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.

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.

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.

Combined aerobic and resistance training improves microcirculation in metabolic syndrome.

BACKGROUND: Exercise intervention improves macrovascular function in metabolic syndrome (MeS) patients, but few studies have evaluated the effect of exercise on microcirculatory dysfunction, which plays a key role in the development of MeS and its correlated organ damage. We carried out this intervention study to evaluate the influence of an aerobic and resistance training on skin microvascular reactivity in MeS patients. METHODS: Postocclusive reactive hyperemia (PORH) of the forearm skin was evaluated, by laser-Doppler flowmetry, before and after a 12-week program of aerobic and resistance training in 15 MeS patients referring to our Lipid Metabolism Outpatients Clinic, together with anthropometric, fitness and metabolic parameters; 15 matched MeS patients who did not exercise, served as a control group. The exercise training consisted of 2 sessions/week of aerobic and resistant exercise. RESULTS: Following exercise program, we observed a significant reduction in body weight, fat mass, fasting blood glucose, serum HbA1c and triglycerides, while HDL-cholesterol significantly increased. The exercise-treated group experienced a significant improvement in the area of hyperemia (AH) after PORH, and in all fitness parameters: VO2max, strength on the pulldown lat machine, chest press, leg press and leg extension. A significant correlation emerged between the increase in AH and the reduction in HbA1c and between increase in AH and strength at the chest press, and at the leg extension. CONCLUSIONS: Our study showed that a short-term combined aerobic-resistance training positively affects microvascular reactivity in MeS patients. This improvement is correlated with the reduction of HbA1c and fitness parameters, and particularly with increased muscle strength at the upper and lower limbs.

Microcirculatory Improvement Induced by Laparoscopic Sleeve Gastrectomy Is Related to Insulin Sensitivity Retrieval.

AIMS: Microvascular dysfunction is a potential factor explaining the association of obesity, insulin resistance, and vascular damage in morbidly obese subjects. The purpose of the study was to evaluate possible determinants of microcirculatory improvement 1 year after laparoscopic sleeve gastrectomy (LSG) intervention. METHODS: Thirty-seven morbidly obese subjects eligible for bariatric surgery were included in the study. Post-occlusive reactive hyperemia (PORH) of the forearm skin was measured as area of hyperemia (AH) by laser-Doppler flowmetry before LSG and after a 1-year follow-up. RESULTS: After intervention, we observed a significant reduction in BMI, HOMA index, HbA1c, and a significant increase of AH in all patients after surgery; this variation was significant only in those patients having insulin resistance or prediabetes/diabetes. Although significant correlation between the increase of AH and the reduction of both BMI, HOMA index, and HbA1c was observed, BMI was the only independent predictor of AH variation after LSG at the linear regression analysis. CONCLUSIONS: Our study shows that LSG intervention is correlated with a significant improvement in the microvascular function of morbidly obese subjects; this improvement seems to be related to the baseline degree of insulin-resistance and to the retrieval of insulin-sensitivity post-intervention.

Microparticles derived from endothelial progenitor cells in patients at different cardiovascular risk.

OBJECTIVES: Exposure to cardiovascular risk factors causes the release of pro-atherogenic microparticles from vascular cells and reduces the number of the atheroprotective endothelial progenitor cells (EPCs). We investigated whether microparticles shedding from EPCs are detectable in cultures of EPCs and in the circulation of subjects with various degrees of cardiovascular risk. We also investigated the relationship of EPCs-derived microparticles to cardiovascular risk factors and aortic stiffness, a marker of cardiovascular risk and impaired vascular repair by EPCs. METHODS AND RESULTS: We estimated the 10-year Framingham risk score in 105 individuals with various degrees of cardiovascular risk and measured the number of circulating EPCs, EPCs-derived microparticles (CD34+/KDR+) and aortic stiffness. Release of CD34+/KDR+ microparticles was tested in cultures of EPCs exposed to hydrogen-peroxide. CD34+/KDR+ microparticles were found in EPCs cultures incubated with hydrogen-peroxide. Framingham risk was associated with EPCs (r=-0.47, p<0.001) and CD34+/KDR+ microparticles (r=0.56, p<0.001). Low EPCs (r=-0.59, p<0.001) and high CD34+/KDR+ microparticle (r=0.57, p<0.001) levels were predictors of aortic stiffness, independent of the Framingham risk. CONCLUSIONS: EPCs undergo fragmentation into microparticles when exposed to a pro-apoptotic milieu. Increased microparticle shedding from EPCs may reduce circulating EPCs levels and may thus contribute to increase aortic stiffness beside traditional risk factors.

Reduced number of circulating endothelial progenitors and HOXA9 expression in CD34+ cells of hypertensive patients.

OBJECTIVE: Circulating endothelial progenitor cells (EPCs) differentiate into mature endothelial cells and regenerate the injured endothelium. The role of homeobox A9 (HOXA9) is critical for endothelial commitment during progenitor cell maturation, postnatal neovascularization and vascular repair. The objective of our study was to measure the expression of HOXA9 in CD34+ cells from hypertensive patients and to investigate its correlation with the number of circulating EPCs. METHODS: Thirty patients with newly diagnosed, never-treated essential hypertension and 30 age- and sex-matched normotensive controls were recruited for the study. Total RNA was extracted from peripheral CD34+ cells and quantitative real-time polymerase chain reaction for measurement of HOXA9 expression was performed. The number of CD34+/human kinase insert domain protein receptor + (KDR+) EPCs was measured and the Framingham risk estimated. RESULTS: Hypertensive patients had reduced HOXA9 expression compared to normotensive subjects (-26%, P < 0.001), and lower levels of peripheral CD34+/KDR+ EPCs (421 +/- 93 versus 582 +/- 101, P < 0.001). HOXA9 expression was inversely associated with systolic blood pressure (r = -0.54, P < 0.001) and the Framingham risk (r = -0.50, P < 0.001). A direct association was observed between the number of EPCs and HOXA9 expression (r = 0.50, P < 0.001), which was independent of blood pressure levels and Framingham risk. In a subgroup of 15 hypertensive patients, a 4-week treatment with ramipril was associated with a significant 15% increase in HOXA9 expression and 25% increase in EPC levels. CONCLUSIONS: In hypertensive patients, downregulation of HOXA9 expression in peripheral CD34+ cells may have a role in the loss of circulating EPCs, thus potentially impairing postnatal neovascularization and vascular repair.

Effects of rosuvastatin on 3-nitrotyrosine and aortic stiffness in hypercholesterolemia.

BACKGROUND AND AIMS: Early atherosclerosis is characterized by reduced large artery distensibility, paralleled by an increased peroxynitrite formation and nitration of tyrosine in proteins. The aim of the present study was to investigate the short-term effect of cholesterol lowering with rosuvastatin on 3-nitrotyrosine (3-NT), a marker of peroxynitrite-mediated oxidative stress, and on arterial stiffness. METHODS AND RESULTS: 71 outpatients with primary hypercholesterolemia were recruited for this randomized open-label intervention study; 35 patients were assigned to 4-week rosuvastatin therapy (10mg daily) with a low-fat diet, and 36 patients to a low-fat diet only. Within the cohort of 71 hypercholesterolemic patients, there was a significant correlation between cholesterol levels, 3-NT and aortic pulse wave velocity (aPWV), that is a reliable measure of aortic stiffness. Among those patients who received rosuvastatin, significant reductions in plasma cholesterol, 3-NT and aPWV were observed. Reductions in both aPWV and 3-NT levels correlated significantly with the decrease in plasma cholesterol. Reduction of plasma cholesterol was the only independent predictor for reduced arterial stiffness following rosuvastatin therapy. CONCLUSION: Cholesterol reduction achieved following short-term rosuvastatin therapy is associated with a decrease in peroxynitrite-mediated oxidative stress and an improvement in large artery distensibility; reduction in arterial stiffness is directly attributable to rosuvastatin-induced cholesterol lowering and not to reduction of plasma 3-NT levels.

Increased ratio of CD31+/CD42- microparticles to endothelial progenitors as a novel marker of atherosclerosis in hypercholesterolemia.

OBJECTIVE: Atherosclerosis may be caused by increased endothelial damage and by a consumptive loss of endothelial repair capacity by endothelial progenitors. Arterial stiffness is a reliable marker of atherosclerosis and a positive correlate of endothelial damage. We investigated whether an increased ratio of CD31+/CD42- microparticles to endothelial progenitors, a possible indicator of endothelial damage and impaired endothelium reparation, may contribute to aortic stiffness in hypercholesterolemia. We also studied the in vitro effect of microparticles from hypercholesterolemic patients on endothelial progenitor survival. METHODS AND RESULTS: Circulating CD31+/CD42- microparticles, endothelial progenitors, and aortic pulse wave velocity (aPWV), a measure of aortic stiffness, were measured in 50 patients with never-treated hypercholesterolemia and 50 normocholesterolemic controls. Hypercholesterolemic patients had more circulating CD31+/CD42- microparticles, less endothelial progenitors, and a stiffer aorta than controls. aPWV was associated with CD31+/CD42- microparticles (r=0.61; P<0.001), endothelial progenitors (r=-0.45, P<0.001), and with cholesterol levels (r=0.51; P<0.001). High plasma cholesterol and a high ratio of CD31+/CD42- microparticles to endothelial progenitors independently predicted an increased aPWV. Microparticles from hypercholesterolemic patients caused a significant endothelial progenitor loss in vitro. CONCLUSIONS: Hypercholesterolemia-related aortic stiffness is promoted by plasma cholesterol directly, increased endothelial damage, and reduced endothelium repair capacity by endothelial progenitors.

Relevance of homocysteine on brachial flow-mediated vasodilatation and carotid and femoral intima-media thickness in patients with hypercholesterolemia.

The relevance of homocysteine to brachial flow-mediated vasodilatation and carotid and femoral intima-media thickness was investigated in 192 patients with hypercholesterolemia. Low-density lipoprotein cholesterol and homocysteine levels predicted brachial flow-mediated vasodilatation, internal carotid mean intima-media thickness, and intima-media thickening at all femoral sites. Homocysteine levels seem to be an additional factor in the initial atherosclerotic damage of patients with hypercholesterolemia.