTH with HFpEF had reduced phosphorylation of a PKA/PKG in the N2B element and increased phosphorylation of one of the PKC sites in the PEVK element.

While the study findings cannot prove the concept that sequential temporal changes occur in the cellular and molecular mechanisms that underlie hypertensive heart disease, the study authors note that the data "clearly support the idea that changes in collagen and titin constitute mechanisms' associated with the progression of disease."

"This is an important study that adds to our understanding of the mechanisms that contribute to myocardial stiffness in HFpEF," says Prashant Vaishnava, MD, in an ACC Journal Scan. "The authors provided novel evidence that changes in both ECM fibrillar collagen and cardiomyocyte titin contribute to myocardial stiffness."


  1. Zile MR, Baicu CF, Ikonomidis J, et al. Circulation. 2015. [Epub ahead of print].

Keywords: CardioSource WorldNews, ACC Publications

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