Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β) murine hearts

Figures

• 

  Fig. 1. Typical electrocardiographic (ECG) (upper panel in each) and simultaneous intracellular action potential (AP) recordings (lower panel in each) obtained during 8 Hz pacing (A) and programmed electrical stimulation (PES) (B), recorded from a young wild type (WT) heart. The timings of stimulus delivery are given in the bar beneath the AP recordings, and corresponding stimulation artefacts can be seen on the ECG and AP traces, preceding the respective complexes. In panel (B), arrows indicate the imposition of S2 extrastimuli. The first two S2 stimuli trigger APs, whereas the third S2 stimulus fails to elicit a response, thus representing a refractory outcome.

• 

  Fig. 2. Typical AP recordings of different abnormal rhythms observed during programmed electrical stimulation (PES) in an aged Pgc-1β−/− heart following an extrasystolic S2 stimulus. These were classified as an individual ectopic beat (A), a couplet of two successive ectopic beats (B), non-sustained ventricular tachycardia (NSVT) (C) and sustained ventricular tachycardia (D). The timings of stimulus delivery are given in the bar beneath the AP recordings and arrows indicate the onset of the abnormal rhythm.

• 

  Fig. 3. Occurrences of episodes of non-sustained ventricular tachycardia or sustained tachycardia recording during PES protocols in (A) young WT, (B) aged WT, (C) young Pgc-1β−/− and (D) aged Pgc-1β−/− hearts, stratified according to the S1–S2 coupling interval (critical coupling interval) that provoked the arrhythmia.

• 

  Fig. 4. Means ± SEM of maximum action potential upstroke rate, (dV/dt)max (A), AP latencies (B) and action potential durations to 90% recovery, APD90 (C) for S2 triggered APs in the four experimental groups for (i) S1–S2 intervals falling from 89 ms to 50 ms during the PES protocols. Panel (ii) for each provides a comparison of these values at the outset and at the end of the pacing protocol, corresponding to a refractory outcome or the onset of sustained arrhythmia. The symbols denote significant differences between each pair, obtained from post hoc Tukey testing, which was conducted if the ANOVA indicated a significant outcome. Single, double and triple symbols denote p < 0.05, p < 0.01 and p < 0.001 respectively.

• 

  Fig. 5. Dependences of AP latency upon (dV/dt)max through the programmed electrical stimulation (PES) protocol compared in (A) young and old WT and (B) young and aged Pgc-1β−/− hearts.

• 

  Fig. 6. (A) Representative examples of histological samples from young ((i) and (iiii)) and old ((ii) and (iv)), WT ((i) and (ii)) and Pgc1β−/− hearts ((iii) and (iv)) used for morphological assessment of fibrotic change (scale bar 1 mm), with (B) typical higher power appearances to illustrate (i) normal tissue architecture in young WT and (ii) tissue structure showing fibrotic change in aged Pgc-1β-/- ventricles (scale bar 100 μm). (C) The degree of fibrotic change was assessed as the proportion of morphometric squares covering tissue that showed positive evidence of fibrotic change as detected by picrosirius red staining. Numbers of hearts examined: young WT (n = 8), aged WT (n = 8), young Pgc-1β-/- (n = 9), aged Pgc-1β-/- (n = 10). Symbols denote pairs of points showing significant differences from post hoc Tukey testing, where single, double and triple symbols denote p < 0.05, p < 0.01 and p < 0.001 respectively (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

• 

  Fig. 7. Dependences of AP wavelength assessed using (dV/dt)max (A(i) and B(i)) and AP latency (A(ii) and B(ii)) through regular 8 Hz pacing (A) and in response to extrasystolic S2 stimulation at different S1-S2 intervals in the PES protocol (B) in young and aged, WT and Pgc-1β−/− hearts. Wavelength was calculated as the product of the respective conduction parameter (either (dV/dt)max or AP latency) and the corresponding ERP for that heart. In panels (A(i)) and (A(ii)), symbols denote significant differences between each pair, obtained from post hoc Tukey testing, which was conducted if the ANOVA indicated a significant outcome. Single, double and triple symbols denote p < 0.05, p < 0.01 and p < 0.001 respectively.