This study is led by Ronald Tompkins, PhD, and Wenzhong Xiao, PhD, in collaboration with David Systrom, MD, at the Brigham & Women’s Hospital and Richard Smith, PhD, John Jacob, PhD, and Wei-Jun Qian, PhD, at Pacific Northwest National Laboratory.
This project aims to understand the origin of postural orthostatic tachycardia syndrome (POTS). POTS is one of the more common symptoms of ME/CFS. This syndrome appears to involve the cardiopulmonary and peripheral vascular systems, both are modulated by the autonomic nervous system. It is unclear why these systems become dysfunctional to cause POTS but understanding the biological pathology underlying it will be relevant to helping understand its relationship to ME/CFS.
Cardiopulmonary exercise testing together with direct measurement through invasive arterial catheters (iCPET) has been useful to define the reason for unexplained dyspnea in general populations thought to be heart or lung in origin. Using this same diagnostic tool, ME/CFS patients have been evaluated and found to demonstrate a preload failure (PLF) pattern under maximum exercise. There are two forms of this PLF that has been observed: low flow and high flow. The low flow phenotype appears to be consistent with a failure of the autonomic nervous system to shift blood from the venous to the arterial side of the circulation or another possibility is a reduced total blood volume. On the other hand, the high flow phenotype appears as an arterial to venous shunt in the peripheral circulation or another possibility is a reduced oxygen delivery to peripheral circulatory beds or a reduced utilization by the mitochondria.
Aspects of this PLF are highly consistent with mechanisms that result in POTS and post-exertional malaise (PEM), which are seen in many ME/CFS patients. These proposed studies offer significant opportunities for the identification of new drug targets and drug therapies for ME/CFS.
A blood tissue repository has been underway at the BWH for ME/CFS patients undergoing iCPET for many years and blood is available to study 84 ME/CFS patients (all with POTS) and 30 healthy participants for comparison. These blood samples are obtained before, during peak, and one hour after an iCPET procedure and will undergo analysis by proteomic, phospho-proteomic, and metabolomic methods.
Phospho-proteomics is an analysis form yet to be conducted on ME/CFS patient samples. Plasma proteomics have been conducted in ME/CFS patients but always at rest and not under stress exercise conditions when fatigue and exercise-induced differences are most likely to become evident.