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Background and objective High resting heart rate (HR) associates with cardiovascular death (CVD) and heart failure hospitalisation (HFH) in patients with reduced ejection fraction (HFrEF), but data are sparse in patients with preserved (HFpEF) or mildly reduced (HFmrEF) ejection fraction. Empagliflozin reduced the risk of CVD and HFH in HFpEF in the EMPEROR-Preserved trial. This study analyses the influence of HR on outcomes in patients with left ventricular ejection fraction (LVEF) >40% in EMPEROR-Preserved and evaluates the effects of empagliflozin across HR categories. Methods Patients (n=5988) with HFpEF (LVEF >40%) were categorised to HR 75 bpm. The composite of CVD or HFH (primary outcome), first HFH, CVD, recurrent HFH and all-cause mortality were studied in the HR groups and in patients separated by sinus rhythm (SR) or atrial fibrillation (AF) and true HFpEF (EF ≥50%) or HFmrEF (EF 40–49%). Results Empagliflozin did not influence HR over time. At HR >75 bpm, the primary outcome (hazard ratio: 1.31, 1.13–1.52, p=0.0003), time to first HFH (hazard ratio: 1.25, 1.04–1.49, p=0.02), recurrent HFH (hazard ratio: 1.29, 1.05–1.60, p=0.02), CVD (hazard ratio: 1.49, 1.21–1.84, p=0.0001) and all-cause mortality (hazard ratio: 1.49, 1.28–1.73, p Conclusions HR in SR, but not in AF, predicts heart failure outcomes in HFpEF and HFmrEF, but the effects of empagliflozin were not modified by HR. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance

Background/Introduction Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is associated with an increased risk of cardiovascular (CV) events. The modifiability of CKD-associated CV risk in patients with T2D across a spectrum of CKD stages remains unknown. Purpose To test whether CKD, as defined jointly by estimated glomerular filtration rate (eGFR) and albuminuria (urine albumin-to-creatinine ratio [UACR]), is a modifiable CV risk factor in patients with T2D. Furthermore, to estimate the population-wide reduction in first CV events in the US if all eligible patients were treated with finerenone. Methods We estimated the incidence rates of CV events (composite of CV death, non-fatal stroke, non-fatal myocardial infarction, or hospitalisation for heart failure) over a median follow-up of 3.0 years in 13,026 patients with CKD and T2D, treated with finerenone or placebo, in a joint analysis by eGFR and UACR categories. Patients were from FIDELITY, a prespecified pooled analysis of two phase III trials, and had an eGFR ≥25 ml/min/1.73 m2 and UACR 30–5000 mg/g at screening.The potential impact of finerenone treatment on the US population was evaluated by simulating the number of first CV events that could be prevented per year with finerenone, using incidence rates from FIDELITY and prevalence rates of CKD in patients with T2D from the National Health and Nutrition Examination Survey (NHANES). Results Lower eGFR and higher UACR categories were associated with higher incidences of CV events in finerenone and placebo recipients (Figure). Finerenone reduced CV risk versus placebo (hazard ratio 0.86; 95% CI 0.78–0.95; p=0.0018) without evidence of moderation of risk reduction by combined eGFR and UACR categories (p interaction = 0.66; Figure 1). Using NHANES, a total of 6.4 million treatment-eligible individuals with CKD and T2D were identified; 75% had CKD with an eGFR ≥60 ml/min/1.73 m2 and 25% had CKD with an eGFR Conclusions Higher albuminuria and lower eGFR are associated with increased CV risk in patients with T2D. Across a range of eGFR and albuminuria categories, CV risk is modifiable. Therefore, CKD is a modifiable CV risk factor in part mediated by mineralocorticoid receptor overactivation. UACR screening to identify patients with T2D and albuminuria with an eGFR ≥60 ml/min/1.73 m2 is likely to provide a significant opportunity for population benefits. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG

Purpose This analysis aims to assess the theoretical impact of atrial flow regulator implantation on mortality by comparing the observed survival rate with the median predicted probability for one-year survival. Methods The prospective, multicentre, open-label, non-randomised PRELIEVE study assessed the safety and efficacy of the atrial flow regulator in patients with symptomatic HFrEF (left ventricular ejection fraction (LVEF) ≥15% and Results A total of 87 patients had undergone successful device implantation for the treatment of HFrEF (53%) and HFpEF (47%). Sixty patients had a complete twelve-month follow-up. The median follow-up was 351 days (interquartile range [IQR] 202–370). A total of six (7%) patients died during follow-up (8.6 deaths per 100 patient-years; 95% confidence interval [CI] 2.7 to 15.5), all of which had HFrEF. The median predicted mortality rate for the overall study population was 12.2 deaths per 100 patient-years (95% CI 10.2 to 14.7). While the observed mortality rate (0 deaths per 100 patient-years) was significantly lower than the median predicted mortality rate (9.3 deaths per 100 patient-years; 95% CI 8.4 to 11.1) in patients with HFpEF (−9.3 deaths per 100 patient-years; 95% CI −11.1 to −8.4), there was no difference in patients with HFrEF (−3.6 deaths per 100 patient-years; 95% CI −9.5 to 3.0) (Figure 1). Four deaths were HF-related deaths (5.7 HF-related deaths per 100 patient-years; 95% CI 1.4 to 11.9; 10.8 HF-related deaths per 100 patient-years; 95% CI 2.5 to 23.1 in the HFrEF subgroup). Conclusion In patients with HFpEF, the mortality rate following atrial flow regulator implantation was lower than the predicted mortality rate. These findings need to be confirmed by larger randomised, controlled trials. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Occlutech International AB

Iron deficiency does not always receive sufficient attention in daily clinical practice. Diagnostic and treatment possibilities are underutilized. This leads to a negative impact on patients' quality of life, exercise capacity, and treatment response, especially in patients with chronic diseases. In this overview, important diagnostic parameters that should be assessed to detect iron deficiency are outlined. In addition, important laboratory parameters are provided. Furthermore, the necessity for early and sufficient iron supplementation for various chronic diseases is presented. In addition, the risks and benefits of currently available oral and intravenous options for iron treatment are outlined.

Anaemia and iron deficiency are frequent co-morbidities in patients with chronic heart failure. Both are bound to worsen an already reduced exercise capacity in these patients. Recent data have demonstrated that iron deficiency alone, i.e. without concomitant anaemia, reduces quality of life, exercise capacity and likely also survival. Two clinical entities should be differentiated in this context: absolute and functional iron deficiency, the first being an absolute deficiency of iron, the second representing a disturbed mobilisation capacity. The FAIR-HF study has shown that intravenous iron administration can improve quality of life and exercise capacity in affected patients. A correct diagnosis can easily be arrived at using parameters such as serum ferritin and transferrin saturation. Replenishing iron stores is most useful using the intravenous route, and administered doses need to be adjusted to individual needs.

OBJECTIVETo evaluate urinary glucocorticoid excretion profiles in a cohort of recently diagnosed young hypertensive patients.METHODSAfter excluding patients with secondary causes, 60 individuals with premature hypertension were recruited (diagnosed by ambulatory blood pressure monitoring before the age of 36 years). In addition, 30 older hypertensive controls (age of onset > 36 years, “middle aged hypertensive controls”), and 30 normal controls (age matched to the young hypertensive group) were studied. All provided 24 hour urine collections for mass spectrometry for total cortisol metabolites and total androgen metabolites by gas chromatography.RESULTSAmong male patients, those with premature hypertension had higher total urinary excretion of cortisol metabolites (mean (SD), 13 332 (6472) μg/day) than age matched normal controls (7270 (1788) μg/day; p = 0.00001) or middle aged hypertensive controls (8315 (3565) μg/day; p = 0.002). A similar increase was seen among the female patients, although the absolute concentrations were lower. There was no significant difference between middle aged hypertensive patients and normal controls. Urinary total androgen excretion profiles in female patients also showed an unusual increase in the premature hypertension group (2958 (1672) μg/day) compared with the other groups (middle aged hypertensive controls, 1373 (748) μg/day, p = 0.0003; normal controls, 1687 (636) μg/day, p = 0.002). In all subjects, serum sodium and creatinine concentrations were within the normal range; serum potassium concentrations were found to be low before the start of treatment.CONCLUSIONSIndividuals presenting with premature hypertension have an abnormally high excretion of glucocorticoid metabolites in the urine. While the mechanism remains uncertain, these findings are compatible with partial resistance of the glucocorticoid receptors, with a compensatory increase in cortisol and androgen metabolites. The mineralocorticoid effects of the latter (sodium and water retention) may contribute to an abnormally high blood pressure and may have implications for targeted selection of first line treatment in young hypertensive patients.

As part of the 2010 focused update of ESC guidelines on device therapy in heart failure, the guidelines on pacemakers in the treatment of heart failure were renewed. A new feature is that cardiac resynchronization therapy (CRT) is indicated for New York Heart Association (NYHA) class III and IV irrespective of the presence of left ventricular dilatation and specified for NYHA class IV (patient ambulatory, stable, life expectancy6 months). Furthermore, NYHA class II (but not class I) has been added when there is left bundle branch block and QRS duration ≥150 ms. CRT is also indicated for patients in NYHA class III-IV with permanent atrial fibrillation and heart failure [left ventricular ejection fraction (LVEF) ≤ 35%] when QRS is ≥ 130 ms and ventricular rate has slowed either spontaneously or by AV node ablation. In patients with heart failure (NYHA class II-IV, LVEF ≤ 35%) who need a pacemaker for AV block, CRT is generally indicated to avoid progression of heart failure caused by right ventricular stimulation, also in cases of intrinsic QRS120 ms. For patients with terminal heart failure who are not eligible for heart transplantation, treatment with a left ventricular assist device can be performed as destination therapy. The new guidelines expand the indication for device therapy in heart failure based on the newest study findings, particularly for patients in NYHA class II, and specify the old guidelines. There are still uncertainties that must be investigated in randomized trials regarding patients with permanent atrial fibrillation, the indication for CRT in heart block, and the question of CRT with pacemaker or defibrillator.

Summary Background An induction of reactive oxygen species (ROS) is characteristic for inflammation but the exact pathways have not been identified for allergic airway diseases so far. Objective The aim of this study was to characterize the role of the tachykinin NK-1 receptor on ROS production during allergen challenge and subsequent inflammation and remodelling. Methods Precision-cut lung slices of ovalbumin (OVA)-sensitized mice were cultivated and ROS-generation in response to OVA challenge (10 μg/mL) was examined by the 2′,7′-dichloroflourescein-diacetate method. Long-term ROS effects on epithelial proliferation were investigated by 5-bromo-2′-deoxyuridine incorporation (72 h). In vivo, the results were validated in OVA-sensitized animals which were treated intra-nasally with either placebo, the tachykinin neurokinin 1 (NK-1) receptor antagonist SR 140333 or the anti-oxidant N-acetylcystein (NAC) before allergen challenge. Inflammatory infiltration and remodelling were assessed 48 h after allergen challenge. Results ROS generation was increased by 3.7-fold, which was inhibited by SR 140333. [Sar9,Met11(O2)]-Substance P (5 nm) caused a tachykinin NK-1 receptor-dependent fourfold increase in ROS generation. Epithelial proliferation was decreased by 68% by incubation with [Sar9,Met11(O2)]-SP over 72 h. In-vivo, treatment with SR 140333 and NAC reduced epithelial damage (91.4% and 76.8% vs. placebo, respectively, P

Chronic heart failure (CHF) represents a major public health burden in developed countries. The introduction of new treatments has helped to improve its prognosis in recent years. However, it is still not possible to directly target the immunological aspects of the disease. In fact, chronic immune activation with the up-regulation of pro-inflammatory substances in the plasma remains an important feature of the disease, independently of its aetiology. Autoimmune mechanisms play a significant role in a subgroup of patients with dilated cardiomyopathy. The interplay between the two systems has not been established so far. This review briefly summarizes immune and autoimmune mechanisms in CHF.

Chronic heart failure (CHF) is an important public health care problem and a leading cause of morbidity and mortality world wide. Anemia is a common finding in CHF and known to cause heart failure. Patients with CHF are limited by exercise capacity and fatigue. A low hemoglobin concentration leads to impairment of both. With increasing severity of heart failure, anemia also becomes more frequent and clinically more relevant. There are many potential reasons for development of anemia in chronic heart failure like bone marrow depression, reduced intestinal iron uptake, and the dilution in consequence of sodium and water retention. However, the anemia seen in CHF is generally an "anemia of chronic illness". Furthermore, it has been shown that hemoglobin levels independently predict increased mortality in CHF.

Elevated levels of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6), have been demonstrated in patients with chronic heart failure (CHF). Evidence suggests that cytokines such as these may play a central role in the pathogenesis of this syndrome. TNF has several properties that are particularly detrimental in CHF, such as negatively inotropic effects, the promotion of left ventricular remodelling, and the induction of dilated cardiomyopathy in humans. Furthermore, TNF can cause skeletal muscle wasting and apoptosis, and, therefore, may be important in the development of cardiac cachexia. Although the precise stimulus for immune activation in CHF is unknown, one hypothesis is that endotoxin may be a significant trigger for cytokine release. This is supported by the finding that decompensated CHF patients have elevated endotoxin levels that normalize on diuretic therapy. The factors that influence endotoxin responsiveness in patients with CHF, in particular the potential importance of serum lipoproteins, will be discussed in this review.

Congestive chronic heart failure (CHF) is a progressive disorder in which a complex interaction of haemodynamic, neurohormonal and metabolic disturbances leads to subsequent immune activation. The greatest attention has been given to the concept that the progression of heart failure is due to neurohormonal abnormalities and this has led to substantial therapeutic benefits for CHF. The aim of this review is to describe a number of the interactions between neurohormonal pathways and metabolic problems relevant in CHF. Besides the renin-angiotensin-aldosterone-system, steroid and thyroid hormones, growth factors, insulin and inflammatory cytokines (e.g. tumour necrosis factor-alpha [TNF-alpha]) are considered. TNF-alpha is potentially a key molecule with enormous interactive opportunities within a regulatory network of energy metabolism, immune function and neuroendocrine and hormonal function. The most dramatic metabolic problem in heart failure patients is the development of cardiac cachexia. Currently, no specific therapy exists and the prognosis is poor. There are promising approaches (counteracting TNF-alpha or applying anabolic growth factors) but these are not without risk and are expensive, and their application may, therefore, be limited to certain subgroups of patients. In the future, it will not be enough to monitor cardiac function and symptomatic status in heart failure patients. Rather, the patients' metabolic status may need to be taken, as well as an assessment of peak oxygen consumption, body composition and hormonal status.

Chronic heart failure (CHF) may be seen as a multi-system disorder with its origin in the heart but including many extracardiac manifestations. Immunological abnormalities are recognized in this context, in particular, changes in the expression of mediators of the innate immune response.Higher levels of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF) are found in the circulation and in the myocardium of patients with chronic heart failure than in controls. TNF has been implicated in a number of pathophysiological processes that are thought to be important to the progression of chronic heart failure. Therapies directed against this cytokine might therefore represent a novel approach to heart failure management.

Chronic heart failure (CHF) is a complex syndrome affecting many body systems. Body wasting (ie, cardiac cachexia) is a serious complication of CHF long known but little investigated. Although no specific diagnostic criteria have been established, we have suggested that cardiac cachexia be defined on the basis of the presence of documented nonintentional and nonedematous weight loss7.5% of the premorbid normal weight, occurring over a time period of6 months. Using this definition, 16% of an unselected CHF outpatient population was found to be cachectic. The cachectic state is predictive of impaired prognosis independently of age, functional disease classification, left ventricular ejection fraction, and peak oxygen consumption. The mortality in the cachectic cohort is 50% at 18 months. Analyzing body composition in detail, it has been found that patients with cardiac cachexia suffer from a general loss of fat tissue (ie, energy reserves), lean tissue (ie, skeletal muscle), and bone tissue (ie, osteoporosis). Cachectic CHF patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. The pathophysiologic alterations leading to cardiac cachexia remain unclear, but initial cross-sectional studies have suggested that humoral neuroendocrine and immunologic abnormalities are linked, independently of established heart failure severity markers, to the presence of body wasting. Comparing the features of cachectic and noncachectic CHF patients with those of healthy control subjects, it is mainly the cachectic CHF patients who show raised plasma levels of epinephrine, norepinephrine, and cortisol; the highest plasma renin activity and aldosterone plasma concentrations; and the lowest plasma sodium level. Several studies have shown that cardiac cachexia is linked to raised plasma levels of tumor necrosis factor-ac. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems may cause the development of body wasting.

Neurohormonal activation is well studied in chronic heart failure, and covers aspects such as abnormalities of plasma catecholamines, particularly since plasma noradrenaline levels have been found to predict impaired prognosis in heart failure patients. This review will concentrate on the information available on circulating levels of adrenaline and noradrenaline. It will discuss how catecholamine levels change during different disease stages from myocardial infarction to severe chronic heart failure. It has been clearly shown that angiotensin converting enzyme (ACE) inhibitors exert particularly beneficial effects in heart failure patients with raised catecholamine levels. Nevertheless, reviewing how a variety of drug and non-drug interventions affect catecholamine levels and patients' survival, it is concluded that the effect on catecholamine levels does not directly correlate with a survival benefit of the respective intervention. Despite their prognostic significance, due to the development of new prognostic markers for patients with chronic heart failure, the overall clinical value of spot catecholamine levels remains limited.

Changing the exercising muscle group alters the ventilatory response to exercise in chronic heart failure. The recognized muscle abnormalities in congestive heart failure may thus contribute to the ventilatory abnormalities of this condition.

Die neue Leitlinie „Herzinsuffizienz“ gilt seit dem 19.5.2012 und ersetzt die Leitlinie von 2008. Sie ist herausgegeben von der Europaischen Gesellschaft fur Kardiologie und ubernommen von der Deutschen Gesellschaft fur Kardiologie. Zusatzlich berucksichtigt wurden 19 randomisierte kontrollierte Studien zur Herzinsuffizienz. Durch die Aktualisierung ergeben sich einige entscheidende Anderungen fur die Therapie.