The mechanisms of potassium loss in acute myocardial ischemia: New insights from computational simulations

Abstract

Acute myocardial ischemia induces hyperkalemia (accumulation of extracellular potassium), a major perpetrator of lethal reentrant ventricular arrhythmias. Despite considerable experimental efforts to explain this pathology in the last decades, the intimate mechanisms behind hyperkalemia remain partially unknown. In order to investigate these mechanisms, we developed a novel computational model of acute myocardial ischemia which couples a) an electrophysiologically detailed human cardiomyocyte model that incorporates modifications to account for ischemia-induced changes in transmembrane currents, with b) a model of cardiac tissue and extracellular K+ transport. The resulting model is able to reproduce and explain the triphasic time course of extracellular K+ concentration within the ischemic zone, with values of [K+]o close to 14 mmol/L in the central ischemic zone after 30 min. In addition, the formation of a [K+]o border zone of approximately 1.2 cm 15 min after the onset of ischemia is predicted by the model. Our results indicate that the primary rising phase of [K+]o is mainly due to the imbalance between K+ efflux, that increases slightly, and K+ influx, that follows a reduction of the NaK pump activity by more than 50%. The onset of the plateau phase is caused by the appearance of electrical alternans (a novel mechanism identified by the model), which cause an abrupt reduction in the K+ efflux. After the plateau, the secondary rising phase of [K+]o is caused by a subsequent imbalance between the K+ influx, which continues to decrease slowly, and the K+ efflux, which remains almost constant. Further, the study shows that the modulation of these mechanisms by the electrotonic coupling is the main responsible for the formation of the ischemic border zone in tissue, with K+ transport playing only a minor role. Finally, the results of the model indicate that the injury current established between the healthy and the altered tissue is not sufficient to depolarize non-ischemic cells within the healthy tissue.

Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study

“…Regional acute myocardial ischaemia was modelled in human 2D and 3D tissues including the (i) core ischaemic zone (CZ), (ii) lateral border zone (BZ), and (iii) endocardial BZ. 15 Ischaemia was modelled as circular/spherical with a diameter of 5 cm (including CZ and BZ), 12 , 15 , 16 , 27 consistent with reported concentric perfusion defects in HCM, 28 which are frequently >3 cm in extent. 29 The lateral BZ was modelled as 0.5 cm in width, and the endocardial BZ was modelled as 0.06 cm in width.…”

A case of short QT‐interval postventricular arrhythmia arrest from Torsade De Pointes, a new phenotype, or the result of tachycardia‐mediated imbalance

“…The likely mechanisms that can explain her transient short QT interval following her tachyarrhythmia include multiple considerations. First, a wide variety of transient metabolic changes occur during ventricular tachyarrhythmias, including increased myocardial intracellular calcium from supply‐demand mismatch, transient acidosis, and elevated serum potassium from tissue ischemia 7 . Additionally, the VR response to changes in heart rate (HR) has also been demonstrated to be maladaptive in patients with LQTS.…”

“…Her genetic test showed LQT2 with a mutation of KCNH2 gene. 7 Additionally, the VR response to changes in heart rate (HR) has also been demonstrated to be maladaptive in patients with LQTS.…”

Real-time prognostic biomarkers for predicting in-hospital mortality and cardiac complications in COVID-19 patients

“…Among the chosen biomarkers, we picked potassium for screening analysis, considering the inherent importance of electrolytes in diagnostics and the clinical role of potassium as a health indicator [12,13,[51][52][53][54][55][56]. Furthermore, several studies have been performed using nextgeneration platforms, showing the differential expression of biomarkers, including omic biomarkers or protein and gene expression of these biomarkers and others related to potassium, in the context of mortality or cardiac complications [57][58][59][60][61][62][63][64][65].…”

“…Several studies revealed a connection between high potassium levels and myocyte ischemia [ 12 , 13 ], which triggers an imbalance of potassium levels, numerous inflammatory markers in the arrhythmogenesis pathway, and damages the myocardium that results in myocarditis and arrhythmias in COVID-19 [ 14 ]. Additional studies have shown that COVID-19 patients with high troponin T levels are at elevated risk for the development of severe disease, mortality, and require ICU admission [ 15 , 16 ].…”