Graphical Abstract
Graphical Abstract
Activation of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) can be triggered by several ligands, favouring atherogenesis, plaque ...instability, and apoptosis of myocardial cells. In parallel, soluble LOX-1 (sLOX-1), which is the ectodomain of LOX-1, is released into the bloodstream by the action of metalloproteinases and disintegrins also stimulated by proinflammatory factors and oxidative stress products. The shedding of sLOX-1 during acute coronary syndrome is mediated by acute phase proteins indicating the cleavage activity but equally the magnitude of the LOX-1 pool expressed on cell membranes. In this setting, sLOX-1 levels predict the risk of recurrent coronary events and cardiovascular mortality.
Atherosclerosis, the underlying cause of cardiovascular disease (CVD), is a worldwide cause of morbidity and mortality. Reducing ApoB-containing lipoproteins-chiefly, LDL (low-density ...lipoprotein)-has been the main strategy for reducing CVD risk. Although supported by large randomized clinical trials, the persistence of residual cardiovascular risk after effective LDL reduction has sparked an intense search for other novel CVD biomarkers and therapeutic targets. Recently, Lox-1 (lectin-type oxidized LDL receptor 1), an innate immune scavenger receptor, has emerged as a promising target for early diagnosis and cardiovascular risk prediction and is also being considered as a treatment target. Lox-1 was first described as a 50 kDa transmembrane protein in endothelial cells responsible for oxLDL (oxidized LDL) recognition, triggering downstream pathways that intensify atherosclerosis via endothelial dysfunction, oxLDL uptake, and apoptosis. Lox-1 is also expressed in platelets, where it enhances platelet activation, adhesion to endothelial cells, and ADP-mediated aggregation, thereby favoring thrombus formation. Lox-1 was also identified in cardiomyocytes, where it was implicated in the development of cardiac fibrosis and myocyte apoptosis, the main determinants of cardiac recovery following an ischemic insult. Together, these findings have revealed that Lox-1 is implicated in all the main steps of atherosclerosis and has encouraged the development of immunoassays for measurement of sLox-1 (serum levels of soluble Lox-1) to be used as a potential CVD biomarker. Finally, the recent development of synthetic Lox-1 inhibitors and neutralizing antibodies with promising results in animal models has made Lox-1 a target for drug development. In this review, we discuss the main findings regarding the role of Lox-1 in the development, diagnosis, and therapeutic strategies for CVD prevention and treatment.
Patients with type 2 diabetes have a several-fold increased risk of developing cardiovascular disease when compared with nondiabetic controls. Myocardial infarction and stroke are responsible for 75% ...of all death in patients with diabetes, who present a 2-4× increased incidence of death from coronary artery disease. Patients with diabetes are considered for cardiovascular disease secondary prevention because their risk level is similar to that reported in patients without diabetes who have already suffered a myocardial infarction. More recently, with a better risk factors control, mainly in intensive LDL cholesterol targets with statins, a significant decrease in acute cardiovascular events was observed in population with diabetes. Together with other major risk factors, type 2 diabetes must be considered as an important cause of cardiovascular disease.Glucagon like peptide-1 receptor agonists represent a novel class of anti-hyperglycemic agents that have a cardiac-friendly profile, preserve neuronal cells and inhibit neuronal degeneration, an anti-inflammatory effect in liver protecting it against steatosis, increase insulin sensitivity, promote weight loss, and increase satiety or anorexia.This review is intended to rationally compile the multifactorial cardiovascular effects of glucagon-like peptide-1 receptor agonists available for the treatment of patients with type 2 diabetes.
Patients with type 2 diabetes (T2DM) have a substantial risk of developing cardiovascular disease. The strong connection between the severity of hyperglycaemia, metabolic changes secondary to T2DM ...and vascular damage increases the risk of macrovascular complications. There is a challenging demand for the development of drugs that control hyperglycaemia and influence other metabolic risk factors to improve cardiovascular outcomes such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina and heart failure (major adverse cardiovascular events). In recent years, introduction of the new drug class of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has changed the treatment landscape as GLP-1RAs have become well-established therapies in T2DM. The benefits of GLP-1RAs are derived from their pleiotropic effects, which include appetite control, glucose-dependent secretion of insulin and inhibition of glucagon secretion. Importantly, their beneficial effects extend to the cardiovascular system. Large clinical trials have evaluated the cardiovascular effects of GLP-1RAs in patients with T2DM and elevated risk of cardiovascular disease and the results are very promising. However, important aspects still require elucidation, such as the specific mechanisms involved in the cardioprotective effects of these drugs. Careful interpretation is necessary because of the heterogeneity across the trials concerning the definition of cardiovascular risk or cardiovascular disease, baseline characteristics, routine care and event rates. The aim of this review is to describe the main clinical aspects of the GLP-1RAs, compare them using data from both the mechanistic and randomized controlled trials and discuss potential reasons for improved cardiovascular outcomes observed in these trials. This review may help clinicians to decide which treatment is most appropriate in reducing cardiovascular risk in patients with T2DM.
Like mutations with loss of function in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, inhibitors of PCSK9 (PCSK9i) may potentially favor the manifestation of diabetes.
A ...meta-analysis of phase 2/3 randomized clinical trials (RCTs) assessed PCSK9i versus placebo in the primary hypercholesterolemia setting. Statins and ezetimibe were used in 98.4% of these studies and balanced between PCSK9i and placebo. We calculated relative risks (RRs) and 95% CIs using random- and fixed-effect models.
We included 68,123 participants (20 RCTs) with median follow-up of 78 weeks. PCSK9i increased fasting blood glucose (weighted mean difference 1.88 mg/dL 95% CI 0.91-2.68;
= 0%;
< 0.001) and HbA
(0.032% 0.011-0.050;
= 15.5%;
< 0.001) when compared with placebo. This effect was not sufficient to increase incidence of diabetes (RR 1.04 0.96-1.13;
= 0%;
= 0.427). Exploratory meta-regression analyses indicated an association between the increased risk of diabetes and the potency (
= 0.029) and duration (
= 0.026) of PCSK9i treatment.
In the short term, PCSK9i therapy favors a small but significant increase in plasma glycemia and HbA
.
The prevalence of aluminum (Al) intoxication has declined over the past 3 decades. However, different groups still report on the diagnosis of Al in bone. Prolonged and low-intensity exposures to Al ...may not be captured by serum Al measurements, preventing its proper diagnosis. We hypothesize that bone Al accumulation may be related to bone and cardiovascular events in the current Era.
To detect the diagnosis of bone Al accumulation; to explore bone and cardiovascular consequences of Al accumulation.
This is a sub-analysis of The Brazilian Registry of Bone Biopsy, a prospective, multicentre cohort, with a mean follow-up of 3.4 years, including patients with CKD undergoing bone biopsy; bone fracture and major cardiovascular events (MACE) were adjudicated; Al accumulation was identified by solochrome-azurine staining; history of previous Al accumulation was registered based on information provided by the nephrologist who performed the bone biopsy; bone histomorphometry parameters, clinical data, and general biochemistry were registered.
275 individuals were considered; 96 (35%) patients have diagnosed with bone Al accumulation and were younger 50 (41-56) vs. 55 (43-61) years; p = 0.026, had lower body mass index 23.5 (21.6-25.5) vs. 24.3 (22.1-27.8) kg/m2; p = 0.017, higher dialysis vintage 108 (48-183) vs. 71 (28-132) months; p = 0.002, presented pruritus 23 (24%) vs. 20 (11%); p = 0.005, tendon rupture 7 (7%) vs. 3 (2%); p = 0.03) and bone pain 2 (0-3) vs. 0 (0-3) units; p = 0.02. Logistic regression reveals that prior bone Al accumulation OR: 4.517 (CI: 1.176-17.353); p = 0.03 and dialysis vintage OR: 1.003 (CI: 1.000-1.007); p = 0.046 as independent determinants of bone Al accumulation; minor perturbations in dynamic bone parameters and no differences in bone fractures rate were noted; MACE was more prevalent in patients with bone Al accumulation 21 (34%) vs. 23 (18%) events; p = 0.016. Cox regression shows the actual/prior diagnosis of bone Al accumulation and diabetes mellitus as independent predictors for MACE: HR = 3.129 (CI: 1.439-6.804; p = 0.004) and HR = 2.785 (CI: 1.120-6.928; p = 0.028.
An elevated proportion of patients have bone Al accumulation, associated with a greater prevalence of bone pain, tendon rupture, and pruritus; bone Al accumulation was associated with minor perturbations in renal osteodystrophy; actual/prior diagnosis of bone Al accumulation and diabetes mellitus were independent predictors for MACE.
Abstract A general concept of clinical benefit of vitamin D supplementation has emerged from the evidence in prevention of osteoporosis. From the cardiovascular point of view, clinical benefit of ...such supplementation remains less clear. Studies in vitro and in animal models demonstrated the expression of vitamin D receptors in endothelial cells, vascular smooth muscle and cardiomyocytes. Vitamin D has been directly implicated in endothelium-mediated vasodilation, anti-coagulant activity and inhibition of the inflammatory response. Indirectly, it may favor the reduction of blood pressure, myocardial hypertrophy and ventricular arrhythmias. In contrast to these mechanistic findings, cross-sectional, longitudinal and small clinical trials have not been consistent in demonstrating association between cardiovascular events and vitamin D. Besides, methodological issues in the tests for serum levels of vitamin D may also contribute to this puzzle. Hence, in the current state of knowledge, it may be too early to consider or to rule out vitamin D as a tool to either estimate or mitigate residual cardiovascular risk. In this review, we discuss recent advances and potential limitations in mechanistic and clinical evidences that are outlining the framework of interaction between vitamin D and cardiovascular risk.
PDF
