Evaluation of high-density lipoprotein-bound long non-coding RNAs in subjects with familial hypercholesterolaemia.

BACKGROUND: Long non-coding RNAs (lncRNAs) could be attractive circulating biomarkers for cardiovascular risk stratification in subjects at high atherosclerotic cardiovascular disease risk such as familial hypercholesterolaemia (FH). Our aim was to investigate the presence of lncRNAs carried by high-density lipoprotein (HDL) in FH subjects and to evaluate the associations of HDL-lncRNAs with lipoproteins and mechanical vascular impairment assessed by pulse wave velocity (PWV). METHODS: This was a retrospective observational study involving 94 FH subjects on statin treatment. Biochemical assays, HDL purification, lncRNA and PWV analyses were performed in all subjects. RESULTS: LncRNA HIF1A-AS2, LASER and LEXIS were transported by HDL; moreover, HDL-lncRNA LEXIS was associated with Lp(a) plasma levels (p < .01). In a secondary analysis, the study population was stratified into two groups based on the Lp(a) median value. The high-Lp(a) group exhibited a significant increase of PWV compared to the low-Lp(a) group (9.23 ± .61 vs. 7.67 ± .56, p < .01). While HDL-lncRNA HIF1A-AS2 and LASER were similar in the two groups, the high-Lp(a) group exhibited a significant downregulation of HDL-lncRNA LEXIS compared to the low-Lp(a) group (fold change -4.4, p < .0001). Finally, Lp(a) and HDL-lncRNA LEXIS were associated with PWV (for Lp(a) p < .01; for HDL-lncRNA LEXIS p < .05). CONCLUSIONS: LncRNA HIF1A-AS2, LASER and LEXIS were transported by HDL; moreover, significant relationships of HDL-lncRNA LEXIS with Lp(a) levels and PWV were found. Our study suggests that HDL-lncRNA LEXIS may be useful to better identify FH subjects with more pronounced vascular damage.

Increased Cardiovascular Risk Associated with Chemical Sensitivity to Perfluoro-Octanoic Acid: Role of Impaired Platelet Aggregation.

Perfluoro-alkyl substances (PFAS), particularly perfluoro-octanoic acid (PFOA), are persisting environmental chemicals showing bioaccumulation in human tissues. Recently, exposure to PFAS has been associated with increased prevalence of cardiovascular diseases (CVDs). However, a causal role of PFAS in atherosclerosis pathogenesis is under-investigated. Here, we investigated the effect of PFOA exposure on platelets' function, a key player in atherosclerosis process. PFOA accumulation in platelets was evaluated by liquid chromatography-mass spectrometry. Changes in platelets' membrane fluidity and activation after dose-dependent exposure to PFOA were evaluated by merocyanine 540 (MC540) and anti P-Selectin immune staining at flow cytometry, respectively. Intracellular calcium trafficking was analyzed with Fluo4M probe, time-lapse live imaging. Platelets' aggregation state was also evaluated with Multiplate® aggregometry analyzer in 48 male subjects living in a specific area of the Veneto region with high PFAS environmental pollution, and compared with 30 low-exposure control subjects. Platelets' membrane was the major target of PFOA, whose dose-dependent accumulation was associated in turn with increased membrane fluidity, as expected by a computational model; increased activation at resting condition; and both calcium uptake and aggregation upon activation. Finally, exposed subjects had higher serum and platelets levels of PFOA, together with increased aggregation parameters at Multiplate®, compared with controls. These data help to explain the emerging association between PFAS exposure and CVD.

The impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy optimization in men and women with familial hypercholesterolemia.

Background and aims: FH women are less likely to receive intensive statin treatment and to obtain a 50% reduction of LDL-C from baseline compared to men with FH. SLCO1B1 rs4149056 might influence statin therapy compliance and thus LDL-C target achievement. Our aim was to evaluate the impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy (LLT) optimization in men and women with FH. Methods: This was a retrospective observational study involving 412 FH subjects with a probable or defined clinical diagnosis of FH who had had genetic analysis from June 2016 to September 2022. Biochemical analysis was obtained from all subjects at baseline and at the last follow-up after LLT optimization. Results: After LLT optimization the percentage of FH subjects on high-intensity statins decreased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was found in LDL-C target distribution (for both p for trend < 0.01). The prevalence of SASE fear increased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was observed in reported myalgia distribution (for both p for trend < 0.01). Logistic regression analysis showed that the W/SCLO1B1-, M/SCLO1B1+ and W/SCLO1B1+ groups were inversely associated with LDL-C target achievement (p for trend < 0.001) and the W/SCLO1B1+ group exhibited the strongest association. Conclusion: A low prevalence of FH women with SLCO1B1 rs4149056 were on high intensity statins and they rarely achieved LDL-C target. The genotype effect of SLCO1B1 rs4149056 could be more pronounced in FH women than men.

Management of Statin Intolerant Patients in the Era of Novel Lipid Lowering Therapies: A Critical Approach in Clinical Practice.

Statins are the cornerstone of lipid-lowering therapies effective for cardiovascular risk reduction. Although they are generally well tolerated, statin intolerance (SI) is frequent in clinical practice, and it is usually related to the onset of muscle symptoms, which are defined under the acronym SAMS (Statin-Associated Muscle Side Effects). These side effects are responsible for statin treatment discontinuation that results in increased cardiovascular risk. The National Lipid Association (NLA) has recently provided an updated definition of statin intolerance, and a distinction between complete and partial statin intolerance has been reported. The evaluation of symptom severity and the presence of muscle damage biomarker alterations make it essential to adopt a patient-centered approach aimed at obtaining a personalized therapeutic strategy. Firstly, it could be useful to administer a different statin, reduce the dosage or adopt an alternate dosage regimen. However, some patients are unable to tolerate any statin at every dosage, or despite taking statins at the maximum tolerated dose, they fail to achieve the recommended LDL-C target, and thus it is necessary to introduce a non-statin hypolipidemic treatment. Ezetimibe, proprotein-convertase subtilisin/kexin type 9 (PCSK9) inhibitors such as monoclonal antibodies (alirocumab and evolocumab) or RNA messenger silencing (inclisiran), bempedoic acid or nutraceuticals are non-statin lipid-lowering therapies that could be used as an alternative or in addition to statins to achieve an early and sustained LDL-C reduction in clinical practice. In this review, we evaluated SI management focusing on non-statin lipid lowering therapies and their implications in lipid lowering approaches in clinical practice.

Is COVID-19 All That Glitters?

Over the last three years, the Coronavirus-19 disease has been a global health emergency, playing a primary role in the international scientific community. Clinical activity and scientific research have concentrated their efforts on facing the pandemic, allowing the description of novel pathologies correlated to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), such as the Multisystemic Inflammatory Syndrome in Children and Adults (MIS-C, MIS-A). Conversely, this shift of attention to COVID-19 disease and its complications could, in some cases, have delayed and underestimated the diagnosis of diseases not associated with SARS-CoV-2, including rare diseases. Here we describe the diagnostic process that led to the definition of a rare vasculitis in a young woman with a recent clinical history of SARS-CoV-2.

Energy threshold changes in volcanic activity at Mt. Etna (Italy) inferred from volcanic tremor.

From the 2010s on, pattern classification has proven an effective method for flagging alerts of volcano unrest before eruptive activity at Mt. Etna, Italy. The analysis has been applied online to volcanic tremor data, and has supported the surveillance activity of the volcano that provides timely information to Civil Protection and other authorities. However, after declaring an alert, no one knows how long the volcano unrest will last and if a climactic eruptive activity will actually begin. These are critical aspects when considering the effects of a prolonged state of alert. An example of longstanding unrest is related to the Christmas Eve eruption in 2018, which was heralded by several months of almost continuous Strombolian activity. Here, we discuss the usage of thresholds to detect conditions leading to paroxysmal activity, and the challenges associated with defining such thresholds, leveraging a dataset of 52 episodes of lava fountains occurring in 2021. We were able to identify conservative settings regarding the thresholds, allowing for an early warning of impending paroxysm in almost all cases (circa 85% for the first 4 months in 2021, and over 90% for the whole year). The chosen thresholds also proved useful to predict that a paroxysmal activity was about to end. Such information provides reliable numbers for volcanologists for their assessments, based on visual information, which may not be available in bad weather or cloudy conditions.

Crustal deformation, active tectonics and seismic potential in the Sicily Channel (Central Mediterranean), along the Nubia-Eurasia plate boundary.

Based on multidisciplinary data, including seismological and geodetic observations, as well as seismic reflection profiles and gravity maps, we analysed the pattern of crustal deformation and active tectonics in the Sicily Channel, a key observation point to unravel the complex interaction between two major plates, Nubia and Eurasia, in the Mediterranean Sea. Our data highlight the presence of an active ~ 220-km-long complex lithospheric fault system (here named the Lampedusa-Sciacca Shear Zone), approximately oriented N-S, crossing the study area with left-lateral strike-slip deformations, active volcanism and high heat flow. We suggest that this shear zone represents the most active tectonic domain in the area, while the NW-SE elongated rifting pattern, considered the first order tectonic feature, appears currently inactive and sealed by undeformed recent (Lower Pleistocene?) deposits. Estimates of seismological and geodetic moment-rates, 6.58 × 1015 Nm/year and 7.24 × 1017 Nm/year, respectively, suggests that seismicity accounts only for ~ 0.9% of crustal deformation, while the anomalous thermal state and the low thickness of the crust would significantly inhibit frictional sliding in favour of creeping and aseismic deformation. We therefore conclude that a significant amount of the estimated crustal deformation-rate occurs aseismically, opening new scenarios for seismic risk assessments in the region.

Short-term detection of volcanic unrest at Mt. Etna by means of a multi-station warning system.

Early-warning assessment of a volcanic unrest requires that accurate information from monitoring is continuously gathered before volcanic activity starts. Seismic data are an optimal source of such information, overcoming safety problems due to dangerous conditions for field surveys or cloud cover that may hinder visibility. We designed a multi-station warning system based on the classification of patterns of the background seismic radiation, so-called volcanic tremor, by using Self-Organizing Maps (SOM) and fuzzy clustering. The classifier automatically detects patterns that are typical footprints of volcanic unrest. The issuance of the SOM colors on DEM allows their geographical visualization according to the stations of detection; this spatial location makes it possible to infer areas potentially impacted by eruptive phenomena. Tested at Mt. Etna (Italy), the classifier forecasted in hindsight patterns associated with fast-rising magma (typical of lava fountains) as well as a relatively long lead time of the outburst (lava flows from eruptive fractures). Receiver Operating Characteristics (ROC) curves gave an Area Under the Curve (AUC) ∼0.8 indicative of a good detection accuracy that cannot be achieved from a mere random choice.