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Highlighted articles March/April 2019

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Volume 282, Issue March 2019
Volume 283, Issue April 2019

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Because of the inverse association between HDL cholesterol and risk of atherosclerotic cardiovascular disease (ASCVD) in many epidemiological studies, as well as many protective likely anti-atherogenic properties of HDL in vitro and in vivo,
HDL has been pursued for a long time as a therapeutic target in cardiovascular medicine.
Futile intervention trials as well as lack of genetic causality shed doubt on the suitability of HDL-cholesterol as a therapeutic target.

The March and April issues of Atherosclerosis contain several articles, which discuss the state of the art of HDL in the management of ASCVD and describe novel approaches to exploit the anti-atherogenic properties of HDL for diagnostics and treatment.

Issue highlights

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Highlighted articles

HDL cholesterol and ASCVD risk stratification: A debate

This debate by Barter and Genest reviews the usefulness of the cholesterol mass within high-density lipoproteins (HDL-C) to predict the risk of atherosclerotic cardiovascular disease (ASCVD).

In the Pro section, Prof. Barter discusses why HDL-C should continue to be used for risk stratification of ASCVD. He emphasizes that there is current confusion regarding the role of high density lipoproteins (HDLs) in ASCVD. While it is an established fact that the concentration of HDL cholesterol is a robust, independent, inverse predictor of the risk of having an ASCVD event, recent studies have questioned whether HDLs actually protect against ASCVD. According to his point of view, this does not challenge the fact that the concentration of HDL cholesterol is a powerful tool to be used in risk stratification of ASCVD.

In the Con section, Prof. Genest argues against the use of HDL-C in ASCVD risk stratification.
The measurement of HDL-C in the 1970 heralded a new area of promising and exciting research in cardiovascular disease.
The measurement of HDL-C has been part of cardiovascular risk stratification for the past three decades. HDL have pleotropic beneficial effects on the arterial vasculature and promote the removal of excess cholesterol from lipid laden macrophages.
These effects are only weakly correlated with HDL-C levels. While HDL-C is associated with atherosclerotic cardiovascular disease, the epidemiological relationship falters at the extremes of measurement.
Mendelian randomization does not support a link of causality and to date, attempts to raise HDL-C pharmacologically have not yielded the expected outcomes.
The time has come to consider abandoning HDL-C for cardiovascular risk prediction and clinical decision making and to double efforts to develop better biomarkers of HDL function.


Very high high-density lipoprotein cholesterol is associated with increased all-cause mortality in South Koreans

It is currently still unclear whether very high-density lipoprotein cholesterol (HDL-C) level is associated with an increased risk of all-cause mortality or cardiovascular mortality, especially in the Asian populations. In this study, Oh et al. aimed to investigate the association between HDL-C and all-cause and cause-specific mortality in Korean adults.

A total of 365,457 participants aged ≥40 years were selected from the Korean National Health Insurance Service–National Sample Cohort from 2009 to 2015. HDL-C level was categorized into <1.0, 1.0–1.19, 1.2–1.39, 1.4–1.59, 1.6–1.79 (reference), 1.8–1.99, 2.0–2.19 and ≥ 2.20 mmol/L. Cox proportional hazard models were used to examine the association between HDL-C level and mortality risk.

In a median 3.5-year follow-up period, 9,350 participants (2.6%) died. Men with HDL-C level of 1.6–1.79 mmol/L and women with HDL-C level of 1.4–1.59 mmol/L had the lowest age-standardized mortality rates for all-cause death. However, for cardiovascular death, men with HDL-C level ≥2.20 mmol/L and women with HDL-C level of 1.8–1.99 mmol/L showed the lowest mortality rate. After adjusting for multiple covariates, the hazard ratios for all-cause and cancer deaths showed a U-shaped relationship with HDL-C level for both sexes. However, there were heterogenetic associations between HDL-C level and mortality risk of subtypes of cardiovascular disease by sex. For other causes of death except for cardiovascular and cancer death, elevated mortality risk was mainly due to external causes.

The results show that in South Korea, very high HDL-C level is associated with increased risk of all-cause death. However, the increased all-cause mortality risk in people with very high HDL-C level is partly due to mortality risk from external causes.

Decrease in oxidized high-density lipoprotein is associated with slowed progression of coronary artery calcification: Subanalysis of a prospective multicenter study

The main component of HDL, apolipoprotein A-I (apoA-I), is very easily oxidized. Oxidized high-density lipoprotein (oxHDL) is characterized by reduced anti-inflammatory properties compared with HDL. However, the role of oxHDL in the pathogenesis of coronary artery calcification (CAC), a marker of subclinical atherosclerosis, remains unclear. Miki et al. prospectively investigated the association between the change in oxHDL and progression of CAC in a subanalysis of a prospective, open-label, multicenter trial.

In the principal study, patients with a CAC score of 1–999 hypercholesterolemia, and no history of CVD were treated with pitavastatin with/without eicosapentaenoic acid. One hundred forty of these patients were then included in the secondary analysis. The primary outcome of the sub-study was the association between the change in oxHDL concentration and the annual CAC progression.

oxHDL levels significantly decreased from 167 at baseline to 122 after treatment. The annual change in CAC was significantly positively associated with changes in oxHDL, triglycerides, and high-sensitivity C-reactive protein but was not associated with changes in low-density lipoprotein cholesterol or HDL-cholesterol. Multiple logistic analysis demonstrated that the decrease in oxHDL per 10 U/ml was independently associated with CAC progression.

The decrease in oxHDL is associated with an attenuation of CAC progression, suggesting that oxHDL is a potential target for atherosclerosis prevention.

Diminished cholesterol efflux mediated by HDL and coronary artery disease in young male anabolic androgenic steroid users

Anabolic androgenic steroids (AAS) abuse among young people is a widespread problem. Adverse events like sudden cardiac death and heart attack have been reported in AAS users, which could be associated with coronary artery disease (CAD). Many studies have shown that the illicit use of AAS changes lipid profile, leading to lower high-density lipoprotein (HDL) and higher low-density lipoprotein (LDL) levels. It is well known that decreased concentration of HDL is a key factor in the atherosclerotic process. Moreover, not only the concentration of HDL, but also its functionality, plays a pivotal role in CAD. In this study, Ribeiro de Souza et al. tested the functionality of HDL by cholesterol efflux and antioxidant capacity and evaluated the prevalence of CAD in AAS users.

Twenty strength-trained AAS users (AASU), 20 age-matched strength-trained AAS nonusers (AASNU), and 10 sedentary controls (SC) were enrolled in this cross-sectional study. Functionality of HDL was evaluated by 14C-cholesterol efflux and the ability of HDL to inhibit LDL oxidation. In addition, coronary artery was assessed with coronary computed tomography angiography.

Cholesterol efflux was lower in AASU compared with AASNU and SC. However, the lag time for LDL oxidation was higher in AASU compared with AASNU and SC. Twenty-five percent of AASU had at least 2 coronary arteries with plaques while none of the AASNU and SC had plaques. The time of AAS use was negatively associated with cholesterol efflux.

This study indicates that AAS abuse impairs HDL-mediated cholesterol efflux. Long-term AAS use seems to be correlated with lower cholesterol efflux and early subclinical CAD in this population.

High-density lipoprotein function is associated with atherosclerotic burden and cardiovascular outcomes in type 2 diabetes

HDL has both anti-inflammatory and anti-oxidative properties, but its primary means of atheroprotection has been attributed to its ability to mediate reverse cholesterol transport (RCT).
HDL carries 1–4 molecules of apolipoprotein A-I (apoA-I), its primary protein component.
Because apoA-I is synthesized primarily in the liver, lipid-poor apoA-I arrives in the intima associated with HDL and must exchange off the HDL particle.
The exchange/dissociation of apoA-I off HDL is a rate-limiting step of RCT. HDL-apoA-I exchange (HAE) reflects HDL capacity for RCT.

In this study, Heier et al. measured HAE in 93 participants (with type 2 diabetes and at least one additional cardiovascular (CVD) risk factor) in the Asker and Bærum Cardiovascular Diabetes study.
At baseline and at 7-year follow-up, the atherosclerotic burden was assessed by invasive coronary angiography. Major CVD events were registered throughout the study.

Linear regression analysis demonstrated a significant inverse association between HAE and atherosclerotic burden. Cox proportional hazard regression analysis showed a significant association between HAE and a composite of major CVD events when controlling for waist-hip ratio.

Despite the relatively small size of the study population and the limited number of CVD events, these findings suggest that HAE provides valuable information in determining the CVD risk.

Alpha-cyclodextrin inhibits cholesterol crystal-induced complement-mediated inflammation: A potential new compound for treatment of atherosclerosis

Cholesterol crystals (CCs), found in extracellular spaces and within macrophages in both early and late atherosclerotic plaques, are an important trigger of inflammation in atherosclerosis.
CCs activate the complement system (a collection of blood and cell surface proteins that help antibodies clear foreign cells through pathogen recognition, opsonisation and lysis) and induce an inflammatory response resulting in phagocytosis of CCs, production of reactive oxygen species (ROS) and release of cytokines.
The cyclodextrin 2-hydroxypropyl-β-cyclodextrin has been found to reduce CC-induced complement activation and induce regression of established atherosclerotic plaques in a mouse model of atherosclerosis.
As such, inhibition of complement with cyclodextrins is a potential new strategy for treatment of inflammation during atherosclerosis. Pilely et al. hypothesized that other cyclodextrins, like α-cyclodextrin, may have related functions.

To test this hypothesis, the effect of cyclodextrins on CC-induced complement activation, phagocytosis, and ROS production from granulocytes and monocytes was investigated by flow cytometry and ELISA.

α-cyclodextrin strongly inhibited CC-induced complement activation by inhibiting binding of the pattern recognition molecules C1q (via IgM) and ficolin-2 to cholesterol crystals.
This resulted in reduced phagocytosis and ROS production in monocytes and granulocytes. Alpha-cyclodextrin was the most effective inhibitor of CC-induced complement activation, with the reduction in deposition of complement activation products being significantly different from the reduction induced by 2-hydroxypropyl-β-cyclodextrin. Moreover, α-cyclodextrin was able to dissolve CCs over time.

These results indicate that α-cyclodextrin is a potential candidate to prevent CC-induced inflammation in atherosclerosis.

Hypercholesterolemia impairs megakaryopoiesis and platelet production in scavenger receptor BI knockout mice

Thrombocytopenia is a condition characterized by abnormally low levels of platelets in the blood. Previous studies have shown that genetic disruption of scavenger receptor BI (SR-BI) function is associated with thrombocytopenia in mice.
SR-BI is a cell surface receptor that mediates the selective uptake of cholesteryl esters from lipoproteins, and is mostly known for its role in reverse cholesterol transport as the functional high-density lipoprotein (HDL) receptor.
Thrombocytopenia in scavenger receptor BI (SR-BI) knockout mice is suggested to result from augmented platelet clearance induced by elevated intracellular unesterified cholesterol (UC) levels. Ouweneel and colleagues hypothesize that SR-BI deficiency may influence platelet production at the level of its precursor cell in the bone marrow, the megakaryocyte.

In this study, the authors compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice.

Megakaryocytes from SR-BI knockout mice exhibited UC accumulation while no accumulation was detectable in wild-type megakaryocytes.
Bone marrow expression of transcription factors involved in megakaryocyte maturation was induced, but megakaryocyte counts were unchanged in bone marrow of SR-BI knockout mice.
Moreover, there was a 62% decrease in proplatelet production by SR-BI knockout megakaryocytes.
SR-BI knockout mice displayed an impaired increase in circulating platelet concentrations and bone marrow megakaryocyte numbers upon thrombopoietin challenge.
Importantly, megakaryocytes from normolipidemic bone marrow-specific SR-BI knockout mice exhibited a normal ability to produce proplatelets.
In addition, bone marrow-specific deletion of SR-BI did not impair the thrombopoietin response or induce thrombocytopenia, confirming that absence of megakaryocyte SR-BI does not underlie the thrombocytopenic phenotype in total body SR-BI knockout mice.

In conclusion, the elevation of plasma unesterified cholesterol levels impairs megakaryopoiesis and platelet production in SR-BI knockout mice.
These results suggest that, in addition to an increased platelet clearance, a decrease in platelet production may also, in part, explain the thrombocytopenic phenotype associated with SR-BI deficiency in mice.

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