Daily Cardiology Research Analysis

AIMS: Fetuin-A, a liver-derived heterodimeric plasma glycoprotein, exhibits abnormal elevation in non-alcoholic fatty liver disease (NAFLD). Plasma fetuin-A levels correlate closely with both morbidity and mortality associated with cardiovascular diseases. However, the precise influence of fetuin-A on NAFLD-related platelet activation and thrombosis remains to be elucidated. METHODS AND RESULTS: Fetuin-A directly amplified agonist-induced platelet aggregation, dense granule adenosine triphosphate release, P-selectin exposure, integrin αIIbβ3 activation, spreading, and clot retraction. Mechanistically, fetuin-A bound to platelet Toll-like receptor-4 (TLR-4), activating TLR-4/MyD88, SFK/PI3 K/AKT, cGMP/PKG, and mitogen-activated protein kinase signalling pathways to enhance platelet activation. TLR-4 specific antagonist TAK-242 and TLR-4-deficient mice confirmed the TLR-4 dependence of these effects. Oral administration of firsocostat, rosuvastatin, or pioglitazone demonstrated efficacy in alleviating thrombosis formation in NAFLD mice by reducing fetuin-A levels and attenuating platelet hyperreactivity. Notably, the fetuin-A-inhibiting antibody potently suppressed platelet activation and inhibited thrombosis formation in NAFLD mice. Administration of this antibody attenuated thromboembolism and microvascular thrombosis in NAFLD mice, thereby safeguarding the lung, heart, and brain from exacerbated tissue infarcts. Finally, a positive correlation between plasma fetuin-A concentration and platelet aggregation was observed in NAFLD patients. CONCLUSION: Fetuin-A emerges as a positive regulator of platelet hyperreactivity in NAFLD. Acting via TLR-4-dependent signalling pathways, plasma fetuin-A directly amplifies platelet activation and promotes in vivo thrombosis. Firsocostat, rosuvastatin, and pioglitazone abrogate these enhancing effects by reducing fetuin-A levels. The fetuin-A-inhibiting antibody presents potential therapeutic advantages to prevent thrombotic complications in NAFLD.

BACKGROUND AND AIMS: Despite optimal management of low-density lipoprotein cholesterol (LDL-C), substantial residual cardiovascular risk persists in patients with cardiovascular disease (CVD), which may be attributed to other atherogenic lipoproteins. We tested the hypotheses that elevated triglycerides (TGs) are related to higher residual CVD and mortality risk in patients with established CVD, and that such relationships depend on guideline-recommended lipid target achievement, high-density lipoprotein cholesterol (HDL-C) levels, and intensity of lipid-lowering therapy (LLT). METHODS: In a prospective cohort study of 9436 patients with manifest CVD, the relationships between log-transformed TG levels and recurrent cardiovascular events and all-cause mortality were analyzed overall using Cox regression models. Subsequently, analyses were stratified by achievement of low-density lipoprotein cholesterol (LDL-C) and non-HDL-C treatment goals, HDL-C levels, and LLT intensity. RESULTS: During a median follow-up of 9.0 years (IQR 4.5-14.1), 2075 recurrent cardiovascular events, 736 myocardial infarctions, 586 strokes, 1231 cardiovascular deaths, and 2729 all-cause deaths occurred. Per 1-unit higher log-TG level, the hazard ratio was 1.17 (95 % CI: 1.07-1.28) for recurrent cardiovascular events, 1.34 (1.16-1.56) for myocardial infarction, 1.10 (0.92-1.30) for stroke, 1.23 (1.09-1.38) for cardiovascular mortality, and 1.12 (1.03-1.21) for all-cause mortality. These hazard ratios did not depend on achievement of LDL-C and non-HDL-C treatment goals, HDL-C levels, or LLT intensity (all p for interaction ≥0.05). CONCLUSIONS: Elevated TGs are related to higher residual CVD and mortality risk in patients with established CVD. These relationships were unrelated to guideline-recommended lipid target achievement, HDL-C levels, and LLT intensity.

BACKGROUND: A pathway incorporating an option for early discharge based on a single low level of high-sensitivity cardiac troponin I (hs-cTnI) at presentation increases the proportion of patients presenting with a potential acute coronary syndrome (ACS) that can be discharged directly from the emergency department (ED), reducing length of stay without any increase in adverse events at 30 days. Here, we report the 1-year outcomes of patients managed using this pathway. METHODS: We recruited two cohorts of patients with a potential ACS, without high-risk features. The 'standard' cohort was managed according to the Australian national guidelines and the Single Troponin Accelerated Triage ('STAT') cohort was managed using the study pathway. 12-month outcomes were assessed using linked administrative data. RESULTS: Between May 2018 and October 2019, we recruited 2255 patients (1131 standard vs 1124 STAT), mean age 55 years, 53% male. 709 (63%) patients managed using the STAT pathway were discharged directly from ED, compared with 403 (38%) patients using the standard pathway, with a 47 min reduction in median hospital length of stay. At 12 months, there were no significant differences in unadjusted all-cause death (STAT 0.62% vs standard 0.97%, p=0.35) or myocardial infarction (MI) (STAT 0.62% vs standard 1.24%, p=0.13). CONCLUSIONS: A clinical pathway which incorporates early discharge based on a single low serum hs-cTnI is associated with an increased proportion of patients with a potential ACS discharged directly from the ED and reduced length of stay, without an increase in death or MI at 1 year.