Orthostatic intolerance (OI) is a condition defined by the inability to tolerate the upright posture and is associated with an increased risk of falls and syncope, cardiovascular disease, orthostatic cognitive dysfunction, increased risk of dementia and all-cause mortality (Cremer, 2017; Freeman et al., 2018; Gibbons et al., 2017; Ma, 2023; Rawlings, 2018; Ricci et al., 2015). OI syndromes are classified into at least 3 categories, including orthostatic hypotension (OH), neurally mediated (reflex) syncope and postural tachycardia syndrome (POTS) (Freeman et al., 2011; Ricci et al., 2015). We previously demonstrated that hemodynamic changes associated with the baroreflex response and changes in end-tidal CO2 (EtCO2) showed a stronger association with the severity of orthostatic symptoms and fatigue than the overall orthostatic heart rate (HR) response in patients with POTS (Wheeler et al., 2022). Since these measures have been shown to be physiological targets for heart rate variability (HRV) biofeedback (HRVB) in a wide variety of studies (Lehrer et al., 2020: Shaffer & Meehan, 2022; Siepmann et al., 2022), these initial findings have clinical and research implications for the evaluation and the development of nonpharmacological treatments for patients with POTS and related forms of OI.
Orthostatic hypotension (OH) is another category of OI syndromes that is observed when adaptive mechanisms fail to compensate for the reduction in venous return that occurs when assuming the standing position (Ricci et al., 2015). OH, is considered a key manifestation of autonomic dysfunction observed in patients with neurogenic (e.g., patients with diabetes mellitus, neurodegenerative disorders, high spinal cord lesions, autoimmune disorders, and small fiber neuropathies) and non-neurogenic disorders (e.g., volume depletion, anemia, polypharmacy and physical deconditioning) (Freeman et al., 2018; Ricci et al., 2015). OH, has been independently associated with increased the risk of major cerebrocardiovascular events (Ricci et. al., 2015). There is evidence to suggest that OH may also contribute to the development of dementia (Cremer et al., 2017; Ma et al., 2023; Rajeev et al., 2023; Rawlings et al., 2018). Management of OH includes both pharmacological and nonpharmacological interventions (Ricci et al., 2015). Since pharmacological interventions increase BP independent of posture and do not restore normal baroreflex control, nonpharmacological treatments are considered the foundation of OH management (Wieling et al., 2022). Nonpharmacological interventions used in OH patients include patient education, avoidance of pharmacologic and nonpharmacologic exacerbators of OH, increase in water and sodium intake, different types of exercises, physical counter maneuvers and conditioning programs (Freeman et al., 2018; Ricci et al., 2017). The use of nonpharmacological interventions has been shown to improve symptoms and the quality of life of OH patients (Freeman et al., 2018; Newton and Frith, 2018; Ricci et al., 2015). However, some nondrug treatments may not be safe for patients with comorbidities and/or disabilities (Logan et al., 2020; Robinson et al., 2022). Since the prevalence of OH increases with age (Low, 2008) and the aging population is expanding rapidly (Cheng et al., 2020), a better understanding of nonpharmacological interventions that are suitable for these at-risk populations are needed.
While there is evidence to suggest that OH patients do not have problems with cerebral autoregulation (Schondorf et al., 2001), symptoms of cerebral hypoperfusion have been reported in OH patients (Freeman et al., 2018; Ricci et al., 2015). Hyperventilation, hypocapnia and cerebral vasoconstriction during severe OH worsen symptoms and increase the susceptibility of syncope (Norcliffe-Hoffman et al., 2018). There is evidence to suggest that reductions in cerebral blood flow velocity (CBFv) during orthostatic stress in OI patients were associated with a decrease in EtCO2 and hypocapnia (EtCO2 under 30 mmHg) (Stewart et al., 2018). Therefore, nonpharmacological strategies aimed at improving the efficacy of autonomic reflex measures but also targeting other concurrent physiological measures associated with OH, including changes in the rate of respiration and EtCO2, may contribute to reducing the risk of cardiovascular events and dementia in OH patients.
Findings from previous studies suggest that biofeedback may be a complementary option to pharmacological interventions for patients diagnosed with hypertension (Chen et al., 2016; Elavally et al., 2020; Lehrer et al., 2020; Moravec, 2008). A meta-analytic review of HRVB showed a modest, but highly significant overall effect sizes, and concluded that HRVB may be useful as a complementary intervention in a variety of fields, including mental health, behavioral medicine, sports psychology, and education (Lehrer et al., 2020). A systematic review investigating the effects of HRVB on clinical outcomes in patients with cardiovascular disease found that HRVB was associated with improvements in readmission rates and left ventricular ejection fraction and reduction in systolic and diastolic blood pressure in pre-hypertensive patients (see Burlacu et al., 2021). In contrast to these findings, evidence supporting the effectiveness of biofeedback as a nonpharmacologic approach for patients with OH is limited (Brucker and Ince, 1977; Ince, 1985; Han et al., 2023; Rau et al., 2003). A recent study found that OH patients enrolled in a 12-week multidisciplinary integrated program that included HRVB training showed an increase in the low-frequency (LF) power of HRV (LF-HRV), a reduction in the orthostatic drops in systolic and diastolic BP and reported fewer orthostatic symptoms (Han et al., 2023). These results support previous studies (Lehrer et al., 2003) and demonstrate that HRVB training increases baroreflex gain in patients with OH (Davies et al., 2002; Rahman et al., 2011). Despite this evidence, a better understanding of the physiological targets for nonpharmacological management of patients with OH and symptoms of cerebral hypoperfusion are needed. The objective of this study was to determine the relationship between cardiovascular autonomic control, EtCO2 and orthostatic cerebral hypoperfusion in patients referred for OH evaluation. This objective was accomplished by determining the differential contributions of cardiovascular autonomic control and EtCO2 to orthostatic cerebral hypoperfusion in OH patients. Findings from this study aim at providing insight into the development of HRVB protocols to complement the standard of care in OH patients with symptoms of orthostatic cerebral hypoperfusion.