Li, Qince

Zhou, Lufang

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122a Sunday, February 16, 2014provide an independent support for the theory of optical stimulation of
excitable tissue.
Supported by APVV-0721-10 and by VEGA 2/0203/11 and VEGA 2/0197/11.
631-Pos Board B386
Electrophysiological and Structural Left Ventricle Remodelling in
Spontaneously Hypertensive Rat Hearts: A Multicellular Study
Samha Alayoubi1,2, Carolina Pinto Ricardo1, Junaid Zaman1,
Priyanthi Dias1, Patrizia Camelliti1, Magdi H. Yacoub1, Cesare Terracciano1.
1NHLI, Imperial college, London, United Kingdom, 2King Fahad Cardiac
Center, King Saud University, Riyadh, Saudi Arabia.
The spontaneously hypertensive rat (SHR) is a well-characterised model for
studies of hypertension and atrial arrhythmias but little is known about
the electrophysiological properties of the left ventricle (LV) and their
relation with ventricular arrhythmias in this model. To investigate the mech-
anisms behind electrophysiological abnormalities in the LV and their links to
the morphological substrate we used myocardial slices, a multicellular
preparation which allows the investigation of functional and structural prop-
erties in the same tissue location. Vibratome-cut myocardial slices (300mm
thick) were prepared from 20 month-old SHR and aged-matched control
LVs, tangentially to the epicardial surface. Slices were point-stimulated
and analysed using a multi-electrode array system; conduction velocity
(CV) and field potential duration (FPD), an index of action potential duration,
were measured. Longitudinal CV was lower in the SHR compared with con-
trols (SHR: 2954 cm/s, n=12 slices; C: 4556 cm/s, n=22 slices; p<0.05),
but transverse CV was unchanged. FPD was not statistically different be-
tween the two groups and showed a similar restitution curve. A high number
of fractionated field potentials were observed at similar levels in both groups
(SHR: 107520 ms, n=6 slices; C: 7452 ms, n=6 slices; p>0.05). In support
of the lower CV, Western blotting analysis revealed a reduction in the gap
junctional protein connexin43 expression in the SHR (p<0.01). A high
amount of interstitial fibrosis, quantified by Sirius red/fast green collagen
quantitative staining kit was found in both groups at similar
levels (P>0.05) and could be ascribed to aging as this was not detected in
slices from 2 month old rats (p <0.05). These results suggest that down
regulation of connexin 43 and not myocardial fibrosis is associated with elec-
trophysiological LV abnormalities in a rat model of chronic hypertension.
632-Pos Board B387
Alternans in Rabbit Heart During Acute Regional Ischemia: Optical
Mapping and Microelectrode Recordings
IrmaMartisien _e1, Jonas Jurevicius1, Ruta Vosyliut _e1, Antanas Navalinskas1,
Rimantas Treinys1, Regina Macianskien _e1, Rimantas Benetis1,
Arvydas Matiukas2, Arkady M. Pertsov1,2.
1Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas,
Lithuania, 2Department of Pharmacology, SUNY Upstate Medical
University, Syracuse, NY, USA.
T-wave alternans during acute ischemia have been determined as a precursor
of ventricular arrhythmias usually resulting in sudden cardiac death. Optical
mapping is often used to investigate the mechanisms of alternans in heart
preparations. Several hypothesis exist that may explain the formation of opti-
cal alternans. One of them is that optical action potential amplitude (OAPA)
alternans may indicate the formation of alternating conduction blocks. In our
study by using optical mapping simultaneously with microelectrode record-
ings we aimed to investigate the occurrence of OAPA alternans during acute
regional ischemia and to determine the electrical origin underlying the alter-
nans formation. Experiments were performed in Langendorff-perfused rabbit
hearts stained with near-infrared dye di-4-ANBDQBS. Optical signals were
registered from left ventricle epicardium. The hearts were stimulated by
applying 300 ms, and 200 ms pacing cycle. Results showed that OAP started
alternate with high and low amplitudes at 200 ms pacing at early ischemia
(4-6 minutes). The alternation zone migrated, shrank and finally disappeared
with increasing ischemia time. In order to elucidate the mechanism of this
phenomenon two glass microelectrodes were used to examine electrical activ-
ity by registering action potentials from subepicardial and deeper (3-5 mm)
myocardial layers simultaneously. Microelectrode recordings revealed that
OAPA alternans is the result of 2:1 conduction blocks in a certain layer whilst
the regular response is held in the other layers. During later ischemia (10-15
minutes) deep myocardial layers lose their excitability remaining optical sig-
nals only with low amplitude. It explains the disappearing of OAPA alternans.
Thus, our experimental data show that OAPA alternans which arise during the
early acute ischemia can be caused by alternation of conduction blocks in a
certain myocardial layers.
Research is funded by the European Social Fund under the Global Grant
measure.633-Pos Board B388
Evaluation of Optical Upstroke Morphology in the Rabbit Heart: Optical
Mapping and Transmural Microelectrode Recordings
Ruta Vosyliut _e, Regina Macianskien _e, Irma Martisien _e,
Antanas Navalinskas, Rimantas Treinys, Birut_e Vaidelyt_e,
Gintaut_e Rutkauskait _e, Jonas Jurevicius.
Lithuanian University of Health Sciences, Kaunas, Lithuania.
Last decade optical mapping technique became a widely-used instrument in
cardiac electrophysiology. Optically recorded action potentials (AP’s) in single
cardiac cells precisely match electrically recorded ones. However, this relation-
ship becomes not so direct in myocardium since optical AP (OAP) is the
depth-weighted average of propagating AP and is affected by optical-
biological processes (absorption, scattering and reflection). The best way to
achieve informative results of electrical activity in the heart is to use both,
optical approaches in combination with microelectrode technique.
In the Langerdorff-perfused rabbit heart AP’s were recorded with glass micro-
electrodes transmurally across the left ventricle (LV) wall from subepicardium
towards subendocardium (3-5 mm, 20-50 steps). Simultaneously we used near-
infrared (NIR) voltage sensitive fluorescent dye di-4-ANBDQBS to obtain
OAP recordings using EMCCD camera (128x128 pixels, 500 frames/s). OAP’s
and electrical AP’s were recorded using pacing from epicardium and
endocardium.
In our experiments we found, that AP activation time dependence on myocar-
dium depth had a different shape, depending on pacing the type, distance, and
LV geometry at recording site. The shape of the curve showed electrical trans-
mural inhomogeneity of myocardium, which possibly was caused by histolog-
ical inhomogeneity and different fibers orientation in different layers of
myocardium. For the upstroke of OAP’s evaluation, optical signals were
compared with electrical AP’s, recorded and summated transmurally through
LV wall depth. Recordings allowed us to evaluate the role of light scattering
and how much tissue inhomogeneity was reflected in the morphology of the
upstroke of OAP.
The obtained data could assist for better understanding of the mechanisms of
the excitation wave propagation and for proper evaluation of optical signal in
LV of the rabbit.
This research is funded by the European Social Fund under the Global Grant
measure.
634-Pos Board B389
Mechanisms Underlying NaD/KD-ATPase Inhibition-Induced Mitochon-
drial Dysfunction and Abnormal Action Potentials
Qince Li, Lufang Zhou.
Division of Cardiovascular Disease and Comprehensive Cardiovascular
Center, University of Alabama at Birmingham, Birmingham, AL, USA.
The proarrhythmic effect of cardiac glycosides has confined their extensive
applications in the treatment of heart failure. The detailed molecular mecha-
nisms underlying glycoside-induced arrhythmogenesis are not fully under-
stood. Recent experimental work shows that glycosides (e.g. Ouabain) impair
mitochondrial energy metabolism and raise reactive oxygen species (ROS) pro-
duction, resulting in abnormal action potentials in cardiomyocytes. In the pre-
sent work, a multiscale cardiomyocyte model that incorporates cellular
electrophysiology, mitochondrial energetics and detailed antioxidant system
is developed to further investigate how glycosides may lead to mitochondrial
dysfunction and abnormal electrophysiology under various physiological/
pathological conditions. In the model, the effect of glycoside is mimicked by
inhibiting Naþ/Kþ pump (a.k.a NKA) activity. Our simulations show that mod-
erate NKA inhibition (e.g. by 50%-70%) causes cytosolic Ca2þ accumulation
and blunted mitochondrial Ca2þ ([Ca2þ]m) uptake, especially during the tran-
sition of increased workload. The suppressed [Ca2þ]m uptake is accompanied
with decreased NADH production and increased ROS accumulation. These
results are consistent with previous experimental data. Interestingly, model
simulations show that under certain conditions (e.g. in stressed cells), blocking
NKA can cause mitochondrial depolarization and trigger sustained mitochon-
drial oscillations. Another finding is that further increasing NKA inhibition
(e.g. by 90%) leads to severe ATP depletion and triggers Ca2þ and action
potential alternans. Finally, simulations reveal that the glycoside-induced mito-
chondrial dysfunctions can be prevented or alleviated by inhibiting mitochon-
drial Ca2þ extrusion via mitochondrial Naþ/Ca2þ exchanger, but not by
increasing mitochondrial Ca2þ uptake via mitochondrial Ca2þ uniporter. These
results suggest that impaired mitochondrial Ca2þ uptake and energy production
are the major factors responsible for NKA inhibition-induced abnormal cellular
electrophysiology. This study, using computational modeling, provides new
insights into the mechanisms underlying the proarrhythmic effect of cardiac
glycosides, and has important implications for developing new glycoside-
based therapies of heart failure.


Mechanisms Underlying Na+/K+-ATPase Inhibition-Induced Mitochondrial Dysfunction and Abnormal Action Potentials 

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Mechanisms Underlying Na+/K+-ATPase Inhibition-Induced Mitochondrial Dysfunction and Abnormal Action Potentials

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