Cardiovascular Risk Estimation and Stratification Among Individuals with Hypercholesterolemia.

PURPOSE OF THE REVIEW: This review aims to assess the variability in considering hypercholesterolemia for cardiovascular risk stratification in the general population. Recent literature on the integration of hypercholesterolemia into clinical risk scores and its interaction with other risk factors will be explored. RECENT FINDINGS: The impact of hypercholesterolemia on risk estimation varies among different cardiovascular risk calculators. Elevated lipid levels during early life stages contribute to atherosclerotic plaque development, influencing disease severity despite later treatment initiation. The interplay between low-density lipoprotein cholesterol (LDLc), inflammatory markers and non-LDL lipid parameters enhances cardiovascular risk stratification. Studies have also examined the role of coronary artery calcium (CAC) score as a negative risk marker in populations with severe hypercholesterolemia. Furthermore, polygenic risk scores (PRS) may aid in diagnosing non-monogenic hypercholesterolemia, refining cardiovascular risk stratification and guiding lipid-lowering therapy strategies. Understanding the heterogeneity in risk estimation and the role of emerging biomarkers and imaging techniques is crucial for optimizing cardiovascular risk prediction and guiding personalized treatment strategies in individuals with hypercholesterolemia.

Implications of GLP-1 Receptor Agonist on Thyroid Function: A Literature Review of Its Effects on Thyroid Volume, Risk of Cancer, Functionality and TSH Levels.

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management.

Malnutrition-Related Liver Steatosis, CONUT Score and Poor Clinical Outcomes in an Internal Medicine Department.

Fatty liver disease has been identified as a marker of malnutrition in different clinical settings. Recently, the COntrolling NUTritional status score (CONUT score) emerged as a promising tool for malnutrition assessment. Our aim was to evaluate short-term outcomes among patients with malnutrition-related liver steatosis in an Internal Medicine department. Furthermore, we evaluated the association of the CONUT score with malnutrition-related liver steatosis. Data from 247 patients hospitalized in an Internal Medicine department were retrospectively collected. The study population was stratified into three groups based on hepatic radiodensity assessed with computed tomography: mild steatosis (≥56.1 HU), moderate steatosis (between 49.7 and 56 HU), and severe steatosis (≤49.6 HU). We then calculated the CONUT score. Severe steatosis patients had higher in-hospital mortality (18.2 vs. 15.5%) and longer in-hospital stays compared with the mild steatosis group (length of in-hospital stay longer than 12 days: 45% vs. 40%). Logistic regression analysis showed that severe steatosis was not significantly associated with in-hospital all-cause death, while a high CONUT score was an independent risk factor for sepsis. We found an independent relationship between malnutrition-associated liver steatosis and the CONUT score. These results identified the CONUT score as a tool for nutritional assessment of hospitalized patients.

GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes.

Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials.

Acute hyperbilirubinemia determines an early subclinical renal damage: Evaluation of tubular biomarkers in cholemic nephropathy.

BACKGROUND AND AIMS: Cholemic nephropathy is a cause of acute kidney injury occurring in patients with jaundice. The aim of this study was to evaluate early renal function impairment in patients with mild acute hyperbilirubinemia in the absence of alterations of the common parameters used in clinical practice (serum creatinine or urea) and with normal renal morphology. We studied urinary biomarkers of tubular damage urinary neutrophil gelatinase-associated lipocalin (u-NGAL), urinary beta-2-microglobulin (u-B2M), urinary osteopontin (u-OPN), urinary trefoil factor 3 (u-TFF3) and urinary Cystatin C (u-Cys). METHODS: This is a case-control study investigating the following urinary biomarkers of tubular damage: u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys, in patients with mild acute hyperbilirubinemia. Seventy-four patients were included in this study: 36 patients with jaundice and 38 patients without jaundice. RESULTS: Subjects with jaundice (total bilirubin 12.4 ± 7.3 mg/dL) showed higher u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys compared with controls. After logistic regression analyses, including the following independent variables: age, estimated Glomerular Filtration Rate (eGFR), haemoglobin, diabetes, hypertension and jaundice, we observed a higher risk of elevated u-NGAL values (OR = 3.8, 95% CI 1.07-13.5, p = .03) and u-B2M (OR = 9.4, 95% CI 2.3-38.9, p = .0018) in jaundiced subjects. Moreover, urinary biomarkers had a direct correlation with serum cholestasis indexes. CONCLUSIONS: This study demonstrated increased urinary biomarkers of tubular damage (u-NGAL, u-B2M, u-OPN, u-TFF3, and u-Cys) in patients with mild hyperbilirubinemia in comparison with a control group. These findings suggest early renal tubular damage in the absence of alterations of the normal parameters used in clinical practice (eGFR, serum urea and renal morphology).

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.

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.

Cardiovascular risk and renal injury profile in subjects with type 2 diabetes and non-albuminuric diabetic kidney disease.

BACKGROUND: In the last years, the classical pattern of diabetic kidney disease (DKD) has been partially overcome, because of the uncovering of a new DKD phenotype with significant renal dysfunction without presence of albuminuria: the non-albuminuric DKD (NA-DKD). To date, the cardiovascular risk associated with this phenotype is still debated. We investigated the cardiovascular risk and renal injury profile of NA-DKD subjects in comparison with other DKD phenotypes. METHODS: Pulse wave velocity (PWV), intima-media thickness, presence of carotid atherosclerotic plaque, renal resistive index (RRI), and a panel of urinary biomarkers of kidney injury were evaluated in 160 subjects with type 2 diabetes, stratified according to estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR) into four groups: controls (UACR < 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), A-DKD (Albuminuric-DKD, UACR ≥ 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), NA-DKD (UACR < 30 mg/g and eGFR < 60 mL/min/1.73 m2), AL-DKD (Albuminuric and Low eGFR-DKD; UACR ≥ 30 mg/g and eGFR < 60 mL/min/1.73 m2). RESULTS: Subjects with NA-DKD showed a higher PWV (11.83 ± 3.74 m/s vs. 10.24 ± 2.67 m/s, P = 0.045), RRI (0.76 ± 0.11 vs. 0.71 ± 0.09, P = 0.04), and prevalence of carotid atherosclerotic plaque (59% vs. 31%, P = 0.009) compared with controls. These characteristics were similar to those of subjects with AL-DKD, whereas the profile of A-DKD subjects was closer to controls. After multiple regression analyses, we found that RRI, that is in turn influenced by eGFR (ß = - 0.01, P = 0.01), was one of the major determinants of PWV (ß = 9.4, P = 0.02). Urinary TreFoil Factor 3, a marker of tubular damage, was higher in NA-DKD subjects vs. controls (1533.14 ± 878.31 ng/mL vs. 1253.84 ± 682.17 ng/mL, P = 0.047). Furthermore, after multiple regression analyses, we found that urinary osteopontin was independently associated with PWV (ß = 2.6, P = 0.049) and RRI (ß = 0.09, P = 0.006). CONCLUSIONS: Our data showed a worse cardiovascular and renal injury profile in NA-DKD subjects. This finding emphasizes the central role of eGFR in the definition of cardiovascular risk profile of diabetic subjects together with albuminuria.

An Uncharacterised lncRNA Coded by the ASAP1 Locus Is Downregulated in Serum of Type 2 Diabetes Mellitus Patients.

Diabetes mellitus (DM) is a complex and multifactorial disease characterised by high blood glucose. Type 2 Diabetes (T2D), the most frequent clinical condition accounting for about 90% of all DM cases worldwide, is a chronic disease with slow development usually affecting middle-aged or elderly individuals. T2D represents a significant problem of public health today because its incidence is constantly growing among both children and adults. It is also estimated that underdiagnosis prevalence would strongly further increase the real incidence of the disease, with about half of T2D patients being undiagnosed. Therefore, it is important to increase diagnosis accuracy. The current interest in RNA molecules (both protein- and non-protein-coding) as potential biomarkers for diagnosis, prognosis, and treatment lies in the ease and low cost of isolation and quantification with basic molecular biology techniques. In the present study, we analysed the transcriptome in serum samples collected from T2D patients and unaffected individuals to identify potential RNA-based biomarkers. Microarray-based profiling and subsequent validation using Real-Time PCR identified an uncharacterised long non-coding RNA (lncRNA) transcribed from the ASAP1 locus as a potential diagnostic biomarker. ROC curve analysis showed that a molecular signature including the lncRNA and the clinicopathological parameters of T2D patients as well as unaffected individuals showed a better diagnostic performance compared with the glycated haemoglobin test (HbA1c). This result suggests that the application of this biomarker in clinical practice would help to improve the diagnosis, and therefore the clinical management, of T2D patients. The proposed biomarker would be useful in the context of predictive, preventive, and personalised medicine (3PM/PPPM).

Indirect Effects of the COVID-19 Pandemic on In-Hospital Outcomes among Internal Medicine Departments: A Double-Center Retrospective Study.

The coronavirus disease 19 (COVID-19) emergency led to rearrangements of healthcare systems with a significant impact on those internal medicine departments that had not been converted to COVID-19 wards. A reduced number of departments, indeed, had to cope with the same number of patients along with a lack of management of patients' chronic diseases. We conducted a retrospective study aimed at examiningthe consequences of the COVID-19 pandemic on internal medicine departments that were not directly managing COVID-19 patients. Data from 619 patients were collected: 247 subjects hospitalized in 2019 (pre-COVID-19 era), 178 in 2020 (COVID-19 outbreak era) and 194 in 2021 (COVID-19 ongoing era). We found that in 2020 in-hospital mortality was significantly higher than in 2019 (17.4% vs. 5.3%, p = 0.009) as well as length of in-hospital stay (LOS) (12.7 ± 6.8 vs. 11 ± 6.2, p = 0.04). Finally, we performed a logistic regression analysis of the major determinants of mortality in the entire study population, which highlighted an association between mortality, being bedridden (ß = 1.4, p = 0.004), respiratory failure (ß = 1.5, p = 0.001), glomerular filtration rate (ß = -0.16, p = 0.03) and hospitalization in the COVID-19 outbreak era (ß = 1.6, p = 0.005). Our study highlights how the COVID-19 epidemic may have caused an increase in mortality and LOS even in patients not directly suffering from this infection.

Identification of a New RNA and Protein Integrated Biomarker Panel Associated with Kidney Function Impairment in DKD: Translational Implications.

Diabetic kidney disease (DKD) is a complication that strongly increases the risk of end-stage kidney disease and cardiovascular events. The identification of novel, highly sensitive, and specific early biomarkers to identify DKD patients and predict kidney function decline is a pivotal aim of translational medicine. In a previous study, after a high-throughput approach, we identified in 69 diabetic patients 5 serum mitochondrial RNAs (MT-ATP6, MT-ATP8, MT-COX3, MT-ND1, and MT-RNR1) progressively downregulated with increasing eGFR stages. Here, we analyzed the protein serum concentrations of three well-validated biomarkers: TNFRI, TNFRII, and KIM-1. The protein biomarkers were gradually upregulated from G1 to G2 and G3 patients. All protein biomarkers correlated with creatinine, eGFR, and BUN. Performing multilogistic analyses, we found that, with respect to single protein biomarkers, the combination between (I) TNFRI or KIM-1 with each RNA transcript and (II) TNFRII with MT-ATP8, MT-ATP6, MT-COX-3, and MT-ND1 determined an outstanding improvement of the diagnostic performance of G3 versus G2 patient identification, reaching values in most cases above 0.9 or even equal to 1. The improvement of AUC values was also evaluated in normoalbuminuric or microalbuminuric patients considered separately. This study proposes a novel, promising multikind marker panel associated with kidney impairment in DKD.

Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk.

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m2, absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.

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.

Controlling Nutritional Status (CONUT) Score as a Potential Prognostic Indicator of In-Hospital Mortality, Sepsis and Length of Stay in an Internal Medicine Department.

The controlling nutritional status (CONUT) score represents poor nutritional status and has been identified as an indicator of adverse outcomes. Our aim was to evaluate the prognostic role of the CONUT score on in-hospital outcomes in an Internal Medicine Department. This is a retrospective study analyzing data from 369 patients, divided into four groups based on the CONUT score: normal (0-1), mild-high (2-4), moderate-high (5-8), and marked high (9-12). In-hospital all-cause mortality increased from normal to marked high CONUT score group (2.2% vs. 3.6% vs. 13.4% vs. 15.3%, p < 0.009). Furthermore, a higher CONUT score was linked to a longer length of hospital stay (LOS) (9.48 ± 6.22 vs. 11.09 ± 7.11 vs. 12.45 ± 7.88 vs. 13.10 ± 8.12, p < 0.013) and an increased prevalence of sepsis. The excess risk of a high CONUT score relative to a low CONUT score remained significant after adjusting for confounders (all-cause mortality: OR: 3.3, 95% CI: 1.1-9.7, p < 0.02; sepsis: OR: 2.7, 95% CI: 1.5-4.9, p < 0.01; LOS: OR: 2.1, 95% CI: 1.2-3.9, p < 0.007). The present study demonstrated that an increased CONUT score is related to a higher risk of short-term in-hospital death and complications.

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.

PCSK9 Inhibitors Have Apolipoprotein C-III-Related Anti-Inflammatory Activity, Assessed by 1H-NMR Glycoprotein Profile in Subjects at High or very High Cardiovascular Risk.

Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of systemic inflammation such as high-sensitivity C-reactive protein (hsCRP). Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation, and their role as inflammatory biomarkers is under clinical evaluation. In this observational study, we evaluate the effects of iPCSK9 on glycoproteins (Glyc) A, B and F. Thirty-nine patients eligible for iPCSK9 therapy were enrolled. One sample before and after one to six months of iPCSK9 therapy with alirocumab was obtained from each patient. Lipids, apolipoproteins, hsCRP and PCSK9 levels were measured by biochemical analyses, and the lipoprotein and glycoprotein profiles were measured by 1H nuclear magnetic resonance (1H-NMR). The PCSK9 inhibitor reduced total (36.27%, p < 0.001), LDL (55.05%, p < 0.001) and non-high-density lipoprotein (HDL) (45.11%, p < 0.001) cholesterol, apolipoprotein (apo) C-III (10%, p < 0.001), triglycerides (9.92%, p < 0.001) and glycoprotein signals GlycA (11.97%, p < 0.001), GlycB (3.83%, p = 0.017) and GlycF (7.26%, p < 0.001). It also increased apoA-I (2.05%, p = 0.043) and HDL cholesterol levels (11.58%, p < 0.001). Circulating PCSK9 levels increased six-fold (626.28%, p < 0.001). The decrease in Glyc signals positively correlated with the decrease in triglycerides and apoC-III. In conclusion, in addition to LDL cholesterol, iPCSK9 therapy also induces a reduction in systemic inflammation measured by 1H-NMR glycoprotein signals, which correlates with a decrease in triglycerides and apoC-III.

Effects of PCSK9 inhibitors on HDL cholesterol efflux and serum cholesterol loading capacity in familial hypercholesterolemia subjects: a multi-lipid-center real-world evaluation.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (-41.6%, p < 0.0001 and -56.7%, p < 0.0001, respectively). Total HDL-CEC was not different between patients before and after treatment. Conversely, despite no changes in HDL-c levels between the groups, ABCG1 HDL-CEC significantly increased after treatment (+22.2%, p < 0.0001) as well as HDL-CEC by aqueous diffusion (+7.8%, p = 0.0008). Only a trend towards reduction of ABCA1 HDL-CEC was observed after treatment. PCSK9-i significantly decreased serum CLC (-6.6%, p = 0.0272). This effect was only partly related to the reduction of LDL-c levels. In conclusion, PCSK9-i treatment significantly increased HDL-CEC through ABCG1 and aqueous diffusion pathways and reduced the serum CLC in FH patients. The favorable effect of PCSK9-i on functional lipid profile could contribute to the cardiovascular benefit of these drugs in FH patients.

Metformin: When Should We Fear Lactic Acidosis?

Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world. Over the sixty years during which it has been used, many benefits have been described, which are not limited to the treatment of diabetes mellitus. However, since metformin is similar to other members of the same drug family, there is still much concern regarding the risk of lactic acidosis. This article aims to highlight the correlation between the use of metformin and the onset of renal damage or lactic acidosis. Metformin-associated lactic acidosis exists; however, it is rare. The appropriate use of the drug, under safe conditions, induces benefits without risks.

Effects of Lipid Lowering Therapy Optimization by PCSK9 Inhibitors on Circulating CD34+ Cells and Pulse Wave Velocity in Familial Hypercholesterolemia Subjects without Atherosclerotic Cardiovascular Disease: Real-World Data from Two Lipid Units.

Background: Circulating CD34+ progenitor cells (CD34+CPCs) are characterized by pronounced tissue regeneration activity. Dyslipidemic subjects seemed to have reduced CD34+CPCs, and statin therapy appeared to restore their levels. We aimed to evaluate the effects of PCSK9 inhibitors (PCSK9-i) on CD34+CPCs and pulse wave velocity (PWV) in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. Methods: We determined CD34+ cell count and its change after PCSK9-i in 30 selected HeFH subjects and 30 healthy controls. Lipid profile and PWV were evaluated at baseline (T0), 6 months after intensive lipid lowering strategy (statin plus ezetimibe, T1), and after 6 months of optimized therapy with PCSK9-i (T2); CD34+ cell count was reported at T1 and T2. Results: At T1, the median value of CD34+ cells was not significantly different between HeFH subjects and controls, and the same result was obtained at T2. PWV was significantly reduced at T1 (ΔPWV − 14.8%, p < 0.001 vs. T0) and T2 (ΔPWV − 10.96%, p < 0.001 vs. T1). Dividing HeFH subjects into two groups of high- and low-CD34+ cell count, CD34+CPCs appeared to be polarized with a significant difference between the two groups (1.2 (0.46) vs. 4.74 (1.92), p < 0.001), also with respect to controls (both p < 0.001). This polarization was no longer observed at T2, and neither with respect to controls. ΔCD34+ was +67.4% in the low-CD34+ group and −39.24% in the high-CD34+ group (p < 0.001). Lastly, we found a significant correlation between ΔCD34+ cell number and ΔPWV in HeFH subjects (rho = −0.365, p < 0.05), particularly in the low-CD34+ group (rho = −0.681, p < 0.001). Conclusion: PCSK9-i exhibited favorable effects on CD34 + CPCs as was on PWV values in a cohort of FH subjects. Our preliminary findings suggest a possible positive role of this novel lipid-lowering strategy on vascular homeostasis.

Mitochondrial RNAs as Potential Biomarkers of Functional Impairment in Diabetic Kidney Disease.

Type 2 diabetes and renal damage are strictly linked. The progressive increase in T2D incidence has stimulated the interest in novel biomarkers to improve the diagnostic performance of the commonly utilized markers such as albuminuria and eGFR. Through microarray method, we analyzed the entire transcriptome expressed in 12 serum samples of diabetic patients, six without DKD and six with DKD; the downregulation of the most dysregulated transcripts was validated in a wider cohort of 69 patients by qPCRs. We identified a total of 33 downregulated transcripts. The downregulation of four mitochondrial messenger RNAs (MT-ATP6, MT-ATP8, MT-COX3, MT-ND1) and other two transcripts (seysnoy, skerdo) was validated in patients with eGFR stage G3 versus G2 and G1. The four messenger RNAs correlated with creatinine and eGFR stages, while seysnoy and skerdo were associated with white blood cell values. All transcripts correlated also with Blood Urea Nitrogen. The four mitochondrial messenger RNAs had a high diagnostic performance in G3 versus G2 discrimination, with AUC values above 0.8. The most performant transcript was MT-ATP6, with an AUC of 0.846; sensitivity = 90%, specificity = 76%, p-value = 7.8 × 10-5. This study led to the identification of a specific molecular signature of DKD, proposing the dosage of RNAs, especially mitochondrial RNAs, as noninvasive biomarkers of diabetes complication.