Cerebrovascular Regulation in Patients with Pulmonary Arterial Hypertension who Present with Symptomatic Orthostatic Hypotension

• Grant number: 22/12176-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2023
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Bruno Moreira Silva
• Grantee: Anas Rashid
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 17/17027-0 - Hormonal systems in renal and cardiovascular diseases: from cell biology to new physiological paradigms with advances for therapeutics, AP.TEM

Abstract

Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension, which primarily affects thearteries in the lungs (pulmonary arteries) and the right side of the heart. This vascular disorder is characterizedby increased pulmonary vascular resistance and pulmonary vascular remodeling leading to right ventricular failureand death. In general, the pulmonary vascular resistance increase is progressive and leads to dyspnea, the mostcommon cause of daily life activities limitation in patients with pulmonary disease. The pulmonary arteriesdysfunction is associated with neurohumoral activation, particularly of the renin-angiotensin-aldosterone systemand the sympathetic nervous system. It is believed that neurohumoral activation, initially, is a criticalcompensatory response capable of generating an increase in cardiac contractility and maintaining cardiac output.However, chronically, neurohumoral activation is up-regulated, becoming excessive and deleterious. Neurohumoralalterations and a fragile cardiorespiratory system can hypothetically make patients prone to dysfunctionalregulation of systemic blood pressure, perhaps leading to hypotension during the transition from a lying to astanding position. However, the origin of orthostatic hypotension symptoms most likely does not depend only onthe low arterial pressure, but also on a dysfunction of the mechanisms that should preserve the cerebral perfusionand oxygenation. Such dysfunction probably encompasses impaired arterial pressure-cerebral blood flowrelationship (i.e., cerebral autoregulation), impaired cerebrovascular responsiveness to changes in arterial CO2(i.e., cerebrovascular reactivity), and impaired flow adjustment according to the neural activity and metabolicdemand (i.e., neurovascular coupling). Therefore, the current project aims to investigate whether cerebrovasculardysregulation is linked to the advent of symptoms during the transition from lying to standing in patients with PAHwho present with orthostatic hypotension. We expect that orthostatic hypotension will be mediated by acombination of low cardiac output and low peripheral vascular resistance. Among all patients who present withorthostatic hypotension, we think that those with worse cerebrovascular regulation will be more likely to presentsymptoms like dizziness, blurred vision, weakness, fatigue, trouble concentrating, and dyspnea during the activestanding maneuver. Therefore, we expect that symptomatic patients will show attenuated cerebral autoregulation,reduced cerebrovascular reactivity to CO2, and less neurovascular coupling compared to patients withoutorthostatic symptoms.