Insights into the emergence and evolution of monkeypox virus: Historical perspectives, epidemiology, genetic diversity, transmission, and preventative measures.

In 2022, just before the COVID-19 pandemic ended, many countries noticed a viral monkeypox outbreak. Monkeypox virus, a zoonotic pathogen, causes a febrile illness in humans and resembles smallpox. Prevention strategies encompass vaccination, strict infection control measures, and avoiding contact with infected persons. As monkeypox and related poxviruses continue to pose challenges, ongoing surveillance, early diagnosis, prompt isolation, and effective control measures are crucial for limiting transmission and mitigating the impact of outbreaks on public health. This review provides valuable insights into the evolution of the monkeypox virus and its various modes of transmission, including postmortem transmission, and offers an overall perspective on the guidelines issued by the Government of India to prevent and effectively control the spread of this disease.

Detection of H275Y oseltamivir resistance gene mutation among Influenza A(H1N1)pdm09 patients by allelic discrimination real-time RT-PCR.

Influenza viruses can mutate genetically and cause a range of respiratory ailments. The H275Y mutation in the neuraminidase (NA) gene reduces the effectiveness of oseltamivir, a widely used drug for the treatment of Influenza A and B virus infection. The World Health Organization (WHO) recommends single-nucleotide polymorphism assays to detect this mutation. The present study aims to estimate the prevalence of H275Y mutation conferring oseltamivir resistance in Influenza A(H1N1)pdm09 virus among hospitalized patients from June 2014 to December 2021. Following the WHO protocol, allelic discrimination real-time RT-PCR was performed for 752 samples. Out of the 752 samples, 1 tested positive for Y275 gene mutation by allelic discrimination real-time RT-PCR. In samples of years 2020 and 2021, neither the H275 nor Y275 genotype was detected. Sequencing of the NA gene of all negative samples showed a mismatch between the NA sequence and the probes used in the allelic discrimination assay. Also, Y275 mutation was detected in only 1 sample from 2020. The prevalence of oseltamivir resistance was estimated as 0.27% among the Influenza A(H1N1)pdm09 patients during 2014-2021. The study highlights that the WHO-recommended probes for detecting H275Y mutation may not be useful to detect 2020 and 2021 circulating strains of Influenza A(H1N1)pdm09, emphasizing the need for continuous monitoring of mutations in the influenza virus.

Colchicine Does Not Reduce Abdominal Aortic Aneurysm Growth in a Mouse Model.

Background and Aims: The nacht domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is upregulated in human abdominal aortic aneurysm (AAA), but its pathogenic role is unclear. The aims of this study were firstly to examine whether the inflammasome was upregulated in a mouse model of AAA and secondly to test whether the inflammasome inhibitor colchicine limited AAA growth. Methods: AAA was induced in eight-week-old male C57BL6/J mice with topical application of elastase to the infrarenal aorta and oral 3-aminopropionitrile (E-BAPN). For aim one, inflammasome activation, abdominal aortic diameter, and rupture were compared between mice with AAA and sham controls. For aim two, 3 weeks after AAA induction, mice were randomly allocated to receive colchicine (n = 28, 0.2 mg/kg/d) or vehicle control (n = 29). The primary outcome was the rate of maximum aortic diameter increase measured by ultrasound over 13 weeks. Results: There was upregulation of NLRP3 markers interleukin- (IL-) 1ß (median, IQR; 15.67, 7.11-22.60 pg/mg protein versus 6.87, 4.54-11.60 pg/mg protein, p = .048) and caspase-1 (109, 83-155 relative luminosity units (RLU) versus 45, 38-65 RLU, p < .001) in AAA samples compared to controls. Aortic diameter increase over 80 days (mean difference, MD, 4.3 mm, 95% CI 3.3, 5.3, p < .001) was significantly greater in mice in which aneurysms were induced compared to sham controls. Colchicine did not significantly limit aortic diameter increase over 80 days (MD -0.1 mm, 95% CI -1.1, 0.86, p = .922). Conclusions: The inflammasome was activated in this mouse model of AAA; however, daily oral administration of colchicine did not limit AAA growth.

Potential of plant secondary metabolite-based polymers to enhance wound healing.

There is a global epidemic of non-healing wounds. Chronic inflammation, overexpression of pro-inflammatory cytokines, oxidative stress and bacterial infection are implicated in delayed wound healing. Natural extracts are a rich source of bioactive molecules called plant secondary metabolites (PSMs) that include terpenes and phenols. These molecules may facilitate wound healing through their antioxidant, anti-inflammatory, and antibacterial activity. After briefly outlining the process of wound healing and how it is compromised in chronic wounds, this review focuses on investigating how PSMs-based polymers may improve wound healing. Best methods for incorporating PSMs into wound dressings are reviewed and critically compared. The exiting body of literature strongly suggests that PSMs-based polymers incorporated into wound dressings could have clinical value in aiding wound healing. STATEMENT OF SIGNIFICANCE: Chronic wounds develop by the persistence of inflammation, oxidative stress and infection. Chronic wounds affect the worldwide population, by reducing quality of life of patients with significant cost to healthcare systems. To help chronic wounds to heal and overcome this burden, materials with anti-inflammatory, antioxidant and antibacterial properties are required. Plant secondary metabolites (PSMs) are volatile materials that have all these properties. PSMs-based polymers can be fabricated by polymerization techniques. The present review provides an overview of the state-of-the-art of the wound healing mechanisms of PSMs. Current developments in the field of PSMs-based polymers are reviewed and their potential use as wound dressings is also covered.

Cohort Study Examining the Association of Optimal Blood Pressure Control at Entry With Infrarenal Abdominal Aortic Aneurysm Growth.

Background and Aim: The benefit of controlling cardiovascular risk factors in slowing the progression of small abdominal aortic aneurysm (AAA) is controversial. This study investigated the association of optimal blood pressure control at entry with the growth of small AAA. Methods and Results: A total of 1,293 patients with initial AAA diameter <50 mm were followed by a median 5 (inter-quartile range, IQR, 3-7) ultrasound scans for a median of 3.6 years (IQR 1.8, 5.3). Optimal blood pressure control was defined as blood pressure ≤140/90 mmHg at recruitment. The association of optimal blood pressure control at entry with AAA growth was assessed using linear mixed effects models adjusted for established risk factors of AAA growth and factors which were unequally distributed among the blood pressure groups. Optimal blood pressure control at entry was not significantly associated with AAA growth. In the risk factor adjusted model the mean difference in AAA growth between blood pressure groups was 0.04 mm/year (95% CI -0.20, 0.13; p = 0.65). The results were similar in sensitivity analyses excluding outliers or focused on systolic or diastolic blood pressure alone. Conclusions: This observational study suggests that optimal blood pressure control at entry is not associated with slower AAA growth.

Mouse models for abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Kallistatin limits abdominal aortic aneurysm by attenuating generation of reactive oxygen species and apoptosis.

Inflammation, vascular smooth muscle cell apoptosis and oxidative stress are believed to play important roles in abdominal aortic aneurysm (AAA) pathogenesis. Human kallistatin (KAL; gene SERPINA4) is a serine proteinase inhibitor previously shown to inhibit inflammation, apoptosis and oxidative stress. The aim of this study was to investigate the role of KAL in AAA through studies in experimental mouse models and patients. Serum KAL concentration was negatively associated with the diagnosis and growth of human AAA. Transgenic overexpression of the human KAL gene (KS-Tg) or administration of recombinant human KAL (rhKAL) inhibited AAA in the calcium phosphate (CaPO4) and subcutaneous angiotensin II (AngII) infusion mouse models. Upregulation of KAL in both models resulted in reduction in the severity of aortic elastin degradation, reduced markers of oxidative stress and less vascular smooth muscle apoptosis within the aorta. Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media reduced apoptosis and downregulated markers of oxidative stress. These effects of KAL were associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tg mice and rodents receiving rhKAL. These results suggest KAL-Sirtuin 1 signalling limits aortic wall remodelling and aneurysm development through reductions in oxidative stress and vascular smooth muscle cell apoptosis. Upregulating KAL may be a novel therapeutic strategy for AAA.

Effect of disease modifying anti-rheumatic drugs on major cardiovascular events: a meta-analysis of randomized controlled trials.

Disease modifying anti-rheumatic drugs (DMARDs) were developed to treat joint inflammation. There is growing evidence that anti-inflammatory drugs prevent major cardiovascular events (MACE). The aim of this systematic review and meta-analysis was to examine whether DMARDs reduce the risk of MACE. A systematic literature search was performed to identify randomized controlled trials (RCTs) testing the effect of DMARDs on cardiovascular events. The primary outcome was MACE defined as the first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke or cardiovascular death. Secondary outcomes were myocardial infarction or stroke alone and all-cause mortality. Safety was assessed by fatal or life threatening infection. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using the Cochrane Collaboration's tool for assessing risk of bias and funnel plots. Twelve RCTs involving 18,056 participants testing three different DMARDs subclasses (Tumor Necrosis Factor inhibitors-4 trials; Janus Kinase inhibitors-5 trials; Interleukin inhibitors-3 trials) were included. Meta-analysis suggested that none of the DMARD subclasses had any effect on MACE, MI alone, stroke alone, risk of fatal or life threatening infection or death. Risk of bias was high, low and unclear in five, six and one studies respectively. Funnel plots suggested a low possibility of publication bias. This meta-analysis suggests that DMARDs do not affect the incidence of MACE. More trials are needed for firm conclusions.

Kallikrein-1 Blockade Inhibits Aortic Expansion in a Mouse Model and Reduces Prostaglandin E2 Secretion From Human Aortic Aneurysm Explants.

Background Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. The kinin B2 receptor agonist, bradykinin, has been implicated in AAA pathogenesis through promoting inflammation. Bradykinin is generated from high- and low-molecular-weight kininogen by the serine protease kallikrein-1. The aims of this study were first to examine the effect of neutralizing kallikrein-1 on AAA development in a mouse model and second to test how blocking kallikrein-1 affected cyclooxygenase-2 and prostaglandin E2 in human AAA explants. Methods and Results Neutralization of kallikrein-1 in apolipoprotein E-deficient (ApoE-/-) mice via administration of a blocking antibody inhibited suprarenal aorta expansion in response to angiotensin (Ang) II infusion. Kallikrein-1 neutralization decreased suprarenal aorta concentrations of bradykinin and prostaglandin E2 and reduced cyclooxygenase-2 activity. Kallikrein-1 neutralization also decreased protein kinase B and extracellular signal-regulated kinase 1/2 phosphorylation and reduced levels of active matrix metalloproteinase 2 and matrix metalloproteinase 9. Kallikrein-1 blocking antibody reduced levels of cyclooxygenase-2 and secretion of prostaglandin E2 and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils. Conclusions These findings suggest that kallikrein-1 neutralization could be a treatment target for AAA.

Risk Factors and Mouse Models of Abdominal Aortic Aneurysm Rupture.

Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults. In clinical practice, the most established predictor of AAA rupture is maximum AAA diameter. Aortic diameter is commonly used to assess AAA severity in mouse models studies. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Previous research suggests that aortic wall structure and strength, biomechanical forces on the aorta and cellular and proteolytic composition of the AAA wall influence the risk of AAA rupture. Mouse models offer an opportunity to study the association of these factors with AAA rupture in a way not currently possible in patients. Such studies could provide data to support the use of novel surrogate markers of AAA rupture in patients. In this review, the currently available mouse models of AAA and their relevance to the study of AAA rupture are discussed. The review highlights the limitations of mouse models and suggests novel approaches that could be incorporated in future experimental AAA studies to generate clinically relevant results.

Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model.

Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

Systematic review and meta-analysis of mouse models of diabetes-associated ulcers.

Mouse models are frequently used to study diabetes-associated ulcers, however, whether these models accurately simulate impaired wound healing has not been thoroughly investigated. This systematic review aimed to determine whether wound healing is impaired in mouse models of diabetes and assess the quality of the past research. A systematic literature search was performed of publicly available databases to identify original articles examining wound healing in mouse models of diabetes. A meta-analysis was performed to examine the effect of diabetes on wound healing rate using random effect models. A meta-regression was performed to examine the effect of diabetes duration on wound healing impairment. The quality of the included studies was also assessed using two newly developed tools. 77 studies using eight different models of diabetes within 678 non-diabetic and 720 diabetic mice were included. Meta-analysis showed that wound healing was impaired in all eight models. Meta-regression suggested that longer duration of diabetes prior to wound induction was correlated with greater degree of wound healing impairment. Pairwise comparisons suggested that non-obese diabetic mice exhibited more severe wound healing impairment compared with db/db mice, streptozotocin-induced diabetic mice or high-fat fed mice at an intermediate stage of wound healing (p<0.01). Quality assessment suggested that the prior research frequently lacked incorporation of key clinically relevant characteristics. This systematic review suggested that impaired wound healing can be simulated in many different mouse models of diabetes but these require further refinement to become more clinically relevant.

Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice.

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein-kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-α-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-α-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression.

Development of a two-stage limb ischemia model to better simulate human peripheral artery disease.

Peripheral arterial disease (PAD) develops due to the narrowing or blockage of arteries supplying blood to the lower limbs. Surgical and endovascular interventions are the main treatments for advanced PAD but alternative and adjunctive medical therapies are needed. Currently the main preclinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) by a 1-stage procedure. Since there are concerns regarding the ability to translate findings from this animal model to patients, we aimed to develop a novel clinically relevant animal model of PAD. HLI was induced in male Apolipoprotein E (ApoE-/-) deficient mice by a 2-stage procedure of initial gradual femoral artery occlusion by ameroid constrictors for 14 days and subsequent excision of the femoral artery. This 2-stage HLI model was compared to the classical 1-stage HLI model and sham controls. Ischemia severity was assessed using Laser Doppler Perfusion Imaging (LDPI). Ambulatory ability was assessed using an open field test, a treadmill test and using established scoring scales. Molecular markers of angiogenesis and shear stress were assessed within gastrocnemius muscle tissue samples using quantitative polymerase chain reaction. HLI was more severe in mice receiving the 2-stage compared to the 1-stage ischemia induction procedure as assessed by LDPI (p = 0.014), and reflected in a higher ischemic score (p = 0.004) and lower average distance travelled on a treadmill test (p = 0.045). Mice undergoing the 2-stage HLI also had lower expression of angiogenesis markers (vascular endothelial growth factor, p = 0.004; vascular endothelial growth factor- receptor 2, p = 0.008) and shear stress response mechano-transducer transient receptor potential vanilloid 4 (p = 0.041) within gastrocnemius muscle samples, compared to animals having the 1-stage HLI procedure. Mice subjected to the 2-stage HLI receiving an exercise program showed significantly greater improvement in their ambulatory ability on a treadmill test than a sedentary control group. This study describes a novel model of HLI which leads to more severe and sustained ischemia than the conventionally used model. Exercise therapy, which has established efficacy in PAD patients, was also effective in this new model. This new model maybe useful in the evaluation of potential novel PAD therapies.

Depletion of CD11c+ dendritic cells in apolipoprotein E-deficient mice limits angiotensin II-induced abdominal aortic aneurysm formation and growth.

OBJECTIVE: The role of chronic inflammation in abdominal aortic aneurysm (AAA) is controversial. CD11c+ antigen-presenting cells (APCs) (dendritic cells (DCs)) have been reported in human AAA samples but their role is unclear. The effect of conditional depletion of CD11c+ cells on experimental AAA was investigated in the angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE-/-) mouse model. APPROACH: CD11c-diphtheria toxin (DT or D.tox) receptor (DTR), ovalbumin (OVA) fragment aa 140-386, and enhanced green fluorescent protein (eGFP)-ApoE-/- (CD11c.DOG.ApoE-/-) mice were generated and CD11c+ cell depletion achieved with D.tox injections (8 ng/g body weight, i.p., every-other-day). AAA formation and growth were assessed by measurement of supra-renal aortic (SRA) diameter in vivo by serial ultrasound and by morphometry assessment of harvested aortas at the end of the study. RESULTS: Depletion of CD11c+ cells by administration of D.tox on alternative days was shown to reduce the maximum diameter of AAAs induced by 28 days AngII infusion compared with controls (D.tox, 1.58 ± 0.03 mm vs Vehicle control, 1.81 ± 0.06 mm, P<0.001). CD11c+ depletion commencing after AAA establishment by 14 days of AngII infusion, was also shown to lead to smaller AAAs than controls after a further 14 days (D.tox, 1.54 ± 0.04 mm vs Vehicle control, 1.80 ± 0.03 mm, P<0.001). Flow cytometry revealed significantly lower numbers of circulating CD44hi CD62Llo effector CD4 T cells, CD44hi CD62Llo effector CD8 T cells and B220+ B cells in CD11c+ cell-depleted mice versus controls. CD11c+ depletion attenuated SRA matrix degradation indicated by decreased neutrophil elastase activity (P=0.014), lower elastin degradation score (P=0.012) and higher collagen content (P=0.002). CONCLUSION: CD11c+ cell-depletion inhibited experimental AAA development and growth associated with down-regulation of circulating effector T cells and attenuated matrix degradation. The findings suggest involvement of autoreactive immune cells in AAA pathogenesis.

Vitamin D as A Protector of Arterial Health: Potential Role in Peripheral Arterial Disease Formation.

Atherosclerotic occlusive diseases and aneurysms that affect large and medium-sized arteries outside the cardiac and cerebral circulation are collectively known as peripheral arterial disease (PAD). With a rise in the rate of aging population worldwide, the number of people diagnosed with PAD is rapidly increasing. The micronutrient vitamin D is an important steroid hormone that acts on many crucial cellular mechanisms. Experimental studies suggest that optimal levels of vitamin D have beneficial effects on the heart and blood vessels; however, high vitamin D concentrations have been implicated in promoting vascular calcification and arterial stiffness. Observations from various clinical studies shows that deficiency of vitamin D has been associated with a greater risk of PAD. Epidemiological studies have often reported an inverse relation between circulating vitamin D status measured in terms of 25-hydroxivitamin D [25(OH)D] levels and increased cardiovascular disease risk; however, randomized controlled trials did not show a consistent positive effect of vitamin D supplementation on cardiovascular disease risk or events. Even though PAD shares all the major risk factors with cardiovascular diseases, the effect of vitamin D deficiency in PAD is not clear. Current evidence suggests a strong role of vitamin D in promoting genomic and epigenomic changes. This review summarises the current literature that supports the notion that vitamin D deficiency may promote PAD formation. A better understanding of underlying pathological mechanisms will open up new therapeutic possibilities which is the main unmet need in PAD management. Furthermore, epigenetic evidence shows that a more holistic approach towards PAD prevention that incorporates a healthy lifestyle, adequate exercise and optimal nutrition may be more effective in protecting the genome and maintaining a healthy vasculature.

Cohort Study Examining the Association Between Blood Pressure and Cardiovascular Events in Patients With Peripheral Artery Disease.

Background Hypertension is an important risk factor for cardiovascular events in patients with peripheral artery disease; however, optimal blood pressure targets for these patients are poorly defined. This study investigated the association between systolic blood pressure ( SBP ) and cardiovascular events in a prospectively recruited patient cohort with peripheral artery disease. Methods and Results A total of 2773 patients were included and were grouped according to SBP at recruitment (≤120 mm Hg, n=604; 121-140 mm Hg, n=1065; and >140 mm Hg, n=1104). Adjusted Cox proportional hazards analyses suggested that patients with SBP ≤120 mm Hg were at greater risk of having a major cardiovascular event (myocardial infarction, stroke, or cardiovascular death) than patients with SBP of 121-140 mm Hg (adjusted hazard ratio, 1.36; 95% CI, 1.08-1.72; P=0.009). Patients with SBP >140 mm Hg had an adjusted hazard ratio of 1.23 (95% CI, 1.00-1.51; P=0.051) of major cardiovascular events compared with patients with SBP of 121-140 mm Hg. These findings were similar in sensitivity analyses only including patients receiving antihypertensive medications or focused on patients with a minimum of 3 months of follow-up. Conclusions This cohort study suggests that patients with peripheral artery disease and SBP ≤120 mm Hg are at increased risk of major cardiovascular events. The findings suggest caution in intensive SBP lowering in this patient group.

A diet enriched with tree nuts reduces severity of atherosclerosis but not abdominal aneurysm in angiotensin II-infused apolipoprotein E deficient mice.

BACKGROUND AND AIMS: Diets enriched with tree nuts have been demonstrated to reduce the risk of atherosclerosis-related cardiovascular events. Abdominal aortic aneurysm (AAA) shares common risk factors with atherosclerosis and AAA patients commonly have atherosclerosis related cardiovascular events. AAA has some distinct pathological and clinical characteristics to those of atherosclerosis. No previous study has examined the effect of a diet enriched with tree nuts on experimental or clinical AAA. This study investigated the effect of a diet enriched with tree nuts on the development and severity of AAA within an experimental rodent model. METHODS: Male apolipoprotein E deficient mice were allocated to a diet enriched with tree nuts or control diet for 56 days (n = 17 per group). After 28 days, all mice were infused with angiotensin II whilst being maintained on their respective diets. The primary outcome was AAA severity assessed by the supra-renal aortic diameter, measured by ultrasound and ex vivo morphometric analysis. The severity of atherosclerosis was assessed by computer-aided analysis of Sudan IV stained aortic arches and sections of brachiocephalic arteries prepared with Van Gieson's stain. RESULTS: The diet enriched with tree nuts did not influence aortic diameter or aortic rupture incidence. Mice receiving the diet enriched with tree nuts had significantly less atherosclerosis within the brachiocephalic artery (p = 0.033) but not in the aortic arch. CONCLUSIONS: This experimental study suggests that a diet enriched with tree nuts does not reduce the severity of AAA, but does reduce the severity of atherosclerosis within the brachiocephalic artery. The study was not powered to identify a moderate effect of the diet on the primary outcome and therefore this cannot be excluded.

Anionic nanoliposomes reduced atherosclerosis progression in Low Density Lipoprotein Receptor (LDLR) deficient mice fed a high fat diet.

Atherosclerosis is a systemic disease characterized by the deposition of cholesterol and inflammatory cells within the arterial wall. Removal of cholesterol from the vessel wall may have an impact on the size and composition of atherosclerotic lesions. Anionic phospholipids or liposome vesicles composed of a lipid bilayer such as nanoliposomes have been suggested as treatments for dyslipidemia. In this study, we investigated the effect of anionic nanoliposomes on atherosclerosis in a mouse model. Low-density lipoprotein receptor knockout mice (Ldlr-/- ) were fed with an atherosclerosis promoting high fat and cholesterol (HFC) diet for 12 weeks. Anionic nanoliposomes including hydrogenated soy phosphatidylcholine (HSPC) and distearoyl phosphatidylglycerol (DSPG) (molar ratio: 1:3) were injected intravenously into HFC-fed Ldlr-/- mice once a week for 4 weeks. Mice receiving nanoliposomes had significantly reduced atherosclerosis within the aortic arch as assessed by Sudan IV staining area (p = 0.007), and reduced intima/media ratio (p = 0.030) and greater collagen deposition within atherosclerosis plaques within the brachiocephalic artery (p = 0.007), compared to control mice. Administration of nanoliposomes enhanced markers of reverse cholesterol transport (RCT) and increased markers of plaque stability in HFC-fed Ldlr-/- mice. Reduced cholesterol accumulation was observed in the liver along with the up-regulation of the major genes involved in the efflux of cholesterol such as hepatic ATP-binding cassette transporters (ABC) including Abc-a1, Abc-g1, Abc-g5, and Abc-g8, Scavenger receptor class B, member 1 (Scarb1), and Liver X receptor alpha (Lxr)-α. Lecithin Cholesterol Acyltransferase activity within the plasma was also increased in mice receiving nanoliposomes. Anionic nanoliposome administration reduced atherosclerosis in HFC-fed Ldlr-/- mice by promoting RCT and upregulating the ABC-A1/ABC-G1 pathway.