Navigating Complexity in Postural Orthostatic Tachycardia Syndrome

Abstract

Postural Orthostatic Tachycardia Syndrome (POTS) affects up to 1% of the US population, predominantly women, and is characterized by a complex, elusive etiology and heterogeneous phenotypes. This review delves into the intricate physiology and etiology of POTS, decoding the roles of the sinoatrial node, the autonomic nervous system, fluid dynamics, and the interplay between the immune and endocrine systems. It further examines key contributing factors such as dysautonomia, thoracic hypovolemia, autonomic neuropathies, sympathetic denervation, autoimmune responses, and associations with conditions such as small-fiber neuropathy and mast cell activation syndrome. Given the numerous mysteries surrounding POTS, we also cautiously bring attention to sinoatrial node and myocardial function, particularly in how the heart responds to stress despite exhibiting a normal cardiac phenotype at rest. The potential of genomic research in elucidating the underlying mechanisms of POTS is emphasized, suggesting this as a valuable approach that is likely to improve our understanding of the genetic underpinnings of POTS. The review introduces a tentative classification system for the etiological factors in POTS, which seeks to capture the condition's diverse aspects by categorizing various etiological factors and acknowledging co-occurring conditions. This classification, while aiming to enhance understanding and optimize treatment targets, is presented as a preliminary model needing further study and refinement. This review underscores the ongoing need for research to unravel the complexities of POTS and to develop targeted therapies that can improve patient outcomes.

Keywords: dysautonomia; genomics; myocardial function; thoracic hypovolemia.

Figure 1

Etiological Factors of POTS. Extended thoracic hypovolemia has the potential to strain the ANS, leading to dysautonomia. Autoimmune responses targeting components of the ANS may trigger dysautonomia. POTS frequently co-occurs with conditions that have inflammatory underpinnings, suggesting inflammatory mechanisms in the pathophysiology of POTS. The diminished venoconstriction resulting from autonomic neuropathies or sympathetic denervation in the lower extremities induces thoracic hypovolemia. The impaired reuptake of norepinephrine due to NET deficiency can result in elevated circulating levels, further contributing to autonomic dysfunction. A decrease in norepinephrine clearance might be attributed to a decline in cardiac output. Molecular mimicry, leading to the formation of cross-reacting autoantibodies, may underlie the risk of POTS associated with HPV vaccination. The mechanisms behind long COVID-19 and POTS may involve hypovolemia, inflammation, and autoimmunity. Additionally, EDS may be linked to POTS due to peripheral neuropathy and thoracic hypovolemia. Endocrine dysfunction, deconditioning, muscle pump dysfunction, mast cell activation disorders, and pregnancy may also contribute to thoracic hypovolemia. Medications may cause dysautonomia. Dysautonomia leads to issues with heart rate regulation, myocardial contractility, and the function of blood vessels. Our research further highlights the significant challenges affecting the heart and circulatory system in POTS patients. Despite the fragmented understanding of POTS risk factors, highlighting a complex interplay of physiological, immunological, and environmental factors, the identification of these diverse factors underscores critical gaps in knowledge, such as the direct involvement of the heart, and offers insights into potential areas for intervention and therapeutic development. Red arrows represent central mechanisms, and blue arrows represent contributing factors.

Figure 2

Cardiac contraction and regulatory mechanisms. The purported role of myocardial function in POTS involves a complex interplay of the acto-myosin complex and multiple regulatory mechanisms. Several key players are outlined.