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It is with great pleasure that we introduce to you, our readers, Volume 4.2 of Cardiac Failure Review. Heart failure with mid-range ejection fraction, HFmrEF, formally introduced into the definition of heart failure phenotypes by the 2016 ESC Heart Failure Guidelines,1 has been the subject of intense investigation and analysis since its launch as a concept. One of these outcomes has been the re-analysis of existing clinical trial databases to establish what treatments can be said to be effective also in HFmrEF in addition to HFrEF. Although what we would like are prospective randomized controlled trials specifically designed to test the hypothesis that a particular treatment would beneficially effect HFmrEF, such trials are unlikely to occur soon, if at all. Until then, the best we can get is detailed analysis of individual patient data, including all outcome trials that included HFmrEF patients without bias. In this issue, Lars Lund of Stockholm explores evidence from the CHARM programme of the effectiveness of Candesartan Cilexetil in the therapy of HFmrEF. In a recently published analysis,2 Lund and colleagues showed the effect of Candesartan when used to treat HFmrEF. He summarised data from observational studies and registries suggesting the prevalence of HFmrEF out of all heart failure (HF) subtypes varied between 10 and 24%. This HFmrEF cohort similarly comprised 17% of the CHARM programme, showing it was within the range of what is seen in the community. In CHARM, despite lower mortality rates in HFmrEF compared to HFrEF, the primary outcome for candesartan versus placebo was similar with a hazard ratio (95% confidence interval) of 0.82 (0.75–0.91, p<0.001) in HFrEF compared to 0.76 (0.61–0.96), p=0.02) in HFmrEF, which was distinctly different to what was seen in HFpEF (0.95 [0.79–1.14] p=0.57). Similar results were seen for recurrent HF hospitalization, with incidence rate ratios of 0.68 (0.58–0.80, p<0.001) for HFrEF and 0.48 (0.33–0.70, p<0.001) for HFmrEF, compared to 0.78 (0.59–1.03, p=0.08) for HFpEF. Taken together with similar analyses for beta-blockers3 and a subgroup report of the effect of spironolactone in TOPCAT,4 this is beginning to suggest that HFmrEF should be treated the same as HFrEF, albeit noting that the evidence for spironolactone is considerably weaker than the other two, because it is a sub-analysis of a single trial, and one that itself was not statistically significant for benefit as designed.

We have an article from the Cleveland Clinic that reviews modern advances in imaging in heart failure. The authors stress developments they see emerging in modern imaging in HF. They predict an expansion of the use of echocardiography in assessing two aspects of importance in modern HF management: diastolic function and exercise-induced changes in ventricular function. They also update us on the usefulness of multi-detector computed tomography and cardiovascular magnetic resonance. They offer a review of what they coin “molecular imaging”, in which radionuclide imaging, using either positron emission tomography (PET) or single-photon emission computed tomography, can be used for characterization of tissue function in myocardial disorders, including 123I-labeled MIBG, as a marker of adrenergic function to risk stratify patients for risk of ventricular arrhythmic sudden cardiac death (SCD), and the progression of HF autonomic dysfunction. Another important area is the accurate assessment of coronary flow reserve with stress myocardial perfusion PET. Lastly, they introduce the exciting future world of hybrid imaging and 3D printing. Cardiac hybrid or fusion imaging combines imaging modalities to enhance functional and structural detail, as well as helping guide interventional procedures with immediately updated images peri-procedure. Based on hybrid imaging, and with the addition of advanced polymer technologies to make realistic tissue “feel”, 3D printing may in future allow careful planning of complex procedures, and aid in teaching and objective credentialing of practical competence in procedures.

We have two articles on the emerging field of the heart–brain–nerve axis in HF. Scherbakov and Doehner review heart–brain interactions in HF, such as the effects of HF on the brain, including cardio-embolic and low perfusion pressure effects, the impairment of higher cortical and brain stem functions (cognitive impairment, sympathetic over-activation, neuro-cardiac reflexes), as well as treatment-related interactions, including drug- and device-related interactions. Peter Hanna and colleagues at the UCLA Neurocardiology Program review the field of autonomic reflex targeted therapies for HF. HF is characterized by significant and potentially mechanistically important autonomic imbalance with increased sympathetic and reduced parasympathetic drive. Despite the success of pharmacological manipulation of the disordered neurohormonal axis, neuromodulation of similar abnormalities in autonomic control of the heart have as yet been very poorly studied, despite mechanistic and pre-clinical studies suggesting significant potential benefit in pursuing these strategies. The small number of clinical trials to date have delivered inconsistent results, which the authors put down to inadequate understanding of the structural and functional organization of the cardiac nervous system. Simple things such as appreciating the importance that the site of stimulation or inhibition of a complex neural network system may have on the outcome of neuromodulation or its stimulation parameters (intensity, frequency, duration and on–off effects) and the background cardioneural pathologic substrate. They conclude that it is highly likely that the optimum neuromodulation approach may require a much more sophisticated fine-tuning, even down to individually personalised approaches as patients' disease progresses. They review many possible approaches and summarise the extent to which these can be said to have shown promise or “proof of concept”. These include vagus nerve stimulation with the aim of increasing parasympathetic tone and restoring integrated cardiac reflex function. This has had variable clinical trial success so far in the ANTHEM-HF, NECTAR-HF and INOVATE HF studies. Spinal cord stimulation (SCS), which already has FDA approval as a therapy for chronic pain syndrome and refractory angina, suppresses the release of cardiac-related afferent neurotransmitters, thereby modulating sympathetic preganglionic neural activity and reducing sympatho-excitation within the intra-thoracic extra-cardiac ganglia. It is suggested to show cardioprotective effects in animal models of myocardial ischaemia and infarction and in HF. Two clinical studies, SCS HEART and DEFEAT-HF, leave the field unproven to date. Baroreflex activation therapy also has a past history; this time as a treatment for resistant hypertension and refractory angina. Through electrical stimulation of the baroreceptor afferent fibres, central sympathetic outflow is reduced, while parasympathetic tone is augmented. Preclinical studies in HF have produced evidence of proof-of-concept in myocardial infarction-induced HF. Human clinical trials include Hope for Heart Failure (HOPE4HF) of 146 patients HFrEF patients with improved NYHA functional class, QOL and 6MWT, with a reduction in NT pro-BNP. This will be followed by the BeAT-HF trial. Renal denervation, initially evaluated for refractory hypertension, also has been shown to have potentially useful effects in animal and early human studies in HF, including the REACH-Pilot study and Symplicity HF. Stellate ganglionectomy, a form of cardiac sympathetic denervation (CSD), was also initially proposed as a treatment for angina and ventricular arrhythmias. One prospective, randomized pilot study has evaluated CSD for heart failure. None of the trials to date in this whole field, however, can be considered large enough to evaluate the potential of the field, but it is highly likely we will see more electro-therapeutic neuromodulatory approaches for disease treatment in the future, given the importance of autonomic dysfunction in the pathophysiology of HF.

Vitale and colleagues in two articles review the important topic of frailty complicating cases of HF in the older patient population and the potential of the metabolic agent trimetazidine. Frailty is a complex clinical syndrome very common in patients with HF, and is associated with dramatically impaired quality of life and prognosis. Vitale and colleagues summarise what we know and gives directions of where future potential treatments may lie. In “Metabolic modulation of cardiac metabolism in heart failure: the role of trimetazidine”, Rosano and Vitale review the metabolic changes that affect both cardiac and skeletal muscles in HF. Abnormalities of high-energy phosphate production both contribute to symptoms and via reflex effects and direct myocardial effects can exacerbate the progression of HF. They summarise metabolic therapy in HF, with a particular focus on trimetazidine. Such agents can partially correct cardiac substrate metabolism directly, and have been shown able to improve symptoms, functional capacity and prognosis in HF on top of guideline-directed medical therapy.

Last but certainly not least, there are topical expert reviews of three specialist sub-topics in HF: exercise training in HF complicated by atrial fibrillation, HF complicated by pulmonary hypertension and postpartum cardiomyopathy, with special consideration of the impact on breastfeeding. We have pleasure in recommending this, the latest issue of Cardiac Failure Review.


  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(27):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 in Heart Failure Collaborative Group. 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(1):26–35.
    Crossref | PubMed
  4. Solomon SD, Claggett B, Lewis EF, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J 2016; 37(5):455–62.
    Crossref | PubMed