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Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia.

ABSTRACT: Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K⁺, Na⁺, Ca²⁺, and/or Mg²⁺ can significantly alter physiological responses in the heart, blood vessels, and intrinsic (intracardiac) autonomic nervous system. We have used mathematical models of the human atrial action potential (AP) to explore the electrophysiological mechanisms that underlie changes in resting potential (V_r) and the AP following decreases in plasma K⁺, [K⁺]_o, that were selected to mimic clinical hypokalemia. Such changes may be associated with arrhythmias and are commonly encountered in patients (i) in therapy for hypertension and heart failure; (ii) undergoing renal dialysis; (iii) with any disease with acid-base imbalance; or (iv) post-operatively. Our study emphasizes clinically-relevant hypokalemic conditions, corresponding to [K⁺]_o reductions of approximately 1.5 mM from the normal value of 4 to 4.5 mM. We show how the resulting electrophysiological responses in human atrial myocytes progress within two distinct time frames: (i) Immediately after [K⁺]_o is reduced, the K⁺-sensing mechanism of the background inward rectifier current (I_K1) responds. Specifically, its highly non-linear current-voltage relationship changes significantly as judged by the voltage dependence of its region of outward current. This rapidly alters, and sometimes even depolarizes, V_r and can also markedly prolong the final repolarization phase of the AP, thus modulating excitability and refractoriness. (ii) A second much slower electrophysiological response (developing 5-10 minutes after [K⁺]_o is reduced) results from alterations in the intracellular electrolyte balance. A progressive shift in intracellular [Na⁺]_i causes a change in the outward electrogenic current generated by the Na⁺/K⁺ pump, thereby modifying V_r and AP repolarization and changing the human atrial electrophysiological substrate. In this study, these two effects were investigated quantitatively, using seven published models of the human atrial AP. This highlighted the important role of I_K1 rectification when analyzing both the mechanisms by which [K⁺]_o regulates V_r and how the AP waveform may contribute to "trigger" mechanisms within the proarrhythmic substrate. Our simulations complement and extend previous studies aimed at understanding key factors by which decreases in [K⁺]_o can produce effects that are known to promote atrial arrhythmias in human hearts.

SUBMITTER: Clerx M

PROVIDER: S-EPMC8188899 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RATIONALE:Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. OBJECTIVE:To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. METHODS AND RESULTS:Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K+] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca2+ overload and increased generation of both spontaneous Ca2+ waves and delayed afterdepolarizations. However, similar Ca2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na+-K+ ATPase and Na+-Ca2+ exchanger proteins within these structures, as reduction in Na+ pump activity locally inhibited Ca2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na+ current, as they were rapidly blocked by tetrodotoxin. Na+ current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K+ current (IKur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes. CONCLUSIONS:Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.

Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Keywords: stimulated atrial myocytes human atrial fibrillation

Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation

Project description:Objective: This study aimed to identify the transcriptome profiles from periodontal tissues of replanted teeth and evaluate the functional differences of transcriptomes between immediate replantation and delayed replantation in a rat teeth avulsion animal model. Background: In dental avulsion, the prognosis of replanted teeth is hardly favorable in delayed replantation. After tooth replantation, complex inflammatory responses occur to return homeostasis in periodontal tissue. Various types of cytokines are produced in inflammatory microenvironment and these cytokines determine the periodontal tissue responses. Methods: Maxillary first molars of Sprague–Dawley rats were extracted and exposed to dry environment, then replanted. The animals were divided into two groups according to extra–oral time: immediate replantation group (dry for 5 min) and delayed replantation (dry for 60 min). Either 3 or 7 days after replantation, the animals were sacrificed. The palatal gingival tissues were harvested for mRNA–sequencing. Hallmark gene set enrichment analysis were performed to predict the function of transcriptomes. Normalized enrichment score (NES) was generated to determine the functional differences between the groups. Results: Hallmark gene sets enriched in delayed replantation at 3 days were oxidative phosphorylation (NES=2.82, q < 0.001) and TNF–α signaling via NF–κB pathway (NES= 1.52, q=0.034). At 7 days, TNF–α signaling via NF–κB pathway (NES=–1.82, q=0.002), angiogenesis (NES=–1.66, q =0.01), and TGF–β signaling pathway (NES=–1.46, q=0.051) were negatively highlighted in delayed replantation compared to immediate replantation. Conclusions: Transcriptome profiles were significantly different between immediate replantation and delayed replantation. The responses of periodontal tissues were associated with TNF–α signaling via NF–κB pathway. However, the enrichment score of this pathway were changed with time–dependent manner between immediate replantation and delayed replantation.

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Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia.

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