Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies

Abstract

The clinical syndrome comprising heart failure (HF) symptoms but with a left ventricular ejection fraction (EF) that is not diminished, eg, HF with preserved EF, is increasingly the predominant form of HF in the developed world, and soon to reach epidemic proportions. It remains among the most challenging of clinical syndromes for the practicing clinician and scientist alike, with a multitude of proposed mechanisms involving the heart and other organs and complex interplay with common comorbidities. Importantly, its morbidity and mortality are on par with HF with reduced EF, and as the list of failed treatments continues to grow, HF with preserved EF clearly represents a major unmet medical need. The field is greatly in need of a more unified approach to its definition and view of the syndrome that engages integrative and reserve pathophysiology beyond that related to the heart alone. We need to reflect on prior treatment failures and the message this is providing, and redirect our approaches likely with a paradigm shift in how the disease is viewed. Success will require interactions between clinicians, translational researchers, and basic physiologists. Here, we review recent translational and clinical research into HF with preserved EF and give perspectives on its evolving demographics and epidemiology, the role of multiorgan deficiencies, potential mechanisms that involve the heart and other organs, clinical trials, and future directions.

Keywords: diastole; heart failure; hypertension; hypertrophy; therapy.

Figure 1

Schematic of myocardial abnormalties revealed in human HFpEF. The left side shows components of the beta-adrenergic (b-AR) pathway from the receptor to adenylcyclase (AC), generation of cyclic AMP (cAMP) to activation of protein kinase A (PKA). The latter is involved with modification of L-type calcium channels, phospholamban (PLN), titin, and other regulatory thin filament proteins (e.g. troponin I, TnI) which influence myofilament stiffness and contractile activation. Evidence suggests a deficiency in this signaling pathway in HFpEF, with increased titin stiffness and depressed β-AR responsiveness. The middle section shows transforming growth factor b (TGFb) and Gq-protein coupled receptor (GqPR) signaling involving transcription factors (Smad), phospholipase C (PLC) and mitogen activated kinases (MAPk) which are involved with activation of pro-fibrotic and hypertrophic cascades. At the right is the nitric oxide synathase (NOS) pathway resulting in NO activation of soluble guanylatecyclase (sGC), generation of cyclic GMP (cGMP) and activation of protein kinase G (PKG). In the middle is reactive oxygen species (ROS) activated by TGFb, b-AR, and GqPR coupled signaling – which inhibits the NOS-cGMP generation and thereby PKG activity, stimulates CamKII which can render sarcoplasmic reticular (SR) calcium release by the ryanodine receptor (RyR2) more promiscuous. ROS and CamKII also impact titin to influence stiffening. Lastly, the upper right depicts the role of matrix modulation by cytokines/inflammation, and the by-directional interaction of these factors with the myocyte. (Illustration credit: Ben Smith)

Figure 2

Schematic of the integrative physiology of HFpEF showing various extracardiac mechanisms and how they are involved. From top left, counterclockwise: lung involvement including primary lung disease leading to PAH, secondary PVH, impaired lung muscle mechanics, and eventual increase pulsatile RV load; abdominal compartment mechanisms including splanchnic circulation (preload), bowel congestion leading to endotoxin translocation and systemic inflammation; skeletal muscle mechanisms including impaired metabolism and peripheral vasodilation; renal mechanisms including passive congestion leading to renal impairment, changes in neurohormonal axis activation, hypertension, abnormal fluid homeostasis, eventual oliguria/renal insufficiency; ventricular-vascular mechanisms including ventricular stiffening leading to systolic and diastolic impairment, diminished systolic reserve, increased cardiac energetic demands and fluid-pressure shift sensitivity. (Illustration credit: Ben Smith)