Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Heart Failure Outcomes Public

Abstract

Background:

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases(TIMPs) are involved in cardiac remodeling through regulation of extracellular matrix. Reports on their association with heart failure (HF) outcomes have been conflicting.

Methods:

We prospectively examined the association of baseline serum levels of MMP 1, 2, and 9, and TIMP 1,2, 3, and 4, with; a) combined outcomes (death or cardiac transplantation or left ventricular assist device implantation), b) HF hospitalization, c) six minute walk distance, and d) KCCQ Scores; in147 ambulatory HF patients. Levels of MMPs and TIMPs were measured by Fluorokine MAPHuman MMP and TIMP Kits.

Results:

Mean age of patients was 57.1± 11.9 years, 67% were male; and 58% were white. Mean ejection fraction (EF) was 24.6 ± 10.9 %. During follow-up of mean 23.1 ± 6.7 months, 49 patients (33%) experienced combined outcome. 22 of these 49 patients had either died, had transplants or LVADS and remaining 27 had HF related hospitalizations . Among the biomarkers of collagen turnover, there were several inter-correlations but MMP-2 and TIMP-2 had the strongest correlation to each other( r= 0.77, p=<.0001). As for cardiac structural and functional parameters, TIMP-2 was significantly and negatively correlated to EF (r = -0.26, p=0.002, n=146) and Six Minute Walk Test(r= -0.19, P=0.03, n=137). TIMP-2 was also positively and significantly correlated to cardiac neurohormone BNP (r=0.20, p=0.03, n=117). In Univariate Cox regression analysis TIMP-2 was the strongest predictor of the outcome among the biomarkers of collagen turnover (HR 1.019, 95%CI(1.007 -1.032) for each 1 pg/ml increase. When dichotomized at 133.82 pg/ml based on linearity, the event rate in the group > 133.82 pg/ml was 59.5% n=37 vs < 133.82 pg/ml was 24.5 % n=110. In Cox regression model controlling for age, gender, EF, past medical history, creatinine, and current therapy, TIMP-2 level > 133.82 was independent predictor of adverse outcomes (OR 6,95%CI 2.22-16.12). The final parsimonious multivariate cox regression Model containing TIMP-2, age, creatinine and sleep apnea, TIMP-2 level > 133.82 had a HR of 4.46(2.1-9.4).

Conclusion:

Elevated serum levels of TIMP-2 were independently associated with adverse outcomes in HF.

Table of Contents

TABLE OF CONTENTS

Introduction and Background…………………………………………………......................................1
Methods ………………………………………………………......................………….............................2
Results……………………………………………….........…………........…………...................................5
Discussion ………………………………………………………..........................................................8
Tables and Figures …………………………………………………...................................................10
Table 1a: Study population baseline characteristics……………………………………….................10
Table 1b: Treatment and management distribution in the cohort…………………………............11
Table 1c: Distribution of the biomarkers in the cohort……………………………………..................12
Table 2a: Correlation among Biomarkers of Collagen Turnover…………………………................13
Table 2b: Correlation of Biomarkers of Collagen turnover with Cardiac Function, functional
capacity and BNP…………………………………………………………………………..................................14
Table 3a: Univariate Cox regression analysis of the biomarkers of collagen turnover……..15
Table 3b: Univariate prediction power of age, EF, BNP and creatinine using cox regression
analysis………………………………………………………………………………………..................................16
Table 3c: Univariate Kaplan-Meier Survival analysis of Epidemiological Variables……........17
Table 3d: Univariate Kaplan-Meier Survival analysis of Past medical history variables…...18
Table 3e: Univariate Kaplan-Meier Survival analysis of Treatment and Management
Variables……………………………………………………………………………………...................................19
Table 4a: Linearity of Events over TIMP-2 Levels………………………………………....................20
Table 4b: Comparing Outcomes in TIMP-2 groups divided based on linearity……………........21
Table 5a: Multivariate Cox regression Analysis……………………………………………...................22
Table 5b: Parsimonious Multivariate Cox regression Model with Interaction.
variable……………………………………………………………………………………....................................23
Figure 1: Kaplan-Meier survival curve of the two groups divide by a cutpoint of TIMP-2 >
133.82 pg/ml…………………………………………………………………………………................................24
Figure 1b: Example KM survival curves plotted for a 50 year old individual (with model
covariates) to display the outcomes with various risk factors………………………………..........25
References ………………………………………………………........................................................26

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, General Health Sciences, Medicine and Surgery Health Sciences, Epidemiology
Mot-clé	Tissue Inhibitor of Matrix Metalloproteinases Matrix Metalloproteinases Outcomes Heart Failure
Committee Chair / Thesis Advisor	Butler, Javed, Emory University
Committee Members	Boring, John R, Emory University Blumberg, Henry Michael, Emory University Ziegler, Thomas R, Emory University

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