Cardiovascular and Autonomic Mechanisms of Symptomatic Orthostatic Hypotension in Patients with Precapillary Pulmonary Hypertension

• Grant number: 24/15350-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2025
• End date: October 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Bruno Moreira Silva
• Grantee: Juliane Franco
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

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 if untreated. Neurohumoral alterations and a fragile cardiorespiratory system of patients with PrecapPH may, hypothetically, be prone to dysfunctional regulation of systemic arterial pressure and hypotension during the transition from a lying to a standing position. However, investigations related to the pathophysiological characteristics, such as cardiovascular and autonomic responses to active stand-up, remain uninvestigated in this population. Thus, the present research project aims to investigate and counteract mechanisms underlying the generation of symptomatic orthostatic hypotension in patients with PrecapPH. To better understand the particularities of the physiological mechanisms during orthostatic stress in these individuals, a first study will be conducted to investigate ventricular-arterial coupling, sympathetic-vascular transduction, baroreflex sensitivity, and cerebral arterial and venous blood flow. A second study will examine the relative roles of lower limb muscle pump (muscle electrical stimulation), generalized sympathetic activation (cold pressor test), and hypocapnia (CO2 inhalation) in mitigating the orthostatic hypotension response and its underlying symptoms in patients with PrecapPH. Regarding study 1, we hypothesize that patients with PrecapPH and symptomatic orthostatic hypotension will show uncoupling between right ventricle and pulmonary circulation, reduced baroreflex sensitivity of sympathetic activity, attenuation of vascular sympathetic transduction, and decreased brain's arterial and venous blood flow due to high pressure in the central circulation compared to patients with PrecapPH who do not experience symptomatic orthostatic hypotension. Regarding study 2, we expect that: a) cold pressor stimulus will increase resting and standing systemic arterial pressure, predominantly affecting the systemic vascular resistance, leading to a rise of cerebral perfusion pressure (CPP) and decreasing orthostatic hypotension symptoms; b) electrical muscle stimulation will increase systemic arterial pressure predominantly by increasing stroke volume, leading to increased cerebral oxygenation and decreased orthostatic hypotension symptoms; and c) CO2 inhalation will increase baseline cerebral blood flow, attenuating the decrease in cerebral oxygenation and resulting in less orthostatic hypotension symptoms, without an important effect on systemic arterial pressure.