Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown.
To examine the effect of progressive weight gain on the substrate for AF.
Thirty sheep ...were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor.
Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels.
Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.
Cardiovascular disease is a leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus. These high-risk patients benefit from aggressive risk factor management, with blood ...pressure and low-density lipoprotein-cholesterol treatment, glycemic control, kidney protection, and lifestyle intervention. There are several recommendation and guideline documents across cardiology, endocrinology, nephrology, and general medicine professional societies from the United States and Europe with recommendations for cardiovascular risk reduction in patients with type 2 diabetes mellitus. Although there are some noteworthy differences, particularly in risk stratification, low-density lipoprotein-cholesterol and blood pressure treatment targets, and the use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, overall there is considerable alignment across recommendations from different professional societies.
Managing hypercholesterolaemia Nelson, Adam J; Nicholls, Stephen J
Australian prescriber,
02/2024, Volume:
47, Issue:
1
Journal Article
Peer reviewed
Open access
Hypercholesterolaemia is one of the most common conditions treated by clinicians in Australia. Low-density lipoprotein cholesterol (LDL-C) plays a causal role in the development and progression of ...atherosclerosis and cardiovascular disease. Every 1 mmol/L reduction in LDL-C concentration is associated with a 21 to 25% reduction in the relative risk of prospective atherosclerotic cardiovascular events, and emerging evidence suggests this benefit increases over time. Absolute cardiovascular risk assessment identifies patients likely to derive the most benefit from lowering LDL-C concentration, and helps determine the intensity of their treatment regimens and targets. Optimal management of LDL-C may require combination treatment with multiple classes of drugs.
Purpose of Review
For more than 20 years there has been considerable interest in the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) by virtue of their ability ...to raise levels of high-density lipoprotein cholesterol. This review endeavors to integrate existing data from prior clinical trials with emerging data to understand whether there is a pathway forward to develop CETP inhibitors to prevent cardiovascular disease.
Recent Findings
Large clinical trials have proved disappointing with successive reports of a failure to reduce cardiovascular events. The one clinical development program that did demonstrate a reduction in cardiovascular risk found adipose tissue accumulation and did not proceed for regulatory approval. More recent observations suggest that less CETP activity may prevent cardiovascular events, but due to lipid lowering rather than raising high-density lipoprotein cholesterol. In addition, treatment with CETP inhibitors appears to have a beneficial impact on glycemic control in the setting of diabetes.
Summary
Advances in the field of CETP inhibition suggest a potentially protective effect on the risk of both cardiovascular disease and diabetes. This has implications for how to best design future clinical development programs and leaves the door open to potentially bring CETP inhibitors to the preventive cardiology clinic.
Lytic bacteriophages (or phages) drive bacterial mortality by elaborating exquisite abilities to bind, breach, and destroy bacterial cell membranes and subjugate critical bacterial cell functions. ...These antimicrobial activities make phages ideal candidates to serve as, or provide sources of, biological control measures for bacterial pathogens. In this study, we isolated the
phage vB_BanS_Bcp1 (here referred to as Bcp1) from landfill soil, using a
host. The antimicrobial activities of both Bcp1 and its encoded endolysin, PlyB, were examined across different
group species, including
,
, and
, with pathogenic potential in humans and multiple different uses in biotechnological applications. The Bcp1 phage infected only a subset (11 to 66%) of each
species group tested. In contrast, functional analysis of purified PlyB revealed a potent bacteriolytic activity against all
isolates tested (
= 79). PlyB was, furthermore, active across broad temperature, pH, and salt ranges, refractory to the development of resistance, bactericidal as a single agent, and synergistic with a second endolysin, PlyG. To confirm the potential for PlyB as an antimicrobial agent, we demonstrated the efficacy of a single intravenous treatment with PlyB alone or combination with PlyG in a murine model of lethal
infection. Overall, our findings show exciting potential for the Bcp1 bacteriophage and the PlyB endolysin as potential new additions to the antimicrobial armamentarium.
Organisms of the
lineage are ubiquitous in the environment and are responsible for toxin-mediated infections ranging from severe food poisoning (
) to anthrax (
). The increasing incidence of many of these infections, combined with the specter of antibiotic resistance, has created a need for novel antimicrobials with potent activity, including bacteriophages (or phages) and phage-encoded products (i.e., endolysins). In this study, we describe a broadly infective phage, Bcp1, and its encoded endolysin, PlyB, which exhibited a rapidly bacteriolytic effect against all
isolates tested with no evidence of evolving resistance. Importantly, PlyB was highly efficacious in a mouse model of lethal bacteremia with
Both the Bcp1 phage and the PlyB endolysin represent novel mechanisms of action compared to antibiotics, with potential applications to address the evolving problem of antimicrobial resistance.
Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable ...biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.
Statins in a Distorted Mirror of Media Nelson, Adam J.; Puri, Rishi; Nissen, Steven E.
Current atherosclerosis reports,
06/2020, Volume:
22, Issue:
8
Journal Article
Peer reviewed
Purpose of Review
Statins have proven efficacy with a favorable safety profile yet, despite being widely affordable, remain profoundly underutilized. Statins have acquired a bad reputation, which is ...likely contributing to high rates of nonadherence and discontinuation. The degree to which negative media perceptions contribute to underutilization is unclear.
Recent Findings
The media has a key role in informing discussion on the public agenda but also on how issues are framed. In this context, the majority of studies evaluating news coverage suggest that the content on statins is predominantly negative and focused on potential harm. Studies utilizing quasi-experimental and interrupted time series design have shown periods of negative news stories on statins in multiple countries are associated with (a) less statin commencement in eligible patients, (b) high rates of discontinuation, and (c) poor long-term adherence.
Summary
This review highlights the deleterious impact of negative media coverage on statin utilization through misattribution of muscle complaints and the nocebo effect. Academia must work with the media to harmonize the public health messaging; however, individual physicians have a critical role in mitigating a harmful narrative of misinformation and actively discredit malinformation.
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of numerous cancers but are associated with increased risk of myocardial infarction. The prevalence of traditional cardiovascular ...risk factors (CVRF) in patients treated with ICIs is unknown. This study sought to describe the frequency of reporting of CVRFs among landmark ICI trials.
A systematic review of all phase 2 or 3 cancer trials employing ICIs that led to United States Food and Drug Administration approval was conducted.
Of the 69 identified trials, only one study reported baseline rates of hypertension, diabetes mellitus, and dyslipidemia. Smoking history was reported in 27 studies (39 %) and three (4 %) reported body mass index. No study reported history of previous cardiovascular disease, although 17 (25 %), six (9 %), and 21 (30 %) studies excluded patients with recent myocardial infarction, revascularization and heart failure respectively. Similarly low rates of cardiovascular risk factor reporting were observed in studies employing concurrent vascular endothelial growth factor inhibitors and recruiting (neo)adjuvant cohorts.
The prevalence of CVRFs is poorly described in ICI trials despite increasingly reported risks of myocardial infarction. A systematic approach to collecting and reporting CVRFs should be considered in future trials and real world populations.
Display omitted
•Immune checkpoint inhibitors (ICI) are associated with myocardial infarction (MI).•Cancer and MI share risk factors such as smoking, diabetes and obesity.•Cardiovascular risk factors (CVRF) are rarely reported in seminal ICI trials.•Future trials should consider CVRF reporting to guide cardiovascular risk reduction.
PDF
