From pathophysiology to treatment : An unresolved problem

Heart failure with preserved ejection fraction (HFpEF) has a significant impact on healthcare resources and while its occurrence in the elderly is increasing, its prognosis has not improved. Despite the prevalence of HFpEF, the understanding of its pathophysiology is still incomplete, and optimal treatment remains largely undefined. The net clinical benefit of medical treatment with ACE inhibitors, aldosterone receptor blockers (ARBs), mineralcorticoid receptor antagonists (MRAs) and beta-blockers has led to the incorporation of these drugs into HF clinical practice guidelines. However, little or no progress has been done for patients with HFpEF and there are no convincing and validated therapies able to reduce mortality or morbidity. HFpEF is a heterogeneous clinical syndrome embracing varieties of phenotypes and could benefit from a phenotype-specific approach. In the era of precision medicine, targeted approaches have proved effective in various disciplinary medical settings and for this reason this modern approach should be encouraged also in cardiology. In elderly patients, multilevel strategies and interventions aimed at improving adherence to guidelines and tailoring therapy, could be the key to improving outcome, and to reducing costs related to HF-related re-admissions. In the present review we briefly discuss current information available regarding pathophysiology, outcome, treatment and safety of the most common drugs used in this “geriatric syndrome”. HFpEF syndrome from pathophysiology to outcome Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome in which patients have symptoms and signs of heart failure (HF) with normal or near normal left ventricular ejection fraction (LVEF). Its diagnosis in the elderly is challenging due to the presence of atypical symptoms related to aging and potential cardiovascular and non-cardiovascular comorbidities. Mortality, morbidity and hospitalization for HF represent a public health dilemma worldwide; in particular short-term hospital readmission for HF occurs within 6 months. The HF syndrome shows a significant impact on the health-care resources and its occurrence is ever increasing in the elderly [1]; among older women, >80% of new cases of HF are HFpEF [2]. HFpEF in elderly patients is a systemic syndrome where advanced age, comorbidities with organ system deterioration, frailty and impaired cognition significantly impact outcome. After hospitalization for acute HF, these co-factors often remain unaddressed thus resulting in higher healthcare systems costs, prolonged physical disability, poor quality-of-life, exercise intolerance and finally with higher rehospitalization rates and mortality [3]. There are a number of potential mechanisms that may trigger and sustain HFpEF. Diastolic dysfunction is regarded as the principal actor but several ageand sex-related modifications in the cardiac structure and function are also present. For example, older women seem to show different heart rate and stroke volume responses to exercise if compared to men; in addition, in female patients, the left ventricle (LV) response to chronic systolic hypertension is impaired LV diastolic function. Conversely, male patients’ response to pressure overload is more frequently a LV dilatation with thin walls and a depressed LVEF. Other pathophysiologic factors may contribute to HFpEF syndrome, such as impaired arterial stiffening and myocardial stiffness associated with an abnormal diastolic relaxation. In fact, reduced vasodilation properties and increased vascular stiffness, together with systemic inflammation, are well established triggers of myocardial microvascular endothelial activation with the expression of adhesion molecules (e.g., ICAM, E-selectin, etc.). Overall, these processes lead to an increased vascular pressure and fibrosis, that are altogether transmitted backward to large vessels and myocardial cells. Last but not least, in older age, reduced myocardial and vascular responsiveness to β-adrenergic stimulation is present together with coronary flow reserve impairment and decreased mitochondrial adenosine triphosphate (ATP) production in response to increased energetic demand [4]. In clinical practice, a specific diagnostic algorithm applicable for early HFpEF recognition is not available yet. SymptomCorrespondence: Matteo Beltrami, Cardio-Thoracic and Vascular Department, University of Florence, Italy. Tel. +39.577. 48982. E-mail: beltrami.matteo1@gmail.com