scholarly journals Cardiac muscle disease and therapeutic targets

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Maike Schuldt ◽  
Larissa Dorsch ◽  
Diederik Kuster ◽  
Jolanda Van der Velden
Keyword(s):  
Gene Mutation ◽  
Troponin T ◽  
Calcium Sensitivity ◽  
Cardiac Performance ◽  
Muscle Disease ◽  
Specific Gene ◽  
Tissue Samples ◽  
Mutation Carriers ◽  
Myofilament Calcium Sensitivity

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ∼50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, SMP), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, SMN). Gene mutations are most often present in genes encoding the sarcomere proteins myosin heavy chain, myosin-binding protein C, and troponin T. Studies in cardiac tissue samples from patients with obstructive HCM that were obtained during myectomy surgery showed increased myofilament calcium sensitivity, increased kinetics and tension cost, and a reduction of the super-relaxed state of myosin, which is associated with an energy-conserving status of the crossbridges. The increase in myofilament calcium sensitivity is observed at a low dose of mutant protein, while the magnitude of the increase in calcium sensitivity depends on the specific mutation location. These mutation-mediated myofilament changes may underlie inefficient in vivo cardiac performance in mutation carriers. Reduced cardiac efficiency has been observed before onset of cardiac hypertrophy and at advanced disease stages. In addition, impaired diastolic function is an early disease characteristic of HCM. Our recent proteomics studies revealed increased detyrosination of microtubules, which may be a cause of diastolic dysfunction. Recent treatments that target inefficient cardiac performance, such as myosin inhibitors and metabolic drug therapies, may have the potential to prevent, delay, or even reverse disease in HCM-mutation carriers. Treatment response may depend on the specific gene mutation in SMP individuals and may explain diverse response of HCM patients to therapy. While mutation-mediated cardiomyocyte defects have become clear in past years, more research is warranted to define the cellular pathomechanisms of cardiac dysfunction in SMN patients.

Association of hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1655-1657 ◽  
Author(s):  
Claudio Graziano ◽  
Simona Carone ◽  
Emanuele Panza ◽  
Flora Marino ◽  
Pamela Magini ◽  
...  
Keyword(s):  
Human Development ◽  
Gene Mutation ◽  
Autosomal Dominant ◽  
Specific Gene ◽  
Autosomal Dominant Disorder ◽  
Distal Limb ◽  
Limb Defects ◽  
First Report

Abstract Hereditary thrombocythemia is a rare autosomal dominant disorder caused by mutations in either the thrombopoietin gene (TPO) or its receptor c-MPL. TPO mutations described so far lead to thrombopoietin overproduction through increased translation of m-RNA. Unilateral transverse reduction limb defects are usually sporadic and generally thought to be caused by vascular disruptions. Reports of inherited unilateral limb defects are extremely rare. In the present study, we describe a family with segregation of G185T TPO mutation in the 5′ UTR region in 4 subjects with thrombocythemia. Three of these patients also present congenital transverse limb defects. Association of these events gives a strong hint of the in vivo involvement of thrombopoietin in vasculogenesis, confirming the role of TPO in human development of the hemangioblast, the embryonic progenitor of the hematopoietic and endothelial lineages. This is the first report showing that vascular disruptions could be secondary to specific gene derangements.

scholarly journals Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity

2010 ◽  
Vol 31 (3) ◽  
pp. 227-239 ◽  
Author(s):  
Ganapathy Jagatheesan ◽  
Sudarsan Rajan ◽  
Rafeeq P. H. Ahmed ◽  
Natalia Petrashevskaya ◽  
Greg Boivin ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Calcium Sensitivity ◽  
Cardiac Performance ◽  
Tropomyosin Isoforms ◽  
Muscle Tropomyosin ◽  
Myofilament Calcium Sensitivity

Abstract 197: Determining the Potential Role of cTnT Isoform Switching In the Development of Early Childhood Tropomyosin-Linked DCM

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Melissa Lynn ◽  
Lauren Tal-Grinspan ◽  
J.P. Jin ◽  
Jil Tardiff
Keyword(s):  
Clinical Management ◽  
Troponin T ◽  
Systolic Function ◽  
Phenotypic Variability ◽  
Calcium Sensitivity ◽  
Maximal Velocity ◽  
Isoform Switching

An oft-noted component of sarcomeric HCM and DCM is the observation that patients within families, carrying the same primary mutation, often exhibit significant phenotypic variability. This lack of a distinct link between genotype and phenotype has greatly complicated clinical management. In a recent study of two large unrelated multigenerational families carrying the tropomyosin (Tm) mutation Asp230Asn (D230N), a striking “bimodal” distribution of severity was observed. In these families, many children (<1 year) with the mutation presented with a severe form of DCM that led to sudden, often fatal congestive heart failure, while adults developed a mild to moderate DCM in mid-life. Of note, children who survived the initial presentation often recovered significant systolic function in adolescence and young adulthood. Therefore, to better understand the mechanism of this “bimodal” phenotype, we began to investigate the potential modulating role of isoform switching by other sarcomeric components. We hypothesize that the age-dependent remodeling seen in children with D230N Tm is a result of temporal isoform switches involving a closely linked Tm binding partner cardiac Troponin T (cTnT). Initial biophysical studies (circular dichroism and regulated in vitro motility, R-IVM) show that while D230N does not alter Tm’s thermal stability it does have a profound impact on myofilament activation. Both maximal velocity of filament sliding and calcium sensitivity were decreased. Furthermore, an additive decrease was observed in these parameters for R-IVM solutions containing cTnT 1 (fetal)+D230N Tm filaments as compared to cTnT 3 (adult)+D230N. Preliminary in vivo studies utilizing our novel double transgenic Tm-D230N x cTnT 1 mice show profound changes in wall thickness and chamber dilation, as compared to age-matched non-transgenic mice and D230N Tm mice. Further studies aim to model the “bimodal” clinical phenotype seen in families with D230N Tm and assess the potential for disease reversibility using a cardiac specific inducible cTnT 1 transgenic mouse model. Our goal is to use a translational approach to better understand the mechanism by which primary mutations lead to distinct clinical phenotypes in order to improve clinical management.

scholarly journals Effects of anesthetic agents on contractions of the pregnant rat myometrium in vivo and in vitro

2020 ◽  
Author(s):  
Motonobu Kimizuka ◽  
Yasuyuki Tokinaga ◽  
Ryu Azumaguchi ◽  
Kosuke Hamada ◽  
Satoshi Kazuma ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Calcium Sensitivity ◽  
Contraction Force ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Anesthetic Agents ◽  
Frequency Changes ◽  
Myofilament Calcium Sensitivity

Abstract Background Several anesthetic agents are used in cesarean sections for both regional and general anesthesia purposes. However, there are no data comparing the in vivo effects of propofol, sevoflurane, and dexmedetomidine on the contraction of the myometrium in pregnant rats. The aim of this study was to investigate the effect of these anesthetic agents on myometrial contraction and elucidate the underlying mechanisms. Methods Contraction force and frequency changes in response to propofol, dexmedetomidine, or sevoflurane were evaluated in vivo and in vitro. To test the effect of arachidonic acid on myometrial contraction enhanced by dexmedetomidine, changes in myometrial contraction with dexmedetomidine after administration of indomethacin were evaluated. The amount of phosphorylated myosin phosphatase target subunit 1 (MYPT1) in the membrane fraction was expressed as a percentage of the total fraction by Western blot analysis. Results This study demonstrated that dexmedetomidine enhances oxytocin-induced contraction in the myometrium of pregnant rats, whereas propofol and sevoflurane attenuate these contractions. The dexmedetomidine-induced enhancement of myometrial contraction force was abolished by the administration of indomethacin. Propofol did not affect oxytocin-induced MYPT1 phosphorylation, whereas sevoflurane attenuated oxytocin-induced MYPT1 phosphorylation. Conclusions Inhibition of myofilament calcium sensitivity may underlie the inhibition of myometrial contraction induced by sevoflurane. Arachidonic acid may play an important role in the enhancement of myometrial contraction induced by dexmedetomidine by increasing myofilament calcium sensitivity. Dexmedetomidine may be used as a sedative agent to promote uterine muscle contraction and suppress bleeding after fetal delivery.

scholarly journals Role of Exercise as a Modulating Factor in Arrhythmogenic Cardiomyopathy

2021 ◽  
Vol 23 (6) ◽  
Author(s):  
Alessandro Zorzi ◽  
Alberto Cipriani ◽  
Riccardo Bariani ◽  
Kalliopi Pilichou ◽  
Domenico Corrado ◽  
...  
Keyword(s):  
Physical Activity ◽  
Gene Mutation ◽  
Ventricular Arrhythmias ◽  
Muscle Disease ◽  
Moderate Intensity ◽  
Moderate Physical Activity ◽  
Fatty Tissue ◽  
Arrhythmogenic Cardiomyopathy ◽  
Mutation Carriers

Abstract Purpose of Review The review addresses the role of exercise in triggering ventricular arrhythmias and promoting disease progression in arrhythmogenic cardiomyopathy (AC) patients and gene-mutation carriers, the differential diagnosis between AC and athlete’s heart and current recommendations on exercise activity in AC. Recent Findings AC is an inherited heart muscle disease caused by genetically defective cell-to-cell adhesion structures (mainly desmosomes). The pathophysiological hallmark of the disease is progressive myocyte loss and replacement by fibro-fatty tissue, which creates the substrates for ventricular arrhythmias. Animal and human studies demonstrated that intense exercise, but not moderate physical activity, may increase disease penetrance, worsen the phenotype, and favor life-threatening ventricular arrhythmias. It has been proposed that in some individuals prolonged endurance sports activity may in itself cause AC (so-called exercise-induced AC). Summary The studies agree that intense physical activity should be avoided in patients with AC and healthy gene-mutation carriers. However, low-to-moderate intensity exercise does not appear detrimental and these patients should not be entirely deprived from the many health benefits of physical activity.

scholarly journals In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers

2014 ◽  
Vol 29 (9) ◽  
pp. 1197-1201 ◽  
Author(s):  
Andre C. Felicio ◽  
Katherine Dinelle ◽  
Pankaj A. Agarwal ◽  
Jessamyn McKenzie ◽  
Nicole Heffernan ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Mutation Carriers ◽  
Serotonergic Dysfunction

scholarly journals Myofilament Calcium Sensitivity: Role in Regulation of In vivo Cardiac Contraction and Relaxation

2016 ◽  
Vol 7 ◽  
Author(s):  
Jae-Hoon Chung ◽  
Brandon J. Biesiadecki ◽  
Mark T. Ziolo ◽  
Jonathan P. Davis ◽  
Paul M. L. Janssen
Keyword(s):  
Calcium Sensitivity ◽  
Cardiac Contraction ◽  
Contraction And Relaxation ◽  
Myofilament Calcium Sensitivity

scholarly journals Pathogenic peptide deviations support a model of adaptive evolution of chordate cardiac performance by troponin mutations

2010 ◽  
Vol 42 (2) ◽  
pp. 287-299 ◽  
Author(s):  
Nathan J. Palpant ◽  
Evelyne M. Houang ◽  
Wayne Delport ◽  
Kenneth E. M. Hastings ◽  
Alexey V. Onufriev ◽  
...  
Keyword(s):  
Large Scale ◽  
Troponin I ◽  
Calcium Sensitivity ◽  
Cardiac Performance ◽  
Computational Alanine Scanning ◽  
Dynamics Simulations ◽  
Contraction And Relaxation ◽  
Myofilament Calcium Sensitivity ◽  
Simulations And Modeling ◽  
Increased Susceptibility

In cardiac muscle, the troponin (cTn) complex is a key regulator of myofilament calcium sensitivity because it serves as a molecular switch required for translating myocyte calcium fluxes into sarcomeric contraction and relaxation. Studies of several species suggest that ectotherm chordates have myofilaments with heightened calcium responsiveness. However, genetic polymorphisms in cTn that cause increased myofilament sensitivity to activating calcium in mammals result in cardiac disease including arrhythmias, diastolic dysfunction, and increased susceptibility to sudden cardiac death. We hypothesized that specific residue modifications in the regulatory arm of troponin I (TnI) were critical in mediating the observed decrease in myofilament calcium sensitivity within the mammalian taxa. We performed large-scale phylogenetic analysis, atomic resolution molecular dynamics simulations and modeling, and computational alanine scanning. This study provides evidence that a His to Ala substitution within mammalian cardiac TnI (cTnI) reduced the thermodynamic potential at the interface between cTnI and cardiac TnC (cTnC) in the calcium-saturated state by disrupting a strong intermolecular electrostatic interaction. This key residue modification reduced myofilament calcium sensitivity by making cTnI molecularly untethered from cTnC. To meet the requirements for refined mammalian adult cardiac performance, we propose that compensatory evolutionary pressures favored mutations that enhanced the relaxation properties of cTn by decreasing its sensitivity to activating calcium.

Biomedical applications: Pitfalls in the practice

1994 ◽  
Vol 52 ◽  
pp. 378-379
Author(s):  
J. D. Shelburne ◽  
Peter Ingram ◽  
Victor L. Roggli ◽  
Ann LeFurgey
Keyword(s):  
Operating Room ◽  
Liquid Nitrogen ◽  
Lung Tissue ◽  
Biomedical Applications ◽  
Microprobe Analysis ◽  
Tissue Sample ◽  
Cellular Level ◽  
Tissue Samples ◽  
Asbestos Fibers

At present most medical microprobe analysis is conducted on insoluble particulates such as asbestos fibers in lung tissue. Cryotechniques are not necessary for this type of specimen. Insoluble particulates can be processed conventionally. Nevertheless, it is important to emphasize that conventional processing is unacceptable for specimens in which electrolyte distributions in tissues are sought. It is necessary to flash-freeze in order to preserve the integrity of electrolyte distributions at the subcellular and cellular level. Ideally, biopsies should be flash-frozen in the operating room rather than being frozen several minutes later in a histology laboratory. Electrolytes will move during such a long delay. While flammable cryogens such as propane obviously cannot be used in an operating room, liquid nitrogen-cooled slam-freezing devices or guns may be permitted, and are the best way to achieve an artifact-free, accurate tissue sample which truly reflects the in vivo state. Unfortunately, the importance of cryofixation is often not understood. Investigators bring tissue samples fixed in glutaraldehyde to a microprobe laboratory with a request for microprobe analysis for electrolytes.

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