Predictors of cardiovascular implantable electronic device dependence at long-term follow-up after alcohol septal ablation in hypertrophic cardiomyopathy patients.

BACKGROUND: The most common complication of alcohol septal ablation (ASA) is transient periprocedural high-grade AV block (HGAVB). To date, no long-term follow-up of cardiovascular implantable electronic device (CIED) utilization after ASA has been reported. We hypothesized that CIED dependence on long-term follow-up can be predicted by ECG or procedural characteristics. METHODS: We analyzed all patients with HCM who underwent ASA from December 1998 to December 2019 and received their first CIED within 30 days after ASA for HGAVB. All follow-up interrogations were reviewed. CIED dependence was defined as ventricular pacing of ≥ 5%. RESULTS: A total of 138 patients with HCM underwent ASA. Of these, 35 had a prior device and were excluded. Of the remaining 103 patients, 25 patients received a CIED for HGAVB within 30 days after ASA. Average follow-up duration was 10.1 years. On long-term follow-up, 16 patients (64%) were found to be CIED-dependent. Baseline characteristics, including pre- and post-ASA ECG, were not significantly different between dependent and non-dependent patients. The only predictor for CIED dependence was > 1 ml of alcohol injected (OR 6.0, p = 0.031). CONCLUSIONS: CIED implantation after ASA is common. Almost two thirds of patients who received a CIED for post-procedural HGAVB were CIED-dependent on long-term follow-up. CIED dependence can be predicted by the amount of injected alcohol > 1 ml.

Cell type-specific roles of PAR1 in Coxsackievirus B3 infection.

Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.

A polyphagous, tropical insect herbivore shows strong seasonality in age-structure and longevity independent of temperature and host availability.

Bactrocera tryoni is a polyphagous fruit fly that is predicated to have continuous breeding in tropical and subtropical Australia as temperature and hosts are not limiting. Nevertheless, in both rainforest and tropical agricultural systems, the fly shows a distinct seasonal phenology pattern with an autumn decline and a spring emergence. Temperature based population models have limited predictive capacity for this species and so the driver(s) for the observed phenology patterns are unknown. Using a demographic approach, we studied the age-structure of B. tryoni populations in subtropical Australia in an agricultural system, with a focus on times of the year when marked changes in population abundance occur. We found that the age-structure of the population varied with season: summer and autumn populations were composed of mixed-age flies, while late-winter and early-spring populations were composed of old to very old individuals. When held at a constant temperature, the longevity of adult reference cohorts (obtained from field infested fruits) also showed strong seasonality; the adults of spring and early autumn populations were short-lived, while late autumn and late winter adults were long-lived. While still expressing in modified landscapes, the data strongly suggests that B. tryoni has an endogenous mechanism which would have allowed it to cope with changes in the breeding resources available in its endemic monsoonal rainforest habitat, when fruits would have been abundant in the late spring and summer (wet season), and rare or absent during late autumn and winter (dry season).

Net benefit and cost-effectiveness of universal iron-containing multiple micronutrient powders for young children in 78 countries: a microsimulation study.

BACKGROUND: Universal home fortification of complementary foods with iron-containing multiple micronutrient powders (MNPs) is a key intervention to prevent anaemia in young children in low-income and middle-income countries. However, evidence that MNPs might promote infection raises uncertainty about whether MNPs give net health benefits and are cost-effective. We aimed to determined country-specific net benefit or harm and cost-effectiveness of universal provision of MNPs to children aged 6 months. METHODS: We developed a microsimulation model to estimate net country-specific disability-adjusted life-years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) due to anaemia, malaria, and diarrhoea averted (or increased) by provision of a 6-month course of MNPs to children aged 6 months, compared with no intervention, who would be followed up for an additional 6 months (ie, to age 18 months). Anaemia prevalence was derived from Demographic and Health Surveys or similar national surveys, and malaria and diarrhoea incidence were sourced from the Global Burden of Disease Study. Programme and health-care costs were modelled to determine cost per DALY averted (US$). Additionally, we explored the effects of reduced MNP coverage in a sensitivity analysis. FINDINGS: 78 countries (46 countries in Africa, 20 in Asia or the Middle East, and 12 in Latin America) were included in the analysis, and we simulated 5 million children per country. 6 months of universal distribution of daily MNPs, assuming 100% coverage, produced a net benefit (DALYs averted) in 54 countries (24 in Africa, 19 in Asia and the Middle East, 11 in Latin America) and net harm in 24 countries (22 in Africa, one in Asia, and one in Latin America). MNP intervention provided a benefit on YLDs associated with anaemia, but these gains were attenuated and sometimes reversed by increases in YLLs associated with malaria and diarrhoea, reducing the benefits seen for DALYs. In the 54 countries where MNP provision was beneficial, the median benefit was 28·1 DALYs averted per 10 000 children receiving MNPs (IQR 20·6-40·4), and median cost per DALY averted was $3576 (IQR 2474-4918). DALY effects positively correlated with moderate and severe anaemia prevalence in Asia, the Middle East, and Latin America, but correlated inversely in Africa. Suboptimal coverage markedly reduced DALYs averted and cost-effectiveness. INTERPRETATION: Net health benefits of MNPs vary between countries, are highest where prevalence of moderate and severe anaemia is greatest but infection prevalence is smallest, and are ameliorated when coverage of the intervention is poor. Our data provide country-specific guidance to national policy makers. FUNDING: International Union of Nutrition Sciences.

The factor Xa inhibitor rivaroxaban reduces cardiac dysfunction in a mouse model of myocardial infarction.

INTRODUCTION: Rivaroxaban selectively inhibits factor Xa (FXa), which plays a central role in blood coagulation. In addition, FXa activates protease-activated receptor-2 (PAR-2). We have shown that PAR-2-/- mice exhibit less cardiac dysfunction after cardiac injury. MATERIAL AND METHODS: Wild-type (WT) and PAR-2-/- mice were subjected to left anterior descending artery (LAD) ligation to induce cardiac injury and heart failure. Mice received either placebo or rivaroxaban chow either starting at the time of surgery or 3 days after surgery and continued up to 28 days. Cardiac function was measured by echocardiography pre-surgery and 3, 7 and 28 days after LAD ligation. We also measured anticoagulation, intravascular thrombi, infarct size, cardiac hypertrophy and inflammation at various times. RESULTS: Rivaroxaban increased the prothrombin time and inhibited the formation of intravascular thrombi in mice subjected to LAD ligation. WT mice receiving rivaroxaban immediately after surgery had similar infarct sizes at day 1 as controls but exhibited significantly less impairment of cardiac function at day 3 and beyond compared to the placebo group. Rivaroxaban also inhibited the expansion of the infarct at day 28. Rivaroxaban did not significantly affect the expression of inflammatory mediators or a neutrophil marker at day 2 after LAD ligation. Delaying the start of rivaroxaban administration until 3 days after surgery failed to preserve cardiac function. In addition, rivaroxaban did not reduce cardiac dysfunction in PAR-2-/- mice. CONCLUSIONS: Early administration of rivaroxaban preserves cardiac function in mice after LAD ligation.

Protease-Activated Receptor 1 Enhances Poly I:C Induction of the Antiviral Response in Macrophages and Mice.

The coagulation cascade is activated during viral infections as part of the host defense system. Coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). Recently, we reported that the activation of PAR-1 enhanced interferon (IFN)ß and CXCL10 expression in cardiac fibroblasts and in the hearts of mice infected with Coxsackievirus B3. In this study, we used the double-stranded RNA mimetic polyinosinic:polycytidylic acid (poly I:C) to induce an antiviral response in macrophages and mice. Activation of PAR-1 enhanced poly I:C induction of IFNß and CXCL10 expression in the murine macrophage cell line RAW264.7, bone-marrow derived mouse macrophages (BMM) and mouse splenocytes. Next, poly I:C was used to induce a type I IFN innate immune response in the spleen and plasma of wild-type (WT) and PAR-1-/- mice. We found that poly I:C treated PAR-1-/- mice and WT mice given the thrombin inhibitor dabigatran etexilate exhibited significantly less IFNß and CXCL10 expression in the spleen and plasma than WT mice. These studies suggest that thrombin activation of PAR-1 contributes to the antiviral response in mice.

Regulation of tissue factor gene expression in monocytes and endothelial cells: Thromboxane A2 as a new player.

Tissue factor (TF) is the primary activator of the coagulation cascade. Under normal conditions, endothelial cells (ECs) and blood cells, such as monocytes, do not express TF. However, bacterial lipopolysaccharide (LPS) induces TF expression in monocytes and this leads to disseminated intravascular coagulation during endotoxemia and sepsis. A variety of stimuli induce TF expression in ECs in vitro, although it is unclear how much TF is expressed by the endothelium in vivo. LPS induction of TF gene expression in monocytic cells and ECs is mediated by various intracellular signaling pathways and the transcription factors NF-ĸB, AP-1 and Egr-1. In contrast, vascular endothelial cell growth factor (VEGF) induces TF gene expression in ECs via the transcription factors NFAT and Egr-1. Similarly, oxidized phospholipids (such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine) induce TF expression in ECs and possibly monocytes via NFAT and Egr-1. Thromboxane A2 (TXA2) can now be added to the list of stimuli that induce TF gene expression in both monocytes and ECs. Interestingly, inhibition of the TX-prostanoid (TP) receptor also reduces TF expression in with tumor necrosis factor (TNF)-α stimulated ECs and LPS stimulated monocytes, which suggests that TP receptor antagonist may be useful in reducing pathologic TF expression in the vasculature and blood.

Regulation of ankyrin repeat and suppressor of cytokine signalling box protein 4 expression in the immortalized murine endothelial cell lines MS1 and SVR: a role for tumour necrosis factor alpha and oxygen.

During vascular development, endothelial cells are exposed to a variety of rapidly changing factors, including fluctuating oxygen levels. We have previously shown that ankyrin repeat and suppressor of cytokine signalling box protein 4 (ASB4) is the most highly differentially expressed gene in the vascular lineage during early differentiation and is expressed in the embryonic vasculature at a time when oxygen tension is rising because of the onset of placental blood flow. To further our understanding of the regulation of ASB4 expression in endothelial cells, we tested the effect of various stressors for their ability to alter ASB4 expression in the immortalized murine endothelial cell lines MS1 and SVR. ASB4 expression is decreased during hypoxic insult and shear stress, whereas it is increased in response to tumour necrosis factor alpha (TNF-α). Further investigation indicated that nuclear factor kappa B (NF-κB) is the responsible transcription factor involved in the TNF-α-induced upregulation of ASB4, placing ASB4 downstream of NF-κB in the TNF-α signalling cascade and identifying it as a potential regulator for TNF-α's numerous functions associated with inflammation, angiogenesis and apoptosis.