Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic ...inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD).
Arterial wall inflammation and bone marrow activity were measured using
F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of
F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 2.07-5.71) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 0.27-0.40;
<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% 86-95, controls 76% 66-81,
=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of
F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953,
for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing.
Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.
Abstract
Aims
Subjects with lipoprotein(a) Lp(a) elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation ...is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a).
Methods and results
In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median interquartile range (IQR): age 60.0 54.0–67.0 years, Lp(a) 200.0 155.5–301.5 nmol/L 80.0 (62.5–121.0) mg/dL; mean standard deviation (SD) LDL-C 3.7 1.0 mmol/L 144.0 (39.7) mg/dL; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% 95% confidence interval (CI) 65.8–55.5 and Lp(a) by 13.9% (95% CI 19.3–8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L 60.1 (28.1) mg/dL, and the median (IQR) Lp(a) level was 188.0 (140.0–268.0) nmol/L 75.2 (56.0–107.2) mg/dL. Arterial wall inflammation most diseased segment target-to-background ratio (MDS TBR) in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (−8.3%) vs. placebo (−5.3%) treatment difference −3.0% (95% CI −7.4% to 1.4%); P = 0.18.
Conclusion
Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.
Abstract
Aims
Elevated lipoprotein(a) Lp(a) is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating ...monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a).
Methods and results
Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) apo(a) antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (−17%, P < 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C).
Conclusion
Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).
Individuals with elevated LDL-cholesterol levels have an increased risk for cardiovascular disease. Despite lipid lowering strategies, however, a significant cardiovascular risk remains. Bekkering ...et al. show that monocytes from patients with familial hypercholesterolemia have a trained immunity phenotype and that lipid lowering with statins does not revert this pro-inflammatory phenotype.
Abstract
Aims
Lipoprotein(a) (Lp(a)) elevation is a causal risk factor for cardiovascular disease (CVD). It has however been suggested that elevated Lp(a) causes CVD mainly in individuals with high ...low-density lipoprotein cholesterol (LDL-C) levels. We hypothesized that the risk associated with high Lp(a) levels would largely be attenuated at low LDL-C levels.
Methods and results
In 16 654 individuals from the EPIC-Norfolk prospective population study, and in 9448 individuals from the Copenhagen City Heart Study (CCHS) parallel statistical analyses were performed. Individuals were categorized according to their Lp(a) and LDL-C levels. Cut-offs were set at the 80th cohort percentile for Lp(a). Low-density lipoprotein cholesterol cut-offs were set at 2.5, 3.5, 4.5, and 5.5 mmol/L. Low-density lipoprotein cholesterol levels in the primary analyses were corrected for Lp(a)-derived LDL-C (LDL-Ccorr). Multivariable-adjusted hazard ratios were calculated for each category. The category with LDL-Ccorr <2.5 mmol/L and Lp(a) <80th cohort percentile was used as reference category. In the EPIC-Norfolk and CCHS cohorts, individuals with an Lp(a) ≥80th percentile were at increased CVD risk compared with those with Lp(a) <80th percentile for any LDL-Ccorr levels ≥2.5 mmol/L. In contrast, for LDL-Ccorr <2.5 mmol/L, the risk associated with elevated Lp(a) attenuated. However, there was no interaction between LDL-Ccorr and Lp(a) levels on CVD risk in either cohort.
Conclusion
Lipoprotein(a) and LDL-C are independently associated with CVD risk. At LDL-C levels below <2.5 mmol/L, the risk associated with elevated Lp(a) attenuates in a primary prevention setting.
Experimental work posits that acute ischaemic events trigger haematopoietic activity, driving monocytosis, and atherogenesis. Considering the chronic low-grade inflammatory state in atherosclerosis, ...we hypothesized that haematopoietic hyperactivity is a persistent feature in cardiovascular disease (CVD). Therefore, we aimed to assess the activity of haematopoietic organs and haematopoietic stem and progenitor cells (HSPCs) in humans.
First, we performed 18F-fluorodeoxyglucose positron emission tomographic (18F-FDG PET) imaging in 26 patients with stable atherosclerotic CVD (ischaemic event >12 months ago), and 25 matched controls. In splenic tissue, 18F-FDG uptake was 2.68 ± 0.65 in CVD patients vs. 1.75 ± 0.54 in controls (1.6-fold higher; P< 0.001), and in bone marrow 3.20 ± 0.76 vs. 2.72 ± 0.46 (1.2-fold higher; P = 0.003), closely related to LDL cholesterol levels (LDLc, r = 0.72). Subsequently, we determined progenitor potential of HSPCs harvested from 18 patients with known atherosclerotic CVD and 30 matched controls; both groups were selected from a cohort of cancer patients undergoing autologous stem cell transplantation. In CVD patients, the normalized progenitor potential, expressed as the number of colony-forming units-granulocyte/monocyte (CFU-GM) colonies/CD34+ cell, was 1.6-fold higher compared with matched controls (P < 0.001). Finally, we assessed the effects of native and oxidized lipoproteins on HSPCs harvested from healthy donors in vitro. Haematopoietic stem and progenitor cells displayed a 1.5-fold increased CFU-GM capacity in co-culture with oxidized LDL in vitro (P = 0.002), which was inhibited by blocking oxidized phospholipids via E06 (P = 0.001).
Collectively, these findings strengthen the case for a chronically affected haematopoietic system, potentially driving the low-grade inflammatory state in patients with atherosclerosis.
Individuals with chronic kidney disease are at an increased risk for cardiovascular disease. This risk may partially be explained by a chronic inflammatory state in these patients, reflected by ...increased arterial wall and cellular inflammation. Statin treatment decreases cardiovascular risk and arterial inflammation in non-CKD subjects. In patients with declining kidney function, cardiovascular benefit resulting from statin therapy is attenuated, possibly due to persisting inflammation. In the current study, we assessed the effect of statin treatment on arterial wall and cellular inflammation. Fourteen patients with chronic kidney disease stage 3 or 4, defined by an estimated Glomerular Filtration Rate between 15 and 60 mL/min/1.73 m
, without cardiovascular disease were included in a single center, open label study to assess the effect of atorvastatin 40 mg once daily for 12 weeks (NTR6896). At baseline and at 12 weeks of treatment, we assessed arterial wall inflammation by
F-fluoro-deoxyglucose positron-emission tomography computed tomography (
F-FDG PET/CT) and the phenotype of circulating monocytes were assessed. Treatment with atorvastatin resulted in a 46% reduction in LDL-cholesterol, but this was not accompanied by an attenuation in arterial wall inflammation in the aorta or carotid arteries, nor with changes in chemokine receptor expression of circulating monocytes. Statin treatment does not abolish arterial wall or cellular inflammation in subjects with mild to moderate chronic kidney disease. These results imply that CKD-associated inflammatory activity is mediated by factors beyond LDL-cholesterol and specific anti-inflammatory interventions might be necessary to further dampen the inflammatory driven CV risk in these subjects.
Abstract
Aims
Circulating monocytes infiltrate the plaque and differentiate into macrophages, contributing to an inflammatory environment which is associated with higher risk of cardiovascular ...events. Although the pivotal role of circulating monocytes in plaque inflammation has been firmly established, the search continues to identify specific monocyte subsets that may be especially atherogenic. Therefore, we evaluated the relation between monocyte phenotype, particularly surface receptor expression, and arterial wall inflammation in patients at increased cardiovascular risk.
Methods and results
We performed a multivariate linear regression analysis in 79 patients at increased cardiovascular risk who had both an 18F-fluorodeoxyglucose positron emission tomography/computed tomography to assess arterial wall inflammation and extensive monocyte characterization (using flow cytometry). We found that CCR2, a monocyte chemokine receptor essential for transmigration, significantly correlates with arterial wall inflammation. This relationship was independent of traditional cardiovascular risk factors and statin use (β = 0.429, P = 0.015). We found no relation between arterial wall inflammation and monocyte count or monocyte subsets, namely CD14+CD16−, CD14+CD16+, CD14+CD16 ++, CCR5+, CD18+, CD11b+, or CD11c+ monocytes.
Conclusion
Monocyte CCR2 expression is associated with arterial wall inflammation in patients at increased cardiovascular risk. Our data warrant further studies to assess if inhibition of CCR2 may attenuate atherosclerotic plaque inflammation.
CKD associates with a 1.5- to 3.5-fold increased risk for cardiovascular disease. Both diseases are characterized by increased inflammation, and in patients with CKD, elevated C-reactive protein ...level predicts cardiovascular risk. In addition to systemic inflammation, local arterial inflammation, driven by monocyte-derived macrophages, predicts future cardiovascular events in the general population. We hypothesized that subjects with CKD have increased arterial and cellular inflammation, reflected by
F-fluorodeoxyglucose (
F-FDG) positron emission tomography computed tomography (PET/CT) of the arterial wall and a migratory phenotype of monocytes. We assessed
F-FDG uptake in the arterial wall in 14 patients with CKD (mean±SD age: 59±5 years, mean±SD eGFR: 37±12 ml/min per 1.73 m
) but without cardiovascular diseases, diabetes, or inflammatory conditions and in 14 control subjects (mean age: 60±11 years, mean eGFR: 86±16 ml/min per 1.73 m
). Compared with controls, patients with CKD showed increased arterial inflammation, quantified as target-to-background ratio (TBR) in the aorta (TBR
: CKD, 3.14±0.70 versus control, 2.12±0.27;
=0.001) and the carotid arteries (TBR
: CKD, 2.45±0.65 versus control, 1.66±0.27;
<0.001). Characterization of circulating monocytes using flow cytometry revealed increased chemokine receptor expression and enhanced transendothelial migration capacity in patients with CKD compared with controls. In conclusion, this increased arterial wall inflammation, observed in patients with CKD but without overt atherosclerotic disease and with few traditional risk factors, may contribute to the increased cardiovascular risk associated with CKD. The concomitant elevation of monocyte activity may provide novel therapeutic targets for attenuating this inflammation and thereby preventing CKD-associated cardiovascular disease.
Atherosclerosis is a chronic disease of the arterial wall largely driven by inflammation; hence, therapeutics targeting inflammatory pathways are considered an attractive strategy in atherosclerotic ...cardiovascular disease (ASCVD). The purpose of this review is to describe the randomized, placebo-controlled clinical trials currently investigating the impact of anti-inflammatory strategies in ASCVD patients, to discuss novel insights and targets into the role of innate immunity in atherosclerosis and to address the promise of local drug delivery as opposed to systemic therapies in atherosclerotic disease.
The first clinical trials using systemic anti-inflammatory drugs in ASCVD patients might be able to strengthen the case for immunomodulation once showing an improved ASCVD outcome. Several specific targets in innate immunity bear therapeutic potential, of which some have already entered the clinical arena. To prevent immunosuppression by systemic effects, drug delivery systems are increasingly being applied to locally attenuate plaque inflammation.
Anti-inflammatory therapies seem promising for future treatment of ASCVD. In view of the risk of immunosuppression in case of long term and systemic use of anti-inflammatory drugs, there is a clinical need for highly selective and targeted therapies in patients with atherosclerosis.
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