Endothelial Dysfunction in Postural Tachycardia Syndrome

Endothelial Dysfunction in Postural Tachycardia Syndrome
Study describes vasodilation abnormalities of this poorly understood condition.

Postural tachycardia syndrome (PoTS) is a confounding syndrome affecting upwards of three million people in the U.S. Largely diagnosed in women, PoTS renders an individual unable to stand without experiencing a rapid increase in heart rate, causing symptoms of dizziness, confusion and extreme fatigue.

A new study published in Hypertension, led by Alfredo Gamboa, M.D., research associate professor of medicine at Vanderbilt University Medical Center, could clarify the root causes of postural tachycardia syndrome and define a path to targeted treatment. The researchers’ findings of impaired vasodilatory function in the brachial artery of PoTS patients is the first to clearly connect the dots between PoTS and endothelial dysfunction.

“Our findings will help us probe why the endothelial cells are dysfunctional in PoTS and provide a metric to track this in future investigations,” he said. “We will be digging deeper into connections between PoTS and the sympathetic system, nitric oxide (NO) release and hypoperfusion.”

Unclear Etiology 

The new postural tachycardia syndrome study grew out of Gamboa’s work researching the role of the autonomic nervous system in cardio-metabolic regulation and endothelial dysfunction in obesity. “We knew our patients with obesity had increases in sympathetic activity and impaired vasodilation. We believed this could also be happening in PoTS patients, even though their phenotype is very different,” Gamboa said.

The etiology is not clear, but evidence suggests PoTS may be a sequalae of physiological trauma or infection. “We have even seen marathoners with this condition – they started with flu-like symptoms and then developed PoTS,” Gamboa said.

While the tilt table test is the gold standard for diagnosis, Gamboa advocates for the simpler method of taking a patient’s vitals both when the patient is supine and standing. Supine vitals are usually normal in patients with PoTS, so considered alone, this has often led to misdiagnoses of psychological problems and standalone recommendations of more exercise, Gamboa explained.

“We knew our patients with obesity had increases in sympathetic activity and impaired vasodilation. We believed this could also be happening in PoTS patients.”

Confirming Conduit Artery Dysfunction 

The study team began with the knowledge that PoTS patients experience symptoms related to cerebral hypoperfusion and sought to learn if prolonged sympathetic activity had a negative impact on endothelial function, affecting vasodilation in these patients.

The team enrolled 19 patients with PoTS (1 male and 18 premenopausal females, ages 18 to 53) and nine healthy volunteers of similar age and weight. To measure the endothelial response, they used a rapid cuff inflation system to induce ischemia both in the brachial artery and separately, in resistance vessels in the legs, for five minutes. This was followed by induction of shear stress upon cuff release. Using ultrasound and strain gauge plethysmography, flow-mediated dilation was assessed in vessels before and after ischemia, and in the microcirculation of the hand with finger sensors.

Release of the cuffs should theoretically trigger tonic NO release, acting as a vasodilator to relax the vessel walls. Yet the researchers found that PoTS participants’ brachial arteries dilated just over half as much those of healthy controls. “This points to the sympathetic nervous system as the culprit in preventing vasodilation, tying PoTS to endothelial dysfunction,” Gamboa said.

Beyond the evidence of increased sympathetic activity, there are other potential mechanisms that may contribute to the observed conduit artery endothelial dysfunction, Gamboa explained. These include the role of angiotensin II, sex hormones and levels of asymmetrical dimethylarginine, an endogenous competitive inhibitor of endothelial NO synthase.

Developing Targeted Strategies

Currently, symptom management includes only dietary changes (increase fluid and salt intake), lifestyle modifications (increased exercise), and off-label drugs. Typically, these are low-dose beta blockers, which blunt the increase in heart rate at the potential expense of limiting exercise tolerance.

To work toward the development of targeted therapies, the team’s next steps involve collecting and studying endothelial cells from PoTS patients. Gamboa’s hope is that this research may lead to the repurposing of drugs that can modify NO bioavailability or decrease inflammation and/or reactive oxygen species for treatment of PoTS.

Gamboa also aims to study PoTS patients longitudinally. “We see these patients for roughly five years, but we don’t know what happens when they are in their 50s or 60s,” he said. His team is currently contacting previous PoTS patients to learn how the disease progresses or if symptoms subside with age, particularly after menopause.