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The role of DSCR1 in the pathophysiology of heart disease in down syndrome
Heart,
Lung
and Circulation
Selected
2003; 12
ratios (E/E med 6.8 f 0.3 vs. E/E lat 5.5 + 0.2, P < 0.001). E lat was better at differentiating normal vs. abnormal diastolic function, however, both E lat and E med were able to differentiate subjects with pseudonormal LVD dysfunction (Table 1). Table 1. TDE according
to path&a
Normal N = 60 E lateral (m/s) E medial (m/s) A lateral (m/s) A medial (m/s) E/E lateral E/E medial
0.17 0.14 0.19 0.15 4.8 5.8
+ + i * k k
0.01 0.01 0.01 0.01 0.2 0.3
Abnormal relaxation N=31 0.14 0.12 0.23 0.19 5.4 6.1
f i k * t k
0.01* 0.01 0.01 0.01* 0.4 0.5
Pseudonormal systolic N=13 0.13 0.71 0.18 0.13 7.0 8.9
+ 0.01s Yk0.02 + 0.01 + 0.01 + 0.6” + 0.9**
Segmental N=12 0.17 0.13 0.21 0.13 4.7 5.9
* t * * t f
0.01 0.01 0.02 0.01 0.3 0.7
‘P < 0.05, -13 < 0.001. Conclusion These findings confirm that TDE techniques are useful in the assessment of left ventricular diastolic function and filling pressures. E med velocities are significantly lower then E lat, which affects estimation of filling pressures (E/E’). TDE is particularly useful in subjects with suspected pseudonormal pattern of diastolic dysfunction with raised filling pressures. Our data would suggest that the lateral mitral annulus is the more appropriate method of determining this. Key words: Diagnostic techniques, Diastole, Echocardiography, transthoracic, Heart failure Impaired Matching Between Left Ventricular Myocardial Consumption and Blood Flow During Dobutamine Infusion in Neonatal Lambs Daniel 1 Penny’, Tetsuya Sane’, Joseph J Smolich2 ‘Department @Cardiology, The Royal Children’s Hospital, Australia; %Ientre for Heart and Chest Research, Monash University, Australia Background The ability of the left ventricle (LV) to match increases in 0, consumption (MVO,) during inotropic stimulation with equivalent rises in blood flow (QLV) and 0, delivery (QO,) is an important homeostatic mechanism in the adult. However, while inotropes are widely used in neonates, it is unknown to what degree this mechanism is developed in the early neonatal period. Methods We measured changes in QLV, aortic (CAOO,) and coronary sinus (CCSO,) 0, content, LVQO, and LVMVO, during an incremental infusion of dobutamine up to 40 ug/kg/min in l-2 day (n = 7) and 7-10 day (n = 8), open-chested, anaesthetized lambs. Results Dobutamine elicited similar increases in LVMVO, in l-2 and 7-10 day lambs (17.4 f 1.2 and 22.0 + 5.3 mL/min/lOO g, respectively, both P < 0.001). However, 7-10 day lambs displayed greater rises in QLV (180 f 6 vs. 338 + 76 mL/min/lOO g; P < 0.05) and LVQO, (20.9 t 0.9 vs. 28.8 i- 7.3 mL/min/lOO g; P < O.Ol), while the LV 0, extraction ratio was unchanged in older animals but elevated by 33 f 9% in 1-2-day-old lambs (P < 0.01). Moreover, the slopes of the LVMVO,-QLV and LVMVO,-LVQO, relationships were close to unity in 7-10 day lambs, but both differed from unity in l-2 day lambs (P < 0.05). Conclusion These results suggest that mechanisms for supporting increases in LV 0, consumption during inotropic stimulation with proportional rises in LV blood flow and LV 0, delivery are poorly developed in the early neonatal myocardium. Key words: Coronary circulation, Inotropic agents, Oxygen consumption The role of DSCRl in the pathophysiology of heart disease in down syndrome Laureane Mittaz Crettol’, Paul Hertzog’, Melanie Pritchard’, Joseph J Smolich2 ‘Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Australia; 2Centre for Heart and Chest Research, Monash University Depnrtment of Medicine, Mona& Medical Crntre, Australia Background Abnormalities of heart development, particularly ‘holes in the heart’, are relatively common, occurring in nearly 1% of all live births. Significantly, holes in the heart occur in 50% of individuals with Down syndrome, a condition resulting from the presence of an extra copy of chromosome 21.
abstracts
from
the XIVth World Congress of Cardiology, May 5-9,2002
A81
Recent evidence suggests that increased expression of a human chromosome 21 gene called DSCRl can place a brake on a crucial cell pathway. DSCRl negatively regulates the calmodulin - calcineurin NF-AT signalling pathway that is known to be involved in normal growth processes of heart muscle cells. Disruption of this pathway in an animal model lacking NF-AT results in impaired development of the septum, a phenotype similar to the Down syndrome holes in the heart. It is also been shown that mice overexpressing DSCRl (MCIPl) under the control of the alpha-MHC promoter have a smaller heart, and that the heart hypertrophy observed in calcineurin transgenic mice is reversed when these mice are crossed with DSCRl transgenic mice. Because DSCRl binds calcineurin to negatively regulate this signalling pathway, we propose that overexpression of DSCRl causes the cardiac defects found in Down syndrome. Methods We are investigating the role of DSCRl in heart development, and in particular in Down syndrome, by generating DSCRl transgenic mice. Results We have produced DSCRl transgenic mice using two different strategies, both employing the homologous DSCRl promoter to mimic the situation in Down syndrome. We have a PAC transgenic harbouring the entire human DSCRl locus, and transgenic mice harbouring a DSCRl minigene, specific for one of the four DSCRl isoforms. Conclusion Information from this study will increase understanding about the formation of heart defects in Down syndrome and may, in the future, provide a means of preventing or treating this abnormality in Down Syndrome as well as in the general population. Also, as a bonus, we may gain an insight into cardiac hypertrophic processes. Key words: Cadiomyopathies, hypertrophic
No Evidence for Left Ventricular Diastolic Dysfunction in Asymptomatic Carriers of Duchenne or Becker Muscular Dystrophy Christine Allman’, Liza Thomas?, Andrew P Hopkins’, David Mowat”, G Morgan4, R Pedersen3, Dominic Y Leung’ ‘Liverpool Hospital, Australia; 2Department of Cardiology, Westmead Hospital, Sydney, Australia; “Sydney Children’s Hospital, Australia; %ydney Children’s Hospital, Australia Background Carriers of Duchenne (DMD) or Becker muscular dystrophic (BMD) genes may develop left ventricular (LV) dysfunction but it is unclear whether asymptomatic carriers have diastolic dysfunction in the absence of systolic dysfunction. Methods 34 unselected, asymptomatic obligate or probable carriers of muscular dystrophy (all females, mean age 40 & 15 years, range lo-70 years, 33 DMD, one BMD) without echocardiographic (Echo) evidence of LV systolic dysfunction underwent transthoracic Echo with pulsed wave and tissue Doppler examination. A group of 43 healthy, age matched (mean age 40 f 14 years) females served as normal controls
.
.
Lung
and Circulation
Selected
2003; 12
ratios (E/E med 6.8 f 0.3 vs. E/E lat 5.5 + 0.2, P < 0.001). E lat was better at differentiating normal vs. abnormal diastolic function, however, both E lat and E med were able to differentiate subjects with pseudonormal LVD dysfunction (Table 1). Table 1. TDE according
to path&a
Normal N = 60 E lateral (m/s) E medial (m/s) A lateral (m/s) A medial (m/s) E/E lateral E/E medial
0.17 0.14 0.19 0.15 4.8 5.8
+ + i * k k
0.01 0.01 0.01 0.01 0.2 0.3
Abnormal relaxation N=31 0.14 0.12 0.23 0.19 5.4 6.1
f i k * t k
0.01* 0.01 0.01 0.01* 0.4 0.5
Pseudonormal systolic N=13 0.13 0.71 0.18 0.13 7.0 8.9
+ 0.01s Yk0.02 + 0.01 + 0.01 + 0.6” + 0.9**
Segmental N=12 0.17 0.13 0.21 0.13 4.7 5.9
* t * * t f
0.01 0.01 0.02 0.01 0.3 0.7
‘P < 0.05, -13 < 0.001. Conclusion These findings confirm that TDE techniques are useful in the assessment of left ventricular diastolic function and filling pressures. E med velocities are significantly lower then E lat, which affects estimation of filling pressures (E/E’). TDE is particularly useful in subjects with suspected pseudonormal pattern of diastolic dysfunction with raised filling pressures. Our data would suggest that the lateral mitral annulus is the more appropriate method of determining this. Key words: Diagnostic techniques, Diastole, Echocardiography, transthoracic, Heart failure Impaired Matching Between Left Ventricular Myocardial Consumption and Blood Flow During Dobutamine Infusion in Neonatal Lambs Daniel 1 Penny’, Tetsuya Sane’, Joseph J Smolich2 ‘Department @Cardiology, The Royal Children’s Hospital, Australia; %Ientre for Heart and Chest Research, Monash University, Australia Background The ability of the left ventricle (LV) to match increases in 0, consumption (MVO,) during inotropic stimulation with equivalent rises in blood flow (QLV) and 0, delivery (QO,) is an important homeostatic mechanism in the adult. However, while inotropes are widely used in neonates, it is unknown to what degree this mechanism is developed in the early neonatal period. Methods We measured changes in QLV, aortic (CAOO,) and coronary sinus (CCSO,) 0, content, LVQO, and LVMVO, during an incremental infusion of dobutamine up to 40 ug/kg/min in l-2 day (n = 7) and 7-10 day (n = 8), open-chested, anaesthetized lambs. Results Dobutamine elicited similar increases in LVMVO, in l-2 and 7-10 day lambs (17.4 f 1.2 and 22.0 + 5.3 mL/min/lOO g, respectively, both P < 0.001). However, 7-10 day lambs displayed greater rises in QLV (180 f 6 vs. 338 + 76 mL/min/lOO g; P < 0.05) and LVQO, (20.9 t 0.9 vs. 28.8 i- 7.3 mL/min/lOO g; P < O.Ol), while the LV 0, extraction ratio was unchanged in older animals but elevated by 33 f 9% in 1-2-day-old lambs (P < 0.01). Moreover, the slopes of the LVMVO,-QLV and LVMVO,-LVQO, relationships were close to unity in 7-10 day lambs, but both differed from unity in l-2 day lambs (P < 0.05). Conclusion These results suggest that mechanisms for supporting increases in LV 0, consumption during inotropic stimulation with proportional rises in LV blood flow and LV 0, delivery are poorly developed in the early neonatal myocardium. Key words: Coronary circulation, Inotropic agents, Oxygen consumption The role of DSCRl in the pathophysiology of heart disease in down syndrome Laureane Mittaz Crettol’, Paul Hertzog’, Melanie Pritchard’, Joseph J Smolich2 ‘Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Australia; 2Centre for Heart and Chest Research, Monash University Depnrtment of Medicine, Mona& Medical Crntre, Australia Background Abnormalities of heart development, particularly ‘holes in the heart’, are relatively common, occurring in nearly 1% of all live births. Significantly, holes in the heart occur in 50% of individuals with Down syndrome, a condition resulting from the presence of an extra copy of chromosome 21.
abstracts
from
the XIVth World Congress of Cardiology, May 5-9,2002
A81
Recent evidence suggests that increased expression of a human chromosome 21 gene called DSCRl can place a brake on a crucial cell pathway. DSCRl negatively regulates the calmodulin - calcineurin NF-AT signalling pathway that is known to be involved in normal growth processes of heart muscle cells. Disruption of this pathway in an animal model lacking NF-AT results in impaired development of the septum, a phenotype similar to the Down syndrome holes in the heart. It is also been shown that mice overexpressing DSCRl (MCIPl) under the control of the alpha-MHC promoter have a smaller heart, and that the heart hypertrophy observed in calcineurin transgenic mice is reversed when these mice are crossed with DSCRl transgenic mice. Because DSCRl binds calcineurin to negatively regulate this signalling pathway, we propose that overexpression of DSCRl causes the cardiac defects found in Down syndrome. Methods We are investigating the role of DSCRl in heart development, and in particular in Down syndrome, by generating DSCRl transgenic mice. Results We have produced DSCRl transgenic mice using two different strategies, both employing the homologous DSCRl promoter to mimic the situation in Down syndrome. We have a PAC transgenic harbouring the entire human DSCRl locus, and transgenic mice harbouring a DSCRl minigene, specific for one of the four DSCRl isoforms. Conclusion Information from this study will increase understanding about the formation of heart defects in Down syndrome and may, in the future, provide a means of preventing or treating this abnormality in Down Syndrome as well as in the general population. Also, as a bonus, we may gain an insight into cardiac hypertrophic processes. Key words: Cadiomyopathies, hypertrophic
No Evidence for Left Ventricular Diastolic Dysfunction in Asymptomatic Carriers of Duchenne or Becker Muscular Dystrophy Christine Allman’, Liza Thomas?, Andrew P Hopkins’, David Mowat”, G Morgan4, R Pedersen3, Dominic Y Leung’ ‘Liverpool Hospital, Australia; 2Department of Cardiology, Westmead Hospital, Sydney, Australia; “Sydney Children’s Hospital, Australia; %ydney Children’s Hospital, Australia Background Carriers of Duchenne (DMD) or Becker muscular dystrophic (BMD) genes may develop left ventricular (LV) dysfunction but it is unclear whether asymptomatic carriers have diastolic dysfunction in the absence of systolic dysfunction. Methods 34 unselected, asymptomatic obligate or probable carriers of muscular dystrophy (all females, mean age 40 & 15 years, range lo-70 years, 33 DMD, one BMD) without echocardiographic (Echo) evidence of LV systolic dysfunction underwent transthoracic Echo with pulsed wave and tissue Doppler examination. A group of 43 healthy, age matched (mean age 40 f 14 years) females served as normal controls
.
.