Heart failure with preserved ejection fraction: New approaches to diagnosis and management

Abstract The majority of older patients who develop heart failure (HF), particularly older women, have a preserved left ventricular ejection fraction (HFpEF). Patients with HFpEF have severe symptoms of exercise intolerance, poor quality‐of‐life, frequent hospitalizations, and increased mortality. The prevalence of HFpEF is increasing and its prognosis is worsening. However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Originally viewed as a disorder due solely to abnormalities in left ventricular (LV) diastolic function, our understanding has evolved such that HFpEF is now understood as a systemic syndrome, involving multiple organ systems, likely triggered by inflammation and with an important contribution of aging, lifestyle factors, genetic predisposition, and multiple‐comorbidities, features that are typical of a geriatric syndrome. HFpEF is usually progressive due to complex mechanisms of systemic and cardiac adaptation that vary over time, particularly with aging. In this review, we examine evolving data regarding HFpEF that may help explain past challenges and provide future directions to care patients with this highly prevalent, heterogeneous clinical syndrome.


| INTRODUCTION
Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in patients older than 65 years and represents >50% of prevalent HF cases in community. 1 In the highest age decile, (≥90 years old), nearly all patients with HF have preserved EF. HFpEF is associated with high morbidity and mortality. After HF hospitalization, the 5-year survival of HFpEF is a dismal 35%, worse than many cancers. 2 The risk of death in patients with HFpEF increases with increasing comorbidity burden. 3 Even after adjustment for comorbid conditions, mortality rates associated with HFpEF are higher than in general population age-matched controls. 4 Patients with HFpEF have similarly high rehospitalization rates as patients with HF with reduced EF (HFrEF). 5 In patients hospitalized with HFpEF, 20% are readmitted within 30 days of hospital discharge and >50% within 1 year. 6 Quality of life in HFpEF is as poor as or worse than HFrEF and is associated with physical activity levels that are as suppressed as those observed in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). 7 Despite this, there are currently few effective therapies for HFpEF, as most approved therapies for HFrEF have been demonstrated to be ineffective for HFpEF, suggesting major differences in fundamental pathophysiology and therapeutic targets in HFpEF compared to HFrEF. We review relatively recent data that have enhanced our understanding of this complex disorder and that may lead to improved care of patients with this highly prevalent disorder.

| CASE STUDY
A 79-year-old woman with long-standing hypertension, obesity, and type II diabetes presents with shortness of breath on exertion that began 6 months earlier and has since gradually worsened and interferes with daily activities. She denies exertional chest pain. While she is able to shop in the local supermarket, carrying her packages home has become increasingly difficult. She desires to return to her previously active life. Current medications include amlodipine 10 mg daily, metfor-

| Making the HFpEF diagnosis: Challenges
Diagnosing HF in older adults poses specific challenges; false-positive clinical diagnoses are not uncommon. 6 The most common symptoms of HFpEF are exertional dyspnea. However, symptoms of reduced exercise tolerance are common in the older adults and have been shown to reflect normal physiological changes related to aging or could be related to non-cardiac etiologies. Furthermore, the diagnosis of HF in the older patients may be difficult due to the presence of comorbidities, some of which can mimic HF signs and further confound the diagnosis of HF. 8 11 Aging is also associated with a decline in a variety of neural, hormonal, and environmental trophic signals; this can leads to loss of muscle mass and mass-specific strength, characteristic changes in body composition, including decreases in lean body mass and muscle strength, and increases in adiposity which increase vulnerability for sarcopenic obesity. 12 In addition, older adults hospitalized with a primary diagnosis of HF often have multiple noncardiac comorbidities (5.5 on average) and high proportions are frail. 13 The adverse impacts of aging, frailty and comorbidities on functional capacity and clinical outcomes are cumulative and synergistic. 14 Indeed, approximately 85% of elderly HFpEF patients are overweight or obese, and the HFpEF epidemic has largely paralleled the obesity epidemic. 15  To date, pharmacologic interventions applied in HFpEF have been principally based upon the assumption of underlying, severe neurohormonal abnormalities. However, neurohormonal derangements appear more limited in breadth and severity in HFpEF than in HFrEF.
Furthermore, diagnosis of HFpEF is challenging due to the lack of a single objective marker that defines the syndrome, such as a reduced LVEF in HFrEF and the high frequency of comorbidities that may mimic or accompany the HFpEF syndrome. In addition, exercise intolerance, the cardinal manifestation of HF regardless of EF, has a complex pathophysiology and is rarely explained by a single process.
Furthermore, most HFpEF studies have only measured diastolic function at rest rather than during exercise where symptoms become manifest. 45,46 So far, clinical trials generally enrolled "all comers" with clinical syndrome of HF and objective evidence of preserved LVEF.
However, evolving evidence indicates that HFpEF is a much more complex disorder than originally thought, influenced by aging processes as explained before, likely systemic in nature, involving many organs and organ systems in addition to the heart, and also involving abnormalities in vascular and skeletal muscle function as well, and likely has multiple phenotypes. These issues and concepts have generally not been addressed in trial designs to date. Given such a multifactorial, complex milieu, it is not surprising that drugs and interventions aimed primarily at a central hemodynamics repeatedly failed to strongly impact overall outcomes in HFpEF. As discussed in more detail below, lifestyle modifications (exercise and diet) have been more consistently successful, likely due to addressing HFpEF as a systemic syndrome, and by addressing peripheral, non-cardiac factors that appear more mutable than cardiac factors.  Table 3 summarizes the practical approaches to managing HFpEF. In older patients, multi-level strategies and interventions aimed at improving adherence to guidelines and tailoring therapy could be the key to improving outcome, and to reducing costs related to HFrelated re-admissions. An important component of treating a patient with HFpEF is treating the contributing factors and comorbidities that are frequently present and significantly impact the clinical course, such as obesity, hypertension, coronary artery disease, diabetes, COPD, anemia, chronic kidney disease, and sleep-disordered breathing. 9 Several hypertension trials, including the systolic BP intervention trial (SPRINT), have shown a reduction in incident HF with treatment of hypertension, although these trials did not differentiate between F I G U R E 1 Systemic and myocardial signaling in heart failure (HF) with preserved ejection fraction (HFpEF). Comorbidities induce systemic inflammation, evident from elevated plasma levels of inflammatory biomarkers, such as soluble interleukin 1 receptor-like 1 (IL1RL1), C-reactive protein (CRP), and growth differentiation factor 15 (GDF15). Chronic inflammation affects the lungs, myocardium, skeletal muscle, and kidneys leading to diverse HFpEF phenotypes with variable involvement of pulmonary hypertension (PH), myocardial remodeling, deficient skeletal muscle oxygen extraction (ΔA-Vo2) during exercise (Ex), and renal Na + retention. Myocardial remodeling and dysfunction begin with coronary endothelial microvascular inflammation manifest from endothelial expression of adhesion molecules, such as vascular cell adhesion molecule (VCAM) and E-Selectin. Expression of adhesion molecules attracts infiltrating leukocytes secreting transforming growth factor β (TGF-β), which converts fibroblasts to myofibroblasts with enhanced interstitial collagen deposition. Endothelial inflammation also results in the presence of reactive oxygen species (ROS), reduced nitric oxide (NO) bioavailability, and production of peroxynitrite (ONOO -). This reduces soluble guanylate cyclase (sGC) activity, cyclic guanosine monophosphate (cGMP) content, and the favorable effects of protein kinase G (PKG) on cardiomyocyte stiffness and hypertrophy. HFpEF indicates heart failure with preserved ejection fraction. (Reproduced with permission from Reference 16) incident HFpEF and HFrEF. [47][48][49] Considering the age distribution in these trials and the age-dependent relative incidence of HFpEF, control of hypertension may be the single most important prevention strategy for HFpEF. In SPRINT, both HFpEF and HFrEF incident cases were significantly reduced, including specifically in older patients ≥75 years old. 50 The BP goals in the ACC/AHA HF guideline are similar to those in the general population, with the exception that the 2017 ACC/AHA HF guideline update recommends the lower systolic BP target of 130 mm Hg. 9,48,51 ACC/AHA HF guidelines support the use of beta-blockers, angiotensin-converting enzyme inhibitors (ACEI), T A B L E 1 Non-pharmacological interventions that were positive in HFpEF on their primary endpoints and has the potential to improve physical function and reduce rehospitalization rates. 67 A larger trial is underway to verify these findings.

| Exercise prescription
A supervised maximal exercise test with monitoring for ischemia should be performed before HFpEF patients beginning an ET program. The ET program for stable HFpEF patients should consist of continuous large muscle mass moderate intensity endurance exercise performed for 20 to 60 minutes per session, 3 to 5 days per week. The exercise is usually performed on a bicycle or treadmill.
The duration and frequency of effort should be up titrated before intensity is increased. Once patients demonstrate a tolerance of aerobic training levels, resistance training activities should be considered.
It is recommended to initiate ET in a structured, supervised, centerbased program. This can be either in-hospital or in a specialized facility, as long as close supervision are available. After supervised setting, depending on individual progress, patients usually should be able to be transitioned to a home exercise maintenance training program. Ideally, a patient-tailored ET program is prescribed instead of a "one size fits all" approach especially in older patients with HFpEF. In addition, to increase long-term adherence to ET, the patient's preferences should be taken into account.  (Table 1). 27,68 This finding was confirmed in more recent analyses of Medicare beneficiaries. 67 The CARDIOMEMS device is a wireless, implanted pulmonary artery pressure monitor implanted in the distal PA during right heart catheterization. Patients transmit hemodynamic data daily using a wireless RF transmitter.  (Table 2). 69 Recently, REDUCE LAP-HF I, a phase 2 randomized parallel-groups, and blinded multi-center sham-controlled trial published short-term results (  In older patients hospitalized primarily for HF, many factors outside the heart such as advanced age, globally reduced organ system reserve capacity, physical frailty, impaired cognition, and comorbidities strongly influence outcomes. 70 In addition, the hospital environment-with immobilization, fasting, sleep deprivation, and disorientation-can dramatically worsen physical frailty with rapid, severe loss of muscle mass and function. 70 When older HF patients are thought to be ready for discharge, careful attention should focus on their multiple comorbidities, globally reduced organ reserve, severe physical deconditioning, and cognitive dysfunction to prevent the "post-hospitalization syndrome," consisting of high rates of rehospitalization, mortality, and nursing home admission, prolonged physical disability, poor quality of life, and high health care costs. 71

| HFpEF management based on clinical phenotypes
A key evolving concept in HFpEF therapy is that the disorder is highly heterogeneous and manifestations can vary markedly from patient to patient even within a specific HFpEF patient population. 72

| Case conclusion
Our 79-year-old woman should be placed on diuretics at the lowest effective dose for symptomatic relief. She should have a home scale and weigh herself daily. We should provide instruction for steps to take diuretics based on weight changes. Her BP was not well controlled and lisinopril to be adjusted to keep SBP < 130 mm of Hg. She should be advised regarding dietary compliance. She should be encouraged to exercise daily. She should be provided comprehensive HF disease management, including education, diet, exercise therapy, and close follow-up.
Ideally as described earlier, she is recommended to participate in a structured, supervised ET program; however, lack of CMS coverage can be a major barrier to formal cardiac rehab in older HFpEF patients.

| CONCLUSIONS
HFpEF is the most common form of HF in the community, its prevalence is increasing, and prognosis has not improved or even worsened. It is nearly unique to older adults and is a true geriatric syndrome. Finally, the complexities of these patients demand an approach that is more holistic by addressing not only direct HF-related conditions but also optimal management of geriatric syndromes, focusing on quality of life. Dr. Upadhya has received research funding from Novarits and Corvia.