PROJECT SUMMARY This project aims to elucidate the pathophysiological basis for the higher prevalence of hypertension and cardiovascular disease in individuals with Autism Spectrum Disorder (ASD). Although it has been suggested that individuals with ASD may have sympathetic hyperactivity, limited studies using indirect measures have been performed. To date, direct measures of resting sympathetic nerve activity (SNA) have not been made in individuals with ASD. An exaggerated blood pressure response to acute exercise is typically seen in individuals with hypertension and other chronic conditions, and such changes in blood pressure are also associated with an increased risk of future stroke and cardiovascular mortality. Identifying neural and vascular mechanisms of elevated blood pressure in the ASD population is an essential first step to inform future research on the efficacy of clinical intervention to lower blood pressure in ASD; thus, it could reduce the risk of cardiovascular mortality. The pressor response evoked during exercise is a result of neural inputs including activation of the exercise pressor reflex to cause sympatho-excitation and activation of arterial baroreflex to cause sympatho- inhibition. We aim to identify whether heightened SNA is a major contributor to augmented blood pressure during exercise in ASD caused by augmented exercise pressor reflex activation (Aim 1). Further, we aim to determine how sympathetically mediated vascular responses contribute to the blood pressure increase during exercise in ASD (Aim 2), and whether impaired arterial baroreflex function contributes to augmented SNA and blood pressure responses in ASD compared to controls (Aim 3). In these studies, we will directly measure muscle SNA, skeletal muscle blood flow, and continuous blood pressure in both young adults with ASD and healthy controls at rest and while they perform exercise. This study will be the first to investigate neural control mechanisms of the cardiovascular system in an ASD population using state-of-the-art techniques. Thus far only indirect measures (e.g., resting heart rate and blood pressure variability) have been employed to understand autonomic dysfunction in ASD population. We will measure muscle SNA directly from the peroneal nerve using microneurography technique for the first time in ASD population both at rest and during exercise. Identifying sympathetic overactivity in ASD is important because it not only contributes to the hypertension but also may accelerate the progression of other health complications including heart disease independent of any rise in blood pressure. In addition, by using the unique noninvasive variable pressure neck chamber technique, we will identify not only arterial baroreflex control of muscle SNA, but also control of blood pressure as an outcome both at rest and during exercise. Collectively, with guidance from SC2 mentors who have expertise in clinical applications of autonomic function and exercise testing and training in health and disease, this study will begin to identify pathophysiology of early hypertension and cardiovascular disease in individuals with ASD. The findings will form the basis for future experimental and clinical studies to determine an effective therapeutic target, enable improved patient care, and ultimately enhance the quality of life for individuals with ASD.

PROJECT NARRATIVE This project aims to elucidate the pathophysiological basis for the higher prevalence of hypertension and cardiovascular disease in individuals with Autism Spectrum Disorder (ASD). We proposed to investigate 1) whether heightened sympathetic nervous system activity is a major contributor to augmented blood pressure during exercise in ASD; it is caused by impaired exercise pressor reflex activation, 2) how sympathetically mediated vascular responses contribute to the blood pressure increase during exercise in ASD, and 3) whether impaired arterial baroreflex function causes exaggerated sympathetic nervous system activity during exercise in ASD. With guidance from SC2 mentors who have expertise in clinical applications of autonomic function and exercise testing and training in health and disease, this study will begin to identify pathophysiology of early hypertension and CVD in individuals with ASD and will form the basis for future experimental and clinical studies to determine an effective therapeutic target, enable improved patient care, and ultimately enhance the quality of life for individuals with ASD.