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.

Background-Changes in matrix metalloproteinase (MMP) and tissue inhibitors of MMPs (TIMPs) contribute to left ventricular (LV) remodeling after myocardial infarction (MI). We tested the hypothesis that a specific plasma MMP/TIMP profile would emerge after MI and be associated with the degree of LV dilation. Methods and Results-LV end-diastolic volume and MMP/TIMP plasma profiles were determined in 53 age-matched control subjects and 32 post-MI patients from day 1 through 180 after MI. LV end-diastolic volume increased by Ͼ38% at day 90 after MI (PϽ0.05). MMP-9 increased by Ͼ150% from control at day 1 after MI (PϽ0.05) and remained elevated. MMP-8 rose to Ͼ120% at day 3 after MI (PϽ0.05) and fell to control values by day 5. TIMP-1 increased by Ͼ60% from control at day 1 after MI (PϽ0.05), whereas TIMP-2 increased only at later time points. Cardiac-specific TIMP-4 fell by 40% at day 5 after MI and remained reduced. A persistent or elevated MMP-9 at day 5 was accompanied by a 3-fold end-diastolic volume increase at day 28 (PϽ0.05). Conclusions-A specific temporal pattern of MMP/TIMPs occurred in post-MI patients that included an early and robust rise in MMP-9 and MMP-8 and a uniform fall in TIMP-4. These findings suggest that a specific MMP/TIMP plasma profile occurs after MI and holds both prognostic and diagnostic significance.

Background Chronic pressure overload (such as arterial hypertension) may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of diastolic heart failure. Changes in the composition of the myocardial extracellular matrix (ECM) may contribute to the development of pressure-overload (PO) induced LV remodeling. We hypothesized that a specific pattern of plasma biomarker expression that reflected changes in these pathophysiologic mechanisms would have diagnostic application to identify: 1-patients who have developed LV hypertrophy and 2-patients with LV hypertrophy who have developed diastolic heart failure. Methods and Results Plasma concentration of 17 biomarkers (MMP-1, 2, 3, 7, 8, 9, TIMP-1, 2, 3, 4, NT-proBNP, cardiotrophin, osteopontin, sRAGE, CITP, PINP, PIIINP), an echocardiogram, and 6-minute hall walk were performed on 241 referent control subjects, 144 patients with LV hypertrophy (LVH) but no evidence of heart failure, and 61 patients with LV hypertrophy and diastolic heart failure (DHF). A plasma multi-biomarker panel consisting of increased MMP-7, MMP-9, TIMP-1, PIIINP, and NT-proBNP predicted the presence of LVH with an AUC of 0.80. A plasma multi-biomarker panel consisting of increased MMP-2, TIMP-4, PIIINP and decreased MMP-8 predicted the presence of DHF with an AUC of 0.79. These multi-biomarkers panels performed better than any single biomarker including NT-proBNP, and better than using clinical co-variates alone (AUC = 0.73 for LVH, 0.68 for DHF). Conclusions Plasma biomarkers reflecting changes in ECM fibrillar collagen homeostasis, combined into a multi-biomarker panel, have discriminative value in identifying the presence of structural remodeling (LVH) and clinical disease (DHF).

A unique matrix metalloproteinase and tissue inhibitor of metalloproteinase portfolio was observed in ascending thoracic aortic aneurysms from patients with bicuspid aortic valve compared with patients with tricuspid aortic valve. These differences, suggesting disparate mechanisms of extracellular matrix remodeling, may provide unique biochemical targets for ascending thoracic aortic aneurysm prognostication and treatment in these 2 groups of patients.