The molecular characterization of Coxsackievirus B3 Pathogenisis

The group B coxsackieviruses (CVBs) cause a variety of clinical manifestations in humans and are often fatal in infants under the age of three months. In the cardiovascular field, CVBs are considered the primary etiologic agent of virus-induced myocarditis. Although often a subclinical illness in adults, myocarditis may lead to chronic dilated cardiomyopathy, arrhythmias and sudden death. Unlike other family members such as poliovirus, there is relatively little understanding of the mechanisms of pathogenesis of coxsackievirus and no vaccine is available. Therefore, the objective of this project was to map genetic regions associated with CVB3 virulence by studying antibody escape mutants which differ in their pathogenesis for heart tissue. In conjunction with previous work from the laboratory, a panel of ten antibody escape mutants was isolated: EM1- EM10. Sequence analysis of the genes encoding the capsid proteins (VP1-VP4) revealed that all but two mutants, EM7 and EM 10, contained a lysine to arginine mutation within the 'puff region' of VP2. In contrast, EM7 and EM10 contained a glutamate to glycine mutation within the 'knob region' of VP3. Both of these regions, the 'puff of VP2 and the 'knob' of VP3, have been shown to be neutralizing and/or immunodominant sites on the capsid surface of other picornaviruses. Complete sequence analysis of EMI and EM 10 revealed further mutations within the viral polymerase gene and the 5' nontranslated region which may be responsible for the phenotypes of these variants. As characterized in previous studies, EMI produces about tenfold lower titres in the hearts of infected mice as compared to the wildtype strain. This inability of EMI to replicate to wildtype levels in the hearts of infected animals does not appear to be the result of an inability to replicate in cardiomyocytes as demonstrated by in vitro analysis. The pathogenic phenotype of EM 10 in A/J mice has also been examined as part of this study. Data from these experiments suggest that EM 10 has a higher level of attenuation than EMI producing 100-1000 fold lower titres in the hearts of infected animals as compared to the wild type CVB3(RK) strain. In an attempt to determine if the lysine to argihine mutation in VP2 was responsible for the reduced myocarditic potential of EMI, this mutation was incorporated into an infectious clone of the wildtype strain. Despite multiple attempts the mutant clones did not produce infectious virus that could be tested for cardiovirulence. In summary this project has identified several loci within the CVB3 genome which may be responsible for the attenuated phenotypes of EMI and EM10. Correlation of such mutations with an alteration in a phenotypic property of interest, such as tropism for heart tissue, will lead to an increased understanding of CVB pathogenesis. This knowledge may be exploited in vaccine development.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

An International Survey of Health Care Providers Involved in the Management of Cancer Patients Exposed to Cardiotoxic Therapy

Cardiotoxicity is the second leading cause of morbidity and mortality in cancer survivors. The objective of this international cardiac oncology survey was to gain a better understanding of current knowledge and practice patterns among HCPs involved in the management of cancer patients exposed to potentially cardiotoxic drugs. Between 2012 and 2013, we conducted an email-based survey of HCPs involved in the management of cardiac disease in cancer patients. 393 survey responses were received, of which 77 were from Canadian respondents. The majority of respondents were cardiologists (47%), followed closely by medical oncologists. The majority of respondents agreed that cardiac issues are important to cancer patients (97%). However, only 36% of total respondents agreed with an accepted definition of cardiotoxicity. While 78% of respondents felt that cardiac medications are protective during active cancer treatment, only 51% would consider prescribing these medications up-front in cancer patients. Although results confirm a high level of concern for cardiac safety, there continues to be a lack of consensus on the definition of cardiotoxicity and a discrepancy in clinical practice between cardiologists and oncologists. These differences in opinion require resolution through more effective research collaboration and formulation of evidence-based guidelines

Clinical Experience of Patients Referred to a Multidisciplinary Cardiac Oncology Clinic: An Observational Study

Cardiotoxicity is the second leading cause of long-term morbidity and mortality among cancer survivors. The purpose of this retrospective observational study is to report on the clinical and cardiac outcomes in patients with early stage and advanced cancer who were referred to our multidisciplinary cardiac oncology clinic (COC). A total of 428 patients were referred to the COC between October 2008 and January 2013. The median age of patients at time of cancer diagnosis was 60. Almost half of patients who received cancer therapy received first-line chemotherapy alone (169, 41.7%), of which 84 (49.7%) were exposed to anthracyclines. The most common reasons for referral to the cardiac oncology clinic were decreased LVEF (34.6%), prechemotherapy assessment (11.9%), and arrhythmia (8.4%). A total of 175 (40.9%) patients referred to the COC were treated with cardiac medications. The majority (331, 77.3%) of patients were alive as of January 2013, and 93 (21.7%) patients were deceased. Through regular review of cardiac oncology clinic referral patterns, management plans, and patient outcomes, we aim to continuously improve delivery of cardiac care to our patient population and optimize cardiac health