1 INTRODUCTION
SIR – We wish to comment on a Letter by Soichiro Yasuda
and colleagues „ Dystrophic heart failure blocked by membrane
sealant poloxamer“ (Nature, 436:1025-1029;2005M).
How can control (C57BL) and mdx-mice be compared
if they differed considerably at baseline concerning endsystolic
volume, end-diastolic volume, end-systolic pressure,
stroke volume, and dP/dtmin?
Left ventricular (LV) end-systolic diameter, LV enddiastolic
diameter, and LV-mass increase and fractional
shortening decreases with age and by age 42w all mdx-mice
have dilated cardiomyopathy. It is not mentioned if all of
the investigated mice had the same age.
Also gender of the investigated mdx-mice is not given.
Gender might be relevant since sex-associated changes in
response to calcium were reported in mdx-mice.
Different parts of the myocardium are differentially affected
by the dystrophic process and myocardial fibrosis in
mdx-mice. It is not mentioned from which part of the heart
cardiomyocytes were taken. Were they taken from the left
or right atrium or ventricle? Was the location of biopsy the
same in control and mdx-mice?
Mdx-mice develop progressive LV dilatation and by age
42 weeks all have dilated cardiomyopathy. How to explain
that in the present study end-diastolic-volume was smaller
in mdx-mice compared to control mice and that there was
diastolic instead of systolic dysfunction? Did any of the
mdx-mice develop dilated cardiomyopathy or restrictive
haemodynamics?
Mdx-mice develop ECG abnormalities, like tachycardia,
similar to those in DMD. Were ECGs registered during the
experiments and did the frequency of ECG abnormalities
differ between P188-treated and untreated mdx-mice? Why
did P188 not affect the heart rate? How to explain heart
rates of 582-600bpm in anaesthetised control and mdxmice
whereas previous studies reported heart rates of 350-
380bpm in anaesthetised C57BL mice?
How to explain that P188 only increases LV end-diastolic
volume without affecting LV end-diastolic pressure? If
P188 actually improves the diastolic function, expressed as
dP/dtmin, a decrease in LV end-diastolic pressure would be
expected.
Since the end-diastolic-pressure did not differ between
control and mdx-mice at baseline, the latter do not seem to
have diastolic dysfunction. Increase in end-diastolic pressure
after P188 indicates ineffectiveness of the agent concerning
diastolic function.
Why was dobutamine chosen as a cardiac stressor, since
isoproterenol or aortic constriction have been acknowledged
as appropriate cardiac stressors in mdx-mice? The study
referenced for giving dobutamine actually used aortic constriction
and isoproterenol, but not dobutamine. How can
one be sure that myocardial P188 concentrations were high
enough after local or intravenous application to be effective?
Differed hearts morphologically or functionally between
control and mdx-mice? What were the pathoanatomic and
histological findings in hearts of P188-treated and untreated
mdx-mice? Did they differ from control mice? Was there a
difference in the amount of damaged cardiomyocytes and
fibrosis? Were there any cases with LV hypertrabeculation/
noncompaction? Why was no echocardiography or cardiac
MRI carried out to monitor the therapeutic effect of
P188?
The presented data do not justify to claiming a
therapeutic effect of P188 for mdx cardiomyopathy
because the study groups were unequal, cardiac changes
after treatment were equivocal, and because of various
other methodological uncertainties.
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