Infection-Related Hospitalization in Heart Failure With Reduced Ejection Fraction: A Prospective Observational Cohort Study

Background: Hospitalization is a common adverse event in people with heart failure and reduced ejection fraction, yet is often not primarily due to decompensated heart failure (HF). We investigated the long-term prognosis following infection-related hospitalization. Methods: We conducted a prospective observational cohort study of 711 people with heart failure and reduced ejection fraction recruited from 4 specialist HF clinics in the United Kingdom. All hospitalization episodes (n=1568) were recorded and categorized as primarily due to decompensated HF, other cardiovascular disease, infection-related, or other noncardiovascular disease. Survival was determined after the first hospitalization. Results: During 2900 patient-years of follow-up, there were a total of 14 686 hospital days. At least one hospitalization occurred in 467 people (66%); 25% of first hospitalizations were primarily due to infection and these were not associated with typical signs including tachycardia and pyrexia. Compared with other categories of hospitalization, infection-related was associated with older age, lower serum albumin, higher blood neutrophil counts, and greater prevalence of chronic obstructive pulmonary disease at recruitment. Median survival after first infection-related hospitalization was 18.6 months, comparable to that after first decompensated HF hospitalization, even after age-sex adjustment. The burden of all-cause rehospitalization was comparable irrespective of the category of first hospitalization, but infection more commonly caused re-hospitalization after index infection hospitalization. Conclusions: Infection is a common driver of hospitalization in heart failure and reduced ejection fraction and often presents without classical signs. It is associated with high mortality rates, comparable to decompensated HF, and a major burden of rehospitalization caused by recurrent episodes of infection

Ambulatory heart rate range predicts mode-specific mortality and hospitalisation in chronic heart failure

Objective: We aimed to define the prognostic value of the heart rate range during a 24 h period in patients with chronic heart failure (CHF). Methods: Prospective observational cohort study of 791 patients with CHF associated with left ventricular systolic dysfunction. Mode-specific mortality and hospitalisation were linked with ambulatory heart rate range (AHRR; calculated as maximum minus minimum heart rate using 24 h Holter monitor data, including paced and non-sinus complexes) in univariate and multivariate analyses. Findings were then corroborated in a validation cohort of 408 patients with CHF with preserved or reduced left ventricular ejection fraction. Results: After a mean 4.1 years of follow-up, increasing AHRR was associated with reduced risk of all-cause, sudden, non-cardiovascular and progressive heart failure death in univariate analyses. After accounting for characteristics that differed between groups above and below median AHRR using multivariate analysis, AHRR remained strongly associated with all-cause mortality (HR 0.991/bpm increase in AHRR (95% CI 0.999 to 0.982); p=0.046). AHRR was not associated with the risk of any non-elective hospitalisation, but was associated with heart-failure-related hospitalisation. AHRR was modestly associated with the SD of normal-to-normal beats (R2=0.2; p<0.001) and with peak exercise-test heart rate (R2=0.33; p<0.001). Analysis of the validation cohort revealed AHRR to be associated with all-cause and mode-specific death as described in the derivation cohort. Conclusions: AHRR is a novel and readily available prognosticator in patients with CHF, which may reflect autonomic tone and exercise capacity

Ischemic Heart Disease Modifies the Association of Atrial Fibrillation With Mortality in Heart Failure With Reduced Ejection Fraction

Background: The CASTLE‐AF (Catheter Ablation versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation) trial recently reported that catheter ablation of atrial fibrillation (AF) improves survival in heart failure (HF) with reduced ejection fraction (HFrEF). However, established AF was not associated with mortality in trials of contemporary HFrEF pharmacotherapies. We investigated whether HFrEF pathogenesis may influence the conclusions of studies evaluating the prognostic impact of AF. Methods and Results: Using a prospective cohort study of 791 patients with HFrEF, with AF determined using 24‐hour ambulatory ECG monitoring, univariable and multivariable Cox regression analyses were used to define the association between AF and mode‐specific mortality (mean follow‐up of 5.4 years). One‐year HF‐related hospitalization was assessed with binary logistic regression analysis. One‐year cardiac remodeling was assessed in a subgroup (n=378) using echocardiography. AF was present in 28.2% of patients, with 9.4% of these being paroxysmal. While AF was associated with increased risk of all‐cause mortality (hazard ratio, 1.27; 95% confidence interval 1.03–1.57), with diverging survival curves after 1 year of follow‐up, this association was lost in age‐sex–adjusted analyses. However, AF was associated with increased risk of age‐sex–adjusted all‐cause mortality in people with ischemic pathogenesis, with a statistically significant interaction between pathogenesis and AF. This was predominantly attributed to progressive HF deaths. After 1 year, HF hospitalization and cardiac remodeling were not associated with AF, even in people with ischemic pathogenesis. Conclusions: AF is associated with increased risk of death in HFrEF of ischemic pathogenesis, predominantly due to progressive HF deaths during long‐term follow‐up. HFrEF pathogenesis should be considered in trial design and interpretation

Diabetes, gender and deterioration in estimated glomerular filtration rate in patients with chronic heart failure: ten-year prospective cohort study

Introduction: We aimed to evaluate the relationship between temporal changes in renal function and long-term mortality in patients with heart failure with reduced ejection fraction (HFrEF) and identify correlates of deteriorating renal function. Methods: A total of 381 patients with HFrEF enrolled in a prospective cohort study between 2006–2014 had eGFR measured at initial visit and at 1 year. Baseline characteristics were used in a multivariate analysis to establish variables that predict deterioration in eGFR. Follow-up data were used to assess whether declining eGFR was related to outcomes. Results: Patients were grouped into tertiles based on percentage change in eGFR. In a multivariate logistic regression analysis, male sex was associated with a 1.77-fold ([95% CI 1.01–2.89]; p = 0.045) and diabetes a 1.66-fold ([95% CI 1.02–2.70]; p = 0.041) greater risk of a decline in eGFR compared to those with stable/improving eGFR. Declining eGFR was associated with a 1.4-fold greater risk of death over 10 years ([95% CI 1.08–1.86]; p = 0.01) and a 3.12-fold ([1.44–6.75]; p = 0.004) greater risk of death at 1 year from second eGFR measurement. Conclusions: In patients with HFrEF diabetes and male sex are independent predictors of a decline in eGFR at 1 year. A decline eGFR over 1 year is associated with higher long-term all-cause mortality

Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.This work was supported by the British Heart Foundation, London, UK, and the Diabetes Research and Wellness Foundation, Portsmouth, UK

Association of heart failure and its comorbidities with loss of life expectancy

Objective Estimating 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. Methods We 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. Results After 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. Conclusions Comorbidity 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

Novel Paracrine Action of Endothelium enhances Glucose Uptake in Muscle and Fat

Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell production of superoxide and a simultaneous reduction in availability of the vasoprotective signalling radical, nitric oxide (NO). We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to insulin like growth factor-1 (IGF-1) mediated glucose lowering and endothelial NO release. Objective: To examine the effect of insulin and IGF-1 resistance specifically in endothelial cells in vivo. Methods and Results: We generated mice expressing mutant IGF-1 receptors (mIGF-1R), which form non-functioning hybrid receptors with native insulin receptors (IR) and IGF-1R, directed to endothelial cells under control of the Tie2 promoter-enhancer. Despite endothelial cell insulin and IGF-1 resistance, mutant IGF-1R endothelial cell over-expressing mice (mIGFREO) had enhanced insulin and IGF-1 mediated systemic glucose disposal, lower fasting free fatty acids and triglycerides. In hyperinsulinaemic-euglycaemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased NADPH oxidase 4 (Nox4) expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO endothelial cells generated increased hydrogen peroxide (H2O2), with no increase in superoxide. Treatment with catalase, a dismutase restored insulin tolerance to wild type levels in mIGFREO. Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favourable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H2O2 generation mediating enhanced whole-body insulin sensitivity

Acapsular Staphylococcus aureus with a non-functional agr regains capsule expression after passage through the bloodstream in a bacteremia mouse model

Selection pressures exerted on Staphylococcus aureus by host factors during infection may lead to the emergence of regulatory phenotypes better adapted to the infection site. Traits convenient for persistence may be fixed by mutation thus turning these mutants into microevolution endpoints. The feasibility that stable, non-encapsulated S. aureus mutants can regain expression of key virulence factors for survival in the bloodstream was investigated. S. aureus agr mutant HU-14 (IS256 insertion in agrC) from a patient with chronic osteomyelitis was passed through the bloodstream using a bacteriemia mouse model and derivative P3.1 was obtained. Although IS256 remained inserted in agrC, P3.1 regained production of capsular polysaccharide type 5 (CP5) and staphyloxanthin. Furthermore, P3.1 expressed higher levels of asp23/SigB when compared with parental strain HU-14. Strain P3.1 displayed decreased osteoclastogenesis capacity, thus indicating decreased adaptability to bone compared with strain HU-14 and exhibited a trend to be more virulent than parental strain HU-14. Strain P3.1 exhibited the loss of one IS256 copy, which was originally located in the HU-14 noncoding region between dnaG (DNA primase) and rpoD (sigA). This loss may be associated with the observed phenotype change but the mechanism remains unknown. In conclusion, S. aureus organisms that escape the infected bone may recover the expression of key virulence factors through a rapid microevolution pathway involving SigB regulation of key virulence factors.Fil: Suligoy Lozano, Carlos Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Díaz, Rocío E.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Gehrke, Ana-katharina Elsa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Ring, Natalie. University of Edinburgh; Reino UnidoFil: Yebra, Gonzalo. University of Edinburgh; Reino UnidoFil: Alves, Joana. University of Edinburgh; Reino UnidoFil: Gómez, Marisa Ileana. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Wendler, Sindy. Universitätsklinikum Jena Und Medizinische Fakultät; AlemaniaFil: Fitzgerald, J. Ross. University of Edinburgh; Reino UnidoFil: Tuchscherr, Lorena. Jena University Hospital; AlemaniaFil: Löffler, Bettina. Jena University Hospital; AlemaniaFil: Sordelli, Daniel Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Noto Llana, Mariangeles. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Buzzola, Fernanda Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin

Diabetes mellitus is associated with adverse structural and functional cardiac remodelling in chronic heart failure with reduced ejection fraction

Background: Diabetes mellitus is associated with an increased risk of death and hospitalisation in patients with chronic heart failure. Better understanding of potential underlying mechanisms may aid the development of diabetes mellitus–specific chronic heart failure therapeutic strategies. Methods: Prospective observational cohort study of 628 patients with chronic heart failure associated with left ventricular systolic dysfunction receiving contemporary evidence-based therapy. Indices of cardiac structure and function, along with symptoms and biochemical parameters, were compared in patients with and without diabetes mellitus at study recruitment and 1 year later. Results: Patients with diabetes mellitus (24.2%) experienced higher rates of all-cause [hazard ratio, 2.3 (95% confidence interval, 1.8–3.0)] and chronic heart failure–specific mortality and hospitalisation despite comparable pharmacological and device-based therapies. At study recruitment, patients with diabetes mellitus were more symptomatic, required greater diuretic doses and more frequently had radiologic evidence of pulmonary oedema, despite higher left ventricular ejection fraction. They also exhibited echocardiographic evidence of increased left ventricular wall thickness and pulmonary arterial pressure. Diabetes mellitus was associated with reduced indices of heart rate variability and increased heart rate turbulence. During follow-up, patients with diabetes mellitus experienced less beneficial left ventricular remodelling and greater deterioration in renal function. Conclusion: Diabetes mellitus is associated with features of adverse structural and functional cardiac remodelling in patients with chronic heart failure