8-hydroxy-2--deoxyguanosine and Myocarditis

Sudden cardiac death (SCD) is the major cause of death in cardiac sarcoidosis (CS). We aimed to identify the prognostic markers for sustained ventricular tachycardia (sVT) and SCD in patients with CS.. We performed a prospective observational cohort study for patients with CS diagnosed according to the Japanese or Heart Rhythm Society guidelines between June 2008 and March 2020 in our hospital. The primary endpoint was a composite of the first sVT and SCD. The levels of urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), a marker of oxidative DNA damage that reflects the inflammatory activity of CS, other biomarkers, and indices of cardiac function and renal function were measured on admission.. U-8-OHdG and presence of VA were powerful predictors of first sVT/SCD in patients with CS, facilitating the stratification of cardiac events and providing relevant information about the substrates of ventricular tachycardia.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Cardiomyopathies; Death, Sudden, Cardiac; Fluorodeoxyglucose F18; Heart Aneurysm; Humans; Myocarditis; Oxidative Stress; Prospective Studies; Risk Factors; Sarcoidosis; Tachycardia, Ventricular

Clozapine (CLZ) is the most effective therapeutic alternative in the treatment of resistant schizophrenia. However, the cardiotoxicity of CLZ, particularly in young patients, has raised concerns about its safety. Captopril is a well-known angiotensin-converting enzyme inhibitor with antioxidant properties effective in treating hypertension and heart failure. The aim of this study was to investigate the protective effect of captopril against clozapine-induced myocarditis in rats and the possible mechanisms behind this effect. The effect of captopril treatment [5 or 10mg/kg/d, injected intraperitoneally (i.p.) for 21days] on the cardiotoxic effect of coadministered CLZ (25mg/kg/d, i.p.) was assessed. Myocarditis was assessed histopathologically, immunohistochemically and biochemically. Frozen heart specimens were used to determine the amount of lipid peroxides product (MDA), nitric oxide (NO), reduced glutathione (GSH), glutathione peroxidase (GSH-Px) activity, proinflammatory cytokines (TNF-α and IL-10) and DNA degradation product(8-OHdG). Coadministration of captopril with the tested doses of CLZ decreased the histological hallmarks and biochemical markers (CK-MP and LDH) of myocarditis. In addition, captopril attenuated the effects of CLZ on oxidative stress parameters, NO and serum and cardiac 8-OHdG levels. Captopril significantly attenuated the effect of CLZ on all measured parameters in a dose-dependent manner. These results suggested that captopril exerts a protective action against CLZ-induced myocarditis. Multiple mechanisms contribute to this effect, including a decrease in cardiac oxidative stress and proinflammatory cytokines production, modulation of antioxidant status and protection from oxidative DNA damage. Hence, captopril may be effective in reducing the incidence and severity of CLZ-induced myocarditis in humans.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antipsychotic Agents; Captopril; Clozapine; Cytokines; Deoxyguanosine; DNA Damage; Gene Expression Regulation; Male; Myocarditis; Oxidative Stress; Rats; Rats, Wistar

Ang II (Angiotensin II) has been shown to play a pivotal role in the pathophysiology of various organs, especially the cardiovascular system. The effects of ARBs (Ang II receptor blockers) in the treatment of hypertension, congestive heart failure and myocardial fibrosis have been analysed extensively in human trials, as well as animal models, and the focus of interest is now directed to its pleiotropic effects, especially on inflammatory disorders. To investigate the effects of a new ARB, olmesartan, on immune-mediated myocardial injury, the protective effects of olmesartan on the development of murine acute myocarditis caused by CVB3 (coxsackievirus B3) were analysed. Olmesartan and a non-specific vasodilator hydralazine lowered systolic blood pressure of mice on day 7 after virus inoculation to a similar extent. Olmesartan significantly decreased myocardial inflammation compared with controls, whereas hydralazine significantly increased this. Olmesartan significantly decreased the expression of IFN-gamma (interferon-gamma), FasL (Fas ligand), iNOS (inducible nitric oxide synthase) and PFP (pore-forming protein) in myocardial tissue, indicating that olmesartan suppressed the activation of infiltrating killer lymphocytes. Olmesartan also decreased the expression of CVB3 genomes in myocardial tissue as well as serum levels of 8-OHdG (8-hydroxy-2'-deoxyguanosine), a biomarker of oxidative-stress-induced DNA damage. The findings suggest that olmesartan prevents myocardial damage and may improve the prognosis of patients with acute myocarditis; however, further investigations are needed before clinical use.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Disease; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Cytokines; Deoxyguanosine; Drug Evaluation, Preclinical; Enterovirus B, Human; Enterovirus Infections; Genome, Viral; Heart Rate; Hydralazine; Imidazoles; Inflammation Mediators; Lymphocyte Activation; Male; Mice; Mice, Inbred C3H; Myocarditis; Tetrazoles; Vasodilator Agents

An important role of redox regulation in myocardial diseases and heart failure has been postulated. Thioredoxin (TRX) is a redox-regulating protein. Recent studies indicated a possible association between plasma TRX concentrations and the severity of heart failure. Accordingly, we investigated the myocardial expression of TRX in patients with myocarditis and cardiomyopathies. Four cases of hypertrophic cardiomyopathy (HCM), 10 of dilated cardiomyopathy (DCM), 6 of myocarditis, and 5 of controls were studied. Right and left ventricular endomyocardial biopsy samples were obtained at the diagnostic cardiac catheterization. The samples were processed for immunohistological staining for TRX, which was done by the indirect immunoperoxidase technique. 8-hydoxy-2'-deoxyguanosine (8-OHdG), one of the major DNA base-modified products, was also detected for an established marker for oxidative stress. TRX immunoreactivity was none or trivial in control specimens. Positive TRX staining was found in 6 cases; 3 in active myocarditis and 3 in DCM. The positive staining was found in infiltrating cells and damaged myocytes in the perinecrotic lesions. Damaged myocytes were also positive for 8-OHdG All the 3 cases of DCM positive for TRX stain showed severe left ventricular hypertrophy on electrocardiogram and highly elevated left ventricular end-diastolic pressure (> 24 mmHg), suggesting the overload of oxidative stress by hemodynamic impairment. Myocardial TRX was upregulated in myocarditis and cardiomyopathies with active necrotic stage associated with DNA damage, which may reflect the oxidative stress overload in hemodynamically uncontrolled status.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biopsy; Cardiomyopathies; Deoxyguanosine; Diastole; DNA; DNA Damage; Heart Ventricles; Humans; Hypertrophy; Immunohistochemistry; Myocarditis; Myocardium; Necrosis; Oxidation-Reduction; Oxidative Stress; Pressure; Thioredoxins; Up-Regulation

To examine the possible involvement of a redox regulating mechanism in the pathogenesis of immune-mediated myocarditis, myocarditis was induced by immunization of porcine cardiac myosin in rats and immunohistochemistry and Western blot for thioredoxin (TRX) were performed. Immunohistochemistry for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear factor kappa-B (NF-kappaB) was also performed. TRX was upregulated in the acute stage, but not in the chronic stage, and the expression was correlated with the severity of the disease. Damaged myocytes were strongly immunostained for 8-OHdG and NF-kappaB. Thus, TRX may be specifically induced by acute inflammatory stimuli, and the development of acute immune-mediated myocarditis may be regulated by the cellular redox state via TRX.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blotting, Western; Deoxyguanosine; Giant Cells; Immunohistochemistry; Myocarditis; Myocardium; Myosins; NF-kappa B; Oxidation-Reduction; Rats; Rats, Inbred Lew; Swine; Thioredoxins; Vaccination