Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.
BACKGROUND
A systemic proinflammatory 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 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 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 analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression 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 heart failure.


RESULTS
Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-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 right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.
['Sanders-van Wijk|Sandra|S|', 'Tromp|Jasper|J|', 'Beussink-Nelson|Lauren|L|', 'Hage|Camilla|C|', 'Svedlund|Sara|S|', 'Saraste|Antti|A|', 'Swat|Stanley A|SA|', 'Sanchez|Cynthia|C|', 'Njoroge|Joyce|J|', 'Tan|Ru-San|RS|', 'Fermer|Maria Lagerström|ML|', 'Gan|Li-Ming|LM|', 'Lund|Lars H|LH|', 'Lam|Carolyn S P|CSP|', 'Shah|Sanjiv J|SJ|']
D000293:Adolescent D000328:Adult D000368:Aged D000369:Aged, 80 and over D002648:Child D015331:Cohort Studies D015897:Comorbidity D005260:Female D006333:Heart Failure D006801:Humans D007249:Inflammation D018836:Inflammation Mediators D038622:Internationality D008297:Male D008875:Middle Aged D011446:Prospective Studies D060066:Protein Interaction Maps D040901:Proteomics D013318:Stroke Volume D055815:Young Adult
heart failure comorbidity analysis inflammation biomarkers echocardiography