EHRA expert consensus document on the management of arrhythmias in frailty syndrome, endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA).

There is an increasing proportion of the general population surviving to old age with significant chronic disease, multi-morbidity, and disability. The prevalence of pre-frail state and frailty syndrome increases exponentially with advancing age and is associated with greater morbidity, disability, hospitalization, institutionalization, mortality, and health care resource use. Frailty represents a global problem, making early identification, evaluation, and treatment to prevent the cascade of events leading from functional decline to disability and death, one of the challenges of geriatric and general medicine. Cardiac arrhythmias are common in advancing age, chronic illness, and frailty and include a broad spectrum of rhythm and conduction abnormalities. However, no systematic studies or recommendations on the management of arrhythmias are available specifically for the elderly and frail population, and the uptake of many effective antiarrhythmic therapies in these patients remains the slowest. This European Heart Rhythm Association (EHRA) consensus document focuses on the biology of frailty, common comorbidities, and methods of assessing frailty, in respect to a specific issue of arrhythmias and conduction disease, provide evidence base advice on the management of arrhythmias in patients with frailty syndrome, and identifies knowledge gaps and directions for future research.

BPA and BPA alternatives BPS, BPAF, and TMBPF, induce cytotoxicity and apoptosis in rat and human stem cells.

Bisphenol A (BPA) is a ubiquitous industrial chemical found in everyday plastic products and materials. Due to scientific findings on the reproductive, developmental, and cellular defects caused by BPA and heightened public awareness, manufacturers have begun to use new chemicals in place of BPA in "BPA-free" products. These alternatives are chemical analogs of BPA and include dozens of new compounds that have undergone relatively little testing and oversight, including: bisphenol S (BPS), bisphenol AF (BPAF), and the recently developed tetramethyl bisphenol F (TMBPF; the monomer of valPure V70). Here, we used adult female rat adipose-derived stem cells (rASCs) and human mesenchymal stem cells (hMSCs) to compare the toxicities and potencies of these BPA alternatives in vitro. Rat and human stem cells were exposed to BPA (1-10 µM), 17ß-estradiol (E2; 10 µM), BPS (1-100 µM), BPAF (3×10-4-30 µM), TMBPF (0.01-50 µM), or control media alone (with 0.01% ethanol) for varying time intervals from 10 min to 24 h. We found significantly decreased cell viability and massive apoptosis in rat and human stem cells treated with each BPA analog, as early as 10 min of exposure, and at low, physiologically relevant doses. BPAF showed extreme cytotoxicity in a dose-dependent manner (LC50 =0.014 µM (rASCs) and 0.009 µM (hMSCs)), whereas TMBPF showed a bimodal response, with low and high concentrations being the most toxic (LC50 =0.88 µM (rASCs) and 0.06 µM (hMSCs)). Activated caspase-6 levels increased in nearly all cells treated with the BPA analogs indicating the majority of cell death was due to caspase-6-mediated apoptosis. These results in both rat and human stem cells underscore the toxicity and potency of these BPA analogs, and establish a rank order of potency of: BPAF>TMBPF>BPA>BPS. Further, these and other recent findings indicate that these newer BPA analogs may be 'regrettable substitutions,' being worse than the original parent compound and lacking proper testing and regulation. This work brings to light the need for further toxicological characterization, better regulation, greater public awareness, and the development of safer, more sustainable chemicals and non-plastic products.

Cardiac arrhythmia services in Africa from 2011 to 2018: the second report from the Pan African Society of Cardiology working group on cardiac arrhythmias and pacing.

AIMS: Cardiac arrhythmia services are a neglected field of cardiology in Africa. To provide comprehensive contemporary information on the access and use of cardiac arrhythmia services in Africa. METHODS AND RESULTS: Data on human resources, drug availability, cardiac implantable electronic devices (CIED), and ablation procedures were sought from member countries of Pan African Society of Cardiology. Data were received from 23 out of 31 countries. In most countries, healthcare services are primarily supported by household incomes. Vitamin K antagonists (VKAs), digoxin, and amiodarone were available in all countries, while the availability of other drugs varied widely. Non-VKA oral anticoagulants (NOACs) were unequally present in the African markets, while International Normalized Ratio monitoring was challenging. Four countries (18%) did not provide pacemaker implantations while, where available, the implantation and operator rates were 2.79 and 0.772 per million population, respectively. The countries with the highest pacemaker implantation rate/million population in descending order were Tunisia, Mauritius, South Africa, Algeria, and Morocco. Implantable cardioverter-defibrillator and cardiac resynchronization therapy (CRT) were performed in 15 (65%) and 12 (52%) countries, respectively. Reconditioned CIED were used in 5 (22%) countries. Electrophysiology was performed in 8 (35%) countries, but complex ablations only in countries from the Maghreb and South Africa. Marked variation in costs of CIED that severely mismatched the gross domestic product per capita was observed in Africa. From the first report, three countries have started performing simple ablations. CONCLUSION: The access to arrhythmia treatments varied widely in Africa where hundreds of millions of people remain at risk of dying from heart block. Increased economic and human resources as well as infrastructures are the critical targets for improving arrhythmia services in Africa.

Management of asymptomatic arrhythmias: a European Heart Rhythm Association (EHRA) consensus document, endorsed by the Heart Failure Association (HFA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Cardiac Arrhythmia Society of Southern Africa (CASSA), and Latin America Heart Rhythm Society (LAHRS).

Asymptomatic arrhythmias are frequently encountered in clinical practice. Although studies specifically dedicated to these asymptomatic arrhythmias are lacking, many arrhythmias still require proper diagnostic and prognostic evaluation and treatment to avoid severe consequences, such as stroke or systemic emboli, heart failure, or sudden cardiac death. The present document reviews the evidence, where available, and attempts to reach a consensus, where evidence is insufficient or conflicting.

Statistics on the use of cardiac electronic devices and interventional electrophysiological procedures in Africa from 2011 to 2016: report of the Pan African Society of Cardiology (PASCAR) Cardiac Arrhythmias and Pacing Task Forces.

Aims: To provide comprehensive information on the access and use of cardiac implantable electronic devices (CIED) and catheter ablation procedures in Africa. Methods and results: The Pan-African Society of Cardiology (PASCAR) collected data on invasive management of cardiac arrhythmias from 2011 to 2016 from 31 African countries. A specific template was completed by physicians, and additional information obtained from industry. Information on health care systems, demographics, economics, procedure rates, and specific training programs was collected. Considerable heterogeneity in the access to arrhythmia care was observed across Africa. Eight of the 31 countries surveyed (26%) did not perform pacemaker implantations. The median pacemaker implantation rate was 2.66 per million population per country (range: 0.14-233 per million population). Implantable cardioverter-defibrillator and cardiac resynchronization therapy were performed in 12/31 (39%) and 15/31 (48%) countries respectively, mostly by visiting teams. Electrophysiological studies, including complex catheter ablations were performed in all countries from Maghreb, but only one sub-Saharan African country (South Africa). Marked variation in cost (up to 1000-fold) was observed across countries with an inverse correlation between implant rates and the procedure fees standardized to the gross domestic product per capita. Lack of economic resources and facilities, high cost of procedures, deficiency of trained physicians, and non-existent fellowship programs were the main drivers of under-utilization of interventional cardiac arrhythmia care. Conclusion: There is limited access to CIED and ablation procedures in Africa. A quarter of countries did not have pacemaker implantation services, and catheter ablations were only available in one country in sub-Saharan Africa.

Optimized FISH methods for visualizing RNA localization properties in Drosophila and human tissues and cultured cells.

Eukaryotic gene expression is orchestrated by a large number of regulatory steps to modulate the synthesis, maturation and fate of various families of protein-coding and non-coding RNA molecules. Defining the subcellular localization properties of an RNA molecule is thus of considerable importance for gleaning its function(s) and for elucidating post-transcriptional gene regulation pathways. For decades, fluorescent In Situ hybridization (FISH) has constituted the gold-standard technique for assessing RNA expression and distribution properties in cultured cells, tissue specimens, and whole mount organisms. Recently, several attempts aimed at advancing multiplex RNA-FISH experiments have been published. However, these procedures are both financially demanding and technically challenging, while their full potential remains unexploited. Here we describe an optimized RNA-FISH method employing the Tyramide Signal Amplification system that robustly enhances resolution and sensitivity needed for exploring RNA localization in Drosophila embryos, tissues and commonly cultured human and insect cell lines. Methodological details and key parameters are outlined for high-throughput analyses conducted in 96-well plate format.

RNA localization: Making its way to the center stage.

Cells are highly organized entities that rely on intricate addressing mechanisms to sort their constituent molecules to precise subcellular locations. These processes are crucial for cells to maintain their proper organization and carry out specialized functions in the body, consequently genetic perturbations that clog up these addressing systems can contribute to disease aetiology. The trafficking of RNA molecules represents an important layer in the control of cellular organization, a process that is both highly prevalent and for which features of the regulatory machineries have been deeply conserved evolutionarily. RNA localization is commonly driven by trans-regulatory factors, including RNA binding proteins at the core, which recognize specific cis-acting zipcode elements within the RNA transcripts. Here, we first review the functions and biological benefits of intracellular RNA trafficking, from the perspective of both coding and non-coding RNAs. Next, we discuss the molecular mechanisms that modulate this localization, emphasizing the diverse features of the cis- and trans-regulators involved, while also highlighting emerging technologies and resources that will prove instrumental in deciphering RNA targeting pathways. We then discuss recent findings that reveal how co-transcriptional regulatory mechanisms operating in the nucleus can dictate the downstream cytoplasmic localization of RNAs. Finally, we survey the growing number of human diseases in which RNA trafficking pathways are impacted, including spinal muscular atrophy, Alzheimer's disease, fragile X syndrome and myotonic dystrophy. Such examples highlight the need to further dissect RNA localization mechanisms, which could ultimately pave the way for the development of RNA-oriented diagnostic and therapeutic strategies. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue.

Delayed AICD therapy and cardiac arrest resulting from undersensing of ventricular fibrillation in a subject with hypertrophic cardiomyopathy-A case report.

Defibrillation testing is no longer routinely performed after automatic implantable cardioverter-defibrillator (AICD) implantation. However, certain subjects undergoing AICD implantation may be at higher risk of undersensing of ventricular arrhythmias resulting in potentially fatal outcomes. We present the case of a 30-year-old woman with hypertrophic cardiomyopathy (HCM; 'asymmetric septal hypertophy' morphologic variant) and prophylactic AICD who experienced an out of hospital cardiac arrest. AICD interrogation revealed undersensing as a result of intermittent high amplitude electrograms during an episode of ventricular fibrillation (VF). The subject underwent replacement and repositioning of the AICD lead along with pulse generator replacement (that utilized a different VF sensing algorithm) with appropriate sensing of VF and successful defibrillation testing. The presence of intermittent high amplitude electrograms during episodes of VF in AICDs using the AGC function should be recognized as a situation that may necessitate interventions to prevent undersensing and consequent delay in therapy.

ZO-1 interacts with YB-1 in endothelial cells to regulate stress granule formation during angiogenesis.

Zonula occludens-1 (ZO-1) is involved in the regulation of cell-cell junctions between endothelial cells (ECs). Here we identify the ZO-1 protein interactome and uncover ZO-1 interactions with RNA-binding proteins that are part of stress granules (SGs). Downregulation of ZO-1 increased SG formation in response to stress and protected ECs from cellular insults. The ZO-1 interactome uncovered an association between ZO-1 and Y-box binding protein 1 (YB-1), a constituent of SGs. Arsenite treatment of ECs decreased the interaction between ZO-1 and YB-1, and drove SG assembly. YB-1 expression is essential for SG formation and for the cytoprotective effects induced by ZO-1 downregulation. In the developing retinal vascular plexus of newborn mice, ECs at the front of growing vessels express less ZO-1 but display more YB-1-positive granules than ECs located in the vascular plexus. Endothelial-specific deletion of ZO-1 in mice at post-natal day 7 markedly increased the presence of YB-1-positive granules in ECs of retinal blood vessels, altered tip EC morphology and vascular patterning, resulting in aberrant endothelial proliferation, and arrest in the expansion of the retinal vasculature. Our findings suggest that, through its interaction with YB-1, ZO-1 controls SG formation and the response of ECs to stress during angiogenesis.

Diagnoses, management patterns, and outcomes of cardiac sarcoidosis in South Africa.

Background: Sarcoidosis is an idiopathic multiorgan disease characterized by tissue infiltration by noncaseating granulomas. Clinical cardiac involvement is reported in approximately 5% of patients. However, the frequency of cardiac involvement is found to be higher on autopsy and in advanced imaging studies such as cardiac magnetic resonance imaging. Objective: The purpose of this study was to determine contemporary diagnoses, management, and outcomes of cardiac sarcoidosis (CS) in South Africa. Methods: Clinical records of patients diagnosed with CS between January 2000 and December 2021 were reviewed. Results: Twenty-two patients were diagnosed with CS during the study period. The patients had a mean (± SD) age of 45.2 ± 12.3 years at the time of presentation. CS diagnostic rates increased from 4.5% in 2000-2005 to 45.5% in 2016-2021. Fifteen of the 22 patients (68.2%) were newly diagnosed with sarcoidosis at the time of CS diagnosis, and 9 of the 15 (60%) had pulmonary involvement. Of the 22 patients diagnosed with CS, 13 (59.1%) presented in combination with heart block, 10 (45.5%) with ventricular arrhythmias, and 4 (18.2%) with heart failure. Five endomyocardial biopsies were performed, and all were nondiagnostic. However, 8 of 8 endobronchial ultrasound (EBUS)-guided biopsies of thoracic lymph nodes were diagnostic of sarcoidosis and, notably, excluded tuberculosis. Fourteen patients (63.6%) were treated with corticosteroids, 7 (31.8%) with azathioprine, 9 (40.9%) with amiodarone, and 16 (72.7%) with a cardiac implantable electronic device. After a mean follow-up period of 64.5 ± 50.5 months, no deaths had occurred. Conclusion: CS diagnostic rates have increased over time. Diagnostic endomyocardial biopsies have a low diagnostic yield, whereas EBUS-guided biopsy of thoracic lymph nodes is of crucial diagnostic utility.

Clinical profile and outcomes of young patients treated with implantable cardioverter defibrillators at a South African tertiary hospital: a review of two decades of implantable cardioverter defibrillator implantation and follow up.

AIM: In young patients without atherosclerotic coronary artery disease, the aetiology of sudden cardiac death (SCD) has been described in Europe and North America. However, there are important regional variations and there are limited data on the aetiology and outcome of SCD in South Africa. The objective of this study was to determine the profile and outcomes of young patients treated with implantable cardioverter defibrillators (ICDs) at a South African tertiary hospital. METHODS: This study was designed as a retrospective review of patients aged 35 years or younger implanted with ICDs at Groote Schuur Hospital. RESULTS: During the study period, 38 patients younger than 35 years were implanted with ICDs. The mean (standard deviation) age at ICD implantation was 25.1 (7.6) years and 63.2% were male. A secondary-prevention ICD was implanted in 57.9% of the patient population, and primary prevention in the remaining 42.1%. Patients with secondary-prevention ICDs presented with ventricular tachycardia (59.1%), ventricular fibrillation (31.8%) and receipt of cardiopulmonary resuscitation but no recorded electrocardiograms (9.1%). Arrhythmogenic right ventricular cardiomyopathy (ARVC) was the leading cause of SCD in the secondary-prevention patient population (36.4%). Idiopathic dilated cardiomyopathy accounted for 50% of the primary-prevention patient population. After a median (interquartile range) follow up 32 (14-90) months, 7.9% died and 5.2% received a heart transplant; 42.1% of the study population received appropriate ICD shock therapies and 18.4% received inappropriate shock therapies. CONCLUSIONS: In this single-centre study from South Africa, ARVC and repaired congenital heart disease were the leading causes of SCD in patients younger than 35 years treated with secondary-prevention ICDs. Primary-prevention ICDs were frequently implanted for idiopathic dilated cardiomyopathy.

Causes of Heart Block in Young and Middle-Aged South Africans.

BACKGROUND: There is a paucity of data regarding the aetiology of atrioventricular heart block (AVB) in young and middle-aged patients, particularly from low- and middle-income countries. OBJECTIVE: To determine the aetiology of AVB in patients ≤ 55 years treated with transvenous pacemakers in a low- or middle-income country. METHODS: We performed a retrospective review of all patients who received a transvenous pacemaker for newly diagnosed AVB from 01/01/2013 to 31/12/2020 at Groote Schuur Hospital, Cape Town, South Africa. RESULTS: One thousand one hundred one (1101) consecutive patients received a permanent transvenous pacemaker for AVB. One hundred thirty-six patients (12.4%) were ≤ 55 years. The study patients' mean (standard deviation) age was 41 (11) years, and 48.5% were female. Third-degree AV block was diagnosed in 73.5%, 2:1 AV block in 8.1%, and Mobitz Ι second degree AV block in 5.9%. The aetiology of AVB could be determined in 97/136 (71.3%) patients. Forty-three of 136 (31.6%) patients were post-surgical, and 16/136 (11.8%) patients had developed AVB from an acute myocardial infarction. Cardiac Magnetic Resonance (CMR) imaging was performed in 26 patients: cardiac sarcoidosis was diagnosed in 7/26 patients. No pathology could be identified in 10/26 patients who had CMR. The aetiology of AVB remained unknown in 39/136 patients (28.7%). CONCLUSION: Prior valve surgery is the leading cause of AVB treated with a transvenous pacemaker in patients ≤ 55 years in this South African referral unit. Cardiac magnetic resonance imaging identified disease processes that require further management in many cases.

Effectiveness of implantable loop recorder and Holter electrocardiographic monitoring for the detection of arrhythmias in patients with peripartum cardiomyopathy.

BACKGROUND: Patients with peripartum cardiomyopathy (PPCM) are at increased risk of sudden cardiac death (SCD). However, the exact underlying mechanisms of SCD in PPCM remain unknown. By means of extended electrocardiographic monitoring, we aimed to systematically characterize the burden of arrhythmias occurring in patients with newly diagnosed PPCM. METHODS AND RESULTS: Twenty-five consecutive women with PPCM were included in this single-centre, prospective clinical trial and randomised to receiving either 24 h-Holter ECG monitoring followed by implantable loop recorder implantation (ILR; REVEAL XT, Medtronic®) or 24 h-Holter ECG monitoring alone. ILR + 24 h-Holter monitoring had a higher yield of arrhythmic events compared to 24 h-Holter monitoring alone (40% vs 6.7%, p = 0.041). Non-sustained ventricular tachycardia (NSVT) occurred in four patients (16%, in three patients detected by 24 h-Holter, and multiple episodes detected by ILR in one patient). One patient deceased from third-degree AV block with an escape rhythm that failed. All arrhythmic events occurred in patients with a severely impaired LV systolic function. CONCLUSIONS: We found a high prevalence of potentially life-threatening arrhythmic events in patients with newly diagnosed PPCM. These included both brady- and tachyarrhythmias. Our results highlight the importance of extended electrocardiographic monitoring, especially in those with severely impaired LV systolic function. In this regard, ILR in addition to 24 h-Holter monitoring had a higher yield of VAs as compared to 24 h-Holter monitoring alone. In settings where WCDs are not readily available, ILR monitoring should be considered in patients with severely impaired LV systolic dysfunction, especially after uneventful 24 h-Holter monitoring. TRIAL REGISTRATION: Pan African Clinical Trials Registry: PACTR202104866174807. Extended electrocardiographic monitoring for the detection of arrhythmias in PPCM. (CHB, complete heart block/third degree AV block; ECG, electrocardiogram; ILR, implantable loop recorder; NSVT, non-sustained ventricular tachycardia; PPCM, peripartum cardiomyopathy).

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits ß-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (ß2AR). Co-treatment with CXCL12 and the ß2AR agonist epinephrine synergistically increases ß-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

Feasibility and safety of interventional electrophysiology and catheter ablation in the South African public sector: Challenges and opportunities for comprehensive cardiac electrophysiology in South Africa.

Aims: The spectrum and outcomes of catheter ablation procedures performed in South Africa are unknown, and therefore, the feasibility of interventional electrophysiology in the South African public sector is undetermined. Methods and Results: This study was a retrospective review of all patients that underwent invasive electrophysiology procedures and catheter ablation at Groote Schuur Hospital (GSH) and the University of Cape Town Private Academic Hospital (UCTPAH) between 01 January 2013 and 31 December 2020.One thousand one hundred eighty-six invasive electrophysiology procedures were performed during the study period. Of these were 1102 catheter ablation procedures. There were 76 redo catheter ablation procedures, predominantly for atrial fibrillation (AF), which accounted for 39% (30/76) of the repeat procedures. There were only 0.8% (9/1102) catheter ablation related complications which were mostly access related. Atrial fibrillation accounted for most of the ablation procedures, 28.9% (318/1102); these were mainly performed at UCTPAH than at GSH, 300 vs 18 p < .0001. Cavotricuspid isthmus (CTI) dependent atrial flutter ablation was the second most commonly performed catheter ablation procedure, accounting for 21.6% (238/1102) of the catheter ablation procedures. More CTI dependent atrial flutter ablations were performed at GSH than a UCTPAH, 156 vs 82 p < .0001. The overall success rate of catheter ablation was 92%. Conclusion: A broad spectrum of catheter ablation procedures was performed with a high success rate and limited complications, thus demonstrating the feasibility of safe cardiac electrophysiology and catheter ablation in the South African public sector.

Two decades of implantable cardioverter defibrillator implantation and follow-up at a South African referral centre: trends, indications and long-term outcomes in a resource-limited setting.

Background: More than two-thirds of cardiovascular deaths occur in low- and middle-income countries. Sudden cardiac deaths (SCD) from ventricular arrhythmias are an important cause of cardiovascular deaths. Implantable cardioverter defibrillators (ICD) are an important therapeutic strategy for detecting and terminating ventricular arrhythmias in patients at risk of SCD. The profile of patients treated with ICDs in South Africa is unknown. Further, with changing lines of evidence, the implantation trends are undetermined. The objectives of this study were to determine the profile of ICD recipients and implantation trends in a South African quaternary hospital. Methods: This was a retrospective review of all patients implanted with ICDs at Groote Schuur Hospital from 01 January 1998 to 31 December 2020. A standardised data collection form was used to collect baseline demographic data, information on clinical presentation and ICD follow-up data for the history of ICD shock therapies. Results: A total of 253 ICDs were implanted; 75% for secondary prevention and 25% for primary prevention. 67.2% of the implanted ICDs were single-chamber ICDs, dual-chamber ICDs were implanted in 12.3% and Cardiac resynchronisation with a defibrillator (CRT-D) in 20.6%. There was an upward trajectory of ICD implantations during the study period. Increasing numbers of dual-chamber devices and CRT-D were implanted over time. ICD recipients had a mean (standard deviation) age of 50 (14) years and were predominantly male (69%). Primary prevention ICD recipients were younger than secondary prevention recipients, with a mean (SD) age of 46 (14) years versus 51 (14) years, p = 0.019. The secondary prevention group presented with ventricular tachycardia in 81%, ventricular fibrillation in 13% and cardiopulmonary resuscitation without documented heart rhythm in 5.3% (10/190). After a median (interquartile range) follow-up of 44 (15; 93) months, there was an overall mortality rate of 16.2%, with no mortality difference between the primary and secondary prevention patient groups. Conclusion: There is an increase in the annual number of ICDs implanted at a South African referral centre. ICDs are predominantly implanted for secondary prevention. However, over time the number of devices implanted for primary prevention is steadily increased. During follow-up, there was no mortality difference between the primary prevention and the secondary prevention groups.

Stroke risk prediction in patients with atrial fibrillation with and without rheumatic heart disease.

AIMS: Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients. METHODS AND RESULTS: We analysed data of 15 400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrolment. A total of 1788 (11.6%) patients had RHD. These patients were younger (51.4±15.7 vs. 67.8±13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA2DS2-VASc score (2.1±1.7 vs. 3.7±2.2) as compared to patients without RHD (all P<0.001). Significant mitral stenosis (average mean transmitral gradient 11.5±6.5 mmHg) was the predominant valve lesion in those with RHD (59.6%). Patients with RHD had a higher baseline rate of anticoagulation use (60.4% vs. 45.2%, P<0.001). Unadjusted stroke rates at 1 year were 2.8% and 4.1% for patients with and without RHD, respectively. The performance of the CHA2DS2-VASc score was modest in both groups [stroke at 1 year, c-statistics 0.69, 95% confidence interval (CI) 0.60-0.78 and 0.63, 95% CI 0.61-0.66, respectively]. In the overall cohort, advanced age, female sex, prior stroke, tobacco use, and non-use of anticoagulation were predictors for stroke (all P<0.05). Mitral stenosis was not associated with stroke risk (adjusted odds ratio 1.07, 95% CI 0.67-1.72, P=0.764). CONCLUSION: The performance of the CHA2DS2-VASc score was modest in AF patients both with and without RHD. In this cohort, moderate-to-severe mitral stenosis was not an independent risk factor for stroke.

Puromycin Labeling Coupled with Proximity Ligation Assays to Define Sites of mRNA Translation in Drosophila Embryos and Human Cells.

Genetic mutations, whether they occur within protein-coding or noncoding regions of the genome, can affect various aspects of gene expression by influencing the complex network of intra- and intermolecular interactions that occur between cellular nucleic acids and proteins. One aspect of gene expression control that can be impacted is the intracellular trafficking and translation of mRNA molecules. To study the occurrence and dynamics of translational regulation, researchers have developed approaches such as genome-wide ribosome profiling and artificial reporters that enable single molecule imaging. In this paper, we describe a complementary and optimized approach that combines puromycin labeling with a proximity ligation assay (Puro-PLA) to define sites of translation of specific mRNAs in tissues or cells. This method can be used to study the mechanisms driving the translation of select mRNAs and to access the impact of genetic mutations on local protein synthesis. This approach involves the treatment of cell or tissue specimens with puromycin to label nascently translated peptides, rapid fixation, followed by immunolabeling with appropriate primary and secondary antibodies coupled to PLA oligonucleotide probes, ligation, amplification, and signal detection via fluorescence microscopy. Puro-PLA can be performed at small scale in individual tubes or in chambered slides, or in a high-throughput setup with 96-well plate, for both in situ and in vitro experimentation.

A comparison of AAIR versus DDDR pacing for patients with sinus node dysfunction: a long-term follow-up study.

OBJECTIVES: The aim of the study was to compare the clinical outcomes [atrial fibrillation (AF), atrio-ventricular (AV) block, device sepsis and lead revision] of patients with sinus node dysfunction (SND) between atrial-pacing atrial-sensing inhibited-response rate-adaptive (AAIR) versus dual-chamber rate-adaptive (DDDR) pacing. The choice of AAIR pacing versus DDDR pacing was determined by AV nodal functional testing at implant. METHODS: We conducted a retrospective review of consecutive patients who underwent AAIR and DDDR pacing over a 10-year period. RESULTS: One hundred and sixteen patients required pacing for symptomatic SND. Fifty-four (46.6%) patients received AAIR pacemakers and 62 (53.4%) received DDDR pacemakers based on AV nodal functional testing at implant. Patients who had AV Wenkebach with atrial pacing at 120 beats per minute received DDDR pacing. Overall the mean age of patients with SND was 65 years and 66.4% were females, 30% were diabetics and 71% were hypertensives. Pre-syncope/syncope (84%) and dizziness (69%) were the most common symptoms. Sinus pauses and sinus bradycardia were the most common ECG manifestations. Over a median follow up of five (IQR: 2-11) years, four patients (7.4%) developed AF in the AAIR group compared to three (4.8%) in the DDDR group (p = 0.70). AV block occurred in one patient in the AAIR group, who required an upgrade to a DDDR pacemaker. There was no difference in device sepsis or need for lead revision between the two groups. CONCLUSIONS: We found that AV nodal functional testing with atrial pacing at the time of pacemaker implantation was a useful tool to help guide the implanter between AAIR or DDDR pacing. Patients who underwent AAIR pacing had a low risk of AF, AV block or lead revision. In resource-limited settings, AAIR pacing guided by AV nodal functional testing should be considered as an alternative to DDDR pacing.