Depressed Frank–Starling mechanism in the left ventricular muscle of the knock-in mouse model of dilated cardiomyopathy with troponin T deletion mutation ΔK210

2013 ◽  
Vol 63 ◽  
pp. 69-78 ◽  
Author(s):  
Takahiro Inoue ◽  
Fuyu Kobirumaki-Shimozawa ◽  
Tatsuya Kagemoto ◽  
Teruyuki Fujii ◽  
Takako Terui ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dilated Cardiomyopathy ◽  
Troponin T ◽  
Left Ventricular ◽  
Deletion Mutation ◽  
Ventricular Muscle

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 Use of Cardiac Biomarkers for Monitoring Improvement of Left Ventricular Function by Immunoadsorption Treatment in Dilated Cardiomyopathy

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 654
Author(s):  
Weinmann ◽  
Werner ◽  
Koenig ◽  
Rottbauer ◽  
Walcher ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Troponin I ◽  
Troponin T ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Lv Function ◽  
Long Term Follow Up ◽  
Acute Changes

Immunoadsorption and subsequent administration of intravenous immunoglobulin (IVIG) have shown beneficial effects on cardiac function and symptoms in patients with dilated cardiomyopathy. Biomarkers play an emerging role in disease monitoring and outcome prediction of heart failure (HF) patients. We aimed to analyze cardiac biomarkers as predictor for improvement of left ventricular (LV) function after immunoadsorption treatment in dilated cardiomyopathy (DCM). Thirty-one patients with dilated cardiomyopathy on optimized HF pharmacotherapy received a single cycle of immunoadsorption for five days followed by IVIG administration. Left ventricular ejection fraction (LVEF) and heart failure biomarkers (hs troponin T, hs troponin I, NT-proBNP and sST2) were evaluated before treatment, after the last cycle of immunoadsorption and during a median follow-up of 30.5 months. We correlated HF biomarkers before immunoadsorption and acute changes of HF biomarkers by immunoadsorption with LV improvement during the long-term follow-up. LV function improved significantly after immunoadsorption from 28.0 to 42.0% during the long-term follow-up (p < 0.0001). Evaluation of biomarker levels showed a significant decrease for hs troponin I (from 9.2 to 5.5 ng/L, p < 0.05) and NT-proBNP (from 789.6 to 281.2 pg/mL, p < 0.005). Correlation of biomarker levels before immunoadsorption and LVEF at the long-term follow-up show good results for hs troponin T (r = −0.40, r2 = 0.16, p < 0.05), hs troponin I (r = −0.41, r2 = 0.17, p < 0.05) and sST2 (r = −0.46, r2 = 0.19, p < 0.05). Correlation of biomarker levels before immunoadsorption and the individual increase in LV function was significant for hs troponin T (r = −0.52, r2 = 0.27, p < 0.005) and hs troponin I (r = −0.53, r2 = 0.29, p < 0.005). To imply a tool for monitoring outcome immediately after immunoadsorption treatment, we investigated the correlation of acute changes of biomarker levels by immunoadsorption treatment and individual increase in LV function. A drop in hs troponin T (r = −0.41, r2 = 0.17, p < 0.05) and hs troponin I (r = −0.53, r2 = 0.28, p < 0.005) levels demonstrate a good correlation to improvement in LVEF during the long-term follow-up. Conclusion: Hs troponin T and I levels correlate with LV function improvement during long-term follow-up. Acute decrease of troponins by immunoadsorption treatment is paralleled by individual improvement of LVEF at the long-term follow-up. Thus, troponins could serve as a monitoring tool for the improvement of LV function after immunoadsorption treatment in dilated cardiomyopathy.

A novel β-myosin heavy chain gene mutation, p.Met531Arg, identified in isolated left ventricular non-compaction in humans, results in left ventricular hypertrophy that progresses to dilation in a mouse model

2008 ◽  
Vol 114 (6) ◽  
pp. 431-440 ◽  
Author(s):  
Tomoya Kaneda ◽  
Chie Naruse ◽  
Atsuhiro Kawashima ◽  
Noboru Fujino ◽  
Toru Oshima ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Dilated Cardiomyopathy ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Chain Gene ◽  
The Novel ◽  
Sarcomeric Protein

Mutations in the βMHC (β-myosin heavy chain), a sarcomeric protein are responsible for hypertrophic and dilated cardiomyopathy. However, the mechanisms whereby distinct mutations in the βMHC gene cause two kinds of cardiomyopathy are still unclear. In the present study we report a novel βMHC mutation found in a patient with isolated LVNC [LV (left ventricular) non-compaction] and the phenotype of a mouse mutant model carrying the same mutation. To find the mutation responsible, we searched for genomic mutations in 99 unrelated probands with dilated cardiomyopathy and five probands with isolated LVNC, and identified a p.Met531Arg mutation in βMHC in a 13-year-old girl with isolated LVNC. Next, we generated six lines of transgenic mice carrying a p.Met532Arg mutant αMHC gene, which was identical with the p.Met531Arg mutation in the human βMHC. Among these, two lines with strong expression of the mutant αMHC gene were chosen for further studies. Although they did not exhibit the features characteristic of LVNC, approx. 50% and 70% of transgenic mice in each line displayed LVH (LV hypertrophy) by 2–3 months of age. Furthermore, LVD (LV dilation) developed in approx. 25% of transgenic mice by 18 months of age, demonstrating biphasic changes in LV wall thickness. The present study supports the idea that common mechanisms may be involved in LVH and LVD. The novel mouse model generated can provide important information for the understanding of the pathological processes and aetiology of cardiac dilation in humans.

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 Titin-Related Dilated Cardiomyopathy: The Sequence of Events and The Role of Circulating Biomarkers in The Clinical Assessment

2021 ◽  
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 ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Sequence Of Events

Abstract Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, the clinical course is not fully understood and it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment. We sought to assess: 1) early signs of cardiotitinopathy including 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) indicators of outcome among TTNtv carriers. Our single-centre cohort included 108 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 2nd, 3rd and 4th decade of life, respectively. It was followed by symptoms of heart failure and elevation of NT-proBNP, linked to severe (persistent or transient) left ventricular systolic dysfunction, and later by arrhythmias, preceding both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF). Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years both MVA and esHF occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/ml was the best predictor of both composite endpoint (MVA and esHF), and of MVA alone. We conclude that assessment of circulating cardiac biomarkers is not useful in the detection of cardiotitinopathies but may be helpful in the risk assessment.

Abstract 1252: A Mouse Model of a Familial Dilated Cardiomyopathy Mutation in Titin Recapitulates the Human Phenotype

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Michael Gramlich ◽  
Beate Michely ◽  
Brenda Gerull ◽  
Christian Krohne ◽  
Ingo Morano ◽  
...  
Keyword(s):  
Mouse Model ◽  
Western Blot ◽  
Dilated Cardiomyopathy ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Autosomal Dominant ◽  
Premature Stop Codon ◽  
Left Ventricular ◽  
Insertion Mutation ◽  
Human Phenotype

Dilated cardiomyopathy (DCM) is the most common form of primary myocardial diseases and the third most common cause of heart failure. Familial occurrence, mostly as an autosomal dominant trait, is responsible for 20 –30% of all DCM cases. We have previously shown that mutations in the giant muscle filament titin ( TTN ) cause dilated cardiomyopathy. In a large DCM kindred (A1) with autosomal dominant inherited DCM, we could identify a 2 bp insertion mutation in exon 326 of TTN . This heterozygous nonsense mutation leads to a framshift generating a premature stop codon after the addition of 4 novel amino acid residues. We have recently evaluated a cardiac biopsy sample from an affected family member of kindred A1 showing that no truncated protein is observed in a western blot analysis. To further investigate the functional consequences of the identified human TTN mutation, we now generated a mouse model that includes the 2bp insertion at the corresponding site in the mouse genome. Heterozygous mice are viable and fertile. As in the human situation, the truncated titin is not detectable in western blot analysis of cardiac tissue indicating haploinsufficiency. The ventricles of the heterozygous animals show a decrease in ventricular stiffness as seen in isolated working heart pressure measurements and transmitral Doppler echocardiography (E:A 1.34 vs. 1.075, p<0.01; IVRT 13.57ms vs. 17.01ms, p<0.05). When exposed to angiotensin II (1.4 mg/kg/d for 14d) as a cardiac stressor, heterozygous animals develop dilatation of the left ventricles (4.45mm vs. 3.77 mm, p<0.05) with impaired fractional shortening (25.12% vs. 32.86%, p<0.01) and a diffuse myocardial fibrosis. Homozygous mice die in utero before E8.0. Whether a defect in the formation of sarcomeres or, alternatively, a defect in yet unknown non-muscle functions of titin account for this early embryonic lethality remains to be determined. Conclusion: Our mouse model shows that a mutation in TTN leads to impaired biomechanical properties of the heart, resulting in left ventricular dilatation and decreased systolic function, thereby recapitulating the human phenotype.

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