Abstract P417: Cardiomyopathy-associated Variant In Troponin T Tail Domain Promotes Disruption Of Both Frank-starling Mechanism And Cardiac Myofilament Performance

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Maicon Landim-Vieira ◽  
Weikang Ma ◽  
Taejeong Song ◽  
Coen Ottenheijm ◽  
Hyun Hwang ◽  
...  
Keyword(s):  
Lattice Spacing ◽  
Troponin T ◽  
Isometric Force ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Dependent Manner ◽  
Tail Domain ◽  
Tail Region ◽  
Cardiac Myofilament ◽  
Osmotic Compression

Missense variant Ile79Asn in human cardiac troponin T (HcTnT-I79N) tail region has been linked to familial hypertrophic cardiomyopathy (HCM), arrhythmia, and sudden cardiac death. It has been reported that inotropic stimulation with high extracellular Ca 2+ or isoproterenol led to diastolic dysfunction in both isolated and in vivo HcTnT-I79N mice hearts. Although HcTnT-I79N effects are acknowledged to be dependent on the inotropic state of the cardiac muscle, little is known about how this pathogenic variant affects the Frank-Starling law of the heart. To further investigate the functional and structural consequences of this deadly variant in a stretch-dependent manner, cardiac tissues were harvested from non-transgenic (NTg) control mice and transgenic mice bearing HcTnT-I79N. Left ventricular papillary muscle bundles were permeabilized and mounted for mechanical measurements. Sarcomere length (SL 1.9, 2.1 or 2.3 μm) was set at pCa 8 using HeNe laser diffraction and then Ca 2+ -dependence of isometric force, sinusoidal stiffness (SS, 0.2% PTP length oscillation) and rate of tension redevelopment ( k TR ) were measured. We observed that HcTnT-I79N tissue exhibited increased myofilament Ca 2+ -sensitivity of force, increased SS, slower k TR at all levels of Ca 2+ -activation, and diminished length-dependent activation (LDA). Small-angle X-ray diffraction revealed that HcTnT-I79N permeabilized cardiac muscles exhibit smaller myofilament lattice spacing at longer SLs (2.1 μm and 2.3 μm) compared to NTg. Using 3% Dextran T500 to osmotically compress the myofilament lattice (SL 2.1 μm), HcTnT-I79N showed no change in myofilament lattice spacing and little change in contractile indices associated with LDA. Interestingly, upon osmotic compression, HcTnT-I79N displayed a decrease in disordered relaxed state (DRX, ON state) of myosin and an increase in super-relaxed state (SRX, OFF state) of myosin. We conclude that altered cardiac myofilament performance, lack of responsiveness to osmotic compression, and reduced LDA observed with HcTnT-I79N are partially due to a combination of smaller myofilament lattice and disturbed ON and OFF states of myosin.

scholarly journals Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models

2009 ◽  
Vol 297 (2) ◽  
pp. H614-H626 ◽  
Author(s):  
Pia J. Guinto ◽  
Todd E. Haim ◽  
Candice C. Dowell-Martino ◽  
Nathaniel Sibinga ◽  
Jil C. Tardiff
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ventricular Myocytes ◽  
Troponin T ◽  
Early Time ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Compensatory Mechanism ◽  
Missense Mutations ◽  
Tail Domain ◽  
Cellular Mechanics

Naturally occurring mutations in cardiac troponin T (cTnT) result in a clinical subset of familial hypertrophic cardiomyopathy. To determine the mechanistic links between thin-filament mutations and cardiovascular phenotypes, we have generated and characterized several transgenic mouse models carrying cTnT mutations. We address two central questions regarding the previously observed changes in myocellular mechanics and Ca2+ homeostasis: 1) are they characteristic of all severe cTnT mutations, and 2) are they primary (early) or secondary (late) components of the myocellular response? Adult left ventricular myocytes were isolated from 2- and 6-mo-old transgenic mice carrying missense mutations at residue 92, flanking the TNT1 NH2-terminal tail domain. Results from R92L and R92W myocytes showed mutation-specific alterations in contraction and relaxation indexes at 2 mo with improvements by 6 mo. Alterations in Ca2+ kinetics remained consistent with mechanical data in which R92L and R92W exhibited severe diastolic impairments at the early time point that improved with increasing age. A normal regulation of Ca2+ kinetics in the context of an altered baseline cTnI phosphorylation suggested a pathogenic mechanism at the myofilament level taking precedence for R92L. The quantitation of Ca2+-handling proteins in R92W mice revealed a synergistic compensatory mechanism involving an increased Ser16 and Thr17 phosphorylation of phospholamban, contributing to the temporal onset of improved cellular mechanics and Ca2+ homeostasis. Therefore, independent cTnT mutations in the TNT1 domain result in primary mutation-specific effects and a differential temporal onset of altered myocellular mechanics, Ca2+ kinetics, and Ca2+ homeostasis, complex mechanisms which may contribute to the clinical variability in cTnT-related familial hypertrophic cardiomyopathy mutations.

Abstract 3435: Left Ventricular Hypertrophy is Resistant to Inhibition of Expression of the R403Q Alpha-Myosin Heavy Chain Cardiac Hypertrophy-Inducing Mutant Protein

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Leah Cannon ◽  
Tadeusz Marciniec ◽  
Bryony Mearns ◽  
Robert M Graham ◽  
Diane Fatkin
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Lv Function ◽  
Dependent Manner ◽  
Cardiovascular Morbidity And Mortality ◽  
Lv Mass

Left ventricular hypertrophy (LVH) develops as a compensatory response to myocardial dysfunction due to diverse causes, but is nonetheless a major risk factor for premature cardiovascular morbidity and mortality. It is thus unclear if regressing LVH is beneficial or may worsen patient outcome. To evaluate the effects of LVH regression, we developed a transgenic mouse model in which the expression of a familial hypertrophic cardiomyopathy (FHC)-inducing mutation (R403Q alpha-MHC) can be regulated in a temporal and dose-dependent manner. In this model, transgene expression can be shut off by feeding with a tetracycline analogue (doxycycline). Serial echocardiography and histology studies were performed in a cohort of mice expressing the FHC mutant (“gene-on”) and in wildtype (WT) littermates. A second cohort of WT and 403/+ mice was randomised to placebo or doxycycline (“gene off”) from 6 (Dox6) or 20 weeks (Dox20) and evaluated at 40 weeks of age. Compared to WT littermates, “gene on” 403/+ mice showed increased LV mass, LV end-diastolic diameter (LVDD) and left atrial diameter (LAD), and reduced fractional shortening (LVFS), with changes evident from 12 weeks of age. LV sections from 403/+ mice showed typical features of FHC: myofibre disarray and interstitial fibrosis. LV mass, LV function and myocardial histology were unchanged in both male and female placebo- vs Dox6 or Dox20 mice at 40 weeks (Table 1 ). Thus, consistent with the major LV thickening in FHC humans occurring in adolescence, overexpression of R403Q for only 6 weeks is sufficient to trigger the complete LVH phenotypic response. Moreover, switching off the genetic trigger for LVH in 403/+ mice at 6 weeks (prior to overt disease manifestation) or 20 weeks (established disease) does not induce regression of LVH or exacerbate contractile dysfunction. Interventions to induce LVH regression may, therefore, need to be directed at downstream factors in hypertrophic pathways. Table 1. Echo data for male WT and 403/+ mice aged 40 weeks

In Vitro Effects of Eltanolone on Rat Myocardium

1995 ◽  
Vol 83 (4) ◽  
pp. 792-798. ◽  
Author(s):  
Bruno Riou ◽  
Patrick Ruel ◽  
Jean-Luc Hanouz ◽  
Olivier Langeron ◽  
Yves Lecarpentier ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Isometric Force ◽  
Left Ventricular ◽  
Inotropic Effect ◽  
Induction Agent ◽  
Dependent Manner ◽  
Rat Myocardium ◽  
Shortening Velocity

Background Eltanolone is a new short-acting intravenous induction agent. However, its effects on intrinsic myocardial contractility remain unknown. Methods The effects of eltanolone and its solvent (soya bean emulsion) on the intrinsic contractility of rat left ventricular papillary muscles were investigated in vitro (Krebs-Henseleit solution, 29 degrees C, pH 7.40, Ca2+ 0.5 mM, stimulation frequency 12 pulses/min). We studied contraction; relaxation; contraction-relaxation coupling under high and low loads; and postrest potentiation. Results Eltanolone (0.1, 0.3, 1, 3, and 10 micrograms.ml-1) induced no significant inotropic effect, as shown by the lack of changes in maximum unloaded shortening velocity and active isometric force. Eltanolone did not significantly modify the contraction-relaxation coupling under low load, suggesting that it did not modify calcium uptake by the sarcoplasmic reticulum. Eltanolone did not significantly modify the contraction-relaxation coupling under high load, suggesting that it did not modify calcium myofilament sensitivity. Eltanolone decreased the postrest potentiation in a concentration-dependent manner (from 150 +/- 14% to 118 +/- 9% at 10 micrograms.ml-1, P < 0.001), suggesting a decrease in the maximum capacity of calcium release by the sarcoplasmic reticulum, whereas its solvent did not. However, eltanolone did not slow postrest potentiation recovery, as shown by the absence of significant changes in the recovery slope, tau (4.5 +/- 1.4 vs. 3.8 +/- 1.0 beats; difference not statistically significant). Conclusions Eltanolone induced no significant inotropic effect on rat myocardium. It induced a decrease in the calcium release function of the sarcoplasmic reticulum, but this effect was not sufficiently important to modify the inotropic properties.

scholarly journals COMPUTATIONAL CHARACTERIZATION OF MUTATIONS IN CARDIAC TROPONIN T KNOWN TO CAUSE FAMILIAL HYPERTROPHIC CARDIOMYOPATHY

2007 ◽  
Vol 06 (03) ◽  
pp. 413-419 ◽  
Author(s):  
PIA J. GUINTO ◽  
EDWARD P. MANNING ◽  
STEVEN D. SCHWARTZ ◽  
JIL C. TARDIFF
Keyword(s):  
Protein Interactions ◽  
Cardiac Troponin ◽  
Thin Filament ◽  
Troponin T ◽  
Structural Data ◽  
Md Simulations ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cardiac Troponin T ◽  
Tail Domain ◽  
Mutation Site

Cardiac Troponin T (cTnT) is a central modulator of thin filament regulation of myofilament activation. The lack of structural data for the TNT1 tail domain, a proposed α-helical region, makes the functional implications of the FHC mutations difficult to determine. Studies have suggested that flexibility of TNT1 is important in normal protein–protein interactions within the thin filament. Our groups have previously shown through molecular dynamics (MD) simulations that some FHC mutations, Arg92Leu (R92L) and Arg92Trp (R92W), result in increased flexibility at a critical hinge region 18 Angstroms distant from the mutation. To explain this distant effect and its implications for FHC mutations, we characterized the dynamics of wild type and mutational segments of cTnT using MD. Our data shows an opening of the helix between residues 105–110 in mutants. Consequently, the dihedral angles of these residues correspond to non-α-helical regions on Ramachandran plots. We hypothesize the removal of a charged residue decreases electrostatic repulsion between the point mutation and the surrounding residues resulting in local helical compaction. Constrained ends of the helix and localized compaction result in expansion within the nearest non-charged helical turn from the mutation site, residues 105–109.

scholarly journals Bisphenol S rapidly depresses heart function through estrogen receptor-β and decreases phospholamban phosphorylation in a sex-dependent manner

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Melissa Ferguson ◽  
Ilka Lorenzen-Schmidt ◽  
W. Glen Pyle
Keyword(s):  
Troponin I ◽  
Heart Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Partial Replacement ◽  
Dependent Manner ◽  
Bisphenol S ◽  
Ventricular Systolic Pressure ◽  
Cardiac Myofilament ◽  
Phospholamban Phosphorylation

Abstract The health effects of the endocrine disruptor Bisphenol A (BPA) led to its partial replacement with Bisphenol S (BPS) in several products including food containers, toys, and thermal paper receipts. The acute effects of BPS on myocardial contractility are unknown. We perfused mouse hearts from both sexes for 15 min with physiologically relevant doses of BPS or BPA. In females BPS (1 nM) decreased left ventricular systolic pressure by 5 min, whereas BPA (1 nM) effects were delayed to 10 min. BPS effects in male mice were attenuated. In both sexes ER-β antagonism abolished the effects of BPS. Cardiac myofilament function was not impacted by BPS or BPA in either sex, although there were sex-dependent differences in troponin I phosphorylation. BPS increased phospholamban phosphorylation at S16 only in female hearts, whereas BPA reduced phosphorylation in both sexes. BPA decreased phospholamban phosphorylation at T17 in both sexes while BPS caused dephosphorylation only in females. This is the first study to compare sex differences in the acute myocardial response to physiologically relevant levels of BPS and BPA, and demonstrates a rapid ability of both to depress heart function. This study raises concerns about the safety of BPS as a replacement for BPA.

scholarly journals Calcium sensitivity of residual force enhancement in rabbit skinned fibers

2014 ◽  
Vol 307 (4) ◽  
pp. C395-C401 ◽  
Author(s):  
V. Joumaa ◽  
W. Herzog
Keyword(s):  
Lattice Spacing ◽  
Sarcomere Length ◽  
Isometric Force ◽  
Calcium Sensitivity ◽  
Skinned Fibers ◽  
Passive Force ◽  
Force Enhancement ◽  
Osmotic Compression ◽  
Residual Force ◽  
Residual Force Enhancement

Isometric force after active stretch of muscles is higher than the purely isometric force at the corresponding length. This property is termed residual force enhancement. Active force in skeletal muscle depends on calcium attachment characteristics to the regulatory proteins. Passive force has been shown to influence calcium attachment characteristics, specifically the sarcomere length dependence of calcium sensitivity. Since one of the mechanisms proposed to explain residual force enhancement is the increase in passive force that results from engagement of titin upon activation and stretch, our aim was to test if calcium sensitivity of residual force enhancement was different from that of its corresponding purely isometric contraction and if such a difference was related to the molecular spring titin. Force-pCa curves were established in rabbit psoas skinned fibers for reference and residual force-enhanced states at a sarcomere length of 3.0 μm 1) in a titin-intact condition, 2) after treatment with trypsin to partially eliminate titin, and 3) after treatment with trypsin and osmotic compression with dextran T-500 to decrease the lattice spacing in the absence of titin. The force-pCa curves of residual force enhancement were shifted to the left compared with their corresponding controls in titin-intact fibers, indicating increased calcium sensitivity. No difference in calcium sensitivity was observed between reference and residual force-enhanced contractions in trypsin-treated and osmotically compressed trypsin-treated fibers. Furthermore, calcium sensitivity after osmotic compression was lower than that observed for residual force enhancement in titin-intact skinned fibers. These results suggest that titin-based passive force regulates the increase in calcium sensitivity of residual force enhancement by a mechanism other than reduction of the myofilament lattice spacing.

scholarly journals Effects of irbesartan on phenotypic alterations in monocytes and the inflammatory status of hypertensive patients with left ventricular hypertrophy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingsi Zhang ◽  
Lina Yang ◽  
Yanchun Ding
Keyword(s):  
Ventricular Hypertrophy ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Left Ventricular ◽  
Target Organ ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Hypertensive Patients ◽  
Inflammatory Status ◽  
Tnf Α

Abstract Background Circulating monocytes and tissue macrophages play complex roles in the pathogenesis of hypertension and the resulting target organ damage. In this study, we observed alterations in the monocyte phenotype and inflammatory state of hypertensive patients with left ventricular hypertrophy (LVH) and studied the effects of irbesartan in these patients. This study might reveal a novel mechanism by which irbesartan alleviates LVH, and it could provide new targets for the prevention and treatment of hypertensive target organ damage. Methods CD163 and CD206 expression on monocytes and IL-10 and TNF-α levels in the serum of hypertensive patients with or without LVH and of healthy volunteers were detected. Furthermore, we treated monocytes from the LVH group with different concentrations of irbesartan, and then, CD163, CD206, IL-10 and TNF-α expression was detected. Results We found, for the first time, that the expression of CD163, CD206 and IL-10 in the LVH group was lower than that in the non-LVH group and healthy control group, but the TNF-α level in the LVH group was significantly higher. Irbesartan upregulated the expression of CD163 and CD206 in hypertensive patients with LVH in a concentration-dependent manner. Irbesartan also increased the expression of IL-10 and inhibited the expression of TNF-α in monocyte culture supernatants in a concentration-dependent manner. Conclusions Our data suggest that inflammation was activated in hypertensive patients with LVH and that the monocyte phenotype was mainly proinflammatory. The expression of proinflammatory factors increased while the expression of anti-inflammatory factors decreased. Irbesartan could alter the monocyte phenotype and inflammatory status in hypertensive patients with LVH. This previously unknown mechanism may explain how irbesartan alleviates LVH. Trail registration The study protocols were approved by the Ethical Committee of the Second Affiliated Hospital of Dalian Medical University. Each patient signed the informed consent form.

scholarly journals Cardiovascular magnetic resonance demonstrates structural cardiac changes following transjugular intrahepatic portosystemic shunt

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ulf K. Radunski ◽  
Johannes Kluwe ◽  
Malte Klein ◽  
Antonio Galante ◽  
Gunnar K. Lund ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Cardiovascular Magnetic Resonance ◽  
Magnetic Resonance ◽  
Transjugular Intrahepatic Portosystemic Shunt ◽  
Troponin T ◽  
Left Ventricular ◽  
Portosystemic Shunt ◽  
Native T1 ◽  
Intrahepatic Portosystemic Shunt

AbstractTransjugular intrahepatic portosystemic shunt (TIPS) reduces portal hypertension in patients with liver cirrhosis. The exact cardiac consequences of subsequent increase of central blood volume are unknown. Cardiovascular magnetic resonance (CMR) imaging is the method of choice for quantifying cardiac volumes and ventricular function. The aim of this study was to investigate effects of TIPS on the heart using CMR, laboratory, and imaging cardiac biomarkers. 34 consecutive patients with liver cirrhosis were evaluated for TIPS. Comprehensive CMR with native T1 mapping, transthoracic echocardiography, and laboratory biomarkers were assessed before and after TIPS insertion. Follow-up (FU) CMR was obtained in 16 patients (47%) 207 (170–245) days after TIPS. From baseline (BL) to FU, a significant increase of all indexed cardiac chamber volumes was observed (all P < 0.05). Left ventricular (LV) end-diastolic mass index increased significantly from 45 (38–51) to 65 (51–73) g/m2 (P =  < 0.01). Biventricular systolic function, NT-proBNP, high-sensitive troponin T, and native T1 time did not differ significantly from BL to FU. No patient experienced cardiac decompensation following TIPS. In conclusion, in patients without clinically significant prior heart disease, increased cardiac preload after TIPS resulted in increased volumes of all cardiac chambers and eccentric LV hypertrophy, without leading to cardiac impairment during follow-up in this selected patient population.

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