Evolution of a Geriatric Syndrome: Pathophysiology and Treatment of Heart Failure with Preserved Ejection Fraction

Abstract

The majority of older adults who develop heart failure (HF), particularly older women, have a preserved left ventricular ejection fraction (HFpEF). The prevalence of this syndrome is increasing, and the prognosis is not improving, unlike that of HF with reduced ejection fraction (HFrEF). Individuals with HFpEF have severe symptoms of effort intolerance, poor quality of life, frequent hospitalizations, and greater likelihood of death. Despite the importance of HFpEF, there are numerous major gaps in our understanding of its pathophysiology and management. Although it was originally viewed as a disorder due solely to abnormalities in left ventricular diastolic function, our understanding has evolved such that HFpEF is now understood as a systemic syndrome involving multiple organ systems, and it is likely that it is triggered by inflammation and other as-yet-unidentified circulating factors, with important contributions of aging and multiple comorbidities, features generally typical of other geriatric syndromes. We present an update on the pathophysiology, diagnosis, management, and future directions in this disorder in older persons.

Keywords: aging; comorbidities; elderly; heart failure; preserved ejection fraction.

Figure 1

Relationship of capillary-to-fiber ratio (A) and percentage of type I muscle fibers (B) with peak O₂ uptake (VO₂) in older patients with heart failure with preserved ejection fraction (■) and age-matched healthy control subjects (▲).

Figure 2

Systemic and myocardial signaling in 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 begins 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 from Circulation with permission. Circulation. 2016;134:73–90.

Figure 3

Effects of a 20-week caloric restriction diet on exercise capacity and quality of life in HFpEF. The graph displays percent changes ± standard errors at the 20-week follow-up relative to baseline by randomized group for peak VO2 (mL·kg–1·min–1, A) and exercise time (min), P values represent effects for AT and CR. AT indicates aerobic exercise training; and CR, caloric restriction diet.