Low-grade inflammation (LGI) represents a key driver of type 2 diabetes (T2D) and its associated cardiovascular diseases (CVDs). Indeed, inflammatory markers such as hs-CRP and IL-6 predict the development of T2D and its complications, suggesting that LGI already increases before T2D diagnosis and remains elevated even after treatment. Overnutrition, unhealthy diets, physical inactivity, obesity, and aging are all recognized triggers of LGI, promoting insulin resistance and sustaining the pathogenesis of T2D. Once developed, and even before frank appearance, people with T2D undergo a pathological metabolic remodeling, with an alteration of multiple CVD risk factors, i.e., glycemia, lipids, blood pressure, and renal function. In turn, such variables foster a range of inflammatory pathways and mechanisms, e.g., immune cell stimulation, the accrual of senescent cells, long-lasting epigenetic changes, and trained immunity, which are held to chronically fuel LGI at the systemic and tissue levels. Targeting of CVD risk factors partially ameliorates LGI. However, some long-lasting inflammatory pathways are unaffected by common therapies, and LGI burden is still increased in many T2D patients, a phenomenon possibly underlying the residual inflammatory risk (i.e., having hs-CRP > 2 mg/dL despite optimal LDL cholesterol control). On the other hand, selected disease-modifying drugs, e.g., GLP-1RA, seem to also act on the pathogenesis of T2D, curbing the inflammatory trajectory of the disease and possibly preventing it if introduced early. In addition, selected trials demonstrated the potential of canonical anti-inflammatory therapies in reducing the rate of CVDs in patients with this condition or at high risk for it, many of whom had T2D. Since colchicine, an inhibitor of immune cell activation, is now approved for the prevention of CVDs, it might be worth exploring a possible therapeutic paradigm to identify subjects with T2D and an increased LGI burden to treat them with this drug. Upcoming studies will reveal whether disease-modifying drugs reverse early T2D by suppressing sources of LGI and whether colchicine has a broad benefit in people with this condition.

Background: Microplastics (MPs) have emerged as significant environmental pollutants, posing a threat to ecosystems and humans. The presence of MPs in atherosclerotic plaques, exacerbating cardiovascular risk, has been recently reported. However, the molecular mechanism underlying the effects of MPs on the vascular endothelium are still undefined. In this regard, this study aims to investigate the effects of MPs on endothelial cell function and redox state and the underlying mechanisms. Methods: Immortalized human aortic endothelial cells (teloHAEC), human umbilical vein endothelial cells (HUVEC), and human coronary artery endothelial cells (HCAEC) were treated with MPs in the form of polyethylene (PE) and polyvinyl chloride (PVC) alone (70 µg/mL) or combined PE (30 µg/mL) + PVC (30 µg/mL) (PE + PVC) for up to 48 h. The effects of MPs on cell viability were evaluated using CCK-8, and its role in endothelial function was evaluated by flow cytometric analyses, enzyme-linked immunosorbent assays (ELISA), and XF HS Seahorse bioanalyzer. Proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Molecular involvement of sirtuin 6 (SIRT6) was investigated through gene silencing. Results: Our study demonstrated that PE and PVC, alone or in combination, upregulated inflammatory mediators monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) ( p < 0.001), modulated the expression of autophagy markers anti-autophagy related 5 (ATG5) and p62, impaired mitochondrial metabolism by reducing maximal and basal respiration and adenosine triphosphate (ATP) production ( p < 0.001), promoted reactive oxygen species (ROS) accumulation ( p < 0.001) and cell cycle perturbations ( p < 0.01), and increased apoptosis cell death ( p < 0.001). These events were accompanied by a downregulation of sirtuin 6 (SIRT6) expression ( p < 0.01) and an upregulation of PCSK9, at protein and messenger RNA (mRNA) levels ( p < 0.01). Treatment with the PCSK9 inhibitor (iPCSK9) evolocumab ameliorated MP-induced cellular redox state imbalance, mitochondrial metabolism alteration, and SIRT6 downregulated levels ( p < 0.01). SIRT6 transient silencing experiments denied the beneficial effects of iPCSK9 treatment, indicating that the pleiotropic functions of iPCSK9 may occur, at least in part, via modulation of SIRT6 and Forkhead box O3 (FOXO3A) expression levels. Conclusions: Overall, the results indicate that PCSK9 inhibition via evolocumab exhibits substantial promise in the prevention of MP-induced endothelial dysfunction, suggesting the PCSK9–SIRT6 axis as a new promising pathway to target in preventive strategies for cardiovascular risk caused by plastic pollution.

Background: Lifestyle interventions halt the progression of prediabetes to frank type 2 diabetes (T2D). However, the feasibility of a diabetes prevention program promoting tailored interventions on a national scale and conducted by primary care physicians is unclear. Methods: General practitioners located in ten different regions throughout Italy enrolled random subjects without known metabolic diseases to identify individuals with prediabetes and prescribe them an intervention based on physical activity. Using a simple stepwise approach, people referring to their primary care physician for any reason were screened for their diabetes risk with a web-based app of the Findrisc questionnaire. Those at risk for T2D, i.e., with a Findrisc score >9, were invited to come back after overnight fasting to measure fasting glycaemia (FG). Those with 100 ≤ FG < 126 mg/dL were considered as people with prediabetes and compiled the Physical Activity Readiness Questionnaire (PAR-Q) to then receive a personalised prescription of physical activity. Results: Overall, 5928 people were enrolled and compiled the questionnaire. Of these, 2895 (48.8%) were at risk for T2D. Among these, FG was measured in 2168 subjects (participation rate 75%). The numbers of individuals with undetected prediabetes and T2D according to FG were 755 and 79 (34.8% and 3.6% of those assessing FG), respectively. Of the 755 subjects in the prediabetes range, 739 compiled the PAR-Q and started a personalised program of physical activity (participation rate 97%). Physicians involved in the study reported a mean of 6 min to perform the screening. Conclusions: Overall, these data suggest the feasibility of a national diabetes prevention program developed by general practitioners using a simple stepwise approach starting from a web app to intercept individuals with prediabetes.

Using data from the Swedish National Diabetes Register, this study examines the gender disparity among patients with type 1 diabetes who have experienced a specific cardiovascular complication, while exploring the association between their weight variability, age group, and gender. Fourteen cardiovascular complications have been considered. This analysis is conducted using three-way correspondence analysis (CA), which allows for the partitioning and decomposition of Pearson’s three-way chi-squared statistic. The dataset comprises information organized in a data cube, detailing how weight variability among these patients correlates with a cardiovascular complication, age group, and gender. The three-way CA method presented in this paper allows one to assess the statistical significance of the association between these variables and to visualize this association, highlighting the gender gap among these patients. From this analysis, we find that the association between weight variability, age group, and gender varies among different types of cardiovascular complications.

Background: Frailty is highly prevalent among older adults with cardiovascular disease (CVD) and strongly predicts disability and mortality after cardiac events. Although cardiac rehabilitation (CR) improves prognosis, frail older patients often face barriers to participating in in-person programs. eHealth-based, home-delivered CR programs incorporating tele-rehabilitation and remote monitoring may improve accessibility, yet evidence regarding their effectiveness on frailty status remains limited. Methods: We designed a multicenter, randomized, parallel-group trial enrolling people ≥65 years recently hospitalized for acute heart failure (AHF) and/or acute coronary syndrome (ACS). Participants were randomized 1:1 to an eHealth home-based tele-rehabilitation program or the usual care. The primary endpoint is frailty prevalence at follow-up, defined by an Essential Frailty Toolset (EFT) score ≥3, with co-primary outcomes being between-group differences in the mean levels of EFT and Short Physical Performance Battery (SPPB) scores after 3–6 months. Secondary endpoints include mortality and hospitalization, among others. Results: The full protocol and study procedures are reported. Between May 2024 and December 2025, 589 patients were screened at the two Italian centers involved; 442 met eligibility criteria and 209 were enrolled and randomized. Baseline characteristics were largely comparable between groups. The mean age was 77 ± 9 years, 70% were male, and 55% had ACS. Lower-than-expected enrollment was mainly attributable to refusal related to difficulties in using digital devices. Conclusions: This randomized trial will evaluate whether a multidomain, eHealth-based CR intervention can reduce the prevalence or degree of frailty in older people after AHF or ACS. We report the study protocol and baseline characteristics of the enrolled cohort, highlighting the challenge of digital illiteracy in contemporary older populations.