Current understanding of fibrosis in genetic cardiomyopathies

Eijgenraam, Tim R.; Silljé, Herman H W; Boer, Rudolf A. de

doi:10.1016/j.tcm.2019.09.003

Cited by 58 publications

(48 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In 2021 we expect the results of the PHOspholamban RElated CArdiomyopathy STudy -Intervention (i-PHORECAST; ClinicalTrials.gov NCT01857856). As myocardial fibrosis is considered to be an early disease manifestation in this cardiomyopathy 7,11,14 , the i-PHORECAST study aims to test the efficacy of the mineralocorticoid receptor antagonist (MRA) eplerenone, which has been shown to exert anti-fibrotic effects 15 , in reducing disease progression or postponing onset of overt disease in asymptomatic mutation carriers.…”

mentioning

confidence: 99%

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

Eijgenraam

Boukens

Boogerd

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.

show abstract

mentioning

confidence: 99%

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

Eijgenraam

Boukens

Boogerd

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Groupmentioning

confidence: 99%

“…The cardiac anatomophysiology results evaluated by echocardiography indicated that hypertrophic cardiomyopathy, characterized by the posterior wall and septum thickness [70], was the only alteration that pBCSSP4 immunotherapy was not able to prevent; however, the treatment was able to prevent other abnormalities that compromise not only the anatomy of the heart but also its functionality. Despite the presence of hypertrophic cardiomyopathy, fibrosis in myocardial tissue was not observed when performing the histological analysis, which is characteristic of many chronic diseases, including Chagas disease [70]. There were differences in the diastolic and systolic diameters when comparing the infected/SS mock-treated group and healthy group; and these results are not consistent with similar measurements performed by others who used young mongrel dogs infected with VL-10 strain of T. cruzi and did not find differences in the end-diastolic and end-systolic volumes when comparing infected and noninfected dogs [71].…”

Section: Groupmentioning

confidence: 99%

DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi

Arce-Fonseca

Carbajal-Hernández

Lozano-Camacho

et al. 2020

Journal of Immunology Research

View full text Add to dashboard Cite

Chagas disease is a chronic and potentially lethal disorder caused by the parasite Trypanosoma cruzi, and an effective treatment has not been developed for chronic Chagas disease. The objective of this study was to determine the effectiveness of a therapeutic DNA vaccine containing T. cruzi genes in dogs with experimentally induced Chagas disease through clinical, pathological, and immunological analyses. Infection of Beagle dogs with the H8 T. cruzi strain was performed intraperitoneally with 3500 metacyclic trypomastigotes/kg body weight. Two weeks after infection, plasmid DNA immunotherapy was administered thrice at 15-day intervals. The clinical (physical and cabinet studies), immunological (antibody and cytokine profiles and lymphoproliferation), and macro- and microscopic pathological findings were described. A significant increase in IgG and cell proliferation was recorded after immunotherapy, and the highest stimulation index (3.02) was observed in dogs treated with the pBCSSP4 plasmid. The second treatment with both plasmids induced an increase in IL-1, and the third treatment with the pBCSSP4 plasmid induced an increase in IL-6. The pBCSP plasmid had a good Th1 response regulated by high levels of IFN-gamma and TNF-alpha, whereas the combination of the two plasmids did not have a synergistic effect. Electrocardiographic studies registered lower abnormalities and the lowest number of individuals with abnormalities in each group treated with the therapeutic vaccine. Echocardiograms showed that the pBCSSP4 plasmid immunotherapy preserved cardiac structure and function to a greater extent and prevented cardiomegaly. The two plasmids alone controlled the infection moderately by a reduction in the inflammatory infiltrates in heart tissue. The immunotherapy was able to reduce the magnitude of cardiac lesions and modulate the cellular immune response; the pBCSP treatment showed a clear Th1 response; and pBCSSP4 induced a balanced Th1/Th2 immune response that prevented severe cardiac involvement. The pBCSSP4 plasmid had a better effect on most of the parameters evaluated in this study; therefore, this plasmid can be considered an optional treatment against Chagas disease in naturally infected dogs.

show abstract

“…Myocardial brosis is characterized by an excessive deposition of extracellular matrix proteins in the heart. Although brosis formation is initially reparative, on-going and excessive myocardial brosis in the long term may lead to arrhythmia, cardiac wall stiffening, and subsequently heart failure [7]. High salt diet (HSD) can induce hypertension and cardiac remodeling in Dahl salt-sensitive rats [8].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-210-5p Alleviates Cardiac Fibrosis via Targeting Transforming Growth Factor-beta Type I Receptor in Rats on High Salt Diet

Zhao¹,

Mao²,

Ye³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: The aim of the present study was to explore whether high salt diet (HSD) caused cardiac fibrosis regardless of blood pressure in rats, and to determine the effects of microRNA (miR)-210-5p on sodium chloride (NaCl)-induced fibrosis in neonatal rat cardiac fibroblasts (NRCFs) and its target. Methods: The rats received 8% HSD in vivo, and NRCFs were treated with NaCl in vitro. Results: The levels of collagen I, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) were increased in the heart of hypertension (HTN), hypertension-prone (HP) and hypertension-resistant (HR) rats on HSD. Middle and high doses (50 mM and 100 mM) of NaCl increased the levels of collagen I, α-SMA and TGF-β in NRCFs. The expression level of miR-210-5p was reduced in NaCl-treated NRCFs by miR high-throughput sequencing. The NaCl-induced increases of collagen I, α-SMA and TGF-β were inhibited by miR-210-5p agomiR, and further enhanced by miR-210-5p antagomiR. Bioinformatics analysis and luciferase reporter assays demonstrated that TGF-β type I receptor (TGFβRI) was a direct target gene of miR-210-5p. These results indicated that HSD resulted in cardiac fibrosis regardless of blood pressure. Conclusion: The upregulation of miR-210-5p could attenuate NRCF fibrosis via targeting TGFβRI. Thus, upregulating miR-210-5p to inhibit TGF-β signaling pathway might be a strategy for the treatment of cardiac fibrosis.

show abstract

Current understanding of fibrosis in genetic cardiomyopathies

Cited by 58 publications

References 82 publications

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi

MicroRNA-210-5p Alleviates Cardiac Fibrosis via Targeting Transforming Growth Factor-beta Type I Receptor in Rats on High Salt Diet

Contact Info

Product

Resources

About

Current understanding of fibrosis in genetic cardiomyopathies

Cited by 58 publications

References 82 publications

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi

MicroRNA-210-5p&nbsp;Alleviates Cardiac Fibrosis via Targeting Transforming Growth Factor-beta Type I Receptor in Rats on High Salt Diet

Contact Info

Product

Resources

About

MicroRNA-210-5p Alleviates Cardiac Fibrosis via Targeting Transforming Growth Factor-beta Type I Receptor in Rats on High Salt Diet