atrial-natriuretic-factor and Myocarditis

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.

Topics: alpha-Methyltyrosine; Angiotensin-Converting Enzyme 2; Antibodies, Monoclonal, Humanized; Antioxidants; Apoptosis; Atrial Natriuretic Factor; Azetidines; Benzyl Compounds; COVID-19; COVID-19 Drug Treatment; Cytokine Release Syndrome; Enzyme Inhibitors; Glucocorticoids; Glycoproteins; Humans; Hypoxia; Interleukin 1 Receptor Antagonist Protein; Myocardial Ischemia; Myocarditis; Myocytes, Cardiac; Oxidative Stress; Oxygen Inhalation Therapy; Respiration, Artificial; SARS-CoV-2; Sphingosine 1 Phosphate Receptor Modulators; Trypsin Inhibitors; Tumor Necrosis Factor Inhibitors

Coronary heart disease (CHD) is the leading cause of death and disability in Europe. For patients presenting with an acute ST-segment elevation myocardial infarction (STEMI), timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous coronary intervention (PPCI) is the most effective therapy for limiting myocardial infarct (MI) size, preserving left-ventricular systolic function and reducing the onset of heart failure. Despite this, the morbidity and mortality of STEMI patients remain significant, and novel therapeutic interventions are required to improve clinical outcomes in this patient group. Paradoxically, the process of myocardial reperfusion can itself induce cardiomyocyte death-a phenomenon which has been termed 'myocardial reperfusion injury' (RI), the irreversible consequences of which include microvascular obstruction and myocardial infarction. Unfortunately, there is currently no effective therapy for preventing myocardial RI in STEMI patients making it an important residual target for cardioprotection. Previous attempts to translate cardioprotective therapies (antioxidants, calcium-channel blockers, and anti-inflammatory agents) for reducing RI into the clinic, have been unsuccessful. An improved understanding of the pathophysiological mechanisms underlying RI has resulted in the identification of several promising mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hyperoxaemia), and pharmacological (atrial natriuretic peptide, cyclosporin-A, and exenatide) therapeutic strategies, for preventing myocardial RI, many of which have shown promise in initial proof-of-principle clinical studies. In this article, we review the pathophysiology underlying myocardial RI, and highlight the potential therapeutic interventions which may be used in the future to prevent RI and improve clinical outcomes in patients with CHD.

Topics: Animals; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Blood Glucose; Calcium; Cardiotonic Agents; Cell Death; Coronary Occlusion; Disease Models, Animal; Hemorrhage; Humans; Hydrogen-Ion Concentration; Hyperbaric Oxygenation; Hypothermia, Induced; Ischemic Postconditioning; Microvessels; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocarditis; Myocytes, Cardiac; Nitric Oxide; Oxidative Stress; Percutaneous Coronary Intervention

The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.

Topics: Animals; Atrial Natriuretic Factor; Biomedical Research; Hemodynamics; Humans; Inflammation; Myocarditis; Myocytes, Cardiac; Natriuretic Peptide, Brain; Sepsis

Amyloidosis is a heterogeneous group of diseases characterized by the pathological deposition of autologous proteins in an antiparallel β-sheet confirmation forming non-branching linear fibrils of indefinite length and an approximate diameter of 10-12 nm. Cardiac amyloidosis is caused by deposits in the heart and may lead to cardiac arrhythmia and low output failure. Following the diagnosis, classification of the amyloid protein and evaluation of further organ involvement is mandatory. Treatment approaches are based on reduction of the production of amyloid precursor proteins. Standard heart failure treatment is usually not well tolerated and the underlying disease remains unaffected. Cardiac amyloidosis, especially of the light chain type, is associated with a poor outcome. The clinical picture is uncharacteristic, therefore correct diagnosis of cardiac amyloidosis is often delayed in many patients. Combination of clinical symptoms of different organ systems should alert the physician to the diagnosis of amyloidosis.

Topics: Age Factors; Amyloid; Amyloidosis; Atrial Natriuretic Factor; Biopsy; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Myocarditis; Myocardium; Prealbumin; Registries; Sex Factors

A number of vasoactive mediators have been identified in plasma and in the heart. Some of them may be liberated in inflammatory heart disease. The action of mediators on coronary vasculature in various animal models and their potential role in inflammatory heart disease is reviewed. Their role in patients remains to be determined.

Topics: Adrenal Glands; Animals; Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Coronary Circulation; Coronary Vessels; Eicosanoids; Endothelium, Vascular; Humans; Myocarditis; Neuropeptides; Renin-Angiotensin System; Sympathetic Nervous System; Vasopressins

Proteinuria associated with acute heart disease was studied prospectively in 160 patients admitted to the coronary care unit with suspected AMI. Series 1 comprised 150 patients, divided into the following groups: AMI, 27 UAP, 43 AP, 22 NIP and 18 excluded. Albumin and creatinine were measured in the first urine passed after admission (sample 1) and the first morning urine the following 2 days (samples 2 and 3). The ACR was significantly higher in the AMI and UAP groups than in the other patient groups (p < 0.0001). There was no significant difference of ACR between the AMI and UAP in sample 1 (p = 0.31). In the AMI, UAP and AP groups ACR was significantly higher in sample 1 than in samples 2 and 3 (p < 0.005). In the NIP group there were no significant differences between sample 1 versus samples 2 and 3 (p = 0.06). Series 2 comprised 10 patients: 8 AMI, 1 UAP and 1 AMYO. ACR were measured in all specimens voided during the period of observation. ACR can oscillate within hours between normal concentrations and concentrations well into or above the microalbuminuric range. We propose the term episodic albuminuria for this reversible, switch-like change in renal function. The albuminuric episodes lasted 90-600 minutes. Maximum values for ACR were between 133-790 mumol/mol or 78-466 mg/g. In healthy, resting individuals ACR is < 50 mumol/mol (< 30 mg/g). The rapid changes in glomerular permeability may reflect systemic changes in endothelial permeability in the affected individuals. We speculate that atrial natriuretic peptide (ANP) may be a mediator of this type of albuminuria.

Topics: Adult; Aged; Albuminuria; Angina, Unstable; Atrial Natriuretic Factor; Biomarkers; Chest Pain; Creatinine; Female; Humans; Kidney Function Tests; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocarditis; Prospective Studies

Carbohydrate sulfotransferase 15 (CHST15) is a sulfotransferase responsible for biosynthesis of chondroitin sulfate E (CS-E), which plays important roles in numerous biological events such as biosynthesis of proinflammatory cytokines. However, the effects of CHST15 siRNA in rats with chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM) have not yet been investigated. CHF was elicited in Lewis rats by immunization with cardiac myosin, and after immunization, the rats were divided into two groups and treated with either CHST15 siRNA (2μg/week) or vehicle. Age matched normal rats without immunizations were also included in this study. After 7weeks of treatment, we investigated the effects of CHST15 siRNA on cardiac function, proinflammatory cytokines, and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by CHST15 siRNA treatment in rats with CHF compared with that of vehicle-treated CHF rats. CHST15 siRNA significantly reduced cardiac fibrosis, and hypertrophy and its marker molecules (left ventricular (LV) mRNA expressions of transforming growth factor beta1, collagens I and III, and atrial natriuretic peptide) compared with vehicle-treated CHF rats. CHF-induced increased myocardial mRNA expressions of proinflammatory cytokines [interleukin (IL)-6, IL-1β], monocyte chemoattractant protein-1, and matrix metalloproteinases (MMP-2 and -9), and CHST15 were also suppressed by the treatment with CHST15 siRNA. Western blotting study has confirmed the results obtained from mRNA analysis as CHST15 siRNA treated rats expressed reduced levels of inflammatory and cardiac remodeling marker proteins. Our results demonstrate for the first time, that CHST15 siRNA treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.

Topics: Animals; Atrial Natriuretic Factor; Carbohydrate Sulfotransferases; Cardiomyopathy, Dilated; Collagen Type I; Collagen Type III; Cytokines; Echocardiography; Hemodynamics; Male; Mast Cells; Matrix Metalloproteinases; Myocarditis; Myocardium; Rats; Rats, Inbred Lew; RNA Interference; RNA, Small Interfering; Sulfotransferases; Survival Rate; Transforming Growth Factor beta1

The cardioprotective effects of carvedilol were studied in a rat model of experimental autoimmune myocarditis (EAM). After immunization, rats were orally administered 10 mg/kg/day carvedilol (group C, n = 15) or a vehicle control (Group V, n = 12) for 3 weeks. On day 21, echocardiography and haemodynamic parameters, myocarditis areas, and cytokine concentrations were measured. Serum carvedilol concentrations ranged from 10.5 +/- 2.6 to 31.7 +/- 9.3 ng/ml over a 24 h period on day 20. Carvedilol decreased the myocarditis areas (23.07 +/- 1.6 versus 33.65 +/- 2.71%, P < 0.0001). The left ventricular fractional shortening and the absolute value of +dP/dt or -dP/dt were significantly higher in Group C. Heart rate, systolic blood pressure, left ventricular end-diastolic pressure and central venous pressure were significantly lower in Group C. The serum and mRNA levels of interleukin (IL)-1beta (53.58 +/- 6.42 versus 98.75 +/- 6.53 pg/ml, P < 0.0001 and 0.298 +/- 0.04 versus 0.818 +/- 0.252, P < 0.0001, respectively) and TNF-alpha (14.82 +/- 1.95 versus 29.52 +/- 3.7 pg/ml, P = 0.0008 and 0.088 +/- 0.006 versus 0.168 +/- 0.072, P = 0.0051, respectively) were markedly decreased, whereas IL-10 (24.92 +/- 2.94 versus 15.25 +/- 3.13 pg/ml, P = 0.015 and 0.302 +/- 0.022 versus 0.107 +/- 0.02, P < 0.0001, respectively) and IL-1 receptor antagonist (1.95 +/- 0.28 versus 0.52 +/- 0.10 pg/ml, P < 0.0001 and 0.112 +/- 0.009 versus 0.051 +/- 0.002, P < 0.0001, respectively) were markedly increased in the Group C. These results indicate that in rats carvedilol protects against EAM.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Carbazoles; Carvedilol; Cytokines; Enzyme-Linked Immunosorbent Assay; Male; Myocarditis; Organ Size; Propanolamines; Rats; Rats, Inbred Lew; Receptors, Adrenergic, beta-2; RNA, Messenger

Exposure to tobacco smoke is known to have deleterious cardiovascular effects. In this study, we tested whether exposure to tobacco smoke exacerbates the severity of viral myocarditis in mice. Viral myocarditis was generated in 4-week-old male BALB/c mice by injection of Encephalomyocarditis virus (EMCV). Four groups were studied: (1) control (C, no smoke and no virus); (2) smoke only (S, exposure to cigarette smoke for 90 min/day for 15 days); (3) virus only (V); and (4) exposure to smoke for 5 days before plus 10 days following virus injection (S+V). We found that viral inoculation preceded by smoke exposure increased mortality more than twofold compared with virus inoculation alone. In addition, the mRNA level of atrial natriuretic factor was significantly higher in S+V than among any of the other 3 groups. Virus injection significantly decreased cardiac function compared with controls, with further deterioration observed in the S+V group. We also observed a significantly increased rate of apoptosis, with an increased activation of apoptosis-inducing factor in hearts exposed to S+V compared with those exposed to V alone. Our results suggest that preexposure to smoke significantly exacerbates the severity of viral myocarditis, likely through increased viral load and increased cardiomyocyte cell death.

Topics: Animals; Apoptosis; Apoptosis Inducing Factor; Atrial Natriuretic Factor; Blotting, Western; Cardiovirus Infections; Encephalomyocarditis virus; Heart; Hemodynamics; Male; Mice; Mice, Inbred BALB C; Myocarditis; Myocardium; Reverse Transcriptase Polymerase Chain Reaction; Tobacco Smoke Pollution; Viral Load

The effect of carperitide, recombinant human atrial natriuretic peptide, on chronic heart failure (HF) has not been clarified. We investigated the beneficial effects of chronic carperitide treatment in rats with HF after experimental autoimmune myocarditis. A 28-day infusion of carperitide (n = 14) or vehicle (n = 14) was administrated to the rats 4 weeks after experimental autoimmune myocarditis induction. After 4 weeks, the myocardial levels of cyclic guanosine monophosphate (cGMP), left ventricular function, myocyte hypertrophy, interstitial fibrosis, myocardial capillary vessel density, and activity of one prominent substrate of cGMP, vasodilator-stimulated phosphoprotein (VASP) that may enhance angiogenesis, were measured. Carperitide treatment increased the myocardial levels of cGMP and attenuated the functional severity along with a decreased myocyte cross-sectional area, interstitial fibrosis, and an increased capillary to myocyte ratio. Furthermore, carperitide treatment enhanced the phosphorylation of VASP at Ser239, which was preferentially phosphorylated by cGMP-dependent protein kinase but not Ser157, which was preferentially phosphorylated by cyclic adenosine monophosphate-dependent protein kinase. Long-term carperitide treatment attenuates ventricular remodeling and ameliorates the progression of chronic HF. The effects of carperitide treatment are associated with increased neovascularization among the residual myocytes and an increase of VASP activation.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Capillaries; Cell Adhesion Molecules; Cell Size; Coronary Vessels; Cyclic GMP; Fibrosis; Heart Failure; Male; Microfilament Proteins; Myocarditis; Myocardium; Neovascularization, Physiologic; Phosphoproteins; Phosphorylation; Random Allocation; Rats; Rats, Inbred Lew; Recombinant Proteins; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling

Fulminant myocarditis with rapid onset of symptoms and hemodynamic compromise is a rare indication for mechanical support. Because of the potentially reversible nature of this illness, advanced mechanical circulatory support is warranted to achieve recovery or as a bridge to transplantation. Circulatory device options currently available allow for a phased implementation of support modalities in a manner that reduces costs and patient risk. We present a patient with fulminant myocarditis where extracorporeal membrane oxygenation (ECMO) support escalated to short-term Levitronix CentriMag (Levitronix, Waltham, MA) biventricular assist devices (BiVADs). These in turn were exchanged, without major surgery, to long-term paracorporeal VADs (Thoratec, Pleasanton, CA). After rehabilitation and nearly total recovery, the patient was weaned from mechanical circulatory support after 104 cumulative days.

Topics: Adult; Anticoagulants; Atrial Natriuretic Factor; Blood Coagulation; Cardiopulmonary Resuscitation; Echocardiography; Extracorporeal Membrane Oxygenation; Female; Heart Arrest; Heart-Assist Devices; Heparin; Humans; Myocarditis; Natriuretic Peptide, Brain; Shock, Cardiogenic; Stroke Volume; Treatment Outcome

Torasemide is a long-acting loop diuretic that combines the effects of both furosemide and spironolactone. It has been reported that torasemide may block the renin-angiotensin-aldosterone system and therefore it might attenuate myocardial remodeling accompanied by left ventricular dysfunction. However, nothing is known about the effect of torasemide on myocardial remodeling in a rat model in which myosin-induced experimental autoimmune myocarditis might develop into dilated cardiomyopathy. Experimental autoimmune myocarditis was elicited in Lewis rats by immunization with porcine cardiac myosin. Twenty-eight days after immunization, we investigated the effects of torasemide on metabolic and neurohumoral parameters, cardiac fibrosis and remodeling in experimental autoimmune myocarditis rats. Diuresis was increased dose-dependently by torasemide; the urinary potassium and sodium excretion was significantly decreased and increased, respectively. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by torasemide treatment in a dose-dependent manner. The area of fibrosis, myocyte size and the myocardial protein levels of transforming growth factor-beta1, collagen III, and aldosterone synthase were significantly decreased, and the sarcoplasmic reticulum Ca2+ ATPase2 protein level was significantly increased by torasemide treatment. Moreover, the plasma levels of angiotensin II and aldosterone were increased and atrial natriuretic peptide was decreased in a dose-dependent manner. Our results indicate that torasemide treatment significantly improved left ventricular function and ameliorated the progression of cardiac remodeling beyond its renal effects in rats with chronic heart failure after experimental autoimmune myocarditis.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Cardiomyopathy, Dilated; Collagen Type III; Disease Progression; Diuretics; Heart Failure; Male; Matrix Metalloproteinase 9; Myocarditis; Myocardium; Rats; Rats, Inbred Lew; RNA, Messenger; Sulfonamides; Torsemide; Transforming Growth Factor beta1; Ventricular Function, Left

The cardiac natriuretic peptides atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are discoordinately regulated in myocardial inflammation associated with acute allograft rejection in humans and during in vitro exposure of cardiocyte cultures to some proinflammatory cytokines. We used experimental autoimmune myocarditis (EAM) to determine whether the discoordinate regulation of ANF and BNP was specific to the situations above or was generally associated with other types of myocardial inflammation. The dependency of this process to angiotensin signaling was also determined, given that previous work demonstrated beneficial effects of the angiotensin receptor blocker olmesartan in myocarditis. Histopathological changes, plasma and cardiac ANF, BNP, and selected cytokines gene expression as well as plasma cytokine levels using a cytokine array were determined in EAM, angiotensin receptor blocker-treated, and control rats. It was found that EAM specifically increases BNP but not ANF circulating levels, thus mimicking the findings in acute cardiac allograft rejection and the effect of some proinflammatory cytokines on cardiocyte cultures in vitro. Plasma cytokine array and real-time PCR revealed that lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-1 were increased in plasma and in the myocardium of EAM rats. Olmesartan treatment reversed virtually all neuroendocrine and histopathological cardiac changes induced by EAM, thus providing a mechanistic insight into this phenomenon. It is concluded that the inflammatory process contributes specific cytokines, leading to the disregulation of cardiac ANF and BNP production observed during myocardial inflammation, and that this process is angiotensin receptor 1 dependent.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Atrial Natriuretic Factor; Blood Pressure; Cytokines; Disease Models, Animal; Imidazoles; Mycobacterium tuberculosis; Myocarditis; Myocardium; Natriuretic Peptide, Brain; Polymerase Chain Reaction; Protein Array Analysis; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; RNA, Messenger; Tetrazoles; Up-Regulation

Chymase has been known as a local angiotensin II-generating enzyme in the cardiovascular system in dogs, monkeys, hamsters, and humans; however, recently it was reported that chymase also has various other functions. Therefore, we decided to examine whether the inhibition of chymase improves disease conditions associated with the pathophysiology of dilated cardiomyopathy in rats and its possible mechanism of action as rat chymase is unable to produce angiotensin II. We examined the effect of TY-51469, a novel chymase inhibitor (0.1 mg/kg/day [group CYI-0.1, n = 15] and 1 mg/kg/day [group CYI-1, n = 15]), in myosin-immunized postmyocarditis rats. Another group of myosin-immunized rats was treated with vehicle (group V, n = 15). Age-matched normal rats without immunization (group N, n = 10) were also included in the study. After 4 weeks of treatment, we evaluated cardiac function; area of fibrosis; fibrogenesis; levels of transforming growth factor (TGF)-beta1 and collagen III; hypertrophy and its marker, atrial natriuretic peptide (ANP); and mast cell activity. Survival rate and myocardial functions improved dose-dependently with chymase inhibitor treatment after myosin immunization. A reduction in the percent area of myocardial fibrosis, fibrogenesis, myocardial hypertrophy, and mast cell activity along with a reduction in TGF-beta1, collagen III, and ANP levels in the myocardium were noted in postmyocarditis rats that received chymase inhibitor treatment. The treatment also decreased myocardial aldosterone synthase levels in those animals. Inhibition of chymase reduces the pathogenesis of postmyocarditis dilated cardiomyopathy and progression to heart failure by preventing the pathological remodeling and residual inflammation in rats.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Cardiomyopathy, Dilated; Chymases; Collagen Type III; Cyclin D1; Disease Progression; Enzyme Inhibitors; Heart Failure; Histamine; Humans; Macaca mulatta; Male; Myocarditis; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sulfonamides; Survival Rate; Thiophenes; Transforming Growth Factor beta1

The aim of the present study was to compare the cardioprotective properties of long-acting calcium channel antagonist pranidipine with amlodipine in rat model of heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were randomized for the oral administration of low-dose amlodipine (1 mg/kg/day), high-dose amlodipine (5 mg/kg/day), pranidipine (0.3 mg/kg/day) or vehicle (0.5% methylcellulose). After oral administration for 1 month, the animals underwent echocardiography and hemodynamic analysis. Histopathology, immunohistochemistry, and Western immunoblotting were carried out in the heart samples. Both pranidipine and high-dose amlodipine increased survival rate. Although the heart rate did not differ among the four groups, left ventricular end-diastolic pressure was significantly decreased and +/-dP/dt was increased in the pranidipine- and high-dose amlodipine-treated rats, but not in low-dose amlodipine-treated rats. In comparison to amlodipine treatment, pranidipine treatment significantly reduced myocyte size and central venous pressure. Furthermore, both pranidipine and high-dose amlodipine treatment significantly reduced myocardial protein levels of atrial natriuretic peptide and inducible nitric oxide synthase, whereas pranidipine only significantly decreased tumor necrosis factor-alpha, and improved sarcoplasmic reticulum Ca2+ ATPase2 protein levels. We conclude that pranidipine ameliorates the progression of left ventricular dysfunction and cardiac remodeling in rats with heart failure after autoimmune myocarditis in a lower dose when compared to amlodipine and which may be a clinically potential therapeutic agent for the treatment of heart failure.

Topics: Administration, Oral; Amlodipine; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Calcium-Transporting ATPases; Cardiac Myosins; Dihydropyridines; Dose-Response Relationship, Drug; Echocardiography; Fibrosis; Heart Failure; Heart Rate; Male; Myocarditis; Myocardium; Nitric Oxide Synthase Type II; Rats; Rats, Inbred Lew; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Survival Rate; Time Factors; Ventricular Function, Left

Hepatitis C virus (HCV) has been reported to be associated with cardiomyopathy. However, the mechanism of cardiomyopathy in chronic HCV infection is still unclear. Therefore, we investigate the development of cardiomyopathy in mice transgenic for the HCV-core gene. After the age of 12 months, mice developed cardiomyopathy that appeared as left ventricular dilatation, and systolic and diastolic dysfunction assessed by Doppler echocardiography. Histologically, hypertrophy of cardiomyocytes, cardiac fibrosis, disarray and scarcity of myofibrils, vacuolization and deformity of nuclei, myofibrillar lysis, streaming of Z-bands, and an increased number of bizarre-shaped mitochondria were found in HCV-core transgenic mice. These histological changes are just consistent with cardiomyopathy. In conclusion, the HCV-core protein directly plays an important role in the development of cardiomyopathy.

Topics: Actin Cytoskeleton; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Echocardiography, Doppler; Fibrosis; Gene Expression Regulation, Viral; Hepacivirus; Hepatitis C; Hypertrophy, Left Ventricular; Male; Mice; Mice, Transgenic; Mitochondria, Heart; Myocarditis; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; NF-kappa B; Organ Size; RNA, Messenger; RNA, Viral; Transcription Factor AP-1; Ventricular Dysfunction, Left; Viral Core Proteins

Topics: Animals; Antiviral Agents; Atrial Natriuretic Factor; Cardiomyopathies; Gene Expression Regulation, Viral; Heart; Heart Failure; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; HLA-D Antigens; Humans; Interferons; Mice; Mice, Transgenic; Myocarditis; Myocardium; Natriuretic Peptide, Brain; NF-kappa B; Paraffin Embedding; Phenotype; Prevalence; RNA, Viral; Species Specificity; Transcription Factor AP-1; Viral Core Proteins

Rat experimental autoimmune myocarditis (EAM) is a T cell-mediated disease that resembled the giant cell myocarditis seen in humans. Soluble CTLA4 improves some autoimmune diseases by blocking costimulatory signals on T cell. We investigated the effect of hydrodynamics-based naked plasmid DNA encoding CTLA4-immunoglobulin (Ig) gene delivery.. Lewis rats were immunized with cardiac myosin and treated with hydrodynamic-based transfection, namely a rapid tail vein injection of a large volume of pCAGGS encoding CTLA4-Ig chimera solution on Day 0. The vector-derived CTLA4-Ig mRNA expressions were mainly detected in the liver and plasma CTLA4-Ig protein levels were maintained at about 2 mug/mL during the experiment period. On Day 17, the ratio of heart to body weight, the amount of mRNA of atrial natriuretic peptide, and the inflammatory areas in CTLA4 group were significantly lower than in the control group treated with empty plasmid. Maximum rate of intraventricular pressure rise and decline (dP/dT), minimum dP/dT, left ventricular end-diastolic pressure, and central venous pressure improved significantly after treatment with CTLA4-Ig. On Day 14, expressions of IL-2 in popliteal lymph nodes in the CTLA4-Ig group were significantly lower than in the control group.. Hydrodynamics-based transfection of plasmid encoding CTLA4-Ig chimera dramatically prevented EAM.

Topics: Abatacept; Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Disease Models, Animal; Genetic Therapy; Immunoconjugates; Interleukin-2; Lymph Nodes; Male; Myocarditis; Plasmids; Popliteal Artery; Rats; Rats, Inbred Lew; RNA, Messenger; Time Factors; Transfection; Ventricular Pressure

The ventricles of the normal heart are virtually devoid of atrial natriuretic peptide (ANP). Although ANP occurs in ventricles submitted to elevated wall stress, it is not clear whether ANP expression is affected by myocarditis. We investigated the immunohistochemical expression of ANP in chronic chagasic cardiomyopathy, an inflammatory cardiomyopathy caused by infection with the protozoan Trypanosoma cruzi.. Necropsy samples from the left and right ventricles of 16 patients exhibiting chronic chagasic cardiomyopathy were evaluated for myocarditis, fibrosis, T. cruzi parasites and ANP immunoreactivity. The diameters of 50 myocytes per sample were measured.. ANP was present in myocytes of the subendocardial region in 13/16 (81.3%) left and 10/16 (62.5%) right ventricular samples (P=0.25). Myocytes present in the inflammatory foci, near the infiltrating inflammatory cells but distant from the subendocardial region, did not express ANP. Trypanosoma cruzi parasites exhibited intense immunoreactivity for ANP. The mean myocyte diameter and the incidence of myocarditis, fibrosis, and T. cruzi parasites was similar between the left and right ventricular samples. No statistical differences were found between the ANP-positive and ANP-negative cases.. In chronic chagasic cardiomyopathy, both ventricles exhibit hypertrophy, fibrosis and ANP in the subendocardial region. The inflammatory infiltrate does not induce ANP expression in the myocytes. Regional stress but not myocarditis itself, is probably responsible for ventricular ANP expression in myocarditis.

Topics: Adolescent; Adult; Aged; Animals; Atrial Natriuretic Factor; Chagas Cardiomyopathy; Child; Chronic Disease; Female; Fibrosis; Heart Ventricles; Humans; Male; Middle Aged; Muscle Fibers, Skeletal; Myocarditis; Trypanosoma cruzi

Topics: Atrial Natriuretic Factor; Heart; Humans; Interferon-beta; Myocardial Infarction; Myocarditis; Natriuretic Peptide, Brain; Predictive Value of Tests; Risk Assessment; Stroke Volume

Heart failure is generally believed to begin with myocyte damage caused by a variety of insults, including ischemia, toxin or myocardial infection. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been hypothesized to play a pathogenetic role in the transition from compensated to decompensated heart failure. Interleukin-18 (IL-18), a recently cloned cytokine synthesized by Kupffer cells, activates macrophages. We examined the therapeutic effect of IL-18 on the modulation of TNF-alpha gene expression in failing heart in a murine model of heart failure caused by viral myocarditis. The heart weight (HW)/ body weight (BW) ratio in IL-18 treated mice 7 days after viral inoculation was significantly lower (P<0.01) than in the untreated controls. Myocardial necrosis and inflammatory cell infiltration were significantly lower in IL-18 treated mice than untreated mice 5 and 7 days after inoculation. The expression of TNF-alpha mRNA in the myocardium was significantly lower on days 5 and 7 in IL-18 treated mice than in infected untreated mice. We conclude that concurrent systemic administration of IL-18 is beneficial in mice with myocarditis, and may be mediated through reduced expression of TNF-alpha in the heart.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Female; Heart; Immunohistochemistry; In Situ Hybridization; Interleukin-18; Mice; Mice, Inbred C3H; Myocarditis; Myocardium; Necrosis; Organ Size; RNA; RNA, Messenger; Tumor Necrosis Factor-alpha

Although myocarditis has been implicated in the pathogenesis of heart failure, a definitive relationship between myocardial inflammation, cardiac dysfunction, and changes in myocyte gene expression has not been established. In this study, we examined the hypothesis that myocardial inflammation and replacement fibrosis following an autoimmune response can progress to cardiac dysfunction and may result in progression to the heart failure phenotype. SWXJ mice were immunized with cardiac myosin on day 0 and day 7, in order to induce an autoimmune response to the myosin protein. Cardiac catheterization via the right carotid artery was performed on days 14, 21, 28, 35, and 42, using a 1.4F Millar transducer-tipped catheter. Hearts were weighed, and cross-sections were cut and stained with either haematoxylin and eosin or Masson's trichrome, in order to identify areas of inflammation and/or fibrosis. Myocardial gene expression was determined by Northern blot analysis. In mice with histological evidence of myocarditis, the heart weight/body weight ratio increased beginning on day 14, and cardiac function decreased beginning on day 21. Myocardial inflammation was accompanied by significant fibrosis beginning on day 21. Quantitation of mRNA showed expression of ventricular atrial naturietic factor, as well as a decrease in myosin heavy chain alpha, beginning on day 21. These data demonstrate that autoimmune inflammation of the heart results in significant cardiac dysfunction, leading to phenotypic alterations similar to those demonstrated in human heart failure and animal models of heart failure.

Topics: Animals; Atrial Natriuretic Factor; Autoantigens; Autoimmune Diseases; Body Weight; Endomyocardial Fibrosis; Gene Expression Regulation; Heart; Heart Failure; Male; Mice; Mice, Inbred Strains; Models, Animal; Molecular Motor Proteins; Muscle Proteins; Myocarditis; Myocardium; Myosin Heavy Chains; Myosins; Organ Size; RNA, Messenger; T-Lymphocytes, Cytotoxic; Ventricular Dysfunction, Left

Myocarditis is defined as an inflammation of the heart muscle and often follows enterovirus infections. Frequently, patients surviving the acute inflammatory stage undergo complete recovery, but myocarditis can result in dilated cardiomyopathy. A murine model of myocarditis has been developed that uses cardiotropic variants of coxsackievirus Group B. Type 3 (CVB3), and either BALB/c (H-2d), MRL+/+ (H-2k), or DBA/2 (H-2d) male mice. Infection of all three mouse strains results in equivalent levels of myocardial inflammation 7 days later. IgG antibodies are detected by immunofluorescent staining in DBA/2 but not BALB/c or MRL+/+ myocardium and correlate with the detection of anti-heart antibodies in the sera of DBA/2 mice by immunofluorescence. CD4+ cell depletion of DBA/2 and MRL+/+ mice prevents myocarditis, but both CD4+ and CD8+ T cells cause cardiac inflammation in BALB/c mice, although CD8+ cells are substantially more pathogenic than CD4+ cells in this strain. No or few CD8+ T cells infiltrate the myocardium of either DBA/2- or MRL+/(+)-infected animals, although this is the predominant T-cell population in BALB/c mice. Apoptosis was measured by terminal deoxynucleotidyl transferase-staining of myocardial sections. No apoptosis was observed in inflamed DBA/2 hearts. Apoptosis was restricted to inflammatory cell infiltrates of infected MRL+/+ hearts, but apoptosis was wide-spread in both the inflammatory cell infiltrates and in myocytes outside inflammatory lesions in BALB/c mice. Atria natriuretic factor (ANF) mRNA expression was only elevated in the left ventricles of BALB/c mice. CD8+ T-cell depletion abrogated the appearance of apoptotic myocytes and ANF mRNA expression. The fact that ventricular ANF production often occurs during cardiac failure suggests that myocardial stress is substantially greater in BALB/c mice than in other strains despite equivalent amounts of cardiac inflammation.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; CD8-Positive T-Lymphocytes; Coxsackievirus Infections; Enterovirus B, Human; Heart Ventricles; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Inbred MRL lpr; Myocarditis; RNA, Messenger; Species Specificity

The effects of combination therapy with the immunomodulators OK432 (derived from the Su strain of Streptococcus pyogenes A3; 1 unit corresponds to 0.1 mg of dried streptococci dissolved in 0.1 ml of saline) and human recombinant interferon-alpha A/D (IFN) on cardiac atrial natriuretic peptide (ANP) gene expression and myocardial hypertrophy were examined in a murine model of viral myocarditis with congestive heart failure. Therapy was started 24 h after inoculation with encephalomyocarditis virus and was continued for 14 days. The plasma ANP concentration in untreated infected mice was significantly (P < .01) increased on day 10 (115 +/- 48 pg/ml) and day 30 (43 +/- 22 pg/ml) after inoculation relative to that in uninfected controls (5 +/- 4 pg/ml), whereas plasma ANP levels in treated mice were significantly (P < .01) reduced on day 10 (14 +/- 13 pg/ml) and day 30 (11 +/- 9 pg/ml) in comparison with untreated infected mice. The atrial and ventricular ANP messenger RNA (mRNA) concentrations in untreated mice showed increases of approximately 1.4- and 29.3-fold, respectively, on day 10 and increases of 1.8- and 34-fold, respectively, on day 30 compared with the concentration in uninfected controls. Combined OK432 and IFN significantly (P < .01) reduced the increase in ANP mRNA concentration in ventricles to 6.0- and 6.7-fold on days 10 and 30, respectively. Neither OK432 nor IFN monotherapy reduced the ANP mRNA concentrations in atria and ventricles compared with those in untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cardiovirus Infections; Encephalomyocarditis virus; Female; Gene Expression Regulation; Humans; Interferon Type I; Interferon-alpha; Mice; Mice, Inbred C3H; Myocarditis; Picibanil; Recombinant Fusion Proteins; Recombinant Proteins; RNA, Messenger

We analyzed the ventricular expression of atrial and brain natriuretic peptides (ANP and BNP) in patients with myocarditis. Immunohistochemical analysis of endomyocardial biopsy specimens showed ANP and BNP immunoreactivity in the early myocarditis group (ANP in 4/10 and BNP in 3/10) and the late myocarditis group (ANP and BNP in 4/10), but not in the controls (0/8). Hemodynamic parameters, such as left ventricular volume indexes, pulmonary capillary wedge pressure, and left ventricular end-diastolic pressure, were higher and the cardiac index and ejection fraction were lower in the patients positive for ANP and/or BNP. Histological changes, including myocyte size, cellular necrosis, inflammatory infiltrates and fibrosis, were more severe in the immunohistochemically positive biopsy specimens. In the autopsy hearts, ANP- or BNP-positive myocytes were noted in the chronic myocarditis or postmyocarditis group, but not in acute fulminant myocarditis or in normal controls. Both ANP and BNP were predominantly localized in the residual myocytes edging the myocardial lesions, and also in the myocytes just beneath the left ventricular endocardium. This study demonstrated augmented ventricular ANP and BNP expressions in patients with myocarditis, and suggested that regional stress is important in the augmentation of these peptides as well as hemodynamic stress.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Biopsy; Female; Follow-Up Studies; Heart Ventricles; Hemodynamics; Humans; Immunohistochemistry; Male; Middle Aged; Myocarditis; Natriuretic Peptide, Brain; Nerve Tissue Proteins

We have developed murine models of viral myocarditis induced by encephalomyocarditis (EMC) virus in which severe myocarditis, congestive heart failure and dilated cardiomyopathy occur in high incidence. From these models, we have learned the natural history and pathogenesis and assessed new diagnostic methods and therapeutic and preventive interventions. Mural thrombi in the atria and ventricles, ventricular aneurysms, conduction disturbance and various arrhythmias were seen in these models. Anti-heart antibody were found in sera of mice and myosin isoenzyme were changed during the course of EMC virus myocarditis. Atrial natriuretic polypeptide was markedly increased in the ventricles in these mice. Successive infection with coxsackievirus and EMC virus developed lesions similar to chronic myocarditis. The myocardial uptake of antimyosin antibody was proved to be a useful method of diagnosis of myocarditis. Treatment with the nucleoside analogue, ribavirin and recombinant alpha interferon effectively inhibited myocardial virus replication and reduced myocardial damage. Passive immunization and virus-specific vaccine prevented development of myocarditis. The use of immunosuppressive therapy was associated with greater mortality when administered early in illness and beneficial effects were not seen by later administration. Angiotensin-converting enzyme inhibitor improved myocardial injury and congestive heart failure. A nonselective beta-adrenergic blocker with intrinsic sympathomimetic activity, carteolol, prevented the development of myocardial lesions similar to those in dilated cardiomyopathy after myocarditis in the chronic stage.

Topics: Adjuvants, Immunologic; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Autoantibodies; Cardiomegaly; Cardiomyopathy, Dilated; Encephalomyocarditis virus; Enterovirus Infections; Heart Aneurysm; Heart Failure; Immunization, Passive; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Myocarditis; Myocardium; Myosins; RNA, Viral

To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure greater than or equal to 8 mm Hg having ANF greater than or equal to 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure less than 8 mm Hg having ANF less than 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean +/- standard deviation 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Function; Atrial Natriuretic Factor; Cardiomyopathy, Dilated; Female; Heart Transplantation; Humans; Male; Middle Aged; Myocarditis; Pulmonary Wedge Pressure; Radioimmunoassay; Regression Analysis

We studied the expression and distribution of atrial natriuretic polypeptide in the ventricles of 27 autopsied children with Kawasaki disease. Fourteen of the children had died in the acute stage of the disease. Three without any coronary artery aneurysms died due to myocarditis, while 11 with coronary artery aneurysms also had myocarditis but died of coronary heart disease. Histologic evidence of acute myocardial infarction was noted in three children who died of coronary heart disease. In the 14 children with acute-stage deaths, no abnormal expression of atrial natriuretic polypeptide was noted in the ventricles, despite the presence of heart failure in seven of them for 2 to 22 days before death. The other 13 patients had coronary artery aneurysms and died in the healed stage. In three patients with granulation tissue and congestive heart failure, myocytes in foci around the granulations were moderate to markedly positive for atrial natriuretic polypeptide. These three patients died over 8 days after the onset of their first myocardial infarct. Of 10 patients with old myocardial infarction, four had a history of congestive heart failure. They demonstrated moderate or marked atrial natriuretic polypeptide expression in extensive regions around sites of massive fibrosis, and foci of slight expression in the inner third of the noninfarcted region of the ventricle. In the other six patients without congestive heart failure, there was slight or moderate expression in foci around sites of massive fibrosis. We concluded that the expression of atrial natriuretic polypeptide appeared more than 1 week after the onset of acute myocardial infarction in the ventricles of children with Kawasaki disease who died in the healed stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Child; Child, Preschool; Female; Heart Ventricles; Humans; Immunohistochemistry; Infant; Male; Mucocutaneous Lymph Node Syndrome; Myocardial Infarction; Myocarditis; Myocardium; Survival Analysis; Time Factors; Tissue Distribution

To elucidate the pathophysiological role of atrial natriuretic polypeptide (ANP) in diseased hearts, ANP levels in atrial and ventricular tissues and plasma were investigated in mice with congestive heart failure after viral myocarditis. The study was performed on day 14 after encephalomyocarditis viral inoculation, when congestive heart failure developed. The atrial ANP level increased to a value two times higher than that of noninoculated age-matched mice (the control mice). The ventricles of the control mice contained an approximately 1,000-fold lower ANP level than the atrial ANP level. The ventricular ANP concentration of the infected mice showed about a 21 times higher level than the control value. The plasma ANP level was also elevated 20 times. On immunofluorescence studies, increase of immunostaining were found in the atrial of the infected mice, and positive staining appeared on the cardiocytes in almost all areas of the remaining ventricular tissues of the infected mice, whereas staining was not found on the ventricles of the control mice. The staining seemed particularly strong in the area surrounding the myocardial lesions. These results indicate that atrial and ventricular ANP synthesis and ANP secretion increase in the heart with viral myocarditis. The marked increase in the ventricular ANP level suggests that the ventricle is another important production site for circulating ANP.

Topics: Animals; Atrial Natriuretic Factor; Fluorescent Antibody Technique; Mice; Mice, Inbred BALB C; Myocarditis; Myocardium; Radioimmunoassay; Virus Diseases

To investigate the mechanism of expression of atrial natriuretic polypeptide (ANP) in human ventricles, we conducted an immunohistochemical study of ANP in biventricular endomyocardial biopsy specimens obtained from a total of 49 patients with cardiac dilatation due to dilated cardiomyopathy (21 patients), postmyocarditis (18 patients), or volume overload (five patients) and subjects with no dilatation as controls (five patients). Four-micron thick sections were stained by an indirect immunoperoxidase method using monoclonal antibody to alpha-human ANP as the primary antibody. The frequency of ANP-present myocytes was calculated in each specimen and compared with clinical, echocardiographic, hemodynamic, angiographic, and histologic parameters. ANP-present myocytes were noted in all of the 21 patients with dilated cardiomyopathy, in 11 of the 18 patients with postmyocarditis, in four of the five patients with volume overload, and in zero of the five controls. The mean percentage of ANP-present myocytes was significantly greater in the left-side specimens (35 +/- 37%) than in the right-side ones (2 +/- 4%). The percentage of ANP-present myocytes in the left-side specimens significantly correlated with peak systolic or end-diastolic wall stress (r = 0.67 and 0.58), left ventricular end-systolic or end-diastolic volume index (r = 0.75 and 0.69), or left ventricular end-diastolic pressure (r = 0.42) and inversely correlated with ejection fraction (r = -0.73), systolic left ventricular wall thickness (r = -0.58), or cardiac index (r = -0.30). Expression of ANP was rarely seen in the cases with normal wall stresses, normal ejection fraction, normal volume, or normal myocyte size. However, it was seen frequently even in hearts with normal levels of left ventricular end-diastolic pressure and cardiac index (compensated hearts). The percent of ANP-present myocytes in both sides significantly correlated with size of myocytes (r = 0.48 at right and r = 0.57 at left side) or degree of fibrosis (r = 0.45 at right and r = 0.48 at left side). These results suggest that ANP expression is augmented in the dilated ventricles regardless of the causes of dilatation and that the augmentation is a compensatory mechanism as prevention against decompensation responding to reduced contractility, excess of wall stresses, or both, concomitantly occurring with cardiac dilatation and myocardial hypertrophy.

Topics: Adult; Atrial Natriuretic Factor; Biopsy; Cardiomegaly; Cardiomyopathy, Dilated; Female; Heart Ventricles; Hemodynamics; Humans; Immunoenzyme Techniques; Male; Myocarditis; Myocardium

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Coxsackievirus Infections; Enterovirus B, Human; Mice; Myocarditis

Previous studies have shown that indomethacin administered during the early phase of experimental myocarditis may exacerbate the disease process. It is unknown whether late administration of this agent is safe. Therefore, the effect of indomethacin administration during the late phase of coxsackievirus B3 murine myocarditis was investigated. Forty 3-week-old CD1 mice each received a 3 x 10(4) median tissue culture-infective dose of coxsackievirus intraperitoneally. On day 10 of infection, mice were randomized to receive either indomethacin or normal saline solution for 10 days, and 10 mice from each group were killed on days 20 and 30 of infection. Heart weight and size and serum atrial natriuretic peptide were similar in both groups on days 20 and 30. On day 20, pathologic scores for the degree of inflammation and necrosis were 1.7 and 1.0 for the indomethacin group versus 1.4 and 1.7 for the saline solution group. On day 30, pathologic scores were 0.3 and 0.6 for the indomethacin group versus 0.5 and 0.6 for the saline solution group. In addition, mineralization was absent in indomethacin-treated animals on day 20 after infection, but it was present in half of the control animals at that time. The degree of mineralization did not differ on day 30 between the two groups. These findings suggest that indomethacin given in the late phase of coxsackievirus myocarditis has no deleterious effects at 30 days.

Topics: Animals; Atrial Natriuretic Factor; Chronic Disease; Coxsackievirus Infections; Disease Models, Animal; Enterovirus B, Human; Indomethacin; Mice; Myocarditis; Myocardium; Necrosis; Organ Size; Random Allocation

Topics: Atrial Natriuretic Factor; Cytoplasmic Granules; Heart Atria; Humans; Microscopy, Electron; Myocarditis; Myocardium