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A Tale of Collagen AND Titin: Myocardial Stiffness in HFPEF | Journal Scan
Study Questions:
Do patients with heart failure and preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness, and are these changes dependent on changes in extracellular matrix fibrillar collagen and/or cardiomyocyte titin?
Methods:
This was an analysis of 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 hypertension [HTN] or diabetes), HTN without HFpEF (n = 31), and HTN with HFpEF (n = 22). Participants underwent echocardiogram, determination of plasma biomarkers, and 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.
Results:
Although there were no significant differences in collagen- and titin-dependent tension between control and HTN(-)HFpEF, both collagen- and titin-dependent tension was significantly increased in HTN(+)HFpEF (with an increase of 220% in collagen-dependent stiffness and 92% in titin-dependent stiffness). Compared with control and HTN(-)HFpEF groups, there was a significant increase in insoluble and total collagen and CVF in the HTN(+)HFpEF group. Compared with both control and HTN(-)HFpEF groups, patients with HTH(+)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.
Conclusions:
Compared to patients without HTN and those with HTN in the absence of HFpEF, patients with HTN with HFpEF had a significant increase in passive myocardial stiffness with an increase in both collagen- and titin-dependent stiffness.
Perspective:
This is an important study that adds to our understanding of the mechanisms that contribute to myocardial stiffness in HFpEF. The authors provided novel evidence that changes in both ECM fibrillar collagen and cardiomyocyte titin contribute to myocardial stiffness. As the authors discuss, although their findings ‘cannot prove the concept that sequential temporal changes occur in the cellular and molecular mechanisms that underlie hypertensive heart disease, our data clearly support the idea that changes in collagen and titin constitute mechanisms’ associated with the progression of disease.
Keywords: Biomarkers, Heart Failure, Hypertension, Coronary Artery Bypass, Extracellular Matrix, Fibrillar Collagens, Matrix Metalloproteinases, Myocytes, Cardiac, Natriuretic Peptide, Brain, Phosphorylation, Protein Isoforms, Metabolic Syndrome
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