Neuronal and hormonal perturbations in postural tachycardia syndrome

REVIEW ARTICLE

Front. Physiol., 16 June 2014 | https://doi.org/10.3389/fphys.2014.0022

Philip L. Mar and Satish R. Raj*

  • Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA

The Postural Tachycardia Syndrome (POTS) is the most common disorder seen in autonomic clinics. Cardinal hemodynamic feature of this chronic and debilitating disorder of orthostatic tolerance is an exaggerated orthostatic tachycardia (≥30 bpm increase in HR with standing) in the absence of orthostatic hypotension. There are multiple pathophysiological mechanisms that underlie POTS. Some patients with POTS have evidence of elevated sympathoneural tone. This hyperadrenergic state is likely a driver of the excessive orthostatic tachycardia. Another common pathophysiological mechanism in POTS is a hypovolemic state. Many POTS patients with a hypovolemic state have been found to have a perturbed renin-angiotensin-aldosterone profile. These include inappropriately low plasma renin activity and aldosterone levels with resultant inadequate renal sodium retention. Some POTS patients have also been found to have elevated plasma angiotensin II (Ang-II) levels, with some studies suggesting problems with decreased angiotensin converting enzyme 2 activity and decreased Ang-II degradation. An understanding of these pathophysiological mechanisms in POTS may lead to more rational treatment approaches that derive from these pathophysiological mechanisms.

 

Introduction

Postural Tachycardia Syndrome (POTS) is a debilitating syndrome that is characterized by symptoms of presyncope when assuming an upright position. This syndrome is the most common disorder seen in autonomic specialty clinics and affects 500,000–3,000,000 individuals in the United States (Robertson, 1999). Young women are disproportionately affected, with nearly 80–85% of cases occurring in women and most of childbearing age (Garland et al., 2007). The cardinal hemodynamic feature of this syndrome is an increase in heart rate (HR) by ≥30 bpm on assuming an upright position within 10 min in the absence of orthostatic hypotension (a drop in systolic blood pressure (BP) >20 mmHg or a drop in diastolic BP >10 mmHg) (Freeman et al., 2011Raj, 2013). In addition, symptoms of orthostatic intolerance (palpitations, light-headedness, chest discomfort, or dyspnea) must accompany this orthostatic tachycardia, improve with recumbency and persist for at least 6 months. Symptoms must also occur in the absence of conditions that cause orthostatic tachycardia, such as prolonged bedrest, use of medications that impair autonomic regulation (vasodilators, diuretics, antidepressants, or anxiolytic agents), or chronic debilitating disorders that cause tachycardia (such as dehydration, anemia, or hyperthyroidism) (Raj, 2013).

Neurohormonal dysregulation has been identified in a number of patients with POTS. We will discuss the data supporting this implication and review the neurologic and hormonal aspects of POTS as it pertains to the pathophysiology of this condition.

 

Pathophysiology of POTS (Table 1)

POTS is a heterogeneous syndrome with several different pathophysiological mechanisms that can result in the typical POTS presentation, and a few more common ones are highlighted in this manuscript (Figure 1) (Raj, 2013). Neuropathic POTS is a condition with a partial neuropathy where there is preferential denervation of sympathetic nerves in the lower limbs that may account for local/regional blood flow abnormalities including venous pooling (Jacob et al., 2000Stewart et al., 2003). A state of hypovolemia also exists in the majority of POTS patients. This phenomenon of low blood and plasma volumes in the presence of inappropriately low levels of renin and aldosterone in POTS patients has been referred to as the “renin-aldosterone paradox” (Raj et al., 2005a). This hypovolemic state can lead to decreased venous return, and contributes to presyncopal symptoms in addition to reflex tachycardia. Though many POTS patients have elevated plasma norepinephrine secondary to partial autonomic neuropathy or hypovolemia, central hyperadrenergic POTS is a variant of POTS where individuals have high levels of upright plasma norepinephrine in the absence of these two findings (Raj et al., 2005aMustafa et al., 2011Raj, 2013). A few patients in one family have a specific genetic abnormality linked to a single point mutation in the norepinephrine transporter with subsequent diminished clearance of norepinephrine (Shannon et al., 2000). This hyperadrenergic state is thought to drive the orthostatic tachycardia in these patients (Figure 1). The different pathophysiological mechanisms are not mutually exclusive, and POTS patients will often have an overlap of features from a number of these aforementioned variants.

Table 1. Some pathophysiological mechanisms of POTS and related treatments.

Table 1. Some pathophysiological mechanisms of POTS and related treatments.

Figure 1. Pathophysiological mechanisms of postural tachycardia syndrome.Cartoon representation of how 3 major neuronal and hormonal abnormalities and their immediate effects may cause symptoms commonly associated with POTS.

Figure 1. Pathophysiological mechanisms of postural tachycardia syndrome. Cartoon representation of how 3 major neuronal and hormonal abnormalities and their immediate effects may cause symptoms commonly associated with POTS.

Neuropathic POTS (Partial Autonomic Neuropathy)

In 1988, Streeten et al. first published a report regarding the pathophysiology of POTS. In 34 patients with symptoms of orthostatic intolerance, 10 patients exhibited orthostatic increases in HR >30 bpm. In these 10 individuals, radioisotopic measurements of orthostatic pooling of blood in the calf was significantly greater compared to healthy subjects (P < 0.01), which was suggestive of at least partial autonomic neuropathy related to a portion of the autonomic system (Streeten et al., 1988).

Abnormal blood flow abnormalities in the lower extremity

Stewart and Weldon confirmed increases in orthostatic leg volume and venous blood flow consistent with excessive pooling in the lower extremities in a pediatric POTS population using strain-gauge measurements (Stewart and Weldon, 2000). They further dichotomized POTS patients into two groups based on lower extremity venous pressure (VP) > 20 mmHg (high-VP POTS) or ≤20 mmHg (low-VP POTS) and found defective vasoconstriction in both groups as evidenced by significantly more blood flow in the calves during orthostasis compared to healthy subjects. While supine, high-VP POTS group had normal arterial resistance but lower blood flow in the lower extremities compared to healthy subjects, and the low-VP POTS group had less arterial resistance and higher blood flow in the lower extremities compared to healthy subjects (Stewart and Weldon, 2001). High-VP POTS patients, also referred to as “low-flow” POTS patients (LFP), had inappropriate vasodilation during orthostasis instead of the vasoconstriction that was seen in healthy subjects and “high-flow” POTS (HFP) patients. The excessive blood pooling in the lower extremities and increased orthostatic leg volume is due to a defect in arteriolar vasoconstriction and not an abnormality of venous capacitance (Stewart, 2002Stewart et al., 2003). These studies indicate there is an abnormal vascular response in the extremities that predisposes POTS patients to venous pooling secondary to arteriolar dysregulation.

Abnormal regional blood volume regulation

Both Doppler ultrasound and segmental impedance plethysmography (Diedrich and Biaggioni, 2004) have indicated that there is abnormal blood flow and pooling in the splanchnic circulation of many POTS patients (Tani et al., 2000Stewart and Montgomery, 2004). Both “low-flow” and “high-flow” patients had significantly greater decreases greater decreases in thoracic blood flow versus healthy subjects during orthostasis (P < 0.025 and P < 0.004 respectively). In addition, “low-flow” POTS patients had increased splanchnic blood flow compared to healthy subjects (P < 0.01) with upright position (Stewart et al., 2006b). “High-flow” POTS patients had increased pooling in the pelvis and legs versus healthy subjects (P < 0.05 and P < 0.025 respectively) (Stewart and Montgomery, 2004).

Partial autonomic neuropathy

An explanation for this adverse blood pooling is a partial autonomic neuropathy. Schondorf and Low initially found evidence of generalized autonomic neuropathy in patients with POTS (Schondorf and Low, 1993). Later, Jacob et al. showed that there was a defect in sympathetic nervous system innervations of the lower extremity in POTS patients (Jacob et al., 2000). They demonstrated that norepinephrine spillover, or the norepinephrine that was released at sympathetic synapses and “spilled over” into the venous circulation, was considerably impaired. This defect in norepinephrine spillover was predominantly in the lower extremities. Using a cold pressor test, a nitroprusside infusion, and tyramine infusion, they demonstrated that there was decreased norepinephrine spillover in POTS patients compared to healthy subjects in each of the 3 tests (P = 0.02, P = 0.01, and P = 0.04 respectively). In contrast, systemic and upper extremity norepinephrine spillovers were unchanged in POTS patients compared to healthy subjects. Taken together, these data suggest that some patients in POTS have inadequate sympathetic tone to the lower extremities leading to diminished vasoconstriction and venoconstriction. At this point, it is unclear if this is due to denervation and/or impaired norepinephrine release at the synaptic cleft of these peripheral sites. Nevertheless, what results is diminished venous return and decreased stroke volume, with a secondary increase in central sympathetic nerve traffic that results in excessive orthostatic tachycardia.

Renin-Angiotensin Aldosterone System (RAAS) and Hypovolemia in POTS

Hypovolemia and the “Renin-Aldosterone Paradox”

In more recent years, hormonal research as it relates to the pathophysiology of POTS has converged on the renin-angiotensin aldosterone system. Low blood volume (red cell volume and plasma volume) has been demonstrated in multiple studies in POTS patients (Jacob et al., 1997Raj et al., 2005aStewart et al., 2006aFu et al., 2010). Raj et al. showed that a cohort of POTS patients specifically have inappropriately normal levels of plasma renin activity (PRA) and paradoxically lower levels of aldosterone (P = 0.017) despite their hypovolemia when compared to healthy subjects (Raj et al., 2005a). PRA activity was similar even after 30 min of standing. In addition, the aldosterone: renin ratio was considerably lower in the POTS group versus the healthy subjects (P = 0.047). Stewart et al. showed that the “low-flow” group of POTS patients specifically had significantly lower levels of PRA when compared to healthy subjects (P < 0.05) (Stewart et al., 2006a). Fu et al. in a study of 10 premenopausal women with POTS, found that PRA significantly rose after 2 hours of standing compared to healthy subjects, while aldosterone did not change significantly (Fu et al., 2010). They also confirmed a reduced aldosterone:renin ratio in POTS patients.

Angiotensin II (Ang-II)

Subsequent work has also shown that plasma Ang-II levels in some POTS patients are elevated when compared to healthy subjects (Stewart et al., 2006aMustafa et al., 2011). Ang-II is the major effector of the RAAS axis, causing systemic vasoconstriction, raising BP, and is critical for maintaining fluid balance homeostasis through aldosterone secretion (Zhuo and Li, 2011). Elevations of Ang-II in POTS patients are on the order of 2-3 times higher than healthy subjects (Stewart et al., 2006aMustafa et al., 2011). The absence of hypertension in these patients is therefore perplexing. Mustafa et al. infused a standard dose of Ang-II into POTS patients and healthy subjects (Mustafa et al., 2012). They found that POTS patients have a blunted systemic vascular and hypertensive response to Ang-II versus healthy subjects. Importantly, Ang-II infusion induced a similar amount of aldosterone production in POTS patients as it did in healthy subjects. Renal blood flow and vascular response was also unchanged between POTS patients and healthy subjects (Mustafa et al., 2012). The full implications of increased plasma Ang-II in POTS patients is still unclear.

Pleiotropic effects of the AT1 receptor (AT1R)

Ang-II exerts most of its physiologic effects though AT1R (De Gasparo et al., 2000). This G-protein coupled receptor elicits multiple cellular responses via coupling to Gq proteins. While most of its action are rapid and attributed to G-protein meditated secondary messengers, there is increasing evidence that the internalization of Ang-II by AT1R can produce long-lasting genomic and gene transcriptional effects via continued activation of intracellular targets (Zhuo and Li, 2011). AT1R is a very pleiotropic receptor, found in a variety of different tissues, including adrenal, neuronal, cardiac, renal, and vascular smooth muscle cells (De Gasparo et al., 2000). Some of its actions are consistent throughout the body, while some will vary based on the location of the receptor. For example, while it generally elicits hypertensive responses via its actions on vascular smooth muscle cells (VSMC) in most tissue beds, it has hyperproliferative effects only on VSMC in the cerebral vasculature, and not on VSMC located peripherally (Hunyady and Catt, 2006). Additionally AT1R also plays an important role in the central nervous system where Ang-II acts like a neurotransmitter, modulating BP, salt intake, thirst mechanisms, and other neuroendocrine processes (De Gasparo et al., 2000). The pleiotropic nature of this receptor, along with its multiple pathways of activation, contributes to the versatility of Ang-II. This concept is relevant to the discussion of POTS physiology because a response will vary based on the specific tissue being studied.

Microvascular nitric oxide dysfunction

Medow et al. found that there was defective cutaneous vasodilation of the microvasculature mediated by nitric oxide with local heating in POTS patients versus healthy subjects (Medow et al., 2005). Neuronal nitrous oxide synthase (nNOS), and not endothelial nitrous oxide synthase (eNOS), was determined to be responsible for causing this phenomenon (Stewart et al., 2007). Ang-II plays an important role in this defect of microvascular vasodilation because the administration of an angiotensin type 1 receptor (AT1R) blocker, losartan, reverses this defect in POTS patients (Stewart et al., 2008). In summary, the skin blood flow defect present in POTS patients can be simulated in healthy subjects by infusing a nNOS inhibitor, and can be reversed in POTS patients by infusing an Ang-II antagonist. These skin findings may play a role in the dependent acrocyanosis seen in many POTS patients. There are not yet any studies that have assessed whether these skin findings have systemic vascular implications.

Angiotensin converting enzyme 2 (ACE2)

ACE2 is a monocarboxypeptidase that metabolizes Ang-II, an octapeptide, into Angiotensin 1-7 [Ang(1-7)]. Ang(1-7) has vasodilatory properties and has actions that generally oppose that of Ang-II (Chappell, 2007Zhuo and Li, 2011). Ang(1-7) also plays a role in skin microvascular dysregulation (Stewart et al., 2009Mustafa et al., 2012).

Stewart et al., showed that with local infusion of losartan and a NOS inhibitor, cutaneous vasodilation due to local heating is reduced in healthy subjects to the level of POTS patients (Stewart et al., 2009). However, even in the presence of losartan and a NOS inhibitor, the infusion of Ang-II can reverse this reduction in cutaneous vasodilation only in healthy subjects, whereas the lack of vasodilation persists in POTS patients. The source of this recovery in vasodilation in healthy subjects after Ang-II infusion is thought to be peripheral conversion of Ang-II into Ang(1-7) as addition of an ACE2 inhibitor will sabotage this vasodilation in healthy subjects. Similarly, in POTS patients, even in the presence of NOS and losartan, infusion of Ang(1-7) can restore normal cutaneous vasodilation. Thus, the source of this dysregulation is thought to represent a deficiency of ACE2 in the skin of POTS patients.

Mustafa et al. also showed that this deficiency in ACE2 extends into the systemic circulation by measuring the ratio of Ang(1-7) to Ang-II and used it as a surrogate for functional ACE2 activity (Mustafa et al., 2011). In the presence of elevated systemic levels of Ang-II with comparable levels of Ang1-7, POTS patients had a significantly lower ratio of Ang(1-7):Ang-II when compared to healthy subjects (P = 0.038).

Further investigations

The source of ACE2 dysfunction in POTS patients is still unclear. A specific genetic mutation could be the cause. Alternatively, ACE2 dysfunction could be a downstream manifestation resulting from POTS. As most POTS patients are intolerant of physical activity, ACE2 dysfunction could be a product of general deconditioning. Prior research has shown that diet, at least in the short term, does not affect level of ACE2 activity (Mustafa et al., 2011).

Another possibility is that the measured Ang-II might not really be Ang-II. Most prior studies that have quantified Ang-II have employed assays that were not sensitive enough to distinguish Ang-II from angiotensin 3 or angiotensin 4 since they typically employed radioimmunoassays that targeted the peptides common to the C-terminus (Stewart et al., 2006aMustafa et al., 2011). It is possible that some of the measured “Ang-II” is actually angiotensin 3 or angiotensin 4.

The exact mechanism of how a defect in ACE2 might trigger the clinical manifestations of POTS is also still poorly understood. While there may be a deficiency in peripheral and cutaneous vasodilation secondary to an ACE2 defect, it is not clear how that produces orthostatic tachycardia and presyncopal symptoms.

In addition to the “renin-aldosterone paradox” with the lack of aldosterone response in the presence of hypovolemia, the high Ang-II levels and low ACE2 activity remains to be explained.

Hyperadrenergic POTS

Previous studies in normal healthy subjects have demonstrated normal supine plasma norepinephrine levels to be around 200 pg/mL (Jacob et al., 1998). With standing, upright norepinephrine levels plateau below 600 pg/mL after 7.5 min. Supine plasma epinephrine levels are around 25 pg/mL and increase with standing up to 70 pg/mL. Numerous studies have documented comparable supine levels of norepinephrine and epinephrine between POTS and healthy subjects, but elevated upright norepinephrine (Jacob et al., 2000Raj et al., 2005aMustafa et al., 2011). Tachycardia is the most salient manifestation of this hyperadrenergic state. Another manifestation of increased SNA during orthostasis in POTS patients includes possibly increasing coherence and blunting cerebral autoregulation leading to decreased cerebral blood flow (Ocon et al., 2009). However, it should be noted that there are several studies in the literature with inconsistent findings related to cerebral blood flow during orthostasis in POTS patients (Jordan et al., 1998Schondorf et al., 2005Ocon et al., 2009).

Using muscle sympathetic nerve activity (MSNA) as measured by microneurography, sympathetic nervous activity (SNA) in POTS patients has been shown to differ from that of healthy subjects at rest (Furlan et al., 1998), during orthostasis (Muenter et al., 2005), or induced hypotension (Bonyhay and Freeman, 2004). Although data available is conflicting regarding resting SNA activity in POTS patients, POTS patients have an exaggerated SNA response compared to healthy subjects during orthostatic and hypotensive challenge (Bonyhay and Freeman, 2004Muenter et al., 2005).

One etiology behind this exaggerated SNA response is attributed to norepinephrine transporter (NET) dysfunction. Administration of a NET inhibitor, reboxetine, to healthy subjects has been shown to produce a POTS phenotype with increase of HR in response to head-up tilt testing by greater than 30 bpm (Schroeder et al., 2002). NET inhibition is thought to increase norepinephrine concentrations acting on postsynaptic adrenoreceptors, which drives the tachycardia in POTS. The disproportionate response in HR can be explained by the heart's essential reliance on the NET (Esler et al., 1991).

This hyperadrenergic state can be “secondary” such as in response to hypovolemia, or “primary” such as one related to a genetic mutation. Shannon et al. demonstrated that a specific genetic mutation can cause POTS. A specific missense mutation in the exon of the norepinephrine transporter gene (SLC6A2) produced an Ala457Pro mutation in the norepinephrine transporter causing 98% loss of function (Shannon et al., 2000). The mutation was isolated in a 33 year old woman with a 20 year history of orthostatic intolerance as well as her identical twin sister. Plasma supine norepinephrine levels were normal for both patients (269 pg/mL and 199 pg/mL), but both patients had upright plasma norepinephrine levels exceeding 900 pg/mL, and 1 patient became hypertensive with standing. Although most patients with hyperadrenergic POTS do not have this genome mutation, epigenetic modification at this gene locus which decreases expression of the NET protein has also been associated with POTS patients. Bayles et al. demonstrated that the promoter of the SCL6A2 gene was especially sensitive to histone modifications that downregulated expression of this protein (Bayles et al., 2012). The data here demonstrates inhibition of the norepinephrine clearance transporters, which is a mechanism of many psychotropic medications, predisposes individuals to elevated levels of upright norepinephrine and can produce a typical POTS phenotype.

There is also some data that the parasympathetic system may contribute to the tachycardia in POTS. Furlan et al. reported that low frequency (0.04–0.15 Hz) R-R interval, a marker of parasympathetic activity, was slightly reduced compared to healthy subjects, though this was not statistically significant (Furlan et al., 1998). Thus, decreased cardiovagal activation due to reduced parasympathetic nervous system activity and its contribution on POTS is still unclear.

 

Treatment Approaches: Addressing Neurohormonal Imbalances (Table 1)

Partial Autonomic Neuropathy—Alpha-1 Agonists

Alpha-1 agonists have been used in POTS patients to restore the lack of adrenergic vasoconstriction due to partial autonomic neuropathy in the lower extremities. Phenylephrine infusions have previously been shown to improve HR and enhance peripheral vasoconstriction in POTS patients. However, phenylephrine infusion also increased BP in these patients (Stewart et al., 2002). Jacob et al. have shown that midodrine, an orally active alpha-1 agonist at 5-10 mg doses, is very effective at reducing the orthostatic tachycardia at 1 and 2 hours after administration. In addition it had very minimal effects on the BP and also reduced supine HR (Jacob et al., 1997). The addition of a beta-blocker in addition to midodrine enhanced the therapeutic efficacy when compared to midodrine alone (Lai et al., 2009). More recently, it was shown that “high-flow” POTS patients were much more responsive to the treatment of midodrine than “low-flow” POTS patients (Ross et al., 2014).

Octreotide is a somatostatin analog that causes vasoconstriction in the splanchnic vascular bed. It has been shown to significantly reduce orthostatic tachycardia in POTS patients to a similar extent that midodrine does (Hoeldtke and Davis, 1991Hoeldtke et al., 2006). Standing times were increased when midodrine was added to octreotide treatment in POTS patients, but neither midodrine nor octreotide alone significantly increased standing times (Hoeldtke et al., 2006).

Hypovolemia and Renin-Angiotensin-Aldosterone Paradox—Volume Loading

Fludrocortisone is a potent fluorinated aldosterone agonist that causes significant sodium and water retention (Thorn et al., 1955). It has been widely and successfully used for the treatment neurogenic orthostatic hypotension (Freeman, 2008Freeman et al., 2011). Fludrocortisone is also considered a first-line treatment for POTS and has been shown to improve symptoms significantly (Freitas et al., 2000Raj, 2013). Before starting blood volume expansion agents, medications that directly antagonize aldosterone, such as spironolactone or drosperinone (which is found in certain oral contraceptives) should be stopped first.

Desmopressin (DDAVP) is an orally available synthetic analog of arginine vasopressin. In a study of 30 POTS patients, the short-term administration of DDAVP orally reduced the degree of orthostatic tachycardia compared to placebo significantly (P < 0.001). In addition, patients reported significant improvements in overall symptoms, and specifically symptoms related to vision, tremulousness, and palpitations (Coffin et al., 2012).

Erythropoietin has also been used to treat the decreased blood volume in POTS patients by artificially increasing erythropoiesis. Hoeldtke et al. initially found no improvement in reducing orthostatic tachycardia in a small study involving 8 patients with orthostatic intolerance after 6–12 weeks of erythropoietin treatment. Furthermore, supine as well as standing BP were elevated (Hoeldtke et al., 1995). In a larger study of 39 POTS patients refractory to conventional treatment, erythropoietin administration garnered no improvement in orthostatic tachycardia. However, a significant proportion (~80%) of these patients reported subjective improvement of their symptoms (Kanjwal et al., 2012).

The use of volume loading with intravenous saline is effective at acutely relieving the symptoms of POTS. Jacob et al. showed that the infusion of 1 liter of normal saline over a time period of 1 h was effective in significantly reducing orthostatic tachycardia at 1 h upon the completion of the infusion (Jacob et al., 1997). The results of this are short-lived. Some patients have pursued chronic IV saline infusions, but this is not widely advised due to concerns about access complications.

Fu et al. conducted a trial before-after exercise training to 3 months of an exercise regimen consisting of 4 sessions per week, each lasting 30–45 min (n = 19) (Fu et al., 2011). The 3 month exercise program was able to increase the aldosterone:renin ratios well as the plasma volumes and blood volumes in these POTS patients. Other benefits included a reduction in orthostatic tachycardia (P < 0.01), and significantly improved quality of life as assessed by the SF-36.Exercise is the only intervention that has been shown to improve the aldosterone:renin ratio and increase plasma and blood volumes over the long term.

Hyperadrenergic State—Heart Rate Control

Attempts to manage the hyperadrenergic state in these individuals center around HR control. The use of beta-blockade to decrease HR has been met with conflicting data. Masuki et al. had previously shown that POTS patients had reduced stroke volumes and required a faster upright HR to maintain cardiac output (Masuki et al., 2007). Stewart et al. showed that acute esmolol infusions did not significantly reduce orthostatic HR (Stewart et al., 2002). However, Raj et al. showed that the use of propranolol at a 20 mg dose acutely and significantly reduced orthostatic tachycardia compared to placebo (P = 0.010) up to 4 h after administration (Raj et al., 2009). Low dose propranolol also improved symptoms significantly during this time. Fu et al. found that long-acting once daily propranolol did not improve quality of life at 1 month (Fu et al., 2011).

Pyridostigmine, an acetylcholinesterase inhibitor, has also been used to manage orthostatic tachycardia (Raj, 2013). The putative mechanism behind using an acetylcholinesterase inhibitor is to increase parasympathetic tone by enhancing cholinergic activity at both the ganglionic nicotinic and the postganglionic muscarinic acetylcholine receptors (Raj et al., 2005b). In a study of 17 patients, standing HR was significantly reduced at 2 and 4 h after pyridostigmine administration vs. placebo (P < 0.001 for both times). Although pyridostigmine also acts to enhance sympathetic transduction at nicotinic ganglia, BP were unaffected. Symptoms also were significantly improved 4 h after administration of pyridostigmine. Subsequent studies by Singer et al. and Kanjwal et al. have confirmed the long-term benefits of using pyridostigmine (Singer et al., 2006Kanjwal et al., 2011).

Given that a defective norepinephrine transporter has been implicated in causing hyperadrenergic POTS, medications that inhibit norepinephrine reuptake worsen tachycardia in POTS patients (Shannon et al., 2000). Vincent et al. showed that in normal healthy individuals, higher doses of duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), caused healthy volunteers to develop a POTS-like phenotype with increased orthostatic tachycardia (Vincent et al., 2004). Green et al. have recently reported that atomoxetine increased standing HR in POTS patients and that it acutely worsened symptom burden in 2/3 of the POTS patients (Green et al., 2013). In addition, selective-serotonin reuptake inhibitors (SSRI) have also been shown to inhibit norepinephrine reuptake, (Shores et al., 2001) and recent reports show that the acute administration of the SSRI, sertraline, acutely worsened symptoms in POTS patients vs. placebo (Mar et al., 2014). These findings must be balanced against their potential long-term benefits in terms of managing anxiety from a chronic illness and coping with POTS. Data for these long-term effects are currently lacking.

 

Conclusions

Over the past 20 years, considerable research has taken place in an effort to understand and explain this enigmatic syndrome. Several neural and hormonal observations have been made in regard to the pathophysiology of POTS. POTS patients have variously been shown to have a partial neuropathic state with impaired lower extremity sympathetic innervations, abnormal venous pooling, a hypovolemic state with inadequate RAAS upregulation, cutaneous blood flow dysregulation, and also increased plasma Ang-II levels. In recent years, pathophysiology research for POTS has shifted toward work on the RAAS, and considerable emphasis has been placed on the Ang-II/ACE2/Ang(1-7) axis (Stewart et al., 20082009Mustafa et al., 20112012).

As the etiology of POTS is not completely understood, it is unclear if the Ang-II/ACE2/Ang(1-7) axis is the unifying pathologic mechanism that drives the pathophysiology for all the manifestations of POTS that do not as of yet have a crystal-clear explanation. Alternatively, the manifestations for each variant may simply be one of several but typical downstream responses to a defective Ang-II/ACE2/Ang(1-7) axis or another unifying pathologic mechanism. If so, then the exact steps that link these manifestations to that unifying pathologic mechanism will need to be elucidated.

 

Research Funding

Supported in part by NIH grants R01 HL102387, P01 HL56693, and UL1 RR024975 (Clinical and Translational Science Award).

 

Conflict of Interest Statement

National Institutes of Health grants R01 HL102387, P01 HL56693, and UL1 RR024975 (Clinical and Translational Science Award). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 

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Raj, S. R., Black, B. K., Biaggioni, I., Harris, P. A., and Robertson, D. (2005b). Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation 111, 2734–2740. doi: 10.1161/CIRCULATIONAHA.104.497594

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Keywords: postural tachycardia syndrome, aldosterone, angiotensin II, blood volume, hyperadrenergic activity, Autonomic Nervous System, neuropathy, orthostatic intolerance

Citation: Mar PL and Raj SR (2014) Neuronal and hormonal perturbations in postural tachycardia syndrome. Front. Physiol5:220. doi: 10.3389/fphys.2014.00220

Received: 07 April 2014; Accepted: 26 May 2014;
Published online: 16 June 2014.

Edited by:

Qi Fu, The Institute for Exercise and Environmental Medicine and UT Southwestern Medical Center, USA

Reviewed by:

Julian Mark Stewart, New York Medical College, USA
David Andrew Low, Liverpool John Moores University, UK

Copyright © 2014 Mar and Raj. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Satish R. Raj, AA3228 Medical Center North, Vanderbilt University, 1161 21st Avenue South, Nashville, TN 37232-2195, USA e-mail: satish.raj@vanderbilt.edu

WHY ART?

We have over 120 awareness artists from 43 countries presently...we look forward to introducing them to you as they join the gallery... Visit the artist here

One of the greatest happenings today, throughout the world is that we often feel removed or unaffected by the dilemmas or circumstances of others--be it in our neighborhoods, towns, cities, provinces, territories, countries or continents--that we reside in. Global issues like climate change, disease, hunger--sometimes these us unaffected; even when we could easily do something to help locally, domestically, internationally and/or globally. Perhaps We are not driven to action because we do not feel strongly enough that WE are part of a global community, part of a larger WE.

Giving people access to data, research, statistics in order to create awareness and hopefully engage them--most often leaves them feeling overwhelmed and disconnected, not empowered or poised for action. This is where ART can make a difference. Art does not show people what to do, yet it is engaging. ART connects you to your senses, body, your culture, your emotions, and mind. ART makes people feel. When one "feels" perhaps...there is then opportunity to spur thinking, engagement, and even action--perhaps, even action within and with YOUR community.

Most of us know the feeling of being moved by a work of art; whether it is a song, a play, a dance, a poem, a novel, a painting, or a spatiotemporal experiment or the artistry of a beautiful flower. When we are touched, we are moved; we are transported to a new place that is, nevertheless, strongly rooted in a physical experience, in our bodies. We become aware of a feeling that may not be unfamiliar to us -- but that which we have longed for. This transformative experience is what art is constantly seeking--the PARTNERSHIP that exists between the viewer or experience-er and the ART "itself".

Engaging with art is not simply a solitary event. Arts and culture communities throughout the world initiate and create opportunities that represent the uniqueness of the medium; in order to engage society and enable people to come together to share an experience -- especially if they see the world in radically different ways. The fundamental aspect that links art or allows art to act  a "bridge", is not that we agree about the experience that we share, but that we consider it worthwhile in sharing that experience at all. In art and other forms of cultural expression, disagreement is accepted and embraced as an essential ingredient. In this sense, the community created by arts and culture is potentially a great source of inspiration for politicians and activists who work to transcend the polarizing populism and stigmatization of other people, positions, and worldviews that are so endemic in public discourse today.

Art also encourages us to cherish intuition, uncertainty, and creativity and to search constantly for new ideas; artists aim to break rules and find unorthodox ways of approaching contemporary issues. Art has no boundaries.

Meet Jessica

dysautonomia

By Jessica Cave

In 2008 my mom and I were in bad car accident. After that, I started to have trouble with my heart racing, severe headaches, dizziness, and fainting.  At first, the doctors said it was anxiety and stress. They told me just To relax, and things would get better. Finally three years later my primary doctor thought I had some form of dysautonomia. I then went to see a neurologist who agreed and sent me to MayoClinic in Rochester. After a week of testing, they confirmed that I had POTS.
     I tried working for awhile as a Bagger in a grocery store. I missed a lot of work due to fatigue and migraines, and when I did go to work, I would faint. One day after I fainted my boss told me to go home and not come back until I could come to work and not faint. Needless to say, I haven't worked since that day.  I now am on Social Security disability.
     I still am always tired, my heart still races, I faint frequently, and cannot walk more than 150-175 feet without fainting, so I use a scooter to go anywhere that involves a lot of walking. Lastly, it seems as if I never have enough spoons to make it through the week.
     Most of my friends have drifted away except those few who have stood by and supported me on this journey. It is because of this unconditional support from my family and friends that I Am a WARRIOR, and why I do not let dysautonomia keep me from living my life.


Complex regional pain syndrome in children: a systematic review of clinical features and movement disorders.

Pain Manag. 2017 Mar;7(2):133-140. doi: 10.2217/pmt-2016-0036. Epub 2017 Feb 1

Abu-Arafeh H1,2, Abu-Arafeh I2.

Author information

Abstract

AIM: 

To ascertain clinical features of complex regional pain syndrome (CRPS) in children with a focus on movement disorders.

METHODS: 

all publications with original data on children with CRPS were assessed. Data were tabulated and descriptive statistics were applied.

RESULTS: 

One population-based study and nine clinic-based studies provided data on demographic and clinical characteristics of childhood CRPS. Mean age of onset was 12.5 years and 85% of patients were females (risk ratio: 1.70; 95% CI: 1.54-1.88). History of trauma in 71% and the lower limbs were affected in 75% of patients. A secondary site involvement was present in 15%. Movement disorders and dystonia were reported in 30% of children.

CONCLUSION: 

Majority of cases of CRPS in children are females with mean age of 12.5 years. Movement disorders (mainly dystonia) affect at least one in three children with CRPS.

PMID: 28142335

DOI: 10.2217/pmt-2016-0036

Please Support the OPEN ACT Orphan Product Extensions Now ~ Accelerating Cures & Treatments

 

Congress should incentivize the repurposing of potentially life-saving approved drugs for rare diseases and pediatric cancers. Similar incentives have been critical in the development of new medicines for underserved patient populations and could lead to hundreds of safe, effective and affordable rare disease treatments within the next five years. The OPEN ACT is sponsored in the House (H.R. 1223) by Representatives Bilirakis (R-FL) and Butterfield (D-NC). Senators Hatch (R-UT) and Klobuchar (D-MN) plan to introduce companion legislation shortly.

Issue: Despite advances made by the Orphan Drug Act, 95 percent of the 7,000 rare diseases still have no treatment approved by the Food and Drug Administration. Most rare disease patients are prescribed treatments off-label, at times with little clinical evidence and variable effectiveness. As a result, obtaining reimbursement for off-label treatments or procedures can be challenging for patients. Biopharmaceutical companies seldom consider repurposing approved therapies to treat rare diseases because there is little incentive for them to do so.

Solution: The OPEN ACT would establish a six-month marketing exclusivity extension, providing an incentive to a sponsor to repurpose an already approved therapy for a rare disease. The sponsor company would need to demonstrate that the repurposed therapy is safe and effective in treating the rare disease and obtain a rare disease indication from FDA on the drug label. The OPEN ACT is modeled on the highly successful Best Pharmaceuticals for Children Act (2002) that has led to more than 500 labeling changes for pediatric populations.

Background: Scientific literature shows that a single-targeted drug is likely to have multiple therapeutic uses and that biopharmaceutical companies can repurpose drugs for the treatment of different diseases. Repurposing drugs are faster, cheaper, and presents fewer risks than traditional drug development. For complex rare diseases with small patient populations, the current economic model of drug development often lacks financial viability. Utilizing targeted, economic incentives has a proven track record of encouraging industry stakeholders to invest in the development of drugs for diseases with unmet need.

Outcomes: The OPEN ACT would leverage the investment already made by biopharmaceutical companies into the development of approved therapies by providing an economic incentive to explore ways to bring more treatments for rare diseases to the marketplace through the process of repurposing drugs, resulting in:

  • Potentially hundreds of well-tested therapies approved and on the label for rare disease patients in the next five years.

  • Major market drug prices, resulting in a reduction in the average cost of rare disease drugs.

  • Fewer rare disease patients using untested and potentially ineffective drugs off–label.

  • A surge in biotech investment, new jobs, and grants to research universities to conduct repurposing

    trials.

    To co-sponsor H.R. 1223, please contact Tom Power, office of Rep. Bilirakis (R-FL), at thomas.power@mail.house.gov or Saul Hernandez, office of Rep. Butterfield (D-NC), at saul.hernandez@mail.house.gov. To be named as an original cosponsor of the Senate bill, please contact Stuart Portman, office of Sen. Hatch (R-UT), at stuart.portman@hatch.senate.gov or Rosa Po, office of Sen. Klobuchar (D-MN) at rosa_po@klobuchar.senate.gov.

 

 

177 Supporting Patient Organizations (partial list):

Ali's Angels Foundation
RASopathies Network USA
International Pemphigus and Pemphigoid Foundation (IPPF) Autoinflammatory Alliance
Children's PKU Network
Global Genes Project
GNE Myopathy International
Gwendolyn Strong Foundation
CureDuchenne
EveryLife Foundation for Rare Diseases
The Nicholas Conor Institute
Castleman Disease Collaborative Network/Castleman's Awareness & Research Effort
RARE Science, Inc.
ISMRD (the International Advocate for Glycoprotein Storage Diseases) Supporting Our Cancer Kids
Gold Rush Cure Foundation
The Coalition for Pulmonary Fibrosis
Myotonic Dystrophy Foundation
National Fragile X Foundation
Cure JM Foundation
National Leiomyosarcoma Foundation
National Organization for Rare Disorders (NORD)
Luck2Tuck Foundation
Desmoid Tumor Research Foundation (DTRF)
Dravet Syndrome Foundation
Kids v Cancer
Genetic Alliance
The Catherine Elizabeth Blair Memorial Foundation
DC Outreach Inc.
POMC Island One boy an Ocean of friends
International FOP Association
Gene Spotlight Inc.
Prader-Willi Syndrome Association
Phelan-McDermid Syndrome Foundation
Caleb's Crusade Against Childhood Cancer
International Waldenstrom's Macroglobulinemia Foundation (IWMF) Noah's Light Foundation
A-T Children's Project
Talia’s Legacy Children’s Cancer Foundation
Joey's Wings Foundation
Sofia's Hope, Inc.
Bert's Big Adventure
The Rally Foundation for Childhood Cancer Research
Sickle Cell Warriors, Inc.
Curing Retinal Blindness Foundation
Noah's Hope
Hope4Bridget Foundation
Klippel-Feil Syndrome Freedom
Hunter Syndrome Research Coalition
The Children's Medical Research Foundation, Inc.
Cure SMA
Bear Necessities Pediatric Cancer Foundation
Cures Within Reach
Aiden's Army
The MAGIC Foundation
Center for Jewish Genetics
Gene Giraffe Project
The Association for Glycogen Storage Disease
Mary Payton's Miracle Foundation
Lymphatic Malformation Institute
Sarcoma Foundation of America
Team Serena
Cure HHT
National Tay-Sachs & Allied Diseases Association (NTSAD) Choroideremia Research Foundation, Inc.
Sophia's Fund
Amyloidosis Research Consortium

Amyloidosis Foundation
Relapsing Polychondritis
Pulmonary Fibrosis Advocates
Info and Resources for Idiopathic Pulmonary Hemosiderosis (IPH-NET) Fabry Support & Information Group

PKD Foundation
Mastocytosis Society
Little Miss Hannah Foundation
Let Them Be Little X2 Inc.
CureCADASIL
CARES Foundation, Inc.
The Kortney Rose Foundation
EDSers United Foundation
The Life Raft Group
Alexa Nawrocki Pediatric Cancer Foundation
The Brooke Healey Foundation
The Champ's Corner
OsteoPETrosis Society
Children's Cardiomyopathy Foundation
EB Research Partnership
Jonah's Just Begun
Hannah's Hope Fund
Cardio-Facio-Cutaneous International
Hereditary Neuropathy Foundation
Team Sanfilippo Foundation
Sephardic Health Organization for Referral & Education
The GIST Cancer Awareness Foundation
The Truth 365
The Arms Wide Open Childhood Cancer Foundation
Pediatric Cancer Foundation
A Kids' Brain Tumor Cure
Hermansky-Pudlak Syndrome Network Inc.
The Adult Polyglucosan Body Disease Research Foundation (APBDRF) Cooley's Anemia Foundation
National MPS Society
Taylor's Tale
Cure AHC
FMD Chat
BRBN Alliance
Princesses on a Mission, Inc.
Cole vs Cancer
The Rare Cancer Research Foundation
Batten Disease Support & Research Association
Fibromuscular Dysplasia Society of America (FMDSA)
Parent Project Muscular Dystrophy
Help Extinguish Hunter Syndrome
Samuel Szabo Foundation
The Global Foundation for Peroxisomal Disorders
LMSarcoma Direct Research Foundation
MLD Foundation
DEFY Foundation
Drew's Hope Scientific Research Foundation
Dominick One in a Million
Rare Disease United Foundation
Cure Sanfilippo Foundation
Chase After a Cure
Saving Case & Friends
Beyond Batten Disease Foundation
The Ryan Foundation
Bridge the Gap - SYNGAP Education and Research Foundation NGLY1.org
Aware of Angels
Abigail Alliance for Better Access to Developmental Drugs
Angioma Alliance
Smashing Walnuts Foundation
Journey4ACure
The Rare Childhood Cancer Advocacy Group
Alex's Army Childhood Cancer Foundation 

http://action.everylifefoundation.org/p/dia/action3/common/public/?action_KEY=16974

http://action.everylifefoundation.org/p/dia/action3/common/public/?action_KEY=16974

Ask Your Legislators to Co-Sponsor the OPEN ACT to Repurpose Drugs for Rare Disease Patients

Take action to support the OPEN ACT - Orphan Product Extensions Now, Accelerating Cures & Treatments (HR 971/S 1421).  The OPEN ACT could bring hundreds of safe, effective, and affordable medicines to rare disease patients within the next several years by incentivizing drug makers to repurpose therapies for the treatment of life-threatening rare diseases and pediatric cancers. EveryLife Foundation, the National Organization for Rare Disorders (NORD), Global Genes, Genetic Alliance and an additional 155 patient organizations support this bipartisan legislation. Please take a minute to phone your legislators and share this action alert on social media! All you have to do is edit the letter below to advocate for your disease community, enter your name, address, and click submit. In order to address your message to the appropriate recipient, we need to identify where you are. Please look up and use your full nine-digit zip for the best results. (If zip code link does not work, please use this link    

Take action to support the OPEN ACT - Orphan Product Extensions Now, Accelerating Cures & Treatments (HR 971/S 1421).  The OPEN ACT could bring hundreds of safe, effective, and affordable medicines to rare disease patients within the next several years by incentivizing drug makers to repurpose therapies for the treatment of life-threatening rare diseases and pediatric cancers. EveryLife Foundation, the National Organization for Rare Disorders (NORD), Global Genes, Genetic Alliance and an additional 155 patient organizations support this bipartisan legislation.

Please take a minute to phone your legislators and share this action alert on social media! All you have to do is edit the letter below to advocate for your disease community, enter your name, address, and click submit.

In order to address your message to the appropriate recipient, we need to identify where you are.
Please look up and use your full nine-digit zip for the best results.

(If zip code link does not work, please use this link
 

 

  Legislative Status The OPEN ACT passed the House in July of 2015, but was not signed into law. The bill was reintroduced in the House on February 27th, 2017.  The bill will be reintroduced in the Senate in early 2017. Click here to download an informational OPEN ACT one-sheet. Issue:  Despite advances made by the Orphan Drug Act, 95 percent of the 7,000 rare diseases still have no FDA-approved treatment. Biopharmaceutical companies seldom consider repurposing already approved therapies to treat rare diseases because there is little incentive for them to do so. Solution:  Modeled on the incentive programs in the Best Pharmaceuticals for Children Act (BPCA), the OPEN ACT establishes an exclusivity extension, which would provide an additional six months of market exclusivity for the drug being repurposed for rare disease treatment. The sponsor company must demonstrate that the repurposed therapy is designated to treat a rare disease and obtains an approved rare disease indication from the FDA on the drug label.  Repurposing drugs is faster, cheaper, and presents fewer risks than traditional drug development. Outcomes: Double the number of treatments for rare disease patients. Many of these drugs would be priced at major market drug prices, thus bringing down the average cost of rare disease drugs. A surge in biotech investment, new jobs, and grants to research universities to conduct clinical trials. Fewer rare disease patients using untested and potentially ineffective drugs off–label.   http://everylifefoundation.org/open-act/

 

Legislative Status

The OPEN ACT passed the House in July of 2015, but was not signed into law. The bill was reintroduced in the House on February 27th, 2017.  The bill will be reintroduced in the Senate in early 2017. Click here to download an informational OPEN ACT one-sheet.

Issue:  Despite advances made by the Orphan Drug Act, 95 percent of the 7,000 rare diseases still have no FDA-approved treatment. Biopharmaceutical companies seldom consider repurposing already approved therapies to treat rare diseases because there is little incentive for them to do so.

Solution:  Modeled on the incentive programs in the Best Pharmaceuticals for Children Act (BPCA), the OPEN ACT establishes an exclusivity extension, which would provide an additional six months of market exclusivity for the drug being repurposed for rare disease treatment. The sponsor company must demonstrate that the repurposed therapy is designated to treat a rare disease and obtains an approved rare disease indication from the FDA on the drug label.  Repurposing drugs is faster, cheaper, and presents fewer risks than traditional drug development.

Outcomes:

Double the number of treatments for rare disease patients. Many of these drugs would be priced at major market drug prices, thus bringing down the average cost of rare disease drugs.

A surge in biotech investment, new jobs, and grants to research universities to conduct clinical trials.

Fewer rare disease patients using untested and potentially ineffective drugs off–label.

 

http://everylifefoundation.org/open-act/

FDA concern over experimental procedures that use balloon angioplasty devices to treat autonomic dysfunction: FDA safety communication

Date issued: March 8, 2017

Audiences:

  • Health care providers who manage the care of patients with autonomic dysfunction, including neurologists, interventionalists (radiologists, vascular surgeons, and neurosurgeons), and clinical researchers
  • People considering treatment options for autonomic dysfunction, including but not limited to Parkinson’s disease, multiple sclerosis (MS), fibromyalgia, multiple system atrophy, postural tachycardia syndrome (POTS), peripheral neuropathies, primary dysautonomia, familial dysautonomia

Medical specialties: neurology, interventional radiology, vascular surgery, neurosurgery

Purpose: To alert the audiences listed above about an experimental procedure called Transvascular Autonomic Modulation (TVAM). This procedure may put patients at risk because is being promoted as treatment for a variety of conditions even though it has not been formally studied in clinical trials. The procedure uses balloon angioplasty devices outside the scope of the FDA-approved indications for use.

This safety communication supplements a 2012 FDA safety communication and an FDA warning letter addressing the risk of serious injuries and death associated with a similar experimental procedure, using the same medical devices, to treat Chronic Cerebrospinal Venous Insufficiency (CCSVI).

Summary of problem and scope: TVAM consists of threading a catheter into a patient’s venous system, such as the jugular vein, where a balloon attached to the catheter inflates to widen the vein walls. At least one physician, Dr. Michael Arata, claims the procedure treats the signs and symptoms of autonomic dysfunction in a number of neurological disorders. The FDA has not reviewed any data that supports the safety and effectiveness of balloon angioplasty devices for this intended use.

The FDA believes that performing a TVAM procedure using these medical devices poses a risk to patients because:

  • The safety and effectiveness of using balloon angioplasty devices in a patient’s venous system has not been established for any clinical condition. The FDA has approved these devices for use only in arteries.
  • There is no clear scientific evidence to support that the treatment of internal jugular venous stenosis: 
    • is safe in any patients, including those with autonomic dysfunction;
    • impacts the symptoms of autonomic dysfunction;
    • changes the overall course of health conditions derived from autonomic dysfunction; or
    • improves the quality of life for patients with autonomic dysfunction.
  • TVAM and other similar experimental procedures have been associated with serious complications. 
    • After the safety communication issued in May 2012, the FDA received at least one medical device report of a balloon rupturing during placement in a patient’s jugular vein. Physicians ultimately determined the balloon had migrated to the patient’s lung, requiring surgery to remove the ruptured balloon.
    • Other serious complications reported to the FDA or discussed in medical journals include: at least one death, blood clots in a vein in the brain (which may lead to a stroke), cranial nerve damage, and abdominal bleeding.

Studies of medical devices, such as balloon angioplasty devices, for use in autonomic dysfunction treatment, carry significant risk and require approval through an Institutional Review Board and the FDA’s Investigational Device Exemption (IDE) program. The IDE regulations help protect the rights, safety, and welfare of patients participating in these studies. The FDA is aware of at least one physician, Dr. Michael Arata, who has continued to conduct unauthorized clinical research using these devices. The expanded list of neurological disorders he claims to treat warrant an update to the 2012 safety communication on the subject.

Recommendations:

For physicians providing care and potential clinical investigators:

  • Be aware that the FDA has not cleared or approved any balloon angioplasty devices for the treatment of autonomic dysfunction, and has not been presented with data to support the use of such devices in treating autonomic dysfunction.
  • Discuss the benefits and risks of all available treatments for autonomic dysfunction with patients, including the adverse events generally associated with catheter-guided endovascular intervention and those related specifically to use of balloon angioplasty devices for TVAM.
  • Inform patients that TVAM is experimental, and that the FDA has not been presented with any data in order to assure the safety and effectiveness of balloon angioplasty devices used in this procedure.
  • If you become aware of patients who have undergone the procedure, monitor them for potential complications such as excessive pain, discomfort, bruising, excessive bleeding from the puncture site, and stroke or stroke-like complications.
  • If any patients have experienced adverse effects from a TVAM procedure, please file a report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.

 

For people with autonomic dysfunction, including but not limited to Parkinson’s disease, MS, fibromyalgia, multiple system atrophy, POTS, peripheral neuropathies, primary dysautonomia, and familial dysautonomia:

  • Discuss the benefits and risks of all available treatments for autonomic dysfunction with your health care provider.
  • If you decide to undergo diagnostic and/or experimental treatment procedures for autonomic dysfunction, continue following the treatment plan outlined by your neurologist or the provider caring for your symptoms related to autonomic dysfunction.
  • Be aware that TVAM is an experimental procedure that has not been studied formally, and that the FDA has not been presented with any data in order to assure the safety and effectiveness of balloon angioplasty devices used in this procedure.
  • Be aware that serious complications such as excessive pain, discomfort, bruising or excessive bleeding from the puncture site can occur after a TVAM procedure. Complications can also include stroke or stroke-like symptoms.
  • If you decide to undergo a TVAM procedure and then experience complications, contact your health care provider immediately. You may also file a report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.

FDA Activities:
On September 13, 2016, the FDA issued a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) letter to Dr. Arata for conducting a TVAM research study without the review and approval of the FDA. This letter is intended to inform the recipient clinical investigator that the FDA is initiating an administrative proceeding to determine whether the clinical investigator should be disqualified from receiving investigational products pursuant to FDA’s regulations. More information regarding the NIDPOE process can be found at FDA’s Clinical Investigators - Disqualification Proceedings site.

The FDA continues to monitor for adverse events related to medical devices (i.e. balloon angioplasty devices) used in experimental procedures for the treatment of symptoms associated with autonomic dysfunction, and will take action when appropriate.

The FDA will continue to monitor this situation and keep the public informed as new information becomes available.

Reporting Problems to the FDA: 
Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices. If you suspect of a problem with angioplasty balloon devices, we encourage you to file a voluntary report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.

User facilities participating in the FDA’s Medical Product Safety Network (MedSun) should report all of their device-related adverse events through the MedSun reporting site, not through MedWatch.

Contact Information:
If you have questions about this communication, please contact the Division of Industry and Consumer Education (DICE) at DICE@FDA.HHS.GOV, 800-638-2041 or 301-796-7100.

https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm545286.htm