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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 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.

Aims While right ventricular (RV) dysfunction is associated with worse prognosis in co‐morbid pulmonary hypertension and heart failure with preserved ejection fraction (PH‐HFpEF), the mechanisms driving RV dysfunction are unclear. We evaluated the extent and clinical correlates of diffuse RV myocardial fibrosis in PH‐HFpEF, as measured by cardiovascular magnetic resonance‐derived extracellular volume (ECV). Methods and results We prospectively enrolled participants with PH‐HFpEF (n = 14), pulmonary arterial hypertension (PAH; n = 13), and controls (n = 8). All participants underwent high‐resolution cardiovascular magnetic resonance, and case subjects (PH‐HFpEF and PAH) additionally underwent right heart catheterization. T1 mapping was performed using high‐resolution modified look‐locker inversion recovery with a 1 × 1 mm2 in‐plane resolution. RV free wall T1 values were quantified, and ECV was calculated. Participants with PH‐HFpEF were older and carried higher rates of hypertension and obstructive sleep apnoea than those with PAH. While RV ECV was similar between PH‐HFpEF and PAH (33.1 ± 8.0 vs. 34.0 ± 4.5%; P = 0.57), total pulmonary resistance was lower in PH‐HFpEF compared with PAH [PH‐HFpEF: 5.68 WU (4.70, 7.66 WU) vs. PAH: 8.59 WU (8.14, 12.57 WU); P = 0.01]. RV ECV in PH‐HFpEF was associated with worse indices of RV structure (RV end‐diastolic volume: r = 0.67, P = 0.01) and RV function (RV free wall strain: r = 0.59, P = 0.03) but was not associated with RV afterload (total pulmonary resistance: r = 0.08, P = 0.79). Conversely, there was a strong correlation between RV ECV and RV afterload in PAH (r = 0.57, P = 0.04). Conclusions Diffuse RV fibrosis, as measured by ECV, is present in PH‐HFpEF and is associated with adverse RV structural and functional remodelling but not degree of pulmonary vasculopathy. In PH‐HFpEF, diffuse RV fibrosis may occur out of proportion to the degree of RV afterload.

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.

Heart failure (HF) with recovered ejection fraction (HFrecEF) is an increasingly recognized yet not well understood phenotype. Little is known about electrical parameters associated with myocardial recovery in acute systolic HF.We identified a subset of 87 patients from a non-ischemic cardiomyopathy cohort with left ventricular ejection fraction (LVEF) 40% during index HF hospitalization. HFrecEF was defined as follow-up LVEF ≥40% and ≥ 10% improvement from baseline. We analyzed baseline and follow up electrocardiograms (ECG) in this group for several electrical parameters known to reflect repolarization heterogeneity.Among 87 patients, 30 (34%) patients recovered in a median of 122 (IQR: 58-275) days after index hospitalization. Baseline demographics were similar among HFrecEF versus persistent HFrEF except for increased diabetes in the persistent HFrEF cohort. Patients with HFrecEF had baseline decreased QRST angle, decreased QT dispersion, and less negative signed JT area compared to persistent HFrEF. Patients with HFrecEF had greater decrease in QT dispersion and QTc duration, and greater increase in the signed JT and TpTe areas over time. Baseline QRST angle correlated with longitudinal and circumferential strain and myocardial systolic performance (MSP). Signed JT area correlated with increased baseline LVEF, smaller baseline LV dimensions, increased longitudinal and circumferential strain, and MSP. Signed TpTe correlated with increased longitudinal and circumferential strain, and MSP.Several conventional and novel ECG parameters that reflect repolarization heterogeneity may differentiate patients with acute HF who ultimately recover LVEF. These parameters are associated with baseline structural parameters and are dynamic during recovery.