Heart failure and chronic obstructive pulmonary disease. A combination not to be underestimated.

Validating the HFA-PEFF score - or how to define a disease?

Chronic obstructive pulmonary disease: a slowly progressive cardiovascular disease masked by its pulmonary effects?

Do Existing Definitions Identify Subgroup Phenotypes or Reflect the Natural History of Heart Failure With Preserved Ejection Fraction?

Rationale: Differences in clinical presentation and outcomes between heart failure (HF) phenotypes in patients with chronic obstructive pulmonary disease (COPD) have not been assessed. Objectives: The aim of this study was to compare clinical outcomes and healthcare resource use between patients with COPD and HF with preserved ejection fraction (HFpEF), mildly reduced ejection fraction (HFmEF), and reduced ejection fraction (HFrEF). Methods: Patients with COPD and HF were identified in the U.S. administrative claims database OptumLabs DataWarehouse between 2008 and 2018. All-cause and cause-specific (HF) hospitalization, acute exacerbation of COPD (AECOPD, severe and moderate combined), mortality, and healthcare resource use were compared between HF phenotypes. Results: From 5,419 patients with COPD, 70% had HFpEF, 20% had HFrEF, and 10% had HFmEF. All-cause hospitalization did not differ across groups; however, patients with COPD and HFrEF had a greater risk of HF-specific hospitalization (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.29-1.84) and mortality (HR, 1.17; 95% CI, 1.03-1.33) than patients with COPD and HFpEF. Conversely, patients with COPD and HFrEF had a lower risk of AECOPD than those with COPD and HFpEF (HR, 0.75; 95% CI, 0.66-0.87). Rates of long-term stays (in skilled-nursing facilities) and emergency room visits were lower for those with COPD and HFrEF than for those with COPD and HFpEF. Conclusions: Outcomes in patients with comorbid COPD and HFpEF are largely driven by COPD. Given the paucity in treatments for HFpEF, better differentiation between cardiac and respiratory symptoms may provide an opportunity to reduce the risk of AECOPD. Risk of death and HF hospitalization were highest among patients with COPD and HFrEF, emphasizing the importance of optimizing guideline-recommended HFrEF therapies in this group.

Early Identification of Asymptomatic Subjects at Increased Risk of Heart Failure and Cardiovascular Events: Progress and Future Directions

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

New heart failure guidelines offer a changing landscape

Asthma and chronic obstructive pulmonary disease (COPD) continue to have considerable impact on disease burden and mortality worldwide. Early diagnosis still remains a challenge, with low uptake of spirometry in many countries. Implementing best practice management for airways disease is a critical goal for health-care systems—the management now includes pharmacological and non-pharmacological approaches to the lung disease, as well as recognition and treatment of comorbidities. Finally, the pathogenesis of airways disease continues to be fertile field of investigation, in order to better prevent disease, slow progression and identify relevant biomarkers. A large number of studies published in Respirology in 2012 have addressed all of these important clinical and scientific issues, and made major contributions to advance this field and hopefully improve outcomes for patients with asthma and COPD. Despite years of research, the origins of asthma remain obscure. Although there is clearly a genetic disposition to developing asthma, gene-association studies have so far failed to reveal clear insights into the development of asthma (reviewed in Respirology in 20111), indicating that asthma is likely to result from a complex interaction between genes and environment. Moreover, marked changes in the prevalence of asthma in recent decades indicate that changing environmental exposures must be to blame. Air pollution is known to exacerbate asthma symptoms and has been one of the factors suspected of causing the disease in the first place. Gowers et al. reviewed the association between air pollution and asthma for the Department of Health in the United Kingdom.2 In fact, they found little evidence for an association between pollution and asthma prevalence. If anything, time trends indicated a negative rather than positive association, but there is some evidence for an increased incidence of asthma in people living very close to roads carrying heavy traffic. The overall impact of this traffic pollution on asthma incidence is not likely to be large. Air pollution of different kind was studied by Havstad et al. who studied the impact of early-life exposure to environmental tobacco smoke on the development of atopy by 2–3 years in a cohort of children.3 Using propensity score matching, they found that tobacco smoke exposure increased the risk of positive skin prick or specific immunoglobulin E (IgE) tests in children whose mothers were not atopic, but paradoxically decreased the risk in those with a positive history of maternal atopy. This interaction between maternal atopy and the effect of environmental tobacco smoke on children's risk for atopy may help to explain some of the conflicting data from previous studies. An accompanying editorial emphasizes that exposing children to tobacco smoke should of course be avoided because of the many other adverse effects,4 but the paper, like that of Gowers et al.,2 demonstrates the need to better understand how genes and environment interact to cause atopy. Other changes in lifestyle and exposures may also help to explain increases in asthma prevalence. The well-recognized association between asthma and obesity was reviewed in Respirology and the mechanism for the association continues to elude researchers.5 Changing dietary exposures could be part of the explanation. A novel association between soft drink consumption, tobacco smoking and airway disease was reported by Shi et al.6 In a large cross-sectional telephone survey of Australian adults, consumption of more than half a litre a day of soft drinks was associated with both asthma and COPD. The association was only apparent among smokers in whom soft drinks and smoking appeared to have additive effects. If these findings are confirmed in other studies, they suggest a lifestyle intervention to prevent airways disease. One of the problems in identifying the origins of asthma is that clinical asthma comprises a number of distinct phenotypes. It has recently been proposed that these phenotypes represent truly different diseases with different causes (also called ‘endotypes’) rather than simply being different and variable expressions of the same underlying pathology.7 Defining asthma phenotypes on the basis of the cellular profile of induced sputum has become increasingly important as studies indicate that eosinophilic airway inflammation responds better to corticosteroid treatment than neutrophilic inflammation.8 Phenotypes are increasingly used to target novel asthma treatments, such as the anti-interleukin (IL)-5 monoclonal antibody targeted to eosinophilic asthma.9 Specific treatments for non-eosinophilic asthma have not been established however. Choi et al. studied sputum inflammatory profiles in patients with refractory asthma requiring high-dose corticosteroid therapy selected from a large asthma cohort.10 Those with persistent airway obstruction had a longer duration of asthma and had predominantly neutrophilic inflammation, whereas refractory asthma without persistent airway obstruction was more likely to be eosinophilic. The authors suggest that this provides a rationale for developing new medications for individualized treatment in these patients. However, two studies in Respirology show that eosinophilic airway inflammation varies over time even in the absence of corticosteroid treatment. Hancox et al. found that the eosinophilic/non-eosinophilic classification was not stable over time in two clinical asthma treatment trails: even though the sputum phenotype was determined at a time when the patients were not taking any steroid treatment, nearly all patients with ‘non-eosinophilic asthma’ had raised sputum eosinophils at some point.11 Similarly, the study of Bacci et al. (discussed in the Airway Biology section) provided evidence that inflammatory phenotypes based on sputum cell analysis are not stable over time.12 Another report last year found that sputum phenotypes are not stable in children either.13 Hence, characterization of asthma and long-term treatment decisions should not be based on a single sputum specimen.14 Induced sputum analysis remains valuable for assessing patients with difficult asthma, but the resources required to obtain and analyse frequent sample will inhibit its widespread use. Although not yet established in the management of asthma, measuring of exhaled nitric oxide (eNO) offers a more practical way to monitor airway inflammation than monitoring of induced sputum.15 Affordable handheld electrochemical nitric oxide analysers are now available, making this a realistic possibility for many services. Kim et al. compared eNO measurements using the handheld Niox Mino (Aerocrine AB, Solna, Sweden) electrochemical analyser with a Sievers (GE Analytical Instruments, Boulder, CO, USA) chemiluminesence analyser.16 Correlation between the two machines was good (r = 0.88), but agreement in absolute values was only moderate: the Mino tended to give about 15% lower readings. The handheld machines are convenient but differences between machines need to be taken into account when interpreting eNO values. Although measuring airway inflammation is appealing, more simple clinical assessments remain the mainstay of asthma management. Ko et al. found that a single measurement of the Asthma Control Test—a score based on a simple 5-item questionnaire—correlated with asthma control assessments by physicians and predicted exacerbations and emergency health-care use over the following 6 months in a cohort of patients attending tertiary care in Hong Kong.17 The baseline Asthma Control Test score was better at predicting exacerbations than lung function, peak flow or eNO measurements. Simple management of asthma was also supported by a large randomized control trial comparing adjustment of inhaled steroid doses using eNO, clinical physician guidance and patient symptom-based adjustment using inhaled corticosteroids (ICS) each time they required β-agonist. No difference was found between the strategies, with the trends favouring patient symptom-led adjustment.9 Improvements in computed tomography (CT) scanning technology and lower radiation doses have enabled the use of high-resolution scans to study airway structure and differentiate between diseases, sites of inflammation and treatment response without the need for tissue biopsies.18 Kurashima et al. found that airway lumens were smaller in the 3rd- to 6th-generation bronchi in asthma but not COPD, whereas both diseases demonstrated airway wall thickening.19 These small airway diameters correlated with lung function in asthma not COPD. Hoshino and Ohtawa used high-resolution CT scans to assess changes in large airway remodelling before and after 24 weeks treatment with combination long-acting β-agonist (LABA) and ICS or ICS alone in a double-blind randomized controlled trial.20 Combination therapy reduced airway wall thickness and increased the airway luminal area to a greater extent than ICS alone. The improvements in airway wall thickness in the combination group correlated with reductions in sputum eosinophils and improvements in forced expiratory volume in 1 s (FEV1). The mechanisms for this positive interaction between ICS and LABA are not known, but the findings offer hope that airway remodelling can effectively treated and/or prevented by combination therapy. An accompanying editorial by King and Farah emphasizes the need for confirmatory and long-term studies as well as investigations of the effects on smaller airways that remain beyond the resolution of the scans.21 The findings of Hoshino and Ohtawa of a positive interaction between LABA and ICS on remodelling is relevant to the current concerns over the safety of LABA in asthma.20 Among the most controversial issues this year is the American Food and Drug Administration requirement that the manufacturers of LABA undertake large safety studies of the combination on LABA with ICS. It is accepted that using LABA without ICS is not acceptable in asthma, but it has been suggested that these large safety studies of combination therapy are futile because they will not be powered to address the question of whether they cause a small excess of asthma deaths.22 In the meantime, a recent meta-analysis demonstrates that withdrawing LABA once asthma control has been achieved, as currently recommended by the Food and Drug Administration, leads to a deterioration in control.23 Cough-variant asthma is another well-recognized but poorly understood phenotype. Ohkura et al. compared coughing during methacholine-induced bronchoconstriction in patients with cough-variant asthma (but normal cough sensitivity to capsaicin challenge) and normal controls.24 Patients with cough-variant asthma had increased cough during even mild methacholine-induced bronchoconstriction. After treatment with inhaled steroids, the number of coughs diminished to be similar to normal controls, indicating that increased cough sensitivity to bronchoconstriction is a feature of this disease variant, but that it responds to anti-inflammatory treatment. For non-asthmatic refractory chronic cough, an exciting discovery this year was that gabapentin is an effective treatment in a double-blind randomized controlled trial.25 Gabapentin is an anticonvulsant that is also used to treat neuropathic pain, suggesting that its effect on chronic cough may be due to suppression of central cough reflexes. The paradigm of Th1- versus Th2-mediated inflammation would suggest that asthma (predominantly a Th2 disease) would be less uncommon in sarcoidosis—regarded as a Th1 disorder. However, Wilsher et al. found that the prevalence of positive specific IgE tests for common aeroallergens (34%) and a history of asthma (21.5%) were similar in patients with sarcoidosis to that reported in the general population.26 In another study from the same group, Young et al. found that 44% of patients with sarcoidosis had airway hyperresponsiveness to histamine (a direct airway challenge), whereas only 11% were hyperresponsive to an indirect challenge using hypertonic saline.27 Hyperresponsiveness to histamine was more common in those with lower baseline FEV1 values and those with fibrotic and reticular patterns on lung CT. The findings suggest that the high prevalence of histamine responsiveness in patients with sarcoidosis is likely to be distinct from asthma (because of the low prevalence of hypertonic saline responsiveness) and is more likely to be due to airway remodelling caused by granulomatous airway inflammation. The development of COPD is related to both genetic and environmental factors. For genetic factors, a recent study by Guan et al. from China found that D2S388-5 microsatellite polymorphism located upstream of the surface lung surfactant protein B gene on chromosome 2 may be associated with susceptibility to COPD in Xinjiang Kazakhs.28 Another genetic factor, nucleotide-binding and oligomerization domain (NOD) 2 genes polymorphism, has also been found to have some potential association with COPD in a study from Japan. The distribution of NOD2 rs1077861 genotypes differed between COPD patients and non-COPD smokers and was associated with a lower FEV1 % predicted value in the TT when compared with the TA/AA genotypes.29 For environmental factors, exposure to noxious particles or gases is associated with the development of COPD.30 A study from Johannessen et al. found that exposure to environmental tobacco smoking during childhood was associated with COPD and respiratory symptoms in adulthood mainly in women in a cross-sectional study in Norway. In men, the most important risk factor is still acting smoking.31 The relationship of air pollution and COPD is reviewed by Ko and Hui.32 Outdoor air pollution (such as ambient air pollution) and indoor pollution (such as second-hand smoking and biomass fuel combustion exposure) are associated with the development of COPD and outdoor air pollution is a significant environmental trigger for acute exacerbation of COPD. Zeng et al. reviewed the aetiology of COPD in non-smoking subjects and risk factors may include genetic factors, long-standing asthma, outdoor air pollution, environmental smoke exposure, biomass smoke, occupational exposure, diet, recurrent respiratory infection in early childhood and tuberculosis.33 Interestingly, statins34 and even soft drink consumption6 have been found to have association with COPD. A cross-sectional study from Japan found that the prevalence of airflow limitation among patients who used statins was approximately five times lower than that among patients who did not use statins. However, statin use was not significantly associated with a lower prevalence of airflow limitation in multivariate analysis.34 Statins thus cannot be advocated for prevention of airflow obstruction at this stage. A study from South Australia assessed the relationship between soft drink consumption and presence of asthma/COPD in over 16 000 subjects.6 and noted the odds ratio for having COPD was 1.79 (95% confidence interval: 1.32–2.43) in multivariate analysis by comparing those who consumed more than half a litre of soft drink per day with those who did not consume soft drinks. The reason behind these associations is unclear and a causative relationship cannot be drawn from these studies. Comorbidities are common in COPD patients and the latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline has also emphasized that comorbid illness in COPD patients should be managed appropriately.30 The link between COPD and coronary artery disease is strong and complex. Coronary artery disease has a strong effect on the severity and prognosis of COPD and vice versa, including acute exacerbations.35 Ito and colleagues found that depression and sleep disorders were both common in patients with COPD.36 McSharry et al. found that sleep quality is poor in severe COPD patients with reduced sleep efficiency and reduced percentage of rapid eye movement sleep. There was a significant association between daytime hypoxaemia and sleep efficiency.37 However, depression, but not sleep disorder, is an independent risk factor for exacerbations and hospitalizations among COPD patients.36 The economic burden of COPD is huge and a recent study from Singapore showed that in 2009, COPD admissions represented 3.4% of all hospital discharges. Hospitalization was found to be the major cost driver, accounting for 73% of the total COPD burden, Between 2005 and 2009, attendances at primary care clinics, emergency departments and specialist clinics accounted for 3%, 5% and 17% of overall COPD costs, respectively.38 There are some new developments in the assessment of COPD using tools like CT and exercise tests. Degree of hyperinflation39 and airway dimensions18, 19 in COPD patients can be measured using CT parameters. Tanabe and colleagues applied a novel CT index to assess lung volume. This DLV% index measures the ratio of lung volume region adjacent to the diaphragm dome (D) to total lung volume (LV). Using this index, it was found that a reduced lung volume around the diaphragm correlated with lung hyperinflation and health-related quality of life, independent of emphysema severity.39 A recent study by Galban et al. adapted the parametric response map, a voxel-wise image analysis technique, for assessing COPD phenotype. In their study, whole-lung CT scans acquired at inspiration and expiration of COPD patients were analysed. Parametric response map identified the extent of functional small airways disease and emphysema as well as provided CT-based evidence that supports the concept that functional small airways disease precedes emphysema with increasing COPD severity.40 Phenotyping COPD by image biomarkers is currently under investigation and offers potential development of personalized therapy for COPD patients. There are also different field and laboratory tests for measuring exercise capacity in COPD patients. Hill and colleagues compared the 6-min walk test, incremental shuttle walk test and endurance shuttle walk test with a ramp cycle ergometer test in a group of patients with moderate COPD and found that these tests all elicited a similar peak rate of oxygen uptake and heart rate response. This suggested that that both self- and externally paced field tests can progress to high intensities.41 Field tests can probably offer a reasonable alternative for the evaluation of patients with moderate COPD.42 The revised was published in were indicated as the or in the treatment of all of patients with COPD. A new of and long-acting have as the most effective for control in patients with COPD. et al. reported the of one such when compared with in patients from 6 for found that provided significant and improvements in and in COPD with that reported in other from clinical indicate that may prevent acute exacerbations of However, the underlying mechanism for this effect is et al. showed that treatment in patients with COPD the and of both and by and This a effect of the in by the of and by the airway The long-term safety of this and its in to other treatment need evaluation before it a acute exacerbation of it is difficult for physicians to differentiate COPD from heart common and comorbidities. and colleagues the of for the diagnosis of in patients with severe acute exacerbations of COPD and in 2 care found that the was more in patients with normal function sensitivity and than those in and required adjustment of the to a et al. in a trial of patients with acute COPD and from heart compared treatment with versus reported more rapid in with the combination treatment but difference in This is a to the and treatment of heart during apparent COPD and sleep disorders are common and important in severe Ito et al. in a study of COPD patients and normal that only depression but not sleep disorders is associated with the increased risk of exacerbations and The management of and depression was the of a by and colleagues in they treatment with the of clinical on this important of COPD with sputum to exacerbations and poor quality of in patients with COPD. In a et al. that inhaled treatment may improve the quality of in patients with by sputum studies are to the of this is an important goal in patients with COPD.30 It quality of and the of greater and pulmonary is an effective way to in COPD long-term monitoring and of at is to the of any exercise In this et al. found that a value was correlated with severe This may be a practical of patients can and to with are and is a intervention for patients with acute exacerbations of COPD who to to treatment. It may be as the current of care in this clinical Moreover, in patients with COPD on the of and mortality from to However, there is a need to improve the practical assessment of the response to in the acute In this et al. reviewed the of for the of during acute However, they were to positive from randomized The clinical may be that of may not be a of response to and should continue to on parameters. the disease the treatment of COPD become less effective and symptoms become more for such patients need to early to complex with about values and for care including of et in a of the the approaches to care at the of in patients with severe interaction susceptibility to airway diseases such as asthma and COPD. association studies have found associations of specific single with the development of asthma or COPD. in Respirology have also on genetic of airway A meta-analysis of studies of the polymorphism in found increased risk of asthma in or with A genetic association study of COPD patients and non-COPD in Japan single in the genes and recognition that The A of single polymorphism rs1077861 in NOD2 was associated with increased risk of COPD, and NOD2 gene in with studies such as these interaction in inflammation and in the development of airway smoking is the major cause of other causes include air pollution and occupational In the development of childhood asthma, an and respiratory are The link between respiratory and Th2 has been demonstrated in asthma in with respiratory in induced airway inflammation and by and reduced to infection may also to asthma pathogenesis and as by studies of airway in In a of asthma, the as an for to by has been as a risk factor for In the Respirology on obesity and respiratory Farah and potential mechanisms for the effects of obesity in including of from tissue and changes that lung have found increased of tissue in patients with The of asthma is by Th2 IgE and cell with of the airway In non-eosinophilic asthma in some patients. In a study of patients with non-eosinophilic asthma of patients also had sputum during over 6 This was more common when they were treated with the alone without inhaled compared with This in Respirology supports the of LABA for asthma and the potential of airway inflammatory phenotype. The airway inflammation of COPD is by and A number of studies in Respirology have on other of are a of that and function more like but also link to the of were lower in the of patients with stable COPD and decreased during acute is a recognition that A study of lung tissue showed that from COPD patients and smokers had increased protein of compared with smoke exposure in increased of and increased and exposure to the smoke could inflammatory to and other of recognition in the Other have also been in COPD. of was in small airway of COPD patients and compared with in with gene of and from that had high Hence, of in the airways could to susceptibility to in the of COPD patients and Airway remodelling is an important feature of chronic In a study in airway of was increased in patients with severe asthma, compared with mild asthma or and was induced following bronchoconstriction with or has been to be for and is a potential of airway remodelling in The pathogenesis of COPD is by a response to environmental to lung that for inflammation, These have been in a number of studies in Respirology in the of may have effects in specific protein of was measured in the lung tissue of COPD with mainly in and was increased in sputum of COPD correlated with of lung function, and correlated with sputum and In another study, and tissue of were measured in from COPD patients and non-COPD of and as well as tissue of 1 and were increased in COPD, the of COPD is by acute as disease A study of patients with an exacerbation of COPD measured inflammatory biomarkers at and before of and were at the of the correlated with exacerbation severity and were reduced by the time of but not to normal of biomarkers behind clinical and could be in monitoring COPD studies into treatment in airways disease. In an asthma study, single in the region of the gene were associated with in a association study of subjects from clinical Although the function of is as yet in of by in airway increased protein of the suggesting a for in In the Respirology on into recent developments in tissue in to the The large airways have been for tissue with and or or In development of for the small airways has been more because of the and number of of the of lung will help to advance this the hope of for lung

Cause-specific mortality adjudication in the UPLIFT® COPD trial: Findings and recommendations

Diabetes mellitus and heart failure: insights from a toxic relationship

Patients with atrial fibrillation (AF) require anticoagulation therapy when at least two clinical risk factors for stroke or thromboembolism are present, as defined in the CHA2DS2-VASc score.1 In this score the C stands for 'congestive heart failure' and nowadays the criteria to qualify for a C in clinical practice are more or less synonymous to the presence of signs/symptoms of heart failure.1 The criteria for the CHA2DS2-VASc score were, however, defined and developed at a time when heart failure was more or less restricted to patients who had left ventricular systolic dysfunction [or reduced left ventricular ejection fraction (LVEF)]. Whether these criteria also apply to patients who have heart failure with preserved ejection fraction (HFpEF), i.e. whether the C in the CHA2DS2-VASc score also 'counts' in this population, is however unknown.2 This is of interest as an increasing proportion of patients with heart failure have HFpEF, AF is more common in HFpEF and these patients have a similar increased risk for stroke or cardiovascular events.3-5 Diagnosing HFpEF has been increasingly important but remains challenging as compared to diagnosing a heart failure with a reduced ejection fraction (HFrEF). This viewpoint will focus on the history of the C in the CHA2DS2-VASc score and why it may or may not be considered to extrapolate the CHA2DS2-VASc criteria to patients with HFpEF and AF as well. In patients with AF, who have a CHA2DS2-VASc risk score of ≥2 (points) in men, and ≥3 (points) in women, anticoagulation therapy is generally recommended (class IA recommendation in the European Society of Cardiology AF management guidelines).1 The clinical characteristics from which the CHA2DS2-VASc score is derived are, however, all based on registry data.6 This is important to realize, since the definition for heart failure has evolved over recent years.3 First, the term generally used nowadays is no longer 'congestive' heart failure, but rather 'chronic' heart failure, which is related to the fact that not all patients have obvious signs of congestion and also the distinction is primarily made between acute and chronic heart failure. Second, and more importantly, since 2016 heart failure is categorized into three groups based on LVEF: reduced (<40%), mid-range (40–49%) and preserved (>50%). In the first description of the CHADS2 score, the precursor of the CHA2DS2-VASc score, the C was classified as recent (i.e. in the last 100 days in one of the studies7) congestive heart failure exacerbation (without a LVEF criterium).8 The CHA2DS2-VASc score is based on the CHADS2 score and uses the same definitions. In the first paper by Lip et al.6 proposing the CHA2DS2-VASc score, the Euro Heart Survey was used as a validation cohort, where congestive heart failure was classified as 'heart failure' or 'left ventricular ejection below 35%'. The group 'heart failure' in that study is possibly reflecting patients with symptoms of heart failure, with and without reduced ejection fraction, so it may be suggested that also HFpEF patients were included, although these data are not reported. The CHADS2 and CHA2DS2-VASc scores were not the first (and not the last) attempts for a reliable stroke prediction risk score in AF.9 The CHADS2 score was the result of previous risk scoring models, namely the Atrial Fibrillation Investigators (AFI) scheme and the Stroke Prevention and Atrial Fibrillation (SPAF) scheme.7 In the AFI risk scheme, data were collected from five other trials: (i) the Atrial Fibrillation, Aspirin, Anticoagulation Study from Copenhagen, Denmark (AFASAK), (ii) the Stroke Prevention in Atrial Fibrillation (SPAF) study, (iii) the Boston Area Anticoagulation Trial in Atrial Fibrillation (BAATAF), (iv) the Canadian Atrial Fibrillation Anticoagulation (CAFA) study, and (v) the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) study. Congestive heart failure was considered as a risk factor, but was not qualified similarly amongst the studies (see Table 1 for an overview of the studies). For example, in the AFASAK trial only patients with symptomatic moderate and severe heart failure were considered to have congestive heart failure.10 Notably, no data on LVEF were provided in any of these trials and it is uncertain what type of heart failure these patients really had (reduced, mid ranged or preserved LVEF). It appears, however, that from a historical perspective, many of these patients must have been HFrEF patients.3 In conclusion, in the original cohorts, predominantly HFrEF patients were included as HFpEF was not acknowledged at that time. Therefore, the C of congestive heart failure, appears to be primarily driven by HFrEF. For HFpEF and HFrEF the same pathophysiology processes are contributing to Virchow's pre-requisites for thrombosis: abnormal blood flow, abnormalities in the blood vessel wall, and abnormal blood constituents (Figure 1).11, 12 Constituent abnormalities are present in the form of abnormal platelets and increased levels of pro-thrombotic markers.11 While the level of many circulating biomarkers increases with severity or worsening of heart failure, as is the case for e.g. the level of plasminogen activator inhibitor and tissue plasminogen activator antigen, both markers of fibrinolysis are elevated in heart failure patients across a wide range of LVEF, and regardless of LVEF.11, 13 The risk of stroke is significantly increased in patients with any reduction in LVEF and increases with a high CHA2DS2-VASc score.14 The influence of LVEF on stroke risk appears to be substantial.13, 15 Recent data, however, suggest that the stroke risk is similarly increased in patients with reduced and preserved LVEF.16 A sub-analysis of patients (from the non-oral anticoagulation arm) participating in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) trials who also had heart failure were categorized as having preserved vs. reduced ejection fraction.16 Data from this study showed that the stroke risk was comparable between the two groups: 4.3% (in patients with HFpEF) and 4.4% (in HFrEF) per 100 person-years.16 In addition, a meta-analysis incorporating seven studies with a total of 33 773 patients with heart failure showed that for patients with HFrEF and HFpEF who also had AF the rate of stroke risk was similar at 1.6% in HFrEF and 1.3% in HFpEF (relative risk 0.85, P = 0.094).15 The most recent AF guidelines do not further differentiate the C (congestive heart failure) in the CHA2DS2-VASc score, and score the 'C' when patients have signs/symptoms of heart failure or objective evidence of reduced LVEF. Indeed, there is no mention of HFpEF with regard to stroke prevention and as a result patients with HFpEF possibly must have more symptoms to receive anticoagulation (since they do not qualify with the LVEF criterium) than those with HFrEF. In the most recent heart failure guidelines it is stated that patients with heart failure (non-specified) and in New York Heart Association (NYHA) functional class II–IV should be considered for anticoagulation, if eligible, as assessed by the CHA2DS2-VASc score. Data on efficacy and safety of anticoagulation in heart failure patients have been published in several post-hoc analyses of the landmark novel oral anticoagulant (NOAC) trials.17-19 In the heart failure substudy of the ROCKET-AF trial, heart failure was defined as a history of heart failure (non-specified) or a LVEF <40%.17 In the ARISTOTLE heart failure substudy, two groups of heart failure were defined. Patients with left ventricular systolic dysfunction (defined as LVEF <40%, or a documentation of moderate or severe left ventricular systolic dysfunction) with or without symptomatic heart failure. Or the second group which were heart failure patients who had symptomatic heart failure and LVEF >40%, normal left ventricular function, or mild left ventricular systolic dysfunction, grouped as HFpEF.18 In the RE-LY trial, heart failure was defined as the presence of NYHA class II or higher in the 6 months before screening, in patients with a history of previous admission for congestive heart failure. Information about LVEF was available in only 2889 patients with heart failure (58.9%).19 A total 43.5% of the heart failure patients had a LVEF <40%, which may suggest that 56.5% of patients in the RE-LY heart failure group had HFpEF (or that no measurement was available). In the ENGAGE AF-TIMI 48 study, heart failure was defined as current presence or history of heart failure class C or D according to the American Heart Association/American College of Cardiology definition. In this study, 49% of patients had LVEF <50%, implying that half of the heart failure patients were HFpEF (of which many were classified as severe heart failure).20 Figure 2 shows the percentages of stroke in the heart failure groups and illustrates that in the heart failure population a significant proportion of patients had HFpEF. Overall the conclusions of these post-hoc NOAC papers were that the effect of NOACs in patients with heart failure and AF is similar, both for efficacy as well as for safety outcomes as compared to AF patients without heart failure. Although one should be cautious to draw strong conclusions from the above studies in patients with HFpEF, these recommendations have in fact been made (from the historical data) for patients with HFrEF. 17-20 Given the recent increase in HFpEF and the fact that the CHA2DS2-VASc is (mainly) based on HFrEF, criteria for anticoagulation for AF and HFpEF are in reality lacking. This is remarkable, given the fact that AF is more common in patients with HFpEF. However, as long as there are no trials performed specifically in this HFpEF population and there is no pathophysiological reason why data would be different in HFpEF, we believe that given the available data, anticoagulation must be seriously considered in many patients with AF and HFpEF. Indeed, recommendations for anticoagulation in AF/HFpEF patients may possibly be similar to those for HFrEF. Conflict of interest: none declared.

Although right-sided filling pressures often mirror left-sided filling pressures in systolic heart failure, it is not known whether a similar relationship exists in heart failure with preserved ejection fraction. Eleven subjects with heart failure with preserved ejection fraction underwent right heart catheterization at rest and under loading conditions manipulated by lower body negative pressure and saline infusion. Right atrial pressure (RAP) was classified as elevated when >or=10 mm Hg and pulmonary capillary wedge pressure (PCWP) when >or=22 mm Hg. If both the RAP and the PCWP were elevated or both not elevated, they were classified as concordant; otherwise, they were classified as discordant. Correlation of RAP and PCWP was determined by a repeated measures model. Among 66 paired measurements of RAP and PCWP, 44 (67%) had a low RAP and PCWP and 8 (12%) a high RAP and PCWP, yielding a concordance rate of 79%. In a sensitivity analysis performed by varying the definition of elevated RAP (from 8 to 12 mm Hg) and PCWP (from 15 to 25 mm Hg), the mean+/-SD concordance of RAP and PCWP was 76+/-10%. The correlation coefficient of RAP and PCWP for the overall cohort was r=0.86 (P<0.0001). Right-sided filling pressures often reflect left-sided filling pressures in heart failure with preserved ejection fraction, supporting the role of estimation of jugular venous pressure to assess volume status in this condition.

Sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction: reasons for optimism.

Chronic obstructive pulmonary disease (COPD) is an important differential diagnosis in patients with heart failure (HF). The primary aims were to determine the prevalence of COPD and to test the accuracy of self-reported COPD in patients admitted with HF. Secondary aims were to study a possible relationship between right and left ventricular function and pulmonary function. Prospective substudy. Systematic screening at 11 centres. Consecutive patients (n = 532) admitted with HF requiring medical treatment with diuretics and an episode with symptoms corresponding to New York Heart Association class III-IV within a month prior to admission. Forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were measured by spirometry and ventricular function by echocardiography. The diagnosis of COPD and HF were made according to established criteria. The prevalence of COPD was 35%. Only 43% of the patients with COPD had self-reported COPD and one-third of patients with self-reported COPD did not have COPD based on spirometry. The prevalence of COPD in patients with preserved left ventricular ejection fraction (i.e. LVEF >or=45%) was significantly higher than in patients with impaired LVEF (41% vs. 31%, P = 0.03). FEV(1) and FVC were negatively correlated with right ventricular end-diastolic diameter and tricuspid annular plane systolic excursion and FVC positively correlated with systolic gradient across the tricuspid valve. Chronic obstructive pulmonary disease is frequent in patients admitted with HF and self-reported COPD only identifies a minority. The prevalence of COPD was high in both patients with systolic and nonsystolic HF.

The Yin and Yang of dyspnea in the emergency department: heart failure or COPD?