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Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

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      Normal hearts exhibit a positive time difference between the end of ventricular contraction and the end of QT interval, which is referred to as the electromechanical (EM) window. Drug-induced prolongation of repolarization may lead to the negative EM window, which was proposed to be a novel proarrhythmic marker. This study examined whether abnormal changes in the EM window may account for arrhythmogenic effects produced by hypokalemia. Left ventricular pressure, electrocardiogram, and epicardial monophasic action potentials were recorded in perfused hearts from guinea-pig and rabbit. Hypokalemia (2.5 mM K +) was found to prolong repolarization, reduce the EM window, and promote tachyarrhythmia. Nevertheless, during both regular pacing and extrasystolic excitation, the increased QT interval invariably remained shorter than the duration of mechanical systole, thus yielding positive EM window values. Hypokalemia-induced arrhythmogenicity was associated with slowed ventricular conduction, and shortened effective refractory periods, which translated to a reduced excitation wavelength index. Hypokalemia also evoked non-uniform prolongation of action potential duration in distinct epicardial regions, which resulted in increased spatial variability in the repolarization time. These findings suggest that arrhythmogenic effects of hypokalemia are not accounted for by the negative EM window, and are rather attributed to abnormal changes in ventricular conduction times, refractoriness, excitation wavelength, and spatial repolarization gradients.

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      Drug-induced prolongation of the QT interval.

       Dan Roden (2004)
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        Serum potassium levels and mortality in acute myocardial infarction.

        Clinical practice guidelines recommend maintaining serum potassium levels between 4.0 and 5.0 mEq/L in patients with acute myocardial infarction (AMI). These guidelines are based on small studies that associated low potassium levels with ventricular arrhythmias in the pre-β-blocker and prereperfusion era. Current studies examining the relationship between potassium levels and mortality in AMI patients are lacking. To determine the relationship between serum potassium levels and in-hospital mortality in AMI patients in the era of β-blocker and reperfusion therapy. Retrospective cohort study using the Cerner Health Facts database, which included 38,689 patients with biomarker-confirmed AMI, admitted to 67 US hospitals between January 1, 2000, and December 31, 2008. All patients had in-hospital serum potassium measurements and were categorized by mean postadmission serum potassium level (<3.0, 3.0-<3.5, 3.5-<4.0, 4.0-<4.5, 4.5-<5.0, 5.0-<5.5, and ≥5.5 mEq/L). Hierarchical logistic regression was used to determine the association between potassium levels and outcomes after adjusting for patient- and hospital-level factors. All-cause in-hospital mortality and the composite of ventricular fibrillation or cardiac arrest. There was a U-shaped relationship between mean postadmission serum potassium level and in-hospital mortality that persisted after multivariable adjustment. Compared with the reference group of 3.5 to less than 4.0 mEq/L (mortality rate, 4.8%; 95% CI, 4.4%-5.2%), mortality was comparable for mean postadmission potassium of 4.0 to less than 4.5 mEq/L (5.0%; 95% CI, 4.7%-5.3%), multivariable-adjusted odds ratio (OR), 1.19 (95% CI, 1.04-1.36). Mortality was twice as great for potassium of 4.5 to less than 5.0 mEq/L (10.0%; 95% CI, 9.1%-10.9%; multivariable-adjusted OR, 1.99; 95% CI, 1.68-2.36), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. In contrast, rates of ventricular fibrillation or cardiac arrest were higher only among patients with potassium levels of less than 3.0 mEq/L and at levels of 5.0 mEq/L or greater. Among inpatients with AMI, the lowest mortality was observed in those with postadmission serum potassium levels between 3.5 and <4.5 mEq/L compared with those who had higher or lower potassium levels.
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          Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart

          Aim Hypokalaemia is associated with a lethal form of ventricular tachycardia (VT), torsade de pointes, through pathophysiological mechanisms requiring clarification. Methods Left ventricular endocardial and epicardial monophasic action potentials were compared in isolated mouse hearts paced from the right ventricular epicardium perfused with hypokalaemic (3 and 4 mm [K+]o) solutions. Corresponding K+ currents were compared in whole-cell patch-clamped epicardial and endocardial myocytes. Results Hypokalaemia prolonged epicardial action potential durations (APD) from mean APD90s of 37.2 ± 1.7 ms (n = 7) to 58.4 ± 4.1 ms (n =7) and 66.7 ± 2.1 ms (n = 11) at 5.2, 4 and 3 mm [K+]o respectively. Endocardial APD90s correspondingly increased from 51.6 ± 1.9 ms (n = 7) to 62.8 ± 2.8 ms (n = 7) and 62.9 ± 5.9 ms (n = 11) giving reductions in endocardial–epicardial differences, ΔAPD90, from 14.4 ± 2.6 to 4.4 ± 5.0 and −3.4 ± 6.0 ms respectively. Early afterdepolarizations (EADs) occurred in epicardia in three of seven spontaneously beating hearts at 4 mm [K+]o with triggered beats followed by episodes of non-sustained VT in nine of 11 preparations at 3 mm. Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K+]o respectively. Early outward K+ current correspondingly fell from 73.46 ± 8.45 to 61.16±6.14 pA/pF in isolated epicardial but not endocardial myocytes (n = 9) (3 mm [K+]o). Conclusions Hypokalaemic mouse hearts recapitulate the clinical arrhythmogenic phenotype, demonstrating EADs and triggered beats that might initiate VT on the one hand and reduced transmural dispersion of repolarization reflected in ΔAPD90 suggesting arrhythmogenic substrate on the other.

            Author and article information

            [1 ]Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
            [2 ]Department of Health Science and Technology, University of Aalborg, Aalborg, Denmark
            The Ohio State University, United States of America
            Author notes

            Competing Interests: The author has declared that no competing interests exist.

            Conceived and designed the experiments: OO. Performed the experiments: OO. Analyzed the data: OO. Contributed reagents/materials/analysis tools: OO. Contributed to the writing of the manuscript: OO.

            Role: Editor
            PLoS One
            PLoS ONE
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            20 August 2014
            : 9
            : 8

            Osadchii. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Pages: 11
            This study was supported by the Novo Nordisk Foundation and the Obel Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Research Article
            Biology and Life Sciences
            Cardiovascular Physiology
            Medicine and Health Sciences
            Cardiovascular Diseases
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