PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.

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.

Objective This study aimed to describe the contemporary aetiology, clinical characteristics and mortality and its predictors in heart failure (HF) in Tanzania. Methods Design; Prospective observational study. Setting; Cardiovascular Center of the Muhimbili National Hospital in Dar es Salaam, Tanzania. Patients ≥18 years of age with HF defined by the Framingham criteria. Main outcome measure All-cause mortality. Results Among 427 included patients, 217 (51%) were females and the mean (SD) age was 55 (17) years. HF aetiologies included hypertension (45%), cardiomyopathy (28%), rheumatic heart disease (RHD) (12%) and ischaemic heart disease (9%). Concurrent atrial fibrillation (AF), clinically significant anaemia, diabetes, tuberculosis and HIV were found in 16%, 12%, 12%, 3% and 2%, respectively, while warfarin was used in 3% of the patients. The mortality rate, 22.4 per 100 person-years over a median follow-up of 7 months, was independently associated with AF, HR 3.4 (95% CI 1.6 to 7.0); in-patient 3.2 (1.5 to 6.8); anaemia 2.3 (1.2 to 4.5); pulmonary hypertension 2.1 (1.1 to 4.2) creatinine clearance 0.98 (0.97 to 1.00) and lack of education 2.3 (1.3 to 4.2). Conclusions In HF in Tanzania, patients are younger than in the developed world, but aetiologies are becoming more similar, with hypertension becoming more and RHD less important. Predictors of mortality possible to intervene against are anaemia, AF and lack of education.

Background— Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. Methods and Results— In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3–like protein 1 (1.35), C–C motif chemokine 20 (1.35), fatty acid–binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e′) and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. Conclusions— In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00774709.