Exploring quality of life, underlying mechanisms, novel diagnostic techniques, and innovative therapies for recurrent syncope.

Syncope, or fainting, refers to a transient loss of consciousness caused by cerebral hypoperfusion. Syncope is highly prevalent, and difficult to diagnose, with many patients referred for extensive, costly clinical investigations, with a significant burden to healthcare resources. Managing syncope is similarly challenging, and often ineffective. Recurrent episodes impact daily life, and can lead to injuries and loss of independence. This thesis aims to advance understanding of the impact of syncope on quality of life (QoL) and provide new insights into underlying mechanisms, while exploring novel diagnostic techniques and innovative therapies to improve the assessment and management of syncope. In Chapter 3, I report the findings of a systematic review and meta-analysis, demonstrating that orthostatic syncope profoundly impairs QoL across physical and mental health domains. Increased syncopal event frequency, increased autonomic symptom severity, and the presence of mental health disorders and/or comorbidities were all associated with more severe QoL impairments. In Chapter 4, I characterize forearm vascular resistance responses to the Valsalva maneuver and explore their potential to discern syncope susceptibility. I demonstrate that maximal forearm vascular resistance responses to this stimulus increase with age, and small responses may indicate increased syncope susceptibility. Venipuncture is a potent stimulus for syncopal reactions; in Chapter 5, I describe the first double-blind, placebo-controlled cross-over study to examine the impact of intravenous instrumentation on syncope susceptibility. I show that pain plays a key role in predisposing to syncope following venipuncture, by reducing capacity to achieve maximal sympathetic activation. Topical anesthetics may be useful to prevent syncope during procedures requiring intravascular instrumentation. Gravitational fluid shifts are also a major contributor to orthostatic syncope susceptibility, and present a key therapeutic target for the management of recurrent episodes. In Chapter 6, I show that intermittent calf compression reduces gravitational fluid shifts, augments orthostatic cardiovascular control and improves tolerance of the upright posture, providing a promising novel intervention for the management of orthostatic syncope. Collectively these studies advance understanding of the impacts of syncope on QoL, elucidate underlying mechanisms, and highlight novel avenues for improved syncope diagnosis and management, with a goal of improving patient QoL.