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We have great pleasure in introducing the latest issue of Cardiac Failure Review. We have been impressed with the extra information that has flooded in concerning the new classification of heart failure (including for the first time heart failure with mid-range ejection fraction [HFmrEF]) popularised by the influential 2016 European Society of Cardiology and Heart Failure Association Guidelines.1 What we were aiming for by introducing this new classification was twofold: a clearer separation between HFrEF, where many treatments had been proven to be effective and heart failure with preserved ejection fraction (HFpEF) where none had, and the encouragement for further analyses and trials in this new group with left ventricular ejection fraction (LVEF) in the range of 40–49 %. The second aim will take some time to complete in terms of new trials, as these take many years to design and complete. The first part of this, however, has come through brilliantly, with new analyses of both the CHARM programme of Candesartan cilexetil2 and the beta-blocker trialists' meta-analysis group.3 In both cases, we can clearly say now that there is prospective evidence that mortality and morbidity outcomes are improved by these two treatment classes also in HFmrEF, and we can also say the absence of benefit in HFpEF still remains. Nadar and Tariq in this issue elegantly review the aetiology and pathophysiology of HFmrEF, its clinical profile, the most appropriate diagnosis and the prognosis for these patients. Yuri Lopatin also reviews the therapies available for HFmrEF, noting that doctors are already treating HFmrEF, with multiple registries showing that the rate of prescription of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists and beta-blockers is quite high in patients with HFmrEF, probably because of analyses showing that HFmrEF patients, in contrast to patients with HFpEF, had a benefit in prognosis similar to those with HFrEF when guideline-recommended therapies were tested. In addition to the two examples we quote above, Lopatin also reviews evidence from a post-hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) that revealed a reduction in the primary endpoint (a composite of death from cardiovascular causes, aborted cardiac arrest or HF hospitalisation) in HFpEF patients on the lower end of the ejection fraction spectrum – LVEF 45–49 %, but not when LVEF was >60 % (LVEF <50 %: HR=0.72; LVEF ≥60 %: HR=0.97, p=0.046). This will not be the end of this particular story, because clinicians are already asking whether we should consider patients with stable LVEF in the 40–49 % range differently to those with recovered ejection fraction, where it has increased from levels <40 % after the introduction of effective therapies for HFrEF. As always, more trials and more analyses are needed to answer this important question.

Later in the issue, Yalta and colleagues review the very contemporary issue of the implication of different clinical patterns of left ventricular dysfunction in the setting of Takotsubo cardiomyopathy. They raise the worrying suggestion that, despite apparent recovery in left ventricular function after a bout of Takotsubo, microscopic changes at the cellular level may cause long-term damage to myocardial function, including persistent diastolic dysfunction and subclinical left ventricular systolic dysfunction. The implications of this phenomenon on subsequent symptomatology and prognosis, particularly exercise- or stress-induced complications among Takotsubo cardiomyopathy survivors, is deserving of further study.

Gallagher and colleagues review the emerging crisis of heart failure in sub-Saharan Africa. The co-existence of multiple trends is impacting on this region. Its growing population, the ageing of its population and the rapidly increasing prevalence of atherosclerotic risk factors are making heart failure much more common, adding ischaemic and age-related heart failure to the hitherto more common aetiologies in Africa, such as rheumatic heart disease and endomyocardial fibrosis. This combined with a relative deficiency in access to care and diagnostic techniques, such as echocardiography, which when combined with a patchy availability of guideline-recommended treatments, means that there is much avoidable mortality and morbidity due to heart failure in this region. They highlight the potential future role of more widespread biomarkers to facilitate access decisions to sub-optimally available resources, such as clinical echocardiography, for these patient populations.

Vitale et al. review which pharmacological interventions we have available to improve the otherwise very limited exercise capacity of some heart failure subjects. This list is not synonymous with treatments that improve prognosis. They conclude, somewhat counterintuitively, if you consider what most doctors consider effective heart failure medication, that the only heart failure drugs recommended in the 2016 European Society of Cardiology heart failure guidelines that have been convincingly shown to increase exercise capacity for heart failure sufferers are ivabradine, trimetazidine and intravenous iron. They then summarise their beneficial effects on HF symptoms, physical performance and quality of life. Intravenous iron is further reviewed in detail by Mordi et al., who conclude that iron deficiency (even without anaemia) is much more common in patients with heart failure than we suspected, and may well be under-diagnosed in routine clinical practice. They summarise the clinical trials of intravenous iron replacement that have shown benefits in exercise capacity and symptoms, and recommend that intravenous iron should be considered in symptomatic heart failure patients with documented iron deficiency (and furthermore, as the guidelines state, that we should investigate heart failure patients for the presence of such iron deficiency). They also highlight that ongoing trials will provide further evidence as to the long-term effects on mortality and hospitalisation of this type of therapy. One word of warning, however; the majority of published studies performed have evaluated ferric carboxymaltose and other forms of intravenous iron and, in particular, oral iron therapy, which might not show the same benefits and therefore cannot be recommended. Whether other intravenous iron preparations provide any benefit, as well as the optimal dose and duration, remains yet to be confirmed, as does whether the benefits will also extend in to HFpEF and HFmrEF populations with iron deficiency.

Other extremely hot topics are reviewed, including the potential for catheter ablation therapy of AF in heart failure after the ground-breaking Catheter Ablation versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and AF (CASTLE-AF) trial,4 and the contemporary role of the therapy of central sleep apnoea (CSA) in heart failure, as reviewed by Abraham et al. Liang and Callans review the increasing dual burdens of AF and heart failure in our ageing population and how the two conditions interact to worsen patient outcomes. They remind us that modern heart failure guidelines recommend the use of the CHA2DS2-VASc and HAS-BLED risk scores is decision-making around oral anticoagulation, which is usually recommended for stroke prophylaxis in this setting. Beta-blockers have long been considered the cornerstone of heart failure therapy in patients with HFrEF, yet the beneficial effect of these medications in patients with HFrEF appears to be mitigated by the co-existence of AF. Large meta-analyses have shown that beta-blockers significantly reduce both all-cause mortality and cardiovascular hospitalisations in patients in sinus rhythm, but not AF, despite similar degrees of ventricular rate reduction in both groups. They review ablation studies in heart failure with AF, noting that, to date, the optimal strategy for rhythm control has remained uncertain. A large number of retrospective observational studies and a few randomised controlled trials had suggested catheter ablation may help clinical outcomes in this setting. The CASTLE-AF study is the most recent randomised controlled trial in this setting. The primary endpoint (the composite of all-cause mortality and unplanned hospitalisation for worsening heart failure) was reduced by 38 % (p=0.007) compared to controls, and all-cause mortality was also reduced (13.4 versus 25 %; HR 0.53, 95 % CI [0.32–0.86], p=0.011). They conclude that although more trials are needed, AF ablation should be considered as an adjunctive treatment strategy for patients with HFrEF and AF. Abraham and colleagues review the treatment of CSA in HFrEF patients following the adverse findings in the SERVE-HF trial.5 They conclude that CSA is an important adverse prognostic factor for HFrEF patients, and that quality of life can be improved with treatment with the novel strategy of an implantable phrenic nerve stimulator. Although improving quality of life in heart failure patients is extremely valuable in its own right, we continue to wait for data demonstrating that the improvements in sleep apnoea events, oxygenation and arousals produced by such a device would lead to improvements in cardiovascular outcomes in the HFrEF population.

Arrigo and colleagues introduce us to the management of a complex part of the heart failure clinical story, that of acute heart failure. After reviewing the clinical features of acute heart failure, they review our management options during the hospital stay and in the crucial early post-discharge period. They review essential early interventions, taking into account clinical presentation, pathophysiological features and any precipitating factors. They stress the important part that comorbidities play in this setting. They recommend individually personalised therapy after a '7-P evaluation': phenotype, pathophysiology, precipitants, pathology, polymorbidity, potential harms and preferences.

Readers are recommended then to consider more specialised topics, such as the article by Naqvi et al. on ambulatory intra aortic balloon pump in advanced heart failure, and that by Koenig and colleagues on the potential for bromocriptine in the treatment of peripartum cardiomyopathy. Lastly, the article by Kerley is helpful for all those doctors, who like us are asked about natural and dietary therapies and their effect in heart failure, in his masterly summary of plant-based diets in the prevention and treatment of heart failure. We hope you enjoy reading our latest issue of Cardiac Failure Review as much as we did in compiling it from the excellent work of our contributors.


  1. Ponikowski P, Voors AA, Anker SD, et al. 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. Eur Heart J 2016;37:2129–200.
    Crossref | PubMed
  2. Lund LH, Claggett B, Liu J, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail 2018; epub ahead of press
    Crossref | PubMed
  3. Cleland JGF, Bunting KV, Flather MD, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018;39:26–35.
    Crossref | PubMed
  4. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–27.
  5. Cowie MR, Hoehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. New Engl J Med 2015;373:1095–105.
    Crossref | PubMed