Wave propagation in atrial sheets with increasing adrenergic spatial density.

We show gradually increasing adrenergic spatial densities at 5% (i), 10% (ii), and 15% (iii). Black and white mesh elements represent non- and adrenergically stimulated sites, respectively. The red dashed square on (A) indicates the area of atrial AP analysis. Comparison of wave propagation at three different time points between baseline atrial sheet(A-C) and adrenergically stimulated atrial sheets with increasing spatial densities at 5% (D-F), 10% (G-I), and 15% (J-L).</p

Atrial action potentials from varying adrenergic spatial densities and activation rates.

(A) Compared to a baseline atrial action potential, a gradual increase in adrenergic spatial density from 5%, 10%, and 15% marginally increases action potential amplitude. It promotes an isopotential phase halfway through repolarization. (B) Increased activation rates in the presence of adrenergic elements also contribute to changes in action potential duration characteristics but are not as drastic as adrenergic stimulation alone. (C) Increased activation rates in the presence of adrenergic elements produce temporal variations in action potential duration characteristics and change the baseline cycle length of captured beats. The location of the sample action potential on the atrial sheet is highlighted in red boxes.</p

S1 Data -

Chronic stress among young patients (≤ 45 years old) could result in autonomic dysfunction. Autonomic dysfunction could be exhibited via sympathetic hyperactivity, sympathetic nerve sprouting, and diffuse adrenergic stimulation in the atria. Adrenergic spatial densities could alter atrial electrophysiology and increase arrhythmic susceptibility. Therefore, we examined the role of adrenergic spatial densities in creating arrhythmogenic substrates in silico. We simulated three 25 cm2 atrial sheets with varying adrenergic spatial densities (ASD), activation rates, and external transmembrane currents. We measured their effects on spatial and temporal heterogeneity of action potential durations (APD) at 50% and 20%. Increasing ASD shortens overall APD, and maximum spatial heterogeneity (31%) is achieved at 15% ASD. The addition of a few (5% to 10%) adrenergic elements decreases the excitation threshold, below 18 μA/cm2, while ASDs greater than 10% increase their excitation threshold up to 22 μA/cm2. Increase in ASD during rapid activation increases APD50 and APD20 by 21% and 41%, respectively. Activation times of captured beats during rapid activation could change by as much as 120 ms from the baseline cycle length. Rapidly activated atrial sheets with high ASDs significantly increase temporal heterogeneity of APD50 and APD20. Rapidly activated atrial sheets with 10% ASD have a high likelihood (0.7 ± 0.06) of fragmenting otherwise uniform wavefronts due to the transient inexcitability of adrenergically stimulated elements, producing an effective functional block. The likelihood of wave fragmentation due to ASD highly correlates with the spatial variations of APD20 (ρ = 0.90, p = 0.04). Our simulations provide a novel insight into the contributions of ASD to spatial and temporal heterogeneities of APDs, changes in excitation thresholds, and a potential explanation for wave fragmentation in the human atria due to sympathetic hyperactivity. Our work may aid in elucidating an electrophysiological link to arrhythmia initiation due to chronic stress among young patients.</div

Effect of increasing adrenergic spatial density to the excitation threshold of an atrial sheet.

Effect of increasing adrenergic spatial density to the excitation threshold of an atrial sheet.</p

Measurement of the effects of varying adrenergic spatial densities, external transmembrane currents, and activation rates to Action Potential Durations (APD) and change to cycle lengths.

(A)Sample log-scale distributions of APD50 and APD20 values across spatial densities of adrenergic stimulation of an atrial sheet. (B)Spatial heterogeneity of APD50 and APD20 values across spatial densities of adrenergic stimulation of an atrial sheet, measured as coefficient of spatial variation (CoSV). (C) Probability of conduction, or the likelihood of tissue excitation, due to changes in external transmembrane current with and without the presence of adrenergic elements across adrenergic spatial densities. The proportion of captured beats for increasing rapid activation rates in the presence of adrenergic elements (D). Effect of increasing activation rates to mean APD50 (E), and APD20 (F) values across spatial adrenergic densities. (E inset) Effect of activation rates to mean APD90 and its temporal heterogeneity. Our analysis of APD90 during increased activation is unremarkable nonetheless we included them for completion. Effect of increasing activation rates to temporal variation of APD50 (G), and APD20 (H) across spatial adrenergic densities. Effect of increasing adrenergic spatial densities to the absolute time difference (|Δ|) between the average cycle length of captured beats during rapid activation and pre-pacing cycle length of 300 ms(I). Probability of wave fragmentation, or the transformation of a uniform wavefront to single or multiple curvilinear ones, due to adrenergic spatial densities across activation rates (J).</p

Wave fragmentation and propagation in a 10% adrenergically stimulated atrial sheets at three rates of rapid activation.

Comparison of wave propagation in a 10% adrenergically stimulated atrial sheet at 10 Hz (A-C), 17 Hz (D-F), and 23 Hz (G-I). Comparison of a wave fragmentation and propagation in an atrial sheet with 10% non-conductive elements during rapid activation (J-L).</p

Spatial heterogeneity of <i>APD</i>₂₀ due to increasing adrenergic spatial densities.

Action potential duration (APD) maps of APD20 show that adrenergic spatial densities (ASD) at 5% (A), 10% (B), and 15% (C) increase overall spatial heterogeneity which could promote arrhythmogenicity in the atria. Note that only the APD maps of 10% and 15% are normalized between 3 ms and 6 ms while the APD map of 5% ASD is illustrated from 9 ms to 12 ms to demonstrate the shortening of APD20 due to increasing ASD.</p

Additional file 2: Figure S2. of Heart rate in patients with reduced ejection fraction: relationship between single time point measurement and mean heart rate on prolonged implantable cardioverter defibrillator monitoring

Bland-Altman analysis for the overall cohort with limits of agreement set to ¹5 bpm from the bias. (TIFF 294 kb

Image_1_Overdrive pacing in the acute management of osimertinib-induced ventricular arrhythmias: A case report and literature review.TIF

QT interval prolongation and ventricular arrhythmias (VAs) induced by osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, are life-threatening complications. However, no consensus has been achieved regarding their management. Overdrive pacing has been shown to be effective in shortening the QT interval and terminating torsade de pointes (TdP). Here, we report a case of osimertinib-induced QT prolongation accompanied by frequent VAs and TdP. Osimertinib was immediately discontinued after it was identified as the etiology for QT prolongation and VAs. A temporary pacemaker and overdrive pacing were used after other anti-arrhythmia treatments had failed and successfully shortened the QTc interval and terminated VAs. Repeated Holter monitoring at 1 week showed no remaining VAs or TdP, and the pacemaker was removed. Routine electrocardiography (ECG) surveillance was conducted afterward, and three- and 6-month follow-ups showed good recovery and normal ECG results. Vigilance is required for rare vital arrhythmias in patients taking osimertinib, and ECG surveillance should be conducted.</p

Cellular phenotypes in primary cultures of human fetal myocardium.

<p>(A) Cells freshly isolated from 22 week fetal myocardium were cultured for 2 days and then immunostained with anti-nk×2.5 (red) and anti-vimentin (green) (top panel) or with anti α-actin (red) and anti ki-67 (green) (bottom panel) antibodies to determine the percentage of the cells with cardiomyocyte or fibroblast phenotypes. Nuclei were marked with DAPI staining (blue). Scale bar, 30 µm. (B) Transmission electron microscopy showing that cultures of cells freshly isolated from human fetal myocardium at day 2 contain primitive cardioblasts with nascent sarcomeres (s) and mitochondrial clusters (m) (left) and cells with the transitional features containing both nascent sarcomeres and deep invaginations containing collagen fibers (cf) (right). (C) Only a subset of cardioblasts expressed cardiac troponin T (cTnT). (D) Phase contrast images (upper panel) and fluorescent images (lower panel) showing the adherent (AC) and non-adherent (NAC) cells 2 days after isolation. Immunostaining with anti-β-MHC antibody demonstrates that non-adherent clusters consist mainly of β-MHC positive cardioblasts. Scale bar, 80 µm (for phase) and 25 µm (for fluorescent imaging).</p