Diagnostic biomarkers, and the role of inflammation and body composition in heart failure

Chapter 2 gives an overview of the available evidence on the diagnostic performance of natriuretic peptides (NPs) to detect left ventricular diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF) based on a systematic review and meta-analysis of 51 studies. The meta-analysis indicated a reasonable diagnostic performance for both NPs for the detection of DD and HFpEF. As the risk of bias of the included studies is high and sensitivity of NPs for detection of DD or HFpEF is low compared to specificity, use of NPs alone to detect DD or HFpEF should be discouraged as recommended by current guidelines. In Chapter 3, we give an overview of the available evidence on the diagnostic performance and risk of bias of novel biomarkers in the detection of HFpEF. We included a total of 28 studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cutoff value for the index test without external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the most important forms of bias. In Chapters 4 and 5, we studied the association between inflammation and heart failure (HF), and HFpEF-associated echocardiographic measures. In Chapter 4, we performed two-sample Mendelian Randomization analyses. Nine inflammatory biomarkers with available genome-wide association studies (GWAS) among individuals of European ancestry were identified and included: C-reactive protein, immunoglobulin E, tumor necrosis factor, interleukin 1 receptor antagonist, interleukin 2 receptor subunit α, interleukin 6 receptor subunit α, interleukin 16, interleukin 17 and interleukin 18. For the associations between the identified SNPs and HF, we used the largest GWAS meta-analysis performed by the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium with 47,309 participants with HF and 930,014 controls. In the analyses, we included 63 SNPs, of which 51 were for C-reactive protein. C-reactive protein, tumor necrosis factor and interleukin 18 were not associated with risk of incident HF: ORs per 1 unit increase in log-transformed biomarker levels of 1.01, 1.11 and 1.01, respectively. Other inflammatory biomarkers were also not associated with risk of incident HF, but may have suffered from weak instrument bias. In Chapter 5, we investigated within-person and betweenpersons associations of biomarkers of inflammation and endothelial dysfunction with left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) and left atrial volume index (LAVI). We included 383 participants of the Hoorn Study, a Dutch population-based cohort, and 491 participants of FLEMENGHO, a Flemish population-based cohort. Both cohorts had inflammatory biomarker and echocardiographic measurements at baseline and ~8 and ~5 years of follow-up, respectively. Overall Z-scores for low-grade inflammation or endothelial dysfunction were not associated with echocardiographic measures. Effect modification by sex was apparent for TNF-α in the Hoorn Study and E-selectin in FLEMENGHO with LVEF. In the Hoorn Study, women whose TNF-α levels increased with 1-SD over time had a decrease in LVEF. In FLEMENGHO, men whose E-selectin levels increased with 1-SD over time had a decrease in LVEF. In Chapter 6, we determined the sex-specific prospective associations between body composition measures and cardiac structure and function after 8 years of follow-up in 321 participants of the Hoorn Study. Total body fat, trunk fat and leg fat were associated with increased LVMI, while lean mass was associated with lower LVMI. Body composition measures were not associated with LVEF or LAVI. These associations were not modified by sex or mediated by inflammation. In Chapter 7, we studied the associations between serum and dietary advanced glycation endproducts and cardiac structure and function. Increased pentosidine and overall serum AGEs Z-scores over time were associated with decreased LVEF at follow-up.