cardiovascular system
• enlarged hearts exhibit thickened walls of all four chambers and the interventricular septum
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• a mild increase in non-myofibrillar and extracellular space is observed
• however, no increases in interstitial fibrosis or inflammation are observed
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• mutant cardiomyocytes appear to be slightly thicker in most areas of the heart muscle relative to controls
• rather than being arrayed in tight parallel bundles, mutant myofibrils show a looser arrangement and a mild disarray, with increased waviness, overlapping, and crossing of myofibrils within cardiomyocytes
• cell nuclei are often enlarged, rounded, or lobulated and frequently contain large nucleoli
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• mutant intercalated discs are sparse in number and often appear broad, jagged, and less distinct or fragmented
• where present, mutant intercalated discs are often highly convoluted and less electron-dense than wild-type
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• both female and male homozygotes display heart enlargement during the first month of life
• however, no spontaneous deaths are observed in either sex up to 12 months of age
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• at 24 weeks of age, homozygotes display increased absolute heart weight as well as increased heart weight/body weight and heart weight/tibia length ratios relative to wild-type controls
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• at 24 weeks of age, homozygotes display increased absolute heart weight as well as increased heart weight/body weight and heart weight/tibia length ratios relative to wild-type controls
• primary cardiac hypertrophy is indicated by lack of overt malformations in heart valves or large vessels, including aorta, pulmonary, carotid, and femoral arteries
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• myocardial hypertrophy is indicated by the increased thickness of LV and RV walls and by the markedly increased absolute heart weight and increased heart weight/body weight and heart weight/tibia length ratios
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• at 3 months of age, homozygotes show a marked increase in end-diastolic and end-systolic volumes of left ventricle, suggesting LV chamber dilation
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• at 3 months of age, homozygotes show increased thickness in both septal and LV free walls at end-diastole; however, no significant change in wall thickness is noted at end-systole
• both LV and RV walls exhibit increased thickness relative to wild-type controls
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• at 3 months of age, homozygotes display reduced cardiac output
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• at 3 months of age, homozygotes display reduced stroke volume
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• at 3 months of age, homozygotes display reduced ejection fractions (EFs), given as stroke volume (SV) divided by LV cavity volume at end-diastole (LVEDV)
• at 3 and 9 months of age, homozygotes show similarly reduced EFs relative to wild-type controls (67% at 3 months and 68% at 9 months of age), indicating that EFs do not deteriorate over time
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• MRI functional analysis revealed that naive male homozygotes show a >50% reduction in LV contractility in both septal and LV free walls, as determined by wall thickness change during contraction
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• homozygotes display markedly increased baseline LV pressures relative to wild-type controls
• in response to dobutamine challenge, homozygotes fail to exhibit increased LV pressure in conjunction with dobutamine-induced increased heart rates, unlike wild-type controls
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• although grossly normal appearance and behavior, 12-week-old homozygotes show a significant reduction in systolic blood pressure
• however, no obvious conductance abnormalities or arrhythmia are observed at this age
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• homozygotes develop a non-progressive cardiomyopathy that presents features of both hypertrophic and dilated forms of cardiomyopathy
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muscle
• a mild increase in non-myofibrillar and extracellular space is observed
• however, no increases in interstitial fibrosis or inflammation are observed
|
• mutant cardiomyocytes appear to be slightly thicker in most areas of the heart muscle relative to controls
• rather than being arrayed in tight parallel bundles, mutant myofibrils show a looser arrangement and a mild disarray, with increased waviness, overlapping, and crossing of myofibrils within cardiomyocytes
• cell nuclei are often enlarged, rounded, or lobulated and frequently contain large nucleoli
|
• mutant intercalated discs are sparse in number and often appear broad, jagged, and less distinct or fragmented
• where present, mutant intercalated discs are often highly convoluted and less electron-dense than wild-type
|
• myocardial hypertrophy is indicated by the increased thickness of LV and RV walls and by the markedly increased absolute heart weight and increased heart weight/body weight and heart weight/tibia length ratios
|
• at 3 months of age, homozygotes display reduced ejection fractions (EFs), given as stroke volume (SV) divided by LV cavity volume at end-diastole (LVEDV)
• at 3 and 9 months of age, homozygotes show similarly reduced EFs relative to wild-type controls (67% at 3 months and 68% at 9 months of age), indicating that EFs do not deteriorate over time
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• MRI functional analysis revealed that naive male homozygotes show a >50% reduction in LV contractility in both septal and LV free walls, as determined by wall thickness change during contraction
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• homozygotes develop a non-progressive cardiomyopathy that presents features of both hypertrophic and dilated forms of cardiomyopathy
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growth/size/body
• both female and male homozygotes display heart enlargement during the first month of life
• however, no spontaneous deaths are observed in either sex up to 12 months of age
|
• at 24 weeks of age, homozygotes display increased absolute heart weight as well as increased heart weight/body weight and heart weight/tibia length ratios relative to wild-type controls
|
• at 24 weeks of age, homozygotes display increased absolute heart weight as well as increased heart weight/body weight and heart weight/tibia length ratios relative to wild-type controls
• primary cardiac hypertrophy is indicated by lack of overt malformations in heart valves or large vessels, including aorta, pulmonary, carotid, and femoral arteries
|
• myocardial hypertrophy is indicated by the increased thickness of LV and RV walls and by the markedly increased absolute heart weight and increased heart weight/body weight and heart weight/tibia length ratios
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