Preface: Heart Failure with Preserved Ejection Fraction: The Future Is Now xiii

        Matthew C. Konerman and Scott L. Hummel

        Epidemiology, Diagnosis, Pathophysiology, and Initial Approach to Heart Failure with Preserved Ejection Fraction 397

        Theresa Anderson, Scott L. Hummel, and Matthew C. Konerman
        Heart failure with preserved ejection fraction (HFpEF) is common and increasing in prevalence. Despite this, HFpEF is challenging to diagnose due in part to its shared clinical features with other comorbid conditions. HFpEF is now understood as a systemic syndrome, often driven by pro-inflammatory comorbidities, rather than solely a cardiac disease. This review summarizes the epidemiology, diagnostic criteria, and pathophysiology of HFpEF and proposes a clinical approach for patients suspected of having or diagnosed with HFpEF.

        Key Phenotypes of Heart Failure with Preserved Ejection Fraction: Pathophysiologic Mechanisms and Potential Treatment Strategies 415

        Kazuki Kagami, Tomonari Harada, Hideki Ishii, and Masaru Obokata
        Pathophysiological heterogeneity is considered the primary reason for the limited effective treatment options for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have focused on HFpEF phenotyping that categorizes patients as pathophysiologically homogeneous groups to develop personalized treatment strategies. This approach relies on comorbidities, cardiac structure and function, central hemodynamics at rest and during exercise, or machine learning techniques. Although some phenotypes have been successfully identified, efforts are still ongoing. This review summarizes the current understanding of phenotyping approaches in patients with HFpEF, highlighting its pathophysiology and potential treatment strategies.

        Approach to Echocardiography in Heart Failure with Preserved Ejection Fraction 431

        C. Charles Jain and Yogesh N.V. Reddy
        As echocardiography is universally performed in the evaluation of suspected heart failure with preserved ejection fraction (HFpEF), a number of structural and functional characteristics relevant to both the diagnosis and phenotyping of HFpEF can be elucidated. Exclusion of alternate causes of heart failure is a critical first step performed principally by echocardiography. Once HFpEF is confirmed, echocardiography may provide insight into pathophysiology and phenotyping by quantifying atrial mechanics, pericardial restraint, degree of pulmonary hypertension, and atrial valvular regurgitation. Although current echo-Doppler assessment of filling pressures is insensitive to diagnose HFpEF, there are emerging technologies such as left atrial (LA) strain that hold promise for noninvasive diagnosis.

        The Role of Multimodality Imaging in the Evaluation of Heart Failure with Preserved Ejection Fraction 443

        Mahesh K. Vidula, Paco E. Bravo, and Julio A. Chirinos
        Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, affecting approximately half of all patients with HF. The diagnosis of HFpEF can be notoriously challenging in clinical practice, given the many overlapping etiologies of dyspnea or reduced exercise tolerance in patients at risk for HFpEF. Multimodality imaging has an important role in establishing the diagnosis of HFpEF and the presence of elevated left ventricular filling pressures, identifying specific etiologies of HFpEF that can benefit from approved therapies, and discerning distinct phenogroups or mechanistic abnormalities that may inform the development of novel therapeutics.

        Hemodynamic Assessment in Heart Failure with Preserved Ejection Fraction 459

        Kazunori Omote, Steven Hsu, and Barry A. Borlaug
        Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by an inability of the heart to perfuse the body without pathologic increases in filling pressure at rest or during exertion. Right heart catheterization provides direct assessment for HF, providing the most robust and direct method to evaluate the central hemodynamic abnormalities, and serves as the gold standard to confirm or refute the presence of HFpEF. This article reviews current understanding of the best practices in the performance and interpretation of hemodynamic assessment, relates important pathophysiologic concepts to clinical care, and discusses current and evidence-based applications of hemodynamics in HFpEF.

        Pharmacologic Therapy for Heart Failure with Preserved Ejection Fraction 473

        Anthony E. Peters and Adam D. DeVore
        The management of heart failure with preserved ejection fraction (HFpEF) is rapidly evolving. The pharmacologic treatment of patients with HFpEF includes symptom management with diuretics and optimization of comorbidities, including hypertension, obesity, diabetes mellitus, and atrial fibrillation. Specific therapies, including angiotensin II receptor blockers, mineralocorticoid receptor antagonists, angiotensin receptor–neprilysin inhibitors, and sodium–glucose cotransporter-2 inhibitors, are well tolerated and can reduce the risk of HF hospitalization, particularly in those on the lower end of the HFpEF left ventricular ejection fraction spectrum. Ongoing trials should continue to inform optimal therapy in this evolving field.

        Nonpharmacological Strategies in Heart Failure with Preserved Ejection Fraction 491

        Natalie J. Bohmke, Hayley E. Billingsley, Danielle L. Kirkman, and Salvatore Carbone
        Patients with heart failure with preserved ejection fraction (HFpEF) suffer from a high rate of cardiometabolic comorbidities with limited pharmaceutical therapies proven to improve clinical outcomes and cardiorespiratory fitness (CRF). Nonpharmacologic therapies, such as exercise training and dietary interventions, are promising strategies for this population. The aim of this narrative review is to present a summary of the literature published to date and future directions related to the efficacy of nonpharmacologic, lifestyle-related therapies in HFpEF, with a focus on exercise training and dietary interventions.

        Device Therapy for Heart Failure with Preserved Ejection Fraction 507

        Husam M. Salah, Allison P. Levin, and Marat Fudim
        Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with few options for effective pharmacologic therapies. Numerous device-based approaches to HFpEF therapy have emerged, which aim to treat the clinical and pathophysiologic features common to the varied causes of this syndrome. This review summarizes the current landscape of device therapy in HFpEF with a focus on structural interventions, such as left-to-right atrial shunts; cardiac contractility modulation; autonomic modulation, such as baroreflex activation therapy and splanchnic nerve modulation; and respiratory modulation, such as phrenic nerve stimulation.

        Geriatric Domains in Patients with Heart Failure with Preserved Ejection Fraction 517

        Parag Goyal, Omar Zainul, Dylan Marshall, and Dalane W. Kitzman
        Because heart failure with preserved ejection fraction (HFpEF) is closely linked to aging processes and disproportionately affects older adults, consideration of geriatric domains is paramount to ensure high-quality care to older adults with HFpEF. Multimorbidity, polypharmacy, cognitive impairment, depressive symptoms, frailty, falls, and social isolation each have important implications on quality of life and clinical events including hospitalization and mortality. There are multiple strategies to screen for these conditions. This narrative review underscores the importance of screening for multiple geriatric conditions, integrating these conditions into decision making, and addressing these conditions when caring for older adults with HFpEF.

        Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction 533

        Victor M. Moles and Gillian Grafton
        Heart failure with preserved ejection fraction (HFpEF) is a common medical condition associated with increased morbidity and mortality. Through different mechanisms, including passive left-sided congestion and/or vasculopathy, patients with HFpEF can develop pulmonary hypertension (PH). This association -PH-HFpEF- is linked with worsening symptomatology and long-term outcomes. Although pulmonary vasodilators have been effective in treating patients with a pulmonary vasculopathy, such as pulmonary arterial hypertension (PAH), these results have not been replicated in those with PH-HFpEF. There is an unmet need to develop effective medical therapy for this challenging population. In this article, we focus on understanding the definition, epidemiology, diagnosis, clinical implications, and treatment for PH in the setting of HFpEF.

        Transthyretin Cardiac Amyloidosis: An Evolution in Diagnosis and Management of an “Old” Disease 541

        Dia A. Smiley, Carlos M. Rodriguez, and Mathew S. Maurer
        Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, and cardiac amyloidosis (CA) is one of the causes of HFpEF, that has established and emerging treatment options. However, it remains an underdiagnosed and often overlooked cause of HFpEF. The importance of early diagnosis cannot be emphasized enough, as emerging therapies are more effective early in the course of the disease. Further, because of the unique physiologic and hemodynamic features of CA, patients poorly tolerate traditional heart failure medications and experience worse outcomes compared with other causes of HFpEF. With the aging of the population, transthyretin (ATTR) CA, once thought to be a rare disease, will become the most common type of systemic amyloidosis. ATTR-CA is increasingly recognized due to enhanced clinical awareness; advances in diagnostic imaging that have led to a diagnostic approach that does not require a biopsy, as well as the recent introduction of novel disease-modifying treatments. ATTR-CA causes restrictive and infiltrative cardiomyopathy that results in heart failure, atrial and ventricular arrhythmias, and conduction disease, and is associated with significant morbidity and mortality. Our goal in this review is to provide an overview of the historical, epidemiologic, diagnostic, and therapeutic evolution of ATTR-CA, and to emphasize the importance of early suspicion and detection of HFpEF.