Advancements in risk stratification and management strategies in primary cardiovascular prevention.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk assessment and management strategies. Although significant progress has been made recently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health.

Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren's Syndrome.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism contributing to cardiovascular (CV) risk in the general population. The relationship between PCSK9 and CV risk in systemic autoimmune diseases has been poorly explored. We investigated the association between plasma PCSK9, measures of immune-inflammatory status and markers of atherosclerosis in 52 consecutive patients with primary Sjögren's syndrome (pSS) in comparison to healthy controls (HCs). Median plasma PCSK9 levels were significantly higher in pSS patients versus HCs (162 (79-255) vs. 53 (39-99) ng/mL). Significantly higher prevalence of subclinical atherosclerosis and lower of dyslipidaemia (61% vs. 85%, p = 0.042) characterized pSS patients versus HCs. In pSS, no significant correlation emerged between PCSK9 and disease activity, atherosclerosis and lipid levels. In HCs, PCSK9 significantly correlated with lipid levels and atherosclerosis. Interestingly, significantly higher PCSK9 levels were found in HCs with high-to-very-high as compared to low-to-moderate CV risk (p = 0.018) while a non-significant trend towards higher PCSK9 levels was detected in pSS patients with low-to-moderate as compared to high-to-very-high CV risk (p = 0.060). This is the first demonstration that pSS patients, despite lower prevalence of dyslipidaemia and higher CV risk profile, are characterized by a 3-fold increase in PCSK9 levels in comparison to HCs. As PCSK9 does not correlate with measures of CV risk, its role in CV morbidity in pSS needs further investigation.

Lipoprotein(a) Does Not Predict Thrombotic Events and In-Hospital Outcomes in Patients with COVID-19.

The prothrombotic and proinflammatory properties of lipoprotein(a) (Lp(a)) have been hypothesized to play a role in the pathogenesis of severe COVID-19; however, the prognostic impact of Lp(a) on the clinical course of COVID-19 remains controversial. This study aimed to investigate whether Lp(a) may be associated with biomarkers of thrombo-inflammation and the occurrence of thrombotic events or adverse clinical outcomes in patients hospitalized for COVID-19. We consecutively enrolled a cohort of patients hospitalized for COVID-19 and collected blood samples for Lp(a) assessment at hospital admission. A prothrombotic state was evaluated through D-dimer levels, whereas a proinflammatory state was evaluated through C-reactive protein (CRP), procalcitonin, and white blood cell (WBC) levels. Thrombotic events were marked by the diagnosis of deep or superficial vein thrombosis (DVT or SVT), pulmonary embolism (PE), stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), and critical limb ischemia (CLI). The composite clinical end point of intensive care unit (ICU) admission/in-hospital death was used to evaluate adverse clinical outcomes. Among 564 patients (290 (51%) men, mean age of 74 ± 17 years) the median Lp(a) value at hospital admission was 13 (10-27) mg/dL. During hospitalization, 64 (11%) patients were diagnosed with at least one thrombotic event and 83 (15%) patients met the composite clinical end point. Lp(a), as either a continuous or categorical variable, was not associated with D-dimer, CRP, procalcitonin, and WBC levels (p > 0.05 for all correlation analyses). In addition, Lp(a) was not associated with a risk of thrombotic events (p > 0.05 for multi-adjusted odds ratios) nor with a risk of adverse clinical outcomes (p > 0.05 for multi-adjusted hazard ratios). In conclusion, Lp(a) does not influence biomarkers of plasma thrombotic activity and systemic inflammation nor has any impact on thrombotic events and adverse clinical outcomes in patients hospitalized for COVID-19.

A tryptophan metabolite prevents depletion of circulating endothelial progenitor cells in systemic low-grade inflammation.

Background: Chronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated. Methods: In this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation. Results: Repeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity. Interpretation: Overall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation.

The impact of statin therapy on in-hospital prognosis and endothelial function of patients at high-to-very high cardiovascular risk admitted for COVID-19.

Statins may protect against adverse outcomes from Coronavirus disease 2019 (COVID-19) through their pleiotropic effects. Endothelial dysfunction seems to be implicated in the pathophysiology of COVID-19, and can be attenuated by statins. This study assessed the role of preadmission statin therapy and its interaction with endothelial function, measured using flow-mediated dilation (FMD) at hospital admission, in predicting in-hospital outcomes among patients with COVID-19 having high-to-very high cardiovascular (CV) risk. We conducted a retrospective cohort study of hospitalized patients with COVID-19 having high-to-very high CV risk, including a subgroup of patients who underwent FMD assessment. Among 342 patients, 119 (35%) were treated with statins at study baseline. Preadmission statin therapy was independently associated with a 75% risk reduction of intensive care unit admission/in-hospital death (adjusted hazard ratio 0.252, 95% confidence interval 0.122-0.521, p < 0.001). In the subgroup of patients with an FMD assessment (245 patients, 40% statin-treated), preadmission statin therapy was independently associated with higher FMD values (ß = 0.159, p = 0.013). However, preadmission statin therapy × FMD interaction was not associated with in-hospital outcomes (F = 0.002, pinteraction = 0.960). Preadmission statin therapy is associated with better in-hospital outcomes among patients with COVID-19 having high-to-very high CV risk, independent of the endothelium-protective effects of these drugs.

The effect of statins on the prevalence and mortality of influenza virus infection: a systematic review and meta-analysis.

Introduction: Influenza virus infection is associated with high morbidity and mortality, and so additional therapeutic strategies to reduce the burden for healthcare systems are needed. Statins, by virtue of their anti-inflammatory and immunomodulatory effects, have been hypothesized as capable of influencing the host's response against the influenza virus. The aim of this meta-analysis was to assess the effect of ongoing statin treatment on susceptibility to influenza virus infection and on influenza-associated mortality. Material and methods: Studies investigating the impact of statin treatment on influenza prevalence and mortality were searched for in the PubMed-Medline, Scopus, ISI Web of Knowledge, Embase, Proquest, OVID, EBSCO, and CINAHL databases (up to 8 November 2021). Fixed- and random-effects models and the generic inverse variance method were used for quantitative data synthesis. Results: In the meta-analysis of 14 arms of 2 eligible studies, including 14,997 flu-vaccinated and unvaccinated patients, treatment with statins was associated with a reduction of influenza virus prevalence (odds ratio (OR) = 0.85, 95% confidence interval (CI): 0.73-0.99; p = 0.040). No significant effect of statins on the susceptibility to influenza infection was observed in the distinct communities of either vaccinated or unvaccinated subjects. Among 9 arms of 6 eligible studies, including 87,204 patients, the use of statins among patients with influenza was associated with a reduced mortality (OR = 0.68, 95% CI: 0.56, 0.82; p < 0.001). This result was confirmed for both 30-day mortality since influenza infection diagnosis (OR = 0.61, 95% CI: 0.47, 0.80; p <0.001) and for up to 90-day mortality (OR = 0.74, 95% CI: 0.55, 1.00; p = 0.042). Conclusions: Reduced influenza prevalence and increased survival from influenza infection was observed in patients on ongoing statin treatment. Further research is needed to define the possible role of statins as adjunctive therapy in patients with influenza infection.

Cholesterol-Lowering Therapy in Patients at Low-to-Moderate Cardiovascular Risk.

Elevated low-density lipoprotein cholesterol (LDL-C) is unanimously recognized as a major modifiable risk factor related to the development of atherosclerotic cardiovascular disease (ASCVD). Consistent evidence confirms that reducing LDL-C is associated with reduction of major adverse cardiovascular events (MACEs), with benefits proportionally related to initial individual CV risk and absolute reduction of LDL-C levels. The recent European guidelines on cardiovascular prevention have proposed a revised approach in cardiovascular risk evaluation, taking into account a renewed consideration of the interaction between risk factors and possible confounding factors (e.g., age). Although for patients considered to be at high and very high cardiovascular risk the need for stringent risk factors treatment is clearly stated, for those who are at low-to-moderate cardiovascular risk the issue is more debated. For those latter subjects, current guidelines indicate that risk factor treatment is generally not necessary, unless the impact of CV risk modifiers, lifetime CV risk and treatment benefit may be substantial. In addition, despite the estimated low-to-moderate short-term CV risk, the early appearance of even mild LDL-C level elevations may contribute to impair long-term CV prognosis. Therefore, encouraging the achievement of desired LDL-C goals through tailored conservative lifestyle changes and, if necessary, pharmacologic strategies should not be excluded categorically in all low-to-moderate risk individuals. In this review, we summarize the most recent evidence that may influence the choice to treat or not to treat LDL-C elevations in subjects at low-to-moderate risk and the suggested therapeutic tools aimed at achieving the recommended LDL-C goals.

Thyroid-Stimulating Hormone Predicts Total Cholesterol and Low-Density Lipoprotein Cholesterol Reduction during the Acute Phase of COVID-19.

A complex dysregulation of lipid metabolism occurs in COVID-19, leading to reduced total cholesterol (TC), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) levels, along with a derangement of thyroid function, leading to reduced thyroid-stimulating hormone (TSH) levels. This study aimed to explore the association between TSH levels during COVID-19 and the variation (Δ) of lipid profile parameters in the period preceding (from 1 month up to 1 year) hospital admission due to COVID-19. Clinical data of 324 patients (mean age 76 ± 15 years, 54% males) hospitalized due to COVID-19 between March 2020 and March 2022 were retrospectively analyzed. The association between TSH levels at hospital admission and either Δ-TC, Δ-LDL-C, or Δ-HDL-C over the selected time frame was assessed through univariable and multivariable analyses. TSH levels were below the lower reference limit of 0.340 µUI/mL in 14% of COVID-19 patients. A significant reduction of plasma TC, LDL-C, and HDL-C was recorded between the two time points (p < 0.001 for all the comparisons). TSH was directly associated with Δ-TC (rho = 0.193, p = 0.001), Δ-LDL-C (rho = 0.201, p = 0.001), and Δ-HDL-C (rho = 0.160, p = 0.008), and inversely associated with C-reactive protein (CRP) (rho = −0.175, p = 0.004). Moreover, TSH decreased with increasing COVID-19 severity (p < 0.001). CRP and COVID-19 severity were inversely associated with Δ-TC, Δ-LDL-C, and Δ-HDL-C (p < 0.05 for all associations). A significant independent association was found between TSH and either Δ-TC (ß = 0.125, p = 0.044) or Δ-LDL-C (ß = 0.131, p = 0.036) after adjusting for multiple confounders including CRP and COVID-19 severity. In conclusion, lower levels of TSH may contribute to explain TC and LDL-C reduction in the acute phase of COVID-19.

The HACOR Score Predicts Worse in-Hospital Prognosis in Patients Hospitalized with COVID-19.

Non-invasive respiratory support (NIRS) is widely used in COVID-19 patients, although high rates of NIRS failure are reported. Early detection of NIRS failure and promptly defining the need for intubation are crucial for the management of patients with acute respiratory failure (ARF). We tested the ability of the HACOR score¸ a scale based on clinical and laboratory parameters, to predict adverse outcomes in hospitalized COVID-19 patients with ARF. Four hundred patients were categorized according to high (>5) or low (≤5) HACOR scores measured at baseline and 1 h after the start of NIRS treatment. The association between a high HACOR score and either in-hospital death or the need for intubation was evaluated. NIRS was employed in 161 patients. Forty patients (10%) underwent intubation and 98 (25%) patients died. A baseline HACOR score > 5 was associated with the need for intubation or in-hospital death in the whole population (HR 4.3; p < 0.001), in the subgroup of patients who underwent NIRS (HR 5.2; p < 0.001) and in no-NIRS subgroup (HR 7.9; p < 0.001). In the NIRS subgroup, along with the baseline HACOR score, also 1-h HACOR score predicted NIRS failure (HR 2.6; p = 0.039). In conclusion, the HACOR score is a significant predictor of adverse clinical outcomes in patients with COVID-19-related ARF.

The detrimental impact of elevated Ferritin to Iron ratio on in-hospital prognosis of patients with COVID-19.

BACKGROUND: Acute viral infections, including coronavirus disease 2019 (COVID-19), are characterized by the dysregulation of iron metabolism, resulting in high serum ferritin and low iron levels. RESEARCH DESIGN AND METHODS: This study aimed to evaluate the prospective impact of iron metabolism dysregulation, as expressed by serum Ferritin-to-Iron Ratio (FIR), on the in-hospital prognosis of patients with COVID-19. Serum levels of ferritin and iron, as well as other iron metabolism markers and recognized prognostic indicators of COVID-19 severity, were measured in 362 patients consecutively hospitalized for COVID-19. The prospective relationship between FIR and the risk of the composite outcome of intensive care unit (ICU) admission/in-hospital death was analyzed. RESULTS: In the population examined (mean age 74 ± 15 years, males 55%), the rates of radiographic signs of pneumonia, respiratory distress, and the need for noninvasive ventilation were higher in patients with high FIR (≥29.2, the 75th percentile) than in those with low FIR (<29.2, the 75th percentile) (p < 0.05 for all comparisons). High FIR was associated with a 1.7-fold (HR 1.709, 95% CI 1.017-2.871, p = 0.043) higher risk of ICU admission/in-hospital death. CONCLUSIONS: Increasing FIR values significantly and independently predicts worse in-hospital prognosis in hospitalized patients with COVID-19.

The association between neutrophil to lymphocyte ratio and endothelial dysfunction in people living with HIV on stable antiretroviral therapy.

BACKGROUND: Residual inflammation is thought to promote endothelial dysfunction and cardiovascular disease risk among people living with HIV (PLWH) receiving antiretroviral therapy (ART). Whether the neutrophil-to-lymphocyte ratio (NLR), a putative marker of systemic inflammation, may be associated with endothelial dysfunction has not been investigated in PLWH on stable ART. RESEARCH DESIGN AND METHODS: In this cross-sectional study, 210 PLWH (mean age 49 years, 79% males, 88/7/5% Caucasians/Africans/Hispanics) on long-term ART (median ART duration 8 years) were enrolled among those who were afferent to an Infectious Diseases outpatient clinic. The association between NLR and brachial flow-mediated dilation (bFMD) was analysed. RESULTS: A curvilinear association was observed between logarithmic-NLR and logarithmic-bFMD (R square = 0.034, p = 0.027), with logarithmic-bFMD decreasing significantly with increasing logarithmic-NLR only in PLWH with high NLR (≥1.47, median NLR) (r = -0.369, p < 0.001). However, NLR had a poor accuracy in the prediction of low bFMD (≤4.55, median bFMD) in PLWH with high NLR (55% sensitivity, 80% specificity, Youden index 0.35 for NLR 2.20). CONCLUSIONS: Although there is an inverse association between NLR and bFMD among long-term ART-treated PLWH with high NLR, NLR has a low discriminatory ability toward endothelial dysfunction in this category of patients.

Neutrophil to lymphocyte ratio is not related to carotid atherosclerosis progression and cardiovascular events in the primary prevention of cardiovascular disease: Results from the IMPROVE study.

Inflammation is a component of the pathogenesis of atherosclerosis and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). The neutrophil to lymphocyte ratio (NLR) is a possible inflammation metric for the detection of ASCVD risk, although results of prospective studies are highly inconsistent on this topic. We investigated the cross-sectional relationship between NLR and carotid intima-media thickness (cIMT) in subjects at moderate-to-high ASCVD risk. The prospective association between NLR, cIMT progression, and incident vascular events (VEs) was also explored. In 3341 subjects from the IMT-Progression as Predictors of VEs (IMPROVE) study, we analyzed the association between NLR, cIMT, and its 15-month progression. The association between NLR and incident VEs was also investigated. NLR was positively associated with cross-sectional measures of cIMT, but not with cIMT progression. The association between NLR and cross-sectional cIMT measures was abolished when adjusted for confounders. No association was found between NRL and incident VEs. Similarly, there were no significant differences in the hazard ratios (HRs) of VEs across NLR quartiles. NLR was neither associated with the presence and progression of carotid atherosclerosis, nor with the risk of VEs. Our findings do not support the role of NLR as a predictor of the risk of atherosclerosis progression and ASCVD events in subjects at moderate-to-high ASCVD risk, in primary prevention. However, the usefulness of NLR for patients at a different level of ASCVD risk cannot be inferred from this study.

Low Brachial Artery Flow-Mediated Dilation Predicts Worse Prognosis in Hospitalized Patients with COVID-19.

BACKGROUND: Endothelial injury can be induced by coronavirus disease 2019 (COVID-19) and seems to exert a crucial pathogenic role in its most severe clinical manifestations. We aimed to investigate the association between brachial artery flow-mediated dilation (bFMD), a potential clinical and non-invasive measure of endothelial function, and in-hospital prognosis of COVID-19 patients. METHODS: Brachial artery flow-mediated dilation was assessed in hospitalized COVID-19 patients within 48 h of hospital admission. The association between bFMD and either intensive care unit (ICU) admission or in-hospital death was explored using univariable and multivariable analyses. RESULTS: Four hundred and eight patients were enrolled. Significantly lower bFMD values emerged in COVID-19 patients with either radiographic signs of pneumonia, respiratory distress, or the need for non-invasive ventilation compared with patients without these signs (p < 0.001, p = 0.001, and p < 0.001, respectively). Forty-two (10%) patients were admitted to the ICU, 76 (19%) patients died, and 118 (29%) patients met the composite endpoint of ICU admission/in-hospital death. At unadjusted Cox regression analysis showed that low bFMD (<4.4%, the median value) was associated with a higher risk for the composite endpoint of ICU admission/in-hospital death compared with high bFMD (≥4.4%, the median value) (HR 1.675, 95% CI 1.155-2.428, p = 0.007). Multi-adjusted Cox regression analyses showed that low bFMD was independently associated with a 1.519- to 1.658-fold increased risk for the composite endpoint of ICU admission/in-hospital death. CONCLUSIONS: Low bFMD predicts an unfavorable in-hospital prognosis in COVID-19 patients. The measurement of bFMD may be clinically useful in the prognostic stratification of COVID-19 patients upon hospital admission.

A systematic review and meta-analysis on the effects of statins on pregnancy outcomes.

BACKGROUND AND AIMS: Statins are contraindicated in pregnancy, due to their potential teratogenicity. However, data are still inconsistent and some even suggest a potential benefit of statin use against pregnancy complications. We aimed to investigate the effects of statins on pregnancy outcomes, including stillbirth, fetal abortion, and preterm delivery, through a systematic review of the literature and a meta-analysis of the available clinical studies. METHODS: A literature search was performed through PubMed, Scopus, and Web of Science up to 16 May 2020. Data were extracted from 18 clinical studies (7 cohort studies, 2 clinical trials, 3 case reports, and 6 case series). Random effect meta-analyses were conducted using the restricted maximum likelihood method. The common effect sizes were calculated as odds ratios (ORs) and their 95% confidence interval (CI) for each main outcome. RESULTS: Finally, nine studies were included in the meta-analysis. There was no significant association between statin therapy and stillbirth [OR (95% CI) = 1.30 (0.56, 3.02), p=0.54; I2 = 0%]. While statin exposure was significantly associated with increased rates of spontaneous abortion [OR (95% CI) = 1.36 (1.10-1.68), p=0.004, I2 = 0%], it was non-significantly associated with increased rates of induced abortion [OR (95% CI) = 2.08 (0.81, 5.36), p=0.129, I2 = 17.33%] and elective abortion [OR (95% CI) = 1.37 (0.68, 2.76), p=0.378, I2 = 62.46%]. A non-significant numerically reduced rate of preterm delivery was observed in statin users [OR (95% CI) = 0.47 (0.06, 3.70), p=0.47, I2 = 76.35%]. CONCLUSIONS: Statin therapy seems to be safe as it was not associated with stillbirth or induced and elective abortion rates. Significant increase after statin therapy was, however, observed for spontaneous abortion. These results need to be confirmed and validated in future studies.

A comprehensive review on the lipid and pleiotropic effects of pitavastatin.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are administered as first line therapy for hypercholesterolemia, both in primary and secondary prevention. There is a growing body of evidence showing that beyond their lipid-lowering effect, statins have a number of additional beneficial properties. Pitavastatin is a unique lipophilic statin with a strong effect on lowering plasma total cholesterol and triacylglycerol. It has been reported to have pleiotropic effects such as decreasing inflammation and oxidative stress, regulating angiogenesis and osteogenesis, improving endothelial function and arterial stiffness, and reducing tumor progression. Based on the available studies considering the risk of statin-associated muscle symptoms it seems to be also the safest statin. The unique lipid and non-lipid effects of pitavastatin make this molecule a particularly interesting option for the management of different human diseases. In this review, we first summarized the lipid effects of pitavastatin and then strive to unravel the diverse pleiotropic effects of this molecule.

Prevalence of vitamin D deficiency and its prognostic impact on patients hospitalized with COVID-19.

OBJECTIVES: Although hypovitaminosis D appears to be highly prevalent in patients with coronavirus disease 2019 (COVID-19), its impact on their prognosis remains unclear. METHODS: In this study, serum 25-hydroxyvitamin D (Vit-D) level was measured in 200 patients hospitalized with COVID-19. The association between Vit-D and the composite endpoint of intensive care unit (ICU) admission/in-hospital death was explored using univariable and multivariable analyses. Also, serum Vit-D level in patients with COVID-19 was compared with that in age- and sex-balanced COVID-19-negative controls (i.e., 50 inpatients with sepsis). RESULTS: Serum Vit-D level was comparable between patients with COVID-19 and COVID-19-negative inpatients with sepsis (P = 0.397). No significant differences were found in serum Vit-D level according to COVID-19 severity at the time of hospital admission (P = 0.299). Incidence rates of the composite endpoint of ICU admission/in-hospital death did not differ significantly between patients with either Vit-D deficiency (i.e., Vit-D <20 ng/mL) or severe Vit-D deficiency (i.e., Vit-D <12 ng/mL) and those without (31% vs 35% with P = 0.649, and 34% vs 30% with P = 0.593, respectively). Vit-D level and status (i.e., Vit-D deficiency and severe Vit-D deficiency) were not prospectively associated with the risk of the composite endpoint of ICU admission/in-hospital death (P > 0.05 for all Cox regression models). CONCLUSIONS: Regardless of the potential usefulness of Vit-D measurement to guide appropriate supplementation, Vit-D does not appear to provide helpful information for the stratification of in-hospital prognosis in patients with COVID-19.

The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study.

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean-max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean-max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean-max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean-max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean-max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.

Statins Attenuate Fibrotic Manifestations of Cardiac Tissue Damage.

Cardiac fibrosis is a maladaptive condition secondary to cardiomyopathy caused by a wide spectrum of stimuli, including myocardial infarction (MI), pressure overload, hyperglycemia, aging, and other factors. Despite having been supposed to be a reparative mechanism, the development of cardiac fibrosis can result in undesirable outcomes like the disruption of excitation-contraction coupling and ventricular hypertrophy, leading finally to heart failure (HF). Statins are known as potent cardioprotective agents widely used to control dyslipidemia; these drugs have exhibited protective effects against manifestations of cardiac fibrosis and hypertrophy. Cumulative evidence has suggested that statins attenuate the severity of fibrotic and hypertrophic manifestations of cardiac damage by affecting a variety of mechanisms like differentiation of myofibroblasts and crosstalk between cells in cardiac tissue as well as altering the expression and function of different molecules involved in cardiac remodeling, including inflammatory cytokines and signaling molecules. It seems that statins can inhibit cardiac fibrosis and hypertrophy not only through their ability to inhibit hydroxymethylglutaryl-CoA reductase but also by their pleiotropic properties. This review aims to discuss the effects of statins on molecular pathways involved in the inhibition of fibrotic and hypertrophic remodeling in the heart, thereby potentially helping to recover proper cardiac size, plasticity, and functioning.

Challenges and pitfalls in the development of liposomal delivery systems for cancer therapy.

Despite considerable advances in the application of liposomal drug delivery systems in cancer treatment, the clinical application of liposomal formulations has been limited by many factors. It seems that there is a wide gap between results of experimental studies and clinical application of liposomes. In this review, we discuss barriers which limit the translation of liposomal delivery systems in cancer therapy. The main focus of this review will be on differences between preclinical and clinical studies and potential approaches to overcome the main pitfalls in the clinical application of liposomal delivery systems.

Antibody-drug conjugates for lung cancer in the era of personalized oncology.

With 9.6 million deaths in 2018, cancer represents one of the most common causes of death, both in men and women. Despite recent advances in the understanding of molecular mechanisms involved in cancer development and progression, treatment options are still limited. Limitations of traditional chemotherapy include the lack of selectivity and the unfavorable safety profile. The efficacy of targeted therapies (e.g., tyrosine kinase inhibitors) is also limited by their cytostatic action, which inhibits tumor cell proliferation without inducing tumor cell death, and by the risk of acquired resistance. Antibody-drug conjugates (ADCs), a newly developed class of engineered anticancer drugs, consist of recombinant monoclonal antibodies against tumor-specific antigens that are covalently bound to cytotoxic agents. They have been designed to overcome the limitations of traditional chemotherapy and targeted therapies by combining the target selectivity of monoclonal antibodies with the high potency of cytotoxic drugs. Currently, ADCs that have received regulatory approval include brentuximab vedotin for CD30-positive Hodgkin lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2-positive breast cancer. However, over 80 novel ADCs are actively being investigated in preclinical studies and early-phase clinical trials. In this review, we will provide a comprehensive overview of the biological rational, efficacy and safety of ADCs as therapeutic agents against non-small cell lung cancer and small cell lung cancer.