Age-dependent electrocardiographic changes in Pgc-1β deficient murine hearts

Abstract

Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc-1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12-16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc-1β^-/- (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1-adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc-1β^-/- genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino-atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc-1β^-/- mice. Moreover, Pgc-1β^-/- mice displayed electrocardiographic features consistent with the existence of a pro-arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc-1β^-/- mice had shorter repolarisation intervals. These were likely attributable to altered K⁺ conductance properties, ultimately resulting in a shortened QT_c interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc-1β^-/- systems in widespread cardiac regions.

Keywords: cardiac arrhythmias; cardiac conduction; electrocardiogram, ECG; peroxisome proliferator activated receptor-γ-coactivator-1 (PGC-1).

Figure 1

Typical ECG and definition of deflections used in quantitative analysis (A) start of P‐wave; (B) P‐wave trough/end of P‐wave; (C) start of QRS complex; (D) R wave peak; (E) trough of S wave; (F) peak of R' deflection; (G) C wave peak; (H) trough or end of C wave. The corrected QT interval, QT_c is taken as the interval from C to H and corrected for RR intervals52

Figure 2

Typical ECG records from Pgc‐1β^−/− heart illustrating (A) normal sinus rhythm; (B) ectopic beat; (C) atrioventricular (AV) dissociation; records obtained from the same mouse. Arrows indicate timings of P‐waves (D) pre‐dobutamine and (E) following dobutamine challenge with ECG showing ST depression

Figure 3

Traces plotting heart rate response curves before and following dobutamine challenge in (A) young WT, (B) aged WT; (C) young Pgc‐1β^−/− and (D) aged Pgc‐1β^−/− mouse

Figure 4

Correlations between heart rates observed pre‐ vs post‐dobutamine challenge in Pgc‐1β^−/− and WT

Figure 5

Mean heart rates in the 5 minute analysis window before and after dobutamine administration in young and aged WT and Pgc‐1β^−/− mice

Figure 6

(A, B) Poincare plots pre‐ (A) and post‐dobutamine (B) in young (a,b) and aged (c,d), WT (a,c) and Pgc‐1β^‐/‐ hearts (b,d) and (C, D) the standard deviations (SDs) of their ΔRR intervals before (C) and following dobutamine challenge (D)

Figure 7

PR intervals reflecting paradoxical AV dysfunction before and following dobutamine challenge in (A) young WT and (B) aged Pgc‐1β^−/− mouse