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. 2018 Feb 2;8(1):2312.
doi: 10.1038/s41598-018-20792-5.

Genetic Background Dominates the Susceptibility to Ventricular Arrhythmias in a Murine Model of β-Adrenergic Stimulation

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Free PMC article

Genetic Background Dominates the Susceptibility to Ventricular Arrhythmias in a Murine Model of β-Adrenergic Stimulation

Marisa Jelinek et al. Sci Rep. .
Free PMC article

Abstract

In cardiovascular research, several mouse strains with differing genetic backgrounds are used to investigate mechanisms leading to and sustaining ventricular arrhythmias. The genetic background has been shown to affect the studied phenotype in other research fields. Surprisingly little is known about potential strain-specific susceptibilities towards ventricular arrhythmias in vivo. Here, we hypothesized that inter-strain differences reported in the responsiveness of the β-adrenergic pathway, which is relevant for the development of arrhythmias, translate into a strain-specific vulnerability. To test this hypothesis, we characterized responses to β-adrenergic blockade (metoprolol) and β-adrenergic stimulation (isoproterenol) in 4 mouse strains commonly employed in cardiovascular research (Balb/c, BS, C57Bl/6 and FVB) using telemetric ECG recordings. We report pronounced differences in the electrical vulnerability following isoproterenol: Balb/c mice developed the highest number and the most complex arrhythmias while BS mice were protected. Balb/c mice, therefore, seem to be the background of choice for experiments requiring the occurrence of arrhythmias while BS mice may give insight into electrical stability. Arrhythmias did not correlate with the basal β-adrenergic tone, with the response to β-adrenergic stimulation or with the absolute heart rates during β-adrenergic stimulation. Thus, genetic factors dominate the susceptibility to ventricular arrhythmias in this model of β-adrenergic stimulation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Cardiac geometry and function. (a) Body weight and (b) heart weight at the time of organ harvesting. (c) Diastolic left ventricular inner diameter (LVIDd) and (d) ejection fraction (EF). Data are given as median and 5–95 percentile. Balb/c n = 6, C57Bl/6 n = 6, BS n = 6, FVB n = 5. *p < 0.05; **p < 0.01; ***p < 0.001 (multiple comparisons were calculated by one-way ANOVA followed by Newman-Keuls post-hoc test).
Figure 2
Figure 2
Heart rate regulation under baseline conditions. HR over 96 hours in (a) Balb/c, (b) C57Bl/6 mice, (c) BS mice and (d) FVB mice. For means of clarity, only mean values of each group are depicted. Upper and lower lines denote maximal and minimal HRs of each group. Day: 7AM-7PM, Night: 7PM-7AM. Balb/c n = 6, C57Bl/6 n = 6, BS n = 6, FVB n = 5.
Figure 3
Figure 3
Heart rate and physical activity under baseline conditions. (a) HR and (b) physical activity during day- and night-time calculated from 96 hours ECG recordings as shown in Fig. 2. Activity was derived as a parameter (activity units; A.U.) from the telemetric transponders and corresponds to the physical activity of the animals in the cage. (c) HR normalized to activity. For this, the absolute activity units (A.U.) were binned in the following classes: 0 = 0 A.U., 1 = 0–5 A.U., 2 = 5–10 A.U., 3 = 10–15 A.U., 4 = 15–20 A.U., 5 = 20–25 A.U., 6 = 25–30 A.U., 7 = 30–300 A.U. HR values were then averaged according to the corresponding activity. Day: 7AM-7PM, Night: 7PM-7AM. Data is given as median and 5–95 percentile (a,b) and as median and interquartile range (c). Balb/c n = 6, C57Bl/6 n = 6, BS n = 6, FVB n = 5. *p < 0.05; **p < 0.01; ***p < 0.001 vs. another strain; #p < 0.05 vs. day, ###p < 0.001 vs. day (multiple comparisons were calculated by two-way ANOVA followed by Sidak post-hoc test).
Figure 4
Figure 4
Heart rate regulation under β-adrenergic blockade. HR under treatment with metroprolol over 96 hours in (a) Balb/c, (b) C57Bl/6 mice, (c) BS mice and (d) FVB mice. For means of clarity, only mean values of each group are depicted. Upper and lower lines denote maximal and minimal HRs of each group. Day: 7AM-7PM, Night: 7PM-7AM. Balb/c n = 6, C57Bl/6 n = 6, BS n = 6, FVB n = 5.
Figure 5
Figure 5
Heart rate under β-adrenergic modulation. (a) HRs under treatment with metoprolol during day- and night-time derived from 96 hours ECG recordings shown in Fig. 4. (b) HR reduction (ΔHR) calculated as the difference between mean HRs under baseline conditions and under β-adrenergic blockade. (c) Maximal HRs and (d) mean HRs over 5 hours following isoproterenol injection. Day: 7AM-7PM, Night: 7PM-7AM. Data is given as median and 5–95 percentile (a,c,d) and as median and interquartile range (b). Balb/c n = 6, C57Bl/6 n = 6, BS n = 6, FVB n = 5. *p < 0.05; **p < 0.01; ***p < 0.001 against another strain; ###p < 0.001 against day. Multiple comparisons were calculated by (a) two-way ANOVA followed by Sidak post-hoc test, and (bd) one-way ANOVA followed by Newman-Keuls post-hoc test.
Figure 6
Figure 6
Representative ECGs and occurrence of ventricular arrhythmias under β-adrenergic stimulation. (a) Sinus rhythm, (b) premature ventricular beats (PVB), (c) coupled beats, (d) ventricular tachycardic events (VT) and (e) ventricular fibrillation events (VF). (f) Number of total arrhythmic events (sum of PVBs, coupled beats, VT and VF) over 5 hours following isoproterenol injection. Data are given as median and 5–95 percentile. Balb/c n = 6, C57Bl/6 n = 6, BS n = 6, FVB n = 5. *p < 0.05; **p < 0.01 (multiple comparisons were calculated by Kruskal-Wallis test followed by Dunn’s post-hoc test).

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