Gap junction remodelling and conduction abnormalities in the heart

Electrical coupling between mammalian cardiac myocytes allows orderly spread of excitation and is mediated by gap junction (GJ) channels composed of connexin (Cx) proteins. In normal myocardium, gap junctions within the intercalated disc allow intercellular transfer of ions and represent low resistance pathways for electrical propagation. GJ remodelling describes either a change in connexin expression and/or redistribution toward the lateral cell borders. This remodelling is thought to play a crucial role in arrhythmogenesis. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. AF becomes more persistent over time (“AF begets AF”). This self perpetuating nature of AF is poorly understood and may be associated with GJ remodelling. The aim of this thesis was to characterise the GJ structural remodelling that occurs alongside electrical changes in AF and to investigate the role of gap junction modulation on changes in electrical propagation, using animal and cell models. The findings of the in vivo goat burst-pacing model suggest that late AF-induced electrical remodelling occurs with a similar time course to connexin remodelling. These consistencies in the timescale of remodelling suggest that structural GJ remodelling is a likely determinant of the development of persistent AF. Although electrical remodelling is unaffected by the angiotensin receptor blocker, candesartan, its administration does attenuate GJ remodelling. HL-1 is a cardiac muscle cell line with a phenotype that is similar to atrial myocytes, particularly in connexin expression. Rapid pacing did not induce a change in the pattern of activation. GJ uncoupling with carbenoxolone resulted in reversible slowing of conduction and could be used as a method of modifying conduction. This thesis provides an insight into the role of gap junctions in conduction propagation both in the intact myocardium in an animal model of AF and in an in vitro cell model

PREVALENCE AND ASSOCIATED FACTORS OF ANTENATAL ANXIETY SYMPTOMS IN BANGLADESH: A REPEATED MEASURES CLUSTER DATA ANALYSIS

Background: Antenatal Anxiety affects the mothers and their child. Spontaneous abortion, preeclampsia, preterm birth, and low birth weight are the most common consequences. In Bangladesh, we have very limited understanding about the burden of antenatal anxiety and its associated factors. We conducted a prospective longitudinal study to estimate the prevalence of anxiety symptoms and identify associated factors in pregnant women. Subjects and methods: A total of 1360 pregnant women were enrolled from 14 antenatal care (ANC) hospitals during September 2015 to August 2017. All selected women were assessed longitudinally at first, second and third trimesters of pregnancy. The State Anxiety Inventory (STAI-S) scale was used to measure the antenatal anxiety symptom. Generalize estimating equations (GEE) and alternating logistic regression (ALR) model were used to measure the risk factors and repetitive anxiety symptom measurements, respectively. Results: Over the study period, more than half (53.18%) of the women reported anxiety in at least one antenatal assessment. The prevalence of anxiety symptom in the first, second, and third trimesters was 29.5%, 23.5%, and 37.5%, respectively. Maternal anxiousness was significantly associated with the trimester, poor education, low blood hemoglobin, and low family income. Conclusion: Women were at high risk of getting anxious during first and third trimesters of pregnancy. Findings of the study can be useful in developing and designing intervention to reduce anxiety in women during pregnancy

PREVALENCE AND ASSOCIATED FACTORS OF ANTENATAL ANXIETY SYMPTOMS IN BANGLADESH: A REPEATED MEASURES CLUSTER DATA ANALYSIS

Background: Antenatal Anxiety affects the mothers and their child. Spontaneous abortion, preeclampsia, preterm birth, and low birth weight are the most common consequences. In Bangladesh, we have very limited understanding about the burden of antenatal anxiety and its associated factors. We conducted a prospective longitudinal study to estimate the prevalence of anxiety symptoms and identify associated factors in pregnant women. Subjects and methods: A total of 1360 pregnant women were enrolled from 14 antenatal care (ANC) hospitals during September 2015 to August 2017. All selected women were assessed longitudinally at first, second and third trimesters of pregnancy. The State Anxiety Inventory (STAI-S) scale was used to measure the antenatal anxiety symptom. Generalize estimating equations (GEE) and alternating logistic regression (ALR) model were used to measure the risk factors and repetitive anxiety symptom measurements, respectively. Results: Over the study period, more than half (53.18%) of the women reported anxiety in at least one antenatal assessment. The prevalence of anxiety symptom in the first, second, and third trimesters was 29.5%, 23.5%, and 37.5%, respectively. Maternal anxiousness was significantly associated with the trimester, poor education, low blood hemoglobin, and low family income. Conclusion: Women were at high risk of getting anxious during first and third trimesters of pregnancy. Findings of the study can be useful in developing and designing intervention to reduce anxiety in women during pregnancy

MENTAL HEALTH OUTCOMES OF ADULTS WITH COMORBIDITY AND CHRONIC DISEASES DURING THE COVID-19 PANDEMIC: A MATCHED CASE-CONTROL STUDY

Background: Individuals with certain pre-existing chronic health conditions have been identified as a high-risk group for fatalities of COVID-19. Therefore, it is likely that individuals with chronic diseases may worry during this pandemic to the detriment of their mental health. This study compares the mental health of Bangladeshi adults affected by chronic disease to a healthy, matched control group during the COVID-19 pandemic. Subjects and methods: A matched case-control analysis was performed with data collected from 395 respondents with chronic diseases and 395 controls matched for age, gender, and residence. Inclusion criteria for cases were respondents who self reported having asthma, cardiovascular disease symptoms and/or diabetes. Respondents were recruited using an online survey, which included the DASS-21 measure to assess symptoms of stress, anxiety, and depression. Chi-square test, t-test, Fisher’s exact test and a conditional logistic regression were performed to examine associations among variables. Results: The prevalence of anxiety symptoms and depression symptoms and the level of stress were significantly higher among cases (59%; 71.6%; 73.7%, respectively) than among controls (25.6%; 31.1%; 43.3%, respectively). Chi-square and t-test showed significant associations and differences between having chronic diseases and mental health outcomes. A conditional logistic regression showed that respondents with asthma, diabetes, cardiovascular disease symptoms, or any combination of these diseases had higher odds of exhibiting symptoms of stress, anxiety, and depression than healthy individuals. Conclusion: These results underscore a subpopulation vulnerable to mental health consequences during this pandemic and indicate the need for additional mental health resources to be available to those with chronic diseases

Violence against Women with Chronic Maternal Disabilities in Rural Bangladesh

This study explored violence against women with chronic maternal disabilities in rural Bangladesh. During November 2006 - July 2008, in-depth interviews were conducted with 17 rural Bangladeshi women suffering from uterine prolapse, stress incontinence, or fistula. Results of interviews showed that exposure to emotional abuse was almost universal, and most women were sexually abused. The common triggers for violence were the inability of the woman to perform household chores and to satisfy her husband's sexual demands. Misconceptions relating to the causes of these disabilities and the inability of the affected women to fulfill gender role expectations fostered stigma. Emotional and sexual violence increased their vulnerability, highlighting the lack of life options outside marriage and silencing most of them into accepting the violence. Initiatives need to be developed to address misperceptions regarding the causes of such disabilities and, in the long-term, create economic opportunities for reducing the dependence of women on marriage and men and transform the society to overcome rigid gender norms

Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multiparametric quantitative cardiac magnetic resonance imaging.

Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the Toll-like receptor 7 (TLR-7) agonist Resiquimod induces auto-antibodies and systemic tissue damage, including in the heart, and is used as an inducible mouse model of systemic lupus erythematosus (SLE). Here, we show that overactivation of the TLR-7 pathway of viral recognition by Resiquimod treatment of CFN mice induces severe thrombocytopenia and internal bleeding, which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2 * relaxation times, and compared results with ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2 * measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes. In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as an acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2 * mapping to CMR protocols for myocarditis diagnosis improves diagnostic sensitivity and interpretation of disease mechanisms.This article has an associated First Person interview with the first author of the paper

Mediastinal Lymphadenopathy, Class-Switched Auto-Antibodies and Myocardial Immune-Complexes During Heart Failure in Rodents and Humans.

Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemic heart failure pointing to an autoimmune response against the heart. T and B cells have been convincingly demonstrated to be activated after myocardial infarction, a prerequisite for the generation of mature auto-antibodies. Yet, little is known about the immunoglobulin isotype repertoire thus pathological potential of anti-heart auto-antibodies during heart failure. We obtained human myocardial tissue from ischemic heart failure patients and induced experimental MI in rats. We found that anti-heart autoimmunity persists during heart failure. Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with mature isotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens are present in rat heart failure serum, and IgG and complement C3 deposits are evident in heart failure tissue of both rats and human patients. Previously established myocardial inflammation, and the herein provided proof of B cell maturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide all the hallmark signs of an established autoimmune response in chronic heart failure

Cross-Priming Dendritic Cells Exacerbate Immunopathology After Ischemic Tissue Damage in the Heart.

BACKGROUND: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of heart failure. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells, and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4 METHODS: We induced type 2 myocardial infarction-like ischemic injury in the heart by treatment with a single high dose of the β-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long-term cardiac immunopathology and functional decline in wild type and RESULTS: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. CONCLUSION: Activation of cytotoxic CD

Timing of Enteral Feeding in Cerebral Malaria in Resource-Poor Settings: A Randomized Trial

BACKGROUND: Early start of enteral feeding is an established treatment strategy in intubated patients in intensive care since it reduces invasive bacterial infections and length of hospital stay. There is equipoise whether early enteral feeding is also beneficial in non-intubated patients with cerebral malaria in resource poor settings. We hypothesized that the risk of aspiration pneumonia might outweigh the potential benefits of earlier recovery and prevention of hypoglycaemia. METHOD AND FINDINGS: A randomized trial of early (day of admission) versus late (after 60 hours in adults or 36 hours in children) start of enteral feeding was undertaken in patients with cerebral malaria in Chittagong, Bangladesh from May 2008 to August 2009. The primary outcome measures were incidence of aspiration pneumonia, hypoglycaemia and coma recovery time. The trial was terminated after inclusion of 56 patients because of a high incidence of aspiration pneumonia in the early feeding group (9/27 (33%)), compared to the late feeding group (0/29 (0%)), p = 0.001). One patient in the late feeding group, and none in the early group, had hypoglycaemia during admission. There was no significant difference in overall mortality (9/27 (33%) vs 6/29 (21%), p = 0.370), but mortality was 5/9 (56%) in patients with aspiration pneumonia. CONCLUSIONS: In conclusion, early start of enteral feeding is detrimental in non-intubated patients with cerebral malaria in many resource-poor settings. Evidence gathered in resource rich settings is not necessarily transferable to resource-poor settings. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN57488577

Sero-prevalence and risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 infection in women and children in a rural district of Bangladesh: A cohort study.

BACKGROUND: Bangladesh reported its first COVID-19 case on March 8, 2020. Despite lockdowns and promoting behavioural interventions, as of December 31, 2021, Bangladesh reported 1.5 million confirmed cases and 27 904 COVID-19-related deaths. To understand the course of the pandemic and identify risk factors for SARs-Cov-2 infection, we conducted a cohort study from November 2020 to December 2021 in rural Bangladesh. METHODS: After obtaining informed consent and collecting baseline data on COVID-19 knowledge, comorbidities, socioeconomic status, and lifestyle, we collected data on COVID-like illness and care-seeking weekly for 54 weeks for women (n = 2683) and their children (n = 2433). Between March and July 2021, we tested all participants for SARS-CoV-2 antibodies using ROCHE's Elecsys® test kit. We calculated seropositivity rates and 95% confidence intervals (95% CI) separately for women and children. In addition, we calculated unadjusted and adjusted relative risk (RR) and 95% CI of seropositivity for different age and risk groups using log-binomial regression models. RESULTS: Overall, about one-third of women (35.8%, 95% CI = 33.7-37.9) and one-fifth of children (21.3%, 95% CI = 19.2-23.6) were seropositive for SARS-CoV-2 antibodies. The seroprevalence rate doubled for women and tripled for children between March 2021 and July 2021. Compared to women and children with the highest household wealth (HHW) tertile, both women and children from poorer households had a lower risk of infection (RR, 95% CI for lowest HHW tertile women (0.83 (0.71-0.97)) and children (0.75 (0.57-0.98)). Most infections were asymptomatic or mild. In addition, the risk of infection among women was higher if she reported chewing tobacco (RR = 1.19,95% CI = 1.03-1.38) and if her husband had an occupation requiring him to work indoors (RR = 1.16,  95% CI = 1.02-1.32). The risk of infection was higher among children if paternal education was >5 years (RR = 1.37, 95% CI = 1.10-1.71) than in children with a paternal education of ≤5 years. CONCLUSIONS: We provided prospectively collected population-based data, which could contribute to designing feasible strategies against COVID-19 tailored to high-risk groups. The most feasible strategy may be promoting preventive care practices; however, collecting data on reported practices is inadequate. More in-depth understanding of the factors related to adoption and adherence to the practices is essential