In Vivo Echocardiographic Detection of Enhanced Left Ventricular Function in Gene-Targeted Mice With Phospholamban Deficiency

Hoit, Brian D.; Khoury, Saeb F.; Kranias, Evangelia G.; Ball, Nancy; Walsh, Richard A.

doi:10.1161/01.res.77.3.632

Cited by 211 publications

(129 citation statements)

References 14 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…Echocardiography and Doppler measurements were performed with a 1-cm gel standoff in a left lateral position similar to the technique used by Hoit et al (12). An Acuson Sequoia C256 system with a linear transducer in 13-MHz mode was used to obtain high resolution two-dimensional and M-mode measurements (17).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inotropic Stimulation Induces Cardiac Dysfunction in Transgenic Mice Expressing a Troponin T (I79N) Mutation Linked to Familial Hypertrophic Cardiomyopathy

Knollmann¹,

Blatt²,

Horton

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and a high incidence of sudden death, despite causing little or no cardiac hypertrophy. In skinned fibers, I79N increased myofilamental calcium sensitivity (Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., deFreitas, F., Gomes, A. V., Culbreath, L., McCue concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts at 0.5 and 1 mmol/liter. At higher Ca 2؉ concentrations, systolic function was not different, but diastolic dysfunction became manifest as increased end-diastolic pressure and time to 90% relaxation. In vivo measurements by echocardiography and Doppler confirmed that base-line systolic function was significantly higher in Tg-I79N mice without evidence for diastolic dysfunction. Inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality in Tg-I79N mice. Doppler studies ruled out aortic outflow obstruction and were consistent with increased chamber stiffness. We conclude that in vivo, the increased myofilament Ca 2؉ sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation. Mutations in cardiac troponin T (TnT)1 have been implicated in familial hypertrophic cardiomyopathy (FHC) (1-5). Individuals with cardiac TnT mutations appear to have a high incidence of sudden cardiac death at a young age, although heterozygote individuals have either little or no cardiac hypertrophy (1, 3, 4). At present, there is no clear understanding as to why TnT mutations in particular pose a high risk for sudden death, as opposed to, for example, mutations in the myosin heavy chain, which usually cause a much greater degree of cardiac hypertrophy. Sudden cardiac death of FHC patients is often caused by ventricular tachyarrhythmias (6), but its cause remains unknown for patients with TnT mutations. In fact, the clinical features of hypertrophic cardiomyopathy have been established mostly without knowledge of the genotype and may not apply to patients carrying specific TnT mutations. Given the paucity of clinical information, a transgenic mouse model provides the opportunity to study the functional consequences of a TnT mutation in an in vivo system.To investigate the mechanisms of how a TnT mutation alters cardiac function and lead to sudden cardiac death, we have generated transgenic mice expressing the human cardiac TnT-I79N mutant (Tg-I79N). Similar to humans carrying this mutation, Tg-I79N mice show no cardiac hypertrophy (7). We found a large increase in Ca 2ϩ sensitivity of the skinned cardiac fibers from Tg-I79N mice compared with fibers from transgenic mice expressing human wild-type TnT (Tg-WT), but maximal developed force was significantly lower in cardiac fibers from Tg-I79N mice (7).In this study, we examined the effect of the I79N mutation on cardiac performance and electrophysiological properties of the whole heart, in vitro and in vivo. We fou...

show abstract

Section: Methodsmentioning

confidence: 99%

“…Mice were initially challenged with a dose of 1.5 mg/kg (high dose) based on reports in the literature (12). After deaths occurred in the Tg-I79N group, we examined the effects of a lower dose (0.1 mg/kg), which was sufficient to produce a significant increase in heart rate in all four groups of mice.…”

Section: Methodsmentioning

confidence: 99%

Inotropic Stimulation Induces Cardiac Dysfunction in Transgenic Mice Expressing a Troponin T (I79N) Mutation Linked to Familial Hypertrophic Cardiomyopathy

Knollmann¹,

Blatt²,

Horton

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Cardiac Remodeling in Older Mice-To assess the contractile and structural consequences the above changes might have on whole heart function, mice (line 21) aged 16 weeks were subjected to echocardiography (34,35). In RLC2v(PϪ) TG mice, shortening fractions were nearly the same.…”

Section: Molecular Markers Of Hypertrophy Show a Dose Response-mentioning

confidence: 99%

Abnormal Cardiac Structure and Function in Mice Expressing Nonphosphorylatable Cardiac Regulatory Myosin Light Chain 2

Sanbe¹,

Fewell²,

Gulick³

et al. 1999

Journal of Biological Chemistry

114

102

View full text Add to dashboard Cite

A role for myosin phosphorylation in modulating normal cardiac function has long been suspected, and we hypothesized that changing the phosphorylation status of a cardiac myosin light chain might alter cardiac function in the whole animal. To test this directly, transgenic mice were created in which three potentially phosphorylatable serines in the ventricular isoform of the regulatory myosin light chain were mutated to alanines. Lines were obtained in which replacement of the endogenous species in the ventricle with the nonphosphorylatable, transgenically encoded protein was essentially complete. The mice show a spectrum of cardiovascular changes. As previously observed in skeletal muscle, Ca 2؉ sensitivity of force development was dependent upon the phosphorylation status of the regulatory light chain. Structural abnormalities were detected by both gross histology and transmission electron microscopic analyses. Mature animals showed both atrial hypertrophy and dilatation. Echocardiographic analysis revealed that as a result of chamber enlargement, severe tricuspid valve insufficiency resulted in a detectable regurgitation jet. We conclude that regulated phosphorylation of the regulatory myosin light chains appears to play an important role in maintaining normal cardiac function over the lifetime of the animal.The roles of the regulatory myosin light chains (RLCs) 1 and the reversible post-translational modifications they undergo in striated muscle are beginning to be defined. In skeletal muscle, a serine at the amino end of the protein can be phosphorylated by a sarcoplasmic kinase (1), and it is now clear that RLCs in the different striated muscles are phosphorylated to differing degrees, leading presumably to different physiological effects. In smooth muscle, RLC phosphorylation by myosin light chain kinase (MLCK), which is activated by a Ca 2ϩ /calmodulin-dependent pathway, is responsible for initiating muscle contraction (2, 3). However, in skeletal and cardiac muscle, in which the thin, rather than thick, filament mediates control of contraction, RLC phosphorylation does not activate contraction but appears to play a modulatory role. In skinned skeletal muscle fibers, RLC phosphorylation increases sensitivity to activating Ca 2ϩ such that there is a significant leftward shift in the force-Ca 2ϩ relationship (4 -6). Increased RLC phosphorylation in skeletal muscle is also associated with potentiation of isometric twitch tension with repeated activation and inactivation of contraction (7, 8), rate of force production (9 -11), and maximum Ca 2ϩ -stimulated MgATPase activity (12). The mechanistic basis for the effects of RLC phosphorylation in striated muscle is hypothesized to be a lessening of the weak interaction of the myosin head with the myosin backbone and is probably due to a net charge change in a critical region of the protein (13). Upon phosphorylation, the myosin heads move away from the backbone to a position closer to actin, which presumably increases the rate at which myosin-actin interaction...

show abstract

“…After baseline hemodynamic data were acquired, atrial pacing was instituted to overdrive the intrinsic heart rate and, unless stated otherwise maintained at a constant rate of 7.5 Hz (450 bpm). In some studies simultaneous echocardiograms were obtained (26).…”

mentioning

confidence: 99%

Transgenic Gαq overexpression induces cardiac contractile failure in mice

D'Angelo

Sakata

Lorenz

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

577

453

View full text Add to dashboard Cite

The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of G␣q-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type G␣q in the heart using the ␣-myosin heavy chain promoter. Two-fold overexpression of G␣q showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases in atrial naturietic factor (Ϸ55-fold), ␤-myosin heavy chain (Ϸ8-fold), and ␣-skeletal actin (Ϸ8-fold) expression, and decreased (Ϸ3-fold) ␤-adrenergic receptor-stimulated adenylyl cyclase activity. All of these signals have been considered markers of hypertrophy or failure in other experimental systems or human heart failure. Echocardiography and in vivo cardiac hemodynamic studies indeed revealed impaired intrinsic contractility manifested as decreased fractional shortening (19 ؎ 2% vs. 41 ؎ 3%), dP͞dt max, a negative force-frequency response, an altered Starling relationship, and blunted contractile responses to the ␤-adrenergic agonist dobutamine. At higher levels of G␣q overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary congestion, and death. The element within the pathway that appeared to be critical for these events was activation of protein kinase C. Interestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated. The G␣q overexpressor exhibits a biochemical and physiologic phenotype resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathogenesis.

show abstract

In Vivo Echocardiographic Detection of Enhanced Left Ventricular Function in Gene-Targeted Mice With Phospholamban Deficiency

Cited by 211 publications

References 14 publications

Inotropic Stimulation Induces Cardiac Dysfunction in Transgenic Mice Expressing a Troponin T (I79N) Mutation Linked to Familial Hypertrophic Cardiomyopathy

Inotropic Stimulation Induces Cardiac Dysfunction in Transgenic Mice Expressing a Troponin T (I79N) Mutation Linked to Familial Hypertrophic Cardiomyopathy

Abnormal Cardiac Structure and Function in Mice Expressing Nonphosphorylatable Cardiac Regulatory Myosin Light Chain 2

Transgenic Gαq overexpression induces cardiac contractile failure in mice

Contact Info

Product

Resources

About