The Continuous Heart Failure Spectrum: Moving Beyond an Ejection Fraction Classification

Filippos Triposkiadis; Javed Butler; Francois M. Abboud; Paul W. Armstrong; Stamatis Adamopoulos; John J. Atherton; Johannes Backs; Johann Bauersachs; Daniel Burkhoff; Robert O. Bonow; Vijay K. Chopra; Rudolf A. de Boer; Leon deWindt; Nazha Hamdani; Gerd Hasenfuss; Stephane Heymans; Jean-Sébastien Hulot; Marvin Konstam; Richard T. Lee; Wolfgang A. Linke; Ida G. Lunde; Alexander R. Lyon; Christoph Maack; Douglas L. Mann; Alexandre Mebazaa; Robert J. Mentz; Petros Nihoyannopoulos; Zoltan Papp; John Parissis; Thierry Pedrazzini; Giuseppe Rosano; Jean Rouleau; Petar M. Seferovic; Ajay M. Shah; Randall C. Starling; Carlo G. Tocchetti; Jean-Noel Trochu; Thomas Thum; Faiez Zannad; Dirk L. Brutsaert; Vincent F. Segers; Gilles W. De Keulenaer

Disclosures

Eur Heart J. 2019;40(25):2155-2163. 

In This Article

Abstract and Introduction

Abstract

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

Introduction

Heart failure (HF) is a progressive, multi-factorial, and heterogeneous syndrome, in which important therapeutic progress has been made based on clinical trials.[1] These trials were initially designed predominantly on logistics more than on pathophysiological considerations, aiming to increase the statistical power and to limit trial costs, by enrolling patients with poor prognosis based on low left ventricular (LV) ejection fraction (LVEF).[2] These practical enrolment criteria, however, had a profound impact on how we perceive the complex syndrome of HF. Clinical diagnosis, management and even basic physiological research has been inseparably linked to LVEF, which has become the foundational biomarker to classify HF. Connotations like 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently even 'HFmrEF' (HF with mid-range LVEF), have now emerged as distinct 'disease' entities, and have been studied as if unrelated syndromes, separated by arbitrary LVEF cut-offs.[3]

In this article, we challenge the epidemiological, clinical, mechanistic, pathophysiological, and therapeutic basis for classifying HF solely according to LVEF. Left ventricular ejection fraction-based taxonomy of HF and its implications have been criticized.[4–6] Here, we advocate the consideration of HF as a syndrome across a spectrum of phenotypes, in which each patient follows a unique trajectory based on the initial trigger(s), the genetic, clinical, and sociodemographic background, and available treatment. As HF progresses, the heart remodels causing functional and structural 'biomarkers' to evolve in unique patterns with levels differing among patients without specifying HF subpopulations. This creates a spectrum of overlapping HF phenotypes necessitating the design of clinical studies based on deeper pathophysiological reasoning.

In this manuscript, we present a consensus opinion authored by 42 scientists studying HF in diverse ways, both clinically and fundamentally. These scientists interacted with each other on several occasions and shared concerns about current HF taxonomy. A few authors took the initiative to summarize arguments, which resulted in a consensus document after several months of intense interactions and input by all authors.

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