Impact of beta-myosin heavy chain expression on cardiac function during stress
Maike Krenz, MD and
Jeffrey Robbins, PhD*
Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Manuscript received June 23, 2004;
revised manuscript received September 1, 2004,
accepted September 14, 2004.
* Reprint requests and correspondence: Dr. Jeffrey Robbins, Molecular Cardiovascular Biology, MLC 7020, Children's Hospital, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039
(Email: jeff.robbins{at}cchmc.org).
OBJECTIVES: In failing mouse and human hearts, a shift in myosin heavy chain (MHC) isoform content from alpha to beta can occur. However, the impact of this phenomenon on disease progression is not well understood. Therefore, using transgenic (TG) mice, we tested how a pre-existing shift from alpha- to beta-MHC affects cardiac function under chronic mechanical or pharmacologic cardiovascular stress.
BACKGROUND: Expression of beta-MHC is considered to be energetically favorable, but this might be offset by depressed cardiac function.
METHODS: Transgenic mice with near-complete replacement of the normally predominant alpha- with beta-MHC were subjected to cardiac stress.
RESULTS: At baseline, TG mice show moderately reduced cardiac contractile function but are otherwise healthy with normal ventricular morphology. After four weeks of swimming, both TG and non-TG animals showed a 20% increase in left ventricular (LV)/body weight ratios. The TG hearts displayed mildly greater end-diastolic and end-systolic LV diameters than nontransgenic hearts after training, but no signs of LV failure were observed. However, chronic stimulation with isoproterenol resulted in augmented LV hypertrophy with signs of LV decompensation in TG mice. Furthermore, in a post-infarction failure model, TG hearts displayed accelerated LV dilation and a faster decline of shortening fraction.
CONCLUSIONS: Expression of beta-MHC appears to be disadvantageous to the mice under severe cardiovascular stress, implying that the alpha beta-MHC isoform shift observed in cardiac disease may be a maladaptive response.
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Abbreviations and Acronyms
| | dP/dtmax = first derivative of left ventricular pressure | | LV = left ventricle/ventricular | | MHC = myosin heavy chain | | NTG = nontransgenic | | TG = transgenic |
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