ObjectiveTo characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF).MethodsWe prospectively observed 1802 patients with CHF and left ventricular ejection fraction (LVEF) ≤45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode-specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year).ResultsA 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality (6% higher risk per 10-unit increase in IMD score; 95% CI 2% to 10%; P=0.004), and non-cardiovascular mortality (9% higher risk per 10-unit increase in IMD score; 95% CI 3% to 16%; P=0.003), but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations (4% increase in duration per 10-unit increase in IMD score; 95% CI 3% to 6%; P<0.0005).ConclusionsSocioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non-cardiovascular events.

Rationale: In the endothelium, insulin stimulates endothelial nitric oxide synthase (eNOS) to generate the anti-atherosclerotic signalling radical NO. Insulin resistant type 2 diabetes is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. Objective: To answer this question we generated a mouse with endothelial cell (EC)-specific over-expression of the human insulin receptor (hIRECO) using the Tie2 promoter-enhancer. Methods and Results: hIRECO demonstrated significant endothelial dysfunction measured by blunted endothelium-dependent vasorelaxation to acetylcholine which was normalized by a specific Nox2 NADPH oxidase inhibitor. Insulin-stimulated phosphorylation of Akt was increased in hIRECO EC as was Nox2 NADPH oxidase-dependent generation of superoxide, whereas insulin and shear stress-stimulated eNOS activation were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of PYK2 which phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of PYK2 improved insulin and shear-induced eNOS activation in hIRECO EC. Conclusions: Enhancing insulin sensitivity specifically in EC leads to a paradoxical decline in endothelial function, mediated by increased tyrosine phosphorylation of eNOS and excess Nox2 derived superoxide. Increased EC insulin sensitivity leads to a pro-atherosclerotic imbalance between NO and superoxide. Inhibition of PYK2 restores insulin-and shearinduced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a pro-atherosclerotic imbalance between NO and superoxide.Key Words: Insulin; Insulin Resistance; Endothelial Dysfunction; PYK2; Reactive oxygen Species; Superoxide Non-standard Abbreviations and Acronyms: NO-nitric oxide, hIR-human Insulin Receptor; hIRECO-endothelial cell (EC)-specific over-expression of the human insulin receptor; EC-endothelial cells; PEC-pulmonary endothelial cells; PYK2-proline-rich tyrosine kinase 2; Akt-protein kinase B; ACh-acetylcholine; PE-phenylephrine; SNP-sodium nitroprusside; eNOS-endothelial nitric oxide synthase.3

Background Noncardiovascular death is increasingly common in people with chronic heart failure ( CHF ), yet its causes remain poorly characterized. We aimed to define the prevalence of sepsis death in people with CHF and to ascertain its risk marker profile. Methods and Results We conducted a prospective cohort study of 1802 patients with CHF and left ventricular ejection fraction ≤45% attending CHF clinics in 4 United Kingdom hospitals between 2006 and 2014. Mode of death was defined over a 10.3‐year follow‐up period (mean 4 years). Competing risk regression defined mode‐specific hazard ratios for sepsis, other noncardiovascular, progressive heart failure, and sudden cardiac death in relation to established heart failure prognostic markers. Of 737 deaths, 173 (23.5%) were due to sepsis; respiratory tract infections accounted for 69.9% (n=121) of these events. Those who died from sepsis were older, had higher platelet counts, and had a higher prevalence of chronic obstructive pulmonary disease than those who died from other causes. Sepsis death was independently associated with older age (hazard ratio=1.05; 95% confidence interval 1.03‐1.07), greater prevalence of chronic obstructive pulmonary disease (2.43; 1.74‐3.40), male sex (1.73; 1.16‐2.60), lower log serum vitamin D (0.68; 0.49‐0.95), and higher platelet count (1.002; 1.000‐1.005) than nonsepsis death. Established heart failure prognostic markers exhibited different patterns of association with sepsis death, other noncardiovascular death, progressive heart failure death, and sudden cardiac death. Conclusions Sepsis is a major contributor to death in people with CHF and has a different risk marker profile from other modes of death, suggesting that it may be amenable to targeted preventative strategies.

ObjectiveEstimating survival can aid care planning, but the use of absolute survival projections can be challenging for patients and clinicians to contextualise. We aimed to define how heart failure and its major comorbidities contribute to loss of actuarially predicted life expectancy.MethodsWe conducted an observational cohort study of 1794 adults with stable chronic heart failure and reduced left ventricular ejection fraction, recruited from cardiology outpatient departments of four UK hospitals. Data from an 11-year maximum (5-year median) follow-up period (999 deaths) were used to define how heart failure and its major comorbidities impact on survival, relative to an age–sex matched control UK population, using a relative survival framework.ResultsAfter 10 years, mortality in the reference control population was 29%. In people with heart failure, this increased by an additional 37% (95% CI 34% to 40%), equating to an additional 2.2 years of lost life or a 2.4-fold (2.2–2.5) excess loss of life. This excess was greater in men than women (2.4 years (2.2–2.7) vs 1.6 years (1.2–2.0); p<0.001). In patients without major comorbidity, men still experienced excess loss of life, while women experienced less and were non-significantly different from the reference population (1 year (0.6–1.5) vs 0.4 years (−0.3 to 1); p<0.001). Accrual of comorbidity was associated with substantial increases in excess lost life, particularly for diabetes, chronic kidney and lung disease.ConclusionsComorbidity accounts for the majority of lost life expectancy in people with heart failure. Women, but not men, without comorbidity experience survival close to reference controls.