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Highlighted articles April

Volume 271 Issue April 2018

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

Diabetes and obesity are prevalent in many populations and contribute to the increasing burden of atherosclerotic cardiovascular diseases (ASCVD). However, there is considerable heterogeneity in the manifestation of ASCVD among obese and diabetic subjects. This issue of Atherosclerosis contains several reviews and original articles, which describe possible pathogenic reasons for the inter-individual differences in risk as well as strategies to differentiate risk for more specific interventions. In addition, preclinical and clinical intervention studies are described. 

Issue highlights


Highlighted articles

The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity

Cardiovascular disease associated with obesity and autoimmunity is the leading cause of death in these populations, and significant residual risk remains despite current treatment approaches. Obesity, type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) are linked to chronic inflammation, and subjects with these disorders have characteristic shifts in their gut microbiome composition. Recent data suggest that alterations in gut microbial and metabolic composition may be responsible, in part, for induction of chronic inflammation, thus promoting cardiovascular disease. Common microbiome changes observed in obesity, T1DM, RA, and SLE include a decrease in the ratio of bacteria, such as Gram-positive Firmicutes to Gram-negative Bacteroidetes, as well as an overabundance or depletion of certain species, including Prevotella copri. The consequent effects of these shifts include alterations in the metabolic composition of the gut, hyper-activation of toll-like receptor 4 (TLR-4), upregulation of inflammatory pathways, e.g. c-Jun N-terminal kinase and nuclear factor-kappa B (NFκB), increased intestinal permeability, increased C-reactive protein, and increased levels of trimethylamine N-oxide (TMAO). Differential microbiome compositions may also explain sex differences observed in autoimmunity, where a male gut microbiome promotes anti-inflammatory processes as compared to a female pro-inflammatory gut microbiome. Intervention at the level of the microbiota appears to attenuate symptoms in these inflammatory syndromes with probiotic treatment, such as Lactobacilli, playing a uniquely beneficial role in restoring intestinal health, decreasing inflammation, and reducing cardiovascular disease. In this review, Kasselman et al. discuss obesity, T1DM, RA, and SLE in the context of how each unique microbiome profile contributes to elevated cardiovascular risk, emphasizing the need for more research in this field.

Biology and function of adipose tissue macrophages, dendritic cells and B cells

The increasing incidence of obesity and its socio-economical impact is a global health issue due to its associated co-morbidities, namely diabetes and cardiovascular disease. Obesity is characterized by an increase in adipose tissue, which promotes the recruitment of immune cells resulting in low-grade inflammation and dysfunctional metabolism. Macrophages are the most abundant immune cells in the adipose tissue of mice and humans, and play a critical role in the maintenance of adipose tissue homeostasis and obesity development. The adipose tissue also contains other myeloid cells (dendritic cells (DC) and neutrophils) and, to a lesser extent, lymphocyte populations, including T cells, B cells, natural killer (NK) and natural killer T (NKT) cells. While the majority of studies have linked adipose tissue macrophages (ATM) to the development of low-grade inflammation and co-morbidities associated with obesity, emerging evidence suggests for a role of other immune cells within the adipose tissue that may act in part by supporting macrophage homeostasis. In this review, Yvanov and colleagues summarize the current knowledge of the functions ATMs, DCs and B cells possess during steady-state and obesity and discuss how DC and B cells emerge as new players in adipose tissue control.

Atherosclerosis imaging to refine cardiovascular risk assessment in diabetic patients: Computed tomography and positron emission tomography applications

The lifetime cardiovascular risk of a diabetic patient is approximately 4–5 times higher than that of an age and sex matched individual without diabetes mellitus. However, despite the well-publicized cardiovascular risk equivalence of diabetes mellitus, it has become apparent that not all diabetic patients are equally at high-risk and many patients may have a level of risk similar to that of the general population. Cardiovascular imaging has been employed to address the dilemma of a more accurate risk stratification of diabetic patients. Two randomized clinical trials aiming at uncovering the presence of unknown obstructive coronary artery disease (CAD) gave disappointing results. In fact, the number of patients with inducible myocardial ischemia and/or severe obstructive disease was lower than expected, and the overall outcome was not improved after bringing the existence of CAD to light. Other techniques that may help identify a diabetic patient susceptible to suffer future events have, therefore, being explored. In this review, P. Raggi discuss two imaging tools that provide anatomical and functional information on pre-clinical coronary atherosclerosis: computed tomography for calcium scoring, and plaque characterization and myocardial ischemia detection and positron emission tomography using tracers to identify functionally unstable plaques. Despite the availability of several imaging techniques, there remain numerous questions as to the utility of imaging to define risk in diabetes mellitus and an optimal approach has yet to be found.

Anthropometric measures of obesity and renal artery calcification: Results from the Multi-Ethnic Study of Atherosclerosis

Several studies have demonstrated an association between higher anthropometric measures and subclinical atherosclerosis. In this study, Ricarde et al. aimed to determine whether anthropometric measures of obesity are associated with the presence of renal artery calcium (RAC), recently emerged as an indicator of subclinical atherosclerosis.

The authors studied 1287 community-dwelling adults enrolled in the Multi-Ethnic Study of Atherosclerosis. Logistic regression models adjusted for cardiovascular disease (CVD) risk factors were used to examine body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) as primary predictors of RAC.
Approximately 33.3% of participants had a RAC score >0. WC and WHR as continuous variables were not significant after adjustment. Subjects with higher WC had increased odds of renal artery calcification while BMI and HC were not significantly associated with increased renal artery calcification.

In conclusion, in this community-based sample of older adults, higher levels of WC were significantly associated with RAC independently of CVD risk factors. Adults who meet World Health Organization criteria for high WC may be at higher risk for complications of calcified atherosclerosis in the renal arteries.

Treatment with omega-3 polyunsaturated fatty acids does not improve endothelial function in patients with type 2 diabetes and very high cardiovascular risk: A randomized, double-blind, placebo-controlled study (Omega-FMD)

Protective effects of fish oil against cardiovascular diseases have been attributed to omega-3 polyunsaturated fatty acids (n-3 PUFAs). Guidelines recommend to consume 1–2 servings of fish per week, one of which should be dark, oily fish. Recent studies conducted in different clinical settings have focused on the benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the prevention of cardiovascular diseases. There is limited evidence that patients with type 2 diabetes (T2D) and very high cardiovascular risk can also benefit from a high dose of n-3PUFAs, especially those on optimal medical therapy as recommended by the guidelines. Siniarski and colleagues assessed the impact of high-dose n-3 PUFA treatment on endothelial function in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD).

They conducted a prospective randomized double-blind, placebo-controlled, 2-center study, in which endothelial function was measured using flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD). Serum fatty acids composition was measured by gas chromatography. All measurements were done at baseline and after 3 months of treatment with PUFAs or placebo.
The majority of the study population was treated with optimal medical therapy. Despite significantly higher concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid in the n-3 PUFA group after 3-month treatment, no significant changes in endothelial function indices (FMD and NMD) were observed. However, in regression analysis, only baseline FMD was associated with EPA concentration before 3 months of n-3 PUFA treatment.

Three-month high-dose n-3 PUFA treatment in very high-risk patients with ASCVD and T2D did not improve the endothelial function indices.


SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr−/− type 1 diabetic mice

Since patients with chronic diabetes often develop dyslipidemia and are at increased risk for atherosclerosis, in this study, the authors examined how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia.

Diabetes was induced using streptozotocin (STZ) in low density lipoprotein receptor (Ldlr) knockout (Ldlr−/−) mice fed a high-cholesterol diet for 4 weeks. To assess the effects of glucose reduction, control and diabetic mice were treated with vehicle or a sodium glucose cotransporter inhibitor (SGLT2i) for the duration of the diet.

The results showed that induction of diabetes resulted in a dramatic increase in plasma cholesterol (TC) and triglyceride (TG) levels. Mice also exhibited an increased number of circulating monocytes and neutrophils. Monocytosis was driven by increased proliferation of progenitor cells in the bone marrow. Reversal of hyperglycemia by SGLT2i treatment not only reduced monocytosis and atherosclerosis but also improved plasma lipoprotein profile. Interestingly, improved lipoprotein profile was not due to decreased TG synthesis or clearance via low density lipoprotein receptor-related protein (Lrp) 1 or scavenger receptor class B member (Scarb1) pathways, but likely mediated by heparin sulfate proteoglycans (HSPG)-dependent clearance mechanisms in the liver and bile acid pathways.

These data suggest that tighter glycemic control in diabetes can improve lipoprotein clearance and has an overall net positive effect on atherosclerosis and indicate that SGLT2 inhibitors can be used as a lipid lowering drug in diabetics with dyslipidemia.

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