Osteopontin and LDLR Are Upregulated in Hearts of Sudden Cardiac Death Victims With Heart Failure With Preserved Ejection Fraction and Diabetes Mellitus.

Mausam Patel,Keyvan Yousefi,Jeffrey J Goldberger,Leonardo J Tamariz,Daniela Rodriguez,Armando J Mendez,Juhani Junttila,Robert J Myerburg,Anastasios Lymperopoulos,Krista John-Williams,Lina A Shehadeh,Ronald B Goldberg

doi:10.3389/fcvm.2020.610282

Abstract

Background: Diabetes mellitus (DM) is associated with increased risk of sudden cardiac death (SCD), particularly in patients with heart failure with preserved ejection fraction (HFpEF). However, there are no known biomarkers in the population with DM and HFpEF to predict SCD risk.Objectives: This study was designed to test the hypothesis that osteopontin (OPN) and some proteins previously correlated with OPN, low-density lipoprotein receptor (LDLR), dynamin 2 (DNM2), fibronectin-1 (FN1), and 2-oxoglutarate dehydrogenase-like (OGDHL), are potential risk markers for SCD, and may reflect modifiable molecular pathways in patients with DM and HFpEF.Methods: Heart tissues were obtained at autopsy from 9 SCD victims with DM and HFpEF and 10 age and gender-matched accidental death control subjects from a Finnish SCD registry and analyzed for the expression of OPN and correlated proteins, including LDLR, DNM2, FN1, and OGDHL by immunohistochemistry.Results: We observed a significant upregulation in the expression of OPN, LDLR, and FN1, and a marked downregulation of DNM2 in heart tissues of SCD victims with DM and HFpEF as compared to control subjects (p < 0.01).Conclusions: The dysregulated protein expression of OPN, LDLR, FN1, and DNM2 in patients with DM and HFpEF who experienced SCD provides novel potential modifiable molecular pathways that may be implicated in the pathogenesis of SCD in these patients. Since secreted OPN and soluble LDLR can be measured in plasma, these results support the value of further prospective studies to assess the predictive value of these plasma biomarkers and to determine whether tuning expression levels of OPN and LDLR alters SCD risk in patients with DM and HFpEF.

Highlights

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure, affecting more than 3 million adults in the United States, and is represented by multiple subgroups or phenotypes [1]
We investigated the expression levels of OPN and correlated proteins, dynamin2 (DNM2), low density lipoprotein (LDLR), 2-oxoglutarate dehydrogenase-like (OGDHL), and fibronectin-1 (FN1), in the hearts of sudden cardiac death (SCD) victims who had both diabetes mellitus (DM) and heart failure with preserved ejection fraction (HFpEF)
We have previously shown that OPN and LDLR are highly expressed in the renal tubules of a mouse model of HFpEF, and that OPN knockcout reduced the pathologically high levels of LDLR and improved renal and cardiac function [8, 14]

Summary

Introduction

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure, affecting more than 3 million adults in the United States, and is represented by multiple subgroups or phenotypes [1]. Type 2 diabetes mellitus (DM) is present in up to 45% of patients with HFpEF, and is associated with higher rates of morbidity and long-term mortality [2]. DM is associated with an increased risk of sudden cardiac death (SCD), in part linked with the presence of microvascular disease and autonomic neuropathy. Risk stratification within the patient population diagnosed with DM and HFpEF remains a challenge. Diabetes mellitus (DM) is associated with increased risk of sudden cardiac death (SCD), in patients with heart failure with preserved ejection fraction (HFpEF). There are no known biomarkers in the population with DM and HFpEF to predict SCD risk

Objectives

Methods

Results

Discussion

Conclusion