European Heart Journal (2018) 39, 1–4 ISSUE @ A GLANCE

doi:10.1093/eurheartj/ehx750

Heart failure subgroups: HFrEF,

HFmrEF, and HFpEF with or without
mitral regurgitation

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Thomas F. Lüscher, MD, FESC
Editorial Office, Zurich Heart House, 8032 Zurich, Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Switzerland and Royal Brompton and Harefield
Hospital Trust and Imperial College, London, SW3 6NP, UK

..
Heart failure has recently undergone major changes: while heart fail- .. findings suggesting that HFrEF and HFmrEF are just the same disease
ure with reduced ejection fraction or HFrEF is declining due to effect- .. with different severities, are put into context in an Editorial by
..
ive revascularization of patients with acute coronary syndromes,1–3 .. Douglas Mann from the Washington University School of Medicine
the prevalence and incidence of heart failure with preserved ejection .. in Saint Louis, Missouri, USA.10
..
fraction or HFpEF, mainly characterized by diastolic dysfunction,4,5 is .. Significant efforts are currently being undertaken to better quan-
increasing due to ageing Western societies.6 In between there is a .. tify11,12 and eventually reduce functional mitral regurgitation in pa-
..
gap, and this has recently been filled in the most recent ESC .. tients with chronic heart failure in the hope of improving
Guidelines on Acute and Chronic Heart Failure7 with the introduc- .. prognosis.13–15 In their manuscript entitled ‘Refining the prognos-
..
tion of a novel category, i.e. HFmrEF or heart failure with mid-range .. tic impact of functional mitral regurgitation in chronic
ejection fraction. The future will tell if this category can survive the
.. heart failure’, Georg Goliasch and colleagues from the Medical
..
test of time. Of note, the reproducibility and precision of echocardi- .. University of Vienna in Austria assessed the impact of functional mi-
ography, the most frequently used imaging modality in these patients,
.. tral regurgitation in HFrEF under optimal medical therapy.16 They
..
is not good enough to categorize such patients reliably. Furthermore, .. prospectively included 576 HFrEF patients in their observational
a subanalysis of the TOPCAT trial suggests that HFmrEF and HFrEF
.. study with a median follow-up of 62 months. Severe functional mitral
..
might be comparable at least in their responsiveness to heart failure .. regurgitation was a significant predictor of mortality with an adjusted
drugs such as spironolactone.8 In a Fast Track paper entitled ‘Beta-
.. hazard ratio of 1.38 independent of clinical and echocardiogrphic
..
blockers for heart failure with reduced, mid-range, and pre- .. confounders. Severe functional mitral regurgitation was associated
..
served ejection fraction: an individual patient-level analysis .. with poor outcome in an intermediate-failure phenotype of heart fail-
of double-blind randomized trials’, Dipak Kotecha and col- .. ure with reduced ejection fraction, i.e. those with NYHA class II,
..
leagues from the University of Birmingham College of Medical and .. moderately reduced left ventricular function, and within the second
Dental Sciences in Birmingham, UK address this issue with an add- .. quartile of NT-proBNP. Thus, in a patient cohort under optimal med-
..
itional heart failure drug in 11 double-blind, randomized, placebo- .. ical therapy, the adverse prognostic impact of functional mitral regur-
controlled trials employing an intention-to-treat analysis.9 In patients .. gitation is predominant in those with intermediate heart failure.
..
in sinus rhythm, beta-blockers reduced all-cause and cardiovascular .. Maladaptions of the peripheral circulation are importantly involved
mortality compared with placebo, an effect that was consistent .. in the pathophysiology of ageing,17 hypertension,18 atherosclerosis,
..
across left ventricular ejection fraction strata, except for those in the .. and heart failure.19 Retinal vessel analysis represents a non-invasive
small subgroup with left ventricular ejection fraction >_50% (Figure 1). .. and reliable method to study the microcirculation and endothelial
..
Left ventricular ejection fraction increased with beta-blockers in all .. function in the eye.20 In a further article entitled ‘Retinal micro-
groups in sinus rhythm except in those with a value of >_ 50%. In pa- .. vascular dysfunction in heart failure’, Andreas Flammer and col-
..
tients with atrial fibrillation, beta-blockers increased left ventricular .. leagues from the University Hospital Zurich in Switzerland assessed
ejection fraction when <50% at baseline, but did not improve prog- .. the extent of retinal microvascular dysfunction in patients with
..
nosis. Thus, beta-blockers improve left ventricular ejection fraction .. chronic heart failure.21 In 74 patients with compensated chronic
and prognosis for patients with heart failure in sinus rhythm with a
.. heart failure with HFrEF, flicker-induced dilatation of retinal arterioles
..
reduced left ventricular ejection fraction. The data are most robust in .. was assessed. Flicker-induced dilatation was significantly reduced in
HFrEF, but similar benefit was observed in HFmrHF. These relevant
.. patients with HFrEF compared with those with risk factors of healthy
.
With thanks to Amelia Meier-Batschelet for help with compilation of this article.
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author(s) 2018. For permissions, please email: [email protected].
2 Issue @ a Glance

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B

Figure 1 Beta-blockers vs. placebo in sinus rhythm according to heart failure phenotype. Kaplan–Meier plots for unadjusted (A) all-cause mortality
and (B) cardiovascular mortality according to baseline left ventricular ejection fraction (LVEF). * Similar results in post-hoc analysis when excluding pa-
tients with an LVEF reported as exactly 40% from the 40–49% group: (A) log-rank P = 0.030 and (B) log-rank P = 0.039; n = 147 placebo, and n = 143
beta-blockers (from Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen
DJ, von Lueder TG, Böhm M, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H, Hjalmarson é,Wikstrand J, Kotecha D; on behalf of
the 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. See pages 26–35).

controls. Similar differences were seen for venular flicker-induced .. Isopretorenol up-regulated inflammasome-dependent activation of
..
dilatation. Of interest, flicker-induced dilatation was less impaired in .. interleukin-18, but not that of interleukin-1b, and promoted early
patients with dilated compared with ischaemic cardiomyopathy.
.. macrophage infiltration. In patients with chest pain, a positive correl-
..
Impaired flicker-induced dilatation was associated with echocardio- .. ation was observed between the serum levels of norepinephrine and
graphically estimated systolic pulmonary artery pressure and left
.. interleukin-18. Genetic deletion of interleukin-18 or the upstream
..
atrial volume index. Thus, flicker-induced dilatation of retinal micro- .. inflammasome NLRP3 significantly attenuated isoproteronol-induced
vascular vessels is impaired in chronic heart failure, which may pro-
.. chemokine expression and macrophage infiltration, as did interleu-
..
vide a new method to monitor microvascular abnormalities in heart .. kin-18-neutralizing antibodies. Moreover, blocking interleukin-18
failure. These findings are commented on in a timely Editorial by
.. early treatment markedly attenuated cardiac inflammation and fibro-
..
Giuseppe Mancia from the Milano-Bicocca University in Italy.22 .. sis in response to isoproteronol. The authors therefore conclude
..
Rapid overactivation of the sympathetic nervous system23 and the .. that b-adrenergic receptor activation activates inflammasome-de-
b-adrenergic receptor in particular upon stress leads to cardiac in- .. pendent and interleukin-18, triggering a cytokine cascade, macro-
..
flammation, a prevailing factor that underlies cardiac injury in infarc- .. phage infiltration, and pathological cardiac remodelling, while specific
tion, heart failure, and peripartum cardiomyopathy.24 However, .. blockade of this pathway successfully prevents inflammatory re-
..
mechanisms by which acute b-adrenergic receptor stimulation in- .. sponses and cardiac injuries (Figure 2). The translational value of these
duce cardiac inflammation remain unknown. In a Basic Science article .. experimental findings is further discussed in a comprehensive
..
entitled ‘Interleukin-18 cleavage triggers cardiac inflamma- .. Editorial authored by Tanja Zeller from the University Heart
tion and fibrosis upon b-adrenergic insult’, Youyi Zhang and .. Center Hamburg in Germany.26
..
colleagues from the Peking University Third Hospital in Beijing, China .. Patients with acute heart failure often require intensive care includ-
investigated the role of the inflammasome and of interleukin-18 in .. ing ventilation due to respiratory failure. Non-invasive ventilation, i.e.
..
cardiac inflammatory cascades upon b-adrenergic receptor insult in .. the application of positive intrathoracic pressure through an inter-
C57BL/6 mice injected with a single dose of isoproterenol or saline.25 .. face, might be a novel, less invasive approach in the management of
Issue @ a Glance 3

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Figure 2 Working model for the b-adrenergic activation-induced cardiac inflammatory cascade which finally results in cardiac remodelling (left)
and therapeutic strategy (right) (from Xiao H, Li H, Wang J-J, Zhang J-S, Shen J, An X-B, Zhang C-C, Wu J-M, Song Y, Wang X-Y, Yu H-Y, Deng X-N,
Li Z-J, Xu M, Lu Z-Z, Du J, Gao W, Zhang A-H, Feng Y, Zhang Y-Y. IL-18 cleavage triggers cardiac inflammation and fibrosis upon b-adrenergic insult.
See pages 60–69).

such patients, an issue that is addressed in a Review entitled .. References

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