Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction

Abstract

Background: A systemic pro-inflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. Methods: In 228 HFpEF patients from the multicenter PROMIS-HFpEF study, 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component (PC) analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted co-expression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HF. Results: Comorbidity burden was associated with abnormal cardiac structure/function and with PCs/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation (TR) velocity; and worse right ventricular function (tricuspid annular plane systolic excursion [TAPSE] and right ventricular. [RV] free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19-35%), E/e' ratio (18-29%), TR velocity (27-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all) but not RV free wall strain. TNF-R1, UPAR, IGFBP-7 and GDF-15 were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. Conclusions: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and RV dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

“…Apart from their role in HF, IL-1β and IL-6 are key pro-inflammatory factors in many diseases, like COPD ( 186 ), diabetes ( 187 ), kidney disease ( 188 ), sarcopenia, obesity, and HF ( 189 ), and the cytokine storm in COVID-19 ( 190 ). A recent study on HFpEF supported that systemic inflammation may be the association between comorbidity and HF ( 191 ). The IL-1β and IL-18 signaling pathways may be novel drug targets for HFpEF, which are important in the mitochondria-inflammation circuit ( 192 ).…”

Cardiac Dysfunction in Rheumatoid Arthritis: The Role of Inflammation

“…These factors, combined with a lack of robust animal models, has hindered the development of new treatments [ 36 ]. It is apparent from both human and murine studies that there is a link between comorbidities associated with systemic inflammation and the development of HFpEF [ 37 , 38 , 39 ], and that inflammation-related biomarkers are strongly associated with HFpEF severity and outcome [ 40 ].…”

“…Inflammation undoubtedly plays a role in both forms of HF albeit via different mechanisms. HFpEF is associated with higher levels of circulating biomarkers of inflammation than HFrEF, which is associated with higher levels of markers of myocyte stress and progressive loss of cardiomyocytes [ 38 , 60 , 61 ]. Systemic inflammation results in increased levels of circulating pro-inflammatory cytokines such as TNF-alpha and interleukin-6, leading to endothelial activation, nitrosative and oxidative stress, increased myocardial stiffness, and fibrosis, ultimately resulting in diastolic dysfunction as a result of impaired relaxation of the myocardium [ 60 ].…”

Mechanisms and Therapeutic Prospects of Diabetic Cardiomyopathy Through the Inflammatory Response

“…Inflammation is widely recognized to play a crucial role in the pathogenesis of both HF with reduced and preserved ejection fraction. Systemic inflammation is frequently associated with abnormal cardiac structure and function in clinical studies ( Suzuki et al, 2008 ; Sanders-van Wijk et al, 2020 ): nevertheless, conflicting outcomes have also been documented. In the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) ( Ridker et al, 2012 ), anti-interleukin (IL)-1β treatment demonstrated a reduction in inflammatory markers in type 2 DM (T2DM); however, over a longer duration, it failed to reduce the risk of cardiovascular events ( Tan et al, 2020 ).…”