Symptomatic Orthostatic Hypotension in Patients with Precapillary Pulmonary Hypertension: A Mechanistic Investigation

• Grant number: 23/08850-5
• Support Opportunities: Regular Research Grants
• Duration: August 01, 2024 - July 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Bruno Moreira Silva
• Grantee: Bruno Moreira Silva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Eloara Vieira Machado Ferreira Alvares da Silva Campos ; Jaquelina Sonoe Ota Arakaki ; Patrice Brassard ; Rudolf Krawczenko Feitoza de Oliveira

Abstract

Precapillary pulmonary hypertension (PrecapPH) is a subtype of pulmonary hypertension that primarily affects the pulmonary arterial circulation and the right side of the heart. This vascular disorder is characterized by increased pulmonary vascular resistance and pulmonary vascular remodeling, leading to right ventricular failure and death. In general, the pulmonary vascular resistance increase is progressive and leads to dyspnea. Neurohumoral alterations and a fragile cardiorespiratory system can hypothetically make patients prone to dysfunctional regulation of systemic arterial pressure, perhaps leading to hypotension during the transition from a lying to a standing position. Importantly, orthostatic hypotension could be associated with symptoms like dizziness, blurred vision, and fatigue, impacting the patient´s quality of life. However, the origin of orthostatic hypotension symptoms most likely depends on multiple factors, including low systemic arterial pressure and dysfunction of mechanisms that preserve cerebral perfusion and oxygenation. Such cerebrovascular dysfunction probably encompasses impaired arterial pressure-cerebral blood flow relationship (i.e., cerebral autoregulation), impaired flow adjustment according to the neural activity and metabolic demand (i.e., neurovascular coupling), and impaired responsiveness to changes in arterial carbon dioxide (i.e., cerebrovascular reactivity). Therefore, the current project first aims to investigate whether cerebrovascular dysregulation is linked to the advent of symptoms during the transition from lying to standing in patients with PrecapPH. We hypothesize that patients with PrecapPH will show attenuated cerebral autoregulation, reduced cerebrovascular reactivity to carbon dioxide, and less neurovascular coupling compared to healthy controls, and within patients with PrecapPH cerebrovascular function will be worse in those with symptomatic (+SOH) than asymptomatic (-SOH) orthostatic hypotension. Secondly, the project aims to counteract mechanisms likely involved in generating orthostatic hypotension and its symptoms. We expect that stroke volume reduction is the most critical factor mediating decreased systemic arterial pressure in patients with PrecapPH +SOH. Therefore, increasing it via electrically-induced lower limb muscle activation will mitigate orthostatic hypotension, whereas increasing systemic vascular resistance via a sympathoexcitatory maneuver (cold pressor stimulus) will not. Additionally, we expect that hypocapnia is involved in cerebral blood flow reduction at rest and standing in patients with PrecapPH. Therefore, CO2 inhalation will decrease orthostatic hypotension symptoms via cerebrovascular effects rather than systemic arterial pressure effects. (AU)