Risk Of Atherosclerotic Disease Research Articles

S775 Major Cardiovascular Adverse Events by Baseline Cardiovascular Risk Stratification in Patients With Ulcerative Colitis Treated With Tofacitinib: Data From the OCTAVE Clinical Program

S775 Major Cardiovascular Adverse Events by Baseline Cardiovascular Risk Stratification in Patients With Ulcerative Colitis Treated With Tofacitinib: Data From the OCTAVE Clinical Program

Association between Lipoprotein Subfractions, Hemostatic Potentials, and Coronary Atherosclerosis.

Background Dyslipidemias are associated with atherosclerotic plaque formation and a prothrombotic state, thus increasing the risk of both atherosclerotic vascular disease and atherothrombotic adverse events. We sought to explore the association between lipoprotein subfractions, overall hemostasis, and coronary calcifications in individuals at intermediate cardiovascular risk. Methods Consecutive statin-naive individuals at intermediate cardiovascular risk referred for coronary artery calcium score (CACS) scanning were included. CACS was assessed using a 128-slice dual-source CT scanner. Traditional lipid profile, high-density lipoprotein (HDL) subfractions 2 and 3, and small dense low-density lipoproteins (sdLDL) were measured with commercially available assays. Overall hemostatic (OHP) and coagulation potentials (OCP) were measured spectrophotometrically, using fibrin aggregation curves after exposure to thrombin and recombinant tissue-type plasminogen activator, respectively. Overall fibrinolytic potential (OFP) was calculated as a difference between the two areas under curves. Results We included 160 patients (median age 63 (interquartile range (IQR), 56-71 years, 52% women, and median CACS 8, IQR 0-173 Agatston units). HDL3 levels—but not sdLDL or hemostatic potentials—were significantly associated with CACS zero, even after adjusting for age, sex, arterial hypertension, dyslipidemia, diabetes, and smoking history (OR 0.980 (0.962-0.999), p = 0.034). HDL3 was also significantly associated with OCP (r = −0.232, p adjusted for age and sex 0.037). Conclusions In patients at intermediate cardiovascular risk, HDL3 is associated with both subclinical atherosclerosis and overall coagulation. Our findings are in line with studies reporting on an inverse relationship between HDL3 and atherosclerosis and provide one possible mechanistic explanation for the association between novel lipid biomarkers and coagulation derangements.

Integrating Advanced Lipid Testing and Biomarkers in Assessment and Treatment.

Our ability to assess and stratify atherosclerotic disease risk in patients is evolving. Recent advances in advanced lipid testing have created opportunities for clinical application of novel biomarkers. Until recently, LDL-C has served largely as the singular biomarker of ASCVD and guide for decisions in treatment for high-risk groups. There are important evolutions in the measurement of LDL-C but even still, the pathogenesis of atherosclerosis and ASCVD is not solely driven by LDL-C. As atherosclerosis is driven by multiple complex pathways including inflammation, it is important to expand our focus beyond LDL-C and utilize multiple biomarkers in the assessment of this disease process. Non-HDL, ApoB, LDL-P, Lp(a), and hsCRP are unique tools to aid in cardiac risk evaluation, especially in higher risk patients, though not limited to this population. A multifaceted approach to advanced lipid testing with novel biomarkers will enhance comprehensive ASCVD risk assessments.

Serum cholesterol increase in statin users associated with antibiotic use: Case-crossover study

Purpose3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (“statins”) reduce risk of atherosclerotic disease. However, statins need secondary bile acids, produced by the gut microbiota, for absorption. Our hypothesis was that a change in the gut microbiota induced by antibiotics might cause a decrease in statin absorption, and decreased statin effectiveness. Our objective was to study the association between antibiotic treatment and increased cholesterol level in statin users. MethodsCase-crossover study, in which an individual serves as his own control, by comparing outcome risk among the same individual at different times, adjusting for time-dependent comorbidity index. The study is based on adherent statin users' cohort and two cohorts of patients not treated with statins, in Clalit Health Services. Exposure were antibiotic prescriptions dispensed in the 3 months prior to LDL-C measurements. ResultsThere were 25,496 statin users and 72,638 time-points. A significant association was found between LDL-C increase and exposure to macrolides and clindamycin, OR = 1.237 (1.138–1.345), p = 6.5*10−7, number needed to harm (NNH) = 19. There was no association between LDL-C increase and negative control objects such as anti-viral treatments; nor between LDL-C and exposure to antibiotics in non-statin users. As a secondary outcome, we have found an association between LDL-C increase and a following atherosclerotic ischemic event. ConclusionAn increase in LDL-C in highly adherent statin users is associated with precedent macrolides or clindamycin treatment.

Mitochondrial Ca2+ Uptake Drives Endothelial Injury By Radiation Therapy.

Background:Radiation therapy strongly increases the risk of atherosclerotic vascular disease, such as carotid stenosis. Radiation induces DNA damage, in particular in mitochondria, but the upstream and downstream signaling events are poorly understood. The objective of this study was to define such mechanisms.Methods:Endothelial-specific MCU (mitochondrial Ca2+ uniporter) knockout and C57Bl6/J mice with or without a preinfusion of a mitoTEMPO (mitochondrial reactive oxygen species [ROS] scavenger) were exposed to a single dose of cranial irradiation. 24, and 240 hours postirradiation, vascular reactivity, endothelial function, and mitochondrial integrity were assessed ex vivo and in vitro.Results:In cultured human endothelial cells, irradiation with 4 Gy increased cytosolic Ca2+ transients and the mitochondrial Ca2+ concentration ([Ca2+]mt) and activated MCU. These outcomes correlated with increases in mitochondrial ROS (mtROS), loss of NO production, and sustained damage to mitochondrial but not nuclear DNA. Moreover, irradiation impaired activity of the ETC (electron transport chain) and the transcription of ETC subunits encoded by mitochondrial DNA (mtDNA). Knockdown or pharmacological inhibition of MCU blocked irradiation-induced mtROS production, mtDNA damage, loss of NO production, and impairment of ETC activity. Similarly, the pretreatment with mitoTEMPO, a scavenger of mtROS, reduced irradiation-induced Ca2+ entry, and preserved both the integrity of the mtDNA and the production of NO, suggesting a feed-forward loop involving [Ca2+]m and mtROS. Enhancement of DNA repair in mitochondria, but not in the nucleus, was sufficient to block prolonged mtROS elevations and maintain NO production. Consistent with the findings from cultured cells, in C57BL/6J mice, head and neck irradiation decreased endothelium-dependent vasodilation, and mtDNA integrity in the carotid artery after irradiation. These effects were prevented by endothelial knockout of MCU or infusion with mitoTEMPO.Conclusions:Irradiation-induced damage to mtDNA is driven by MCU-dependent Ca2+ influx and the generation of mtROS. Such damage leads to reduced transcription of mitochondrial genes and activity of the ETC, promoting sustained mtROS production that induces endothelial dysfunction. Our findings suggest that targeting MCU and mtROS might be sufficient to mitigate irradiation-induced vascular disease.

Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes

Dapagliflozin was shown to reduce the cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. However, data are limited on the relationship of the effect and safety with the concurrent use of CV medications in patients with type 2 diabetes. To assess whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without background use of CV medications commonly used for heart failure (HF) and kidney disease in patients with type 2 diabetes. This study is a prespecified secondary analysis of DECLARE-TIMI 58, which was a randomized trial of dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and either atherosclerotic disease or multiple risk factors for CV disease. Patients were stratified by baseline use of the following CV medications: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), β-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022. Dapagliflozin or placebo. The outcomes of interest were the composite of CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death). Among 17 160 patients, 13 950 (81%) used ACEI/ARBs, 9030 (53%) used β-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Changes in blood pressure and eGFR at 48 months with dapagliflozin compared with placebo did not differ regardless of concurrent therapy (placebo-corrected change, -1.6 mm Hg [95% CI, -4.2 to 1.0] to -2.6 mm Hg [95% CI, -3.3 to -2.9]; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and the kidney-specific composite outcome regardless of background use of selected medications (hazard ratio [HR] range: HR, 0.50; 95% CI, 0.39-0.63; to HR, 0.82; 95% CI, 0.72-0.95; P > .05 for each interaction). In patients receiving ACEI/ARBs + β-blockers + diuretics (n = 4243), dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% (HR, 0.76; 95% CI, 0.62-0.93) and 38% (HR, 0.62; 95% CI, 0.44-0.87), respectively. There were no significant treatment interactions with the concomitant CV medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia (range: HR, 0.12; 95% CI, 0.02-0.99; to HR, 1.04; 95% CI, 0.83-1.32; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV and kidney outcomes irrespective of background use of various CV medications without any treatment interaction for key safety events. These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy. ClinicalTrials.gov Identifier: NCT01730534.

Sustained Proinflammatory Effects of Hypoglycemia in People With Type 2 Diabetes and in People Without Diabetes.

Iatrogenic hypoglycemia activates the immune system and is associated with an increased risk for atherosclerotic disease. We determined acute and long-term effects of insulin-induced hypoglycemia on inflammatory markers in humans with or without type 2 diabetes. A total of 15 adults with type 2 diabetes and 16 matched control subjects (17 men and 14 women, age 59.6 ± 7.1 years, BMI 28.5 ± 4.3 kg/m2) underwent a hyperinsulinemic-euglycemic (5.31 ± 0.32 mmol/L) hypoglycemic (2.80 ± 0.12 mmol/L) glucose clamp. Blood was drawn during euglycemia and hypoglycemia and 1, 3, and 7 days later to determine circulating immune cell composition, function, and inflammatory proteins. In response to hypoglycemia, absolute numbers of circulating lymphocytes and monocytes significantly increased and remained elevated for 1 week. The proportion of CD16+ monocytes increased, and the proportion of CD14+ monocytes decreased, which was sustained for 1 week in people without diabetes. During hypoglycemia, ex vivo stimulated monocytes released more tumor necrosis factor-α and interleukin 1β, and less interleukin 10, particularly in people with diabetes. hs-CRP and 25 circulating inflammatory proteins increased, remaining significantly elevated 1 week after hypoglycemia. While levels at euglycemia differed, responses to hypoglycemia were broadly similar in people with or without type 2 diabetes. We conclude that hypoglycemia induces a proinflammatory response at the cellular and protein level that is sustained for 1 week in people with type 2 diabetes and control subjects.

Design, methods and baseline characteristics of the Beijing Hospital Atherosclerosis Study: a prospective dynamic cohort study.

BackgroundThe atherosclerotic coronary artery disease (CAD) risk assessment based on conventional risk factors have only moderate performance, and residual risks still exist. Thus, we reported here a cohort study that aims to identify and validate the new biosignatures (especially the metabolomics, lifestyle biomarkers and biological age), and elucidate their predictive effect on CAD and subsequent cardiovascular events.MethodsThis prospective, single-center, cohort study commenced in March 2017 and seeks to examine patients undergoing coronary angiography (CAG) at the Beijing Hospital. Patients’ baseline demographic and medical history data are captured by questionnaires. Blood samples are taken before CAG for clinical laboratory tests and metabolomics analyses. Traditional CAD risk factors are analyzed by routine assays. CAD-related metabolites from different metabolic pathways and lifestyle biomarkers are measured by liquid chromatography-tandem mass spectrometry methods. Biological ages are calculated based on the laboratory and metabolomics data. The enrolled patients attend annual follow-up examinations for 10 years. The primary end points are the composite end points of major adverse cardiovascular events, including death from any cause, non-fatal myocardial infarction, and non-fatal stroke. Quality management and control are carried out through the entire research process, including standardized baseline and follow-up investigation, intra- and inter-run quality controls for laboratory measurements, etc.ResultsBaseline data of the enrolled 2,970 patients from 2017 to 2020 were collected and are presented in this article. Among them, there were more males (62.5%) than females, and the patients tended to be old and overweight. The percentages of diagnosed hypertension and diabetes were 67.3% and 35.2%, respectively. A total of 8.5% had a family history of premature CAD. Their lipid profiles were within the normal range, probably due to the use of statins.ConclusionsThis study has successfully initiated an investigation into the roles of new biosignatures in predicting CAD among Chinese Han patients undergoing CAG. To the best of our knowledge, this cohort is the first study systematically focusing on the association of lifestyle biomarkers and biological age with CAD risk. Findings from this study will provide biomarkers to discriminate the presence of CAD and to predict subsequent cardiovascular events.

Mechanism, clinical consequences, and management of dyslipidemia in children with nephrotic syndrome

Dyslipidemia in nephrotic syndrome (NS) is often characterized by marked increases in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and other lipoproteins, such as very low-density lipoprotein, intermediate-density lipoprotein, and lipoprotein(a). It has been suggested that impaired catabolism of lipoproteins and cholesterol is mainly due to decreased lipoprotein lipase and hepatic lipase activity, and increased biosynthesis of lipoproteins in the liver. The management strategies for dyslipidemia in patients with NS consist of lifestyle modification, lipid-lowering agents represented by statins, second-line agents such as fibrates and bile acid sequestrants, and lipid apheresis. Compared with dyslipidemia in adult NS patients, whose risks of atherosclerotic disease and progressive renal injury are considered high, clinical data on dyslipidemia in pediatric NS patients are limited. Therefore, it is necessary to pay more attention to the evaluation and management of dyslipidemia in pediatric patients with NS in clinical practice.

Hyperlipidemia in Children and Adolescents.

While coronary artery disease (CAD) is thought to be a disease of adulthood, atherosclerosis can originate in childhood and adolescence. There is a paucity of randomized controlled treatment trials regarding dyslipidemia among the younger population. However, it is apparent that childhood dyslipidemia is associated with an earlier onset of CAD. Most recent guidelines by the American College of Cardiology (ACC) and American Heart Association (AHA) focus on lifestyle modification and lifetime risk of atherosclerotic disease, as well as adequate screening measures. Genetic factors, environmental contributors such as pollution, obesity linked to poor nutrition, and sedentary lifestyles are shown to be associated with increased lipid levels and early CAD among children and adolescents. Familial hyperlipidemia is one of the most prevalent genetic diseases and can affect 1 in 250 individuals. A multimodal treatment plan is most effective for children and adolescents with dyslipidemia including lifestyle changes (a modified diet and moderate physical activity) and pharmacologic intervention. The mainstay of pharmacologic treatment for childhood dyslipidemia is similar to that of adults. Statins are the most widely used medications. Newer medications have proven integral in treatment for genetic dyslipidemias including evolocumab and evinacumab.

Effect of bariatric surgery on cardiac function in obese patients: An echocardiographic assessment.

Objectives:To analyze the clinical and echocardiographic changes in individuals with morbid obesity who underwent bariatric surgery.Methods:In total, 59 obese patients with body mass index >35 kg/m 2 were prospectively enrolled. We assessed baseline pre-operative and a 6-month post-operative lipid profile, hemoglobin A1c, echocardiography, lifetime, and a 10-year risks of atherosclerotic disease for all patients.Results:The mean patients’ age was 37±12 years, with 40 (67.8%) women. We found that the pre-operative total cholesterol (4.2±1.1 vs. 4.4±1.1, p=0.014) and triglyceride levels (1.4±0.7 vs. 1.8±0.8, p<0.0001) were significantly lower than post-operative levels, while post-operative high-density lipoprotein levels were significantly higher (1.5±0.5 vs. 1.2±0.3, p<0.0001). The calculated 10-year risk of atherosclerotic cardiovascular disease was significantly lower post-operatively (1.1±1.6% vs. 1.6±1.8%, p<0.0001). Echocardiography follow-up revealed that diastolic dysfunction was more prevalent pre-operatively than that post-operatively (41% vs. 10%, p<0.0001). Post-operative left ventricular (LV) mass was significantly lesser than the pre-operative mass (168±252 g vs. 187±255 g, p=0.019), whereas the post-operative LV diastolic (46.5±7 mm vs. 38.5±18 mm, p=0.002) and systolic dimensions (31±5 mm vs. 25±11 mm, p=0.001) were significantly smaller.Conclusion:Bariatric surgery resulted in a significant amelioration in lipid profile, reduction in LV mass, and LV cavity dimensions.

172-OR: Eligibility and Utilization of SGLT2i and GLP1-RA in T2D by Cardiovascular and Renal Indications

Background: SGLT2i and GLP1-RA improve cardiovascular (CV) and renal outcomes in patients with T2D who are at elevated cardiac or renal risk; however, prescription rates are low despite guidelines recommending their use. We aimed to evaluate the eligibility for and utilization of SGLT2i and GLP-1 in a large health system (HS) . Methods: The electronic health record (EHR) at a quaternary HS in the Northeastern US was queried to identify patients with T2D with CV, renal disease, or at high CV risk based on comorbidities and 10-year atherosclerotic CV disease (ASCVD) risk score. Demographics, medications, comorbidities, indications, and contraindications for SGLT2i and/or GLP1-RA therapy were assessed. Results: The population of individuals with T2D on metformin therapy consists of 122,537 patients: 55% male, 8% Black, 13% non-English speaking. Of patients eligible for SGLT2i, 12% were prescribed an SGLT2i. Of patients eligible for GLP1-RA therapy, 17% were prescribed GLP1-RA. Of patients eligible for either SGLT2i or GLP1-RA therapy not currently receiving either therapy, 41% had 10-year ASCVD risk &amp;gt;10%, 56% had ASCVD, 29% had chronic kidney disease (CKD) , and 18% had heart failure. Conclusion: While advantages of novel therapies have demonstrated benefits, opportunities from provider, patient, and systems to eliminate barriers to uptake and dissemination of therapy to improve outcomes for patients exist. Disclosure A.Blood: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. B.M.Scirica: Consultant; Allergan, Boehringer Ingelheim International GmbH, ESPERION Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Novo Nordisk, Research Support; Better Therapeutics, Eisai Co., Ltd., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc., Stock/Shareholder; Heath At Scale. F.Waterman: Employee; Novo Nordisk. G.Stern: None. D.Zelle: None. L.Chang: Consultant; Alosa Health, Pri-Med LLC, Other Relationship; Applied Therapeutics, Better Therapeutics, Eli Lilly and Company, Fractyl Health, Inc., Sanofi, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk. C.A.Colling: None. D.Gabovitch: None. C.M.Hamersky: Employee; Novo Nordisk. E.Durden: Employee; Novo Nordisk A/S. C.Holt: Employee; Novo Nordisk. J.Noone: Employee; Novo Nordisk. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck &amp; Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. Funding Novo Nordisk

CLINICAL EVENT REDUCTIONS IN HIGH-RISK HYPERTENSION PATIENTS TREATED WITH RENAL DENERVATION: 10-YEAR PROJECTIONS BASED ON 3-YEAR FOLLOW-UP FROM THE GLOBAL SYMPLICITY REGISTRY

Objective: Clinical event rates over 3 years have been published for patients with uncontrolled hypertension treated with radiofrequency renal denervation (RDN) in the Global SYMPLICITY Registry (GSR). We estimated 10-year clinical event reductions following RDN vs. a simulated control group without RDN, for two high-risk subgroups and the full GSR cohort. Design and method: A Markov model was used to compare projected 10-year clinical events [stroke, myocardial infarction (MI), cardiovascular death (CVD), heart failure (HF), all-cause death (ACD), and a composite of major adverse cardiac events (MACE, calculated as sum of stroke, MI, and CVD)] for RDN patients vs. a hypothetical control for the high atherosclerotic vascular disease risk (ASCVD) subgroup (n = 737; 69 ± 8 years), the type-2 diabetes mellitus (T2DM) subgroup (n = 1,007; 64 ± 10 years), and for all GSR patients (n = 2,651; 61 ± 12 years). The simulated control assumed maintenance of baseline office systolic blood pressure (oSBP) over time. The model was calibrated to 3-year stroke and MI events reported in the GSR and used published meta-regression data to calculate risk reduction based on cohort-specific changes in oSBP from baseline. Relative risks (RRs), events avoided, and numbers needed to treat (NNTs) were calculated at 3 and 10 years, along with the ratio of 10- vs. 3-year projected events avoided. Results: 10-year MACE events were 35.8% vs. 48.5% (-12.7%, RR = 0.74) for RDN vs. control for all GSR patients, 37.8% vs. 52.4% (-14.6%, RR = 0.72) for the high ASCVD risk cohort, and 40.5% vs. 54.0% (-13.5%, RR = 0.75) for the T2DM cohort. Across all three cohorts, events avoided were highest for stroke and lowest for MI. 10-year NNTs for MACE were comparable between the three cohorts, estimated between 7 to 8. The ratio of model-projected MACE at 10- vs. 3-years was 5.20, 5.46, and 5.03 for the full GSR, high ASCVD risk, and T2DM cohorts, respectively. Conclusions: Model-based projections based on 3- year events observed in the GSR suggest meaningful event reductions after treatment with radiofrequency RDN at 10 years that might be up to 5-times higher than the projected events avoided at 3 years under the assumption of maintained treatment effect versus baseline.

238-OR: A Single Hypoglycemic Event Causes a Prolonged Immune Response

Hypoglycemia acutely activates the immune system and is associated with an increased risk for atherosclerotic disease. Since atherosclerosis is driven by inflammation, we set out to determine the duration of the pro-inflammatory response to a hypoglycemic event in people with and without diabetes. Adults with type 1 diabetes (n = 47) or insulin-treated type 2 diabetes (n = 15) , and age-matched controls without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic (5.2 ± 0.4 mmol/L) -hypoglycemic (2.8 ± 0.1 mmol/L) glucose clamp. Before, during and up to a week thereafter, blood was drawn to determine circulating immune cell composition and function combined with measurements of and circulating hs-CRP concentrations. At baseline, participants with diabetes had higher counts of produced cytokines and hs-CRP compared to individuals without diabetes (all p &amp;lt; 0.01) . In response to hypoglycemia, absolute numbers of lymphocytes (1.57 ± 0.53 vs. 2.69 ± 0.95·103/µL) and monocytes (0.40 ± 0.14 vs. 0.62 ± 0.22·103/µL) increased acutely and remained elevated for one week in all subgroups (all p &amp;lt; 0.001) . During hypoglycemia, the proportion of pro-inflammatory CD16+-monocytes increased from 26.9 ± 13.3% to 38.1 ± 14.9% and the proportion of phagocytotic CD14+-monocytes decreased from 65.2 ± 14.4% to 54.5 ± 15.9% in all subgroups (all p &amp;lt; 0.01) . Stimulated monocytes released more TNF-α and IL-1β, and less IL-during hypoglycemia. Similarly, hs-CRP concentrations increased from 2.± 3.20 µg/mL to 2.71 ± 3.57 µg/mL 1 day after the clamp (p &amp;lt; 0.001) and remained elevated for one week (p &amp;lt; 0.001) thereafter to similar extent in all subgroups. In conclusion, a single hypoglycemic event induces a prolonged immune response in humans independent of the presence of diabetes. Disclosure C.E.Verhulst: None. J.Van heck: None. T.W.Fabricius: None. R.Stienstra: None. C.Tack: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. B.E.De galan: Research Support; Novo Nordisk. Hypo-resolve consortium: n/a. Funding The Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 777460. The JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, International Diabetes Federation (IDF) , The Leona M. and Harry B. Helmsley Charitable Trust.

Coronary Endothelial Dysfunction in People Living With HIV Is Related to Body Fat Distribution.

People living with HIV (PLWH) on antiretroviral therapy (ART) are at increased risk of atherosclerotic disease. Abnormal adipose distribution is common in PLWH and may contribute to atherosclerosis. Because coronary artery endothelial function (CEF) is impaired in early atherosclerosis, predicts future cardiovascular events, and is reduced in PLWH, we investigated associations between body fat distribution and CEF in PLWH. Prospective cohort study. PLWH on stable ART underwent MRI to quantify CEF, measured as change in coronary cross-sectional area from rest to that during isometric handgrip exercise, an endothelial-dependent stressor. Abdominal visceral and subcutaneous fat area (axial L4 level) and liver fat fraction were quantified using MRI. Linear regression was used to determine associations between CEF and independent variables. Among 84 PLWH (52 ± 11 years; 33% women), mean cross-sectional area change was 0.74 ± 11.7%, indicating impaired CEF. On univariable regression analysis, CEF was inversely related to waist circumference (R = -0.31, P = 0.014), hip circumference (R = -0.27, P = 0.037), and subcutaneous fat area (R = -0.25, P = 0.031). We did not observe significant relationships between CEF and liver fat fraction, waist/hip ratio, or visceral fat area. On multivariable regression adjusted for age, sex, and race, CEF was associated with waist circumference, hip circumference, subcutaneous fat, and liver fat fraction. Waist and hip circumference and subcutaneous fat area are associated with impaired CEF, an established metric of abnormal vascular health in PLWH on stable ART, and may contribute to the increased rate of heart disease in this population.

Cardiac Biomarkers and Risk of Atherosclerotic Cardiovascular Disease in Patients with CKD.

Several cardiac biomarkers of cardiac stress, inflammation, and fibrosis (N-terminal pro brain-type natriuretic peptide [NT-proBNP], high-sensitivity troponin T [hsTnT], growth differentiation factor 15 [GDF-15], and soluble ST2 [sST2]) have been associated with atherosclerotic disease in the general population. We hypothesized that these cardiac biomarkers may also be associated with the atherosclerotic cardiovascular disease in patients with CKD. We analyzed levels of NT-proBNP, hsTnT, GDF-15, and sST2 in a cohort of 2732 participants with mild to moderate CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. Outcomes included incident atherosclerotic disease, defined as the first instance of myocardial infarction, stroke, or peripheral vascular disease. We used Cox proportional hazard models to the test the association of each cardiac biomarker with risk of incident atherosclerotic disease, adjusting for multiple possible confounders. When modeled continuously (per SD increase in the log-transformed biomarker), NT-proBNP, hsTnT, GDF-15, and sST2 were significantly associated with incident atherosclerotic disease after adjustment for multiple potential confounders: (NT-proBNP HR, 1.51; 95% CI, 1.27 to 1.81; hsTnT HR, 1.61; 95% CI, 1.38 to 1.89; GDF-15 HR, 1.44; 95% CI, 1.19 to 1.73; and sST2 HR, 1.19; 95% CI, 1.04 to 1.36). NT-proBNP, hsTnT, GDF-15, and sST2 were significantly associated with incident atherosclerotic cardiovascular disease in patients with CKD. These associations may highlight important mechanisms for the development of atherosclerotic disease in CKD.

A big data-driven eHealth approach to prevent, detect, and reduce atherosclerotic cardiovascular disease burden

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Netherlands Organisation for Scientific Research (NWO) eHealth is a promising tool to support citizens and patients to reduce their risk of future atherosclerotic vascular disease (ASCVD). Currently, many eHealth initiatives are developed, however their use is limited. To improve the adoption of eHealth initiatives, personalization is needed according to preferences and understanding of the individual. Together with stakeholders, we used the design thinking method to create a dream user-scenario for an eHealth solution to improve cardiovascular outcomes. This point-of-view shows the essential concepts of such an eHealth initiative and focuses on scientific solutions and the most important challenges faced during its development. In the user-scenario a federated data infrastructure collects distributed medical and non-medical data from different organizations, while ensuring maximal privacy. This data, that is currently not available, is used in a screening model to identify citizens with an increased risk for ASCVD. Citizens at risk are offered the use of an eCoach, which is connected to a counterfactual prediction model to calculate a residual risk for hypothetical interventions. This risk is visualized in a personalized way to support the shared decision making process of personalized lifestyle and healthcare goals. eHealth modules, integrated in the eCoach, encourages the patient in achieving these goals. Relevant outcomes are monitored and are used to adjust the intensity of the modules and follow-up accordingly. To realize this federated data infrastructure, an ethical and legal framework should be developed to ensue responsible data handling.

The role of ω3-polyunsaturated fatty acids in the prevention of atherogenic cardiovascular diseases starting in childhood

Diseases of the cardiovascular system are one of the main causes of morbidity, disability and mortality. One of the most significant risk factors for their development is atherogenic dyslipidemia. Atherosclerotic vascular damage occurs long before clinical manifestation and often begins to progress as early as childhood. This is why children represent the most important cohort for the prevention of cardiovascular diseases of atherosclerotic genesis. Studies show that taking ₃-polyunsaturated fatty acids reduces the risk of atherosclerotic vascular disease in adults and children. The effect is achieved by multidirectional effects on risk factors such as insulin resistance, obesity, diabetes mellitus, dyslipidaemia, arterial hypertension, inflammation and endothelial dysfunction. In children with primary dyslipidemia (heterozygous familial hypercholesterolemia) taking ₃-polyunsaturated fatty acids leads to normalization of serum triglycerides and a moderate decrease in total cholesterol and low-density lipoprotein cholesterol. The most significant therapeutic and prophylactic effects are observed in patients with secondary dyslipidemias caused by obesity and diabetes mellitus, when, besides the decrease in triglycerides and the increase in HDL cholesterol, ₃-polyunsaturated fatty acids increase the insulin sensitivity of cells and tissue, body weight reduction, increase in muscle mass, stabilization of blood pressure and improvement of liver function are observed. Considering pleiotropic protective effect and good tolerability, ₃-polyunsaturated fatty acids can be widely used for primary and secondary prevention of atherosclerotic cardiovascular diseases in children and adolescents.

A Novel Dual Incretin Agent, Tirzepatide (LY3298176), for the Treatment of Type 2 Diabetes Mellitus and Cardiometabolic Health.

The incretin hormone system is the target of multiple type 2 diabetes mellitus (T2DM) treatments because defects in this system play major roles in the pathogenesis of diabetes. Currently, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with atherosclerotic cardiovascular (CV) disease and those at high risk for atherosclerotic CV disease. In addition to the favorable CV effects, GLP-1 RAs also provide robust lowering of hemoglobin A1c and weight. Although these factors make GLP-1 RAs attractive options for T2DM, the currently available agents have no effect on glucose-dependent insulinotropic polypeptide (GIP). Patients with T2DM are known to have GIP defect which is significant due to its profound insulinotropic effects. Tirzepatide is a novel incretin agent currently recently approved by the Food and Drug Administration for the treatment of T2DM. This first-in-class agent serves as a coagonist for both the GLP-1 and GIP receptors. In this review, we report on the pharmacologic mechanism of GLP-1, GIP, and coagonist effects on the cardiometabolic system. In addition, we review the glycemic lowering, weight loss effects, and other cardiometabolic outcomes of tirzepatide based on phase 2 and 3 data. The safety profile of tirzepatide is consistent across all phase 3 trials. The most common adverse effects are gastrointestinal symptoms, but they generally have a low risk for discontinuation. Overall, preliminary data suggest that tirzepatide is an efficacious and safe agent for the treatment of T2DM.

Abstract 257: Heavy Clot Burden Despite Enoxaparin Therapy In The Setting Of Covid Pneumonia

Case: A 71-year-old male with a past medical history of hypertension, tobacco use, and hyperlipidemia was admitted to the hospital for COVID-19 pneumonia. Initial CT scan was negative for a pulmonary embolism. He was intubated on day 4, and his follow-up CT showed bilateral pulmonary emboli despite prophylactic Enoxaparin 40 mg subcutaneously daily since admission. He was subsequently put on a therapeutic dose of 1mg/kg every 12 hours. The following day he was found to have a pneumothorax that necessitated a chest tube, and that same evening, he developed acute lower limb ischemia in the setting of therapeutic anticoagulation for 24 hours. Arterial doppler ultrasound revealed extensive occlusive thrombus in the major arteries of the left lower extremity. Emergent thromboembolectomy of the left iliac artery, superficial femoral artery, popliteal artery, and tibial artery and a 4-compartment fasciotomy on the lower leg was performed, but 2 days later he necessitated an above knee amputation. Thereafter, the patient’s right lower extremity became cool, but an arterial doppler showed collateral flow suggestive of chronic arterial disease. Discussion: This patient with no known history of prior blood clots or arrhythmias sustained heavy clot burden and limb amputation despite prophylactic and eventual therapeutic anticoagulation and not to mention barotrauma. Notably, his right lower extremity became cool concerning for micro-coagulopathy in the setting of an unremarkable ultrasound. Little guidance is available regarding anticoagulation strategy on individuals with COVID, let alone those at risk of blood clots. The question remains as to whether practitioners need to anti-coagulate all critically ill patients with COVID-19 more aggressively, anti-coagulate individuals at risk for atherosclerotic disease more aggressively, or consider agents such as antiplatelet agents for arterial thrombosis prophylaxis.