Myocardial Stiffness in Patients With Heart Failure and a Preserved Ejection Fraction

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 are dependent on changes in extracellular matrix fibrillar collagen and/or cardiomyocyte titin. Methods and Results Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intra-operative left ventricular (LV) epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes), 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. Compared with controls, patients with HTN(-)HFpEF had no change in LV end diastolic pressure (LVEDP), myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers of inflammation (CRP, sST2, TIMP-1). Compared with both control and HTN(-)HFpEF, patients with HTN(+)HFpEF had increased LVEDP, left atrial volume, NT-proBNP, 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 is dependent on changes in both collagen and titin homeostasis.

Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

“…Regarding to the magnitude of changes, previously published studies found similar differences as reported here. Increase in PEVK element phosphorylation (Ser-12742 in the rat sequence) was 31% in human HTN (45) and 23% in patients with dilated cardiomyopathy (26), being similar to the 32.6% in mRen2 rats as reported here. A more prominent change (ϳ70% decrease) in PEVK phosphorylation level was found in a different site within the PEVK region of titin (Ser-12884) in a metabolic model of HFpEF (19).…”

“…PEVK Ser-12742 hyperphosphorylation was previously demonstrated in mice with transverse aortic constriction (22), in an old HTN dog model (18), as well as in human HF (17,26). Moreover, a recent translational work implicated the hyperphosphorylation of the very same site (Ser-12742) in human HFpEF (45). It suggested that a significant rise in collagen-and titin-dependent stiffness is paralleled by explicit changes in titin phosphorylation levels, e.g., hypophosphorylation of PKA/PKG sites in the N2-Bus element and PKC␣-dependent hyperphosphorylation at Ser-11878 (Ser-12742 in the rat) in the PEVK element.…”

Liver fibrosis score predicts mortality in heart failure patients with preserved ejection fraction

“…HF and chronic liver disease) 29, 30. Collagen‐dependent ventricular stiffness is increased in HFpEF 1, 2, 3, 4, 5. The cardiac extracellular matrix is predominantly composed of fibrillar collagen type I (85%) and type III (11%) 29.…”

“…It has several pathophysiological aspects including cardiac hypertrophy and interstitial fibrosis1, 2, 3, 4, 5 and/or impaired functional reserve of multiple organs, such as lungs, vessels, skeletal muscle, kidney, and liver 1, 2, 6. The abdominal compartment (e.g.…”

Clinical Phenotypes in Heart Failure With Preserved Ejection Fraction

“…Cardiac troponin T, alone or in combination with N‐terminal fragment of the prohormone of B‐type natriuretic peptide (NT‐proBNP), and products of collagen metabolism have been evaluated for identification of hypertensive patients at risk for HF 84, 85, 86, 87…”