Background - It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score for survival in HFrEF patients (HFrEF-PRS). Methods - Patients meeting Framingham criteria for HF with EF<50% were enrolled (n=1017) and plasma underwent SOMAscan® profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and N-Terminal pro-B-Type Natriuretic Peptide (NTproBNP), then was tested in the validation cohort. Risk stratification improvement was evaluated by C-statistic, integrated discrimination index (IDI), continuous net reclassification index (NRI), and median improvement in risk score (MIRS) for 1-year and 3-year mortality. Results - Participants' mean age was 68 years, 48% identified as African American, 35% were female and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio (HR) =2.27 [95% Confidence interval (95%CI) 1.84-2.82], p =6.3x10 -14 ), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles ( p =2.2x10 -6 ), and it remained significant after adjustment for clinical score and NTproBNP (HR=1.37, 95%CI 1.05-1.79, p =0.021). The HFrEF-PRS improved metrics of risk stratification (C-statistic change=0.009, p =0.612; IDI=0.041, p =0.010; NRI=0.391, p =0.078; MIRS=0.039, p =0.016) and associated with cardiovascular death and HF phenotypes (e.g. 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF. Conclusions - A plasma multi-protein score improved risk stratification in HFrEF patients and identified novel candidates.

Overexpression of EP4 improves cardiac function post MI. This may be mediated through reductions in adverse cardiac remodeling or via inhibition of cytokine/chemokine production.

Background Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously we reported that cardiomyocyte-specific EP4 KO mice develop dilated cardiomyopathy with reduced ejection fraction. We thus hypothesized that PGE2 increases contractility via EP4 but decreases contractility via EP3. Methods and Results The effects of PGE2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse langendorff preparation and in adult mouse cardiomyocytes (AVM). Isolated hearts of adult male C57Bl/6 mice were perfused with PGE2 (10−6M) or sulp (10−6M) and compared to vehicle. Both PGE2 and sulprostone decreased +dp/dt (p<0.01) and left ventricular developed pressure, LVDP, (p<0.001) with reversal by an EP3 antagonist. In contrast, the EP4 agonist had the opposite effect. AVM contractility was also reduced after treatment with either PGE2 or sulprostone for 10 min. We then examined the acute effects of PGE2, sulprostone and the EP4 agonist on expression of phosphorylated phospholamban (PLN) and SERCA2a in AVM using Western blot. Treatment with either PGE2 or sulprostone decreased expression of phosphorylated PLN corrected to total PLN whereas treatment with the EP4 agonist had the opposite effect. SERCA2a expression was unaffected. Finally, we examined the effect of these compounds in vivo using pressure volume loops. Both PGE2 and sulprostone decreased +dp/dt while the EP4 agonist increased +dp/dt. Conclusions Contractility is reduced via the EP3 receptor but increased via EP4. These effects may be mediated through changes in PLN phosphorylation and has relevance to detrimental effects of inflammation.