State of precision medicine for heart failure with preserved ejection fraction in a new therapeutic age

Abstract

Heart failure with preserved ejection fraction (HFpEF) is defined by heart failure (HF) with a left ventricular ejection fraction (LVEF) of at least 50%. HFpEF has a complex and heterogeneous pathophysiology with multiple co-morbidities contributing to its presentation. Establishing the diagnosis of HFpEF can be challenging. Two algorithms, the 'Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elderly age >60, elevated Filling pressures' (H₂FPEF) and the 'Heart Failure Association Pre-test assessment, Echocardiography and natriuretic peptide, Functional testing, Final aetiology' (HFA-PEFF), can help to determine the likelihood of HFpEF in individuals with symptoms of HF. Phenotype clusters defined largely by the total number and types of co-morbidities may delineate groups of patients with HFpEF with different management needs. It is important to recognize alternative diagnoses or HFpEF mimics such as infiltrative cardiomyopathies, coronary artery disease, lung disease, anxiety, depression, anaemia, severe obesity, and physical deconditioning, among others. Treatment with sodium-glucose co-transporter 2 inhibitors (dapagliflozin and empagliflozin) is recommended for all patients with HFpEF unless contraindicated. Future research should consider alternative approaches to guide the initial diagnosis and treatment of HFpEF, including phenotype clustering models and artificial intelligence, and consider whether LVEF is the most useful distinguishing feature for categorizing HF. Ongoing clinical trials are evaluating novel pharmacological and device-based approaches to address the pathophysiological consequences of HFpEF.

Keywords: Clinical algorithms; Diagnosis; Heart failure with preserved ejection fraction; Management; Phenotypes; Precision medicine; SGLT2i; Sodium‐glucose co‐transporter 2 inhibitors; Treatment.

Figure 1

Temporal trends in the relative prevalence of HFpEF, HFmrEF, and HFrEF among patients hospitalized for HF. Based on results from Get With the Guidelines‐Heart Failure (GWTG‐HF) Study., HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Figure 2

HFpEF diagnosis and management, summarized based on guidance in Atherton et al. 2018, and Kittleson et al. 2023, and recent clinical trial data. AF, atrial fibrillation; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor‐neprilysin inhibitor; BMI, body mass index; BNP, B‐type natriuretic peptide; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; LA, left atrial; LV, left ventricular; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PCWP, pulmonary capillary wedge pressure; SBP, systolic blood pressure; SGLT2i, sodium‐glucose co‐transporter 2 inhibitor.

Figure 3

Major trials in HFpEF. Number line indicates year of primary publication. ^aValues for follow‐up are median. ^bValues for follow‐up are mean. ^cWorsening HF was defined in DELIVER as either an unplanned hospitalization for HF or an urgent visit for HF. ^d P value for comparisons was NR in the DIG ancillary trial in HFpEF; the risk ratio was 0.99 (95% CI: 0.76–1.28). 6MWTD, 6‐min walk test distance; ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor‐neprilysin inhibitor; BMI, body mass index; CHARM‐Preserved, candesartan in HF assessment of reduction in mortality and morbidity trial; CI, confidence interval; CV, cardiovascular; DELIVER, dapagliflozin evaluation to improve the lives of patients with HFpEF trial; DIG‐HFpEF, digitalis investigation group trial ancillary study in patients with HFpEF; EMPERIAL‐Preserved, effect of empagliflozin on exercise ability and HF symptoms in patients with chronic HFpEF; EMPEROR‐Preserved, empagliflozin outcome trial in patients with chronic HFpEF; FC, functional class; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; I‐Preserve, irbesartan in HFpEF trial; KCCQ‐CSS, Kansas City Cardiomyopathy Questionnaire clinical summary score; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NR, not reported; NYHA, New York Heart Association; PARAGON‐HF, prospective comparison of ARNi with ARB global outcomes in HFpEF trial; PEP‐CHF, perindopril in elderly people with chronic HF trial; PRESERVED‐HF, dapagliflozin in preserved ejection fraction HF trial; SGLT2i, sodium‐glucose co‐transporter 2 inhibitor; STEP‐HFpEF, effect of semaglutide on function and symptoms in subjects with obesity‐related HFpEF; T2DM, type 2 diabetes mellitus; TOPCAT, treatment of preserved cardiac function HF with an aldosterone antagonist trial.

Figure 4

Demographic and clinical characteristics of patients with HF, by ejection fraction. Data are from a pooled analysis of EMPEROR‐Reduced and EMPEROR‐Preserved trial data. Up arrows indicate an increase in the characteristic with increasing LVEF; down arrows indicate a decrease in the characteristic with increasing LVEF. ^aIn the past 12 months. AF, atrial fibrillation; BMI, body mass index; eGFR, estimated glomerular filtration rate; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SBP, systolic blood pressure; SD, standard deviation; T2DM, type 2 diabetes mellitus.

Figure 5

HFpEF phenotypes, simplified summary based on recent analyses from TOPCAT, , and reviews by Meijs et al. 2023⁶⁵ and Rucker et al. 2022. ^aAssessed by echocardiography. ^bAssessed by carotid‐femoral pulse wave velocity. ^cAssessed by serum biomarkers. AF, atrial fibrillation; LV, left ventricular; HFpEF, heart failure with preserved ejection fraction; T2DM, type 2 diabetes mellitus.