Heart Failure with Mid-Range Ejection Fraction: A Transition Phenotype?

This article refers to ‘A comprehensive population-based characterization of heart failure with mid-range ejection fraction’ by A.S. Koh et al., published in this issue on pages 1624–1634. ‘Eppur si muove!’ Galileo Galilei (1564–1642). Heart failure (HF) is traditionally categorized according to left ventricular systolic function based on left ventricular ejection fraction (LVEF). The diagnosis of HF encompasses a wide range of patients—from those with normal LVEF [≥50%; HF with preserved LVEF (HFpEF)] to those with reduced LVEF [<40%; HF with reduced LVEF (HFrEF)]. Compared to HFrEF patients, HFpEF patients tend to be older, female, and more often have a history of hypertension, obesity, diabetes, metabolic syndrome, atrial fibrillation, anaemia, or chronic kidney disease. On the other hand, patients with HFrEF tend to be younger and are more often afflicted with coronary artery disease (CAD).1 In 2014, Lam and Solomon coined the term ‘heart failure with mid-range ejection fraction’ (HFmrEF) to describe patients with HF having an LVEF of between 40–49%, who were traditionally neglected by investigators and clinical trials.2 Indeed, for many years, this was referred to as the grey zone. Although different guidelines recommended different cut-off points, patients with LVEF in this range were often excluded. The 2016 European Society of Cardiology (ESC) guidelines on HF picked up the term HFmrEF, officially introducing this new HF phenotype.1 These guidelines include a table that clearly defines the range for HFmrEF, and the criteria for establishing its diagnosis. In the official guideline presentation in Florence in 2016, Adriaan Voors expanded on the reasons for including this new phenotype, and implored investigators to perform more research on this entity to better elucidate its clinical characteristics, outcomes, and pathophysiology. From a quick search in PubMed, it seems this suggestion was acted upon. Only one entry from 2014 uses the term ‘heart failure with mid-range ejection fraction’ (the Lam–Solomon editorial). In 2015, there were four such entries. In 2016, after presentation of the new guidelines, the number rose to 17, and from January to June in 2017, 28 such papers have already been published. The reported data regarding HFmrEF are mainly derived from observational single-centre or multicentre studies, sub-analyses of clinical trials, and large registries such as the ESC HF Long-Term Registry.3-5 In the present issue of the Journal, Koh and colleagues report data from the SwedeHF registry, a real-world contemporary and well-characterized nationwide registry-based cohort of patients with HF founded in 2000.6 The authors analysed data from 42 061 patients, of whom 56% had HFrEF, 21% HFmrEF, and 23% HFpEF. They report HFmrEF clinical characteristics that are broadly consistent with prior reports. HFmrEF resembled HFrEF in terms of six characteristics, resembled HFpEF with regard to seven characteristics, and showed no pattern for 10 characteristics. Collectively, the investigators found that HFmrEF was an intermediate phenotype between HFrEF and HFpEF, in which the presence of CAD shifted the disease to appear more like HFrEF. CAD was as common in HFmrEF as in HFrEF (more common than in HFpEF), all-cause mortality in HFmrEF was similar to that in HFpEF (lower than in HFrEF), and CAD portended a greater risk of death in HFmrEF than in HFpEF. It is possible that establishment of the Stent for Life initiative by the ESC has sufficiently improved the door-to-balloon time in acute coronary syndromes to reduce the myocardial tissue at risk, consequently increasing the prevalence of HFmrEF vs. HFrEF. In terms of treatment, the Authors report high use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and β-blockers across all three HF groups, despite the current lack of evidence-based guidelines for treatment of HFmrEF or HFpEF. The available studies provide a good static picture of HFmrEF, but do not elucidate temporal trends. Analysis of the dynamic nature of HFmrEF may reveal subsets of patients, including patients with HFrEF who recover LVEF (for example, in recovery after myocarditis or stress-induced cardiomyopathy/takotsubo syndrome), well-treated patients with CAD showing limited LVEF loss, or HFpEF patients showing a progressive decline in LVEF (Figure 1). Further complicating the subject when using static LVEF as reference—LVEF is dependent on heart rate, and patients with atrial fibrillation and rapid ventricular response may present with a falsely low LVEF. Moreover, in patients with left bundle branch block or ventricular pacing due to pacemaker implantation, interventricular and intraventricular dyssynchrony confounds accurate estimation of LVEF. To date, the majority of data regarding HFmrEF is based on single time-point LVEF measurements. Nevertheless, HF includes multiple diverging patient-oriented time trajectories, resulting in a wide spectrum of different phenotypes. Following any form of cardiac dysfunction, each patient will follow an individual trajectory within a large spectrum of LVEF, depending on the number of disease modifiers. This raises the question of whether patients with HFmrEF are truly a distinct pathophysiologic entity or rather represent a transitional phenotype between HFrEF and HFpEF. In many instances, HFmrEF may be a transition phenotype of patients with HFrEF who are recovering,7 or of patients with HFpEF who are declining. Indeed, in a cohort of patients with HF from Olmsted County, Minnesota, the change in LVEF over time was quantified, demonstrating that LVEF decreased by ∼6% over 5 years in the HFpEF group, and increased by ∼7% over 5 years in the HFrEF group.8 In our series, HFrEF recovery occurred in up to 25% of patients,7 while HFpEF decline was much less frequent (6.5% of patients—unpublished data). Lam and Solomon boldly proposed a new HF phenotype—HFmrEF—encouraging further study of this patient group. Here we wish to expand on this classification, and introduce two additional transition phenotypes: HFrEF-recovered and HFpEF-declined (Figure 1). Patients in the HFrEF-recovered and HFpEF-declined categories may exhibit the same LVEF, but they likely differ in pathophysiology and clinical outcomes, and probably should be treated differently. Similar to HFmrEF, these two transition phenotypes have been quite neglected, partly due to the increased complexity of acquiring repeated LVEF measures. An ideal HF classification system would group together patients with common pathophysiologies who may respond similarly to clinical management and targeted therapy. Forthcoming studies including repeated measurements of all-corner HF patients are expected to evaluate the pattern of transition among LVEF categories, the clinical determinants and prognostic significance of such changes, the efficacy and safety of advanced individualized HF therapies in each HF phenotype, and confirmation of HFmrEF as a stable phenotype or just a snapshot on the way towards recovering or declining left ventricular systolic function. Conflict of interest: none declared.