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Recent studies suggest that atrial fibrillation (AF) is maintained by fibrillatory conduction emanating from a small number of high-frequency reentrant sources (rotors). Our goal was to study the ionic correlates of a rotor during simulated chronic AF conditions. We utilized a two-dimensional (2-D), homogeneous, isotropic sheet (5 × 5 cm 2) of human atrial cells to create a chronic AF substrate, which was able to sustain a stable rotor (dominant frequency ∼5.7 Hz, rosette-like tip meander ∼2.6 cm). Doubling the magnitude of the inward rectifier K + current ( I K1) increased rotor frequency (∼8.4 Hz), and reduced tip meander (∼1.7 cm). This rotor stabilization was due to a shortening of the action potential duration and an enhanced cardiac excitability. The latter was caused by a hyperpolarization of the diastolic membrane potential, which increased the availability of the Na + current ( I Na). The rotor was terminated by reducing the maximum conductance (by 90%) of the atrial-specific ultrarapid delayed rectifier K + current ( I Kur), or the transient outward K + current ( I to), but not the fast or slow delayed rectifier K + currents ( I Kr/ I Ks). Importantly, blockade of I Kur/ I to prolonged the atrial action potential at the plateau, but not at the terminal phase of repolarization, which led to random tip meander and wavebreak, resulting in rotor termination. Altering the rectification profile of I K1 also slowed down or abolished reentrant activity. In combination, these simulation results provide novel insights into the ionic bases of a sustained rotor in a 2-D chronic AF substrate.

Mathematical models were developed to reconstruct the action potentials (AP) recorded in epicardial and endocardial myocytes isolated from the adult rat left ventricle. The main goal was to obtain additional insight into the ionic mechanisms responsible for the transmural AP heterogeneity. The simulation results support the hypothesis that the smaller density and the slower reactivation kinetics of the Ca 2+-independent transient outward K + current ( I t) in the endocardial myocytes can account for the longer action potential duration (APD), and more prominent rate dependence in that cell type. The larger density of the Na + current ( I Na) in the endocardial myocytes results in a faster upstroke (d V/d t max). This, in addition to the smaller magnitude of I t, is responsible for the larger peak overshoot of the simulated endocardial AP. The prolonged APD in the endocardial cell also leads to an enhanced amplitude of the sustained K + current ( I ss), and a larger influx of Ca 2+ ions via the L-type Ca 2+ current ( I CaL). The latter results in an increased sarcoplasmic reticulum (SR) load, which is mainly responsible for the higher peak systolic value of the Ca 2+ transient [Ca 2+] i, and the resultant increase in the Na +-Ca 2+ exchanger ( I NaCa) activity, associated with the simulated endocardial AP. In combination, these calculations provide novel, quantitative insights into the repolarization process and its naturally occurring transmural variations in the rat left ventricle.

Heart failure (HF) causes complex, chronic changes in atrial structure and function, which can cause substantial electrophysiological remodeling and predispose the individual to atrial fibrillation (AF). Pharmacological treatments for preventing AF in patients with HF are limited. Improved understanding of the atrial electrical and ionic/molecular mechanisms that promote AF in these patients could lead to the identification of novel therapeutic targets. Animal models of HF have identified numerous changes in atrial ion currents, intracellular calcium handling, action potential waveform and conduction, as well as expression and signaling of associated proteins. These studies have shown that the pattern of electrophysiological remodeling likely depends on the duration of HF, the underlying cardiac pathology, and the species studied. In atrial myocytes and tissues obtained from patients with HF or left ventricular systolic dysfunction, the data on changes in ion currents and action potentials are largely equivocal, probably owing mainly to difficulties in controlling for the confounding influences of multiple variables, such as patient's age, sex, disease history, and drug treatments, as well as the technical challenges in obtaining such data. In this review, we provide a summary and comparison of the main animal and human electrophysiological studies to date, with the aim of highlighting the consistencies in some of the remodeling patterns, as well as identifying areas of contention and gaps in the knowledge, which warrant further investigation.

We describe a mutation (E299V) in KCNJ2 , the gene that encodes the strong inward rectifier K ⁺ channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward I K₁ at potentials above −55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His–Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.

Our mathematical model of the rat ventricular myocyte (Pandit et al., 2001) was utilized to explore the ionic mechanism(s) that underlie the altered electrophysiological characteristics associated with the short-term model of streptozotocin-induced, type-I diabetes. The simulations show that the observed reductions in the Ca 2+-independent transient outward K + current ( I t) and the steady-state outward K + current ( I ss), along with slowed inactivation of the L-type Ca 2+ current ( I CaL), can result in the prolongation of the action potential duration, a well-known experimental finding. In addition, the model demonstrates that the slowed reactivation kinetics of I t in diabetic myocytes can account for the more pronounced rate-dependent action potential duration prolongation in diabetes, and that a decrease in the electrogenic Na +-K + pump current ( I NaK) results in a small depolarization in the resting membrane potential ( V rest). This depolarization reduces the availability of the Na + channels (I Na), thereby resulting in a slower upstroke ( dV/ dt max) of the diabetic action potential. Additional simulations suggest that a reduction in the magnitude of I CaL, in combination with impaired sarcoplasmic reticulum uptake can lead to a decreased sarcoplasmic reticulum Ca 2+ load. These factors contribute to characteristic abnormal [Ca 2+] i homeostasis (reduced peak systolic value and rate of decay) in myocytes from diabetic animals. In combination, these simulation results provide novel information and integrative insights concerning plausible ionic mechanisms for the observed changes in cardiac repolarization and excitation-contraction coupling in rat ventricular myocytes in the setting of streptozotocin-induced, type-I diabetes.

Metabolic syndrome (MetS) describes a condition associated with multiple diseases concomitantly such as diabetes, hypertension, obesity, and dyslipidemia. It has been linked with higher prevalence of cardiovascular disease, atrial fibrillation, and sudden cardiac death. One of the underlying mechanisms could be altered automaticity, which would reflect modifications of sinus node activity. These phenomena can be evaluated analyzing the components of heart rate variability (HRV). Our aim was to examine the modifications of sinus node variability in an isolated heart model of diet-induced obesity and MetS. Male NZW rabbits were randomly assigned to high-fat (HF, n  = 8), control (HF-C, n  = 7), high-fat, high-sucrose (HFHS, n  = 9), and control (HFHS-C, n  = 9) groups, fed with their respective diets during 18/28 weeks. After euthanasia, their hearts were isolated in a Langendorff system. We recorded 10–15 min of spontaneous activity. Short RR time series were analyzed, and standard HRV parameters were determined. One-way ANOVA, Kruskal-Wallis test, and bivariate correlation were used for statistical analysis ( p  < 0.05). We did find an increase in the complexity and irregularity of intrinsic pacemaker activity as shown by modifications of approximate entropy, sample entropy, minimum multiscale entropy, and complexity index in HFHS animals. Even though no differences were found in standard time and frequency-domain analyses, spectral heterogeneity increased in HFHS group. Animal weight and glucose intolerance were highly correlated with the modifications of intrinsic pacemaker variability. Finally, modifications of intrinsic HRV seemed to be reliant on the number of components of MetS present, given that only HFHS group showed significant changes towards an increased complexity and irregularity of intrinsic pacemaker variability.

Heart failure (HF) causes complex, chronic changes in atrial structure and function, which can cause substantial electrophysiological remodeling and predispose the individual to atrial fibrillation (AF). Pharmacological treatments for preventing AF in patients with HF are limited. Improved understanding of the atrial electrical and ionic/molecular mechanisms that promote AF in these patients could lead to the identification of novel therapeutic targets. Animal models of HF have identified numerous changes in atrial ion currents, intracellular calcium handling, action potential waveform and conduction, as well as expression and signaling of associated proteins. These studies have shown that the pattern of electrophysiological remodeling likely depends on the duration of HF, the underlying cardiac pathology, and the species studied. In atrial myocytes and tissues obtained from patients with HF or left ventricular systolic dysfunction, the data on changes in ion currents and action potentials are largely equivocal, probably owing mainly to difficulties in controlling for the confounding influences of multiple variables, such as patient's age, sex, disease history, and drug treatments, as well as the technical challenges in obtaining such data. In this review, we provide a summary and comparison of the main animal and human electrophysiological studies to date, with the aim of highlighting the consistencies in some of the remodeling patterns, as well as identifying areas of contention and gaps in the knowledge, which warrant further investigation.

We describe a mutation (E299V) in KCNJ2 , the gene that encodes the strong inward rectifier K + channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward I K1 at potentials above −55 mV ( P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His–Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.

Mathematical models were developed to reconstruct the action potentials recorded in murine (rat, mouse) ventricular myocytes. The equations in these models (Hodgkin-Huxley-type) are based on biophysical, experimentally-derived descriptors of ionic currents and antiporters. The simulation results demonstrate that the differential density and reactivation kinetics of the Ca2+ -independent transient outward K+ current (It ), and the transmural gradient in the Na+ channel (I Na) density underlie the intrinsically heterogeneous nature of excitation, repolarization and excitation-contraction (E-C) coupling characteristics in the adult rat ventricle. The longer endocardial action potential duration (APD) results in a net increase of the associated Ca2+ fluxes and the sarcoplasmic reticulum (SR) Ca2+ load. This leads to a higher peak systolic value of the Ca2+ transient ([Ca 2+]i) in the endocardial cells, compared to epicardial ones. Model simulations indicate that the electrophysiological alterations (prolonged APD, abnormal [Ca2+]i) associated with the type-I form of diabetes in rat right ventricular myocytes is the result of concomitant changes in the properties of It, the steady-state outward K+ current (ISS), the L-type Ca2+ current (ICaL), the Na+-K+ pump current (IKslow), and a depressed uptake of Ca2+ ions into the SR. Model analysis also shows that the repolarization differences between rat and mouse cardiac action potentials can be mainly attributed to the presence of the slowly inactivating, delayed rectifier K+ current (IKslow) in mouse, but not in rat. In conclusion, these results provide novel, semi-quantitative insights into the ionic basis of cardiac repolarization and excitation-contraction coupling in murine ventricular myocytes isolated from healthy and diseased hearts.

Introduction The lateral intercostal artery perforator flap (LICAP) has emerged as one of the safest and less morbid flaps for lateral and central breast defects. We hereby describe a reproducible no Doppler single position (NDSP) technique to harvest it in single position without handheld Doppler, making it a versatile flap for lateral breast defects in resource-limited setting also. Materials and Methods With this technique, we performed a total of 22 LICAP turnover flaps over a period of 18 months from January 2020 to June 2021. In all 22 cases, the indication of flap was to fill the post-breast conservation surgery (BCS) defects in outer quadrant of breast. All LICAP flaps were harvested by surface marking of anatomical landmarks and without handheld Doppler. Results Out of 22 LICAP turnover flaps, thirteen were harvested for left breast and nine for right breast. The median width and length of the flap were 12.2 cm and 19.6 cm, respectively. The additional mean operative time was 41 min. All LICAP flaps survived well, and grade 1 Clavien-Dindo morbidity was documented in four cases. Mean hospital stay was 2.6 days. All patients received radiotherapy on their stipulated schedule . Early cosmetic outcome was good, and long-term outcomes are awaited. Conclusion NDSP-LICAP flap is a workhorse for lateral breast defects. Precise knowledge of perforators and anatomical landmarks can be used for harvesting these flaps, thus avoiding ultrasound Doppler and dedicated training for perforator localization. This technique has short learning curve without the need for any plastic surgery training. The early cosmetic outcomes are good.