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

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, J., Wang, Y., Xu, Y., Kerrick, W. G., and Potter, J. D. (2001)J. Biol. Chem. 276, 3743–3755). To further study the functional consequences of this mutation, we compared the cardiac performance of transgenic mice expressing either human TnT-I79N or human wild-type TnT. In isolated hearts, cardiac function was different depending on the Ca2+ concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts at 0.5 and 1 mmol/liter. At higher Ca2+ 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 Ca2+ sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation. 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, J., Wang, Y., Xu, Y., Kerrick, W. G., and Potter, J. D. (2001)J. Biol. Chem. 276, 3743–3755). To further study the functional consequences of this mutation, we compared the cardiac performance of transgenic mice expressing either human TnT-I79N or human wild-type TnT. In isolated hearts, cardiac function was different depending on the Ca2+ concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts at 0.5 and 1 mmol/liter. At higher Ca2+ 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 Ca2+ sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation. cardiac troponin T familial hypertrophic cardiomyopathy wild type end-diastolic pressure left ventricle electrocardiogram transgenic Mutations in cardiac troponin T (TnT)1 have been implicated in familial hypertrophic cardiomyopathy (FHC) (1Watkins H. McKenna W.J. Thierfelder L. Suk H.J. Anan R. O'Donoghue A. Spirito P. Matsumori A. Moravec C.S. Seidman J.G. Seidman C.E. N. Engl. J. Med. 1995; 332: 1058-1064Crossref PubMed Scopus (782) Google Scholar, 2Watkins H. Seidman C.E. Seidman J.G. Feng H.S. Sweeney H.L. J. Clin. Invest. 1996; 98: 2456-2461Crossref PubMed Scopus (112) Google Scholar, 3Moolman J.C. Corfield V.A. Posen B. Ngumbela K. Seidman C. Brink P.A. Watkins H. J. Am. Coll. Cardiol. 1997; 29: 549-555Crossref PubMed Scopus (305) Google Scholar, 4Varnava A. Baboonian C. Davison F. de Cruz L. Elliott P.M. Davies M.J. McKenna W.J. Heart. 1999; 82: 621-624Crossref PubMed Scopus (93) Google Scholar, 5Ho C.Y. Lever H.M. DeSanctis R. Farver C.F. Seidman J.G. Seidman C.E. Circulation. 2000; 102: 1950-1955Crossref PubMed Scopus (128) Google Scholar). 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 (1Watkins H. McKenna W.J. Thierfelder L. Suk H.J. Anan R. O'Donoghue A. Spirito P. Matsumori A. Moravec C.S. Seidman J.G. Seidman C.E. N. Engl. J. Med. 1995; 332: 1058-1064Crossref PubMed Scopus (782) Google Scholar, 3Moolman J.C. Corfield V.A. Posen B. Ngumbela K. Seidman C. Brink P.A. Watkins H. J. Am. Coll. Cardiol. 1997; 29: 549-555Crossref PubMed Scopus (305) Google Scholar, 4Varnava A. Baboonian C. Davison F. de Cruz L. Elliott P.M. Davies M.J. McKenna W.J. Heart. 1999; 82: 621-624Crossref PubMed Scopus (93) Google Scholar). 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 (6Maron B.J. Shen W.K. Link M.S. Epstein A.E. Almquist A.K. Daubert J.P. Bardy G.H. Favale S. Rea R.F. Boriani G. Estes III, N.A. Spirito P. N. Engl. J. Med. 2000; 342: 365-373Crossref PubMed Scopus (862) Google Scholar), 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 (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). We found a large increase in Ca2+ 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 (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). 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 found that the effect of the mutant protein was dependent on the inotropic state of the heart; under base-line conditions, systolic function was higher in Tg-I79N mice, with little effect on diastolic function. However, during inotropic stimulation with high extracellular Ca2+ or with isoproterenol, diastolic function was impaired, both in the isolated heart and in vivo. Based on these results, we conclude that the increased myofilament Ca2+ sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation. In humans carrying the TnT-I79N mutation, this mechanism may contribute to excess mortality during exercise or in pathophysiological states with high levels of endogenous catecholamines, even in the absence of significant cardiac hypertrophy. All studies were carried out according to National Institutes of Health and by the and To the effect of the I79N mutation on cardiac performance and we compared transgenic mice expressing either human wild-type or mutant cardiac TnT and and The and in vitro of this transgenic model has been (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). All transgenic high levels of the transgenic with and of endogenous mouse TnT and were with a of was a the heart was and the was by of and Tg-I79N mice were isolated and in the as for mouse hearts R. N. C.S. Am. J. 1999; Google Scholar). In the was the heart was and the was the was carried out at a pressure of at The of was a the of the left 0.5 and was at the time of the To a heart the was and the hearts were at a on the of the were to for base-line left ventricular pressure were To the of different inotropic the heart was with of and was A. PubMed Scopus Google Scholar). measurements were at the of at the All were with for at 1 to the a of of was the the left ventricle an in the left as R. N. C.S. Am. J. 1999; Google Scholar). was the and the The was to the end-diastolic pressure at and the was for the of the The left ventricular pressure was at with the of a The with the of a pressure with a response to to the of the pressure The of cardiac performance were and from at and at the of Ca2+ concentration left ventricular systolic developed pressure systolic pressure and the and of the of left ventricular pressure and of and time to systolic time to and time from systolic pressure to 90% To the time of pressure the left ventricle pressure was from the time of to a the of the an function as R. N. C.S. Am. J. 1999; Google Scholar). the mice were either with and or with of were in a with in to The of the was to a to a during the To the from mice, which have the high heart and a a was a high response and large and and was to leads in as J. 2000; PubMed Scopus Google Scholar). were at 1 a National with and were from in leads and and the were a time the of the as the as A. G. Am. J. Google Scholar). the effect of and on The heart was as the the and the was in the lead with the and pressure and heart were in and mice a were as for the measurements and on a to a during the and Doppler measurements were with a in a left to the by N. 1995; PubMed Scopus Google Scholar). with a in was to high and measurements J.C. C. J. J. Clin. Invest. 1999; PubMed Scopus Google Scholar). of the was in at the of the and the of the The was confirmed by the and measurements in the Doppler measurements of aortic outflow and were were only from to that the maximal was In this was an that to an the was during echocardiography and both on for and on the The were from and measurements a and end-diastolic and and were for from the outflow aortic aortic time to and and and time were from the Doppler in and the to was To left ventricular systolic and heart of were was as a base-line and echocardiography been were with a of on in the N. 1995; PubMed Scopus Google Scholar). in the Tg-I79N we examined the of a lower which was to a significant increase in heart in of mice. All and were at a significant increase in heart was by Seidman C.E. Seidman J.G. 1996; PubMed Scopus Google was to the of of the different were by were to the by with a by were by The was in were for to the exercise sudden mouse that during the isoproterenol was to out of death as is were death was due to a from the to the was from further We not evidence for in of the of mice Tg-I79N were to the heart and mice of mouse was with of the The heart was and were The heart was its and in were from the at and with and for and for The were examined for the of or without knowledge of degree of exercise or in vivo in and Tg-I79N was by on a of the model of J.D. Potter J.D. J. Full Text PDF PubMed Scopus Google and a model T. J. K. Y. S. J. H. H. Am. J. 1997; Google an of the for Ca2+ on force A. S. Am. J. 1999; 276: Google Scholar). have been (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). All ventricular and were in in to the and measurements were by a was to the were a of significant were were compared with without for were compared the were significant the was as and To the functional consequences of the I79N mutation in the whole we of cardiac performance in the isolated of the and has been to both systolic and diastolic function in R. N. C.S. Am. J. 1999; Google Scholar, J.C. C. J. J. Clin. Invest. 1999; PubMed Scopus Google Scholar, Sweeney H.L. Seidman C.E. Seidman J.G. J. Clin. Invest. PubMed Scopus Google Scholar, D. Seidman Seidman J.G. Med. 1999; PubMed Scopus Google Scholar). function was from systolic time to and of pressure function was from the of pressure and from time to 90% and the time of hearts were at and end-diastolic pressure was at systolic performance was not different and hearts However, the of pressure was in Tg-I79N hearts time to significantly in the Tg-I79N hearts the time to 90% and the time were significantly in the Tg-I79N hearts compared with both and hearts The pressure of 1 the of the Tg-I79N The of to which to diastolic function to systolic function C.S. L. L. Am. J. Google Scholar), was significantly increased in Tg-I79N mice the at an end-diastolic pressure of was lower in Tg-I79N mice these that Tg-I79N hearts significantly diastolic contractile of mouse hearts pressure to pressure to to 90% Tg-I79N or of by in a Tg-I79N or of by were as during of and Tg-I79N ventricular of Ca2+ from troponin and (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). I79N which is consistent with the in We examined the in cardiac performance in response to in At of 0.5 and 1 developed pressure was significantly higher in Tg-I79N in hearts At higher developed pressure was not significantly different the there was a of the in Tg-I79N of diastolic function a different at of 0.5 and 1 was significantly lower in I79N hearts time to 90% was not significantly different from At higher was significantly higher and time to 90% was significantly in I79N hearts in hearts I79N hearts increased systolic performance at but performance with that of at a or the diastolic function is with that of at but significantly at high and Doppler measurements have been to the cardiac of transgenic mouse G. Wang Y. Am. J. 1997; Google Scholar). We cardiac of systolic and diastolic ventricular by and Doppler the of systolic contractile function and were significantly higher in both Tg-I79N compared with for increased contractility was on measurements by Tg-I79N mice a significantly time to outflow diastolic by Doppler were not different the isolated systolic function was increased in Tg-I79N mice, but diastolic function to for this may to the heart by the We the echocardiography and Doppler measurements a different which much there were no large in the cardiac Tg-I79N and we compared Tg-I79N with mice and mice. increased to a in function was significantly different Tg-I79N by of at these heart the end-diastolic was significantly in Tg-I79N mice both and in mice or in mice Doppler of diastolic were not significantly the only in of the examined and Doppler measurements under and for isoproterenol heart end-diastolic heart of outflow aortic aortic and only in of mice under of by for isoproterenol in a heart end-diastolic heart of outflow aortic aortic and only in of mice under of by To the that the in were due to a in we the pressure in mice pressure was not significantly different mice not these that Tg-I79N mice have increased systolic cardiac performance in vivo. for the the systolic function in vivo and in the isolated heart is the of mouse in of was which is significantly lower the for the base-line isolated heart In of we examined the increased systolic function in Tg-I79N mice. pressure was not significantly different Tg-I79N and mice not on the was significantly lower in Tg-I79N mice remains to the heart of Tg-I79N mice a response to the increased cardiac a cause of sudden were from and Tg-I79N mice The significant was that Tg-I79N a the time from the to the The was of the not and was in mice in the degree of to to the of the mutant TnT with higher levels of Tg-I79N with lower protein is not a in FHC left is often hypertrophy in Tg-I79N mice was on and heart were not different, but the was significantly in Tg-I79N mice were not in Tg-I79N mice at Based on the from the isolated heart studies and the diastolic function 1 and To this in vivo, we examined the effect of inotropic stimulation with isoproterenol, is to in vivo without causing significant To in diastolic was for echocardiography and Doppler on from the base-line Doppler of compared with mice were with isoproterenol, Tg-I79N mice echocardiography and Doppler studies were with a lower of isoproterenol isoproterenol a increase in contractility in and mice increased by in Tg-I79N mice a inotropic response increased only by and in and and In fact, out of Tg-I79N mice, but of the mice, developed and Doppler measurements that this inotropic response was not caused by an outflow both and I79N aortic outflow ventricular and increased diastolic chamber as by the of and increased on Doppler measurements in I79N mice to the cardiac dysfunction. To further investigate the of mice, we the isoproterenol with At the lower of the examined Tg-I79N mice in and and of isoproterenol significant developed in the Tg-I79N mice. a maximal heart in the significant in the Tg-I79N mice was and were not different the At a higher of isoproterenol Tg-I79N mice in and and of the of with the in heart of mice, the isoproterenol resulted only in a increase in heart in Tg-I79N mice, by and death The in the in in and that developed isoproterenol tachyarrhythmias were only in a mice and were a Tg-I79N mice with on with and and no evidence for these that the were not caused by ventricular remains to the were the cause of the or were a as a of and that developed of the cardiac response and heart response and of isoproterenol The the in with mice Tg-I79N mice a by a in heart which is by in of and Tg-I79N mice from and and degree and mice of in the and the Tg-I79N in exercise was the for the increase in in Tg-I79N mice there were no or found in studies the of the exercise of Tg-I79N were and and mice, with a significantly heart as in the (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). However, we found evidence for left hypertrophy 1 which was significantly different the were for the lower ventricular of Tg-I79N mice of and ventricular from and Tg-I79N and no the and Tg-I79N may have in the and of the the mice. and and or no the were exercise no effect on cardiac in either The of this study is that significant in cardiac contractile and properties in transgenic mice carrying the TnT-I79N In the isolated the effect of the I79N mutation on cardiac performance on the Ca2+ concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts only at 0.5 and 1 with no in diastolic function. At higher diastolic dysfunction became manifest as both an increase in end-diastolic pressure and in time to 90% and 1 and vivo measurements with echocardiography and Doppler confirmed at systolic function was significantly higher in Tg-I79N mice without evidence for diastolic dysfunction and However, inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality only in Tg-I79N mice Doppler studies ruled out aortic outflow obstruction and were consistent with diastolic and ruled out ventricular tachyarrhythmias as a cause of death and in and and studies ruled out significant ventricular or consistent with the that the increased myofilament Ca2+ sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction under inotropic stimulation. mechanism may contribute to excess mortality during exercise or states with high levels of endogenous catecholamines, even in the absence of significant cardiac hypertrophy. In the isolated heart of I79N mice, systolic function was and was no from humans or transgenic carrying the I79N mutation have been in a mouse model expressing the mutation J.C. C. J. J. Clin. Invest. 1999; PubMed Scopus Google Scholar, Sweeney H.L. Seidman C.E. Seidman J.G. J. Clin. Invest. PubMed Scopus Google Scholar, D. Seidman Seidman J.G. Med. 1999; PubMed Scopus Google Scholar), systolic function has been in an transgenic mouse model of the mutations L. K. J. F. R. J. Cardiol. 2000; Full Text PDF PubMed Scopus Google Scholar). may for the at the inotropic effect of the in Ca2+ sensitivity of skinned fibers At higher or during inotropic may levels to the of the in I79N mice, and little force is conditions, the due to the increased myofilamental the cardiac performance on the inotropic state of the and may depending on the the of Ca2+ have to the in systolic function under base-line increased in vivo, but no in the isolated is that end-diastolic pressure was at for the isolated heart to contractile performance of hearts of different but developed pressure diastolic is H. A. G. C.S. J.P. Am. J. 1997; PubMed Google Scholar). However, the lower of I79N hearts consistent with a diastolic diastolic was in the I79N hearts at a of systolic performance may have been in isolated heart by echocardiography significantly by in and to that the in vivo in systolic as by systolic was not significantly different Tg-I79N and we not the end-diastolic pressure in vivo, the end-diastolic as a heart and diastolic the were significantly in the Tg-I79N mice, that either was or was in Tg-I79N mice. in to the for the increase of the in the I79N mice. In the Tg-I79N mice, ventricular was to under conditions, on studies and at a of or on the isolated heart studies we not evidence for on Doppler under base-line is that the Doppler is not to in diastolic chamber stiffness. is the in mouse In the isolated heart diastolic were not significantly different at of 0.5 or 1 and was significantly higher in the compared with Tg-I79N hearts increase of at is but has been in the isolated heart and is to to the the pressure the systolic pressure during Sweeney H.L. Seidman C.E. Seidman J.G. J. Clin. Invest. PubMed Scopus Google Scholar). in the mouse model of FHC M.J. Seidman C.E. Seidman J.G. J. Clin. Invest. 1997; PubMed Scopus Google Scholar), ventricular were not in or I79N mice at However, this may not during the of in study, even in FHC patients ventricular and on (6Maron B.J. Shen W.K. Link M.S. Epstein A.E. Almquist A.K. Daubert J.P. Bardy G.H. Favale S. Rea R.F. Boriani G. Estes III, N.A. Spirito P. N. Engl. J. Med. 2000; 342: 365-373Crossref PubMed Scopus (862) Google Scholar). transgenic mice expressing TnT-I79N a on The was of the was to and was in The of the is by from the to the ventricle and is by the system. increase in for the and a mechanism to increased cardiac contractility of I79N mice the The heart of I79N mice is consistent with this hypertrophy has been with in mouse of cardiac hypertrophy J. 2000; PubMed Scopus Google Scholar). We found significant hypertrophy in I79N mice, and this may have to the The hypertrophy from I79N by the which in the in the ventricle A. W.K. J. S. J. J. J. Biol. Chem. Full Text PDF PubMed Google Scholar), or a response to diastolic of the or hypertrophy has been in mice expressing the mutation J.C. C. J. J. Clin. Invest. 1999; PubMed Scopus Google Scholar). Based on echocardiography and Doppler isoproterenol little effect on systolic but resulted in significantly measurements of diastolic in Tg-I79N mice. as end-diastolic and contribute to the of Doppler during Doppler to diastolic J.D. Circulation. 1995; PubMed Scopus Google have that in particular the time is with diastolic chamber of in this even the increase of diastolic chamber that P.A. C.S. R. Am. J. Cardiol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, P.A. C.S. R. J. Am. Coll. Cardiol. PubMed Scopus Google Scholar). with the from the isolated heart and the the significantly time and in both transgenic that isoproterenol an increased diastolic chamber in Tg-I79N mice. an cardiac study have to these in the was the high mortality of Tg-I79N mice the isoproterenol Based on echocardiography and Doppler the were not caused by an aortic outflow which is a cause of death in human FHC H. W.G. Circulation. 1995; PubMed Scopus Google Scholar). were not due to ventricular cause of death in FHC patients (6Maron B.J. Shen W.K. Link M.S. Epstein A.E. Almquist A.K. Daubert J.P. Bardy G.H. Favale S. Rea R.F. Boriani G. Estes III, N.A. Spirito P. N. Engl. J. Med. 2000; 342: 365-373Crossref PubMed Scopus (862) Google Scholar), or Tg-I79N mice isoproterenol in of and and heart not with cardiac in FHC patients that a cardiac Epstein L. J. Am. Coll. Cardiol. PubMed Scopus Google and a in the mortality of Tg-I79N mice. of evidence that have to the isoproterenol mortality as Tg-I79N evidence of an increase in heart due to and heart to in In FHC dysfunction cause an in at high K. Heart. PubMed Scopus Google and has been in a carrying a TnT mutation A. Baboonian C. Davison F. de Cruz L. Elliott P.M. Davies M.J. McKenna W.J. Heart. 1999; 82: 621-624Crossref PubMed Scopus (93) Google Scholar). this the that both and Doppler significant was and have to the Tg-I79N but not the of the remains to why excess mortality was to the isoproterenol under and not during the which have a endogenous that the of was to the Tg-I79N mice. the sudden death in response to exercise is a even in patients with and exercise of in a of mice not have been to significant in a in an to from skinned fibers to the we the mechanisms for the The increased Ca2+ sensitivity of (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google cardiac contractility and but the of the Ca2+ and force or the increase in that causing diastolic dysfunction and The of the myofilamental the of contractile at (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google by diastolic the may evidence for or I79N fibers may force at provides little increase in the fibers to the of the the lower maximal force (7Miller T. Szczesna D. Housmans P.R. Zhao J. deFreitas F. Gomes A.V. Culbreath L. McCue J. Wang Y. Xu Y. Kerrick W.G. Potter J.D. J. Biol. Chem. 2001; 276: 3743-3755Abstract Full Text Full Text PDF PubMed Scopus (105) Google the contractile to increase cardiac in response to The cardiac may ventricular and cause in which contribute to and death in response to In Tg-I79N mice may a model to mechanisms of sudden death by the TnT-I79N We for the of the of contractility measurements in the isolated mouse