The neuronal noradrenaline transporter, anxiety and cardiovascular disease

Abstract

Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses. The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients. Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic 'co-morbidity' perhaps underlies the clinical concordance. Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

Psychiatric profile and attention deficits in postural tachycardia syndrome

“…Several studies have reported that patients with POTS have comorbid psychiatric symptoms, particularly anxiety and panic disorder 8 25. Using the Structured Clinical Interview for DSM-IV axis I disorders, we found that there was no significant difference in lifetime prevalence of major depressive disorder in patients with POTS compared with a general population sample 17.…”

Psycho-physiologic emergentism; four minds in a body

“…Aberrant (not mental) stimuli can reach either the parasympathetic or sympathetic components of the autonomic component of concrete mind, such that our mental existence experiences either an unexplainable (free-floating) anxiety (unjustified by mental data), or low mood and behavior/ aversion to activity in the form of depression (23,24).…”

Mechanisms Involved in Cardiac Sensitization by Volatile Anesthetics: General Applicability to Halogenated Hydrocarbons?

“…Another line of evidence suggests that cardiac sensitization by faulty neuronal noradrenaline uptake might be the primary cause for the increased risk for sudden cardiac death in patients with panic disorder (Esler et al, 2006). Panic disorder affects 2-5% of the general population, is associated with cardiac symptoms, and prospective epidemiologic studies suggest an association between (phobic) anxiety, fatal coronary heart disease, and in particular sudden cardiac death (Kawachi et al, 1994a(Kawachi et al, , 1994b.…”

“…In patients with panic disorder, sympathetic nervous activity and adrenal medullary activity as measured by clinical microneurography were increased during panic attacks, and epinephrine spillover from the heart was elevated at rest (Wilkinson et al, 1998;Esler et al, 2004). These phenomena were not due to loss of function mutations in the coding region of the norepinephrine transporter gene, but could be traced back to hypermethylation in its promotor region leading to gene silencing (Esler et al, 2006). Thus, a faulty catecholamine reuptake associated with panic disorder might confer a particularly high risk to a susceptible human subpopulation to experience sudden cardiac death due to cardiac sensitization in the presence of halocarbons.…”