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

Characterisation of Anti-Arrhythmic Drug Effects on Cardiac Electrophysiology using Physics-Informed Neural Networks

The ability to accurately infer cardiac electrophysiological (EP) properties is key to improving arrhythmia diagnosis and treatment. In this work, we developed a physics-informed neural networks (PINNs) framework to predict how different myocardial EP parameters are modulated by anti-arrhythmic drugs. Using $\textit{in vitro}$ optical mapping images and the 3-channel Fenton-Karma model, we estimated the changes in ionic channel conductance caused by these drugs. Our framework successfully characterised the action of drugs HMR1556, nifedipine and lidocaine - respectively, blockade of $I_{K}$, $I_{Ca}$, and $I_{Na}$ currents - by estimating that they decreased the respective channel conductance by $31.8\pm2.7\%$ $(p=8.2 \times 10^{-5})$, $80.9\pm21.6\%$ $(p=0.02)$, and $8.6\pm0.5\%$ $(p=0.03)$, leaving the conductance of other channels unchanged. For carbenoxolone, whose main action is the blockade of intercellular gap junctions, PINNs also successfully predicted no significant changes $(p>0.09)$ in all ionic conductances. Our results are an important step towards the deployment of PINNs for model parameter estimation from experimental data, bringing this framework closer to clinical or laboratory images analysis and for the personalisation of mathematical models.Comment: Accepted for publication in the 21st IEEE International Symposium on Biomedical Imaging 202

Standardised framework for quantitative analysisof fibrillation dynamics

The analysis of complex mechanisms underlying ventricular fibrillation (VF) and atrial fibrillation (AF) requires sophisticatedtools for studying spatio-temporal action potential (AP) propagation dynamics. However, fibrillation analysis tools are oftencustom-made or proprietary, and vary between research groups. With no optimal standardised framework for analysis, resultsfrom different studies have led to disparate findings. Given the technical gap, here we present a comprehensive framework andset of principles for quantifying properties of wavefront dynamics in phase-processed data recorded during myocardial fibrillationwith potentiometric dyes. Phase transformation of the fibrillatory data is particularly useful for identifying self-perpetuating spiralwaves or rotational drivers (RDs) rotating around a phase singularity (PS). RDs have been implicated in sustaining fibrillation,and thus accurate localisation and quantification of RDs is crucial for understanding specific fibrillatory mechanisms. In thiswork, we assess how variation of analysis parameters and thresholds in the tracking of PSs and quantification of RDs couldresult in different interpretations of the underlying fibrillation mechanism. These techniques have been described and appliedto experimental AF and VF data, and AF simulations, and examples are provided from each of these data sets to demonstratethe range of fibrillatory behaviours and adaptability of these tools. The presented methodologies are available as an opensource software and offer an off-the-shelf research toolkit for quantifying and analysing fibrillatory mechanisms

Rotigaptide Infusion for the First 7 Days After Myocardial Infarction–Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border-Zone and Arrhythmia Inducibility

Background Survivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction–reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis. Methods and Results Infarction–reperfusion surgery was carried out in male Sprague‐Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion‐weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7‐day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, P=0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: −5% versus −15%; P=0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, P=0.042), and remodeling of the 3‐dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, P=0.013) and the dispersion (9° versus 12°, P=0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality. Conclusions Enhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation–induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarction management to reduce late arrhythmic risk

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

Determinants of new wavefront locations in cholinergic atrial fibrillation

AimsAtrial fibrillation (AF) wavefront dynamics are complex and difficult to interpret, contributing to uncertainty about the mechanisms that maintain AF. We aimed to investigate the interplay between rotors, wavelets, and focal sources during fibrillation.Methods and resultsArrhythmia wavefront dynamics were analysed for four optically mapped canine cholinergic AF preparations. A bilayer computer model was tuned to experimental preparations, and varied to have (i) fibrosis in both layers or the epicardium only, (ii) different spatial acetylcholine distributions, (iii) different intrinsic action potential duration between layers, and (iv) varied interlayer connectivity. Phase singularities (PSs) were identified and tracked over time to identify rotational drivers. New focal wavefronts were identified using phase contours. Phase singularity density and new wavefront locations were calculated during AF. There was a single dominant mechanism for sustaining AF in each of the preparations, either a rotational driver or repetitive new focal wavefronts. High-density PS sites existed preferentially around the pulmonary vein junctions. Three of the four preparations exhibited stable preferential sites of new wavefronts. Computational simulations predict that only a small number of connections are functionally important in sustaining AF, with new wavefront locations determined by the interplay between fibrosis distribution, acetylcholine concentration, and heterogeneity in repolarization within layers.Conclusion We were able to identify preferential sites of new wavefront initiation and rotational activity, in order to determine the mechanisms sustaining AF. Electrical measurements should be interpreted differently according to whether they are endocardial or epicardial recordings