Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) ...coimmunoprecipitated with connexin 43 (Cx43), which was N...-lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 N...-lysine acetylation and restored its association to GAP junctions (GJs) at intercalated discs. Noteworthy, in normal as well as mdx mice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3 was also part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-3-(3-fluorophenyl)-3-oxo-1-propen-1-yl-1-methyl-1H-pyrrol-2-yl}-N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeability was significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 N...-lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function. (ProQuest: ... denotes formulae/symbols omitted.)
Understanding the relations between the architecture of myocardial fibers, the spread of excitation, and the associated ECG signals is necessary for addressing the forward problem of ...electrocardiography, that is, predicting intracardiac and extracardiac ECGs from known intracardiac activity. So far, these relations have been studied experimentally only in small myocardial areas. In this study, we tested the hypothesis that potential distributions measured over extensive epicardial regions during paced beats reflect the direction of superficial and intramural fibers through which excitation is spreading in both the initial and later stages of ventricular excitation. We also tried to establish whether the features of the epicardial potential distribution that correlate with fiber direction vary as a function of pacing site, intramural pacing depth, and time elapsed after the stimulus. An additional purpose was to compare measured epicardial potentials with recently published numerical simulations depicting the three-dimensional spread of excitation in the heart muscle and the associated potential fields.
The hearts of 18 mongrel dogs were exposed and 182 to 744 unipolar electrograms were recorded from epicardial electrode arrays (2.3 x 3.0 to 6.5 x 6.5 cm). Hearts were paced at various intramural depths through an intramural needle. The overall number of pacing sites in 18 dogs was 241. Epicardial potential distributions, electrographic waveforms, and excitation time maps were displayed, and fiber directions in the ventricular wall underlying the electrodes were determined histologically. During the early stages of ventricular excitation, the position of the epicardial maxima and minima revealed the orientation of myocardial fibers near the pacing site in all cases of epicardial and intramural pacing and in 60% of cases of endocardial or subendocardial pacing. During later stages of propagation, the rotation and expansion of the positive areas correlated with the helical spread of excitation through intramurally rotating fibers. Marked asymmetry of potential patterns probably reflected epicardial-endocardial obliqueness of intramural fibers. Multiple maxima appeared in the expanding positive areas.
For 93% of pacing sites, results verified our hypothesis that epicardial potential patterns elicited by ventricular pacing reflect the direction of fibers through which excitation is spreading during both the initial and later stages of propagation. Epicardial potential distributions provided information on the site of origin and subsequent helical spread of excitation in an epicardial-endocardial, endocardial-epicardial, or double direction. Results were in agreement with previously published numerical simulations except for the asymmetry and fragmentation of the positive areas.
Ventricular activation is impaired in aged rat hearts ROSSI, Stefano; BARUFFI, Silvana; BRISINDA, Donatella ...
American journal of physiology. Heart and circulatory physiology,
2008, Letnik:
64, Številka:
6
Journal Article
1 Dipartimento di Biologia Evolutiva e Funzionale-Sezione
Fisiologia, 2 Dipartimento di Biologia Evolutiva e
Funzionale-Sezione Biologia Umana, and 4 Istituto di Anatomia
Patologica, Università ...degli Studi di Parma, 43100 Parma; and
3 Dipartimento di Farmacologia Preclinica e Clinica,
Università degli Studi di Firenze, 50134 Florence, Italy
In 47 male adult Wistar rats with 4-wk
aortic coarctation (AC) and 39 age-matched sham-operated rats (SO)
chronically instrumented for telemetry electrocardiogram recording, we
investigated the mechanisms of arrhythmogenesis in moderate cardiac
hypertrophy, with an approach from "in vivo" toward the cellular
level, analyzing 1 ) stress-induced cardiac arrhythmias in
all rats and 2 ) myocardial fibrosis in 35 animals and action
potential duration and density of hyperpolarization-activated current
in 19 others at the ventricular level. Aortic banding increased
arterial blood pressure, cardiac weight, and ventricular myocyte volume
by 11, 25, and 14%, respectively ( P < 0.001-0.05). Ventricular arrhythmias occurred at similar rates in
AC and SO rats throughout the stress procedure. Action potential
duration and hyperpolarization-activated current were about twice as
great and myocardial fibrosis about four times greater in AC animals
( P < 0.005-0.05). Electrocardiogram data also
revealed more supraventricular arrhythmias in AC rats during the
baseline period and after stress and fewer atrioventricular block
episodes after stress ( P < 0.05). Thus stress-induced
supraventricular and atrioventricular nodal, but not ventricular,
arrhythmias were affected in moderate cardiac hypertrophy when
ventricular morphofunctional alterations were evident.
mechanisms of cardiac arrhythmias; myocardial fibrosis; membrane
potential; hyperpolarization-activated current; social stress
1 Dipartimento di Biologia
Evolutiva e Funzionale, Sezione Fisiologia, and
2 Istituto di Anatomia ed
Istologia Patologica, Università degli Studi, 43100 Parma, Italy;
and 3 Cardiovascular Research
...and Training Institute, University of Utah, Salt Lake City, Utah 84112
The purpose of this study is to report new
methods for manufacturing precision electrode arrays for recording
high-resolution potential distributions from epicardial surfaces of
small-animal hearts. Electrode arrays of 64 leads (8 × 8) and 121 leads (11 × 11) were constructed with a tulle substrate
to which insulated, fine silver wires (60-µm diameter) were attached
by knots at mesh node intervals of 540 × 720 µm. Insulation was
removed at the tips of the knots. Potential distributions and waveforms
were recorded from saline solutions and rat heart epicardium during ventricular paced beats and during passive current injection in the
diastolic interval. Electrical responses obtained from rat epicardium
compared favorably with those observed in studies of larger-animal
hearts, which used arrays having greater electrode spacing, and
revealed the effects of myocardial anisotropy. Epicardial potentials
measured early after stimulation in the region surrounding the pacing
site were interpreted in terms of potentials generated by an equivalent
quadrupolar source. We conclude that electrode arrays for epicardial
mapping of small hearts can be constructed with sufficient ease and
precision to allow detailed study of fiber structure and
electrophysiology in these hearts in normal and pathological conditions.
high-resolution cardiac mapping; epicardial electrode arrays; epicardial potential distributions in rat heart; cardiac anisotropy; ventricular paced beat
Stimulation of myocardium by either a native pacemaker or an artificial stimulus requires the initiation of a self-propagating wave of depolarization originating from the site of initial activation. ...In the present study we perform artificial stimulation at a site of focal discharge with the aim to compare the two mechanisms of impulse formation. High resolution epicardial mapping in senescent rat hearts provided examples of focal discharge during sinus rhythm at a single epicardial breakthrough (BKT) point emerging from an isolated Purkinje-ventricular muscle junction (PMJ) site. Stimulation was also performed at the same BKT point and potential distributions recorded during spontaneous and artificial stimulation were compared. During excitation latency, the negative potential pattern was elongated perpendicularly to fiber direction at both pacing and BKT point, in agreement with virtual cathode membrane polarization predicted by the bidomain model during point stimulation. During impulse initiation, activation wave fronts were initially circular around pacing site or BKT point and then elongated along local fiber direction. The similarity between impulse initiation during focal discharge and point stimulation in cardiac muscle suggests that high resolution pace mapping studies can help to elucidate the mechanism of abnormal impulse formation.
In 47 male adult Wistar rats with 4-wk aortic coarctation (AC) and 39 age-matched sham-operated rats (SO) chronically instrumented for telemetry electrocardiogram recording, we investigated the ...mechanisms of arrhythmogenesis in moderate cardiac hypertrophy, with an approach from "in vivo" toward the cellular level, analyzing 1) stress-induced cardiac arrhythmias in all rats and 2) myocardial fibrosis in 35 animals and action potential duration and density of hyperpolarization-activated current in 19 others at the ventricular level.
The purpose of this study is to report new methods for manufacturing precision electrode arrays for recording high-resolution potential distributions from epicardial surfaces of small-animal hearts. ...Electrode arrays of 64 leads (8 X 8) and 121 leads (11 x 11) were constructed with a tulle substrate to which insulated, fine silver wires (60-mum diameter) were attached by knots at mesh node intervals of 540 X 720 mum.
![N^sup [epsilon]^-lysine ace...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0027-8424/small "N^sup [epsilon]^-lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart")
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