Phenotypes Associated with This Genotype

Genotype
MGI:5904828

• Allelic Composition: Tg(Myh6-CACNA1C)M1Aschw/0
• Genetic Background: involves: FVB/N

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:134761 )

• mice begin to die at 8-10 months of age from heart failure, with very few surviving more than 1 year

growth/size/body

enlarged heart ( J:134761 )

• severe cardiomegaly in all 4 cardiac chambers by 8 months of age

cardiac hypertrophy ( J:129494 )

• heart-to-body weight differences are increased, indicating a mild hypertrophy without ventricular dysfunction

cardiovascular system

abnormal heart morphology ( J:134761 )

• calcium-laden cells occur at a low frequency in 8 month old hearts

abnormal myocardial fiber morphology ( J:129494 , J:134761 )

• average cell capacitance is larger in ventricular cardiomyocytes, indicating cellular hypertrophy (J:129494)

• cardiomyocytes from 2, 4, and 8 month old mice show an increase in calcium channel density (J:134761)

thick interventricular septum ( J:134761 )

• mild thickening at 8 months of age

enlarged heart ( J:134761 )

• severe cardiomegaly in all 4 cardiac chambers by 8 months of age

cardiac hypertrophy ( J:129494 )

• heart-to-body weight differences are increased, indicating a mild hypertrophy without ventricular dysfunction

abnormal heart left ventricle morphology ( J:129494 )

• left ventricular mass is increased 23%

• left ventricular end-diastolic dimension is minimally increased

abnormal heart ventricle wall thickness ( J:129494 )

• minimal increase in left ventricular posterior wall thickness

cardiac interstitial fibrosis ( J:134761 )

• extensive interstitial fibrosis separates groups of myocytes in ventricles

• fibrosis and repair are present in 2 and 4 month old hearts

dilated cardiomyopathy ( J:134761 )

• hypertrophic myopathy (4-chamber dilation with mild thickening of the interventricular septum) in 8 month old hearts

increased cardiac muscle contractility ( J:129494 )

• basal heart contractility and relaxation are higher than in controls

• hearts in ex vivo show increased basal contractility

• however, no differences are seen in left ventricular end-systolic dimension, septal wall thickness, or fractional shortening percentage

increased cardiac muscle relaxation ( J:129494 )

• basal heart relaxation is higher than in controls

abnormal myocardial fiber calcium currents ( J:129494 )

• L-type voltage-dependent calcium channel current amplitude is larger in ventricular myocytes indicating increased calcium current

• isolated ventricular myocytes stimulated with isoproterenol or forskolin show lower increases in peak calcium channel currents compared to controls

• however, when the current amplitude is normalized for cell capacitance, there is no difference between transgenic and nontransgenic cardiomyocytes

• no differences are seen in the voltage dependence of activation or the activation/inactivation kinetics of the channels

congestive heart failure ( J:134761 )

• mice begin to show signs of heart failure beginning at 8 months of age, showing lethargic movement, labored breathing, ruffled fur, hunched posture, peripheral edema, ascites, hepatomegaly and edematous lungs

cellular

cardiac interstitial fibrosis ( J:134761 )

• extensive interstitial fibrosis separates groups of myocytes in ventricles

• fibrosis and repair are present in 2 and 4 month old hearts

increased cardiomyocyte apoptosis ( J:134761 )

• 8 month old, but not 2 or 4 month old, hearts show presence of apoptosis

homeostasis/metabolism

abnormal atrial thrombosis ( J:134761 )

• white gelatinous zones are seen in the atria by 8 months of age, suggesting organized thrombi

edema ( J:134761 )

• mice exhibit peripheral edema at heart failure

pulmonary edema ( J:134761 )

• edematous lungs are seen at heart failure

ascites ( J:134761 )

• ascites is seen at heart failure

decreased physiological sensitivity to xenobiotic ( J:129494 )

• infusion of the beta-adrenergic receptor agonist, isoproterenol, does not elicit the expected inotropic and lusitropic (relaxation, diastole) increases seen in controls

• the increase in contractility induced by forskolin is decreased in mutant hearts compared to controls

• isoproterenol-stimulated adenylyl cyclase activity is absent in membranes of cardiomyocytes

muscle

abnormal myocardial fiber morphology ( J:129494 , J:134761 )

• average cell capacitance is larger in ventricular cardiomyocytes, indicating cellular hypertrophy (J:129494)

• cardiomyocytes from 2, 4, and 8 month old mice show an increase in calcium channel density (J:134761)

dilated cardiomyopathy ( J:134761 )

• hypertrophic myopathy (4-chamber dilation with mild thickening of the interventricular septum) in 8 month old hearts

increased cardiac muscle contractility ( J:129494 )

• basal heart contractility and relaxation are higher than in controls

• hearts in ex vivo show increased basal contractility

• however, no differences are seen in left ventricular end-systolic dimension, septal wall thickness, or fractional shortening percentage

increased cardiac muscle relaxation ( J:129494 )

• basal heart relaxation is higher than in controls

increased cardiomyocyte apoptosis ( J:134761 )

• 8 month old, but not 2 or 4 month old, hearts show presence of apoptosis

respiratory system

pulmonary edema ( J:134761 )

• edematous lungs are seen at heart failure

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
congestive heart failure		DOID:6000		J:134761
hypertrophic cardiomyopathy		DOID:11984		J:134761