Abstract P439: Harnessing Multiscale Models Of A Dilated Cardiomyopathy Mutation For Precision Medicine

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Lina Greenberg ◽  
W. Tom Stump ◽  
Andrea L Bredemeyer ◽  
Kory J Lavine ◽  
Michael J Greenberg
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Precision Medicine ◽  
Thin Filament ◽  
Troponin T ◽  
Molecular Complexes ◽  
Multiscale Approach ◽  
Familial Dilated Cardiomyopathy ◽  
Omecamtiv Mecarbil ◽  
Human Mutation

Familial dilated cardiomyopathy (DCM) is a leading cause of both adult and pediatric heart failure. Currently, there is no cure for DCM, and the 5-year transplant free survival rate is <50%. There is therefore an outstanding need to develop new therapeutics. Prior studies have established a strong genetic basis for DCM and identified causative genetic mutations. These observations provide unique opportunities to apply precision medicine approaches that target and circumvent the effects of deleterious mutations. Here, we used a multiscale approach to study the consequences of a human mutation in troponin T that causes DCM, ΔK210. We found that at the molecular scale ΔK210 changes the positioning of tropomyosin along the thin filament, leading to molecular hypocontractility. Using genome edited human stem cell derived cardiomyocytes heterozygous for the mutation, we show reduced cellular contractility at the single cell and tissue levels. Importantly, we demonstrate that mutant tissues show a reduced Frank-Starling response, increased stiffness, and misaligned myocytes. Based on our molecular mechanism, we hypothesized that treatment of ΔK210 with Omecamtiv Mecarbil (OM), a thin filament activator in clinical trials for heart failure, would improve the function of mutant tissues. We found that treatment of ΔK210 molecular complexes and tissues with OM causes a dose-dependent increase in cardiac function, reversing the mutation-induced contractile defect. Taken together, our study demonstrates how mechanistic molecular studies can be harnessed to identify precision medicine therapeutics.

Biological variation of high sensitive Troponin T in stable heart failure patients with ischemic or dilated cardiomyopathy

2011 ◽  
Vol 100 (8) ◽  
pp. 633-640 ◽  
Author(s):  
Lutz Frankenstein ◽  
Andrew Remppis ◽  
Evangelos Giannitis ◽  
Joerdis Frankenstein ◽  
Georg Hess ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Biological Variation ◽  
Heart Failure Patients ◽  
High Sensitive Troponin

scholarly journals Familial Dilated Cardiomyopathy: Risk Stratification for Sudden Cardiac Death

2020 ◽  
Author(s):  
Gustav Mattsson ◽  
Peter Magnusson
Keyword(s):  
Heart Failure ◽  
Health Care ◽  
Sudden Cardiac Death ◽  
Risk Stratification ◽  
Dilated Cardiomyopathy ◽  
Health Care Providers ◽  
Cardiac Death ◽  
Reduced Ejection Fraction ◽  
Improve Risk Stratification ◽  
Familial Dilated Cardiomyopathy

Heart failure implies a considerable burden for patients and resources for the health care system. Dilated cardiomyopathy is defined as left ventricular dilation and reduced systolic function, not solely explained by ischemic heart disease or abnormal loading conditions. Numerous genes have been identified in familial cases of dilated cardiomyopathy. Heart failure with reduced ejection fraction increases the risk for sudden cardiac death. Implantable cardioverter defibrillator therapy can provide a means of preventing sudden cardiac death in those deemed to be at high risk. Health care providers are in need of better tools in order to improve risk stratification. This chapter aims to provide an overview of the current knowledge about risk of arrhythmia and sudden death in patients with familial dilated cardiomyopathy, in particular for those patients with a specific mutation.

scholarly journals A Troponin T Variant Linked with Pediatric Dilated Cardiomyopathy Reduces the Coupling of Thin Filament Activation to Myosin and Calcium Binding

2021 ◽  
pp. mbc.E21-02-0082
Author(s):  
Samantha K. Barrick ◽  
Lina Greenberg ◽  
Michael J. Greenberg
Keyword(s):  
Dilated Cardiomyopathy ◽  
Calcium Binding ◽  
Thin Filament ◽  
Troponin T ◽  
Calcium Sensitivity ◽  
Cellular Level ◽  
In Vitro Motility Assay ◽  
In Vitro Motility ◽  
Fluorescence Measurements

Dilated cardiomyopathy (DCM) is a significant cause of pediatric heart failure. Mutations in proteins that regulate cardiac muscle contraction can cause DCM; however, the mechanisms by which molecular-level mutations contribute to cellular dysfunction are not well-understood. Better understanding of these mechanisms might enable the development of targeted therapeutics that benefit patient subpopulations with mutations that cause common biophysical defects. We examined the molecular- and cellular-level impacts of a troponin T variant associated with pediatric-onset DCM, R134G. The R134G variant decreased calcium sensitivity in an in vitro motility assay. Using stopped-flow and steady-state fluorescence measurements, we determined the molecular mechanism of the altered calcium sensitivity: R134G decouples calcium binding by troponin from the closed-to-open transition of the thin filament and decreases the cooperativity of myosin binding to regulated thin filaments. Consistent with the prediction that these effects would cause reduced force per sarcomere, cardiomyocytes carrying the R134G mutation are hypocontractile. They also show hallmarks of DCM that lie downstream of the initial insult, including disorganized sarcomeres and cellular hypertrophy. These results reinforce the importance of multiscale studies to fully understand mechanisms underlying human disease and highlight the value of mechanism-based precision medicine approaches for DCM.

scholarly journals Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy

2019 ◽  
Vol 116 (36) ◽  
pp. 17831-17840 ◽  
Author(s):  
Sarah R. Clippinger ◽  
Paige E. Cloonan ◽  
Lina Greenberg ◽  
Melanie Ernst ◽  
W. Tom Stump ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Heart Tissue ◽  
Substrate Stiffness ◽  
Cellular Organization ◽  
Sarcomeric Proteins ◽  
Critical Gap ◽  
Cellular Hypertrophy ◽  
Familial Dilated Cardiomyopathy ◽  
Cellular Phenotypes

Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results help link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.

scholarly journals GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy

2016 ◽  
Vol 310 (11) ◽  
pp. H1808-H1815 ◽  
Author(s):  
Rasha M. S. M. Mohamed ◽  
Sachio Morimoto ◽  
Islam A. A. E.-H. Ibrahim ◽  
Dong-Yun Zhan ◽  
Cheng-Kun Du ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dilated Cardiomyopathy ◽  
Glycogen Synthase ◽  
Troponin T ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Myosin Heavy Chain Isoform ◽  
Familial Dilated Cardiomyopathy ◽  
Gsk 3Β

Glycogen synthase kinase-3β (GSK-3β) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3β in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3β (GSK-3β+/− KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3β+/− KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3β+/− KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac β-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3β+/− KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3β is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.

scholarly journals Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment

Diagnostics ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 13
Author(s):  
Przemysław Chmielewski ◽  
Grażyna Truszkowska ◽  
Ilona Kowalik ◽  
Małgorzata Rydzanicz ◽  
Ewa Michalak ◽  
...  
Keyword(s):  
Heart Failure ◽  
Risk Assessment ◽  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Left Ventricular Systolic Dysfunction ◽  
Multivariable Analysis ◽  
Disease Onset ◽  
Left Ventricular ◽  
Cardiac Biomarkers

Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, it is unclear whether circulating cardiac biomarkers are helpful in detection and risk assessment. We sought to assess 1) early indicators of cardiotitinopathy including the serum biomarkers high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) predictors of outcome among TTNtv carriers. Our single-center cohort consisted of 108 TTNtv carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the second, third and fourth decade of life, respectively. It was followed by symptoms of heart failure, linked to NT-proBNP elevation and severe left ventricular systolic dysfunction, and later by arrhythmias. Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years, both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF) occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/mL was the best predictor of both composite endpoints (MVA and esHF) and of MVA alone. In conclusion, echocardiographic abnormalities are the first detectable anomalies in the course of cardiotitinopathies. The assessment of circulating cardiac biomarkers is not useful in the detection of the disease onset but may be helpful in risk assessment.

scholarly journals Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy

2019 ◽  
Vol 5 (9) ◽  
pp. eaax2066 ◽  
Author(s):  
Rebecca C. Ahrens-Nicklas ◽  
Christopher T. Pappas ◽  
Gerrie P. Farman ◽  
Rachel M. Mayfield ◽  
Tania M. Larrinaga ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Transplantation ◽  
Thin Filament ◽  
Force Production ◽  
Actin Binding ◽  
Isolated Cardiomyocytes ◽  
Thin Filaments ◽  
Familial Dilated Cardiomyopathy ◽  
Filament Assembly ◽  
Explanted Heart

Neonatal heart failure is a rare, poorly-understood presentation of familial dilated cardiomyopathy (DCM). Exome sequencing in a neonate with severe DCM revealed a homozygous nonsense variant in leiomodin 2 (LMOD2, p.Trp398*). Leiomodins (Lmods) are actin-binding proteins that regulate actin filament assembly. While disease-causing mutations in smooth (LMOD1) and skeletal (LMOD3) muscle isoforms have been described, the cardiac (LMOD2) isoform has not been previously associated with human disease. Like our patient, Lmod2-null mice have severe early-onset DCM and die before weaning. The infant’s explanted heart showed extraordinarily short thin filaments with isolated cardiomyocytes displaying a large reduction in maximum calcium-activated force production. The lack of extracardiac symptoms in Lmod2-null mice, and remarkable morphological and functional similarities between the patient and mouse model informed the decision to pursue cardiac transplantation in the patient. To our knowledge, this is the first report of aberrant cardiac thin filament assembly associated with human cardiomyopathy.

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