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Myofilament Calcium De-Sensitization and Contractile Uncoupling Prevent Pause-Triggered Ventricular Tachycardia in Mouse Hearts with Chronic Myocardial Infarction
Title
Myofilament Calcium De-Sensitization and Contractile Uncoupling Prevent Pause-Triggered Ventricular Tachycardia in Mouse Hearts with Chronic Myocardial Infarction.
Creator
Venkataraman, Raghav, Baldo, Marcelo, Hwang, Hyun, Veltri, Tiago, Pinto, Jose, Baudenbacher, Franz, Knollmann, Björn C.
Abstract/Description
Myocardial infarction (MI) is a major risk for ventricular arrhythmia. Pause-triggered ventricular arrhythmia can be caused by increased myofilament Ca binding due to sarcomeric mutations or Ca-sensitizing compounds. Myofilament Ca sensitivity is also increased after MI. Here we hypothesize that MI increases risk for pause-triggered ventricular arrhythmias, which can be prevented by myofilament Ca-desensitization and contractile uncoupling. To test this hypothesis, we generated a murine...
Show moreMyocardial infarction (MI) is a major risk for ventricular arrhythmia. Pause-triggered ventricular arrhythmia can be caused by increased myofilament Ca binding due to sarcomeric mutations or Ca-sensitizing compounds. Myofilament Ca sensitivity is also increased after MI. Here we hypothesize that MI increases risk for pause-triggered ventricular arrhythmias, which can be prevented by myofilament Ca-desensitization and contractile uncoupling. To test this hypothesis, we generated a murine chronic MI model using male B6SJLF1/J mice (n=40) that underwent permanent ligation of the left anterior descending coronary artery. 4 weeks post MI, cardiac structure, function and myofilament Ca sensitivity were evaluated. Pause-dependent arrhythmia susceptibility was quantified in isolated hearts with pacing trains of increasing frequency, followed by a pause and an extra stimulus. Coronary ligation resulted in a mean infarct size of 39.6±5.7% LV and fractional shortening on echocardiography was reduced by 40% compared to non-infarcted controls. Myofilament Ca sensitivity was significantly increased in post MI hearts (pCa50: Control=5.66±0.03; MI=5.84±0.05; P
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Date Issued
2013
Identifier
FSU_migr_biomed_faculty_publications-0057, 10.1016/j.yjmcc.2013.03.022
Format
Citation
Late Onset Sporadic Dilated Cardiomyopathy Caused by a Cardiac Troponin T Mutation
Title
Late Onset Sporadic Dilated Cardiomyopathy Caused by a Cardiac Troponin T Mutation.
Creator
Morales, Ana, Pinto, Jose, Siegfried, Jill, Li, Duanxiang, Norton, Nadine, Hofmeyer, Mark, Vallin, Marta, Morales, Azorides R., Potter, James, Hershberger, Ray
Abstract/Description
Mutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy (DCM). This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset DCM. Further, the trigger for late onset DCM remains enigmatic. A 70-year-old woman, previously healthy with a left ventricular ejection fraction of 50%-55% at age 69, presented with DCM of unknown cause and a 4-month history progressive heart failure requiring...
Show moreMutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy (DCM). This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset DCM. Further, the trigger for late onset DCM remains enigmatic. A 70-year-old woman, previously healthy with a left ventricular ejection fraction of 50%-55% at age 69, presented with DCM of unknown cause and a 4-month history progressive heart failure requiring cardiac transplantation. Clinical genetic testing revealed a novel TNNT2 R139H mutation but no relevant variants in 18 other DCM genes. Her explanted heart showed partial fatty replacement in the right ventricle. Sequencing for five arrhythmogenic right ventricular dysplasia genes was negative. Functional studies in porcine cardiac skinned fibers reconstituted with the mutant R139H troponin T protein showed decreased Ca(2+) sensitivity at pH 7, characteristic of DCM. Because fatty infiltration may acidify the myocellular environment, maximal force development examined at pH 6.5 was diminished, suggesting a possible environmental trigger. We conclude that the TNNT2 R139H mutation was likely to be disease causing. Further, later age of onset may not be relevant to exclude genetic testing for TNNT2 mutations.
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Date Issued
2010
Identifier
FSU_migr_biomed_faculty_publications-0054, 10.1111/j.1752-8062.2010.00228.x
Format
Citation
Cardiac Troponin Mutations and Restrictive Cardiomyopathy
Title
Cardiac Troponin Mutations and Restrictive Cardiomyopathy.
Creator
Parvatiyar, Michelle, Pinto, Jose, Dweck, David, Potter, James
Abstract/Description
Mutations in sarcomeric proteins have recently been established as heritable causes of Restrictive Cardiomyopathy (RCM). RCM is clinically characterized as a defect in cardiac diastolic function, such as, impaired ventricular relaxation, reduced diastolic volume and increased end-diastolic pressure. To date, mutations have been identified in the cardiac genes for desmin, alpha-actin, troponin I and troponin T. Functional studies in skinned muscle fibers reconstituted with troponin mutants...
Show moreMutations in sarcomeric proteins have recently been established as heritable causes of Restrictive Cardiomyopathy (RCM). RCM is clinically characterized as a defect in cardiac diastolic function, such as, impaired ventricular relaxation, reduced diastolic volume and increased end-diastolic pressure. To date, mutations have been identified in the cardiac genes for desmin, alpha-actin, troponin I and troponin T. Functional studies in skinned muscle fibers reconstituted with troponin mutants have established phenotypes consistent with the clinical findings which include an increase in myofilament Ca(2+) sensitivity and basal force. Moreover, when RCM mutants are incorporated into reconstituted myofilaments, the ability to inhibit the ATPase activity is reduced. A majority of the mutations cluster in specific regions of cardiac troponin and appear to be mutational "hot spots". This paper highlights the functional and clinical characteristics of RCM linked mutations within the troponin complex.
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Date Issued
2010
Identifier
FSU_migr_biomed_faculty_publications-0053, 10.1155/2010/350706
Format
Citation
Functional Effects of a Restrictive-Cardiomyopathy-Linked Cardiac Troponin I Mutation (R145W) in Transgenic Mice
Title
Functional Effects of a Restrictive-Cardiomyopathy-Linked Cardiac Troponin I Mutation (R145W) in Transgenic Mice.
Creator
Wen, Yuhui, Xu, Yuanyuan, Wang, Yingcai, Pinto, Jose, Potter, James, Kerrick, W.
Abstract/Description
The human cardiac troponin I (hcTnI) mutation R145W has been associated with restrictive cardiomyopathy. In this study, simultaneous measurements of ATPase activity and force in skinned papillary fibers from hcTnI R145W transgenic mice (Tg-R145W) were explored. Tg-R145W fibers showed an approximately 13-16% increase in maximal Ca(2+)-activated force and ATPase activity compared to hcTnI wild-type transgenic mice. The force-generating cross-bridge turnover rate (g) and the energy cost (ATPase...
Show moreThe human cardiac troponin I (hcTnI) mutation R145W has been associated with restrictive cardiomyopathy. In this study, simultaneous measurements of ATPase activity and force in skinned papillary fibers from hcTnI R145W transgenic mice (Tg-R145W) were explored. Tg-R145W fibers showed an approximately 13-16% increase in maximal Ca(2+)-activated force and ATPase activity compared to hcTnI wild-type transgenic mice. The force-generating cross-bridge turnover rate (g) and the energy cost (ATPase/force) were the same in all groups of fibers. Also, the Tg-R145W fibers showed a large increase in the Ca(2+) sensitivity of both force development and ATPase. In intact fibers, the mutation caused prolonged force and intracellular [Ca(2+)] transients and increased time to peak force. Analysis of force and Ca(2+) transients showed that there was a 40% increase in peak force in Tg-R145W muscles, which was likely due to the increased Ca(2+) transient duration. The above cited results suggest that: (1) there would be an increase in resistance to ventricular filling during diastole resulting from the prolonged force and Ca(2+) transients that would result in a decrease in ventricular filling (diastolic dysfunction); and (2) there would be a large (approximately 53%) increase in force during systole, which may help to partly compensate for diastolic dysfunction. These functional results help to explain the mechanisms by which these mutations give rise to a restrictive phenotype.
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Date Issued
2009
Identifier
FSU_migr_biomed_faculty_publications-0060, 10.1016/j.jmb.2009.07.080
Format
Citation
Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients with Dilated Cardiomyopathy
Title
Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients with Dilated Cardiomyopathy.
Creator
Hershberger, Ray, Pinto, Jose, Parks, Sharie, Kushner, Jessica, Li, Duanxiang, Ludwigsen, Susan, Cowan, Jason, Morales, Ana, Parvatiyar, Michelle, Potter, James
Abstract/Description
BACKGROUND: A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. METHODS AND RESULTS: We recently undertook bidirectional resequencing of TNNT2, the cardiac troponin T gene, in 313 probands with DCM. We identified 6 TNNT2 protein...
Show moreBACKGROUND: A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. METHODS AND RESULTS: We recently undertook bidirectional resequencing of TNNT2, the cardiac troponin T gene, in 313 probands with DCM. We identified 6 TNNT2 protein-altering variants in 9 probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the 9 probands had DCM without a family history, and 5 probands had familial DCM. Only 1 mutation (Lys210del) could be attributed as definitively causative from previous reports. Four of the 5 missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, and Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree, and molecular genetic data, these 5 mutations were considered possibly or likely disease causing. To further clarify their potential pathophysiologic impact, we undertook functional studies of these mutations in cardiac myocytes reconstituted with mutant troponin T proteins. We observed decreased Ca(2+) sensitivity of force development, a hallmark of DCM, in support of the conclusion that these mutations are disease causing. CONCLUSIONS: We conclude that the combination of clinical, pedigree, molecular genetic, and functional data strengthen the interpretation of TNNT2 mutations in DCM.
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Date Issued
2009
Identifier
FSU_migr_biomed_faculty_publications-0059, 10.1161/CIRCGENETICS.108.846733
Format
Citation
Myofilament Ca2+ Sensitization Causes Susceptibility to Cardiac Arrhythmia in Mice
Title
Myofilament Ca2+ Sensitization Causes Susceptibility to Cardiac Arrhythmia in Mice.
Creator
Baudenbacher, Franz, Schober, Tilmann, Pinto, Jose, Sidorov, Veniamin, Hilliard, Fredrick, Solaro, R. John, Potter, James, Knollmann, Björn C.
Abstract/Description
In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing...
Show moreIn human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca2+-sensitizing agent EMD 57033 and prevented by myofilament Ca2+ desensitization with blebbistatin. Ca2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.
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Date Issued
2008
Identifier
FSU_migr_biomed_faculty_publications-0050, 10.1172/JCI36642
Format
Citation