Catherine Duffy, Richard T. Lee, Christine E. Seidman and J.G. Seidman
Joachim P. Schmitt, Christopher Semsarian, Michael Arad, Joseph Gannon, Ferhaan Ahmad,
Consequences of Pressure Overload on Sarcomere Protein Mutation-Induced
Print ISSN: 0009-7322. Online ISSN: 1524-4539
Copyright © 2003 American Heart Association, Inc. All rights reserved.
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2003;108:1133-1138; originally published online August 18, 2003;
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pressure overload or a sarcomere protein gene mutation; the
same amount of fibrosis was observed in banded 129SvEv
and BS ?MHC403/?mice. Because a BS background modifier
gene has been previously recognized to alter the hypertrophic
response to a sarcomere protein gene missense mutation,14
this same modifier gene or another likely accounts for the
amplified hypertrophic response to the combined stimulus of
pressure overload and sarcomere protein gene mutation. By
extrapolation, we suggest that modifying genes may cause a
modest effect on the hypertrophic phenotype of individuals
with both sarcomere protein mutations and hypertension.
The conclusion that pressure overload and sarcomere
protein gene mutations lead to hypertrophy by independent
pathways has important implications for human HCM. First,
investigators have noted that the distribution of hypertrophy
differs when produced by pressure overload versus sarcomere
protein mutations.7,16Asymmetric septal hypertrophy is the
most common morphology of human HCM.17Hypertrophy in
?MHC403/?mice can also be asymmetric.12Although the
mechanism for this asymmetry remains controversial, one
hypothesis has been that differences in regional wall stress
influence cardiac remodeling.18Pressure overload in both
wild-type19and ?MHC403/?mice caused concentric LV hy-
pertrophy. Consistent with the conclusion that pressure over-
load did not exacerbate the hypertrophic response to a
sarcomere protein mutation, changes in ventricular pressure
distribution that must accompany aortic banding did not lead
to asymmetric or other specific patterns of hypertrophy in
?MHC403/?mice. We conclude that other factors, both genetic
and environmental, must be responsible for the patterning of
hypertrophy in individuals with sarcomere protein mutations.
Second, the less than additive effect of LV mass observed in
mice with hypertrophic cardiomyopathy and hypertension
suggests a favorable clinical outcome in terms of both
morbidity and mortality in humans with coexistent disease.
Patients with coexisting HCM and hypertension should re-
ceive only standard therapy for each disorder. Furthermore,
substantial cardiac hypertrophy in hypertension is unlikely to
reflect unrecognized HCM.
The Howard Hughes Medical Institute supported this work. Dr
Semsarian is the recipient of a National Heart Foundation of
Australia scholarship, and Dr Schmitt was supported by the Henrietta
and Frederick Bugher Foundation.
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September 2, 2003
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