Subclinical thyroid dysfunction and incident atrial fibrillation - a systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): This project was supported by the MRes programme in the Institute of Life Course and Medical Sciences at The University of Liverpool. Thyroid hormones can act directly and indirectly on the cardiovascular system and studies have demonstrated associations between overt and subclinical thyroid dysfunction and adverse cardiovascular outcomes including heart failure, myocardial infarction, and coronary heart disease. The aim of this study was to assess the association between subclinical thyroid dysfunction and atrial fibrillation (AF).  The protocol was registered on PROSPERO (CRD42020221565). MEDLINE and Scopus were searched from inception to 13th November 2020 for studies investigating subclinical thyroid dysfunction and incident AF. Risk of bias was assessed using the Risk of Bias Assessment Tool (RoBANS). The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. Subgroup analysis was performed for post-operative and non-post-operative AF. 5413 records were identified. Nine cohort studies were suitable for inclusion in the systematic review, of which seven studies were included in the meta-analysis. The meta-analysis comprised 595,058 patients. Subclinical hyperthyroidism was associated with a 99% increase in the risk of incident AF (Risk ratio (RR): 1.99; 95% confidence intervals (CI); 1.43 to 2.77; p &amp;lt; 0.0001; I² = 67%). Subclinical hypothyroidism was also associated with a greater risk of AF (RR: 1.24; 95% CI; 1.05 to 1.47; p = 0.01; I² = 65%). Subgroup analysis demonstrated a 76% increase in the risk of post-operative AF in patients with subclinical hypothyroidism compared to euthyroid post-operative patients (RR: 1.76; 95% CI; 1.36 to 2.28; p &amp;lt; 0.0001; I² = 0%). Six studies were rated as low risk of bias and three as medium risk of bias according to the RoBANS tool. The quality of evidence for AF in subclinical hyper- and hypothyroid patients was low. Subclinical hyperthyroidism and subclinical hypothyroidism were associated with a higher risk of incident AF and post-operative AF, respectively. The quality of the current evidence is low and ideally a randomised controlled trial should be conducted to confirm these associations and assess impacts of treatments. Abstract Figure. </jats:sec

Subclinical thyroid dysfunction and the risk of incident atrial fibrillation: A systematic review and meta-analysis

Background Thyroid hormones act on the cardiovascular system directly by modulating its function and indirectly by transcriptional regulation of gene expression in the heart and the vasculature. Studies have shown associations between overt and subclinical thyroid disorders and cardiovascular outcomes. The aim of this study was to perform a systematic review and meta-analysis to assess the potential relationships between subclinical hyper- and hypothyroidism and risk of atrial fibrillation (AF), and post-operative AF. Methods MEDLINE and Scopus databases were searched from inception to 18th February 2023 for randomised controlled trials, case-control studies, and cohort studies which assessed the relationship between subclinical thyroid dysfunction and incident AF events. Risk of bias and the quality of evidence were assessed using the RoBANS tool and GRADE approach, respectively. Meta-analysis was conducted in Review Manager 5.4 using the Mantel-Haenszel statistical method and a random-effects model. Data are presented as risk ratios with 95% confidence intervals. Statistical heterogeneity amongst studies was assessed by the chi-squared (χ2) test and I2 statistic. p≤0.05 were considered significant. Results A total of 6467 records were identified, of which 10 cohort studies met the inclusion criteria. Both subclinical hyperthyroidism and subclinical hypothyroidism were associated with an increased risk of incident AF (risk ratio (RR), 1.99; 95% confidence interval (CI), 1.43–2.77; n = 5 studies; p<0.0001 and RR, 1.19; CI, 1.03–1.39; n = 7 studies; p = 0.02, respectively). Subgroup analysis for post-operative AF revealed marked heterogeneity between studies (I2 = 84%) and association with subclinical hypothyroidism was not significant (RR, 1.41; CI, 0.89–2.22; n = 3 studies; p = 0.15). Conclusions The current evidence suggests that both subclinical hyperthyroidism and subclinical hypothyroidism are associated with increased risk of incident AF. Further investigation is required to determine potential causal links that would guide future clinical practice

Atrioventricular Node Dysfunction and Ion Channel Transcriptome in Pulmonary Hypertension

Background: Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. Methods and Results: The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV node); and quantitative PCR revealed a widespread downregulation of ion channel and related genes in the AV node (eg, >50% downregulation of Cav1.2/3 and HCN1/2/4 channels). Computer modeling predicted that the changes in the transcriptome if translated into protein and function would result in heart block. Conclusions: Pulmonary hypertension results in a derangement of the ion channel transcriptome in the AV node, and this is the likely cause of AV node dysfunction in this disease

Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit

BACKGROUND: Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs. METHODS: Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. RESULTS: Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P=0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca2+-handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca2+-channels, and K+-channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P<0.0001), and arrhythmic events in HF. Similar electrical remodeling was seen at the left PF-ventricular junction. In the failing left ventricle, upstroke velocity and amplitude were increased, but action potential duration at 90% repolarization was unaffected. CONCLUSIONS: Severe volume- followed by pressure-overload causes rapidly progressing HF with extensive remodeling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodeling may increase the risk of fatal arrhythmias in HF patients

Evaluation of Huawei Smart Wearables for Detection of Atrial Fibrillation in Patients Following Ischaemic Stroke: The Liverpool-Huawei Stroke Study.

Atrial fibrillation (AF) often remains undetected following stroke. Documenting AF is critical to initiate oral anticoagulation, which has proven benefit in reducing recurrent stroke and mortality in patients with AF. The accuracy and acceptability of using smart wearables technology to detect AF in patients following stroke is unknown. The aims of the Liverpool-Huawei Stroke Study are to determine the effectiveness, cost-effectiveness and patient and staff acceptability of using Huawei smart wearables to detect AF following ischaemic stroke. The study plans to recruit 1000 adults aged ≥18 years following ischaemic stroke from participating hospitals over 12 months. All participants will be asked to wear a Huawei smart band for four weeks post-discharge. If participants do not have access to a compatible smartphone required for the study, they will be provided with a smartphone for the four-week AF monitoring period. Participants with suspected AF detected by the smart wearables, without previous known AF, will be referred for further evaluation. To determine the effectiveness of the Huawei smart wearables to detect AF, the positive predictive value will be determined. Patient acceptability of using this technology will also be examined. Additional follow-up assessments will be conducted at six and 12 months, and clinical outcomes recorded in relation to prevalent and incident AF post-stroke. The study opened for recruitment on 30/05/2022, and is currently open at four participating hospitals; the first 106 participants have been recruited. One further hospital is preparing to open for recruitment. This prospective study will examine the effectiveness and acceptability of the use of smart wearables in patients following ischaemic stroke. This could have important implications for detection of AF and therefore, earlier prophylaxis for recurrent stroke. The study is registered on https://www.isrctn.com/ (Identifier ISRCTN30693819)

Inherent Atrial Fibrillation Vulnerability in the Appendages Exacerbated in Heart Failure

Atrial fibrillation (AF) frequently accompanies heart failure (HF), however, the causal mechanism underlying their atrial electrophysiological substrates remains unclear. In the present study, we evaluated the effects of abnormal anatomical characteristics on the electrophysiology of rabbit atria with HF. Micro-CT images from adult New Zealand white rabbit hearts (n = 4 HF and n = 4 control) were acquired. Novel imaging methods were used to reconstruct atrial myofiber architecture at a high resolution of 21 µm3/voxel for quantitative analysis of the structural remodelling. Effects of this structural remodelling on the vulnerability to atrial re-entrant waves was analysed using computer simulation. Reconstructed data showed increased chamber lumen and an uneven reduction in wall thickness across the appendages in HF. Anatomically, myofibers in epicardial walls of the appendages were identified to be circumferential, perpendicular to the pectinate muscles (PMs). The relative ratio of average PM thickness to the atrial wall was larger in HF vs. control (right atrial appendages: 3.5 versus 2.7 and left atrial appendages: 4.4 versus 3.7, p &amp;lt; 0.001). Furthermore, the uncoupled myofiber orientation between the PMs and atrial wall was verified using confocal microscopy at a spatial resolution of 0.2 µm3. Computer simulations suggested (1) uncoupled myofiber orientation of the PMs and the atrial wall may increase the vulnerability to AF; and (2) decreased atrial thickness and dilated chambers may amplify the unstable substrates leading to re-entry formation in HF. Our ex-vivo to in-silico results demonstrate that uncoupled myofiber orientation in the atria is an important component of the structural remodelling, facilitating the development and maintenance of AF in HF.</p