Atherosclerosis plus最新文献

Background and aims

Lipoprotein(a) [Lp(a)] and interleuking-6 (IL-6), an inflammation biomarker, have been established as distinct targets of the residual atherosclerotic cardiovascular disease (ASCVD) risk. We aimed to investigate the association between them, and the potential clinical implications in ASCVD prevention.

Methods

A literature search was conducted in PubMed until December 31st, 2022, using relevant keywords.

Results

Elevated lipoprotein(a) [Lp(a)] levels constitute the most common inherited lipid disorder associated with ASCVD. Although Lp(a) levels are mostly determined genetically by the LPA gene locus, they may be altered by acute conditions of stress and chronic inflammatory diseases. Considering its resemblance with low-density lipoproteins, Lp(a) is involved in atherosclerosis, but it also exerts oxidative, thrombotic, antifibrinolytic and inflammatory properties. The cardiovascular efficacy of therapies lowering Lp(a) by >90% is currently investigated. On the other hand, interleukin (IL)-1b/IL-6 pathway also plays a pivotal role in atherosclerosis and residual ASCVD risk. IL-6 receptor inhibitors [IL-6(R)i] lower Lp(a) by 16–41%, whereas ongoing trials are investigating their potential anti-atherosclerotic effect. The Lp(a)-lowering effect of IL-6(R)i might be attributed to the inhibition of the IL-6 response elements in the promoter region of the LPA gene.

Conclusions

Although the effect of IL-6(R)i on Lp(a) levels is inferior to that of available Lp(a)-lowering therapies, the dual effect of the former on both inflammation and apolipoprotein (a) synthesis may prove of equal or even greater significance when it comes ASCVD outcomes. More trials are required to establish IL-6(R)i in ASCVD prevention and elucidate their interplay with Lp(a) as well as its clinical significance.

Background and aims

OxLDL modulates innate and adaptive immunity, and extracellular vesicles (EVs) released from both non-immune and immune cells are proposed key players in atherosclerosis development. In the present study, we aimed to investigate EVs expressing markers related to adaptive immunity-driven inflammation and endothelial activation/dysfunction in hypercholesterolemic patients.

Methods

EVs were phenotyped in thirty patients with familial hypercholesterolemia (FH) and twenty-three healthy controls using the Extracellular Vesicle (EV) Array with antibodies targeting proteins expressed on B and T cells, and endothelial cells.

Results

FH patients had a higher atherosclerotic burden, as determined by the mean carotid intima-media thickness (IMT) (0.64 ± 0.12 mm vs. 0.58 ± 0.07 mm; p = 0.033), higher oxLDL levels (p < 0.0001), and showed increased levels of EV-specific markers: CD9 (p = 0.017), CD63 (p = 0.045), CD81 (p = 0.003), Annexin V (p = 0.018), and EV markers related to adaptive/lymphocyte immunity: CD28 (p = 0.034), CD4 (p = 0.049), CD152 (p = 0.029), LFA-1 (p = 0.024), and endothelial function: CD62E (p = 0.032), CD144 (p = 0.018), tPA (p = 0.017), CD31 (p = 0.024). Linear regression revealed a positive relationship between carotid IMT and several of the increased markers observed within the FH group, including CD9 (β = 0.33; p = 0.022), CD63 (β = 0.35; p 225 = 0.026), CD28 (β = 0.37; p = 0.026), CD4 (β = 0.40; p = 0.025), CD152 (β = 0.41; p = 0.017), LFA-1 (β = 0.42; p = 0.014) and CD62E (β = 0.38; p = 0.024).

Conclusion

EVs associated with adaptive immunity and endothelial dysfunction are elevated in FH patients, and several markers related to a higher atherosclerotic burden.

Background and aims

To evaluate the effect of hydroxychloroquine (HCQ) on serum and lipoprotein lipids and serum biomarkers of cholesterol synthesis and absorption in myocardial infarction patients with a high-dose statin.

Methods

Myocardial infarction patients (n = 59) with a constant statin dose were randomized to receive hydroxychloroquine 300 mg (n = 31) or placebo (n = 28) daily for six months and followed up for one year.

Results

Statin reduced total-c (−26 ± 22% in hydroxychloroquine and −28 ± 19% in placebo group, P = 0.931), LDL-c (−38 ± 26% vs. −44 ± 23%, respectively, P = 0.299), and cholesterol synthesis biomarkers zymostenol, desmosterol, and lathosterol ratios from baseline to one year (e.g., serum lathosterol ratio −17 ± 45% vs. −15 ± 41%, respectively, P < 0.001 for both, P = 0.623 between groups). Compensatorily, cholesterol absorption increased during the intervention (e.g., serum campesterol ratio 125 ± 90% vs. 113 ± 72%, respectively, P < 0.001 for both, P = 0.488 between groups). Hydroxychloroquine did not affect cholesterol concentrations or cholesterol absorption. It prevented the statin-induced increase in cholesterol precursor, desmosterol ratio, from six months to one year in the hydroxychloroquine group (P = 0.007 at one year compared to placebo).

Conclusions

Combined with a high-dose statin, hydroxychloroquine had no additional effect on serum cholesterol concentration or cholesterol absorption. However, the findings suggest that hydroxychloroquine interferes with lanosterol synthesis, and thereafter, it temporarily interferes with the cholesterol synthesis pathway, best seen in halting the increase of the desmosterol ratio.

Trial Registration ClinicalTrials.gov Identifier: NCT02648464.

In this short narrative review, we aim at defining the pathophysiological role endothelial dysfunction in the observed COVID-19–associated rise in risk of cardiovascular disease. Variants of the SARS-CoV-2 virus have caused several epidemic waves of COVID-19, and the emergence and rapid spread of new variants and subvariants are likely. Based on a large cohort study, the incidence rate of SARS-CoV-2 reinfection is about 0.66 per 10 000 person-weeks. Both the first infection and reinfection with SARS-CoV-2 increase cardiac event risk, particularly in vulnerable patients with cardiovascular risk factors and the accompanying systemic endothelial dysfunction. By worsening pre-existing endothelial dysfunction, both the first infection and reinfection with ensuing COVID-19 may turn the endothelium procoagulative and prothrombotic, and ultimately lead to local thrombus formation. When occurring in an epicardial coronary artery, the risk of an acute coronary syndrome increases, and when occurring in intramyocardial microvessels, scattered myocardial injuries will ensue, both predisposing the COVID-19 patients to adverse cardiovascular outcomes. In conclusion, considering weakened protection against the cardiovascular risk-enhancing reinfections with emerging new subvariants of SARS-CoV-2, treatment of COVID-19 patients with statins during the illness and thereafter is recommended, partly because the statins tend to reduce endothelial dysfunction.

Background and aims

Non-alcoholic fatty liver disease (NAFLD), a high incidence liver pathology, is associated with a ∼1.5-fold higher cardiovascular disease risk. This phenomenon is generally attributed to the NAFLD-associated increase in circulating levels of pro-atherogenic apolipoprotein B100-containing small dense low-density lipoprotein and plasma hypertriglyceridemia. However, also a significant reduction in cholesterol transported by anti-atherogenic high-density lipoproteins (HDL) is frequently observed in subjects suffering from NAFLD as compared to unaffected people. In this review, we summarize data regarding the relationship between NAFLD and plasma HDL-cholesterol levels, with a special focus on highlighting potential causality between the NAFLD pathology and changes in HDL metabolism.

Methods and results

Publications in PUBMED describing the relationship between HDL levels and NAFLD susceptibility and/or disease severity, either in human clinical settings or genetically-modified mouse models, were critically reviewed for subsequent inclusion in this manuscript. Furthermore, relevant literature describing effects on lipid loading in cultured hepatocytes of models with genetic alterations related to HDL metabolism have been summarized.

Conclusions

Although in vitro observations suggest causality between HDL formation by hepatocytes and protection against NAFLD-like lipid accumulation, current literature remains inconclusive on whether relative HDL deficiency is actually driving the development of fatty liver disease in humans. In light of the current obesity pandemic and the associated marked rise in NAFLD incidence, it is of clear scientific and societal interest to gain further insight into the relationship between HDL-cholesterol levels and fatty liver development to potentially uncover the therapeutic potential of pharmacological HDL level and/or function modulation.

Background and aims

Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines.

Methods

We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients.

Results

Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH.

Conclusions

FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

Background and aim

The primary transcript of fibronectin (FN) undergoes alternative splicing to generate different isoforms, including FN containing the Extra Domain A (FN_EDA+), whose expression is regulated spatially and temporarily during developmental and disease conditions including acute inflammation. The role of FN_EDA+ during sepsis, however, remains elusive.

Methods

Mice constitutively express the EDA domain of fibronectin (EDA^+/+); lacking the FN EDA domain (EDA^−/−) or with a conditional ablation of EDA + inclusion only in liver produced FN (alb-CRE⁺EDA floxed mice) thus expressing normal plasma FN were used. Systemic inflammation and sepsis were induced by either LPS injection (70 mg/kg) or by cecal ligation and puncture (CLP) Neutrophils isolated from septic patients were tested for neutrophil binding ability.

Results

We observed that EDA^+/+ were protected toward sepsis as compared to EDA^−/− mice. Also alb-CRE⁺EDA floxed mice presented reduced survival, thus indicating a key role for EDA in protecting toward sepsis. This phenotype was associated with improved liver and spleen inflammatory profile. Ex vivo experiments showed that neutrophils bind to a larger extent to an FN_EDA + coated surface as compared to FN, thus potentially limiting their over-reactivity.

Conclusions

Our study demonstrates that the inclusion of the EDA domain in fibronectin dampens the nflammatoryi consequences of sepsis.

Background and aims

Patients who underwent carotid endarterectomy (CEA) still have a residual risk of 13% of developing a major adverse cardiovascular event (MACE) within 3 years. Inflammatory processes leading up to MACE are not fully understood. Therefore, we examined blood cell characteristics (BCCs), possibly reflecting inflammatory processes, in relation to MACE to identify BCCs that may contribute to an increased risk.

Methods

We analyzed 75 pretreatment BCCs from the Sapphire analyzer, and clinical data from the Athero-Express biobank in relation to MACE after CEA using Random Survival Forests, and a Generalized Additive Survival Model. To understand biological mechanisms, we related the identified variables to intraplaque hemorrhage (IPH).

Results

Of 783 patients, 97 (12%) developed MACE within 3 years after CEA. Red blood cell distribution width (RDW) (HR 1.23 [1.02, 1.68], p = 0.022), CV of lymphocyte size (LACV) (HR 0.78 [0.63, 0.99], p = 0.043), neutrophil complexity of the intracellular structure (NIMN) (HR 0.80 [0.64, 0.98], p = 0.033), mean neutrophil size (NAMN) (HR 0.67 [0.55, 0.83], p < 0.001), mean corpuscular volume (MCV) (HR 1.35 [1.09, 1.66], p = 0.005), eGFR (HR 0.65 [0.52, 0.80], p < 0.001); and HDL-cholesterol (HR 0.62 [0.45, 0.85], p = 0.003) were related to MACE. NAMN was related to IPH (OR 0.83 [0.71–0.98], p = 0.02).

Conclusions

This is the first study to present a higher RDW and MCV and lower LACV, NIMN and NAMN as biomarkers reflecting inflammatory processes that may contribute to an increased risk of MACE after CEA.

Background and aims

The presence of aortic arch plaques (AAP) is significantly associated with increased cardiovascular morbidity and mortality. Few studies have examined the incidence of AAP progression and factors which may contribute to it using transthoracic echocardiography (TTE). The objective of this study was to utilize sequential imaging of the aortic arch using TTE to examine the rate of AAP progression and its risk factors in a cohort of older adults.

Methods

Participants enrolled in both the Cardiovascular Abnormalities and Brain Lesion study (years 2005–2010) and the Subclinical Atrial Fibrillation and Risk of Ischemic Stroke study (2014–2019) who underwent TTE with assessment of aortic arch plaques at both time points represent the study cohort.

Results

300 participants were included in the study. Mean age was 67.8 ± 7.5 years at baseline, and 76.7 ± 6.8 years at follow-up; 197 (65.7%) were women. At baseline, 87 (29%) had no significant AAP, 182 (60.7%) had evidence of small AAP (2.0–3.9 mm) and 31 (10.3%) had evidence of large (≥4 mm) AAP. At the time of follow-up assessment, 157 (52.3%) of participants exhibited progression of AAP with 70 (23.3%) having mild progression and 87 (29%) having severe progression. There were no significant demographic or clinical predictors of AAP progression except baseline plaque thickness itself which was significantly lower in the group with AAP progression.

Conclusions

Our study demonstrates a high prevalence of AAP on TTE exam in a population-based cohort of older adults with a high incidence of AAP progression. TTE is a useful test for baseline and follow up imaging of AAP, even in subjects with no or little AAP at baseline.

Low HDL-cholesterol (HDL-C) concentrations are a typical trait of the dyslipidemia associated with chronic kidney disease (CKD). In this condition, plasma HDLs are characterized by alterations in structure and function, and these particles can lose their atheroprotective functions, e.g., the ability to promote cholesterol efflux from peripheral cells, anti-oxidant and anti-inflammatory proprieties and they can even become dysfunctional, i.e., exactly damaging. The reduction in plasma HDL-C levels appears to be the only lipid alteration clearly linked to the progression of renal disease in CKD patients. The association between the HDL system and CKD development and progression is also supported by the presence of genetic kidney alterations linked to HDL metabolism, including mutations in the APOA1, APOE, APOL and LCAT genes. Among these, renal disease associated with LCAT deficiency is well characterized and lipid abnormalities detected in LCAT deficiency carriers mirror the ones observed in CKD patients, being present also in acquired LCAT deficiency. This review summarizes the major alterations in HDL structure and function in CKD and how genetic alterations in HDL metabolism can be linked to kidney dysfunction. Finally, the possibility of targeting the HDL system as possible strategy to slow CKD progression is reviewed.