Paradoxical impact of socioeconomic factors on outcome of atrial fibrillation in Europe: trends in incidence and mortality from atrial fibrillation

Aims: To understand the changing trends in Atrial Fibrillation (AF) incidence and mortality across Europe from 1990 to 2017, and how socioeconomic factors and sex differences play a role. Methods and Results: We performed a temporal analysis of data from the 2017 Global Burden of Disease Database for 20 countries across Europe using Joinpoint regression analysis. Age-adjusted incidence, mortality and mortality to incidence ratios (MIRs) to approximate case fatality rate are presented. Incidence and mortality trends were heterogenous throughout Europe, with Austria, Denmark and Sweden experiencing peaks in incidence in the middle of the study period. Mortality rates were higher in wealthier countries with the highest being Sweden for both men and women (8.83 and 8.88 per 100,000, respectively) in 2017. MIRs were higher in women in all countries studied, with the disparity increasing the most over time in Germany (43.6% higher in women versus men in 1990 to 74.5% higher in women in 2017). Conclusion: AF incidence and mortality across Europe did not show a general trend, but unique patterns for some nations were observed. Higher mortality rates were observed in wealthier countries, potentially secondary to a survivor effect where patients survive long enough to suffer from AF and its complications. Outcomes for women with AF were worse than men, represented by higher MIRs. This suggests there is widespread healthcare inequality between the sexes across Europe, or that there are biological differences between them in terms of their risk of adverse outcomes from A

OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine

Background and Purpose Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia-induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia-activated prodrug of lidocaine. Experimental Approach The rat Langendorff-perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results In isolated hearts, OCT2013 and lidocaine prevented ischaemia-induced VF equi-effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi-effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg⁻¹ i.v., whereas lidocaine reduced it even at 1 mg·kg⁻¹. In adult rat ventricular myocytes, OCT2013 had no effect on Ca²⁺ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate-dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi-effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013-perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications OCT2013 is inactive but is bio-reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia-activated and ischaemia-selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity

Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in β-adrenergic signaling and enhances apoptosis

The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typically progresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development of cardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles in both cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application to isolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts following myocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating the β-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-2 targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, we demonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygen species generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. In conclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30 overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotective and anti-tumorigenic strategy for anthracyclines

Targeting the ectopy-triggering ganglionated plexuses without pulmonary vein isolation prevents atrial fibrillation

Background Ganglionated plexuses (GPs) are implicated in atrial fibrillation (AF). Endocardial high-frequency stimulation (HFS) delivered within the local atrial refractory period can trigger ectopy and AF from specific GP sites (ET-GP). The aim of this study was to understand the role of ET-GP ablation in the treatment of AF. Methods Patients with paroxysmal AF indicated for ablation were recruited. HFS mapping was performed globally around the left atrium to identify ET-GP. ET-GP was defined as atrial ectopy or atrial arrhythmia triggered by HFS. All ET-GP were ablated, and PVs were left electrically connected. Outcomes were compared with a control group receiving pulmonary vein isolation (PVI). Patients were followed-up for 12 months with multiple 48-h Holter ECGs. Primary endpoint was ≥30 s AF/atrial tachycardia in ECGs. Results In total, 67 patients were recruited and randomized to ET-GP ablation (n = 39) or PVI (n = 28). In the ET-GP ablation group, 103 ± 28 HFS sites were tested per patient, identifying 21 ± 10 (20%) GPs. ET-GP ablation used 23.3 ± 4.1 kWs total radiofrequency (RF) energy per patient, compared with 55.7 ± 22.7 kWs in PVI (p = <.0001). Duration of procedure was 3.7 ± 1.0 and 3.3 ± 0.7 h in ET-GP ablation group and PVI, respectively (p = .07). Follow-up at 12 months showed that 61% and 49% were free from ≥30 s of AF/AT with PVI and ET-GP ablation respectively (log-rank p = .27). Conclusions It is feasible to perform detailed global functional mapping with HFS and ablate ET-GP to prevent AF. This provides direct evidence that ET-GPs are part of the AF mechanism. The lower RF requirement implies that ET-GP targets the AF pathway more specifically

Viruses exacerbating chronic pulmonary disease: the role of immune modulation

Chronic pulmonary diseases are a major cause of morbidity and mortality and their impact is expected to increase in the future. Respiratory viruses are the most common cause of acute respiratory infections and it is increasingly recognized that respiratory viruses are a major cause of acute exacerbations of chronic pulmonary diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. There is now increasing evidence that the host response to virus infection is dysregulated in these diseases and a better understanding of the mechanisms of abnormal immune responses has the potential to lead to the development of new therapies for virus-induced exacerbations. The aim of this article is to review the current knowledge regarding the role of viruses and immune modulation in chronic pulmonary diseases and discuss avenues for future research and therapeutic implications

Bidirectional Push Down Automata

We de ne a new model of automata for the description of bidirectional parsing strategies for context-free grammars and a tabulation mechanism that allow them to be executed in polynomial time. This new model of automata provides a modular way of de ning bidirectional parsers, separating the description of a strategy from its execution

Retrospective questions and correlations

renewal theory, recall effects, latent variables, measurement error,

Abundance of a cryptic generalist parasite reflects degradation of an ecosystem

Ecosystem degradation due to anthropogenic activities is the primary issue of our times. Theoretical analyses as well as efforts to restore and manage ecosystems depend on comprehensive metrics of ecosystem function. In the case of complex ecosystems such as tropical coral reefs-especially where monitoring, management, and restoration are important-multiple metrics reflecting key functional groups are required to accurately reflect ecosystem function and when necessary, diagnose degree and kind of ecosystem degradation. We propose inclusion of the generalist ectoparasite functional group as a measure of ecosystem function of coral reefs. This functional group is adaptable to loss of other community members and may experience an increase in abundance as ecosystem function declines. Fish-parasitic gnathiid isopods are a member of this group, resident though inconspicuous in coral-reef communities. On Caribbean coral reefs, based on 938 light-trap samples, we observed a negative correlation between abundance of smaller-sized gnathiids and abundance of live coral, a natural predator of gnathiids. Plots grouped by coral cover-a measure of success of the ecosystem engineer-and ectoparasite abundance varied significantly in community composition including abundance of macroalgae, turf algae, and farming Stegastes spp. damselfish reflecting shifts in community structure. Changes in gnathiid abundance with respect to the abundance of organisms participating in each of the core functional processes driving coral-reef ecosystems reflect broad connectivity of gnathiid parasites across the ecosystem. We conclude that the hyperabundance of a small, cryptic, generalist parasite, when used in combination with a metric of abundance of the primary ecosystem engineer, can provide one nuanced measure of the ecosystem vulnerability to collapse