The risk of HFpEF increases with age and is associated with an increase in the prevalence of extracardiac comorbidities and risk factors, including chronic kidney disease (kidney), chronic obstructive pulmonary disease (lung), and obesity (adipose tissue). Advanced age and multiple comorbidities in HFpEF patients contribute to a heightened level of systemic inflammation, which promotes myocardial infiltration of CCR2+ monocytes and differentiation into cardiac macrophages. Expression of IL-10 by macrophages leads to autocrine induction of osteopontin, a cytokine associated with cardiac fibrosis. Osteopontin activates cardiac fibroblasts, promoting excess collagen deposition and interstitial fibrosis. These pathologic processes impair cardiomyocyte relaxation and contribute to diastolic dysfunction.