The pre-HFpEF stage: a new entity that requires proper phenotyping for better management

An ounce of prevention is worth a pound of cure. Benjamin Franklin, Pennsylvania Gazette, 4 February 1734. The diagnosis of heart failure (HF) with preserved ejection fraction remains challenging. In heart failure with preserved ejection fraction (HFpEF), left ventricular ejection fraction (LVEF) is normal and signs and symptoms of HF are often non-specific and do not allow for clear discrimination of HF from other clinical conditions. According to the 2016 European Society of Cardiology guidelines for HF diagnosis and treatment,1 improving the specificity of HFpEF diagnosis requires that the following criteria be met: the presence of symptoms and/or signs of HF, a ‘preserved’ ejection fraction (LVEF ≥50%), elevated levels of natriuretic peptides (B-type natriuretic peptide >35 pg/mL and/or N-terminal prohormone B-type natriuretic peptide (NT-proBNP) >125 pg/mL) and objective evidence of other cardiac functional and structural alterations underlying HF. These features may include relevant structural heart disease criteria (such as left ventricular mass index ≥115g/m2 for men and ≥ 95 g/m2 for women and/or left atrial enlargement >34 mL/m2) and/or diastolic dysfunction (E/E′ ≥ 13). This definition has recently been updated to account for many additional comorbidities needed to support a proper diagnosis of HFpEF syndrome.2 Even as defining HFpEF represents a daunting task, a new entity is being characterised: the ‘pre-HFpEF stage’. The pre-HFpEF stage may affect even a larger number of patients than other HF entities and requires the urgent attention of practising clinicians. A few questions relate to what is and is not the pre-HFpEF stage. First, is pre-HFpEF the same as the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) stage A,3 defined by a high risk of HF but without structural heart disease or symptoms of HF? No, it is not. Second, is pre-HFpEF the same as ACCF/AHA stage B, defined by structural heart disease without signs or symptoms of HF?3 No, it is not that either. The definition of pre-HFpEF is taking shape as presenting in an asymptomatic patient (absence of signs or symptoms of HF) with preserved LVEF, structural heart abnormalities (similar to those reported for HFpEF), and elevated biomarker surrogates of cardiac dysfunction (mainly natriuretic peptides, with cut-point values similar to those reported for HFpEF; Table 1). In contrast to ‘true HFpEF’, the key clinical component of pre-HFpEF is the absence of HF signs and symptoms. Granularity in phenotyping the pre-HFpEF stage may require evaluation of structural and molecular abnormalities assessed on an increasing gradient of risk. Pre-HFpEF may thus be recognised as a combination of AHA stages A and B plus cardiac biomarkers of risk. Pre-HFpEF and HFpEF phenotypes. HF: heart failure; HFpEF: heart failure with preserved ejection fraction; LVEF: left ventricular ejection fraction. The cardiac structural abnormalities in pre-HFpEF are to be defined, but are likely to be similar to those valid for true HFpEF. Currently natriuretic peptides; other biomarkers to be considered. Pre-HFpEF and HFpEF phenotypes. HF: heart failure; HFpEF: heart failure with preserved ejection fraction; LVEF: left ventricular ejection fraction. The cardiac structural abnormalities in pre-HFpEF are to be defined, but are likely to be similar to those valid for true HFpEF. Currently natriuretic peptides; other biomarkers to be considered. In the current issue of the European Journal of Preventive Cardiology, Gori et al. report on this incompletely characterised clinical phenotype.4 These authors explored the value of predicting new-onset HF and death by combining diastolic dysfunction (DD; E/E′ >15) and NT-proBNP values in an asymptomatic population at risk of AHA HF stages A and B (n = 623). This group was selected in northern Italy (Bergamo) from among 4047 patients aged 55–80 years and followed up in a primary care setting (DAVID-BERG study). The authors identified four risk categories by combining DD (present/absent) and NT-proBNP values (high/low), with positive DD/high NT-proBNP conveying the highest risk of incident HF and death. This latter subgroup was what we here term ‘pre-HFpEF stage’ (Table 1). The authors concluded that this stratification may aid in the early and correct identification of patients who are at increased risk of incident HF and death and thus may be suitable candidates for more stringent preventive strategies. Despite the relevance of the reported data, several limitations must be acknowledged, as the authors have done. First, the percentage of participants with obesity was rather low in this selected cohort. Second, the main cardiovascular feature in this pre-HFpEF cohort was hypertension, which was present in almost 90% of participants, with only a third having diabetes and/or dyslipidemia. Third, analyses of the echo data were not centralised, precluding the exclusion of indication bias. Despite these potential limitations, however, this cohort remains rather representative and allows for some generalisability of the findings. These data, together with results from previous reports,5 support the value of the prompt identification of subjects at the pre-HFpEF stage for better management and prognosis. The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Preventive Cardiology or of the European Society of Cardiology. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.