Novel diagnostic methods and potential treatments in cardiovascular autonomic dysfunction

General Aim: To investigate novel diagnostic tools and treatment options for cardiovascular autonomic dysfunction (CVAD) patients, focusing on syncope, orthostatic intolerance, and heart failure (HF).

Background: CVAD includes common clinical entities such as vasovagal syncope (VVS) postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH). Also, CVAD plays an important role in HF. Monitoring of cerebral tissue oxygenation (SctO2) during orthostasis may aid in understanding mechanisms in CVAD. For POTS, studies indicate autoimmune activity against G-protein coupled receptors (GPCRs), however, data is sparse. Exercise training is recommended in POTS, but little is known about clinical implementation.

Subjects: Patients in paper 1-4 (n=68-342) are from the Syncope Study of Unselected Population in Malmö (SYSTEMA), a cohort of patients evaluated for syncope and orthostatic intolerance at Skåne University Hospital (SUS), Malmö, Sweden. Paper 3 also includes patients (n=61) from the HeArt and bRain failure inVESTigation study (HARVEST) of admitted HF patients from SUS. Study 5 will include POTS-patients (n=200) from the Syncope Unit, SUS.

Methods and Results: Patients underwent active standing or head-up tilt test (HUT). Non-invasive cerebral oximetry measured SctO2 during HUT in paper 1, 3 and 4. GPCR activity in POTS versus controls and its association with symptoms were studied (paper 2). A cross-over study protocol of a 16-week exercise program was constructed. POTS (p=0.023) and HF patients (p<0.001) had lower SctO2 during orthostasis compared to SYSTEMA participants with normal HUT. Older patients with VVS and OH exhibited lower SctO2 prior to syncope than younger patients (p<0.01). Proteins activating adrenergic, muscarinic, and nociceptin receptors were highly predictive of POTS (Area-under-the-curve
0.88; 95% confidence interval 0.80-0.97).

Conclusion: Cerebral deoxygenation during orthostasis is notable in POTS, VVS, OH and HF, and may relate to aging in VVS and OH. The role of altered SctO2 in HF therapy and cognitive function should be further examined. High GPCR activity is predictive of POTS supporting autoimmune involvement. Exercise training in POTS warrants further studies for effective clinical implementation.