Faculty Bibliography

BACKGROUND:Macrophage cholesterol efflux capacity has been identified as a predictor for cardiovascular disease. We assessed the relationship between adipocyte-derived extracellular vesicle microRNAs and macrophage cholesterol efflux capacity. METHODS:) for: (1) cholesterol efflux capacity and lipoprotein profiles; (2) adipocyte-derived extracellular vesicle microRNAs in serum; (3) the role of visceral adipose tissue extracellular vesicle in regulation of cholesterol efflux and cholesterol efflux gene expression in THP-1 macrophages in vitro. RESULTS:Efflux capacity was significantly associated with HDL (r = 0.30, p = 0.01) and LDL (r = 0.33, p = 0.005) particle size. Multivariate-analysis identified six microRNAs associated (p < 0.05) with cholesterol efflux capacity: miR-3129-5p (Beta = 0.695), miR-20b (0.430), miR9-5p (0.111), miR-320d (- 0.190), miR301a-5p (0.042), miR-155-5p (0.004). In response to increasing concentrations (1 μg/mL vs. 3 μg/mL) of VAT extracellular vesicle, cholesterol efflux (66% ± 10% vs. 49% ± 2%; p < 0.01) and expression of ABCA1 (FC = 1.9 ± 0.8 vs 0.5 ± 0.2; p < 0.001), CD36 (0.7 ± 0.4 vs. 2.1 ± 0.8, p = 0.02), CYP27A1 (1.4 ± 0.4 vs. 0.9 ± 0.5; p < 0.05), and LXRA (1.8 ± 1.1 vs. 0.5 ± 0.2; p < 0.05) was altered in THP-1 cells in vitro. CONCLUSION/CONCLUSIONS:Adipocyte-derived extracellular vesicle microRNAs may, in part, be involved macrophage cholesterol efflux regulation.

Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite multiple treatment options. In addition to elevated lipid levels, oxidative stress and inflammation are key factors driving atherogenesis and CVD. New strategies are required to mitigate risk and most urgently for statin-intolerant patients. The neuropeptide hormone oxytocin, synthesized in the brain hypothalamus, is worthy of consideration as a CVD ancillary treatment because it moderates factors directly linked to atherosclerotic CVD such as inflammation, weight gain, food intake and insulin resistance. Though initially studied for its contribution to parturition and lactation, oxytocin participates in social attachment and bonding, associative learning, memory and stress responses. Oxytocin has shown promise in animal models of atherosclerosis and in some human studies as well. A number of properties of oxytocin make it a candidate CVD treatment. Oxytocin not only lowers fat mass and cytokine levels, but also improves glucose tolerance, lowers blood pressure and relieves anxiety. Further, it has an important role in communication in the gut-brain axis that makes it a promising treatment for obesity and type 2 diabetes. Oxytocin acts through its receptor which is a class I G-protein-coupled receptor present in cells of the vascular system including the heart and arteries. While oxytocin is not used for heart disease at present, residual CVD risk remains in a substantial portion of patients despite multidrug regimens, leaving open the possibility of using the endogenous nonapeptide as an adjunct therapy. This review discusses the possible role for oxytocin in human CVD prevention and treatment.

BACKGROUND:Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disorder that increases the risk of developing cardiovascular disease. There is accumulating evidence that the RA disease state accelerates the formation of atherosclerotic plaques. Treatments for RA improve joint symptomatology and may reduce inflammation, but consideration of their effects on the cardiovascular system is generally low priority. OBJECTIVE:Since cardiovascular disease is the leading cause of mortality in RA patients, the impact of RA therapies on atherosclerosis is an area in need of attention and the focus of this review. RESULTS:The drugs used to treat RA may be analgesics, conventional disease-modifying anti-rheumatic drugs, and/or biologics, including antibodies against the cytokine tumor necrosis factor-α. Pain relievers such as non-selective non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors may adversely affect lipid metabolism and cyclooxygenase inhibitors have been associated with increased adverse cardiovascular events, such as myocardial infarction and stroke. Methotrexate, the anchor disease-modifying anti-rheumatic drug in RA treatment, has multiple atheroprotective advantages and is often combined with other therapies. Biologic inhibitors of tumor necrosis factor-α may be beneficial in preventing cardiovascular disease because tumor necrosis factor-α promotes initiation and progression of atherosclerosis. However, some studies show a worsening of the lipid profile in RA with blockade of this cytokine, leading to higher total cholesterol and triglycerides. CONCLUSION/CONCLUSIONS:Greater understanding of the pharmacologic activity of RA treatments on the atherosclerotic process may lead to improved care, addressing both damage to the joints and damage to the heart.

Mineral bone disease (MBD) is a common complication of chronic kidney disease (CKD) characterized by disruption of normal mineral homeostasis within the body. One or more of the following may occur: hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism (SHPT), decreased vitamin D and vascular calcification (VC). The greater the decrease in renal function, the worse the progression of CKD-MBD. These abnormalities may lead to bone loss, osteoporosis and fractures. CKD-MBD is a major contributor to the high morbidity and mortality among patients with CKD. Another well-known complication of CKD is cardiovascular disease (CVD) caused by increased atherosclerosis and VC. CVD is the leading cause of morbidity and mortality in CKD patients. VC is linked to reduced arterial compliance that may lead to widened pulse pressure and impaired cardiovascular function. VC is a strong predicator of cardiovascular mortality among patients with CKD. Elevated phosphorus levels and increased calcium-phosphorus product promote VC. Controlling mineral disturbances such as hyperphosphatemia and SHPT is still considered among the current strategies for treatment of VC in CKD through restriction of calcium based phosphate binders in hyperphosphatemic patients across all severities of CKD along with dietary phosphate restriction and use of calciminetics. Additionally, Vitamin D insufficiency is common in CKD and dialysis patients. The causes are multifactorial and a serious consequence is SHPT. Vitamin D compounds remain the first-line therapy for prevention and treatment of SHPT in CKD. Vitamin D may also have atheroprotective effects on the arterial wall, but clinical studies do not show clear evidence of reduced cardiovascular mortality with vitamin D administration. This review discusses the issues surrounding CKD-MBD, cardiovascular disease and approaches to treatment.

A major feature of Alzheimer's disease (AD) pathology is the plaque composed of aggregated amyloid-β (Aβ) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aβ as the primary noxious form. Aβ oligomers can be generated both extracellularly and intracellularly. Aβ is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton. Current treatments for AD are limited and palliative. Much research and effort is being devoted to reducing Aβ production as an approach to slowing or preventing the development of AD. Aβ formation results from the amyloidogenic cleavage of human amyloid precursor protein (APP). Reconfiguring this process to disfavor amyloid generation might be possible through the reduction of APP or inhibition of enzymes that convert the precursor protein to amyloid.

Dyslipidemia, and specifically elevated low-density lipoprotein (LDL) cholesterol, is one of the most important cardiovascular risk factors. Statins are considered first line therapy for the primary and secondary prevention of cardiovascular disease. However, statins may not be adequate treatment for elevated circulating LDL levels and are ineffective in certain familial hypercholesterolemias. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulatory protein that affects LDL receptors, offers a new alternative for these patients. Moreover, gain-of-function PCSK9 mutations were discovered to be the root cause of familial autosomal dominant hypercholesterolemia. Inhibition of PSCK9 reduces plasma LDL levels, even in patients for whom statins are ineffective or not tolerated. Alirocumab and evolocumab, human monoclonal antibodies that inhibit PCSK9, have been approved to lower LDL levels. While there are drawbacks to these treatments, including adverse events, administration by subcutaneous injection, and high cost, these drugs are indicated for the treatment of atherosclerotic cardiovascular disease and familial hypercholesterolemia as adjunct to diet and maximally tolerated statin therapy. PCSK9 inhibitors may work synergistically with statins to lower LDL. Novel approaches to PCSK9 inhibition are currently in development with the aim of providing safe and effective treatment options to decrease cardiovascular event burden, ideally at lower cost and with oral bioavailability.

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. This review will discuss obesity, T1DM, RA, and SLE in the context of how each unique microbiome profile contributes to elevated cardiovascular risk.