Effects of elevated Homocysteine hormone on electrical activity in the human atrium: A simulation study

Abstract

Atrial fibrillation (AF) accounts for a large proportion of healthcare expenditure world wide. Mechanisms underlying the genesis and maintenance of AF are still poorly understood. Though AF is largely thought to be caused and perpetuated by dysfunctions of cellular ion channels, disrupted intercellular gap junctional electrical coupling, and/or structural changes in the atria, it is also associated with abnormal secretion of hormones, such as a high level of Homocysteine (Hcy). It was found that a high concentration Hcy induces electrical remodeling of ion channels in human atrial cells that include the ultra rapid potassium, inward rectifier potassium and transient outward potassium currents. Such Hcy-induced ion channel remodeling in repolarising potassium currents has been hypothesized to be pro-arrhythmic. In this study, we carried out multi-scale simulations to evaluate the effects of Hcy-induced changes in potassium currents on the electrical activity of human atrium at single cell, 1D strand of tissue, and 3D anatomical models. We found that high Hcy concentration produced marked changes in atrial action potentials, including a more hyperpolarized resting potential, elevated plateau potential during early stages of repolarization and abbreviated action potential duration (APD). Losses in rate dependent accommodation of APD and effective refractory period were observed. In the tissue models, high Hcy concentration slowed down atrial excitation conduction at low rates, but facilitated it at high rates. Simulated re-entrant scroll waves in the 3D model self-terminated under Control condition, but sustained under high Hcy condition. These results collectively demonstrate the pro-arrhythmic effects of a high level Hcy in promoting and sustaining AF.

Elevated Homocysteine Levels Associated with Atrial Fibrillation and Recurrent Atrial Fibrillation

“…20,21) Law, et al showed that elevated homocysteine resulted in marked changes in atrial action potentials, such as a more hyperpolarized resting potential, elevated plateau potential during the early stages of repolarization, and abbreviated action po- tential duration (APD). 22) They also found that simulated re-entrant scroll waves were sustained under high homocysteine conditions compared with self-terminated under control conditions, demonstrating the pro-arrhythmic effects of elevated homocysteine in promoting and sustain-ing AF. 22) Thus, these studies likely reflect progressive electrophysiological and structural remodeling in both atria, making sources of the arrhythmia more stable and long-lasting.…”

“…22) They also found that simulated re-entrant scroll waves were sustained under high homocysteine conditions compared with self-terminated under control conditions, demonstrating the pro-arrhythmic effects of elevated homocysteine in promoting and sustain-ing AF. 22) Thus, these studies likely reflect progressive electrophysiological and structural remodeling in both atria, making sources of the arrhythmia more stable and long-lasting. Some clinical studies have shown that aging influences the development and prognosis of patients with AF.…”

Understanding the Beat-to-Beat Variations of P-Waves Morphologies in AF Patients During Sinus Rhythm: A Scoping Review of the Atrial Simulation Studies

“…The effect of specific ion currents and electrolyte concentration on arrhythmogeneity was studied (Kuijpers et al, 2006; Aslanidi et al, 2008; Law et al, 2009; Varela et al, 2014; Voigt et al, 2014; Onal et al, 2017) whereas electrical remodeling, induced by AF, and its role on episodes induction is discussed by Colman et al (2013) and Lee et al (2016). Furthermore, Morgan et al (2014) reported that co-existence of structural and electrical remodeling can promote AF initiation.…”

Association of homocysteine and smoking with cerebral microemboli in patients with mechanical heart valves: a transcranial Doppler study

“…Many studies showed that hyperhomocysteinaemia is associated with procoagulant activity, 16 left atrial thrombus formation, 17 thromboembolic complications, 18 19 stroke in atrial fibrillation 19 and persistent arrhythmia after successful epicardial ablation of atrial fibrillation. 20 21 In addition, homocysteine may have arrhythmogenic effects due to changes in atrial action potentials 4 and inhibition of atrial myocyte potassium channels. 22 Therefore, a higher number of solid microemboli in our patients with hyperhomocysteinaemia might be due to a combination of arrhythmogenic and coagulopathic effects of homocysteine.…”

“… 3 The vascular effects of homocysteine are not limited to arterial atherosclerosis or venous thrombosis. 3 Hyperhomocysteinaemia also increases the risk of embolic events, 4 including embolic strokes. 5 Patients with carotid stenosis and microemboli on transcranial Doppler (TCD) have significantly higher levels of tHcy, 6 as do patients with paradoxical embolism.…”