M icroRNAs (miRNAs) are small noncoding RNAs with cell-type specific expression patterns that are released by cells into the circulation as part of membranous particles or protein complexes.1 Thus, miRNAs can be readily quantified by real-time polymerase chain reactions (qPCRs) in plasma and serum and have generated increasing interest as potential new biomarkers.2 Our group has previously identified plateletrelated miRNA signatures that are predictive of cardiovascular events. 3 In addition, we measured miRNAs in healthy volunteers and in patients with symptomatic atherosclerosis before and after initiation of dual antiplatelet therapy and demonstrated reduced plasma levels of platelet-related miRNAs on platelet inhibition. Kaudewitz et al Plasma MicroRNAs and Platelet Function 421Dual oral antiplatelet therapy (acetylsalicylic acid [ASA]+a P2Y 12 inhibitor) is commonly used for the management of non-ST-segment-elevation acute coronary syndromes (ACS) and ST-segment-elevation myocardial infarction.5 ASA irreversibly inhibits cyclooxygenase 1 in platelets, thereby repressing thromboxane A 2 (TxA 2 ) synthesis and, consequently, platelet activation. Clopidogrel, prasugrel, and ticagrelor target the P2Y 12 receptor for ADP. However, interindividual variability in the platelet response to clopidogrel has been reported. Prasugrel and ticagrelor exhibit a more consistent antiplatelet effect and have shown benefits over clopidogrel in patients with ACS but also increase the risk of bleeding. 6,7 It is currently unclear whether plasma levels of platelet-related miRNAs correlate with the residual platelet activity in patients with ACS and how different antiplatelet agents alter miRNAs.In this study, we used RNA sequencing to characterize small RNAs in plasma. Then, we compared the effect of different antiplatelet agents and explored the association of small RNAs (miRNAs and YRNAs) with platelet function tests in patients with ACS. Moreover, we correlated their plasma levels to platelet activation markers in the prospective, population-based Bruneck study 3 and investigated whether a single-nucleotide polymorphism (SNP) that facilitates miR-126 processing 8 alters circulating miR-126 levels and platelet reactivity. These epidemiological observations were complemented by preclinical studies, assessing platelet function in mice on treatment with antagomiRs directed against miR-126 and by mechanistic studies measuring miR-126 targets. MethodsAn expanded Methods section is available in the Online Data Supplement. Next-Generation SequencingSmall RNA libraries were generated from non-normalized RNA (ranging from 375 pg to 1 ng) extracted from equal volumes of platelet-poor plasma (PPP) and platelet-rich plasma (PRP) from healthy human volunteers. Before library preparation, RNA was spiked with equal amounts of C. elegans miR-39 star (cel-miR-39*) to assist in normalization. Libraries were prepared using the small RNA library preparation kit version 2.0 (Illumina Cambridge Ltd) according to manufacturer's protocol with limi...

AimsAcute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS.Methods and resultsA phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31–29.64); placebo group, 43.5 mg day/L (31.15–60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32–0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group [IL-1ra; 3.50 mg/L (2.65–4.62): placebo; 2.21 mg/L (1.67–2.92), P = 0.022]. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group.ConclusionIL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety.Clinical Trial RegistrationEUCTR: 2006-001767-31-GB: .

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

We have developed a model of intracoronary physiology based upon a rotational coronary angiogram. Significant lesions were identified with 97% accuracy. The FFR was reliably predicted without the need for invasive measurements or inducing hyperemia.