scholarly journals Viruses in the Heart: Direct and Indirect Routes to Myocarditis and Heart Failure

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1924
Author(s):  
Colton R. Martens ◽  
Federica Accornero
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Viral Infections ◽  
Heart Function ◽  
Viral Myocarditis ◽  
Therapeutic Interventions ◽  
Cardiovascular Risks ◽  
Immune Systems

Viruses are an underappreciated cause of heart failure. Indeed, several types of viral infections carry cardiovascular risks. Understanding shared and unique mechanisms by which each virus compromises heart function is critical to inform on therapeutic interventions. This review describes how the key viruses known to lead to cardiac dysfunction operate. Both direct host-damaging mechanisms and indirect actions on the immune systems are discussed. As viral myocarditis is a key pathologic driver of heart failure in infected individuals, this review also highlights the role of cytokine storms and inflammation in virus-induced cardiomyopathy.

scholarly journals Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Eric D. Abston ◽  
Michael J. Coronado ◽  
Adriana Bucek ◽  
Djahida Bedja ◽  
Jaewook Shin ◽  
...  
Keyword(s):  
Viral Infections ◽  
Heart Function ◽  
Viral Myocarditis ◽  
Alternative Activation ◽  
Toll Like Receptor ◽  
T Helper ◽  
Chronic Myocarditis ◽  
First Time ◽  
Deficient Mice

Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.

Abstract 865: Gata-4 Is An Angiogenic Survival Factor Of The Infarcted Heart

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Olli Tenhunen ◽  
Hanna Leskinen ◽  
Raisa Serpi ◽  
Jaana Rysä ◽  
Harri Pennanen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Gene Transfer ◽  
Dna Binding ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Cardiac Stem Cells

Recent data suggest that the cardiac-restricted transcription factor GATA-4 is an anti-apoptotic factor required for adaptive responses as well as a key regulator of hypertrophy and hypertrophy-associated genes in the heart. As a leading cause of chronic heart failure, reversal of post-infarction left ventricular remodeling represents an important target for therapeutic interventions. Here we studied the role of GATA-4 as a mediator of post-infarction remodeling. Rats were subjected to experimental myocardial infarction (MI) by ligating the left anterior descending coronary artery (LAD). Ligation of the LAD decreased the DNA binding activity of GATA-4 by 69 % at day 1 after MI (P<0.001, n=7– 8) as assessed by gel mobility shift assays. At 2 weeks the GATA-4 DNA binding was significantly upregulated (2.4-fold, P<0.05, n=7), and returned to baseline at 4 weeks. To determine the functional role of GATA-4, rats underwent LAD ligation followed by peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4. Hearts treated with the GATA-4 gene transfer exhibited significantly increased ejection fraction (58±5% vs. 38±3% in LacZ-treated control animals with MI, P<0.001, n=8 –9) and fractional shortening (28±3% vs. 16±1%, P<0.001, n=8 –9) 2 weeks after MI. Accordingly, the infarct size was significantly reduced (26±4% vs. 45±4%, P<0.01, n=8 –9). To determine the cardioprotective mechanisms of GATA-4, the number of cardiac stem cells, apoptotic cardiomyocytes and capillaries were assessed. The number of capillaries (59±4/field vs. 48±3/field, P<0.051, n=7– 8) and c-kit positive stem cells (13±5 cells vs. 4±2 cells, P<0.05, n=7– 8) were increased in GATA-4 treated hearts, and a tendency to decreased apoptosis was observed in TUNEL-stained histological sections. These results indicate that the reversal of reduced GATA-4 activity prevents adverse post-infarction remodeling through increased angiogenesis, recruitment of cardiac stem cells and anti-apoptosis. GATA-4-based gene transfer may represent a novel, efficient therapeutic approach for heart failure.

scholarly journals Emerging Role of Mitophagy in the Heart: Therapeutic Potentials to Modulate Mitophagy in Cardiac Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yi Luan ◽  
Ying Luan ◽  
Qi Feng ◽  
Xing Chen ◽  
Kai-Di Ren ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Supply ◽  
Heart Function ◽  
High Energy ◽  
Normal Function ◽  
Cardiac Diseases ◽  
Normal Heart ◽  
Beneficial Effects ◽  
Physiological Processes

The normal function of the mitochondria is crucial for most tissues especially for those that demand a high energy supply. Emerging evidence has pointed out that healthy mitochondrial function is closely associated with normal heart function. When these processes fail to repair the damaged mitochondria, cells initiate a removal process referred to as mitophagy to clear away defective mitochondria. In cardiomyocytes, mitophagy is closely associated with metabolic activity, cell differentiation, apoptosis, and other physiological processes involved in major phenotypic alterations. Mitophagy alterations may contribute to detrimental or beneficial effects in a multitude of cardiac diseases, indicating potential clinical insights after a close understanding of the mechanisms. Here, we discuss the current opinions of mitophagy in the progression of cardiac diseases, such as ischemic heart disease, diabetic cardiomyopathy, cardiac hypertrophy, heart failure, and arrhythmia, and focus on the key molecules and related pathways involved in the regulation of mitophagy. We also discuss recently reported approaches targeting mitophagy in the therapy of cardiac diseases.

scholarly journals Neutrophil Extracellular Traps (NETs) in Severe SARS-CoV-2 Lung Disease

2021 ◽  
Vol 22 (16) ◽  
pp. 8854
Author(s):  
Monika Szturmowicz ◽  
Urszula Demkow
Keyword(s):  
Lung Injury ◽  
Nuclear Dna ◽  
Viral Infections ◽  
Prognostic Significance ◽  
Neutrophil Extracellular Traps ◽  
Organ Damage ◽  
Therapeutic Interventions ◽  
Extracellular Traps ◽  
Alveolar Capillary

Neutrophil extracellular traps (NETs), built from mitochondrial or nuclear DNA, proteinases, and histones, entrap and eliminate pathogens in the course of bacterial or viral infections. Neutrophils’ activation and the formation of NETs have been described as major risk factors for acute lung injury, multi-organ damage, and mortality in COVID-19 disease. NETs-related lung injury involves both epithelial and endothelial cells, as well as the alveolar-capillary barrier. The markers for NETs formation, such as circulating DNA, neutrophil elastase (NE) activity, or myeloperoxidase-DNA complexes, were found in lung specimens of COVID-19 victims, as well as in sera and tracheal aspirates obtained from COVID-19 patients. DNA threads form large conglomerates causing local obstruction of the small bronchi and together with NE are responsible for overproduction of mucin by epithelial cells. Various components of NETs are involved in the pathogenesis of cytokine storm in SARS-CoV-2 pulmonary disease. NETs are responsible for the interplay between inflammation and thrombosis in the affected lungs. The immunothrombosis, stimulated by NETs, has a poor prognostic significance. Better understanding of the role of NETs in the course of COVID-19 can help to develop novel approaches to the therapeutic interventions in this condition.

P1616L-2-hydroxyglutarate dehydrogenase (L2HGDH) is a novel target for heart failure due to pressure overload

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Remes ◽  
L Ding ◽  
B Kamlage ◽  
U E E Rennefahrt ◽  
P Ternes ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ribosomal Protein ◽  
Mitochondrial Membrane ◽  
Heart Function ◽  
Mtor Signaling ◽  
Heart Weight ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Ribosomal Protein S6

Abstract Background We have found L-2-hydroxyglutarate dehydrogenase (L2HGDH) to be downregulated in the myocardium of mice subjected to transverse aortic constriction (TAC). L2HGDH is an important regulator of mitochondrial bioenergetics by catalyzing the conversion of L-2-hydroxyglutarate (L2-HG) to α-ketoglutarate. However, the connection between L2-HG accumulation and heart failure is not yet understood. Purpose Purpose of our study was to investigate the role of increased L2-HG levels in heart failure and the potential role of L2HGDH overexpression as therapeutic strategy. Methods For in vitro studies, primary rat neonatal cardiomyocytes (NRVCMs) were incubated with L2-HG. L2HGDH was overexpressed using adeno-associated virus (AAV) 6 vectors. Mitochondrial membrane potential was measured using TMRE (tetramethylrhodamine ethyl ester) dye. Mitochondrial reactive oxygen species production was monitored using MitoSOX. We further determined activation of fetal gene program by real time qPCR and macrophage migration using RAW 264.7 cells and transwell inserts. mTOR activation was analyzed by Western blot with antibodies against phosphorylated mTOR and ribosomal protein S6. AAV9 expressing L2HGDH or luciferase was injected in C57BL/6N mice two weeks prior to TAC and heart function was monitored by echocardiography for 6 weeks. Results L2-HG acts as a pro-hypertrophic stimulus in NRVCMs as shown by upregulation of a fetal gene expression pattern and an increase in cardiomyocyte cross-sectional area upon L2-HG treatment. Furthermore, mRNA levels of macrophage chemoattractant protein 1 were increased in L2-HG treated cells, which correlated with enhanced macrophage migration towards supernatant of L2-HG treated NRVCMs. Furthermore, we could confirm that L2-HG augmented mTOR signaling by affecting the phosphorylation status of ribosomal protein S6. AAV-mediated L2HGDH overexpression in NRVCMs led to a significant 2.1-fold decrease in the accumulation of ROS production. Moreover, we found an inhibition of endothelin-1 induced mitochondrial membrane depolarization in AAV6-L2HGDH transduced cells. Pretreatment of mice with AAV9-L2HGDH prior to TAC resulted in significantly reduced heart weight to tibia length ratios (HW/TL) and cardiomyocyte area. Importantly, heart function was notably improved in mice receiving gene therapy (ejection fraction, EF: 36.18±6.63%, fractional shortening, FS: 16.72±4.01%) whereas control animals showed marked decline in myocardial contractility (EF: 20.14±8.24%, FS: 12.66±6.66%). Conclusion L2-HG causes cardiomyocyte dysfunction by activating mTOR signaling pathway, a well-characterized critical inducer of myocyte hypertrophy, and enhancing macrophage migration, leading to establishment of a pro-inflammatory environment in the myocardium. Moreover, our results point out towards a novel preventive approach for cardiac hypertrophy and heart failure by cardiomyocyte-specific L2HGDH overexpression. Acknowledgement/Funding DZHK (Deutsches Zentrum für Herz-Kreislaufforschung)

Abstract 50: Therapeutic Silencing of miRNA-652 Restores Cardiac Function and Attenuates Pathological Remodeling in a Mouse Model of Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Bianca C Bernardo ◽  
Sally S Nguyen ◽  
Catherine E Winbanks ◽  
Xiao-Ming Gao ◽  
Esther J Boey ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Pressure Overload ◽  
Post Treatment ◽  
Locked Nucleic Acid ◽  
Luciferase Assay ◽  
Sham Operation

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but was silenced in hearts of mice administered LNA-antimiR-652 (95% decrease, n=3-7, P<0.05). In mice subjected to pressure overload, inhibition of miR-652 improved cardiac function (29±1% at 4 weeks post TAC compared to 35±1% post treatment, n=7, P<0.001) and attenuated cardiac hypertrophy. Functional and morphologic improvements in hearts of treated mice were associated with reduced cardiac fibrosis, apoptosis, cardiomyocyte size; decreased B-type natriuretic peptide gene expression; and preserved angiogenesis (all P<0.05, n=4-7/group). Mechanistically, we identified Jagged1, a Notch1 ligand, as a direct target of miR-652 by luciferase assay. Jagged1 and Notch1 mRNA were upregulated in hearts of TAC treated mice (1.2-1.7 fold, n=7, P<0.05). Importantly, chronic knockdown of miR-652 was not associated with any notable toxicity in other tissues. Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.

Abstract 519: Talin is Required for Normal Adult Heart Function

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yoshitake Cho ◽  
Ruixia Li ◽  
Ana M Manso ◽  
Robert S Ross
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Development ◽  
Heart Function ◽  
Left Ventricular ◽  
Mass Spectrometry Analysis ◽  
Adult Heart ◽  
Spectrometry Analysis ◽  
Functional Changes

Talin (Tln) is a component of muscle costameres that links integrins to other components of the cellular cytoskeleton and plays an important role in maintaining the cellular integrity of cardiac myocytes (CM). There are two talin genes, Tln1 and Tln2, expressed in the heart. Tln1 is ubiquitously expressed, and Tln2 is dominantly expressed in CM. In our previous study, we show that the global deletion of Tln2 in mice (T2KO) caused no structural or functional changes in the heart, presumably because CM Tln1 became up-regulated. However, we found that mice lacking both CM Tln1 and Tln2 exhibit cardiac dysfunction by 4 weeks (w) of age with 100% mortality by 6 months (m), showing Tln plays an essential role in cardiac development and in maintaining cardiac function. In this study, we produced a tamoxifen (Tamo)-inducible mouse model in which Tln1 could be explicitly reduced in the adult CM (T1icKO), and then generate T1icKO:T2KO (T1/2dKO), so that the function of Tln could be assessed in the postnatal heart. T2KO and Tln1/2dKO mice were injected with Tamo at 8w. Echocardiograms were performed to evaluate cardiac function up to 8w post-Tamo injection. While T2KO mice showed normal cardiac function, T1/2dKO exhibited a gradual decrease in function post-Tamo injection. At 8w post-Tamo injection, T1/2dKO mice showed cardiac hypertrophy, fibrosis, and heart failure. To understand the mechanism by which deletion CM talin leads to cardiac dysfunction, left ventricular tissue protein lysates from T2KO and T1/2dKO mice at 4w post-Tamo when cardiac function (echo) and structure were preserved in dKO. The protein lysates were subjected to quantitative mass spectrometry analysis. We found there are 1,100 proteins differentially expressed in T2KO and T1/2dKO hearts. Pathway analysis was performed, and the results showed that proteins involved in vesicle transport, protein folding, and innate immunity are most up-regulated in the T1/2dKO heart. Taken together, our results show that Tln is required for maintaining proper cardiac function in the adult heart. The deletion of Tln in CM results in the up-regulation of multiple intracellular pathways, and we are currently studying the role of each pathway in the pathogenesis of heart failure induced by CM Tln deletion.

The association among biomarkers of renal and heart function in patients with heart failure: the role of NGAL

2018 ◽  
Vol 12 (12) ◽  
pp. 1323-1330 ◽  
Author(s):  
Evangelos Oikonomou ◽  
Sotiris Tsalamandris ◽  
Dimitris Karlis ◽  
Gerasimos Siasos ◽  
Christina Chrysohoou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Function ◽  
Patients With Heart Failure

scholarly journals Etiology and Risk Factors of Febrile Seizure – An Update

2012 ◽  
Vol 34 (3) ◽  
pp. 103-112 ◽  
Author(s):  
Gopen Kumar Kundu ◽  
F Rabin ◽  
ER Nandi ◽  
Naveen Sheikh ◽  
Shaheen Akhter
Keyword(s):  
Risk Factors ◽  
World Literature ◽  
Viral Infections ◽  
Febrile Seizures ◽  
Causative Factor ◽  
Etiologic Agent ◽  
Therapeutic Interventions ◽  
Diagnostic Tools ◽  
Familial Predisposition

Febrile seizures (FS) are the most common convulsive event in children. This condition has been described since the time of Hippocrates. The etiology of the febrile seizures are still unclear. In FS, there is a strong familial predisposition. This does not exclude infections as a causative factor because subtle genetic polymorphisms have been demonstrated to affect the course of infections. In an earlier review of the world literature (1924-1964), except for roseola infantum, viral infections as a cause of febrile seizures were rarely diagnosed. Reports of viral infections in the etiology of febrile seizures have increased in number in the past decade. In the first half of the twentieth century, infections identified with febrile seizures were mainly upper respiratory in type and the etiologic agent was unknown or bacterial. We review i) the role of infection – viral and bacterial; ii) the role of genetic and environmental factors; iii) the role of electrolyte and metabolic factors; and iv) the role of cytokines. With the help of new diagnostic tools such as PCR, the viral agents are detected in CSF far more often than previously thought, even in the absence of pleocytosis of the CSF. This makes it difficult to distinguish FS from acute encephalitis. FS may be caused by neuroinvasion or intracerebral activation of viruses. By reviewing etiology and risk factors of FS we can identify the points to be focused in therapeutic interventions and trials and also the fields of future studies will be explored. DOI: http://dx.doi.org/10.3329/bjch.v34i3.10361 BJCH 2010; 34(3): 103-112

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