Pathophysiology of primary HFpEF. Several risk factors (obesity, hypertension, aging, and physical inactivity) contribute to create a systemic proinflammatory status and/or haemodynamic stress that promote a primary myocardial diastolic dysfunction (impaired myocardial relaxation and compliance) leading to concentric remodeling/hypertrophy, and elevated LV filling pressures and/or impaired cardiac output. Moreover, co-morbid conditions and contributing factors (obesity, abnormal ventriculoarterial coupling, deconditioning, ventilatory inefficiency, pulmonary diseases, diabetes mellitus, and malnutrition) further contribute to exercise intolerance and clinical symptoms in patients with primary HFpEF. HFpEF = heart failure with preserved ejection fraction; LV = left ventricle; NO = nitrogen oxygen SVR = systemic vascular resistance; V/Q = ventilation/perfusion ratio.