Heart failure with preserved ejection fraction: everything the clinician needs to know

Heart failure with preserved ejec�on frac�on (HFpEF) is increasingly recognized and diagnosed in clinical prac�ce, a trend driven by an ageing popula�on and a rise in contribu�ng comorbidi�es such as obesity and diabetes. Represen�ng at least half of all heart failure cases, HFpEF is recognized as a complex clinical syndrome. Its diagnosis and management are challenging due to its diverse pathophysiology, varied epidemiological paterns, and evolving diagnos�c and treatment approaches. This review synthesizes the latest insights on HFpEF, integra�ng findings from recent clinical trials, epidemiological research, and the latest guideline recommenda�ons. It delves into the defini�on, pathogenesis, epidemiology, diagnos�c criteria, and management strategies (non pharmacological and pharmacological) for HFpEF. It highlights ongoing clinical trials and future developments in the field. Specifically, this review offers prac�cal guidance tailored for primary care prac��oners, generalists, and cardiologists who do not specialize in heart failure, simplifying the complexi�es in the diagnosis and management of HFpEF. It provides prac�cal, evidence-based recommenda�ons, emphasizing the importance of addressing co morbidi�es and integra�ng the latest pharmacological treatments like sodium-glucose co transporter 2 inhibitors. Search strategy and selec�on criteria Search strategies used for heart failure with preserved ejection fraction were up to 28th September 2023. Searches were limited to retrieve material published in English. Searches were run in PubMed, Clinicaltrials.gov, and the Cochrane Library (Wiley). Search terms included randomized controlled trial, meta-analysis, systematic reviews, epidemiological studies, population studies, review article, editorial. Specific search terms include heart failure preserved ejection fraction, epidemiology, prognosis, pathogenesis, inflammation, phenotypes, contributing co-morbidities, diagnosis, HFpEF mimics, congestion management, SGLT2i, GLP-1 receptor agonist, sacubitril/valsartan, mineralocorticoid receptor agonists, tirzepatide, Ziltivekimab, self-care, rehabilitation. DEFINITION Heart failure with preserved ejec�on frac�on (HFpEF), simply put, is when a person has a diagnosis of heart failure (HF) and their le� ventricular (LV) ejec�on frac�on (EF) is ≥50%. The defini�on of HFpEF offered by the European Society of Cardiology (ESC) is more complex: “Those with symptoms and signs of HF, with evidence of structural and/or func�onal cardiac abnormali�es and/or raised natriure�c pep�des (NPs), and with an LVEF ≥50%, have HFpEF”.1 This nuanced and lengthy defini�on makes it more difficult to diagnose HFpEF than HF with reduced EF (≤40%) or mildly reduced EF (41-49%). One example of the challenge of diagnosing HFpEF is that approximately 20% of pa�ents with HFpEF (mostly those living with obesity) have normal NP levels.2 There is therefore not one simple defini�on which specifies a combina�on of imaging or NPs that gives a binary rule-in or rule out assessment of whether an individual has HFpEF. Clinical trials in HFpEF have adopted a relatively simple definition of HFpEF (see figure 1). Typically, this includes a combination of LVEF >40% (although HFpEF is technically defined as ≥50%) and elevated NT-proBNP levels (usually above 300 pg/mL in sinus rhythm and 600 pg/mL in atrial fibrillation) in combination with a structural abnormality (usually LV hypertrophy or an enlarged left atrium) on echocardiography. Many clinicians use this combination to diagnose HFpEF in clinical practice, however, guidelines use LVEF >50% as the cut-point and also recommend functional abnormality assessment with tissue Doppler imaging to define increased LV stiffness with impaired relaxation, and increased LV filling pressures.1 EPIDEMIOLOGY Because of a growing and ageing popula�on and increasing prevalence of condi�ons that contribute to the pathophysiology of HFpEF such as obesity, hypertension and diabetes, the total number of pa�ents living with HFpEF con�nues to rise.3 In developed countries, the prevalence of known HF is generally es�mated at 1-2% of the general adult popula�on, with an es�mated 50% of those having HFpEF. However, these es�mates are largely based on administra�ve claims data or electronic health records. There are no modern prospec�ve, popula�on-based studies using NPs and detailed echocardiography to assess the true prevalence of HFpEF. If such a study were to be conducted, especially with a liberal interpreta�on of the ESC’s defini�on of HFpEF, it is likely the prevalence of HFpEF would be much higher than currently cited. A meta-analysis of echocardiographic screening studies in the general popula�on reported a prevalence of ‘all type’ HF in those aged 65 years and over in developed countries of 11·8%, with over ¾ of these cases being HFpEF. This gives a calculated prevalence of all-type HF in the general popula�on of 4·2% (around 3% HFpEF); twice as high as the typical reported prevalence.4 Epidemiological data indicate that the prevalence of HFpEF rela�ve to HFrEF is increasing at a rate of 1% per year, indica�ng that HFpEF is becoming the most common type of HF.5 The three signatory epidemiological features of HFpEF are increasing prevalence with advancing age, female sex, and comorbidi�es which either contribute to the myocardial s�ffness (e.g., metabolic and inflammatory) or exacerbate the func�onal abnormality (e.g., atrial fibrilla�on, valve disease). These three factors interact, as females have greater life expectancy, and advancing age accrues comorbidi�es. There is significant international variation in the prevalence of HFpEF and its contributing factors. For example, compared to high-income countries, low-income countries have a higher prevalence of hypertension, which contributes to HFpEF populations being younger.6 Sex and socio-economic status HFpEF is more common in women, with one study showing women with HF had HFpEF in 67% of cases, compared to 42% of men with HF having HFpEF.7 This supports the no�on that sex may play a pathophysiological role in this condi�on.3 This higher prevalence of HFpEF in women than men may be partly related to obesity and diabetes. Women are more o�en obese than men, and the rela�onship between obesity and incident HFpEF seems stronger in women.4 Diabetes confers a higher risk for HF, mainly driven by HFpEF, in women (rela�ve risk 1·95, 95% CI 1·70–2·22) compared to men (rela�ve risk 1·74, 95% CI 1·55–1·95).8 Low socioeconomic status assessed by all common measures (educa�on, income, occupa�on and region) is independently associated with greater risk of incident heart failure, including HFpEF by 62%,9 possibly related to a higher prevalence of unfavourable behavioural risk factors, including physical inac�vity, poor diet, smoking, and medica�on non-adherence.10 PROGNOSIS Although HFpEF is thought to have beter survival than HFrEF based on findings from clinical trial data,11 most observa�onal studies show that this difference is ‘negligible’.1 Data from the Karolinska-Rennes (KaRen) study of pa�ents with HFpEF revealed 1, 3, 5, and 10 year mortality rates of 15%, 31%, 47%, and 74% respec�vely.12 Although the dominant cause of death is cardiovascular in both HFrEF and HFpEF, non-cardiovascular death does assume a greater propor�on of deaths in HFpEF.13 It has previously been noted that there is no difference between HFpEF and HFrEF in terms of hospitalisa�on rate, hospitalisa�on dura�on and impact on quality of life (QoL).10 More recent data from the ESC Long Term HF Registry, however, show percentages of patients hospitalised for HF in the HFrEF, HFmrEF and HFpEF groups were 14·6%, 8·7% and 9·7%, respectively and for all cause admission were 31·9%, 22% and 23·5% respectively.14 ARIC surveillance data recently indicated an increase in admissions for acute decompensated HF, primarily driven by HFpEF.15 PATHOGENESIS Originally, HFpEF was viewed as a disorder due solely to abnormali�es in LV diastolic func�on. Our understanding has evolved so that HFpEF is now understood as a systemic syndrome, perhaps