Neutrophil peptidylarginine deiminase 4 is essential for detrimental age-related cardiac remodelling and dysfunction in mice.

Mice fully deficient in peptidylarginine deiminase 4 (PAD4) enzyme have preserved cardiac function and reduced collagen deposition during ageing. The cellular source of PAD4 is hypothesized to be neutrophils, likely due to PAD4's involvement in neutrophil extracellular trap release. We investigated haematopoietic PAD4 impact on myocardial remodelling and systemic inflammation in cardiac ageing by generating mice with Padi4 deletion in circulating neutrophils under the MRP8 promoter (Ne-PAD4-/-), and ageing them for 2 years together with littermate controls (PAD4fl/fl). Ne-PAD4-/- mice showed protection against age-induced fibrosis, seen by reduced cardiac collagen deposition. Echocardiography analysis of structural and functional parameters also demonstrated preservation of both systolic and diastolic function with MRP8-driven PAD4 deletion. Furthermore, cardiac gene expression and plasma cytokine levels were evaluated. Cardiac genes and plasma cytokines involved in neutrophil recruitment were downregulated in aged Ne-PAD4-/- animals compared to PAD4fl/fl controls, including decreased levels of C-X-C ligand 1 (CXCL1). Our data confirm PAD4 involvement from circulating neutrophils in detrimental cardiac remodelling, leading to cardiac dysfunction with old age. Deletion of PAD4 in MRP8-expressing cells impacts the CXCL1-CXCR2 axis, known to be involved in heart failure development. This supports the future use of PAD4 inhibitors in cardiovascular disease. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Revascularization strategies in patients with multivessel coronary artery disease: a Bayesian network meta-analysis.

Treatment modalities for multivessel disease have rapidly evolved, yet the preferred strategy remains controversial. This meta-analysis compared outcomes after on-pump (ONCAB), off-pump coronary artery bypass grafting (OPCAB), percutaneous coronary intervention (PCI) or hybrid coronary revascularization. A comprehensive search for observational studies and randomized controlled trials published by August 2020 was performed. A Bayesian network meta-analysis was conducted for early (<30 days) and late (>12 months) outcomes. A total of 119 studies were included (n = 700 458 patients). The main analysis was confined to 31 randomized controlled trials (n = 24 932 patients). PCI was associated with lower early mortality [odds ratio (OR) 0.50, 95% confidence interval (CI) 0.31-0.79] and stroke (OR 0.22, 95% CI 0.06-0.60) rates compared with ONCAB, whereas a reduced risk of early myocardial infarction was observed with OPCAB compared with ONCAB (OR 0.53, 95% CI 0.32-0.83). Late target vessel revascularization and major adverse cardiac and cerebrovascular events were both increased with PCI compared with ONCAB, OPCAB and hybrid coronary revascularization (by 127-203% and 59-64%, respectively), and late major adverse cardiac events were increased in PCI compared with ONCAB and OPCAB (by 64% and 59%). However, PCI was associated with a significantly lower risk of late stroke compared with ONCAB (OR 0.70, 95% CI 0.52-0.89). Sensitivity analyses (i) including observational studies and (ii) limiting to studies with recent cohorts confirmed the findings of the main analysis. Surgical approaches for revascularization remain superior to PCI in patients with multivessel disease. Hybrid coronary revascularization might be viable for some patients, although more evidence from randomized controlled trials is warranted.