There are multiple explanations for the excessive increase in HR in these POTS patients: a norepinephrine transporter dysfunction, resulting in a lower-than-normal norepinephrine clearance from the synaptic cleft [59], increased sympathetic firing with an increased cardiac norepinephrine spill-over [60], a baroreflex dysfunction with marked vagal impairment [61], an impairment of the renin-angiotensin system with a disturbed vasoconstrictor response [62], or an excessive sympathetic stimulation due to an increased venous pooling [63]. This evidence concerns the gene REN and postural orthostatic tachycardia syndrome.