Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. In addition to established risk factors such as hypertension, dyslipidemia and smoking, genetic variations may modulate individual susceptibility to CVD. The rs66698963 insertion–deletion (indel) polymorphism in the fatty‑acid desaturase (FADS) gene cluster increases fatty‑acid desaturase 1 activity and elevates circulating arachidonic acid (AA) relative to eicosapentaenoic acid (EPA). We hypothesize that carriers of the rs66698963 insertion allele develop a pro‑inflammatory AA‑dominant lipid profile that predisposes them to a greater risk of CVD. This article summarizes existing evidence linking FADS genetics, the AA/EPA ratio and inflammation and proposes observational and intervention studies to test this hypothesis. If confirmed, genotype‑based screening and targeted dietary or pharmacologic interventions could advance precision cardiovascular medicine.

Cardiovascular disease (CVD) morbidity and mortality are increasing globally, including among patients living with human immunodeficiency virus (HIV). We aimed to determine the risk of all-cause mortality and morbidity in patients with CVD, comparing those with and without HIV infection, and whether mortality differed by HIV status during hospitalization for Major Adverse Cardiovascular Events (MACE) components (stroke, acute myocardial infarction (AMI), and heart failure) in northern Uganda. We conducted a retrospective cohort study at two hospitals in northern Uganda, comparing outcomes in CVD patients with and without HIV hospitalized from January 2015 to June 2023. We utilized a logistic regression model for crude, adjusted, and stratified analyses of MACE components and mortality by HIV status. Among 2,127 CVD patient records analyzed, 292 (13.7

INTRODUCTION:We have previously shown an association between metabolic syndrome (MS) and heart failure (HF) outcomes in patients with implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy with defibrillator (CRT-D). However, the role of MS in predicting outcomes was not assessed in non-obese patients. We aimed to examine how the presence of MS and its components predicts the risk of HF/death in non-obese ICD or CRT-D patients. METHODS:We included obese and non-obese patients, enrolled in Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Patients needed at least 2 of the 3 criteria, dyslipidaemia, diabetes, or hypertension, to be considered for having MS. Kaplan-Meier analyses were used to assess the rate of HF/death by MS. Multivariate Cox-proportional analyses were performed to assess the risk of HF/death by MS. RESULTS:From 1180 (65%) non-obese patients in MADIT-CRT, 672 (57%) presented with MS. Among non-obese patients with MS, 284 (42%) had diabetes mellitus. Non-obese MS patients had a significantly higher, 34% cumulative probability of HF/death at 3 years, as compared to the 20% of non-obese patients without MS (log-rank P < .001) (hazard ratio: 1.64, 95% CI: 1.15-2.32, P & .006). Within non-obese MS patients, those with diabetes had a significantly higher rate of HF/death with 28% vs. 20% in non-diabetics at 2.5 years (log-rank P < .001). Reverse remodelling was similar in all subgroups. CONCLUSION:MS in non-obese ICD or CRT-D patients is associated with a higher risk of HF/Death, most prominent in those with diabetes, necessitating early intervention.

BACKGROUND:Familial hypercholesterolemia (FH) is a genetic condition that significantly increases the risk of coronary artery disease if left unmanaged. Although FH remains underdiagnosed globally, early detection enables timely therapy and reduces cardiovascular risk. Traditional FH criteria, such as the Dutch Lipid Clinic Network and Simon Broome diagnostic criteria, rely on clinical data often missing in real-world practice. Artificial intelligence (AI) offers potential to improve FH case identification. OBJECTIVE:To review recent advances in simplified FH screening criteria, summarize applications of AI models in FH detection, compare model performance, and evaluate limitations and advantages. METHODS:A literature search was conducted to identify peer-reviewed studies on AI in FH screening, diagnosis, or management. The search used Medical Subject Headings and free-text terms for FH and AI technologies. Titles and abstracts were reviewed, and full texts were assessed if potentially eligible. RESULTS:Machine learning models generally outperform simplified criteria. Logistic regression models remain the most commonly used and are valued for interpretability. Performance comparisons between models are limited by differences in cohort characteristics. Predictive variables commonly used by models include established examples such as family history, lipid profiles, demographics, and prescription records. CONCLUSION:AI models that leverage electronic health record (EHR) data can outperform traditional criteria, uncover missed cases, and complement cascade screening. Challenges include external validation, workflow integration, and model transparency. To ensure clinical utility, further work is needed to standardize comparison metrics, broaden applicability, increase interpretability, and address EHR integration complexities.

Lipoprotein(a) [Lp(a)], an atherogenic low-density lipoprotein cholesterol (LDL-C)-like molecule, has emerged as an important risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). This review summarizes the evidence supporting Lp(a) as a causal risk factor for ASCVD and calcific aortic valve stenosis (CAVS). Lp(a) is largely ( 90

Numerous studies have established lipoprotein(a) [Lp(a)] as an independent and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). As such Lp(a) has become the focus of targeted drug therapy development with the goal of reducing Lp(a) serum concentrations and improving outcomes. This review aims to inform readers on the investigational agents currently in clinical trials and highlight key differences including dosing intervals and routes of administration that may facilitate uptake and retention of a particular potential medication in certain patient populations. Five investigational agents are currently undergoing various stages of clinical trials for the treatment of elevated Lp(a). Three potential therapies are small interfering RNA (siRNA) molecules and a fourth is an antisense oligonucleotide (ASO) all of which are subcutaneously injected. A fifth agent is a small molecule inhibitor that is orally administered. A sixth agent, a cholesteryl ester transfer protein (CETP) inhibitor that is primarily being studied for LDL-C reduction has shown promise for reducing Lp(a). A seventh agent based on gene-editing is currently in the developmental stage. Results have revealed notable reductions in Lp(a) with favorable tolerability and safety. Phase 3 trials will be crucial in determining the viability of lowering Lp(a) with such therapies and improving cardiovascular outcomes. Promising results indicate the potential in the near future to have medications primarily for lowering Lp(a) which has thus far eluded targeted drug therapy. As such advances stand to benefit large segments of the population living with and at risk for ASCVD, future research is vital to validate safety and efficacy in the long-term as well to understand how to optimize uptake and retention among patients with diverse circumstances.

Lipoprotein apheresis is used as a treatment to lower levels of low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia when LDL-C is not adequately controlled on maximally tolerated medications. Although it raises circulating levels of bradykinin, it is generally well tolerated and systemic reactions to lipoprotein apheresis are rare. Icatibant treats bradykinin-induced angioedema. We describe the first documented case of angioedema-like systemic reactions occurring post COVID-19 in a patient who previously tolerated lipoprotein apheresis and the prevention of such reactions with icatibant. Knowledge of successful treatment of severe bradykinin-induced reactions to lipoprotein apheresis with icatibant may help other patients with such reactions.

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INTRODUCTION:Electrocardiographic (ECG) changes in heart failure with reduced, mildly reduced, and preserved ejection fractions can be critical in clinical assessment while waiting to perform echocardiograms or when it is unavailable. This integrative review aimed to identify ECG characteristics among hospitalized patients demonstrating three types of heart failure during acute decompensation.METHODS:We searched an electronic database of PubMed, Web of Science, EMBASE, Scopus, Google Scholar, and ClinicalTrials.gov using medical subject headings (MeSH) terms and keywords. Sixteen studies were synthesized and reported.RESULTS:Heart failure with reduced ejection fraction (HFrEF) was more common in men, comorbid with coronary artery diseases and diabetes mellitus, higher BNP/Pro-BNP, wide QRS, and left bundle branch block on ECG. On average, clients with heart failure with preserved ejection fraction (HFpEF) were older and more likely to have a history of atrial fibrillation, valvular heart diseases, hypertension, chronic obstructive pulmonary, and atrial fibrillation (AF) on ECG. Patients with mildly reduced (HFmrEF) were more similar to HFpEF in older patients, comorbid with hypertension, AF and valvular diseases, and AF on ECG.CONCLUSIONS:ECG characteristics might be related to left ventricular ejection fraction. Demographics, BNP/Pro-BNP, and ECG changes might help differentiate different heart failure types. Therefore, ECG might be a prognostic tool while caring for heart failure patients when highly skilled resources are unavailable. These identified ECG characteristics help generate research hypotheses and warrant validation in future research.

Objective Most older adults in the United States (U.S.) prefer to remain in their current housing as they age, but difficulty with mobility (e.g., walking) may make this more challenging. We estimated the association between difficulty with mobility (mobility) and residential relocation in the following year.Methods We included adults aged >= 65 participating in >= 2 rounds (years 2011-2019) of the National Health and Aging Trends Study. Mobility was self-reported and change in permanent address was captured by study staff. We used a prospective cohort design and logistic regression with a clustering correction to estimate adjusted associations.Results We did not find evidence that mobility was associated with relocation versus no relocation in our sample of 26,444 observations from 5699 older adults. However, mobility was positively associated with moves to housing with fewer environmental barriers.Discussion Mobility is associated with relocation to housing that is more accessible and may be an indicator of greater need for supports to age in place.

Background: We have shown that ω3 polyunsaturated fatty acids (PUFAs) reduce risk for heart failure, regardless of ejection fraction status. Ventricular remodeling and reduced ventricular performance precede overt hear failure, however there is little insight into how PUFAs contribute to maladaptive signaling over time. PUFAs are agonists for regulatory activity at g-protein coupled receptors such as Ffar4, and downstream as substrates for monooxygenases (e.g lipoxygenase, cytochrome p450, or cyclooxygenase (COX)) which mediate intracellular adaptive signaling. Methods: Plasma phospholipid PUFA abundance at Exam 1 as mass percent EPA, DHA, and arachidonic acid (AA) from the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using pathway modeling to determine the association with time-dependent changes in left ventricular (LV) mass (LVM), end-diastolic LV volume (EDV), and end-systolic volume (ESV) measured by cardiac MRI at Exams 1 and 5. Ejection fraction (EF) and mass:volume (MV) were calculated posteriorly from the first three. Results: 2,877 subjects had available MRI data. Participants with low AA and EPA had accelerated age-dependent declines in LVM. Males with low AA and EPA also had accelerated declines in EDV, but among females there was no PUFA association with EDV declines and exam 5 EDV status was positively associated with AA. Both sexes had nearly the same positive association of AA with changes in ESV. Conclusion: Plasma phospholipid AA and EPA are prospectively associated with indices of heart remodeling, including ventricular remodeling and performance. Combined AA and EPA scarcity was associated with the most accelerated age-related changes and exam 5 status, while the greatest benefits were found among participants with both PUFAs. This suggests that both PUFAs are required for optimal slowing of age-related declines in ventricular function.

Background/Synopsis Limited data exist regarding familial hypercholesterolemia (FH) diagnosis and treatment in diverse populations. Objective/Purpose We sought to assess patient characteristics and current treatment patterns among individuals with FH and/or elevated low-density lipoprotein cholesterol (LDL-C) in a diverse real-world cohort within the United States. Methods We examined data from the NIH Precision Medicine Initiative All of Us Research Program, a cross-sectional study beginning in 2015 inclusive of historically underrepresented groups. Among participants with >1 LDL-C measurement, we examined lipid-lowering medication utilization and treatment patterns among participants with and without FH diagnosis stratified by LDL-C. We additionally examined whether sex differences existed in treatment and diagnosis. Results Among 369,483 All of Us participants age ≥18 years, our study sample included 113,153 individuals who had at least one LDL-C measurement. Of these, 4018 (3.5%) had LDL-C ≥160 mg/dL, 733 (0.26%) had LDL-C ≥190 mg/dL, and 434 were diagnosed with FH (0.37%). Statin usage was found to be higher among men compared to women both in those with FH (84% vs. 70.3%, p=0.002) and without FH (54.2% vs. 39.2%, p<0.001) irrespective of LDL-C measures. Women tended to have higher mean LDL-C levels compared to men (130.9 mg/dL vs. 105.8 mg/dL, p<0.001 in those with FH and 106.9 mg/dL vs. 98.8 mg/dL p<0.001 in those without FH). Participants with FH were also more likely to be on statin therapy (75.2% vs 44.8%, p-value <0.001) with 18.4% on two or more types of lipid-lowering agents. Despite this, a higher percentage of FH participants had a history of >1 major ASCVD event (19.4% vs 10.7%, p-value <0.001), and exhibited higher mean LDL-C levels (121.9 mg/dL vs 103.9 mg/dL) compared to non-FH participants. Notably, only 30.5% of FH participants achieved the recommended LDL-C<100 mg/dL compared to 45.7% of those without FH (p-value<0.001). Furthermore, a majority (60.6%) of those already diagnosed with FH had LDL-C <130 mg/dL, including those not taking a lipid-lowering drug (Figure 1), questioning whether FH is being incorrectly diagnosed in some patients. Conclusions This study highlights the under and possible inappropriate diagnosis of FH and inadequate treatment of those diagnosed with FH among a real-world population.

Study Funding The STOP-ADENOMA project (NIHR128210) was funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. MAH is a NIHR Senior Investigator. Mark Hull is supported by Cancer Research UK grant C23434/A24939. Background/Synopsis We report that a functional FADS2 indel polymorphism (rs66698963) stratifies participants that gain colorectal polyp prevention benefit from the n-3 PUFA EPA. This gene x treatment interaction was specific for EPA as opposed to aspirin, compatible with current understanding of the mechanism of action of both agents whereby EPA competes with arachidonic acid (AA) as a substrate for COX-dependent PGE2, whereas aspirin inhibits COX-dependent synthesis of PGE2 from AA. Objective/Purpose A 22 base-pair insertion-deletion (Indel) polymorphism (rs66698963) in fatty acid desaturase 2 (FADS2) controls FADS1-dependent synthesis of the n-6 highly unsaturated fatty acid (HUFA-AA), which drives tumorigenesis and antagonized by the n-3 HUFA eicosapentaenoic acid (EPA). We tested the hypothesis that the FADS2 Indel “I” allele predicts colorectal polyp prevention efficacy of EPA in the seAFOod trial based on current understanding that EPA competes with elevated bioavailability of AA in “I” allele carriers. Methods The seAFOod trial was a multicenter, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial, of patients aged 55-73 years who were identified during colonoscopy as being at high risk in the English Bowel Cancer Screening Programme (BCSP; ≥3 adenomas if at least one was ≥10 mm in diameter or ≥5 adenomas if these were <10 mm in diameter). Patients were randomly allocated to receive 2 g/d of EPA-free fatty acid (FFA - either as the FFA or triglyceride), 300 mg aspirin per day, both treatments in combination, or placebo for 12 months. Research staff and participants were masked to group assignment. The primary endpoint was the adenoma detection rate at 1 year surveillance colonoscopy analyzed in all participants with observable follow-up data using a so-called at-the-margins approach, adjusted for BCSP site and repeat endoscopy at baseline. Results In a secondary analysis of the 2 × 2 factorial seAFOod polyp prevention trial of EPA and aspirin, EPA allocation, irrespective of FADS2 Indel genotype, had a null effect on colorectal polyp risk (incidence rate ratio [IRR] 0.92, 95% confidence interval 0.74, 1.16) mirroring the original seAFOod trial analysis. However, presence of the rs66698963 insertion [I] allele identified individuals with an elevated red blood cell AA/linoleic acid (LA) ratio, for whom treatment with EPA 2 g daily significantly reduced colorectal polyp number (IRR 0.50 [0.28, 0.90]). Aspirin effect had no such relationship with the allele. Conclusions Further evaluation of a precision medicine approach to cancer and cardiovascular disease prevention by n-3 HUFAs based on FADS2 Indel rs66698963 genotype is warranted.

Study Funding Kaneka Pharma America: “Lipoprotein(a) Testing at URMC and Referral to Preventive Cardiology Program". Background/Synopsis Lipoprotein(a) (Lp(a)) is a cholesterol-containing, genetically determined molecule in our blood. Studies show that an elevated level of Lp(a) can independently predict an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. There are currently no FDA-approved drugs to reduce Lp(a) and cardiovascular disease event risk. Objective/Purpose Using the electronic health record (EHR) from the University of Rochester Medical Center (URMC), we determined how well Lp(a) levels predict future cardiovascular disease events currently and over time. Methods Data were collected from the URMC EHR database of patients >= 18 years with and without at least one Lp(a) measurement from January 1st, 2011 to August 1st 2023 . Cox regression analysis was performed to investigate the effect of Lp(a) level on ASCVD events, while adjusting for several demographic factors and previous ASCVD event status. The Lp(a) level was dichotomized into a normal-level group (<=30 mg/dL) and a high-level group (>30 mg/dL). Results From January 1st, 2011 to August 1st, 2023, we identified 2,698 patients with at least one Lp(a). Among these individuals, 1,594 did not have an ASCVD event after a baseline Lp(a), while 611 individuals did have an ASCVD event after an Lp(a) baseline measurement. The remaining individuals did not have data on ASCVD status. The mean Lp(a) level was 48 mg/dL among all patients, 45.2 mg/dL among patients without an ASCVD event, and 55.2 mg/dL among patients with an ASCVD event. The normal Lp(a) level range in the URMC lab is <30 mg/dL. Among patients without ASCVD history at baseline, the hazard of an ASCVD event in the high Lp(a) level group is 1.44 times the hazard for the normal Lp(a) level group, with a p-value of 0.008. For patients with a previous ASCVD event, the hazard of an ASCVD event in the high Lp(a) level group is 0.87 times the hazard for the normal Lp(a) level group but not at a statistically significant level (p-value = 0.206). Conclusions The level of Lp(a) has a varied effect on the hazard of a future ASCVD event. While high Lp(a) level increased the hazard of future ASCVD event for patients with no ASCVD history, high Lp(a) level does not significantly affect the hazard of future ASCVD event for patients with an ASCVD history. It is vital to measure Lp(a) levels to make active steps toward prevention of ASCVD events in the future.

BACKGROUND:A fatty acid desaturase (FADS) insertion-deletion (Indel) polymorphism (rs66698963) influences the expression of FADS1, which controls the synthesis of n-6 highly unsaturated fatty acid (HUFA) arachidonic acid (AA). The anti-inflammatory activity of the n-3 HUFA eicosapentaenoic acid (EPA) may be explained by competition with AA for proinflammatory lipid mediator synthesis. A precision medicine approach based on stratification by FADS Indel genotype could identify individuals, who benefit from greatest disease risk reduction by n-3 HUFAs. OBJECTIVES:We tested the hypothesis that the FADS insertion (I) allele predicts colorectal polyp risk reduction in a secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2000 mg daily and aspirin 300 mg daily for 12 mo (ISRCTN05926847). METHODS:Participant Indel genotype was determined by polymerase chain reaction (PCR) blind to trial outcomes. Colorectal polyp outcomes were included in negative binomial (polyp number) and logistic (polyp detection rate [PDR; percentage with one or more polyps]) regression models comparing each active intervention with its placebo. Presence of ≥1 Indel I allele and an interaction term (I allele × active intervention) were covariates. RESULTS:In 528 participants with colonoscopy and FADS Indel data, EPA use irrespective of Indel genotype, was not associated with reduced colorectal polyp number (incidence rate ratio [IRR]: 0.92; 95% confidence interval: 0.74, 1.16), mirroring original seAFOod trial analysis. However, the presence of ≥1 I allele identified EPA users with a significant reduction in colorectal polyp number (IRR: 0.50 [0.28, 0.90]), unlike aspirin, for which there was no interaction. Similar findings were obtained for the PDR. CONCLUSIONS:The FADS Indel I allele identified individuals, who displayed colorectal polyp prevention by EPA with a similar effect size to aspirin. Assessment of rs66698963 as a biomarker of therapeutic response to n-3 HUFAs in other populations and healthcare settings is warranted. The seAFOod polyp prevention trial and STOP-ADENOMA study were registered at International Standard Randomised Controlled Trial Number registry as ISRCTN05926847.

BACKGROUND:Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States. Case-based learning using electronic delivery of the modules can educate clinicians and improve translation of evidence-based guidelines into practice for high-risk ASCVD patients.OBJECTIVE:To develop and optimize module design, content, and usability of e-learning modules to teach clinicians evidence-based management in accordance with multi-society guidelines for high-risk ASCVD patients that will be implemented and evaluated in U.S. health systems in the TEACH-ASCVD study.METHODS:Seven e-learning modules were created by a committee of lipid experts. Focus groups were conducted with lipid experts to elicit feedback on case content followed by interviews with a target audience of clinicians to assess usability of the online module platform. Responses from both groups were evaluated, and appropriate changes were made to improve the e-learning modules. Design of the TEACH-ASCVD study is presented.RESULTS:Feedback regarding case content by lipid experts included providing more detailed patient histories, clarifying various diagnostic criteria, and emphasizing clinical best practices based on evidence-based guidelines. The target audience clinician group reported an agreeable experience with the e-learning modules but noted a discordance between the evidence-based guidelines and clinical decision-making in their own practices. Participants felt the modules would help educate clinicians in managing high-risk ASCVD patients.CONCLUSION:Clinicians must be informed of best practices as the field of lipidology continues to evolve. E-learning modules provide a concise, valuable, and accessible mechanism for educating clinicians regarding changes in the field to deliver the best patient care.

Individuals with low-density lipoprotein cholesterol ≥190 mg/dL are at high risk for atherosclerotic cardiovascular disease events. Our goal was to determine if adults with this condition would express important psychological, health, and motivation themes when generating lyrics during music therapy. Thirty-one participants each created their own original song with the help of a music therapist. The lyrics were analyzed using a deductive approach guided by Self-Determination Theory (specifically the satisfaction or frustration of basic psychological needs): (1) for each entire song (macro-analysis) and (2) line-by-line (micro-analysis). Song lyrics generated during music therapy sessions by patients with a low-density lipoprotein cholesterol ≥190 mg/dL revealed the presence of the three basic needs (autonomy, competence, and relatedness) of Self-Determination Theory. The most prevalent theme identified in the macro-analysis of songs was autonomy satisfaction, coded in 25 songs (27.17% of all macro codes), and followed by competence satisfaction in 17 songs (18.48%) and relatedness satisfaction in 15 songs (16.3%). Line-by-line micro-analysis of lyrics revealed that at least one basic need of Self-Determination Theory was present in 277 of the unique lyric lines (50%); 107 (19%) for relatedness, 101 (18%) for autonomy, and 69 (13%) for competence. Need satisfaction occurred more frequently than need frustration in both analyses. However, depending on the level of analysis (macro or micro), results differed as to which themes were most prevalent. These results indicate that therapeutic songwriting may be a unique way to identify the basic psychological needs that, when satisfied, indicate self-determination.

Structured Abstract Background Sedentary behavior is associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. Little is known about this relationship in an ethnically diverse population. The objective of our study is to assess the effects of leisure time and occupational sedentary behavior on multiple cardiovascular outcomes in a multi-ethnic cohort. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) includes 2619 Caucasian, 1495 Hispanic, 1891 Black, and 804 Chinese-American adults aged 45-84 years and free of clinical CVD at enrollment, Sedentary behavior was self-reported at baseline. Participants were followed for an average of 13.6 years, and 14 types of cardiovascular outcomes were ascertained. Hazards of each cardiovascular outcome were modeled with adjustment for potential confounders, including physical activity. Results Every one hour per day increase in leisure time sedentary behavior predicts a 6% increase in the adjusted hazards for CVD death ( P < 0.05). Every one hour increase in occupational sedentary time predicts a 21% and 20% decrease in the hazard for PVD and other revascularization, respectively ( P < 0.05). Conclusions Leisure time sedentary behavior was associated with increased hazards for CVD death, but occupational sedentary time appears to be protective of peripheral vascular disease and other revascularization. Condensed Abstract Sedentary behavior has been consistently associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. The Multi-Ethnic Study of Atherosclerosis (MESA) consists of a racially and ethnically diverse cohort of adults age 45-84, free from CVD at baseline. Greater levels of leisure time sedentary behavior predicted increased hazards for PVD and CVD death after an average follow up of 13.6 years whereas occupational sedentary behaviors predicted reduced PVD. These results underscore the importance of reducing time spent sitting in addition to advocating for meeting physical activity targets across ethnicities.

Complications with atherosclerosis can often lead to fatal clot formation and blood vessel occlusion - also known as atherothrombosis. A key component to the development of atherosclerosis and atherothrombosis is the endothelium and its ability to regulate the balance between prothrombotic and antithrombotic activities. Endothelial surface glycocalyx has a critical role in maintenance of vascular integrity. The endothelial glycocalyx, nitric oxide, prostacyclins, heparan sulfate, thrombomodulin, and tissue factor pathway inhibitor all prevent thrombosis, while P-selectin, among many other factors, favors thrombosis. However, endothelial dysfunction gives rise to the acceleration of thrombotic development and eventually the requirement of antithrombotic therapy. Most FDA-approved anticoagulant and antiplatelet therapies today carry a side effect profile of major bleed. Within the past five years, several preclinical studies using different endothelial targets and nanotechnology as a drug delivery method have emerged to target the endothelium and to enhance current antithrombosis without increasing bleed risk. While clinical studies are required, this review illustrates the proof-of-concept of nanotechnology in promoting a greater safety and efficacy profile through multiple in vitro and in vivo studies.

Background The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain.Methods Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures.Findings Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% con-fidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding.Interpretation The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease.Copyright (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).