ABC | Volume 114, Nº1, January 2019

Review Article Fernandes et al. Heart Failure with Preserved Ejection Fraction Arq Bras Cardiol. 2020; 114(1):120-129 Figure 1 – Pathophysiology of HFpEF - possible mechanisms involved. AF: atrial fibrillation; CAD: coronary artery disease; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; HFpEF: heart failure with preserved ejection fraction; HT: arterial hypertension; NO-cGMP-PKG: nitric oxide, reduced cyclic guanosine monophosphate and protein kinase G; PH: pulmonary hypertension; RAAS: renin-angiotensin-aldosterone system; RV: right ventricle. Autonomic dysfunction Chronotropic incompetence RAAS Diastolic and systolic dysfunction Fibrosis, hypertrophy Cardiac remodeling Microvascular dysfunction Increased filling pressures Vascular dysfunction Endothelial dysfunction Vascular stiffening NO-cGMP- PKG deregulation Systemic alterations Inflammation Myopathy Comorbidities and pro-inflammatory state Age, COPD, CAD, HT, Diabetes, CKD, anaemia, iron deficiency, obesity Atrial, pulmonary and RV compromise Edema, malabsorption, hepatopathy, cardiorenal syndrome and cachexia AF PH Neurohormonal changes HFpEF PATHOPHYSIOLOGY Pathophysiology of HFpEF of the cases and associated with a worse prognosis, also seems to contribute to the disease progression. 7 The onset of right ventricular dysfunction, with systemic venous congestion, also predicts worse results, associated with edema, malabsorption, congestive hepatopathy, cardiorenal syndrome and cachexia. Another mechanism involved is chronotropic incompetence, with inadequate heart rate (HR) variations, probably due to autonomic nervous system dysfunctions. 4 Electrical and/or mechanical, systolic and diastolic asynchronies were also observed in some patients. 7 Its magnitude is related to the extent of diastolic dysfunction and exercise capacity. 4 Many of these changes are not apparent, nor do they entail any impairment at rest, with functional reserve limitations being evident only under stress. Neurohormonal alterations, such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system (RAAS) are also important mechanisms involved. 4 At the vascular level, we can observe endothelial dysfunction, systemic inflammation, increased vessel stiffness and impaired vasodilation. A potential mechanism could be the deregulation of the NO-sGC-cGMP-PKG signaling pathway (nitric oxide, soluble guanylate cyclase, reduced cyclic guanosine monophosphate and protein kinase G), which is responsible for smooth muscle relaxation, cardiac protection, gene transcription, endothelial permeability and platelet inhibition. 5 At the peripheral level, musculoskeletal changes seem to contribute to aerobic capacity reduction, with less exercise tolerance. Both the age and the several comorbidities intensify these mechanisms and contribute to disease progression. The interaction between the various pathophysiological factors and comorbidities and the relative dominance of each of them makes this pathology complex and heterogeneous, making its diagnosis and treatment extremely difficult. A subgroup analysis with certain phenotypes can facilitate this process by allowing a more particular and direct approach. 4 Diagnosis The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF. There have been several proposed classifications and inclusion criteria in the conducted studies, contributing to the enormous heterogeneity of patients assessed in the clinical trials. 1 The current guidelines proposed by the European Society of Cardiology suggest the existence of 3 diagnostic criteria: symptoms and signs of HF, LVEF ≥ 50%, elevated levels of natriuretic peptides and relevant structural heart disease and/or diastolic dysfunction. 3 Notwithstanding these 121