Phenotyping Dysautonomia in Unexplained Syncope: Diagnostic Yield and Therapeutic Implications in a Moroccan Cohort

Background and objective Unexplained syncope remains a frequent and challenging clinical problem, even after guideline-directed cardiovascular and neurological evaluation. In a substantial proportion of patients, syncope remains without an identified etiology after conventional investigations, suggesting alternative underlying mechanisms. Autonomic nervous system (ANS) dysfunction plays a central role in cardiovascular regulation and has been increasingly recognized as a key contributor to unexplained syncope. ANS testing allows objective evaluation of cardiovascular autonomic reflexes, including sympathetic and parasympathetic responses to orthostatic and physiological stressors. The objective of this study was to assess autonomic profiles using standardized ANS testing in patients referred for unexplained syncope and to characterize dysautonomic patterns that may contribute to syncope mechanisms. Methods We conducted a retrospective mono-centric study including 90 consecutive adult patients referred to a tertiary autonomic unit for syncope remaining without an identified etiology after conventional evaluation between January 2024 and June 2025. All patients underwent a standardized ANS testing battery, including an active standing (orthostatic) test, a deep-breathing test, an isometric handgrip test, and a mental stress test. Demographic data, cardiovascular risk factors, clinical presentation, and ANS test results were systematically collected and analyzed. Results ANS testing identified autonomic abnormalities considered clinically relevant in a high proportion of patients with unexplained syncope despite routine conventional investigations. The most frequent findings included exaggerated vagal responses, orthostatic intolerance syndromes such as postural orthostatic tachycardia syndrome, sympathetic alpha-adrenergic dysfunction leading to orthostatic hypotension, and mixed autonomic profiles. Overlapping autonomic phenotypes were frequently observed within the same patient, underscoring the complexity of dysautonomic syncope. Conclusion ANS testing provides a high diagnostic yield in patients with syncope remaining without an identified etiology after standard evaluation by revealing clinically relevant autonomic dysregulation. Integration of ANS testing as a second-line diagnostic approach may improve etiological classification and support individualized management strategies in selected patients.