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Highlighted articles September

Volume 276 Issue September 2018

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

In addition to lipid accumulation, inflammation is a hallmark of atherosclerotic lesions. The present issue of Atherosclerosis contains several review articles that summarize the current state of our knowledge on the role of inflammation and its interaction with lipoproteins in the pathogenesis of atherosclerosis and as a therapeutic target. Several original articles provide novel examples in support of the pathogenic role of inflammation in vascular diseases.

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Highlighted articles

Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions

Rudolph Virchow (1821–1902) recognized inflammation in histological preparations of coronary arteries and proposed that inflammation plays a causal role in atherosclerosis.
Despite this seminal observation, the main focus of research and drug development programs has been cholesterol alone, and inflammation received less attention over time.

However, during the past several decades extensive observations supported the importance of inflammation in the development and destabilization of atherosclerosis.
Studies in patients affected by rheumatological diseases suggested an interaction between chronic inflammation and atherosclerotic cardiovascular disease.
Randomized clinical studies with lipid lowering agents suggested that part of the beneficial effect may have been related to reduction in inflammation.

More recently, a few studies were designed to directly address the role of anti-inflammatory treatments in reducing risk of atherosclerotic heart disease beyond traditional risk factors. 

In this review, Raggi et al. discuss the pathophysiologic contribution of inflammation to atherosclerosis, biomarkers of inflammation and the evidence collected in observational studies regarding the role of chronic inflammation in the development of atherosclerotic heart disease.
Moreover, they discuss the most recent randomized clinical trials of anti-inflammatory agents directed at stemming atherosclerotic cardiovascular disease.


Immunotherapy for the prevention of atherosclerotic cardiovascular disease: Promise and possibilities

Cardiovascular disease remains the leading cause of death worldwide, with coronary atherosclerotic heart disease being the largest contributor. Immune dysregulation and inflammation are key contributors to the development of an atherosclerotic plaque and its progression to acute coronary syndromes.

Increased circulating levels of biomarkers of systemic inflammation including hsCRP correlate with a higher cardiovascular risk. Targeting specific inflammatory pathways implicated in atherosclerotic plaque formation is an exciting area of ongoing research. Therapies targeting pro-inflammatory cytokines (such as IL-1β, IL-6, TNFα, and CCL2) slow the progression of atherosclerosis in animal models and improve cardiovascular outcomes in humans. Most notably, treatment with the monoclonal antibody canakinumab, which directly targets and neutralizes IL-1β, was recently shown to be associated with reduced risk of adverse cardiovascular events compared to placebo in a randomized, placebo-controlled trial. Several other therapies including colchicine, methotrexate and leukotriene inhibitors show a potential for lowering cardiovascular risk through immunomodulation. In this review, Khambhati et al. discuss the current literature on the role of inflammation in atherosclerosis and the development of targeted immunotherapies, an evolving area of research becoming clinically relevant for the 21st century cardiac patient.

Dietary inflammatory index and cardiometabolic risk in US adults

Diet is one of the main modulators of subclinical inflammation, which can be evaluated in humans through levels of markers (including tumor necrosis factor-α (TNFα), high sensitivity C-reactive protein (hsCRP), or cell adhesion molecules). Some studies have reported a link between these markers and dietary patterns. The Dietary Inflammatory Index (DII®) was developed to specifically measure the dietary inflammatory potential, which is a contributor to many chronic conditions. DII assesses the inflammatory potential of the diet based on the balance of pro- and anti-inflammatory properties of its components, including macronutrients, vitamins, minerals, flavonoids and specific food items. In this study, Mazidi et al. investigated the association between DII scores and cardio-metabolic risk factors singly and in combination as metabolic syndrome (MetS).

To this purpose, data from participants selected from the US National Health and Nutrition Examination Survey (NHANES), ongoing repeated cross-sectional surveys conducted by the US National Center for Health Statistics (NCHS), were used. Analyses were restricted to participants with data available on dietary intake, biochemical data, and anthropometric measurements from 2005 to 2012. Statistical analyses used the SPSS® Complex Samples v22.0 and accounted for the survey design and sample weights. Energy-adjusted-DII (E-DII®) expressed per 1000 kcal was calculated from 24-h dietary recalls. Of the 17,689 participants with evaluable data, 8607 were men. The mean age was 45.8 years in the overall sample, with men being slightly younger than women.

In multivariable-adjusted regression models, the odds of MetS, its components, as well as obesity, and elevated high-sensitivity C-reactive protein (hsCRP) increased across increasing quartiles of E-DII. In age, sex, race, income-to-poverty ratio-adjusted models, these and other cardiovascular disease risk factors (triglycerides/high density lipoprotein cholesterol (HDL-C) ratio, apolipoprotein (B) and HbA1C) increased across quartiles of the E-DII, while HDL-C levels decreased.

This study suggests associations between MetS, its components, subclinical inflammation, and DII, reinforcing the view that diet plays an important role in the occurrence of cardiovascular diseases.

Plasma high density lipoproteins: Therapeutic targeting and links to atherogenic inflammation

In this Anitschkow Lecture of the European Atherosclerosis Society (2017), A.R. Tall discussed the athero-protective functions of plasma high density lipoprotein (HDL) and links to atherogenic inflammation. Plasma HDL levels have an inverse relationship to coronary artery disease (CAD) risk, which led to the idea that increasing HDL levels therapeutically would ameliorate atherosclerosis.

Human genetic deficiency of cholesteryl ester transfer protein (CETP) caused markedly elevated HDL and moderately reduced non-HDL cholesterol levels, suggesting that CETP inhibitors might produce cardiovascular benefit. The CETP inhibitor anacetrapib reproduced the phenotype of homozygous CETP deficiency and showed a highly significant benefit for CAD in the REVEAL trial (an international clinical trial that aims to assess whether treating cholesterol with anacetrapib will decrease the risk of heart attacks, deaths from heart disease and other vascular diseases). However, the magnitude of this effect was moderate, and the mechanism of benefit remains unclear. Insights into the mechanisms underlying macrophage cholesterol efflux and reverse cholesterol transport have come from monogenic human disorders and transgenic mouse studies. In particular, the importance of the ATP binding cassette transporters ABCA1 and ABCG1 in promoting cholesterol efflux from myeloid and other hematopoietic cells has been shown and linked to aberrant myelopoiesis and macrophage inflammation. Recent studies have shown that myeloid deficiency of ABCA1 and ABCG1 leads to macrophage and neutrophil inflammasome activation, which in turn promotes atherosclerotic plaque development and notably the formation of neutrophil extracellular traps (NETs) in plaques. In addition, clonal hematopoiesis has emerged as an important CAD risk factor, likely involving macrophage inflammation and inflammasome activation. Further elucidation of the mechanisms linking plaque accumulation of cholesterol and oxidized lipids to myeloid cell inflammation may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for CAD.

C1q tumor necrosis factor-related protein 9 in atherosclerosis: Mechanistic insights and therapeutic potential

C1q tumor necrosis factor-related protein 9 (CTRP9), a newly discovered adipokine, is the closest paralog of adiponectin. After proteolytic cleavage, it can release the globular domain (gCTRP9) that serves as the major circulatory isoform. Upon binding to adiponectin receptor 1 (AdipoR1) and N-cadherin, CTRP9 can activate a variety of signaling pathways to regulate glucose and lipid metabolism, vascular relaxation and cell differentiation. Circulating CTRP9 levels are significantly decreased in patients with coronary atherosclerosis disease. Data obtained from in vitro experiments and animal models suggest that CTRP9 exerts an atheroprotective effect by altering multiple pathological processes involved in atherosclerosis, including inflammation, foam cell formation, endothelial dysfunction, insulin resistance, and vascular smooth muscle cell dedifferentiation, proliferation and migration. In this review, Yu et al. summarize the latest advances regarding the roles of CTRP9 in atherosclerosis with an emphasis on its potential as a novel therapeutic target in cardiovascular disease.


PDZK1 in leukocytes protects against cellular apoptosis and necrotic core development in atherosclerotic plaques in high fat diet fed ldl receptor deficient mice

PDZK1 (post-synaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1) stabilizes the high density lipoprotein (HDL) receptor protein, SR-B1, in the liver, and mediates SR-B1 signaling outside of the liver. Complete knockout of pdzk1 increases atherosclerosis in apoE-deficient mice, but the effect of PDZK1 in leukocytes is not known. In this study, Yu et al. tested the role of leukocyte PDZK1 in atherosclerosis development using bone marrow transplantation to generate ldlr deficient mice lacking PDZK1 in leukocytes.

Ldlr−/−mice were transplanted with either pdzk1−/− or pdzk1+/+ bone marrow and fed a high-fat diet to induce atherosclerosis.

Leukocyte PDZK1 deficiency increased plaque apoptosis and necrotic core formation in high fat diet-fed ldlr knockout mice. PDZK1 deficiency prevented HDL dependent protection of macrophages from apoptosis in vitro and sensitized peritoneal macrophages to apoptosis in situ. PDZK1 deficiency in macrophages also impaired their ability to engulf apoptotic cells, and attenuated the IL-4 dependent induction of mannose receptor in vitro and mannose receptor protein levels in macrophages in atherosclerotic plaques.

PDZK1 is required for anti-atherogenic responses in macrophages, including HDL dependent protection against apoptosis and macrophage mediated efferocytosis, and limits the accumulation of apoptotic cells within atherosclerotic plaques protecting against necrotic core development.

Effect of irradiation and bone marrow transplantation on angiotensin II-induced aortic inflammation in ApoE knockout mice

Angiotensin is a peptide hormone that causes vasoconstriction and increases blood pressure. Angiotensin II (Ang II) infusion promotes the development of aortic aneurysms and accelerates atherosclerosis in ApoE−/− mice via mechanisms involving monocyte-macrophage recruitment and vascular wall remodeling. Accordingly, Ang II-induced vascular inflammation can be studied by treating hyperlipidaemic mice with Ang II to investigate long-term, chronic inflammatory responses such as plaque formation, or short-term acute inflammatory processes such as cellular infiltration. To elucidate the role of hematopoietic cells in these pathologies, irradiation and bone marrow transplantation (BMT) are commonly utilized. Previous studies by Patel et al., investigating the formation of abdominal aortic aneurysms (AAA) induced by Ang II in ApoE−/− mice that had undergone irradiation and BMT, showed that these procedures affect the degree of AAA development and rupture in ApoE−/− mice receiving bone marrow. In this study, the authors aimed to assess the effects of irradiation and BMT on abdominal and thoracic aortic aneurysm formation and acute leukocyte recruitment in the aortic root and descending aorta, in an experimental mouse model of aortic aneurysm formation.

ApoE−/− mice were either lethally irradiated and reconstituted with ApoE−/− bone marrow or non-irradiated. Following engraftment, mice were treated with Ang II to induce aortic inflammation and accelerate atherosclerosis. Ang II infusion in BMT mice resulted in reduced aortic aneurysms and atherosclerosis, with decreased leukocyte infiltration in the aorta compared to non-BMT mice, receiving the same dose of Ang II. Furthermore, the reduced aortic infiltration in BMT mice was accompanied by increased levels of monocytes in the spleen and bone marrow. A dose of 3 mg/kg/day Ang II was required to achieve a similar incidence of aneurysm formation as achieved with 0.8 mg/kg/day in non-BMT mice.

This study provides evidence that BMT can alter inflammatory cell recruitment in experimental mouse models of aortic aneurysm formation and atherosclerosis and suggests that irradiation and BMT have a considerably more complex effect on vascular inflammation, which should be evaluated.

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