In Vivo Analysis of Troponin C Knock-In (A8V) MiceCLINICAL PERSPECTIVE

Slides:

Advertisements

Similar presentations

The Expression of NPPA Splice Variants During Cardiac Differentiation of Mouse Mesenchymal and Embryonic Stem Cells Masoumeh Fakhr Taha PhD, Arash Javeri.

Advertisements

Homozygous mice that lack the proline-alanine rich region and C1 domain of cMyBP-C (p/a-C1 -/- mice, Figure 1) were developed by Witt et al.. 4 Figure.

18 Sept 07 K Sept 07 Cardiac Contractile Element 1.

The Steps of The Cardiac Cycle “The Rhythm is gonna get you”

The cardiovascular system in action 1/Cardiac function and cardiac output 2/ Cardiac cycle.

© 2015 Pearson Education, Inc. Figure Pressure and Volume Relationships in the Cardiac Cycle. Aorta Electro- cardiogram (ECG) QRS complex P T ONE.

Date of download: 5/28/2016 Copyright © The American College of Cardiology. All rights reserved. From: Contractile Function During Angiotensin-II Activation:

Date of download: 6/3/2016 Copyright © The American College of Cardiology. All rights reserved. From: Irreversible Triggers for Hypertrophic Cardiomyopathy.

Date of download: 6/22/2016 Copyright © The American College of Cardiology. All rights reserved. From: Clinical Features of Hypertrophic Cardiomyopathy.

Date of download: 7/7/2016 Copyright © The American College of Cardiology. All rights reserved. From: Frequency and clinical expression of cardiac troponin.

Date of download: 7/8/2016 Copyright © The American College of Cardiology. All rights reserved. From: A combination of oral endothelin-areceptor antagonist.

Two-dimensional echocardiogram from a patient with severe hypertrophic cardiomyopathy. There is a severe increase in left ventricular wall thickness, with.

Not Necessarily a Myocardial Infarction: New Left Bundle Branch Block

Cardiac Physiology Class 1.

Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive HypertensionNovelty and Significance by Andrew.

Figure 5 Effect of concomitant PDE3 and PDE4 inhibition on SR Ca2+ load and fractional release in ARVMs. (A) Representative traces of Ca2+

Journal of Molecular and Cellular Cardiology

Left-Sided Cardiac Valvulitis in Tristetraprolin-Deficient Mice

Volume 20, Issue 12, Pages (December 2012)

A. Parasternal views during diastole (left) and systole (right) from a normal individual. Upper panels: long-axis plane; lower panels: short-axis plane.

Targeted Ablation of PINCH1 and PINCH2 From Murine Myocardium Results in Dilated Cardiomyopathy and Early Postnatal Lethality by Xingqun Liang, Yunfu Sun,

The Electrocardiogram

Soluble Tumor Necrosis Factor Receptor Abrogates Myocardial Inflammation but Not Hypertrophy in Cytokine-Induced Cardiomyopathy by Toru Kubota, George.

by Yingmei Zhang, Ming Yuan, Katherine M

Mechanical Stress Conditioning and Electrical Stimulation Promote Contractility and Force Maturation of Induced Pluripotent Stem Cell-Derived Human Cardiac.

Evaluation of Left Ventricular Enlargement as a Marker of Early Disease in Familial Dilated CardiomyopathyClinical Perspective by Diane Fatkin, Thomas.

Choline Diet and Its Gut Microbe–Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload–Induced Heart FailureCLINICAL PERSPECTIVE by.

Circ Arrhythm Electrophysiol

Dapper-1 Induces Myocardial Remodeling Through Activation of Canonical Wnt Signaling in CardiomyocytesNovelty and Significance by Marco Hagenmueller, Johannes.

Loss of Secreted Frizzled-Related Protein-1 Leads to Deterioration of Cardiac Function in Mice and Plays a Role in Human CardiomyopathyCLINICAL PERSPECTIVE.

by Xuefei Ma, and Robert S. Adelstein

High Incidence of Cardiac Malformations in Connexin40-Deficient Mice

Striking In Vivo Phenotype of a Disease-Associated Human SCN5A Mutation Producing Minimal Changes in VitroClinical Perspective by Hiroshi Watanabe, Tao.

Neuregulins Regulate Cardiac Parasympathetic Activity

Sarcomere Mutation-Specific Expression Patterns in Human Hypertrophic CardiomyopathyClinical Perspective by Adam S. Helms, Frank M. Davis, David Coleman,

Mice Lacking the Vascular Endothelial Growth Factor-B Gene (Vegfb) Have Smaller Hearts, Dysfunctional Coronary Vasculature, and Impaired Recovery From.

Parvalbumin Corrects Slowed Relaxation in Adult Cardiac Myocytes Expressing Hypertrophic Cardiomyopathy-Linked α-Tropomyosin Mutations by Pierre Coutu,

Replacement of Connexin40 by Connexin45 in the Mouse

Supravalvular Aortic Stenosis

Quantitative Proteome Analysis Reveals Increased Content of Basement Membrane Proteins in Arteries From Patients With Type 2 Diabetes Mellitus and Lower.

A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill by W. Antoinette Groenewegen, Mehran Firouzi,

by Richard L. Moss, Daniel P. Fitzsimons, and J. Carter Ralphe

Myosin Cross-Bridge Dynamics in Patients With Hypertension and Concentric Left Ventricular RemodelingClinical Perspective by Cameron Donaldson, Bradley.

Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy–Associated Cardiomyopathy by Michelle S. Parvatiyar, Jamie.

Volume 99, Issue 3, Pages (October 1999)

Dual-Chamber Pacing for Cardiomyopathies: A 1996 Clinical Perspective

Bindiya Patel et al. BTS 2018;3:

Left ventricular and aortic dysfunction in cystic fibrosis mice

Stress Pathways and Heart Failure

The Genetic Basis for Cardiomyopathy

The heart reinnervates after transplantation

Ventricular and pulmonary vascular remodeling induced by pulmonary overflow in a chronic model of pretricuspid shunt Daniele Linardi, MD, Alessio Rungatscher,

Prevalence and clinical significance of acquired left coronary artery fistulas after surgical myectomy in patients with hypertrophic cardiomyopathy Aurelio.

Biodegradable vs Nonbiodegradable Cardiac Support Device for Treating Ischemic Cardiomyopathy in a Canine Heart Mutsunori Kitahara, MD, Shigeru Miyagawa,

Volume 100, Issue 10, Pages (May 2011)

Volume 25, Issue 11, Pages (November 2017)

Marinus A. Borgdorff, Beatrijs Bartelds, Michael G

Volume 14, Issue 6, Pages (June 2008)

Volume 21, Issue 6, Pages (November 2017)

Induction of heart failure by minimally invasive aortic constriction in mice: Reduced peroxisome proliferator-activated receptor γ coactivator levels.

Prachi Umbarkar et al. BTS 2019;j.jacbts

Volume 110, Issue 6, Pages (September 2002)

CARDIC CYCLE Dr. Haseeb Sattar.

Volume 6, Issue 1, Pages (July 2007)

Volume 24, Issue 2, Pages (February 2016)

Patrick O’Gara et al. JIMG 2008;1:

Volume 8, Pages (October 2018)

Volume 17, Issue 1, Pages (July 2015)

SKO mice display hypertrophic cardiomyopathy with systolic and diastolic dysfunction. SKO mice display hypertrophic cardiomyopathy with systolic and diastolic.

The Steps of The Cardiac Cycle

Presentation transcript:

In Vivo Analysis of Troponin C Knock-In (A8V) MiceCLINICAL PERSPECTIVE by Adriano S. Martins, Michelle S. Parvatiyar, Han-Zhong Feng, J. Martijn Bos, David Gonzalez-Martinez, Milica Vukmirovic, Rajdeep S. Turna, Marcos A. Sanchez-Gonzalez, Crystal-Dawn Badger, Diego A.R. Zorio, Rakesh K. Singh, Yingcai Wang, J.-P. Jin, Michael J. Ackerman, and Jose R. Pinto Circ Genom Precis Med Volume 8(5):653-664 October 20, 2015 Copyright © American Heart Association, Inc. All rights reserved.

Echo- and electro-cardiograms of the TNNC1-A8V patient. Echo- and electro-cardiograms of the TNNC1-A8V patient. A, ECHO image from apical 4-chamber showing mild to moderate left atrial enlargement (white arrow). B, ECHO image from parasternal long axis showing basal to midanteroseptal and posterior wall hypertrophy (white arrows) as an indication of concentric left ventricle hypertrophy. C–G, ECG tracing from patient showing sinus rhythm, pathological Q-waves suggesting prior ischemia or hypertrophic cardiomyopathy (C–F), increased QRS amplitude suggesting left ventricular hypertrophy (E and G). Ao indicates aorta; LA, left atria; LV, left ventricle; and RV, right ventricle. Adriano S. Martins et al. Circ Cardiovasc Genet. 2015;8:653-664 Copyright © American Heart Association, Inc. All rights reserved.

Echocardiography and ex vivo working heart function of the KI-TnC-A8V mice. Echocardiography and ex vivo working heart function of the KI-TnC-A8V mice. A representative ECHO image of the left ventricle is shown in A from a 14 m wild-type (WT) mouse and in B from a 14 m KI-TnC-A8V+/+ mouse. The response to β-adrenergic stimulation in ex vivo working heart function in 12 to 13 m mice is shown in C. Stroke volume normalized to the heart weight; D, LVPmax (maximal left ventricular pressure); E, LVPmin (minimal left ventricular pressure); F, +dP/dt (rate of rise of left ventricular pressure); G, −dP/dt (rate of fall of left ventricular pressure). Data are shown as mean±SE, n=5 mice. **P<0.01 and ***P<0.001 KI vs WT; ##P<0.01 and ###P<0.001 KI-TnC-A8V+/+ vs KI-TnC-A8V+/− using 2-way ANOVA with Tukey adjustment. &P<0.05 KI-TnC-A8V+/+ vs KI-TnC-A8V+/−, and $P<0.05 KI-TnC-A8V+/+ vs WT and KI-TnC-A8V+/− without ISO treatment using 1-way ANOVA with Tukey adjustment. ISO indicates isoproterenol. Adriano S. Martins et al. Circ Cardiovasc Genet. 2015;8:653-664 Copyright © American Heart Association, Inc. All rights reserved.

Heart weight and hypertrophic cardiomyopathy gene expression profile in KI-TnC-A8V mice. Heart weight and hypertrophic cardiomyopathy gene expression profile in KI-TnC-A8V mice. The body weight (A); the ratio heart weight/body weight (B); the left atria weight (C); and the ratio left atria/heart weight (D). A–D are data from 12 to 13 m mice. Data are shown as mean±SE, n=5 mice. *P<0.05, **P<0.01, and *** P<0.001 KI vs WT; ##P<0.01 and ###P<0.001 KI-TnC-A8V+/+ vs KI-TnC-A8V+/−. E and F, The mRNA expression levels of cardiac hypertrophic markers in 16 to 18 m mice. Data are shown as mean±SE, n=6 mice. *P<0.05 KI vs WT; #P<0.05 KI-TnC-A8V+/+ vs KI-TnC-A8V+/−. ANP indicates atrial natriuretic peptide; BNP, brain natriuretic peptide; and MHCβ, myosin heavy chain isoform β. Adriano S. Martins et al. Circ Cardiovasc Genet. 2015;8:653-664 Copyright © American Heart Association, Inc. All rights reserved.

Histopathologic analysis of KI-TnC-A8V mouse hearts at 16 to 18 months of age. Histopathologic analysis of KI-TnC-A8V mouse hearts at 16 to 18 months of age. Representative Masson trichrome stained sections were imaged at 10× magnification. A–C, The black arrows indicate the location of papillary muscles. Papillary muscle hypertrophy can be seen in KI-TnC-A8V+/− and KI-TnC-A8V+/+ mouse hearts. Evidence of papillary muscle hypertrophy can also be seen at lower magnification in Figure IIA–IIC in the Data Supplement. E–F, Interstitial fibrosis can be seen in heart sections obtained from the same group of mice. G, The retention time of the cTnC peptides separated by liquid chromatography mass spectrometry. The graphs show the ratio cTnC A8V:WT in the KI-TnC-A8V+/− hearts quantified by the abundance of 15 and 11 amino acid peptides. n=3. Adriano S. Martins et al. Circ Cardiovasc Genet. 2015;8:653-664 Copyright © American Heart Association, Inc. All rights reserved.

Sarcomere length (SL) and intracellular Ca2+ levels in KI-TnC-A8V intact cardiomyocytes at different frequencies of stimulation. Sarcomere length (SL) and intracellular Ca2+ levels in KI-TnC-A8V intact cardiomyocytes at different frequencies of stimulation. A, SL is measured under resting conditions; B, Percentage of SL shortening; C, Diastolic intracellular Ca2+ levels; D, Ca2+ amplitude is represented as the percentage of increase above diastolic intracellular Ca2+ levels in cardiomyocytes obtained from 3-mo-old mice. Data are shown as mean±SE, n=3 to 4 mice. *P<0.05 KI vs WT; #P<0.05, KI-TnC-A8V+/+ vs KI-TnC-A8V+/− at the same frequency of stimulation. The values for each point are presented in Table I in the Data Supplement. Adriano S. Martins et al. Circ Cardiovasc Genet. 2015;8:653-664 Copyright © American Heart Association, Inc. All rights reserved.

Kinetics of contractility and Ca2+ transients in KI-TnC-A8V intact cardiomyocytes electrically stimulated at 4 and 6 Hz. A, Time for the sarcomere length (SL) to return to 50% of baseline (RT, relaxation time); the rate of cell relengthening (−dL/dt); and time for SL shortening to achieve the peak value. Kinetics of contractility and Ca2+ transients in KI-TnC-A8V intact cardiomyocytes electrically stimulated at 4 and 6 Hz. A, Time for the sarcomere length (SL) to return to 50% of baseline (RT, relaxation time); the rate of cell relengthening (−dL/dt); and time for SL shortening to achieve the peak value. B, Time for intracellular Ca2+ to return to 50% of baseline and the time for intracellular Ca2+ to achieve peak during systole. Data are shown as mean±SE, n=3 to 4 mice. *P<0.05 KI vs WT; #P<0.05, KI-TnC-A8V+/+ vs KI-TnC-A8V+/−. The values for each point are presented in Table II in the Data Supplement. Adriano S. Martins et al. Circ Cardiovasc Genet. 2015;8:653-664 Copyright © American Heart Association, Inc. All rights reserved.

The Ca2+ sensitivity of force development and rate of relaxation in papillary skinned fibers and immunoblots of Ca2+-handling proteins in KI-TnC-A8V hearts. The Ca2+ sensitivity of force development and rate of relaxation in papillary skinned fibers and immunoblots of Ca2+-handling proteins in KI-TnC-A8V hearts. A, The Ca2+ dependence of force generation in cardiac skinned fibers from 4-mo-old mice. Data are shown as mean±SE, n=9 to 11. *P<0.05 KI vs WT; #P<0.05 KI-TnC-A8V+/+ vs KI-TnC-A8V+/−. B, A representative tracing measuring the rate of relaxation in cardiac skinned fibers investigated by Diazo-2 on flash photolysis. The amplitudes (A, %) and rate constants (k, s−1) obtained from 4-mo-old mice were as follows; WT: A1=83.82±2.06, k1=15.48±0.9, A2=14.56±2.47, and k2=2.01±0.53; KI-TnC-A8V+/+: A1=84.24±5.06, k1=9.42±0.84, A2=14.28±4.36, and k2=0.75±0.18. k1 and k2 are statistically different between WT and KI-TnC-A8V+/+ (P<0.05). The t1/2 (ms) of skinned fiber relaxation was also statistically different between WT (55.62±4.25) and KI-TnC-A8V+/+ (82.86±6.78), n=8 to 11. C, Representative immunoblots for the detection of SERCA2, PLN-T, phosphorylated PLN at serine 16 (PLN-PSer16), NCX1, CASQ2 and phosphorylated cTnI at serines 23, 24 (cTnI-P) in the left ventricle of 9 mo-old WT, KI-TnC-A8V+/− (+/−), and KI-TnC-A8V+/+ (+/+) mice. For all experiments, tubulin was used as an internal control. D, Quantification of the protein expression and phosphorylation levels. Data are shown as mean±SE, n=6 mice. *P<0.05 KI vs WT; #P<0.05 KI-TnC-A8V+/+ vs KI-TnC-A8V+/−. Adriano S. Martins et al. Circ Cardiovasc Genet. 2015;8:653-664 Copyright © American Heart Association, Inc. All rights reserved.