Risk Of Vascular Disease Research Articles

Extracellular vesicles and insulin-mediated vascular function in metabolic syndrome.

Metabolic Syndrome (MetS) raises cardiovascular disease risk. Extracellular vesicles (EVs) have emerged as important mediators of insulin sensitivity, although few studies on vascular function exist in humans. We determined the effect of insulin on EVs in relation to vascular function. Adults with MetS (n=51, n=9M, 54.8 ± 1.0 years, 36.4 ± 0.7kg/m2 , ATPIII: 3.5 ± 0.1a.u., VO2 max: 22.1 ± 0.6ml/kg/min) were enrolled in this cross-sectional study. Peripheral insulin sensitivity (M-value) was determined during a euglycemic clamp (40 mU/m2 /min, 90 mg/dl), and blood was collected for EVs (CD105+, CD45+, CD41+, TX+, and CD31+; spectral flow cytometry), inflammation, insulin, and substrates. Central hemodynamics (applanation tonometry) was determined at 0 and 120 min via aortic waveforms. Pressure myography was used to assess insulin-induced arterial vasodilation from mouse 3rd order mesenteric arteries (100-200 μm in diameter) at 0.2, 2 and 20 nM of insulin with EVs from healthy and MetS adults. Adults with MetS had low peripheral insulin sensitivity (2.6 ± 0.2 mg/kg/min) and high HOMA-IR (4.7 ± 0.4 a.u.) plus Adipose-IR (13.0 ± 1.3 a.u.). Insulin decreased total/particle counts (p < 0.001), CD45+ EVs (p=0.002), AIx75 (p=0.005) and Pb (p=0.04), FFA (p < 0.001), total adiponectin (p=0.006), ICAM (p=0.002), and VCAM (p=0.03). Higher M-value related to lower fasted total EVs (r=-0.40, p=0.004) while higher Adipose-IR associated with higher fasted EVs (r=0.42, p=0.004) independent of VAT. Fasting CD105+ and CD45+ derived total EVs correlated with fasting AIx75 (r=0.29, p < 0.05) and Pb (r=0.30, p < 0.05). EVs from MetS participants blunted insulin-induced vasodilation in mesenteric arteries compared with increases from healthy controls across insulin doses (all p < 0.005). These data highlight EVs as potentially novel mediators of vascular insulin sensitivity and disease risk.

Sex and gender-specific aspects in prediabetes and diabetes mellitus-clinical recommendations (Update 2023)

Metabolic diseases dramatically affect the life of men and women from infancy up to old age in different and manifold ways and are amajor challenge for the healthcare system. The treating physicians are confronted with the different needs of women and men in the clinical routine. Gender-specific differences affect pathophysiology, screening, diagnostic and treatment strategies of diseases as well as the development of complications and mortality rates. Impairments in glucose and lipid metabolism, regulation of energy balance and body fat distribution and therefore the associated cardiovascular diseases, are greatly influenced by steroidal and sex hormones. Furthermore, education, income and psychosocial factors play an important role in the development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at ayounger age and at alower body mass index (BMI) compared to women but women feature adramatic increase in the risk of diabetes-associated cardiovascular diseases after the menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with ahigher increase in vascular complications in women but ahigher increase of cancer deaths in men. In women prediabetes or diabetes are more distinctly associated with ahigher number of vascular risk factors, such as inflammatory parameters, unfavourable changes in coagulation and higher blood pressure. Women with prediabetes and diabetes have amuch higher relative risk for vascular diseases. Women are more often morbidly obese and less physically active but may have an even greater benefit in health and life expectation from increased physical activity than men. In weight loss studies men often showed ahigher weight loss than women; however, diabetes prevention is similarly effective in men and women with prediabetes with arisk reduction of nearly 40%. Nevertheless, along-term reduction in all cause and cardiovascular mortality was so far only observed in women. Men predominantly feature increased fasting blood glucose levels, women often show impaired glucose tolerance. Ahistory of gestational diabetes or polycystic ovary syndrome (PCOS) as well as increased androgen levels and decreased estrogen levels in women and the presence of erectile dysfunction or decreased testosterone levels in men are important sex-specific risk factors for the development of diabetes. Many studies showed that women with diabetes reach their target values for HbA1c, blood pressure and low-density lipoprotein (LDL)-cholesterol less often than their male counterparts, although the reasons are unclear. Furthermore, sex differences in the effects, pharmacokinetics and side effects of pharmacological treatment should be taken more into consideration.

Outcomes of the V-Healthy education and awareness program that empowers high school students to understand and diagnose vascular disease risk factors

IntroductionV-Healthy (Center for Vascular Awareness Inc, Latham NY) is a grassroots vascular health education and awareness campaign that educates high school students about the importance of the vascular disease risks they face today and its impact decades later, and empowers health care professionals and schoolteachers to lead vascular health education in their communities. This study evaluates the impact of the V-Healthy initiative in empowering and educating adolescents about the implications of vascular disease risk factors and in creating a blueprint for a community outreach program that focuses on vascular health and disease education and awareness. MethodsThe V-Healthy program is an initiative that connects community vascular health care professionals and educators with high school students, for a day of vascular health education. The V-Healthy program curriculum is provided in two distinct stages. Stage I consists of didactic vascular health education and takes place in the classroom for the duration of one class period (40-50 minutes). The class period is divided into four sessions including a PowerPoint presentation to teach the impact of vascular disease risk factors (hypertension, diabetes, hyperlipidemia, smoking/vaping, and genetics) on the development of peripheral arterial disease, venous disease, aortic disease, and stroke, and three hands-on sessions that introduce students to vascular innovation and technology, vascular patients, and the diagnosis of a vascular disease risk factor such as hypertension. Stage I concludes with a student questionnaire aimed to gauge students’ retention of the material and attitude toward the program. Stage II offers students (with parental consent) the opportunity to participate in the “Diagnosing Hypertension” study. Students were provided automated blood pressure monitors and taught to measure blood pressure in their parents daily for 1 week. Findings are recorded in designated blood pressure logs, which are then categorized using the 2018 American Heart Association blood pressure categorization system: normal (<120/<80), elevated (120-129/<80), stage I (130-139/80-89), or stage II (≥140/≥90). No identifiable student or guardian information is collected. ResultsOver 3 years, more than 12,000 students participated in the V-Healthy program and 5120 students completed student surveys, which indicated that 97% improved their understanding of vascular health, >93% could identify vascular disease risk factors, 84% wanted to educate their families, and 76% wanted more vascular health education. A total of 1064 students participated in the “Diagnosing Hypertension” study and diagnosed hypertension in 73% of their parents: 34% for stage I hypertension and 39% for stage II hypertension. Over a 3-year period of this study, the number of schools participating increased 20-fold (from 1 to 20), the number of volunteer vascular health professionals and schoolteachers increased 13-fold (from 16 to 210), and our ability to connect with and impact high school students grew 15-fold (from 800 to over 12,000). ConclusionsV-Healthy is the first program to connect over 12,000 students to vascular health professionals in their communities to empower them to diagnose and understand vascular disease risk factors and their implications on the development of vascular disease. Furthermore, the V-Healthy program has displayed substantial growth over a 3-year period in impacting high school students and vascular health care professionals, and has the potential to be used as a blueprint for community-based vascular health education and awareness initiatives.

694 DRUG INDUCED KIDNEY INFARCTION: A CASE REPORT

Abstract Isotretinoin (ISO) is a synthetic analog of vitamin A. Notwithstanding the well-known long-term efficacy in the treatment of severe resistant cystic acne, ISO induces several side effects too. Dyslipidemia, increased liver enzymes, as well as reduction of biotidinase have been already reported [1]. Homocysteine (HCY), a sulfur-containing amino acid, is recycled into methionine by a transmethylation reaction requiring folate and vitamin B12. Given that during ISO treatment elevated liver enzymes (SGOT, SGPT) are often observed, it has been hypothesized that iatrogenic liver dysfunction could affect cystathionine-b-synthase, an enzyme involved in HCY metabolism, [2]. Several studies have highlighted that elevated plasma HCY concentrations are associated with an increased risk of premature occlusive vascular disease. We hereby report a case of drug-induced kidney infarction after ISO therapy. A previously healthy 18-year-old male, on therapy with 40 mg/die isotretinoin for acne, was admitted to the Emergency Unit for abdominal pain, nausea and vomiting and dyspnea. A trans-thoracic echocardiogram showed dilated and hypocontractile left ventricle. During the hospitalization he had a total body CT that showed the presence of an ischemic lesion on left kidney without other pathological findings. He started therapy with 12 IU/kg UFH as soon as a surgical emergency was excluded. Subsequently, he underwent a coronary angiogram that resulted unremarkable. Cardiac MRI showed extensive delayed gadolinium late enhancement with intramural linear pattern. In the hypothesis of drug-induced vasculitis, an extensive serological testing was performed. Elevation of serum liver enzymes (SGOT, SGPT), CRP, LDH was found. Mutations on MTHFR gene and Leiden Factor were not detected, neither alteration in coagulation parameters. Finally the dosage of plasmatic HCY resulted over the range of normality and ISO was discontinued. The patient was discharged on optimized medical therapy for heart failure. He is currently managed as outpatient. HCY levels could be found elevated in patients with ischemic events during ISO treatment. Given the widespread use of this drug for acne, it could be reasonable to dose HCY in patients with suspected liver dysfunction. Physicians should be aware of this scenario and should act swiftly to avoid uneventful outcomes. [1] Schulpis KH et al. Elevated plasma homocysteine levels in patients on isotretinoin therapy for cystic acne. Int J Dermatol. 2001 Jan;40(1):33-6. [2] Polat M, et al. Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study. J Dermatolog Treat. 2008;19(4):229-32.

Review on Toxicity of Antihypertensive Drugs

Adverse drug reactions are common and pose a serious health problem, limiting treatment options, causing compliance issues, and even leading to therapy discontinuation. Hypertension is a chronic disease that is regarded as a major risk factor for cardiovascular disease. To achieve a target blood pressure in an individual patient, a wide range of anti-hypertensive agents are available as single or combination therapy, whereas combination therapy increases the risk of developing Adverse Drug Reaction. Hypertensive patients frequently have coexisting disease conditions such as hyperlipidemia, impaired glucose metabolism, and renal impairment, which increase the risk of Cardio Vascular morbidity and mortality. When treating hypertensive patients, comprehensive management of both hypertension and concomitant Cardio Vascular Disease risk factors is essential. Some of the rare and serious Adverse Drug Reactions that occurred in patients treated with these drugs included beta-blockers causing psoriasis, calcium channel blockers causing gingival hyperplasia, peripheral oedema, Angiotensin Converting Enzyme inhibitors causing ankle oedema, and thiazide diuretics causing hyponatremia and hyperglycemia. Asymptomatic hypertension is more common and necessitates lifelong treatment with antihypertensive agents, predisposing to Adverse Drug Events.In order to improve treatment outcomes and reduce morbidity and mortality associated with adverse drug reactions, healthcare professionals must monitor adverse drug reactions in patients taking antihypertensive drugs. Keywords: Adverse drug reactions, Hypertension, hyperlipidemia, glucose metabolism

Prognostic value of multiparametric cardiac magnetic resonance in sickle cell patients.

The aim of this multicenter study was to prospectively assess the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in sickle cell disease (SCD) patients. Among all patients with hemoglobinopathies consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network, we selected 102 SCD patients (34.38 ± 12.67years, 49 females). Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect focal myocardial fibrosis. At baseline CMR, only two patients had significant MIO (global heart T2* < 20ms). During a mean follow-up of 63.01 ± 24.95months, 11 cardiovascular events (10.8%) were registered: 3 pulmonary hypertension, 2 supraventricular arrhythmias, 1 heart failure, 1 death for heart failure, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, and 1 death after acute chest syndrome. In the multivariate analysis, the independent CMR predictors of cardiovascular events were left ventricular (LV) ejection fraction (hazard ratio-HR = 0.88; p = 0.025) and right ventricular (RV) mass index (HR = 1.09; p = 0.047). According to the receiver-operating characteristic curve analysis for adverse events, an LV ejection fraction < 58.9% and an RV mass index > 31g/m2 were optimal cut-off values. Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that CMR may be added as a screening tool for identifying SCD patients at high risk for cardiopulmonary and vascular diseases.

The intracellular signaling pathways governing macrophage activation and function in human atherosclerosis.

Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and plaque formation in arterial vessel walls. Atherosclerotic plaques narrow the arterial lumen to increase the risk of heart attacks, ischemic stroke and peripheral vascular disease, which are major and worldwide health and economic burdens. Macrophage accumulation within plaques is characteristic of all stages of atherosclerosis and their presence is a potential marker of disease activity and plaque stability. Macrophages engulf lipids and modified lipoproteins to form foam cells that express pro-inflammatory and chemotactic effector molecules, stress inducing factors and reactive oxygen species. They control plaque stability and rupture through secretion of metalloproteinases and extracellular matrix degradation. Although macrophages can worsen disease by propagating inflammation, they can stabilize atherosclerotic plaques through tissue remodeling, promoting the formation of a fibrous cap, clearing apoptotic cells to prevent necrotic core formation and through vascular repair. In atherosclerosis, macrophages respond to dyslipidaemia, cytokines, dying cells, metabolic factors, lipids, physical stimuli and epigenetic factors and exhibit heterogeneity in their activation depending on the stimuli they receive. Understanding these signals and the pathways driving macrophage function within developing and established plaques and how they can be pharmacologically modulated, represents a strategy for the prevention and treatment of atherosclerosis. This review focusses on the current understanding of factors controlling macrophage heterogeneity and function in atherosclerosis. Particular attention is given to the macrophage intracellular signaling pathways and transcription factors activated by biochemical and biophysical stimuli within plaques, and how they are integrated to regulate plaque formation and stability.

Update on diverse vascular cognitive impairment (VCID)

Background. As the US population becomes increasingly older and more diverse, the number of Americans with dementia is expected to rise substantially, particularly the number of those with concomitant vascular disease. Moreover, the impact of vascular disease on dementia risk may be exacerbated in African Americans and Hispanics, who are at greater risk for vascular disease and for whom vascular disease may play a larger role in clinical dementia. As public health awareness of dementia increases, it is becoming common to see individuals presenting for clinical assessment with minor cognitive complaints. Neuroimaging studies of these individuals frequently identify “incidental” white matter hyperintensities (WMH), usually ascribed to “microvascular disease” by radiologists, raising concerns in patients about their brain health and future risk for dementia.&#x0D; Methods. To date, however, we are not aware of any studies designed to examine the baseline and future impact of white matter (WM) injury in the clinical setting, particularly among diverse populations where age-related WMH volumes are known to be higher1 or comprehensively examined the impact of individual and combined magnetic resonance imaging (MRI) measures of white matter injury on cognitive performance among a diverse, non-demented, stroke-free population with cognitive complaints over an extended period of observation. For this presentation, I summarized the available evidence of the impact of WMH and cognition and reviewed the design of a new study to prospectively assess this outcome in a diverse population and develop a risk factor profile to assist in the diagnosis of those at risk for dementia.&#x0D; Results. There is substantial evidence that WMH are common, increase in amount and prevalence with age,2 impact cognition and dementia,3 and are a measure of vascular brain injury. The significance of studying WM injury is buoyed by the fact that dementia risk scales emphasize the role of vascular risk in dementia prediction4 and that institution of effective treatment could lessen the burden of dementia on population.5 Yet, a complete understanding of WMH as markers of vascular brain injury contributing to cognitive complaints and possibly vascular cognitive impairment (VCI) requires a comprehensive determination of the full spectrum of WM injury associated with vascular risk, potential mechanisms of WMH formation and progression, ethnoracial, other genetic influences and how WMH interact with neurodegenerative pathologies, in particular Alzheimer’s disease (AD). Evidence of the importance of “asymptomatic” vascular brain injury on present cognition and future cognitive decline led to the design of a new multi-site study of diverse individuals with cognitive complaints and WMH, that aims to develop a predictive risk factor score that can be widely used in future treatment trials called diverse VCID. Diverse VCID is a multi-site study of 2250 individuals of non-Hispanic Whites, Hispanic/Latinos, and Black African Americans who will be followed for approximately 3 years to deliver a clinical risk score that predicts dementia based on neuroimaging, plasma biomarkers, genetic and clinical data.&#x0D; Conclusions. Vascular diseases are now recognized to be a major contributor to cognitive impairment and dementia disproportionately affecting individuals from diverse backgrounds. Diverse VCID is designed to address this critical issue and to facilitate future treatment studies of vascular cognitive impairment.

Classification of Blood Pressure Levels Based on Photoplethysmogram and Electrocardiogram Signals with a Concatenated Convolutional Neural Network.

Hypertension is a severe public health issue worldwide that significantly increases the risk of cardiac vascular disease, stroke, brain hemorrhage, and renal dysfunction. Early screening of blood pressure (BP) levels is essential to prevent the dangerous complication associated with hypertension as the leading cause of death. Recent studies have focused on employing photoplethysmograms (PPG) with machine learning to classify BP levels. However, several studies claimed that electrocardiograms (ECG) also strongly correlate with blood pressure. Therefore, we proposed a concatenated convolutional neural network which integrated the features extracted from PPG and ECG signals. This study used the MIMIC III dataset, which provided PPG, ECG, and arterial blood pressure (ABP) signals. A total of 14,298 signal segments were obtained from 221 patients, which were divided into 9150 signals of train data, 2288 signals of validation data, and 2860 signals of test data. In the training process, five-fold cross-validation was applied to select the best model with the highest classification performance. The proposed concatenated CNN architecture using PPG and ECG obtained the highest test accuracy of 94.56-95.15% with a 95% confidence interval in classifying BP levels into hypotension, normotension, prehypertension, hypertension stage 1, and hypertension stage 2. The result shows that the proposed method is a promising solution to categorize BP levels effectively, assisting medical personnel in making a clinical diagnosis.

Exercise modulates APOE expression in brain cortex of female APOE3 and APOE4 targeted replacement mice

Apolipoprotein E (ApoE) is the main cholesterol carrier of the brain and the ε4 gene variant (APOE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold. Several studies indicate that APOE4 modulates critical factors for neuronal function, including brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Both proteins show exercise-induced upregulation, which is presumed to mediate many of the beneficial effects of physical activity including improved cognition; however, there is variability in results between individuals potentially in-part due to genetic variations including APOE isoform. This study aimed to determine if the two most prevalent human APOE isoforms influence adaptive responses to exercise-training. Targeted replacement mice, homozygous for either APOE3 or APOE4 were randomized into exercised and sedentary groups. Baseline locomotor function and voluntary wheel-running behavior was reduced in APOE4 mice. Exercised groups were subjected to daily treadmill running for 8 weeks. ApoE protein in brain cortex was significantly increased by exercise in both genotypes. PGC-1α mRNA levels in brain cortex were significantly lower in APOE4 mice, and only tended to increase with exercise in both genotypes. Hippocampal BDNF protein were similar between genotypes and was not significantly modulated by treadmill running. Behavioral and biochemical variations between APOE3 and APOE4 mice likely contribute to the differential risk for neurological and vascular diseases and the exercise-induced increase in ApoE levels suggests an added feature of the potential efficacy of physical activity as a preventative and therapeutic strategy for neurogenerative processes in both genotypes.

Abstract 10075: Hematopoietic Mosaic Chromosomal Alterations and Cardiovascular Disease-Related Deaths Among Cancer Survivors: An Analysis of the UK Biobank

Introduction: Cancer survivors are at an increased risk for cardiovascular (CV)-related deaths. Recently, clonal hematopoiesis (CH) was described as a novel risk factor for both cancer and CV disease. However, the influence of CH on CV outcomes in cancer survivors has not been explored. Hypothesis: We hypothesized that CH captured by mosaic chromosomal alterations (mCA) could predict the risk of CV outcomes and death following cancer diagnosis. Methods: In the UK Biobank, we identified patients with a history of selected cancer types known for their high CV risk. mCAs were detected using DNA genotyping array intensity data. The association of mCA with CV-death, coronary artery disease (CAD)-death, and any cause death was performed using Cox proportional hazards regression, adjusting for age, sex, smoking, chemotherapy, radiotherapy, and ancestry. Exploratory analyses also included incident CV phenotypes. The specificity of the effect was assessed using a model with an interaction term between mCA and cancer history. Results: Among 48 919 unrelated individuals with a cancer diagnosis, 10 070 patients (20.6%) carried ≥1 mCA clone. Of those, 2432 were autosomal carriers and 1910 had a mCA in ≥10% of peripheral leukocytes. mCA prevalence increased with age: from 4.8% among those aged &lt;49 years old to 30.4% for those aged ≥70 years old. mCA was associated with an increased risk of CAD-death (HR 1.37, 95% CI 1.09-1.71, P= 0.006) and overall mortality (HR 1.07, 95% CI 1.02-1.11, P =0.006). In exploratory analyses, mCA was associated with higher risks of incident STEMI (HR 1.18, 95% CI 1.02-1.37, P =0.022) and peripheral vascular disease (HR 1.17, 95% CI 1.04-1.31, P =0.007). The effect of mCA was specific to cancer survivors for any cause of death ( P interaction &lt;0.001) but not for CAD-death ( P interaction =0.96). Conclusions: Our findings indicate that among cancer survivors, CH captured by mCA was associated with a higher risk of CAD death and overall mortality. Cancer survivors with CH may benefit from targeted CV screening and preventive measures to better manage individual CV risk.

Cardiovascular risk factors, haemostasis and antithrombotic treatment in retinal vessel occlusion

Venous and arterial retinal vascular occlusions are age-related disorders, generally associated with classical cardiovascular risk factors, rather than an isolated ocular disease. As affected patients often also have an increased general risk for other vascular diseases, such as ischemic stroke, an interdisciplinary clarification of cardiovascular risk factors and systemic comorbidities is essential for all patients. Extended hemostaseological investigations may be recommended in those patients who do not match the typical risk profile. Patients at a young age by the time of manifestation, without conventional risk factors as well as patients with an increased risk of developing antiphospholipid syndrome may require a selective clinical investigation including testing for thrombophilic risk factors. Recent studies have clearly demonstrated an association between coagulation and lipid metabolism disorders and the development of both retinal vein and artery occlusions in specific subgroups of patients. Therapeutic approaches to treat retinal vascular occlusions or reduce the long-term risk of recurrences with anticoagulant or antiplatelet drugs have not gained widespread acceptance. However, intravenous thrombolysis may be avaluable treatment option for central retinal artery occlusions within a short time to treatment therapeutic window. For defined disorders of the coagulation system, the administration of antithrombotic drugs to reduce the general vascular risk can be a reasonable approach. This article provides an overview of cardiovascular risk factors, the general vascular risk and the current state of knowledge on ophthalmologically relevant disorders of coagulation and lipid metabolism in patients with venous and arterial retinal vascular occlusions.

Single-cell profiling of vascular endothelial cells reveals progressive organ-specific vulnerabilities during obesity

Obesity promotes diverse pathologies, including atherosclerosis and dementia, which frequently involve vascular defects and endothelial cell (EC) dysfunction. Each organ has distinct EC subtypes, but whether ECs are differentially affected by obesity is unknown. Here we use single-cell RNA sequencing to analyze transcriptomes of ~375,000 ECs from seven organs in male mice at progressive stages of obesity to identify organ-specific vulnerabilities. We find that obesity deregulates gene expression networks, including lipid handling, metabolic pathways and AP1 transcription factor and inflammatory signaling, in an organ- and EC-subtype-specific manner. The transcriptomic aberrations worsen with sustained obesity and are only partially mitigated by dietary intervention and weight loss. For example, dietary intervention substantially attenuates dysregulation of liver, but not kidney, EC transcriptomes. Through integration with human genome-wide association study data, we further identify a subset of vascular disease risk genes that are induced by obesity. Our work catalogs the impact of obesity on the endothelium, constitutes a useful resource and reveals leads for investigation as potential therapeutic targets.

Prehospital stroke care in Africa: The reality and potential solutions.

Prehospital stroke care in Africa: The reality and potential solutions.

Platelet-Neutrophil Interaction and Thromboinflammation in Diabetes: Considerations for Novel Therapeutic Approaches.

Thromboinflammation has become a topic of key interest in cardiovascular disease and the prevention of diabetes complications because of the interplay between thrombosis and inflammation in diabetes. Specifically, the significant risk of vascular thrombotic disease in diabetes highlights the need for new and better therapeutic targets to help manage and prevent vascular thrombo-occlusive disease in this condition. Similarly, the prominent role of inflammation in diabetes has sparked interest in anti-inflammatory agents to better prevent and control vascular disease. Investigations on the effects of anticoagulation and antiplatelet interventions in patients with diabetes and cardiovascular disease show a potential role for these agents in decreasing morbidity and mortality. Neutrophils and platelets are key players in inflammation and wound-healing response, respectively. The interaction between neutrophils and platelets is thought to be an important driver of thromboinflammation. Therefore, this review describes the mechanisms involved in platelet-neutrophil interactions that contribute to the development or exacerbation of thromboinflammation in the context of diabetes and its associated comorbidities. The effects observed by the antithrombotic/antidiabetic treatments and physical activity/dietary interventions on attenuating thromboinflammation are discussed. These data suggest that mechanisms involved in platelet-neutrophil interaction, platelet activation/aggregation, and the recruitment of neutrophils have a promising potential to become therapeutic targets to decrease thromboinflammation in patients with diabetes.

Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study)

BackgroundOffspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease.MethodsFollow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013.SettingExploratory sub-study using data from the nationwide EPICOM study.ParticipantsAdolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code.Main outcome measuresThis study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples.ResultsWe identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM.Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX).ConclusionsThese findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.

Serial assessment of thrombogenicity and hemodynamics in patients with type II diabetes in a clinical research unit: Evidence for circadian variations in clot formation

Circadian fluctuations in thrombogenicity and hemostasis play a role in acute cardiovascular thrombotic events occurring in the early morning hours. There is a lack of data assessing thrombogenicity, platelet function, and hemodynamics to investigate diurnal variations in a high cardiovascular risk population. This was an exploratory, single-center study conducted in aspirin-treated patients with Type II Diabetes Mellitus (T2DM) (n = 37) with documented vascular disease and/or multiple cardiovascular risk factors. Hemodynamic monitoring and blood sample collection for thromboelastography (TEG) and platelet function testing were done serially at 7-9 AM (morning), 7-9 PM (evening), 11 PM-1 AM (night), and at 5-7 AM (awakening). R-value measured by TEG was shorter during awakening hours than during the night and day hours (p < 0.05). There were no changes in platelet reactivity in response to arachidonic acid, adenosine diphosphate, and collagen between time points. Pulse pressure (PP) was highest during awakening hours (p < 0.05). Study findings provide a mechanistic explanation for increased thrombotic events observed in the early waking hours among diabetics with multiple cardiovascular risk factors. The role of chronotherapy in reducing coagulability and PP to improve clinical outcomes should be explored.

Dysbetalipoproteinemia Is Associated With Increased Risk of Coronary and Peripheral Vascular Disease.

Dysbetalipoproteinemia (DBL) is a disorder in which remnant lipoproteins accumulate in the plasma due to a genetic apolipoprotein E dysfunction in conjunction with the presence of secondary metabolic factors. An increased risk of both coronary and peripheral vascular disease (PVD) has been observed in these patients in retrospective studies. The primary objective was to compare the incidence of atherosclerotic cardiovascular disease (ASCVD) and PVD in a cohort of patients with DBL compared with normolipidemic controls. As a secondary objective, the incidence of ASCVD and PVD was compared between patients with DBL and patients with familial hypercholesterolemia (FH). A total of 221 patients with DBL, 725 patients with FH, and 1481 normolipidemic controls were included in the study. The data were obtained by review of medical records. In patients with DBL, there was an overall excess risk of PVD (hazard ratio [HR] 13.58, 95% CI 4.76-38.75) and ASCVD (HR 3.55, 95% CI 2.17-5.83) (P < .0001) when compared with normolipidemic controls. When compared with patients with FH, an increased risk of PVD (HR 3.89, 95% CI 1.20-12.55, P = .02) was observed in patients with DBL. We demonstrated that the risks of ASCVD and PVD in DBL are >3-fold and >13-fold higher, respectively, than normolipidemic controls. Furthermore, the risk of PVD is ∼4-fold higher in DBL than in FH. Adequate screening of DBL is imperative to improve the clinical care of these patients by preventing the development of ASCVD.

Abstract P127: Systemic Immune-Inflammatory Index (SII) In Hypertensive Adults

Aside from age, hypertension is the most predominant cardiovascular disease risk factor worldwide. In the United States, ~45% of the adult population have blood pressure higher than 130/80 mmHg. Hypertension is associated with increased risk of myocardial infarction, heart failure, stroke and vascular disease. Systemic immune-inflammation index (SII) is a novel biomarker of systemic inflammation and immunity. Clinical interest in SII has intensified due to its association with major cardiovascular events and prognostic value in cardiovascular outcomes. Indeed, the index has been shown to be a strong prognostic marker for coronary artery disease, heart failure, cardiac death and stroke. It is currently unknown whether SII is elevated in adults with elevated blood pressure. We tested the hypothesis that hypertension is associated with an elevated SII, independent of other cardiometabolic risk factors and/or disease. Fifty-six adults (age range: 43 to 66 years) were studied: 22 normotensive (NT: 10M/12F; age 57 + 1 yr; BMI: 27.7 + 1.0 kg/m 2 ; BP: 120/75 + 1/1 mmHg) and 34 hypertensive (HT: 23M/11F; age 57 + 1 yr; 28.4 + 0.6 kg/m 2 ; BP 140/85 + 1/1 mmHg). All subjects were sedentary, non-smokers, normolipidemic, normoglycemic, non-medicated, and free of overt cardiometabolic diseases. SII was calculated as total peripheral platelets count x neutrophil-to-lymphocyte ratio. SII was significantly higher (~20%) in the HT (479.6 + 25.0) vs NT (402.5 + 27.8) group. There was no significant sex by blood pressure interaction with SII. SII was similar and equally elevated in HT males (487.7 + 34.7) and females (462.7 + 28.7) than NT males (364.4 + 30.8) and females (425.9 + 39.9). SII was independently associated with systolic (r=0.30; P&lt;0.05) and mean arterial (r=0.26; P&lt;0.05) blood pressure; SII was not significantly associated with any other anthropometric, hemodynamic or metabolic variable. Hypertension is associated with elevated SII indicative of greater systemic immune-inflammatory activation. Increased immune activation and inflammatory burden contribute not only to atherosclerosis but to progression of hypertension. Given the link between SII and poor prognosis, SII may aid in identifying high risk hypertensive groups.

ROLE OF MPV IN COMPLICATION OF DIABETES MELLITUS 2

Diabetes mellitus (DM) is a global health problem with increased risk of vascular disease. Platelets may contribute to the development of vascular complications in subjects with diabetes. Larger platelets are more reactive than smaller ones therefore, mean platelet volume (MPV) can be used as a marker for platelet activity. Aim and Objectives: To determine the role of MPV in severity and complications of DM2 as compared to non diabetic patients and to determine the effect of glycemic control and duration of diabetes on platelet parameters. This is a cross-sectional prospective study to evaluate MPV in patients with diabetes mellitus 2 versus non-diabetic patients and to investigate the potential association between MPV and chronic diabetic complications. Our study revealed that MPV is increased in Diabetes mellitus (DM) and that platelets become more reactive and aggregable. The increased platelet size may be a risk factor for atherosclerosis associated with DM and its vascular complications. MPV was found to be higher in subjects with Type-2 diabetes and significantly increased in diabetics with poor glycemic control and In patient with complications. having a longer duration of diabetes. MPV can be used as a prognostic marker of vascular complications in patients with DM.