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

Bharathi Upadhya, MD; Barbara Pisani, MD; Dalane W. Kitzman, MD

Disclosures

J Am Geriatr Soc. 2017;65(11):2431-2440. 

In This Article

New Paradigm for the Pathophysiology of HFpEF

The involvement of this broad array of abnormalities in individuals with HFpEF, the recognition of the high frequency, severity, and effect of multiple noncardiac comorbidities; systemic, multiorgan involvement; and its nearly exclusive existence in older persons has led to recognition of HFpEF as a true geriatric syndrome. It has also led to a new paradigm of HFpEF, whereby aging along with multiple comorbidities in HFpEF may initiate or aggravate chronic systemic inflammation, which may affect myocardial remodeling and dysfunction in individuals with HFpEF through a signaling cascade, which may begin with coronary microvascular endothelial dysfunction (Figure 2).[8,75] This reduces myocardial nitric oxide bioavailability and leads to low protein kinase G (PKG) activity in cardiomyocytes, which become stiff and hypertrophied.[8] These alterations also promote microvascular rarefaction and dysfunction in cardiac[24] and skeletal muscle.[57,76]

Figure 2.

Systemic and myocardial signaling in heart failure 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 during exercise (Δ(A-VO2)EX), and renal sodium (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 beta (TGF-β), which converts fibroblasts to myofibroblasts with enhanced interstitial collagen deposition. Endothelial inflammation also results in the presence of reactive oxygen species (ROS), lack of 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. Reproduced with permission:97 Shah SJ, Kitzman DW, Borlaug BA et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: A multiorgan roadmap. Circulation 2016;134:73–90. [Color figure can be viewed at wileyonlinelibrary.com]

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