Di Lang

Gregory Lanza

Igor Efimov

Junjie Chen

Samuel A Wickline

Shelton D Caruthers

Ya-Jian Cheng

Journal of Cardiovascular Magnetic Resonance

PubMed

Springer - Publisher Connector

Regional expression of myocardial sheet dysfunction in dystrophin-deficient cardiomyopathy elucidated with diffusion tensor MRI and optical calcium mapping

ORAL PRESENTATION Open Access
Regional expression of myocardial sheet
dysfunction in dystrophin-deficient
cardiomyopathy elucidated with diffusion tensor
MRI and optical calcium mapping
Ya-Jian Cheng1,2*, Di Lang1, Shelton D Caruthers2, Gregory Lanza2, Igor Efimov1, Junjie Chen2,
Samuel A Wickline2,1
From 15th Annual SCMR Scientific Sessions
Orlando, FL, USA. 2-5 February 2012
Summary
Duchene Muscular Dystrophy (DMD) is a lethal disease
caused by ubiquitous lack of dystrophin, but the interac-
tion with regional cardiac mechanical forces that may
facilitate eventual expression of abnormal contractile
function is unknown. Diffusion tensor MRI (DTI) was
used to evaluate function in Langendorff perfused hearts
in the mdx mouse model of DMD. Abnormal calcium
kinetics (by optical mapping) and sheet mechanics (by
DTMRI) occurred more prominently at the mid-upper
ventricle, suggesting that regional mechanics influence
the development of heart failure.
Background
The relationship between abnormal sarcoplasmic Ca2+
handling and cardiac structural mechanics in mdx mice
has not been defined. DTI has been used to quantify the
contribution of myocardial sheet architecture in ventri-
cular wall thickening mechanics. In this study, DTI was
employed to assess altered sheet mechanics that might
be influenced by impaired calcium homeostasis. Further-
more, optical mapping of AP and CaT were employed
to characterize local difference in ex vivo beating hearts.
Methods
Sixteen-month old mdx (n = 10) and age matched wild-
type (WT, n = 10) mouse hearts were prepared for Lan-
gendorff perfusion by sequentially cardiac arrest in
diastole and systole for DTI: The first group (WT-NC &
mdx-NC) was perfused with regular St. Thomas’ cardio-
plegic solution containing normal [Ca2+] (1.2 mM) to
arrest hearts in diastole. To assess the regulatory effect
of [Ca2+] on diastolic sheet mechanics, the second
group (WT-LC & mdx-LC) was perfused with modified
cardioplegic solution containing low [Ca2+] (0.078 mM).
All hearts were then reperfused with Krebs buffer to
resume beating followed by 2.5mM barium-induced sys-
tolic arrest for DTI. Absolute values of sheet angles, |b|
s, in each heart were calculated from the diffusion ten-
sors. MANOVA was used for statistical analysis.
Another set of Langendorff beating mouse hearts from
WT (n=2) and mdx (n=3) mice were optically mapped.
RH237 and Rhod-2 AM were used as membrane poten-
tial and calcium probes. Steady state restitution pacing
protocol was applied to estimate the calcium dynamics
at different heart rates.
Results
In diastole, mdx hearts exhibited lower |b| in mid-upper
ventricle than WT did. Reducing [Ca2+] in cardioplegic
solution normalized the diastolic |b| in mdx hearts but
had no detectable effect on WT hearts. No significant
difference of systolic |b| was observed between mdx and
WT hearts. (Fig. 1) Optical mapping of CaT showed a
localized Ca alternans and Ca rising time (Fig. 2)
abnormality in mdx mice’s mid-upper ventricle.
Conclusions
The observed lower diastolic |b| in mdx hearts indicates
that mdx cardiomyocytes fail to fully relax in diastole.
1Biomedical Engineering, Washington University in Saint Louis, Saint Louis,
MO, USA
Full list of author information is available at the end of the article
Cheng et al. Journal of Cardiovascular Magnetic Resonance 2012, 14(Suppl 1):O31
http://www.jcmr-online.com/content/14/S1/O31
© 2012 Cheng et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The regulatory effect of [Ca2+] on diastolic |b| of mdx
hearts suggests that the myocardial sheet diastolic dys-
function is reversible despite the advance age of mdx
mice. Optical mapping of CaT in beating hearts further
confirmed the DTI-detected localized calcium-depen-
dent abnormality, indicating that the ubiquitous dystro-
phin deficiency in mdx mice depends on regional
cardiac features for its affection. In conclusion, the dis-
turbed sheet mechanics may reflect functional conse-
quences of abnormal Ca2+ handling in vivo, which
likely correlates with membrane calcium channel dys-
function that precedes eventual cardiac failure.
Funding
RO1 HL073646.
Author details
1Biomedical Engineering, Washington University in Saint Louis, Saint Louis,
MO, USA. 2Cardiovascular Division, Washington University in Saint Louis,
School of Medicine, Saint Louis, MO, USA.
Published: 1 February 2012
doi:10.1186/1532-429X-14-S1-O31
Cite this article as: Cheng et al.: Regional expression of myocardial
sheet dysfunction in dystrophin-deficient cardiomyopathy elucidated
with diffusion tensor MRI and optical calcium mapping. Journal of
Cardiovascular Magnetic Resonance 2012 14(Suppl 1):O31.
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Figure 1 DTI measured |b| from base to apex in diastole (A) and systole (B). Normal calcium concentration perfused mdx heart (mdx-NC) exhibit
lower |b| than all other three groups at mid-upper ventricle. Surprisingly, while mdx hearts were perfused with low calcium concentration (mdx-
LC), the |b| was restored to normal level. *, p =0.04; **, p=0.001; †, p = 0.003; ++, p < 0.02. Data are shown as mean ± SEM. N = 5 for each
group.
Figure 2 Calcium transient rise time from 10% to 90% amplitude
based on optical mapping signals in both WT and mdx mice. The
signals from base area, apex area and the whole ventricle were
statistically compared. Significantly longer rise time in mdx mice
ventricle base was observed comparing to WT group.
Cheng et al. Journal of Cardiovascular Magnetic Resonance 2012, 14(Suppl 1):O31
http://www.jcmr-online.com/content/14/S1/O31
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Regional expression of myocardial sheet dysfunction in dystrophin-deficient cardiomyopathy elucidated with diffusion tensor MRI and optical calcium mapping

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