Journal: bioRxiv

Article Title: Classifying drugs by their arrhythmogenic risk using machine learning

doi: 10.1101/545863

Figure Lengend Snippet: We characterize calcium transients in ventricular cardiomyocytes in response to drugs, both computationally (top) and experimentally (bottom) and identify the ion channels that most likely generate early afterdepolarizations (left). We then screen the concentration space of the two most relevant channels and identify the classification boundary between the arrhythmic and non-arrhythmic domains using high performance computing and machine learning (center). We validate our approach using electrocardiograms, both computationally and experimentally, in whole heart simulations and isolated Langendorff perfused hearts (right). We demonstrate the potential of our new classifier by risk stratifying 23 common drugs and comparing the result against the reported risk categories of these compounds.

Article Snippet: We excised the hearts from anesthetized rats (2.5% isoflurane in 95% oxygen and 5% carbon dioxide), immediately cannulated the aorta, connected it to a constant pressure perfusion Langendorff system (Harvard Apparatus, Massachusetts) with Krebs solution (118mM NaCl, 4.75mM KCl, 25mM NaHCO 3 , 1.2mM KH 2 PO 4 , 1.2mM MgSO 4 , 1.5mM CaCl 2 , 11mM glucose, and 2mM Pyruvate), warmed to 37° C, and bubbled with 95% oxygen and 5% carbon dioxide.

Techniques: Concentration Assay, Isolation

Journal: Scientific Reports

Article Title: Concomitant genetic ablation of L-type Ca v 1.3 (α 1D ) and T-type Ca v 3.1 (α 1G ) Ca 2+ channels disrupts heart automaticity

doi: 10.1038/s41598-020-76049-7

Figure Lengend Snippet: Rhythm dissociation in mutant hearts following concomitant deletion of SAN-VGCCs. ( A ) Line plots of atrial (green line) and ventricular (blue line) rates (left panel) and sample ECGs (right panel) recorded ex vivo on isolated Langendorff perfused heart under control conditions in n = 8 WT , n = 6 Ca v 3.1 −/ − , n = 8 Ca v 1.3 −/ − and n = 7 Ca v 1.3 −/ − /Ca v 3.1 −/ − . ( B ) P wave rates in isolated wild-type and mutant hearts under control conditions. ( C ) Differences between atrial and ventricular rates of isolated hearts. Statistics: one-way ANOVA followed by Tukey’s multiple comparisons. Whiskers indicate mean ± the SEM. (#) Indicates comparison with wild-type.

Article Snippet: Excised hearts with aortic cannula were quickly mounted on a Langendorff apparatus (Isolated heart system; EMKA Technologies) at a pressure of 70–80 mm Hg imposed by the working heart with normal Tyrode’s solution containing (mM): NaCl, 140; KCl, 5.4; MgCl 2 , 1; CaCl 2 , 1.8; Hepes, 5 and glucose, 5.5 (pH adjusted to 7.4 with NaOH).

Techniques: Mutagenesis, Ex Vivo, Isolation, Control, Comparison

Journal: Scientific Reports

Article Title: Concomitant genetic ablation of L-type Ca v 1.3 (α 1D ) and T-type Ca v 3.1 (α 1G ) Ca 2+ channels disrupts heart automaticity

doi: 10.1038/s41598-020-76049-7

Figure Lengend Snippet: Pacemaker arrest by concomitant inhibition of I f and I Na ( TTX ) in Ca v 1.3 −/ − SAN/atria preparations. ( A ) Atrial rates of n = 7 WT , n = 6 Ca v 3.1 −/ − , n = 7 Ca v 1.3 −/ − and n = 6 Ca v 1.3 −/ − /Ca v 3.1 −/ − isolated Langendorff hearts under ivabradine (IVA, 10 µM) perfusion. ( B ) Atrial rates of isolated hearts under IVA 10 µM + TTX 100 nM perfusion. ( C ) Sample snapshots of the localization of leading regions under IVA 10 µM perfusion (left panels) and averaged rates of depolarization in n = 7 WT , n = 7 Ca v 3.1 −/ − , n = 6 Ca v 1.3 −/ − and n = 6 Ca v 1.3 −/ − /Ca v 3.1 −/ − SAN/atria preparations. ( D ) Same representation as in ( C ) with leading region in IVA 10 µM + TTX 100 nM perfusion. Statistics: one-way ANOVA followed by Tukey’s multiple comparisons test. Whiskers indicate mean ± the SD. (#) Indicates comparison with wild-type.

Article Snippet: Excised hearts with aortic cannula were quickly mounted on a Langendorff apparatus (Isolated heart system; EMKA Technologies) at a pressure of 70–80 mm Hg imposed by the working heart with normal Tyrode’s solution containing (mM): NaCl, 140; KCl, 5.4; MgCl 2 , 1; CaCl 2 , 1.8; Hepes, 5 and glucose, 5.5 (pH adjusted to 7.4 with NaOH).

Techniques: Inhibition, Isolation, Comparison