Heart Failure With Preserved Ejection Fraction With CKD: A Narrative Review of a Multispecialty Disorder

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome with varying phenotypic expression. The phenotype chronic kidney disease (CKD) associated HFpEF is increasing in prevalence globally and is associated with increased morbidity and mortality compared to other HFpEF variants. These 2 conditions share common risk factors, including obesity, diabetes, and metabolic syndrome, as well as similar pathophysiology, including systemic inflammation, oxidative stress, elevated neurohormones, mineralocorticoid-receptor activation, and venous congestion. Given the coexistence of CKD and HFpEF, the diagnosis of HFpEF can be difficult. Moreover, treatment options for HFpEF have remained limited despite the success seen in its counterpart, heart failure with reduced ejection fraction. HFpEF encompasses complex multisystem pathophysiological perturbations beyond neurohormones, it is unlikely that a single agent can have significant benefit in this population. Recent data on sodium–glucose cotransporter 2 (SGLT2) inhibitors in HFpEF and CKD, and on glucagon-like peptide-1 (GLP-1) agonists and mineralocorticoid-receptor antagonists in metabolic syndrome, which target multiple pathways simultaneously, have led to promising therapeutics for HFpEF and CKD. In this perspective, our goal is to increase awareness of HFpEF as a multisystem disorder that shares the same disease processes seen in CKD and to emphasize that its management in individuals with CKD warrants a collective and multidisciplinary approach. Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome with varying phenotypic expression. The phenotype chronic kidney disease (CKD) associated HFpEF is increasing in prevalence globally and is associated with increased morbidity and mortality compared to other HFpEF variants. These 2 conditions share common risk factors, including obesity, diabetes, and metabolic syndrome, as well as similar pathophysiology, including systemic inflammation, oxidative stress, elevated neurohormones, mineralocorticoid-receptor activation, and venous congestion. Given the coexistence of CKD and HFpEF, the diagnosis of HFpEF can be difficult. Moreover, treatment options for HFpEF have remained limited despite the success seen in its counterpart, heart failure with reduced ejection fraction. HFpEF encompasses complex multisystem pathophysiological perturbations beyond neurohormones, it is unlikely that a single agent can have significant benefit in this population. Recent data on sodium–glucose cotransporter 2 (SGLT2) inhibitors in HFpEF and CKD, and on glucagon-like peptide-1 (GLP-1) agonists and mineralocorticoid-receptor antagonists in metabolic syndrome, which target multiple pathways simultaneously, have led to promising therapeutics for HFpEF and CKD. In this perspective, our goal is to increase awareness of HFpEF as a multisystem disorder that shares the same disease processes seen in CKD and to emphasize that its management in individuals with CKD warrants a collective and multidisciplinary approach. Heart failure (HF) is one of the most common chronic diseases affecting approximately 1% of individuals 65 years and older in the US and is responsible for one million hospitalizations and 3 million outpatient visits yearly.1Lazzeri C. Valente S. Tarquini R. et al.Cardiorenal syndrome caused by heart failure with preserved ejection fraction.Int J Nephrol. 2011; 2011634903Crossref PubMed Google Scholar Currently, heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of the HF population. However, its prevalence is increasing compared to that of heart failure with reduced ejection fraction (HFrEF), and it is becoming a global health care burden.1Lazzeri C. Valente S. Tarquini R. et al.Cardiorenal syndrome caused by heart failure with preserved ejection fraction.Int J Nephrol. 2011; 2011634903Crossref PubMed Google Scholar More importantly, despite improvements in the prognosis of HFrEF with modern evidence-based treatments, the prognosis of patients with HFpEF has been stagnant over the same time. One of the reasons for the disparity between advances in treatment of HFpEF and HFrEF is that the distinct pathophysiological mechanisms that cause HFpEF have not been well-elucidated. It is increasingly recognized that instead of cardiac ailment as the primary inciting event, HFpEF is a syndrome of multisystem processes that act synergistically to cause clinical expression of HFpEF. Kidney disease is highly prevalent in patients with HFpEF and is considered to play a central role in this paradigm. In this review, we examine HFpEF through the lens of its major underlying comorbidity, kidney disease, and explore the cardiorenal pathophysiology that leads to dysfunction in both the cardiac and kidney systems. Our goal is to increase awareness of HFpEF as a systemic disorder and to emphasize that its management warrants a collective and multidisciplinary approach. For the purpose of this manuscript, the discussion is focused on individuals with kidney disease not requiring maintenance dialysis or transplant. The chief problem in HFpEF is diastolic dysfunction which is a functional abnormality in left ventricular relaxation due to fibrosis and negative cardiovascular remodeling of the left ventricle (LV) and the great vessels. The reduced ventricular compliance and increased passive stiffness lead to heightened sensitivity to changes in load. As a result, HFpEF patients require remarkable increases in filling pressure to increase end-diastolic volume. Therefore, while the ejection fraction may be normal at baseline, during periods of increased stress, such as exercise, tachycardia, or hypertension, end-diastolic volume is unable to increase appropriately, resulting in a fixed stroke volume that is inappropriate for stress.2Kawaguchi M. Hay I. Fetics B. et al.Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations.Circulation. 2003; 107: 714-720Crossref PubMed Scopus (786) Google Scholar, 3Abudiab M.M. Redfield M.M. Melenovsky V. et al.Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction.Eur J Heart Fail. 2013; 15: 776-785Crossref PubMed Scopus (256) Google Scholar, 4Borlaug B.A. Melenovsky V. Russell S.D. et al.Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction.Circulation. 2006; 114: 2138-2147Crossref PubMed Scopus (542) Google Scholar The clinical manifestations of decrease in left ventricular compliance are rapid onset pulmonary edema after increases in load and hypotension after small decreases in load. The suggested criteria to diagnose HFpEF include (a) clinical signs or symptoms of HF, (b) evidence of preserved or normal LV ejection fraction (EF) but elevated LV or right ventricle filling pressures and/or reduced cardiac output, and (c) evidence of a structural abnormality of the heart derived from chest radiography, electrocardiogram, assays for B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), or right heart catheterization.5Dunlay S.M. Roger V.L. Redfield M.M. Epidemiology of heart failure with preserved ejection fraction.Nat Rev Cardiol. 2017; 14: 591-602Crossref PubMed Scopus (767) Google Scholar Figure 1 summarizes 2 noninvasive approaches called H2FPEF score and HFA-PEFF (Heart Failure Association-PEFF) score, which rely on simple clinical characteristics and echocardiography to diagnose HFpEF. These 2 scores enable discrimination of HFpEF from noncardiac causes of dyspnea, assist in determination of the need for further diagnostic testing, and can be useful for predicting future composite cardiovascular events as well as HF-related events in HFpEF patients.6Reddy Y.N.V. Carter R.E. Obokata M. et al.A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction.Circulation. 2018; 138: 861-870Crossref PubMed Scopus (576) Google Scholar,7Egashira K. Sueta D. Komorita T. et al.HFA-PEFF scores: prognostic value in heart failure with preserved left ventricular ejection fraction.Korean J Intern Med. 2022; 37: 96-108Crossref PubMed Scopus (8) Google Scholar It is important to note that obese patients have plasma BNP values below the traditional cutoff used to diagnose congestive HF. Hence, if used in isolation, a cutoff of BNP ≤ is for congestive HF in obese patients As to BNP of in and obese patients for both diagnosis and C. et and natriuretic BNP and mechanisms and diagnostic implications for heart J Cardiol. PubMed Scopus Google Scholar Moreover, in patients with chronic kidney disease plasma BNP and are elevated as a of reduced as well volume or LV cutoff values are S. et congestive heart and natriuretic peptide from the of in the Cardiol. 2006; PubMed Scopus Google Scholar The H2FPEF score not and can be of in patients with and kidney The HFA-PEFF score the underlying and kidney while the one can its in However, are to the HFpEF prevalence increases with and with such as hypertension, obesity, metabolic syndrome, CKD, disease, chronic pulmonary disease, and The underlying pathophysiological mechanisms for HFpEF include (a) systemic and oxidative (b) elevated neurohormones, and (c) venous K. et heart failure with preserved ejection fraction and the role of dysfunction and J Heart Fail. PubMed Scopus Google Scholar pathophysiological mechanisms are by CKD as In the we CKD and to dysfunction in CKD and HFpEF the role of as the risk for both CKD and HFpEF. 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