Altered Sympathetic Nervous Reactivity and Norepinephrine Transporter Expression in Patients With Postural Tachycardia Syndrome

Human Neurotransmitter Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia.
Circulation Arrhythmia and Electrophysiology (Impact Factor: 4.51). 06/2008; 1(2):103-9. DOI: 10.1161/CIRCEP.107.750471
Source: PubMed


Clinical observations in patients with postural tachycardia syndrome (POTS) suggest abnormal sympathetic nervous system activity and a dysfunction of the norepinephrine (NE) transporter (NET).
We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81+/-2 bpm versus 66+/-2 bpm in healthy subjects [HS], P<0.01). Head-up tilt to 40 degrees induced a greater rise in heart rate in patients with POTS (+24+/-4 bpm versus +13+/-2 bpm in HS, P<0.001). During rest in the supine position, muscle sympathetic nerve activity, arterial NE concentration, and whole-body NE spillover to plasma were similar in both groups. Muscle sympathetic nerve activity response to head-up tilt was greater in the POTS group (+29+/-3 bursts/min in patients with POTS and +13+/-2 bursts/min in HS, P<0.001), but the NE spillover rise was similar in both groups (51% in the POTS subjects and 50% in the HS). Western blot analysis of NET protein extracted from forearm vein biopsies in patients with POTS and HS demonstrated a decrease in the expression of NET protein in patients with POTS.
Patients with POTS exhibit a decrease in NET protein in their peripheral sympathetic nerves. Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt.

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    • "Some investigations (Streeten et al., 1988; Schondorf and Low, 1993; Furlan et al., 1998; Jacob et al., 1999), but not all (Jacob et al., 2000; Lambert et al., 2008), have reported that POTS patients have greater systemic plasma noradrenaline concentrations at rest or during orthostasis compared with healthy controls, suggesting that POTS is associated with a hyperadrenergic state. More robust and precise assessment of sympathetic activity by direct measurements of total body and regional noradrenaline spillover have been performed in a few investigations and the results have been variable. "
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    Frontiers in Physiology 07/2014; 5:280. DOI:10.3389/fphys.2014.00280 · 3.53 Impact Factor
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    • "It is likely that the association between depression and cognitive performance reflects the underlying neurobiology of depression, with alterations in brain monoamines influencing both depression and cognition (Lambert et al., 2000; Austin et al., 2001; Schmitt et al., 2006; Barton et al., 2008; Wingen et al., 2008; Chalermpalanupap et al., 2013). Noradrenaline transporter (NET) dysfunction is evident in patients with POTS (Shannon et al., 2000; Lambert et al., 2008) and in untreated patients with major depressive disorder (Barton et al., 2007). Interestingly, genetic variation in the NET gene has been associated with deficits in memory and attention in patients with ADHD (Thakur et al., 2012). "
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    Frontiers in Physiology 06/2014; 5:230. DOI:10.3389/fphys.2014.00230 · 3.53 Impact Factor
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    • "A point mutation in the coding region of the NET gene (SLC6A2) was identified that encoded a dysfunctional protein with dramatically reduced norepinephrine reuptake compared to wild‐type NET. While neither this mutation, nor single nucleotide polymorphisms (SNPs) in the NET gene have been found in other unrelated POTS patients, Lambert et al33 have found that some POTS patients have decreased NET protein expression when compared with healthy subjects. This may be attributable to altered posttranscriptional modification.34 "
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