Race and sex differences in nitroso-redox balance and arterial stiffness in patients with heart failure with reduced ejection fraction Open Access

Abstract

Background: Black patients and women with heart failure with reduced ejection fraction (HFrEF) have worse health status than White patients and men, respectively. We sought to determine if differences in oxidative stress and arterial stiffness in these groups may explain the pathophysiology underlying these disparities.

Methods: Patients with HFrEF (N=205, 51% female, 62% Black) were recruited at Emory University from 2015-2019. At a single study visit, indices of arterial stiffness and wave reflections were measured including carotid-femoral pulse wave velocity (PWV), augmentation index normalized at heart rate of 75 (AIx @ HR 75), and reflection magnitude (RM). Plasma levels of nitrites and aminothiol markers of oxidative stress (OS) reduced (cysteine [Cys] and glutathione [GSH]) and oxidized (cystine [CySS] and glutathione disulphide [GSSG]) were quantified by high performance liquid chromatography to assess systemic nitroso-redox balance. Multivariable linear regression was used to determine the association between OS and arterial stiffness measures. The association between arterial stiffness and a composite clinical endpoint (death, left ventricular assist device implantation, or heart transplant) was assessed using cox proportional hazards analysis. Significant interactions between race, sex, OS biomarkers, and arterial stiffness were tested within adjusted models using natural cubic splines.

Results: Levels of OS and arterial stiffness were similar between Black and White patients. Compared to men, women had lower levels of OS (Cys: 8.2 [6.5, 9.7] v. 7.5 [5.4, 9.5] µM, P=0.034, GSSG: 0.04 [0.01, 0.06] v. 0.05 [0.02, 0.10] µM, P=0.023) and greater wave reflections (AIx @ HR 75: 22.0 [17.3, 30.1] v. 17.3 [5.3, 25.5] %, P=0.007). OS biomarkers were not associated with arterial stiffness. There was no association between any arterial stiffness measures and the composite primary endpoint (PWV: hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.29-1.32, AIx @ 75 HR: 0.91, 95% CI 0.65-1.28, RM: HR 0.77, 95% CI 0.32-1.90).

Conclusion: In a cohort of well-treated patients with HFrEF, OS was not associated with impaired arterial stiffness, and arterial stiffness measures were not predictive of clinical outcomes.

Table of Contents

·      Introduction

·      Methods

·      Results

·      Discussion

·      Conclusion

·      References

·      Table 1. Baseline characteristics of cohort overall, stratified by race, and stratified by sex.

·      Table 2A & 2B. Oxidative stress metabolites (A) and arterial stiffness measurements (B) stratified by race and sex.

·      Table 3. Linear Regression Analysis of Nitroso-Redox Biomarkers and Arterial stiffness Measurements.

·      Table 4A and 4B. Cox Proportional Hazards Models for Arterial Stiffness Measurements and Composite Outcomes.

·      Figure 1. Diagram of nitroso-redox balance and surrogate measurements.

·      Figure 2. Cubic spline model of interaction between cystine and reflection magnitude by sex.

·      Figure 3A and 3B. Cubic spline model of interaction between pulse wave velocity and primary and secondary composite endpoints by sex (A) and race (B).

·      Supplemental Table 1. Terminology dictionary for measures of arterial stiffness.

·      Supplemental Figure 1. Directed acyclic graph for linear regression and cox proportional hazards models.

·      Supplemental Figure 2. Diagram showing effect of arterial stiffness on cardiac function, adapted from Weber and Chirinos

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Medicine and Surgery
Keyword	black patients heart failure with reduced ejection fraction arterial stiffness heart failure hfref women oxidative stress nitroso-redox balance
Committee Chair / Thesis Advisor	Matthew Magee MPH PhD, Emory University
Committee Members	Neal Dickert MD PhD, Emory University Alanna A. Morris MD MSc, Emory University

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