Military Hospital

BACKGROUND: Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia. METHODS: We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 microg per liter or between 100 and 299 microg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life. RESULTS: Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. CONCLUSIONS: Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780).

AIMS: The objective of the EuroHeart Failure Survey II (EHFS II) was to assess patient characteristics, aetiology, treatment, and outcome of acute heart failure (AHF) in Europe in relation to the guidelines on the diagnosis and treatment of AHF published by the European Society of Cardiology. METHODS AND RESULTS: Patients hospitalized for AHF were recruited by 133 centres in 30 European countries. Three thousand five hundred and eighty patients were entered into the database by the end of August 2005. Mean age was 70 years, and 61% of patients were male. New-onset AHF (de novo AHF) was diagnosed in 37%, of which 42% was due to acute coronary syndromes (ACS). Clinical classification according to the guidelines divided AHF patients into (i) decompensated HF (65%), (ii) pulmonary oedema (16%), (iii) HF and hypertension (11%), (iv) cardiogenic shock (4%), and (v) right HF (3%). Coronary heart disease, hypertension, and atrial fibrillation were the most common underlying conditions. Arrhythmias, valvular dysfunction, and ACS were each present as precipitating factor in one-third of cases. Preserved left ventricular ejection fraction (> or =45%) was observed in 34%. Valvular disorders were common, especially mitral regurgitation (MR) which was reported on echocardiography in 80% of patients. Median length of stay was 9 days, and in-hospital mortality 6.7%. At discharge, 80% of patients were on angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers, whereas 61% were taking beta-blocker medication. CONCLUSION: Decompensated HF is the most common clinical presentation of AHF patients. More than one-third of AHF patients do not have a previous history of HF, and new-onset HF is often caused by ACS. Preserved systolic function is found in a substantial proportion of the patients. The prevalence of valvular dysfunction is strikingly high and contributes to the clinical presentation. The EHFS II on AHF verified that the use of evidence-based HF medication was well adopted to clinical practice.

Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine interleukin-17F (IL-17F). IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.

AIMS: The ESC-HF Pilot survey was aimed to describe clinical epidemiology and 1-year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry. METHODS: The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 Cardiology Centres in 12 European countries selected to represent the different health systems across Europe. All outpatients with HF and patients admitted for acute HF on 1 day per week for eight consecutive months were included. From October 2009 to May 2010, 5118 patients were included: 1892 (37%) admitted for acute HF and 3226 (63%) patients with chronic HF. The all-cause mortality rate at 1 year was 17.4% in acute HF and 7.2% in chronic stable HF. One-year hospitalization rates were 43.9% and 31.9%, respectively, in hospitalized acute and chronic HF patients. Major regional differences in 1-year mortality were observed that could be explained by differences in characteristics and treatment of the patients. CONCLUSION: The ESC-HF Pilot survey confirmed that acute HF is still associated with a very poor medium-term prognosis, while the widespread adoption of evidence-based treatments in patients with chronic HF seems to have improved their outcome profile. Differences across countries may be due to different local medical practice as well to differences in healthcare systems. This pilot study also offered the opportunity to refine the organizational structure for a long-term extended European network.

Patients with acute heart failure (AHF) require urgent in-hospital treatment for relief of symptoms. The main reason for hospitalization is congestion, rather than low cardiac output. Although congestion is associated with a poor prognosis, many patients are discharged with persistent signs and symptoms of congestion and/or a high left ventricular filling pressure. Available data suggest that a pre-discharge clinical assessment of congestion is often not performed, and even when it is performed, it is not done systematically because no method to assess congestion prior to discharge has been validated. Grading congestion would be helpful for initiating and following response to therapy. We have reviewed a variety of strategies to assess congestion which should be considered in the care of patients admitted with HF. We propose a combination of available measurements of congestion. Key elements in the measurement of congestion include bedside assessment, laboratory analysis, and dynamic manoeuvres. These strategies expand by suggesting a routine assessment of congestion and a pre-discharge scoring system. A point system is used to quantify the degree of congestion. This score offers a new instrument to direct both current and investigational therapies designed to optimize volume status during and after hospitalization. In conclusion, this document reviews the available methods of evaluating congestion, provides suggestions on how to properly perform these measurements, and proposes a method to quantify the amount of congestion present.

AIMS: To evaluate how recommendations of European guidelines regarding pharmacological and non-pharmacological treatments for heart failure (HF) are adopted in clinical practice. METHODS AND RESULTS: The ESC-HF Long-Term Registry is a prospective, observational study conducted in 211 Cardiology Centres of 21 European and Mediterranean countries, members of the European Society of Cardiology (ESC). From May 2011 to April 2013, a total of 12,440 patients were enrolled, 40.5% with acute HF and 59.5% with chronic HF. Intravenous treatments for acute HF were heterogeneously administered, irrespective of guideline recommendations. In chronic HF, with reduced EF, renin-angiotensin system (RAS) blockers, beta-blockers, and mineralocorticoid antagonists (MRAs) were used in 92.2, 92.7, and 67.0% of patients, respectively. When reasons for non-adherence were considered, the real rate of undertreatment accounted for 3.2, 2.3, and 5.4% of the cases, respectively. About 30% of patients received the target dosage of these drugs, but a documented reason for not achieving the target dosage was reported in almost two-thirds of them. The more relevant reasons for non-implantation of a device, when clinically indicated, were related to doctor uncertainties on the indication, patient refusal, or logistical/cost issues. CONCLUSION: This pan-European registry shows that, while in patients with acute HF, a large heterogeneity of treatments exists, drug treatment of chronic HF can be considered largely adherent to recommendations of current guidelines, when the reasons for non-adherence are taken into account. Observations regarding the real possibility to adhere fully to current guidelines in daily clinical practice should be seriously considered when clinical practice guidelines have to be written.

The seemingly inexorable spread of antibiotic resistance genes among microbial pathogens now threatens the long-term viability of our current antimicrobial therapy to treat severe bacterial infections such as sepsis. Antibiotic resistance is reaching a crisis situation in some bacterial pathogens where few therapeutic alternatives remain and pan-resistant strains are becoming more prevalent. Non-antibiotic therapies to treat bacterial infections are now under serious consideration and one possible option is the therapeutic use of specific phage particles that target bacterial pathogens. Bacteriophage therapy has essentially been re-discovered by modern medicine after widespread use of phage therapy in the pre-antibiotic era lost favor, at least in Western countries, after the introduction of antibiotics. We review the current therapeutic rationale and clinical experience with phage therapy as a treatment for invasive bacterial infection as novel alternative to antimicrobial chemotherapy.

Background: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 (sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms (“atrial fibrillation,” “atrial flutter”). Results: Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68–0.95]; P =0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFL: HR, 0.79 [95% CI, 0.58–1.09]; no AF/AFL: HR, 0.81 [95% CI, 0.67–0.98]; P for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 [95% CI, 0.66–1.04]) versus multiple risk factors (HR, 0.78 [95% CI, 0.62–0.99]; P for interaction 0.72) or a history of HF (HF: HR, 0.78 [95% CI, 0.55–1.11]; No HF: HR, 0.81 [95% CI, 0.68–0.97]; P for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A 1c , body mass index, blood pressure, or estimated glomerular filtration rate (all P for interaction &gt;0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 [95% CI, 0.64–0.92]; P =0.005). Conclusions: Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient’s previous history of AF, atherosclerotic cardiovascular disease, or HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre-existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline-directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress-mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease-specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter-defibrillators, cardiac resynchronization therapy and implanted long-term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.

The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti-cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under-represent older patients and those with significant co-morbidities. The risk of adverse events may also increase when novel agents, which frequently modulate survival pathways, are used in combination with each other or with other conventional cytotoxic chemotherapeutics. The extent to which survival and growth pathways in the tumour cell (which we seek to inhibit) coincide with those in cardiovascular cells (which we seek to preserve) is an open question but one that will become ever more important with the development of new cancer therapies that target intracellular signalling pathways. It remains unclear whether potential cardiovascular problems can be predicted from analyses of such basic signalling mechanisms and what pre-clinical evaluation should be undertaken. The screening of patients, optimization of therapeutic schemes, monitoring of cardiovascular function during treatment, and the management of cardiovascular side effects are likely to become increasingly important in cancer patients. This paper summarizes the deliberations of a cross-disciplinary workshop organized by the Heart Failure Association of the European Society of Cardiology (held in Brussels in May 2009), which brought together clinicians working in cardiology and oncology and those involved in basic, translational, and pharmaceutical science.

AIMS: The primary objective of the new ESC-HF Pilot Survey was to describe the clinical epidemiology of outpatients and inpatients with heart failure (HF) and the diagnostic/therapeutic processes applied across 12 participating European countries. This pilot study was specifically aimed at validating the structure, performance, and quality of the data set, for continuing the survey into a permanent registry. METHODS AND RESULTS: The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 cardiology centres from 12 European countries selected to represent the different health systems and care attitudes across Europe. All outpatients with HF and patients admitted for acute HF were included during the enrolment period (1 day per week for 8 consecutive months). From October 2009 to May 2010, 5118 patients were included in this pilot survey, of which 1892 (37%) were admitted for acute HF and 3226 (63%) for chronic HF. Ischaemic aetiology was reported in about half of the patients. In patients admitted for acute HF, the most frequent clinical profile was decompensated HF (75% of cases), whereas pulmonary oedema and cardiogenic shock were reported, respectively, in 13.3 and 2.3% of the cases. The total in-hospital mortality rate was 3.8% and was cardiovascular in 90.1% of the cases. Lowest and highest mortality rates were observed in hypertensive HF and in cardiogenic shock, respectively. More than 80% of patients with chronic HF were treated with renin-angiotensin-aldosterone system blockers and β-adrenergic blockers. However, target doses of such drugs were reached in one-third to one-fourth of the patients only. CONCLUSION: The ESC-HF Pilot Survey is an example of the possibility of utilizing an observational methodology to get insights into the current clinical practice in Europe, whose picture will be completed by the 1-year follow-up. Moreover, this study offered the opportunity to refine the organizational structure of a long-term, extended European network.

Therapy has improved the survival of heart failure (HF) patients. However, many patients progress to advanced chronic HF (ACHF). We propose a practical clinical definition and describe the characteristics of this condition. Patients that are generally recognised as ACHF often exhibit the following characteristics: 1) severe symptoms (NYHA class III to IV); 2) episodes with clinical signs of fluid retention and/or peripheral hypoperfusion; 3) objective evidence of severe cardiac dysfunction, shown by at least one of the following: left ventricular ejection fraction<30%, pseudonormal or restrictive mitral inflow pattern at Doppler-echocardiography; high left and/or right ventricular filling pressures; elevated B-type natriuretic peptides; 4) severe impairment of functional capacity demonstrated by either inability to exercise, a 6-minute walk test distance<300 m or a peak oxygen uptake<12-14 ml/kg/min; 5) history of >1 HF hospitalisation in the past 6 months; 6) presence of all the previous features despite optimal therapy. This definition identifies a group of patients with compromised quality of life, poor prognosis, and a high risk of clinical events. These patients deserve effective therapeutic options and should be potential targets for future clinical research initiatives.

Natural products, including bee products, are particularly appreciated by consumers and are used for therapeutic purposes as alternative drugs. However, it is not known whether treatments with bee products are safe and how to minimise the health risks of such products. Among others, bee pollen is a natural honeybee product promoted as a valuable source of nourishing substances and energy. The health-enhancing value of bee pollen is expected due to the wide range of secondary plant metabolites (tocopherol, niacin, thiamine, biotin and folic acid, polyphenols, carotenoid pigments, phytosterols), besides enzymes and co-enzymes, contained in bee pollen. The promising reports on the antioxidant, anti-inflammatory, anticariogenic antibacterial, antifungicidal, hepatoprotective, anti-atherosclerotic, immune enhancing potential require long-term and large cohort clinical studies. The main difficulty in the application of bee pollen in modern phytomedicine is related to the wide species-specific variation in its composition. Therefore, the variations may differently contribute to bee-pollen properties and biological activity and thus in therapeutic effects. In principle, we can unequivocally recommend bee pollen as a valuable dietary supplement. Although the bee-pollen components have potential bioactive and therapeutic properties, extensive research is required before bee pollen can be used in therapy. © 2016 Society of Chemical Industry.

AIMS: Classification of acute heart failure (AHF) patients into four clinical profiles defined by evidence of congestion and perfusion is advocated by the 2016 European Society of Cardiology (ESC)guidelines. Based on the ESC-EORP-HFA Heart Failure Long-Term Registry, we compared differences in baseline characteristics, in-hospital management and outcomes among congestion/perfusion profiles using this classification. METHODS AND RESULTS: We included 7865 AHF patients classified at admission as: 'dry-warm' (9.9%), 'wet-warm' (69.9%), 'wet-cold' (19.8%) and 'dry-cold' (0.4%). These groups differed significantly in terms of baseline characteristics, in-hospital management and outcomes. In-hospital mortality was 2.0% in 'dry-warm', 3.8% in 'wet-warm', 9.1% in 'dry-cold' and 12.1% in 'wet-cold' patients. Based on clinical classification at admission, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: 'wet-warm' vs. 'dry-warm' 1.78 (1.43-2.21) and 'wet-cold' vs. 'wet-warm' 1.33 (1.19-1.48). For profiles resulting from discharge classification, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: 'wet-warm' vs. 'dry-warm' 1.46 (1.31-1.63) and 'wet-cold' vs. 'wet-warm' 2.20 (1.89-2.56). Among patients discharged alive, 30.9% had residual congestion, and these patients had higher 1-year mortality compared to patients discharged without congestion (28.0 vs. 18.5%). Tricuspid regurgitation, diabetes, anaemia and high New York Heart Association class were independently associated with higher risk of congestion at discharge, while beta-blockers at admission, de novo heart failure, or any cardiovascular procedure during hospitalization were associated with lower risk of residual congestion. CONCLUSION: Classification based on congestion/perfusion status provides clinically relevant information at hospital admission and discharge. A better understanding of the clinical course of the two entities could play an important role towards the implementation of targeted strategies that may improve outcomes.

AIMS: The aim of this study was to assess the net clinical and prognostic effects of intravenous (i.v.) iron therapy in patients with systolic heart failure (HF) and iron deficiency (ID). METHODS AND RESULTS: We performed an aggregate data meta-analysis (random effects model) of randomized controlled trials that evaluated the effects of i.v. iron therapy in iron-deficient patients with systolic HF. We searched electronic databases up to September 2014. We identified five trials which fulfilled the inclusion criteria (509 patients received i.v. iron therapy in comparison with 342 controls). Intravenous iron therapy has been shown to reduce the risk of the combined endpoint of all-cause death or cardiovascular hospitalization [odds ratio (OR) 0.44, 95% confidence interval (CI) 0.30-0.64, P < 0.0001], and the combined endpoint of cardiovascular death or hospitalization for worsening HF (OR 0.39, 95% CI 0.24-0.63, P = 0.0001). Intravenous iron therapy resulted in a reduction in NYHA class (data are reported as a mean net effect with 95% CIs for all continuous variables) (-0.54 class, 95% CI -0.87 to -0.21, P = 0.001); an increase in 6-min walking test distance (+31 m, 95% CI 18-43, P < 0.0001); and an improvement in quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ) score +5.5 points, 95% CI 2.8-8.3, P < 0.0001; European Quality of Life-5 Dimensions (EQ-5D) score +4.1 points, 95% CI 0.8-7.3, P = 0.01; Minnesota Living With Heart Failure Questionnaire (MLHFQ) score -19 points, 95% CI:-23 to -16, P < 0.0001; and Patient Global Assessment (PGA) +0.70 points, 95% CI 0.31-1.09, P = 0004]. CONCLUSION: The evidence indicates that i.v. iron therapy in iron-deficient patients with systolic HF improves outcomes, exercise capacity, and quality of life, and alleviates HF symptoms.

(1801). XLIX. Observations on the oil extracted from the female cornel or dog-berry tree, the cornus sanguinea of linnœus, class 4th; Tetrandria Monogynia. The Philosophical Magazine: Vol. 10, No. 40, pp. 318-320.

AIMS: To evaluate the anti-anginal and anti-ischaemic efficacy of the selective I(f) current inhibitor ivabradine in patients with chronic stable angina pectoris receiving beta-blocker therapy. METHODS AND RESULTS: In this double-blinded trial, 889 patients with stable angina receiving atenolol 50 mg/day were randomized to receive ivabradine 5 mg b.i.d. for 2 months, increased to 7.5 mg b.i.d. for a further 2 months, or placebo. Patients underwent treadmill exercise tests at the trough of drug activity using the standard Bruce protocol for randomization and at 2 and 4 months. Total exercise duration at 4 months increased by 24.3 +/- 65.3 s in the ivabradine group, compared with 7.7 +/- 63.8 s with placebo (P < 0.001). Ivabradine was superior to placebo for all exercise test criteria at 4 months (P < 0.001 for all) and 2 months (P-values between <0.001 and 0.018). Ivabradine in combination with atenolol was well tolerated. Only 1.1% of patients withdrew owing to sinus bradycardia in the ivabradine group. CONCLUSION: The combination of ivabradine 7.5 mg b.i.d. and atenolol at the commonly used dosage in clinical practice in patients with chronic stable angina pectoris produced additional efficacy with no untoward effect on safety or tolerability.

The practical management of heart failure remains a challenge. Not only are heart failure patients expected to adhere to a complicated pharmacological regimen, they are also asked to follow salt and fluid restriction, and to cope with various procedures and devices. Furthermore, physical training, whose benefits have been demonstrated, is highly recommended by the recent guidelines issued by the European Society of Cardiology, but it is still severely underutilized in this particular patient population. This position paper addresses the problem of non-adherence, currently recognized as a main obstacle to a wide implementation of physical training. Since the management of chronic heart failure and, even more, of training programmes is a multidisciplinary effort, the current manuscript intends to reach cardiologists, nurses, physiotherapists, as well as psychologists working in the field.

BACKGROUND: Peripheral chemoreceptor hypersensitivity is a feature of abnormal cardiorespiratory reflex control in chronic heart failure (CHF) and may contribute to sympathetic overactivity, attenuated baroreflex sensitivity (BRS), and excessive ventilation during exercise. We studied whether augmented peripheral chemosensitivity carries independent prognostic significance. METHODS AND RESULTS: We assessed peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalation of pure nitrogen) and BRS (phenylephrine and spectral methods) in 80 consecutive CHF patients (age 58+/-9 years; left ventricular ejection fraction [LVEF] 24+/-12%; peak oxygen consumption [peak VO(2)] 18+/-7 mL(-1). min(-1)). CHF patients demonstrated augmented peripheral chemosensitivity and decreased BRS (all P<0.01 versus reference values). During follow-up (median 41 months, >3 years in all survivors), 37 patients died. High peripheral chemosensitivity (>0.72 L. min(-1). %SaO(2)(-1)) predicted impaired survival (hazard ratio 3.2, 95% CI 1.6 to 6.0, P=0.0006). In the 27 patients (34%) with high peripheral chemosensitivity, 3-year survival was 41% (95% CI 22% to 60%) compared with 77% (66% to 89%) in 53 patients with normal chemosensitivity (P=0.0002). In multivariate analyses, augmented chemosensitivity independently predicted death (hazard ratio 2.8, 95% CI 1.5 to 5.5, adjusted for age, peak VO(2), and VE/VCO(2) [P=0.002]; hazard ratio 2.6, 95% CI 1.3 to 5.1, adjusted for age, LVEF, and peak VO(2) [P=0.008]). Depressed BRS was related to unfavorable prognosis in univariate analysis (P=0.05) but not in multivariate analyses. CONCLUSIONS: Hypersensitivity of the peripheral chemoreceptors independently predicts adverse prognosis in ambulatory patients with CHF. This hyperactive excitatory reflex, through its inhibitory effect on the baroreflex, may be the reason for the previously observed prognostic association of the latter.

Abstract Aims Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. Methods and results Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF &amp;gt; 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11–1.21), P &amp;lt; 0.001], all-cause mortality [1.22 (1.16–1.29), P &amp;lt; 0.001] and CV as well as non-CV mortality [1.16 (1.09–1.24), P &amp;lt; 0.001; 1.31 (1.18–1.45), P &amp;lt; 0.001], but did not improve discrimination in previously published risk models. Conclusions In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations.