Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of torsades de pointes in the chronic atrioventricular block dog

Abstract

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and Torsades de Pointes (TdP, defined as >5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic AV-block (CAVB) dog by dofetilide (IKr-blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (>3 TdPs/10') CAVB dogs were observed for 10' from the start of dofetilide infusion (0.025mg/kg, 5'). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARI) on the intracardiac EGM, using the formula: . The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion prior to first 1) sEB (occurrence at 100±35"), 2) mEB (224±96"), and 3) non self-terminating TdP (454±298"). STVARI increased from 2.15±0.32ms at BL to 3.73±0.99ms* prior to the first sEB and remained increased without further significant progression to mEB (4.41±0.45ms*) and TdP (5.07±0.84ms*) (*p<0.05 compared to BL). SDR3D did not change from 31±11ms at BL to 43±13ms prior to sEB, but increased significantly prior to mEB (68±7ms*) and to TdP (86±9ms*+) (+p<0.05 compared to sEB). An increase in STV contributes to the initiation of sEB whereas an increase in SDR is important for the perpetuation of non self-terminating TdPs.

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals

“…In terms of species used, the majority of these studies (∼67%) used rodents, with approximately equal distribution between mice ( 23 – 33 ) and rats ( 34 – 42 ). Guinea pig ( 43 – 45 ) and porcine hearts ( 46 – 48 ) were each used in ∼10% of studies, followed by a small number of reports in rabbit ( 49 ), zebrafish ( 50 ), quail ( 51 ), and canine ( 52 ) hearts. Overall, there was good reporting of sex, age, and strain, yet only ∼30% of studies evaluated both male and female animals, whereas ∼40% exclusively reported data from male animals.…”

“…In terms of disease models, genetically modified mice ( 23 , 26 , 28 – 33 ) or specific rat strains (e.g., spontaneously hypertensive rat) ( 34 , 35 , 40 ) were most commonly assessed (∼37% of studies), and myocardial infarction, ischemia, or hypoxia were evaluated in ∼27% of studies ( 25 , 31 , 35 , 38 , 42 , 44 , 45 , 47 ). Around 16% of investigations used pharmacological modulation ( 24 , 43 , 49 , 50 , 52 ). A small number of studies investigated environmental effects [including herbicide ( 36 ), vaping ( 27 ), and alcohol ( 51 )], aging and development ( 25 , 28 , 41 ), nonischemic heart failure ( 39 ), and the remaining studies performed electrophysiological assessments in nondiseased hearts ( 37 , 46 , 48 ).…”

“…A small number of studies investigated environmental effects [including herbicide ( 36 ), vaping ( 27 ), and alcohol ( 51 )], aging and development ( 25 , 28 , 41 ), nonischemic heart failure ( 39 ), and the remaining studies performed electrophysiological assessments in nondiseased hearts ( 37 , 46 , 48 ). The most commonly used techniques to evaluate electrophysiological parameters and arrhythmia susceptibility were in vivo electrocardiogram (ECG) or electrode recordings in conscious or anesthetized animals (∼56% of studies) ( 23 – 28 , 30 , 32 , 36 , 38 , 40 – 42 , 46 – 48 , 52 ) or optical mapping in excised hearts or tissues (∼47% of studies) ( 27 , 30 , 31 , 33 – 35 , 39 , 41 , 43 – 45 , 49 – 51 ). The remaining studies used electrode-based or ECG recordings in excised hearts and tissues ( 24 , 25 , 29 , 31 , 32 , 35 , 40 , 41 , 50 ) or in vivo ECG telemetry ( 27 , 29 , 33 , 37 ), and often, a combination of multiple approaches were used to rigorously evaluate electrophysiological properties (including experiments in isolated cardiomyocytes, which are not covered in detail in these guidelines).…”

High-rate pacing suppresses Torsade de Pointes arrhythmias and reduces spatial dispersion of repolarization in the chronic AV-block dog model

“…Previous studies have identified several important factors that promote arrhythmogenesis in the CAVB dog model by encouraging triggered activity and/or modulating the arrhythmogenic substrate. Triggered activity, resulting from early or delayed after depolarizations, has been shown to initiate TdP ( Vandersickel et al, 2017 ; Smoczynska et al, 2021 ). These after-depolarizations arise as a result of the diminished repolarization reserve, rendering cardiomyocytes unable to compensate for additional repolarization impediments ( Varro and Baczko, 2011 ).…”

“…Secondly, TdP arise from a location with a high spatial dispersion repolarization (SDR), and insusceptibility for TdP is associated with the absence of such regions of high SDR ( Dunnink et al, 2017 ). Whereas triggered activity initiates arrhythmic episodes, advancement to more critical arrhythmias hinges on the presence of adequate SDR ( Dunnink et al, 2017 ; Smoczynska et al, 2021 ). Finally, high-rate pacing (HRP) is a well-established method to suppress and prevent arrhythmias in both the CAVB dog model ( Wijers et al, 2017 ; Smoczynska et al, 2020a ) and patients ( Eldar et al, 1987 ; Fisher et al, 1987 ; Gronefeld et al, 2002 ).…”