Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Dec 1;102(12):1619-1634.
doi: 10.1113/EP086589. Epub 2017 Oct 29.

Pro-arrhythmic Atrial Phenotypes in Incrementally Paced Murine Pgc1β -/- Hearts: Effects of Age

Affiliations
Free PMC article

Pro-arrhythmic Atrial Phenotypes in Incrementally Paced Murine Pgc1β -/- Hearts: Effects of Age

Haseeb Valli et al. Exp Physiol. .
Free PMC article

Abstract

What is the central question of this study? Can we experimentally replicate atrial pro-arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age-dependent atrial arrhythmic phenotypes in Langendorff-perfused murine Pgc1β-/- hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro-arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12-16 week) and aged (>52 week) wild-type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)-deficient (Pgc1β-/- ) Langendorff-perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole-heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β-/- hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dtmax ) were reduced in Pgc1β-/- hearts. Action potential latencies were increased by the Pgc1β-/- genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90 ) were shorter in Pgc1β-/- hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β-/- hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β-/- genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β-/- genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β-/- hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here.

Keywords: action potential; atria; cardiac arrhythmia; peroxisome proliferator activated receptor-γ coactivator-1 (PGC-1).

Figures

Figure 1
Figure 1. Electrocardiographic features of pro‐arrhythmic phenotypes in Pgc‐1β −/− atria
A, typical ECG recordings from S1S2 protocols, demonstrating premature atrial complexes; dashed section is shown in B, with an expanded time base. Continuous downward‐pointing arrows denote atrial complexes as a result of stimulation. The dashed arrow indicates a premature atrial complex with no preceding stimulation spike. Continuous upward‐pointing arrows denote ventricular complexes. C illustrates atrial tachycardia in response to an S2 stimulus.
Figure 2
Figure 2. Electrocardiographic and intracellular recordings during incremental pacing
A, typical recordings from incremental pacing protocols illustrating steady‐state ECG recordings (i) from a wild‐type (WT) heart as well as the corresponding intracellular action potential (AP) recordings (ii). Ectopic activity (arrow) from an aged Pgc1β −/− heart is shown in B, with the corresponding ECG (i) and intracellular AP recordings (ii). C, evidence of atrial fibrillation in the ECG (i) recording of an aged Pgc1β −/− heart, with concurrent intracellular AP recording (ii). D illustrates AP duration alternans in an AP recording from a young WT heart.
Figure 3
Figure 3. Kaplan–Meier plot of probability of 1:1 capture as basic cycle length (BCL) is varied for each experimental group
Figure 4
Figure 4. Dependence of maximal rate of action potential depolarization (dV/dt max; A), AP latency (B), AP durations to 90% recovery (APD90; C), resting membrane potential (RMP; D) and diastolic interval (DI90; E) on basic cycle length (BCL) in young and aged WT and Pgc1β −/− hearts
Number of replicates: young WT, n = 20; young Pgc1β −/−, n = 23; aged WT, n = 22; and aged Pgc1β −/−, n = 22.
Figure 5
Figure 5. Incidence of alternans out of 100 beats at each BCL in the activation variables of maximal rate of AP depolarization, dV/dt max (A) and AP latency (B), and the recovery variables of APD90 (C) and RMP (D) in young WT (open circles), young Pgc1β −/− (filled circles), old WT (open triangles) and Pgc1β −/− hearts (filled triangles)
Number of replicates: young WT, n = 20; young Pgc1β −/−, n = 23; aged WT, n = 22; and aged Pgc1β −/−, n = 22.
Figure 6
Figure 6. Magnitude of alternans as a percentage of the previous beat at each BCL for dV/dt max (A), AP latency (B), APD90 (C) and RMP (D)
Number of replicates: young WT, n = 20; young Pgc1β −/−, n = 23; aged WT, n = 22; and aged Pgc1β −/−, n = 22.
Figure 7
Figure 7. Restitution plots of APD90 against DI90 (A) and of active AP wavelength (B) and passive wavelength (C) observed at different BCLs through the incremental pacing procedure in young and old WT and Pgc1β −/− hearts
Number of replicates: young WT, n = 20; young Pgc1β −/−, n = 23; aged WT, n = 22; and aged Pgc1β −/−, n = 22.

Similar articles

See all similar articles

Cited by 5 articles

References

    1. Adabag S, Huxley RR, Lopez FL, Chen LY, Sotoodehnia N, Siscovick D, Deo R, Konety S, Alonso A & Folsom AR (2015). Obesity related risk of sudden cardiac death in the atherosclerosis risk in communities study. Heart 101, 215–221. - PMC - PubMed
    1. Akar FG, Aon MA, Tomaselli GF, O'Rourke B & Tomaselli G (2005). The mitochondrial origin of postischemic arrhythmias. J Clin Invest 115, 3527–3535. - PMC - PubMed
    1. Akar FG & O'Rourke B (2011). Mitochondria are sources of metabolic sink and arrhythmias. Pharmacol Ther 131, 287–294. - PMC - PubMed
    1. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel‐Duby R, Rosenzweig A, Ingwall JS & Spiegelman BM (2005). Transcriptional coactivator PGC‐1α controls the energy state and contractile function of cardiac muscle. Cell Metab 1, 259–271. - PubMed
    1. Ausma J, Wijffels M, Thoné F, Wouters L, Allessie M & Borgers M (1997). Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 96, 3157–3163. - PubMed

Publication types

MeSH terms

Substances

Feedback