Abstract

This study aimed to determine the within-person and between-persons associations of low-grade inflammation (LGI) and endothelial dysfunction (ED) with echocardiographic measures related to diastolic dysfunction (DD) in two general populations and whether these associations differed by sex. Biomarkers and echocardiographic measures were measured at both baseline and follow-up in the Hoorn Study (n = 383) and FLEMENGHO (n = 491). Individual biomarker levels were combined into either a Z-score of LGI (CRP, SAA, IL-6, IL-8, TNF-α and sICAM-1) or ED (sICAM-1, sVCAM-1, sE-selectin and sTM). Mixed models were used to determine within-person and between-persons associations of biomarker Z-scores with left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) and left atrial volume index (LAVI). These associations were adjusted for a-priori selected confounders. Overall Z-scores for LGI or ED were not associated with echocardiographic measures. Effect modification by sex was apparent for ED with LVEF in both cohorts (P-for interaction = 0.08 and 0.06), but stratified results were not consistent. Effect modification by sex was apparent for TNF-α in the Hoorn Study and E-selectin in FLEMENGHO with LVEF (P-for interaction≤0.05). In the Hoorn Study, women whose TNF-α levels increased with 1-SD over time had a decrease in LVEF of 2.2 (-4.5;0.01) %. In FLEMENGHO, men whose E-selectin levels increased with 1-SD over time had a decrease in LVEF of 1.6 (-2.7;-0.5) %. Our study did not show consistent associations of LGI and ED with echocardiographic measures. Some evidence of effect modification by sex was present for ED and specific biomarkers.

Highlights

  • As the prevalence of heart failure (HF) is increasing, this common disease is an emerging public health problem [1, 2]

  • Effect modification by sex was apparent for tumor necrosis factor-α (TNF-α) in the Hoorn Study and E-selectin in FLEMENGHO with left ventricular ejection fraction (LVEF) (P-for interaction 0.05)

  • In the Hoorn Study, women whose TNF-α levels increased with 1-standard deviation (SD) over time had a decrease in LVEF of 2.2 (-4.5;0.01) %

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Summary

Introduction

As the prevalence of heart failure (HF) is increasing, this common disease is an emerging public health problem [1, 2]. Over half of the HF patients have heart failure with preserved ejection fraction (HFpEF), a syndrome characterized by a normal ejection fraction and elevated left ventricular filling pressures [3]. A new paradigm has been proposed where systemic inflammation and endothelial dysfunction is induced by comorbidities, causing structural changes with consequent HFpEF development [8]. Hypertension and type 2 diabetes are the most common comorbidities, that lead to increased levels of inflammatory biomarkers such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher levels of these inflammatory biomarkers would trigger a myriad of reactions, eventually leading to stiffer cardiomyocytes and left ventricular diastolic dysfunction (LVDD). This study aimed to determine the within-person and between-persons associations of lowgrade inflammation (LGI) and endothelial dysfunction (ED) with echocardiographic measures related to diastolic dysfunction (DD) in two general populations and whether these associations differed by sex

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