Project summary Postural orthostatic tachycardia syndrome (POTS) is a chronic disorder causing disabling symptoms and substantial loss of productivity. Not all POTS patients are the same, and the causes and significance of different subtypes are not known. For example, some patients may have abnormal regulation of their immune system while others may have problems with the response of their muscles to activity. Exercise training has been shown to be a beneficial treatment for POTS, but about 25% of patients are unable to complete the exercise program. Our research study will examine the different types of POTS by systematically and comprehensively studying a large diverse group of patients. This will include careful assessment of symptoms, blood tests, and heart structure as well as a detailed analysis of the muscle response to exercise. This study will be the first to define the full picture of different POTS subtypes and the relationship between these subtypes. Our studies will allow clinicians to better evaluate and individualize treatment and will guide future POTS research.