Mouse Genome Informatics
cn1
    Mybpc3tm2.1Rmos/Mybpc3tm2.1Rmos
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129 * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• gross cardiac morphology is normal 8 weeks after tamoxifen treatment (J:202199)
• myocyte disarray in tamoxifen-treated mice 12 weeks after transaortic constriction
• at 20 weeks in tamoxifen-treated mice
• increased posterior wall thickness in diastole after 20 weeks of tamoxifen treatment
• increased left ventricle internal dimension in tamoxifen-treated mice after transaortic constriction
• however, internal dimension is normal after 20 weeks of tamoxifen treatment
• in tamoxifen-treated mice 12 weeks after transaortic constriction
• highly variable focal and diffuse 20 weeks after tamoxifen treatment
• decreased ejection fraction and isovolumic relaxation time in tamoxifen-treated mice
• reduced fractional shortening in tamoxifen-treated mice after transaortic constriction
• however, tamoxifen-treated mice exhibit normal left ventricle posterior wall thickness and left ventricle internal diameter
• following transaortic constriction, tamoxifen-treated mice exhibit increased left ventricle internal dimension and reduced fractional shortening compared with control mice

homeostasis/metabolism
• following transaortic constriction, tamoxifen-treated mice exhibit increased left ventricle internal dimension and reduced fractional shortening compared with control mice

muscle
• myocyte disarray in tamoxifen-treated mice 12 weeks after transaortic constriction
• at 20 weeks in tamoxifen-treated mice
• decreased ejection fraction and isovolumic relaxation time in tamoxifen-treated mice
• reduced fractional shortening in tamoxifen-treated mice after transaortic constriction
• however, tamoxifen-treated mice exhibit normal left ventricle posterior wall thickness and left ventricle internal diameter


Mouse Genome Informatics
cn2
    Ptgs2tm1Gaf/Ptgs2tm1Gaf
Tg(Myh6-cre/Esr1*)1Jmk/?

involves: 129/Sv * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• hypertrophy of cardiomyocytes occurs after 6 weeks of aortic banding to mice that have had cre expression induced
• left ventricular end systolic volume is increased after cre induction from 0.017 cm3/g to 0.021 cm3/g
• after cre induction, the left ventricular ejection fraction is depressed from 0.65 cm3/g to 0.60 cm3/g
• heart rate is depressed after cre induction from 443 bpm to 441 bpm
• male mice with cre induction and intracardiac electrical stimulation have more ventricular tachycardia episodes than controls (17 vs. 3)
• duration of these episodes are also about 3-fold longer than controls

growth/size
• mice in which cre expression is induced have more weight loss than controls in response to exercise

homeostasis/metabolism
• mice with cre expression have a reduced exercise capacity

muscle
• hypertrophy of cardiomyocytes occurs after 6 weeks of aortic banding to mice that have had cre expression induced
• after cre induction, the left ventricular ejection fraction is depressed from 0.65 cm3/g to 0.60 cm3/g

behavior/neurological
• mice with cre expression have a reduced exercise capacity


Mouse Genome Informatics
cn3
    Mcattm1.1Ssmi/Mcattm1.1Ssmi
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129P2/OlaHsd * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype
• tamoxifen-treated mice appear normal


Mouse Genome Informatics
cn4
    Atp2a2tm1.1Iemr/Atp2a2tm1.1Iemr
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129P2/OlaHsd * C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• tamoxifen-treated mice do not exhibit myocardial disarray or necrosis (J:157143)
• 4 and 7 weeks after tamoxifen treatment, left atrial diameter is increased compared to in Atp2a2tm1.1Iemr homozygotes
• after tamoxifen treatment
• after tamoxifen treatment
• tamoxifen-treated mice exhibit an increase in the time constant of isovolumetric pressure decay compared with Atp2a2tm1.1Iemr homozygotes
• 7 weeks after tamoxifen treatment, mice exhibit diastolic dysfunction compared with Atp2a2tm1.1Iemr homozygotes
• 4 and 7 weeks after tamoxifen treatment
• 4 weeks after tamoxifen treatment, mice exhibit reduced contractile function compared with Atp2a2tm1.1Iemr homozygotes as determined by Doppler imaging
• at low stimulation frequency, cardiomyocytes from tamoxifen-treated mice exhibit reduced contraction magnitude compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 7 weeks after tamoxifen treatment, fractional shortening is reduced compared to in Atp2a2tm1.1Iemr homozygotes
• 4 and 7 weeks after tamoxifen treatment, end-diastolic pressure compared to in Atp2a2tm1.1Iemr homozygotes
• 4 and 7 weeks after tamoxifen treatment, mice exhibit reduced maximum positive and minimum derivatives of the left ventricular pressure compared with Atp2a2tm1.1Iemr homozygotes
• 4 and 7 weeks after tamoxifen treatment, anesthetized mice exhibit decreased heart rate compared with Atp2a2tm1.1Iemr homozygotes
• cardiomyocytes from tamoxifen-treated mice exhibit reduced magnitude of calcium ion transients and prolonged time to half decay of calcium ion transients compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• when stimulated at a 6 Hz frequency, cardiomyocytes from tamoxifen-treated mice exhibit shorter diastolic sarcomere length and a greater increase in the contractile response per unit during systole compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• during the slow decline of caffeine transients in the presence of nickel ions, cardiomyocytes from tamoxifen-treated mice exhibit shorter sarcomere length compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 4 weeks after tamoxifen treatment, cardiomyocytes exhibit reduced sarcoplasmic reticulum calcium ion content compared with cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 7 weeks after treatment with tamoxifen, mice exhibit reduced maximal rate of cardiomyocyte relaxation compared with Atp2a2tm1.1Iemr homozygotes
• 7 weeks after tamoxifen treatment

homeostasis/metabolism
• in tamoxifen-treated mice at 4 and 7 weeks

muscle
• 4 weeks after tamoxifen treatment, mice exhibit reduced contractile function compared with Atp2a2tm1.1Iemr homozygotes as determined by Doppler imaging
• at low stimulation frequency, cardiomyocytes from tamoxifen-treated mice exhibit reduced contraction magnitude compared with similarly treated cardiomyocytes from Atp2a2tm1.1Iemr homozygotes
• 7 weeks after tamoxifen treatment, fractional shortening is reduced compared to in Atp2a2tm1.1Iemr homozygotes
• 4 and 7 weeks after tamoxifen treatment, end-diastolic pressure compared to in Atp2a2tm1.1Iemr homozygotes


Mouse Genome Informatics
cn5
    Tgfbr1tm1.1Karl/Tgfbr1tm1.1Karl
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S/Sv * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• by 6 days following IP tamoxifen treatment (80 mg/kg BW for 5 days), 60% mortality of treated mice is observed

cardiovascular system
N
• treatment of mice with oral dose of 160 mg/kg BW per day raloxifene for 21 days resulted in similar recombinase activity as the tamoxifen regimen, but does not cause any cardiac dysfunction; lower (20 mg/kg BW) oral tamoxifen treatment for 21 days does not cause dysfunction (J:164749)
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly

muscle
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly


Mouse Genome Informatics
cn6
    Hcn4tm1.1Ggc/Hcn4tm1.1Ggc
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S/SvEv * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• develop severe bradycardia when injected daily with tamoxifen which leads eventually to death
• heart rate reduced by 32% after 2 days of treatment and by 47% after 6 days
• isolated cells from the sino-atrial node of mice treated with tamoxifen beat spontaneously but more slowly than control cells and become progressively slower as treatment is continued to 5 days
• mice injected with isoproterenol experience heart beat acceleration similar to that occurring in control mice
• when injected daily with tamoxifen, atrioventricular block becomes a 2nd degree block
• conduction ratio progresses from 2:1 to 4:1 or more
• when mice are injected daily with tamoxifen, a prolonged PQ interval is observed
• f-channel current densities from atrioventricular cells isolated from mice after 2 and 5 days of treatment with tamoxifen are lower than for control cells
• there is a time dependent decrease in f-channel conductance

mortality/aging
• no mice survive beyond 8.5 days of treatment with tamoxifen


Mouse Genome Informatics
cn7
    Atg5tm1Myok/Atg5tm1Myok
Tg(Myh6-cre/Esr1*)1Jmk/?

involves: 129S/SvEv * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• cardiomyocyte fiber cross-sectional area is increased following tamoxifen treatment
• however, cardiomyocyte fibers are otherwise normal
• increase in the heart to body weight ratio following tamoxifen treatment
• following tamoxifen treatment
• following tamoxifen treatment
• calcium cycling is impaired following tamoxifen treatment
• decrease in the autophagy levels following tamoxifen treatment

respiratory system
• increase in the lung to body weight ratio following tamoxifen treatment

muscle
• cardiomyocyte fiber cross-sectional area is increased following tamoxifen treatment
• however, cardiomyocyte fibers are otherwise normal
• following tamoxifen treatment


Mouse Genome Informatics
cn8
    Ldb3tm4Chen/Ldb3tm4Chen
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S1/Sv * 129X1/SvJ * Black Swiss * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• all mice die between 1 and 16 weeks after tamoxifen treatment

cardiovascular system
• after tamoxifen treatment
• both ventricles are severely dilated after tamoxifen treatment
• both ventricles are severely dilated after tamoxifen treatment
• decreased heart function one month after tamoxifen treatment
• after tamoxifen treatment

muscle
• after tamoxifen treatment

Mouse Models of Human Disease
OMIM IDRef(s)
Cardiomyopathy, Dilated, 1C; CMD1C 601493 J:144739


Mouse Genome Informatics
cn9
    Cacna1ctm3Hfm/Cacna1ctm4Hfm
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die within 3 weeks of tamoxifen treatment

muscle
• vetricular cardiomyocytes from tamoxifen-treated mice exhibit reduced current-voltage relation of current compared with cells from control mice


Mouse Genome Informatics
cn10
    Cacna1ctm1Ggm/Cacna1ctm1Ggm
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S1/Sv * 129X1/SvJ * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• average survival time of 11.9 +/- 3 days following tamoxifen treatment for 5 days

cardiovascular system
• increase in ventricular end diastolic volume after tamoxifen treatment
• profound decrease in myocardial contractility, as assessed by fractional shortening, after tamoxifen treatment

muscle
• profound decrease in myocardial contractility, as assessed by fractional shortening, after tamoxifen treatment


Mouse Genome Informatics
cn11
    Txniptm1Rlee/Txniptm1Rlee
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S4/SvJae * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• robust increase in glucose uptake in 4-hydroxytamoxifen treated mice compared to controls
• mice treated with 4-hydroxytamoxifen to induce recombination display a decrease in pressure overload induced progressive hypertrophy during the early phase compared to controls

muscle
• robust increase in glucose uptake in 4-hydroxytamoxifen treated mice compared to controls

homeostasis/metabolism
• mice treated with 4-hydroxytamoxifen to induce recombination display a decrease in pressure overload induced progressive hypertrophy during the early phase compared to controls


Mouse Genome Informatics
cn12
    Ptentm1Hwu/Ptentm1Hwu
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S4/SvJae * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• hearts of mutants treated with tamoxifen for 3 weeks to induce cre-expression develop significantly better function recovery in response to 30 min ischemia followed by 120 min reperfusion than controls, showing significantly improved end-diastolic pressure, left ventricle developed pressure (LVDP) and LVDP recoveries, and improved systolic and diastolic contractility of hearts
• at 60 min post reperfusion, recovery of left ventricular diastolic pressure reaches 77.9% of pre-ischemia in hearts versus 44% in controls
• hearts have significantly fewer apoptosis positive cardiomyocytes after ischemia/reperfusion (I/R) injury than controls
• mutants treated with tamoxifen to induce cre-expression exhibit a significant reduction in infarct size after ischemia

homeostasis/metabolism
• hearts of mutants treated with tamoxifen for 3 weeks to induce cre-expression develop significantly better function recovery in response to 30 min ischemia followed by 120 min reperfusion than controls, showing significantly improved end-diastolic pressure, left ventricle developed pressure (LVDP) and LVDP recoveries, and improved systolic and diastolic contractility of hearts
• at 60 min post reperfusion, recovery of left ventricular diastolic pressure reaches 77.9% of pre-ischemia in hearts versus 44% in controls
• hearts have significantly fewer apoptosis positive cardiomyocytes after ischemia/reperfusion (I/R) injury than controls
• mutants treated with tamoxifen to induce cre-expression exhibit a significant reduction in infarct size after ischemia


Mouse Genome Informatics
cn13
    Pik3catm1.1Rzl/Pik3catm1.1Rzl
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S4/SvJaeSor * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• in tamoxifen-treated mice
• mildly in tamoxifen-treated mice
• posterior wall thickness in tamoxifen-treated mice is slightly decreased compared to in wild-type mice
• in tamoxifen-treated mice
• myocytes of tamoxifen-treated mice exhibit reduced inward calcium ion current density compared with wild-type cells

muscle
• in tamoxifen-treated mice


Mouse Genome Informatics
cn14
    Pik3cbtm1.1Rzl/Pik3cbtm1.1Rzl
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S4/SvJaeSor * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• in tamoxifen-treated mice exhibit normal myocyte reduced inward calcium ion current density (J:166421)
• slightly in tamoxifen-treated mice


Mouse Genome Informatics
cn15
    Cdh2tm1Glr/Cdh2Gt(OST49160)Lex
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S5/SvEvBrd * 129S6/SvEvTac * C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants die about 2 months after tamoxifen treatment

cardiovascular system
• modest dilation of the atria after tamoxifen treatment
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
• after tamoxifen treatment intercalated disc structures are absent
• after tamoxifen treatment hearts appear elongated and flacid
• modest dilation of the ventricles after tamoxifen treatment
• modest dilation of the ventricles after tamoxifen treatment
• left ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased
• about 5 weeks after tamoxifen treatment, mutant heart rate is significantly reduced
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
• tachyarrhythmia is initiated by premature ventricular depolarization

muscle
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
• after tamoxifen treatment intercalated disc structures are absent
• left ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased


Mouse Genome Informatics
cn16
    Plce1tm2Avsm/Plce1tm2Avsm
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S6/SvEvTac * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• following transverse aortic constriction, mice exhibit diminished cardiac hypertrophy compared with control mice

homeostasis/metabolism
• following transverse aortic constriction, mice exhibit diminished cardiac hypertrophy compared with control mice


Mouse Genome Informatics
cn17
    Tgfbr2tm1.2Hlm/Tgfbr2tm1.2Hlm
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S6/SvEvTac * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• treatment of mice with oral dose of 160 mg/kg BW per day raloxifene for 21 days resulted in similar recombinase activity as the tamoxifen regimen, but does not cause any cardiac dysfunction; lower (20 mg/kg BW) oral tamoxifen treatment for 21 days does not cause dysfunction (J:164749)
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly

mortality/aging
• by 6 days following IP tamoxifen treatment (80 mg/kg BW for 5 days), 60% mortality of treated mice is observed

muscle
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing significantly


Mouse Genome Informatics
cn18
    Juptm1.1Glr/Juptm1.1Glr
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S6/SvEvTac * C57BL/6 * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• increase in cardiac death compared to controls beginning about 3 months after tamoxifen treatment

cardiovascular system
N
• unlike in human patients with Arrhythmogenic Right Ventricular Dysplasia replacement of myocytes with adipocytes is not seen in tamoxifen treated mice and tamoxifen treated mice are not more susceptible to induced arrhythmias (J:170618)
• decrease in the number and length of desmosomes in tamoxifen treated mice
• adherens-type junctions with less submembranous electron-dense material are prominently seen in tamoxifen treated mice
• mislocalization of desmosomal proteins to the intercalated disc in tamoxifen treated mice
• increase in cardiomyocyte cross sectional area with age in tamoxifen treated mice
• increase in the heart to body weight ratio with age in tamoxifen treated mice
• by about 5 months after tamoxifen treatment
• mild left ventricle hypertrophy in tamoxifen treated mice
• modest left ventricle dilation in tamoxifen treated mice
• progressive thinning of the right ventricular free wall is seen after tamoxifen treatment
• by about 5 months after tamoxifen treatment
• focal areas of myocyte loss and replacement with fibrous tissue are seen after tamoxifen treatment
• increased apoptosis is seen at 5 months after tamoxifen treatment
• apoptotic cells are associated with fibrotic areas
• heart failure is seen in some tamoxifen treated mice
• reduction of left ventricular fractional shortening and ejection fraction in tamoxifen treated mice
• infiltration of activated macrophages/monocytes in areas adjacent to apoptotic myocytes in tamoxifen treated mice
• neutrophil infiltrations are also seen in tamoxifen treated mice

muscle
• decrease in the number and length of desmosomes in tamoxifen treated mice
• adherens-type junctions with less submembranous electron-dense material are prominently seen in tamoxifen treated mice
• mislocalization of desmosomal proteins to the intercalated disc in tamoxifen treated mice
• increase in cardiomyocyte cross sectional area with age in tamoxifen treated mice
• reduction of left ventricular fractional shortening and ejection fraction in tamoxifen treated mice
• cardiomyocyte sarcomeres appear distorted and compressed in tamoxifen treated mice
• decreased cardiomyocyte sarcomere length in tamoxifen treated mice
• cardiomyocyte sarcomeres have wider, less dense Z lines in tamoxifen treated mice

homeostasis/metabolism
• seen at 9 - 12 months after tamoxifen treatment, associated with heart failure
• increase in the IL6 and IL1B levels in heart lysates from tamoxifen treated mice
• increase in cytokine expression is associated with the severity of myocyte loss

immune system
• infiltration of activated macrophages/monocytes in areas adjacent to apoptotic myocytes in tamoxifen treated mice
• neutrophil infiltrations are also seen in tamoxifen treated mice
• increase in the IL6 and IL1B levels in heart lysates from tamoxifen treated mice
• increase in cytokine expression is associated with the severity of myocyte loss

respiratory system
• seen at 9 - 12 months after tamoxifen treatment, associated with heart failure


Mouse Genome Informatics
cn19
    Cdh2tm1Glr/Cdh2tm1Hyn
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129S6/SvEvTac * C57BL/6J * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants die about 2 months after tamoxifen treatment

cardiovascular system
• modest dilation of the atria after tamoxifen treatment
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
• after tamoxifen treatment intercalated disc structures are absent
• after tamoxifen treatment hearts appear elongated and flacid
• modest dilation of the ventricles after tamoxifen treatment
• modest dilation of the ventricles after tamoxifen treatment
• eft ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased
• about 5 weeks after tamoxifen treatment, mutant heart rate is significantly reduced
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
• about 6 weeks after tamoxifen treatment, 2 mutants showed abrupt onset of ventricular tachyarrhythmia followed by sudden death
• tachyarrhythmia is initiated by premature ventricular depolarization

muscle
• after tamoxifen treatment enlarged hyperchromatic myocyte nuclei are seen
• after tamoxifen treatment intercalated disc structures and intercellular space are absent
• after tamoxifen treatment sarcomeres appear distorted and compressed with wider, less dense Z-lines
• after tamoxifen treatment intercalated disc structures are absent
• eft ventricular end-diastolic and end-systolic volume in the cavity are increased and left ventricular ejection fraction is decreased


Mouse Genome Informatics
cn20
    Ctnna1tm1Efu/Ctnna1tm1Efu
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: 129X1/SvJ * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• progressive 8 months after tamoxifen treatment

muscle
• progressive 8 months after tamoxifen treatment


Mouse Genome Informatics
cn21
    Cxadrtm1Mgot/Cxadrtm1Mgot
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• the volume of the atrioventricular node is reduced by about a third compared to controls 8 weeks after cre induction
• sinus node tachycardia is noted in about 17% of mice that have had cre expression induced
• sinus bradycardia is observed in about a third of the mice that have had cre expression induced
• long term monitoring of mice indicates a general increase in heart rate in the weeks after induction of cre
• the prolongation of the PR interval is a hallmark of atrioventricular block
• partial failure of AV conduction (25%) or total dissociation of atrial and ventricular rhythms (37.5%) occurs by 4 weeks after cre induction
• half of the mice have accelerated junctional rhythms that originate in the AV node
• not all the excitations successfully traverse the AV node at slower heart rates (i.e. increased Wenckebach periodity)
• dye-coupling experiments reveals leakiness between cardiomyocytes starting three weeks after cre induction
• mice have a prolonged PR-interval after induction of cre expression
• the length of the interval increases the longer after induction of cre
• by 4 weeks after induction of cre, the length of the interval has more than doubled


Mouse Genome Informatics
cn22
    Abcb8tm1Hard/Abcb8tm1Hard
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• subcellular disorganization, with accumulation of vacuoles, mitochondria showing diversity in size, profoundly disrupted alignment, and a rounder and more densely packed appearance after tamoxifen treatment
• loss of mitochondrial cristae and smaller average mitochondria size after tamoxifen treatment
• elevated mitochondrial iron content but not heme levels 4 weeks after tamoxifen treatment
• distorted and wavy myofiber architecture 4 weeks after tamoxifen treatment
• mitochondrial deformities accompanied by electron-dense material are present after tamoxifen treatment
• 8 weeks after tamoxifen treatment
• increased left ventricular diastolic diameter at 8 weeks after tamoxifen treatment
• 8 weeks after tamoxifen treatment
• elevated lipid peroxidation and reactive oxygen species after tamoxifen treatment
• as early as 4 weeks after tamoxifen treatment
• reduced heart pump function as measured by fractional shortening and ejection fraction 4 and 8 weeks after tamoxifen treatment
• decreased strength of contraction (dP/dtmax) at 8 weeks after tamoxifen treatment
• decreased relaxation (dP/dtmin) at 8 weeks after tamoxifen treatment
• lower end systolic pressure at 8 weeks after tamoxifen treatment
• mild after tamoxifen treatment

homeostasis/metabolism
• elevated mitochondrial iron content but not heme levels 4 weeks after tamoxifen treatment

muscle
• distorted and wavy myofiber architecture 4 weeks after tamoxifen treatment
• mitochondrial deformities accompanied by electron-dense material are present after tamoxifen treatment
• reduced heart pump function as measured by fractional shortening and ejection fraction 4 and 8 weeks after tamoxifen treatment
• decreased strength of contraction (dP/dtmax) at 8 weeks after tamoxifen treatment
• decreased relaxation (dP/dtmin) at 8 weeks after tamoxifen treatment
• mild after tamoxifen treatment


Mouse Genome Informatics
cn23
    Tg(CAG-DMPK*)1323Coop/0
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants treated with tamoxifen at 8-9 weeks of age to induce Cre-mediated recombination die within 2 weeks of tamoxifen injection

cardiovascular system
• cardiomyocyte cytoplasm of tamoxifen treated mutants appears pale in patchy areas and contains variably prominent numbers of pink granules; focally abundant mitochondria correlate with the pink granules
• in some myocytes of tamoxifen treated mutants, aggregates of proliferating membranes of the sarcoplasmic reticulum are seen
• however, sarcomeres and Z-lines appear normal
• mutants treated with tamoxifen exhibit myocyte hypertrophy with enlarged, irregular myocyte nuclei
• dilation of the left ventricle after treatment with tamoxifen
• thinning of the left ventricular wall after treatment with tamoxifen
• rare degenerating myocytes and focal areas of mild interstitial fibrosis are seen in mutants treated with tamoxifen
• mutants treated with tamoxifen exhibit cardiac dysfunction in both systolic and diastolic parameters
• mutants treated with tamoxifen at 8-9 weeks of age to induce Cre-mediated recombination develop dilated cardiomyopathy
• peak early diastolic filling velocity is decreased by more than 30% in mutants treated with tamoxifen
• systolic function of mutants treated with tamoxifen exhibits a 50% or greater decrease in peak aortic flow velocity and both mean and peak acceleration
• isovolumic relaxation time is prolonged by more than 50% in mutants treated with tamoxifen
• standard deviation of RR intervals is increased 5-fold after tamoxifen administration
• at 4 days after the last day of tamoxifen administration, mice show 2:1 atrioventricular block
• progressive lengthening of the PR interval is seen beginning 2 days after the last day of tamoxifen administration
• widening of the QRS complex is seen beginning 2 days after the last day of tamoxifen administration

muscle
• cardiomyocyte cytoplasm of tamoxifen treated mutants appears pale in patchy areas and contains variably prominent numbers of pink granules; focally abundant mitochondria correlate with the pink granules
• in some myocytes of tamoxifen treated mutants, aggregates of proliferating membranes of the sarcoplasmic reticulum are seen
• however, sarcomeres and Z-lines appear normal
• mutants treated with tamoxifen exhibit myocyte hypertrophy with enlarged, irregular myocyte nuclei
• mutants treated with tamoxifen at 8-9 weeks of age to induce Cre-mediated recombination develop dilated cardiomyopathy
• systolic function of mutants treated with tamoxifen exhibits a 50% or greater decrease in peak aortic flow velocity and both mean and peak acceleration
• isovolumic relaxation time is prolonged by more than 50% in mutants treated with tamoxifen

Mouse Models of Human Disease
OMIM IDRef(s)
Myotonic Dystrophy 1; DM1 160900 J:127391


Mouse Genome Informatics
cn24
    Irx3tm3Hui/Irx3tm3Hui
Irx5tm3Hui/Irx5tm3Hui
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• in tamoxifen treated mice
• in tamoxifen treated mice


Mouse Genome Informatics
cn25
    Hif1atm1Stom/Hif1atm1Stom
Tg(Myh6-cre/Esr1*)1Jmk/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• reduced number of microvessels form 2 weeks after transverse aortic constriction
• attenuated development of hypertrophy as a result of transverse aortic restriction
• impaired cardiac function


Mouse Genome Informatics
tg26
    Tg(Myh6-cre/Esr1*)1Jmk/0
involves: 129S/Sv * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• patchy interstitial mononuclear infiltration is observed at day 10, but resolves by 3 weeks; no myocyte hypertrophy is observed
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing
• marked transient systolic and diastolic depression occurs, with full recovery observed by 3 weeks after stopping tamoxifen treatment

muscle
• mice die by 6 days post-treatment (80 mg/kg BW IP for 5 days) from severe dilated cardiomyopathy
• oral delivery of 80 mg/kg BW tamoxifen for 7 days does not result in any mortality but treated mice exhibit a significant but reversible dilated cardiomyopathy
• 3 days after oral tamoxifen treatment, cardiac depression peaks with fractional shortening decreasing from 61 to 27% and end-diastolic dimension increasing
• marked transient systolic and diastolic depression occurs, with full recovery observed by 3 weeks after stopping tamoxifen treatment