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1.  Acute viral myocarditis 
European Heart Journal  2008;29(17):2073-2082.
Acute myocarditis is one of the most challenging diagnosis in cardiology. At present, no diagnostic gold standard is generally accepted, due to the insensitivity of traditional diagnostic tests. This leads to the need for new diagnostic approaches, which resulted in the emergence of new molecular tests and a more detailed immunohistochemical analysis of endomyocardial biopsies. Recent findings using these new diagnostic tests resulted in increased interest in inflammatory cardiomyopathies and a better understanding of its pathophysiology, the recognition in overlap of virus-mediated damage, inflammation, and autoimmune dysregulation. Novel results also pointed towards a broader spectrum of viral genomes responsible for acute myocarditis, indicating a shift of enterovirus and adenovirus to parvovirus B19 and human herpes virus 6. The present review proposes a general diagnostic approach, focuses on the viral aetiology and associated autoimmune processes, and reviews treatment options for patients with acute viral myocarditis.
doi:10.1093/eurheartj/ehn296
PMCID: PMC2519249  PMID: 18617482
Myocarditis; Virus; Heart failure; Inflammation
2.  Analysis of sudden unexpected death in southern Ontario, with emphasis on myocarditis. 
The records of all 2427 autopsies performed at the Brantford (Ont.) General and Paris (Ont.) Willett hospitals from Jan. 1, 1969 to Aug. 15, 1978 were reviewed. Of the 1299 cases of sudden unexpected death investigated by a coroner almost 28% were due to unnatural causes--violence or poisoning. The main cause of natural sudden death was coronary artery disease, which accounted for 43.3% of all the sudden unexpected deaths. In 20 cases the cause of death was thought to be viral myocarditis, and in 9 of the 20 there was serologic evidence of at least previous coxsackievirus disease. Two of the nine cases were of special interest because of the finding of giant-cell myocarditis in one and aortic valve disease in the other. Eleven of the 20 persons were aged 13 to 46 years. These findings support the view that the most serious manifestation of enterovirus infection today is cardiac damage by coxsackieviruses.
Images
PMCID: PMC1819176  PMID: 436050
3.  Coxsackievirus B3 sequences in the myocardium of fatal cases in a cluster of acute myocarditis in Greece 
Journal of Clinical Pathology  2005;58(4):357-360.
Aim: The investigation of three fatal cases during a nationwide cluster of cases of an upper respiratory tract infection (URTI) associated with myocarditis and/or pericarditis in Greece in 2002.
Methods: In the three women who died, necropsies were performed and tissue sections were taken for histological examination, antigen detection by immunohistochemistry and indirect immunofluorescence assay (IFA), amplification of viral genomes by nested reverse transcription polymerase chain reaction (RT-PCR), and sequence analysis.
Results: All samples showed histological signs of active myocarditis. Immunohistochemistry revealed the presence of the enterovirus VP1 family of proteins and IFA revealed the presence of coxsackievirus B3 antigen. Nested RT-PCR amplified enteroviral alleles of the 5′-untranslated region which were identical to each other and to the coxsackievirus B3 sequences.
Conclusions: This study provides pathological evidence of enteroviral infection among fatal myocarditis cases in a nationwide URTI cluster of cases associated with myocarditis and/or pericarditis.
doi:10.1136/jcp.2004.020099
PMCID: PMC1770614  PMID: 15790697
acute myocarditis; enterovirus; immunofluorescence; immunohistochemistry; sequencing
4.  Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity 
Methods (San Diego, Calif.)  2007;41(1):118-122.
Excellent animal models are available of virus-induced and autoimmune heart disease that are remarkably similar to human disease. Developing good animal models for heart disease is crucial because cardiovascular disease is now the leading cause of death in the United States and is estimated to be the leading cause of death in the world by the year 2020. A significant proportion of heart disease in Western populations is associated with inflammation. Myocarditis, or inflammation of the heart muscle, is the major cause of sudden death in young adults. Although most individuals recover from acute myocarditis, genetically susceptible individuals may go on to develop chronic myocarditis and dilated cardiomyopathy (DCM) resulting in congestive heart failure. In this article, we describe a model of autoimmune myocarditis and DCM induced by inoculation with heart-passaged coxsackievirus B3 (CVB3). Intraperitoneal inoculation of susceptible mice with CVB3 induces acute cardiac inflammation from days 7 to 14 post infection (pi) that progresses to chronic myocarditis and DCM from day 28 to at least 56 pi. The model of CVB3-induced myocarditis presented here allows dissection of the contribution of viral infection and xenobiotics on immune dysregulation and inflammation in the heart. An improved understanding of the interaction between environmental exposures and the development of heart disease represents a clear challenge for immunotoxicologists.
doi:10.1016/j.ymeth.2006.07.009
PMCID: PMC1764911  PMID: 17161308
immunotoxicology; autoimmunity; myocarditis; coxsackievirus; animal model
5.  Characterization of Enterovirus Isolates from Patients with Heart Muscle Disease in a Selenium-Deficient Area of China 
Journal of Clinical Microbiology  2000;38(10):3538-3543.
An association of enterovirus infection with endemic cardiomyopathy (Keshan disease [KD]) and outbreaks of myocarditis in selenium-deficient rural areas of southwestern China has been established. Enteroviruses have been isolated from patients with KD or during outbreaks of myocarditis in last two decades. Six of these isolates grew readily in cell lines (Vero or HEp-2) and were investigated by a novel molecular typing method apart from serotyping and pathogenicity. A neutralization assay identified two isolates from KD as coxsackievirus serotype B2 (CVB2) and two isolates from myocarditis as coxsackievirus serotype B6 (CVB6) but failed to type the remaining two isolates, also from myocarditis. Direct nucleotide sequencing of reverse transcription-PCR products amplified from the 5′ nontranslated region (5′NTR) of these viruses confirmed that they belong to a phylogenetic cluster consisting of coxsackie B-like viruses, including some echovirus serotypes. Sequence analysis of the coding region for viral capsid protein VP1 showed that two isolates serotyped as CVB2 have the highest amino acid sequence homology with CVB2 and that the remaining four isolates, two CVB6 and the two unknown serotypes, are most closely related to the sequence of CVB6. Sequences among these isolates varied from 82.3 to 99% in the 5′NTR and from 69 to 99% in VP1, indicating no cross contamination. The pathogenicity of these viruses in adult and suckling mice was assessed. None caused pathologic changes in the hearts of adult MF-1 or SWR mice, although pancreatitis was evident. However, the four CVB6-like viruses caused death in suckling mice, similar to a virulent coxsackievirus group B3 laboratory strain. In conclusion, the sequence data confirm that coxsackievirus group B serotypes are predominant in the region in which KD is endemic and may be the etiological agents in outbreaks of myocarditis. VP1 genotyping of enteroviruses is accurate and reliable. Animal experiments indicate that isolates may differ in pathogenicity.
PMCID: PMC87433  PMID: 11015360
6.  Postpartum HELLP syndrome—the case of lost battle 
Unexpected rapid maternal death after delivery due to HELLP syndrome is rarely encountered and may become the subject of forensic expertise. Unexpectedness, suddenness, and fulminant course of this syndrome as well as absence of classical signs of pre-eclampsia can confuse physicians and lead to diagnostic delay. A definitive post-mortem diagnosis of HELLP syndrome in questionable cases of maternal death should be based on accepted laboratory criteria and characteristic histopathological alterations. We present a case of acute postpartum HELLP syndrome complicated by disseminated intravascular coagulation and acute renal failure which caused rapid maternal death only 20 hours after a caesarean section following an uncomplicated pregnancy.
doi:10.3109/03009734.2012.725431
PMCID: PMC3572672  PMID: 23033875
Acute renal failure; DIC; HELLP syndrome; maternal death
7.  The importance of cardiac MRI as a diagnostic tool in viral myocarditis-induced cardiomyopathy 
Netherlands Heart Journal  2009;17(12):481-486.
Myocarditis is an acute or chronic inflammatory disease of the myocardium which can be viral, postinfectious immune or primarily organ-specific autoimmune. Clinical manifestations of acute and chronic myocarditis are extremely varied, ranging from mild to severe. Affected patients may recover or develop (dilated) cardiomyopathy (DCM) with life-threatening symptoms including heart failure, conduction disturbances, arrhythmias, cardiogenic shock or sudden cardiac death.
The diagnosis of myocarditis is a challenging process and not only because of a diverse presentation; other problems are limited sensitivity of endomyocardial biopsies (EMB) and overlapping symptoms. Furthermore, the diagnosis is not well defined. However, early diagnosis is mandatory to address specific aetiology-directed therapeutic management in myocarditis that influences patient morbidity and mortality.
Currently, EMB remains the only way to confirm the presence of a viral genome and other histopathological findings allowing proper treatment to be implemented in cases of myocarditis. Increased recognition of the role of myocardial inflammatory changes has given rise to interest in noninvasive imaging as a diagnostic tool, especially cardiovascular magnetic resonance imaging (CMR). In this review we discuss the current role of CMR in the evaluation of myocarditis-induced inflammatory cardiomyopathies. (Neth Heart J 2009;17:481-6.)
PMCID: PMC2804081  PMID: 20087452
myocarditis; cardiac magnetic resonance imaging; cardiomyopathy
8.  Fatal parvoviral myocarditis: A case report and review of literature 
Diagnostic Pathology  2008;3:21.
Background
Histologically documented cases of parvoviral myocarditis are exceedingly rare.
Case presentation
Here, we report a 41-year old African American immunocompetent patient who died of parvoviral myocarditis after a 10 day illness characterized by fever, headaches, generalized arthralgias, and a maculopapular rash.
Autopsy revealed an infiltrate myocarditis composed primarily of T-lymphocytes and macrophages associated with extensive myocardial fibrosis. The diagnosis of parvovirus was determined by polymerase chain reaction (PCR) on both pre-mortem serum and post-mortem myocardial tissue
Methods
DNA was extracted from tissue and serum and primers were used to amplify DNAsequences of parvovirus B19 using nested polymerase chain reaction (PCR).
Conclusion
The diagnosis of parvovirus should be considered in cases of fatal myocarditis, and diagnosis can be confirmed at autopsy by molecular techniques.
doi:10.1186/1746-1596-3-21
PMCID: PMC2396599  PMID: 18447927
9.  Improved crystallization of the coxsackievirus B3 RNA-dependent RNA polymerase 
The first crystal of a coxsackievirus RNA-dependent RNA polymerase is reported.
The Picornaviridae virus family contains a large number of human pathogens such as poliovirus, hepatitis A virus and rhinoviruses. Amongst the viruses belonging to the genus Enterovirus, several serotypes of coxsackievirus coexist for which neither vaccine nor therapy is available. Coxsackievirus B3 is involved in the development of acute myocarditis and dilated cardiomyopathy and is thought to be an important cause of sudden death in young adults. Here, the first crystal of a coxsackievirus RNA-dependent RNA polymerase is reported. Standard crystallization methods yielded crystals that were poorly suited to X-­ray diffraction studies, with one axis being completely disordered. Crystallization was improved by testing crystallization solutions from commercial screens as additives. This approach yielded crystals that diffracted to 2.1 Å resolution and that were suitable for structure determination.
doi:10.1107/S1744309107020416
PMCID: PMC2335076  PMID: 17554171
coxsackievirus B3; RNA-dependent RNA polymerase
10.  Complete Genome Sequence of a Coxsackievirus B3 Isolated from a Sichuan Snub-Nosed Monkey 
Journal of Virology  2012;86(23):13134-13135.
Coxsackievirus B3 (CVB3) is an enterovirus in the family Picornaviridae that is significant to human health, being associated with myocarditis, aseptic meningitis, and pancreatitis, among other conditions. In addition to humans, Sichuan snub-nosed monkeys can be infected and killed by CVB3. Here, we report the first complete genome sequence of a novel coxsackievirus B3 strain, SSM-CVB3, which was isolated from a deceased Sichuan snub-nosed monkey with severe myocarditis. Our findings may aid in understanding the evolutionary characteristics and molecular pathogenesis of this virus.
doi:10.1128/JVI.02365-12
PMCID: PMC3497664  PMID: 23118460
11.  Myocarditis, Disseminated Infection, and Early Viral Persistence Following Experimental Coxsackievirus B Infection of Cynomolgus Monkeys 
PLoS ONE  2013;8(9):e74569.
Coxsackievirus B (CVB) infection is a common cause of acute viral myocarditis. The clinical presentation of myocarditis caused by this enterovirus is highly variable, ranging from mildly symptoms to complete hemodynamic collapse. These variations in initial symptoms and in the immediate and long term outcomes of this disease have impeded development of effective treatment strategies. Nine cynomolgus monkeys were inoculated with myocarditic strains of CVB. Virological studies performed up to 28 days post-inoculation demonstrated the development of neutralizing antibody in all animals, and the presence of CVB in plasma. High dose intravenous inoculation (n = 2) resulted in severe disseminated disease, while low dose intravenous (n = 6) or oral infection (1 animal) resulted in clinically unapparent infection. Transient, minor, echocardiographic abnormalities were noted in several animals, but no animals displayed signs of significant acute cardiac failure. Although viremia rapidly resolved, signs of myocardial inflammation and injury were observed in all animals at the time of necropsy, and CVB was detected in postmortem myocardial specimens up to 28 days PI. This non-human primate system replicates many features of illness in acute coxsackievirus myocarditis and demonstrates that myocardial involvement may be common in enteroviral infection; it may provide a model system for testing of treatment strategies for enteroviral infections and acute coxsackievirus myocarditis.
doi:10.1371/journal.pone.0074569
PMCID: PMC3767629  PMID: 24040287
12.  Direct Gene Transfer with IP-10 Mutant Ameliorates Mouse CVB3-Induced Myocarditis by Blunting Th1 Immune Responses 
PLoS ONE  2011;6(3):e18186.
Background
Myocarditis is an inflammation of the myocardium that often follows the enterovirus infections, with coxsackievirus B3 (CVB3) being the most dominant etiologic agent. We and other groups previously reported that chemokine IP-10 was significantly induced in the heart tissue of CVB3-infected mice and contributed to the migration of massive inflammatory cells into the myocardium, which represents one of the most important mechanisms of viral myocarditis. To evaluate the direct effect of IP-10 on the inflammatory responses in CVB3 myocarditis, herein an IP-10 mutant deprived of chemo-attractant function was introduced into mice to antagonize the endogenous IP-10 activity, and its therapeutic effect on CVB3-induced myocarditis was evaluated.
Methodology/Principal Findings
The depletion mutant pIP-10-AT, with an additional methionine after removal of the 5 N-terminal amino acids, was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection. Compared with vector or no treatment, pIP-10-AT treatment had significantly reduced heart/body weight ratio and serum CK-MB level, increased survival rate and improved heart histopathology, suggesting an ameliorated myocarditis. This therapeutic effect was not attributable to an enhanced viral clearance, but to a blunted Th1 immune response, as evidenced by significantly decreased splenic CD4+/CD8+IFN-γ+ T cell percentages and reduced myocardial Th1 cytokine levels.
Conclusion/Significance
Our findings constitute the first preclinical data indicating that interfering in vivo IP-10 activity could ameliorate CVB3 induced myocarditis. This strategy may represent as a new therapeutic approach in treating viral myocarditis.
doi:10.1371/journal.pone.0018186
PMCID: PMC3062568  PMID: 21445362
13.  Post-Mortem Echocardiography as a Guide to Cardiac Autopsy—A Worthwhile Concept? 
Sudden and unexpected death in the young is a common and worldwide problem. Sudden, unexpected death in infancy (SUDI), clinically unexpected death in an infant between one week and one year of age, affects around 1 in 1000 infants. Autopsy will reveal a specific cause of death in only one third of cases. This has led to various ancillary examinations in an effort to increase the diagnostic yield of the autopsy.
In this case report it is suggested that another diagnostic modality, that of the post-mortem echocardiogram might be a worthwhile concept to explore.
PMCID: PMC2941138  PMID: 20859531
autopsy; echocardiogram; SUDI
14.  Infection of Cardiomyocytes and Induction of Left Ventricle Dysfunction by Neurovirulent Polytropic Murine Retrovirus▿  
Journal of Virology  2007;81(22):12307-12315.
Viral infections of the heart are a causative factor of myocarditis as well as of sudden, unexpected deaths of children, yet the mechanisms of pathogenesis remain unclear, in part due to the relatively few animal models of virus-induced myocarditis. In the current study, we examined the ability of polytropic murine retroviruses to infect the heart and induce cardiac dysfunction. In situ hybridization and immunohistochemistry analysis detected virus-infected cardiomyocytes and macrophages in the heart. A significant decrease in left ventricle function, as measured by fractional shortening, was detected in mice infected with the neurovirulent retrovirus Fr98 but not in mice infected with the nonneurovirulent retrovirus Fr54. Virus infection was not associated with consistent findings of fibrosis or substantial cellular infiltrate. Fr98-induced left ventricle dysfunction was associated with a higher virus load, increased mRNA expression of the macrophage marker F4/80, increased chemokine production, and a small number of apoptotic cells in the heart.
doi:10.1128/JVI.01002-07
PMCID: PMC2168971  PMID: 17855522
15.  Myocarditis mimicking acute myocardial infarction: role of endomyocardial biopsy in the differential diagnosis 
Heart  2000;84(3):245-250.
OBJECTIVE—To test the hypothesis, using endomyocardial biopsies, that unexplained cases of apparent acute myocardial infarction were caused by myocarditis.
MATERIAL—Between 1992 and 1998, 12 patients were admitted to the coronary care unit with severe chest pain, ST segment elevation, increased serum creatine kinase and MB isoenzyme, and with wall motion abnormalities on echocardiogram highly suggestive of acute myocardial infarction. These patients were further investigated by endomyocardial biopsy, as their coronary angiograms were normal. A diagnosis of myocarditis was made according to the Dallas criteria. A panel of antibodies was used for immunohistochemical characterisation of inflammatory cell infiltrate. Polymerase chain reaction (PCR) was used to detect viral genomes in seven cases.
RESULTS—Haematoxylin and eosin staining of the endomyocardial biopsy showed active myocarditis in six patients and borderline myocarditis in one. Immunohistochemistry was positive for inflammatory cell infiltrates in 11 patients, including all the seven who were positive on haematoxylin and eosin staining according to the Dallas criteria. Only one patient had no evidence of inflammation. PCR was positive in two patients, both for Epstein-Barr virus. Follow up showed complete resolution of echocardiographic abnormalities in all patients except one.
CONCLUSIONS—Myocarditis can mimic acute myocardial infarction in patients with angiographically normal coronary arteries, leading to errors of treatment. In patients with apparent myocardial infarction and a normal coronary angiogram, endomyocardial biopsy may help in the diagnosis of myocarditis. The sensitivity of endomyocardial biopsy was enhanced by using immunohistochemical and molecular biological techniques.


Keywords: acute myocardial infarction; endomyocardial biopsy; myocarditis
doi:10.1136/heart.84.3.245
PMCID: PMC1760950  PMID: 10956283
16.  Molecular detection and serotypic analysis of enterovirus RNA in archival specimens from patients with acute myocarditis. 
British Heart Journal  1995;74(5):522-527.
OBJECTIVE--To determine whether enterovirus RNA can be demonstrated in archival necropsy material in acute myocarditis. DESIGN--Analysis of paraffin embedded myocardial tissue from cases of acute myocarditis. SETTING--University virology department. METHODS--Extraction of RNA from tissue followed by polymerase chain reaction (PCR) and DNA sequence analysis. PATIENTS--Six patients with histologically proven myocarditis and eight controls. RESULTS--Enterovirus RNA was identified in 5 of 6 patients with myocarditis and in none of the controls. The nucleotide sequences of the PCR products showed greatest similarity to group B coxsackieviruses, particularly coxsackievirus B3. CONCLUSION--This study indicates that archival tissue samples, even histologically stained tissue sections, can be used to study the role of enteroviruses in myocardial disease using molecular detection techniques. If a predominant role for coxsackievirus B3 in myocarditis is confirmed by further study, this may have implications for the development of a specific vaccine.
Images
PMCID: PMC484072  PMID: 8562237
17.  Cardiovascular magnetic resonance risk stratification in patients with clinically suspected myocarditis 
Background
The diagnosis of myocarditis is challenging due to its varying clinical presentation. Since myocarditis can be associated with significant 5-year mortality, and postmortem data show myocarditis in almost 10% of all adults suffering sudden cardiac death, individual risk stratification for patients with suspected myocarditis is of great clinical interest. We sought to demonstrate that patients with clinically suspected myocarditis and a normal cardiovascular magnetic resonance (CMR) according to our definition have a good prognosis, independent of their clinical symptoms and other findings.
Methods
Prospective clinical long-term follow-up of consecutive patients undergoing CMR for work-up of clinically suspected myocarditis at our institution in 2007-2008.
Results
Follow-up was available for n = 405 patients (all-comers, 54.8% inpatients, 38% outpatient referrals from cardiologists). Median follow-up time was 1591 days. CMR diagnosis was “myocarditis” in 28.8%, “normal” in 55.6% and “other pathology” in 15.6%. Normal CMR was defined as normal left ventricular (LV) volumes and normal left ventricular ejection fraction (LV-EF) in the absence of late Gadolinium Enhancement (LGE). The overall mortality was 3.2%. There were seven cardiac deaths during follow-up, in addition one aborted SCD and two patients had appropriate internal cardioverter defibrillator (ICD) shocks – all of these occurred in patients with abnormal CMR. Kaplan-Meier analysis with log-rank test showed significant difference for major adverse cardiac events (cardiac death, sudden cardiac death (SCD), ICD discharge, aborted SCD) between patients with normal and abnormal CMR (p = 0.0003).
Conclusion
In our unselected population of consecutive patients referred for CMR work-up of clinically suspected myocarditis, patients with normal CMR have a good prognosis independent of their clinical symptoms and other findings.
doi:10.1186/1532-429X-16-14
PMCID: PMC3913958  PMID: 24461053
Cardiovascular magnetic resonance; Risk stratification; Myocarditis; Outcome
18.  A highly divergent Encephalomyocarditis virus isolated from nonhuman primates in Singapore 
Virology Journal  2013;10:248.
Background
In 2001 and 2002, fatal myocarditis resulted in the sudden deaths of four, two adult and two juvenile, orang utans out of a cohort of 26 in the Singapore Zoological Gardens.
Methods
Of the four orang utans that underwent post-mortem examination, virus isolation was performed from the tissue homogenates of the heart and lung obtained from the two juvenile orang utans in Vero cell cultures. The tissue culture fluid was examined using electron microscopy. Reverse transcription and polymerase chain reaction with Encephalomyocarditis virus (EMCV)-specific primers targeting the gene regions of VP3/VP1 and 3D polymerase (3Dpol) confirmed the virus genus and species. The two EMCV isolates were sequenced and phylogenetic analyses of the virus genes performed. Serological testing on other animal species in the Singapore Zoological Gardens was also conducted.
Results
Electron microscopy of the two EMCV isolates, designated Sing-M100-02 and Sing-M105-02, revealed spherical viral particles of about 20 to 30 nm, consistent with the size and morphology of members belonging to the family Picornaviridae. In addition, infected-Vero cells showed positive immunoflorescence staining with antiserum to EMCV. Sequencing of the viral genome showed that the two EMCV isolates were 99.9% identical at the nucleotide level, indicating a similar source of origin. When compared with existing EMCV sequences in the VP1 and 3Dpol gene regions, the nucleotide divergence were at a maximum of 38.8% and 23.6% respectively, while the amino acid divergence were at a maximum of 33.9% and 11.3% respectively. Phylogenetic analyses of VP1 and 3Dpol genes further grouped the Sing-M100-02 and Sing-M105-02 isolates to themselves, away from existing EMCV lineages. This strongly suggested that Sing-M100-02 and Sing-M105-02 isolates are highly divergent variants of EMCV. Apart from the two deceased orang utans, a serological survey conducted among other zoo animals showed that a number of other animal species had neutralizing antibodies to Sing-M105-02 isolate, indicating that the EMCV variant has a relatively wide host range.
Conclusions
The etiological agent responsible for the fatal myocarditis cases among two of the four orang utans in the Singapore Zoological Gardens was a highly divergent variant of EMCV. This is the first report of an EMCV infection in Singapore and South East Asia.
doi:10.1186/1743-422X-10-248
PMCID: PMC3750836  PMID: 23914943
Encephalomyocarditis virus; Variant virus; Fatal acute myocarditis; Orang utan
19.  Coxsackievirus B3 Infection Induces cyr61 Activation via JNK To Mediate Cell Death 
Journal of Virology  2004;78(24):13479-13488.
Coxsackievirus B3 (CVB3), an enterovirus in the Picornavirus family, is the most common human pathogen associated with myocarditis and idiopathic dilated cardiomyopathy. We found upregulation of the cysteine-rich protein gene (cyr61) after CVB3 infection in HeLa cells with a cDNA microarray approach, which is confirmed by Northern blot analysis. It is also revealed that the extracellular amount of Cyr61 protein was increased after CVB3 infection in HeLa cells. cyr61 is an early-transcribed gene, and the Cyr61 protein is secreted into the extracellular matrix. Its function is related to cell adhesion, migration, and neuronal cell death. Here, we show that activation of the cyr61 promoter by CVB3 infection is dependent on JNK activation induced by CVB3 replication and viral protein expression in infected cells. To explore the role of Cyr61 protein in infected HeLa cells, we transiently overexpressed cyr61 and infected HeLa cells with CVB3. This increased CVB3 growth in the cells and promoted host cell death by viral infection, whereas down-expression of cyr61 with short interfering RNA reduced CVB3 growth and showed resistance to cell death by CVB3 infection. In conclusion, we have demonstrated a new role for cyr61 in HeLa cells infected with CVB3, which is associated with the cell death induced by virus infection. These data thus expand our understanding of the physiological functions of cyr61 in virus-induced cell death and provide new insights into the cellular factors involved.
doi:10.1128/JVI.78.24.13479-13488.2004
PMCID: PMC533934  PMID: 15564459
20.  Molecular autopsy in the sudden cardiac death of a young woman: A first Canadian report 
The Canadian Journal of Cardiology  2007;23(11):904-906.
Standard autopsy of young victims with sudden cardiac death commonly does not identify a specific pathological diagnosis. In such cases, sudden cardiac death may be secondary to a genetic condition predisposing the patient to ventricular arrhythmias. Failure to identify a genetic etiology for an unexpected sudden death may leave surviving family members at risk for a similar tragedy. The case of a 21-year-old woman who died suddenly while at rest is presented. Molecular genetic analysis of tissue retrieved from the regional coroner’s office identified a novel missense mutation in the KCNH2 gene, a gene known to cause the long QT syndrome.
PMCID: PMC2651371  PMID: 17876385
Arrhythmia; Genetics; Long QT syndrome; Sudden cardiac death
21.  Apoptosis in Coxsackievirus B3-Caused Diseases: Interaction between the Capsid Protein VP2 and the Proapoptotic Protein Siva 
Journal of Virology  2000;74(9):4284-4290.
Coxsackievirus B3 (CVB3) is a common factor in human myocarditis. Apoptotic events are present in CVB3-induced disease, but it is unclear how CVB3 is involved in apoptosis and which viral proteins may induce the apoptotic pathway. In this report we demonstrate that the human and murine proapoptotic protein Siva specifically interact with the CVB3 capsid protein VP2. Furthermore, the transcription of Siva is strongly induced in tissue of CVB3-infected mice and is present in the same area which is positively stained for apoptosis, CD27, and CD70. It has been proposed that Siva is involved in the CD27/CD70-transduced apoptosis. Therefore, we suggest a molecular mechanism through which apoptotic events contributes to CVB3-caused pathogenesis.
PMCID: PMC111945  PMID: 10756043
22.  Diagnosis and Treatment of Viral Myocarditis 
Mayo Clinic Proceedings  2009;84(11):1001-1009.
Myocarditis, an inflammatory disease of heart muscle, is an important cause of dilated cardiomyopathy worldwide. Viral infection is also an important cause of myocarditis, and the spectrum of viruses known to cause myocarditis has changed in the past 2 decades. Several new diagnostic methods, such as cardiac magnetic resonance imaging, are useful for diagnosing myocarditis. Endomyocardial biopsy may be used for patients with acute dilated cardiomyopathy associated with hemodynamic compromise, those with life-threatening arrhythmia, and those whose condition does not respond to conventional supportive therapy. Important prognostic variables include the degree of left and right ventricular dysfunction, heart block, and specific histopathological forms of myocarditis. We review diagnostic and therapeutic strategies for the treatment of viral myocarditis. English-language publications in PubMed and references from relevant articles published between January 1, 1985, and August 5, 2008, were analyzed. Main keywords searched were myocarditis, dilated cardiomyopathy, endomyocardial biopsy, cardiac magnetic resonance imaging, and immunotherapy.
PMCID: PMC2770911  PMID: 19880690
23.  Sex-specific signaling through Toll-Like Receptors 2 and 4 contributes to survival outcome of Coxsackievirus B3 infection in C57Bl/6 mice 
Background
Coxsackievirus B3 (CVB3) induces myocarditis, an inflammatory heart disease, which affects men more than women. Toll-like receptor (TLR) signaling has been shown to determine the severity of CVB3-induced myocarditis. No direct role for signaling through TLR2 had been shown in myocarditis although published studies show that cardiac myosin is an endogenous TLR2 ligand and stimulates pro-inflammatory cytokine expression by dendritic cells in vitro. The goal of this study is to determine which TLRs show differential expression in CVB3 infected mice corresponding to male susceptibility and female resistance in this disease.
Methods
Male and female C57Bl/6 mice were infected with 102 PFU CVB3 and killed on day 3 or 6 post infection. Hearts were evaluated for virus titer, myocardial inflammation, and TLR mRNA expression by PCR array and microarray analysis. Splenic lymphocytes only were evaluated by flow cytometry for the number of TLR+/CD3+, TLR+/CD4+, TLR+F4/80+ and TLR+/CD11c+ subpopulations and the mean fluorescence intensity to assess upregulation of TLR expression on these cells. Mice were additionally treated with PAM3CSK4 (TLR2 agonist) or ultrapure LPS (TLR4 agonist) on the same day as CVB3 infection or 3 days post infection to confirm their role in myocarditis susceptibility.
Results
Despite equivalent viral titers, male C57Bl/6 mice develop more severe myocarditis than females by day 6 after infection. Microarray analysis shows a differential expression of TLR2 at day 3 with female mice having higher levels of TLR2 gene expression compared to males. Disease severity correlates to greater TLR4 protein expression on splenic lymphocytes in male mice 3 days after infection while resistance in females correlates to preferential TLR2 expression, especially in spleen lymphocytes. Treating male mice with PAM reduced mortality from 55% in control CVB3 infected animals to 10%. Treating female mice with LPS increased mortality from 0% in control infected animals to 60%.
Conclusion
CVB3 infection causes an up-regulation of TLR2 in female and of TLR4 in male mice and this differential expression between the sexes contributes to disease resistance of females and susceptibility of males. While previous reports demonstrated a pathogenic role for TLR4 this is the first report that TLR2 is preferentially up-regulated in CVB3 infected female mice or that signaling through this TLR directly causes myocarditis resistance.
doi:10.1186/2042-6410-3-25
PMCID: PMC3586360  PMID: 23241283
24.  Chromosome Y Regulates Survival Following Murine Coxsackievirus B3 Infection 
G3: Genes|Genomes|Genetics  2012;2(1):115-121.
Coxsackievirus B3 (CVB3) contributes to the development of myocarditis, an inflammatory heart disease that predominates in males, and infection is a cause of unexpected death in young individuals. Although gonadal hormones contribute significantly to sex differences, sex chromosomes may also influence disease. Increasing evidence indicates that Chromosome Y (ChrY) genetic variants can impact biological functions unrelated to sexual differentiation. Using C57BL/6J (B6)-ChrY consomic mice, we show that genetic variation in ChrY has a direct effect on the survival of CVB3-infected animals. This effect is not due to potential Sry-mediated differences in prenatal testosterone exposure or to differences in adult testosterone levels. Furthermore, we show that ChrY polymorphism influences the percentage of natural killer T cells in B6-ChrY consomic strains but does not underlie CVB3-induced mortality. These data underscore the importance of investigating not only the hormonal regulation but also ChrY genetic regulation of cardiovascular disease and other male-dominant, sexually dimorphic diseases and phenotypes.
doi:10.1534/g3.111.001610
PMCID: PMC3276194  PMID: 22384388
heart disease; sexual dimorphism; heterochromatin
25.  Sudden death associated with group A streptococcal infection in an 8-year-old girl with undiagnosed hypertrophic cardiomyopathy. 
Postgraduate Medical Journal  1998;74(877):673-674.
An 8-year-old girl died suddenly without prior symptoms. Post-mortem examination identified both systemic group A streptococcal infection and hypertrophic cardiomyopathy. She had no history of cardiac symptoms and was not in a high-risk group for sudden death due to hypertrophic cardiomyopathy. We believe the disseminated but asymptomatic group A streptococcal infection precipitated her early death from hypertrophic cardiomyopathy. Sudden unexpected death during systemic infection should be followed by post-mortem examination to look for evidence of hypertrophic cardiomyopathy, as this diagnosis has genetic implications for other family members.
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PMCID: PMC2431614  PMID: 10197214

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