Polycystic ovary syndrome: A review of diagnosis and management, with special focus on atherosclerotic cardiovascular disease prevention.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy worldwide with a heterogeneous clinical presentation including reproductive, metabolic, and endocrine elements. However, the assessment and management of PCOS remains inconsistent, with many women undiagnosed and untreated. We now also understand that the management of PCOS should extend throughout a woman's lifespan as many elements of the syndrome persist after menopause. Management has traditionally focused on the treatment of hyperandrogenism and oligomenorrhea. Women with PCOS often have dyslipidemia, hypertension, obesity, and metabolic syndrome, which may be worsened by the hormonal abnormalities, and are therefore at higher risk for cardiovascular disease morbidity and mortality, a risk that increases after menopause. While treatment with hormonal therapy, in particular combined oral contraceptives, may improve cardiovascular risk factors, management plans should incorporate specific diagnosis and management of these factors, if present, because of the strong contribution to the risk for atherosclerotic cardiovascular disease. Given the complexities of the syndrome, optimal management often requires a multi-disciplinary approach including the lipid and cardiometabolic specialist to provide counseling and support for lifestyle modification along with pharmacologic therapy as indicated to address the full range of any reproductive, endocrine, and cardiometabolic abnormalities.

Fatty acid desaturase insertion-deletion polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid eicosapentaenoic acid: a secondary analysis of the seAFOod polyp prevention trial.

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.

The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

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% confidence 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. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Aspirin and omega-3 polyunsaturated fatty acid use and their interaction in cardiovascular diseases and colorectal adenomas.

Aspirin (acetylsalicylic acid, ASA) is inexpensive and is established in preventing cardiovascular disease (CVD) and colorectal adenomas. Omega-3 (n3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have also shown benefit in preventing CVD. The combination could be an effective preventative measure in patients with such diseases. ASA and n3 PUFA reduced the risk of CVD in ASA-resistant or diabetic patients. EPA- and DHA-deficient patients also benefited the most from n3 PUFA supplementation. Synergistic effects between ASA and EPA and DHA are 'V-shaped' such that optimal ASA efficacy is dependent on EPA and DHA concentrations in blood. In colorectal adenomas, ASA (300 mg/d) and EPA reduced adenoma burden in a location- and subtype-specific manner. Low doses of ASA (75-100 mg/d) were used in CVD prevention; however, ultra-low doses (30 mg/d) can also reduce thrombosis. EPA-to-DHA ratio is also important with regard to efficacy. DHA is more effective in reducing blood pressure and modulating systemic inflammation; however, high-dose EPA can lower CVD events in high-risk individuals. Although current literature has yet to examine ASA and DHA in preventing CVD, such combination warrants further investigation. To increase adherence to ASA and n3 PUFA supplementation, combination dosage form may be required to improve outcomes.

Awareness, diagnosis and treatment of heterozygous familial hypercholesterolemia (HeFH) - Results of a US national survey.

BACKGROUND: HeFH is a common inherited disorder that leads to markedly elevated LDL-cholesterol from birth and premature cardiovascular disease. HeFH is frequently underdiagnosed and undertreated. OBJECTIVE: To compare how well primary care physicians and cardiologists recognize and treat HeFH. METHODS: The National Lipid Association surveyed 500 primary care physicians and 500 cardiologists in the US who have patients with baseline LDL-cholesterol ≥ 190 mg/dL. The survey was conducted between August 29 and September 30, 2019. RESULTS: For a hypothetical case of HeFH, 57% of cardiologists versus 43% of primary care physicians made the correct diagnosis (P<0.001). Among respondents, 21% of cardiologists versus 29% of primary care physicians have never made a diagnosis of HeFH in a patient with an LDL-cholesterol ≥ 190 mg/dL (P<0.004). Only 7% of cardiologists versus 5% of primary care physicians would refer to a lipid specialist (P=0.05). For additional LDL-cholesterol lowering after statins, 58% of cardiologists versus 48% of primary care physicians would prescribe a PCSK9 inhibitor (P=0.004); however, 30% of cardiologists versus 53% of primary care physicians have never prescribed a PSCK9 inhibitor in an HeFH patient (P<0.001). CONCLUSION: Although cardiologists compared to primary care physicians are somewhat more likely to recognize and treat HeFH patients according to guidelines, both physician specialties do not adequately recognize or treat HeFH. There is a need for more education and training in recognizing and treating HeFH, greater access to lipid specialists, and fewer barriers for PCSK9 inhibitor use.

Perceptions and Barriers on the Use of Proprotein Subtilisin/Kexin Type 9 Inhibitors in Heterozygous Familial Hypercholesterolemia (From a Survey of Primary Care Physicians and Cardiologists).

Heterozygous familial hypercholesterolemia (HeFH) results in significant elevations in LDL-C and premature atherosclerotic cardiovascular disease (ASCVD). Current guidelines recommend add-on proprotein subtilisin/kexin type 9 inhibitor (PCSK9i) therapy for additional LDL-C lowering beyond statins. Data are sparse, however, regarding treatment patterns and barriers relating to PCSK9i in HeFH patients. We examined physician attitudes, use, and barriers for treatment in patients with HeFH. We surveyed 1,000 physicians (500 primary care providers [PCPs] and 500 cardiologists in the US regarding their preferred treatments, experience and barriers associated with using PCSK9is. Cardiologists compared to PCPs were more likely to rank a PCSK9i as most important for an HeFH patient needing additional LDL-C lowering (68.6% vs. 64.8%; p <0.05), as well as prescribing and having a patient on a PCSK9i. PCPs vs. cardiologists were less likely (odds ratio [OR] [95% confidence interval] = 0.46 [0.34-0.63]), private vs. academic practice more likely (OR = 1.53 [1.02-2.28]), and those who would prescribe a PCSK9i in an HeFH patient with (OR = 3.86 [2.57-5.78]) or without (OR = 1.96 [1.40-2.72]) ASCVD needing additional LDL-C reduction beyond a statin were more likely to actually prescribe a PCSK9i. Those practicing in an urban vs. rural setting were less likely (OR = 0.56 [0.34-0.93]), and those indicating they would prescribe a PCKS9i in an HeFH patient with (OR = 2.80 [1.74-4.49]) or without (OR = 1.43 [1.02-2.02]) ASCVD needing additional LDL-C lowering beyond a statin were more likely to face difficulty prescribing a PCSK9i (all p <0.05 to p <0.01). Greater physician education and assistance among both cardiologists and PCPs are needed to address the gaps in understanding and treatment regarding PCSK9is.

Predicting Risk for Incident Heart Failure With Omega-3 Fatty Acids: From MESA.

OBJECTIVES: The aim of this study was to determine if plasma eicosapentaenoic acid (EPA) abundance (%EPA) is associated with reduced hazard for primary heart failure (HF) events in the MESA (Multi-Ethnic Study of Atherosclerosis) trial. BACKGROUND: Clinical trials suggest that omega-3 polyunsaturated fatty acids (ω3 PUFAs) prevent sudden death in coronary heart disease and HF, but this is controversial. In mice, the authors demonstrated that the ω3 PUFA EPA prevents contractile dysfunction and fibrosis in an HF model, but whether this extends to humans is unclear. METHODS: In the MESA cohort, the authors tested if plasma phospholipid EPA predicts primary HF incidence, including HF with reduced ejection fraction (EF) (EF <45%) and HF with preserved EF (EF ≥45%) using Cox proportional hazards modeling. RESULTS: A total of 6,562 participants 45 to 84 years of age had EPA measured at baseline (1,794 black, 794 Chinese, 1,442 Hispanic, and 2,532 white; 52% women). Over a median follow-up period of 13.0 years, 292 HF events occurred: 128 HF with reduced EF, 110 HF with preserved EF, and 54 with unknown EF status. %EPA in HF-free participants was 0.76% (0.75% to 0.77%) but was lower in participants with HF at 0.69% (0.64% to 0.74%) (p = 0.005). Log %EPA was associated with lower HF incidence (hazard ratio: 0.73 [95% confidence interval: 0.60 to 0.91] per log-unit difference in %EPA; p = 0.001). Adjusting for age, sex, race, body mass index, smoking, diabetes mellitus, blood pressure, lipids and lipid-lowering drugs, albuminuria, and the lead fatty acid for each cluster did not change this relationship. Sensitivity analyses showed no dependence on HF type. CONCLUSIONS: Higher plasma EPA was significantly associated with reduced risk for HF, with both reduced and preserved EF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

Glycerol derived process contaminants in refined coconut oil induce cholesterol synthesis in HepG2 cells.

Despite its 50-year history, the conventional diet-heart hypothesis holding that dietary saturated fats raise serum cholesterol, and with it, cardiovascular risk, remains controversial. Harsh chemical and physical treatment generates process contaminants, and refined oils raise serum and tissue cholesterol in vivo independent of saturated fat content. We developed an in vitro bioassay for rapidly assessing the influence of oils on cholesterol metabolism in the human liver HepG2 cell line, and tested it using coconut oil (CO) of various stages of refinement. CO was dissolved with dipalmitoyl phosphatidylcholine (DPPC) surfactant, solvent evaporated, and emulsified into fat-free cell culture media. After 24 h treatment cellular cholesterol and triacylglycerol increased; HMG-CoA Reductase (HMGCR) increased and CYP7A1 (cholesterol 7α-hydroxylase) decreased with sequential processing steps, deacidification, bleaching, deodorization, while fatty acid profiles were not affected. Glycerol-derived process contaminants glycidyl esters and monochloropropandiol (MCPD) increased with processing. Addition of glycidyl or MCPD to virgin CO (VCO) had similar effects to processing, while addition of phenolic antioxidants to fully refined CO reduced HMGCR and increased CYP7A1. We conclude that harsh processing creates contaminants that raise cholesterol levels in vitro, consistent with a role as a contributing atherosclerotic factor.

Immediate and Sustained Decrease in Smoking Urges After Acute Insular Cortex Damage.

INTRODUCTION: Smoking urges are fundamental aspects of nicotine dependence that contribute significantly to drug use and postquit relapse. Recent evidence has indicated that damage to the insular cortex disrupts smoking behaviors and claims to reduce urges associated with nicotine use, although tools that assess urge have yet to be used to validate these findings. We examined the effect of insular versus non-insular damage on urge using a well-accepted urge scale. METHODS: This 3-month observational prospective cohort study consisted of 156 current smokers hospitalized for acute ischemic stroke (38 with insular infarctions, 118 with non-insular infarctions). During hospitalization, the Questionnaire of Smoking Urges (QSU)-brief was assessed retrospectively based on experiences before the stroke (baseline, T0), prospectively immediately following the stroke (T1) and once more via telephone at 3-month follow-up (T2), with higher scores indicating greater urge. Bivariate statistics and multivariable linear regression were used to evaluate differences in QSU-brief scores, relative to baseline, between exposure groups, controlling for age, baseline dependence, stroke severity, use of nicotine replacement, and damage to other mesocorticolimbic regions. RESULTS: A greater reduction in QSU-brief score was seen in the insular group compared to the non-insular group from T0 to T1 (covariate-adjusted difference in means of -1.15, 95% CI: -1.85, -0.44) and similarly from T0 to T2 (covariate-adjusted difference in means of -0.93, 95% CI: -1.79, -0.07). CONCLUSIONS: These findings confirm the potential role of the insula in regulating nicotine-induced urges and support the growing evidence of its novelty as a key target for smoking cessation interventions. IMPLICATIONS: Human lesioning studies that evaluate the insula's involvement in maintaining nicotine addiction make inferences of the insula's role in decreasing urge, but do not use validated instruments that directly assess urges. This study corroborates prior findings using the continuous Questionnaire of Smoking Urges to quantify changes in urge from before lesion onset to immediate and 3-month follow-up time points.

Nausea and disturbed sleep as predictors of cancer-related fatigue in breast cancer patients: a multicenter NCORP study.

PURPOSE: Cancer-related fatigue (CRF) is a prevalent and distressing side effect of cancer and its treatment that remains inadequately understood and poorly managed. A better understanding of the factors contributing to CRF could result in more effective strategies for the prevention and treatment of CRF. The objectives of this study were to examine the prevalence, severity, and potential predictors for the early onset of CRF after chemotherapy cycle 1 in breast cancer patients. METHODS: We report on a secondary data analysis of 548 female breast cancer patients from a phase III multi-center randomized controlled trial examining antiemetic efficacy. CRF was assessed by the Brief Fatigue Inventory at pre- and post-chemotherapy cycle 1 as well as by the four-day diary. RESULTS: The prevalence of clinically relevant post-CRF was 75%. Linear regression showed that pre-treatment CRF, greater nausea, disturbed sleep, and younger age were significant risk factors for post-CRF (adjusted R2 = 0.39; P < 0.0001). Path modeling showed that nausea severity influenced post-CRF both directly and indirectly by influencing disturbed sleep. Similarly, pre-treatment CRF influenced post-CRF directly as well as indirectly through both nausea severity and disturbed sleep. Pearson correlations showed that changes in CRF over time were significantly correlated with concurrent changes in nausea severity (r = 0.41; P < 0.0001) and in disturbed sleep (r = 0.20; P < 0.0001). CONCLUSION: This study showed a high prevalence (75%) of clinically relevant CRF in breast cancer patients following their initial chemotherapy, and that nausea severity, disturbed sleep, pre-treatment CRF, and age were significant predictors of symptom.

Brief report of virtual clinician research tools for tobacco dependence or dyslipidemia.

Health avatars were created to deliver previously tested live interventions for tobacco dependence and cholesterol management. The exploratory aims were to develop and test whether the avatar can be reliably assessed for autonomy supportiveness using the Health Care Climate Questionnaire and estimate the mean changes in motivation variables and correlate the avatars' autonomy supportiveness with the motivation variables and health outcomes. The avatars were found to be reliably assessed for autonomy supportiveness on the Health Care Climate Questionnaire. Autonomy support was positively correlated with the change in motivations and reduction in low-density lipoprotein. These findings suggest that health avatars may be tested in clinical trials.

Damage to the insula leads to decreased nicotine withdrawal during abstinence.

BACKGROUND AND AIMS: Current pharmacotherapies for tobacco dependence are generally well tolerated, but have relatively high rates of relapse. They target primarily the brains' mesocorticolimbic 'reward' pathway. However, recent evidence suggests that the insular cortex, a central cerebral hemispheric region historically overlooked in addiction models, may also play an important role in cognitive and emotional processes that facilitate drug use. We examined whether insular versus non-insular damage from ischemic stroke attenuated acute withdrawal from cigarette smoking and reduced the likelihood of nicotine replacement therapy (NRT) use during hospitalization. DESIGN: Data were derived from a longitudinal study with 3 months' follow-up, beginning June 2013 and ending May 2014. SETTING: Three acute care hospitals in Rochester, NY, USA. PARTICIPANTS: One-hundred and fifty-six current smokers hospitalized for acute ischemic stroke (38 with insular infarctions and 118 with non-insular infarctions, assessed by three neuroradiologists). MEASUREMENTS: The Wisconsin Smoking Withdrawal Scale (WSWS) and Minnesota Nicotine Withdrawal Scale (MNWS) were administered during hospitalization (a period of forced abstinence) to assess the frequency and severity of withdrawal symptoms. NRT use was also assessed during hospitalization. FINDINGS: On average, smokers with insular damage had a lower WSWS score during admission [mean=5.89, standard deviation (SD)=4.72] compared with those with non-insular damage (mean=9.20, SD=4.71; P<0.001) [covariate-adjusted difference in means of -3.12, 95% confidence interval (CI)=-4.97, -1.27]. A similar difference was also noted when the MNWS was used (P=0.02). Furthermore, participants with insular lesions appeared to be less likely to use NRT during admission compared with those with non-insular lesions [odds ratio (OR)=0.72, 95% CI=0.32, 1.64]. CONCLUSIONS: Current smokers with damage to their insular cortex brain region appear to experience fewer and less severe tobacco withdrawal symptoms, and appear to be less likely to require nicotine replacement therapy during hospitalization, compared with smokers with non-insular damage. These findings support the potential role of the insular cortex in regulating withdrawal during abstinence, a motivator responsible for the maintenance of addictive behaviors.

Smoking cessation behaviors three months following acute insular damage from stroke.

BACKGROUND: Recent evidence suggests that the insular cortex may play an important role in cognitive and emotional processes that facilitate drug use but it is unclear whether changes to the insula would result in sustained abstinence. To better understand the role of the insula in maintaining abstinence, we examined quitting patterns in smokers with acute damage to their insula relative to other regions. DESIGN: Prospective cohort study with 3month follow-up, beginning June 2013 and ending May 2014. SETTING: Three acute care hospitals in Rochester, NY. PARTICIPANTS: One-hundred-fifty-six current smokers hospitalized for acute ischemic stroke; 38 with insular infarctions and 118 with non-insular infarctions, assessed by 3 neuroradiologists. MEASUREMENTS: Self-reported smoking status (seven-day point prevalence and continuous abstinence), complete abstinence from any nicotine product, and disruption of smoking addiction (defined by criteria on smoking status, difficulty of quitting, and urge) were assessed at three months post-stroke. Time to relapse (in days) after discharge was also assessed. RESULTS: Insular damage was associated with increased odds of three-month continuous abstinence (OR=3.71, 95% CI: 1.59, 8.65) and complete cessation from any nicotine product (OR=2.72, 95% CI: 1.19, 6.22). Average time to relapse was longer in the insular-damaged group (17.50days, SD=19.82) relative to non-insular damage (10.42days, SD=18.49). Among quitters, insular damage was also associated with higher relative odds of experiencing a disruption of addiction compared to non-insular damage (adjusted OR=5.60, 95% CI: 1.52, 20.56). CONCLUSIONS: These findings support the potential role of the insular cortex in maintaining smoking and nicotine abstinence. Further research is needed to establish whether the insula may be a novel target for smoking cessation interventions.

The effects of aspirin and fish oil consumption on lysophosphatidylcholines and lysophosphatidic acids and their correlates with platelet aggregation in adults with diabetes mellitus.

Many diabetics are insensitive to aspirin's platelet anti-aggregation effects. The influence of co-administration of aspirin and fish oil (FO) on plasma lysophospholipids in subjects with diabetes is poorly characterized. Thirty adults with type 2 diabetes mellitus were treated with aspirin (81mg/day) for seven days, then with FO (4g/day) for 28 days, then in combination for another seven days. Lysophospholipids and platelet measures were determined after acute (4h) and chronic (7 days) ingestion of aspirin, FO, or both in combination. FO ingestion reduced all lysophosphatidic acid (LPA) concentrations, while EPA (20:5n-3) and DHA (22:6n-3) lysophosphatidylcholine (LPC) concentrations significantly increased after FO alone and in combination with aspirin. In vitro arachidonic acid-induced platelet aggregation was most strongly correlated with palmitoleic (16:1) and oleic (18:1) LPA and LPC concentrations at all time points. The ingestion of these agents may reduce cardiovascular disease risk in diabetic adults, with a disrupted lipid milieu, via lysolipid mediated mechanisms.

Effects of low-dose aspirin and fish oil on platelet function and NF-kappaB in adults with diabetes mellitus.

INTRODUCTION: Many diabetics are insensitive to aspirin's platelet anti-aggregation effects. The possible modulating effects of co-administration of aspirin and fish oil in subjects with diabetes are poorly characterized. PARTICIPANTS AND METHODS: Thirty adults with type 2 diabetes mellitus were treated with aspirin 81 mg/d for 7 days, then with fish oil 4 g/day for 28 days, then the combination of fish oil and aspirin for another 7 days. RESULTS: Aspirin alone and in combination with fish oil reduced platelet aggregation in most participants. Five of 7 participants classified as aspirin insensitive 1 week after daily aspirin ingestion were sensitive after the combination. Although some platelet aggregation measures correlated positively after aspirin and fish oil ingestion alone and (in combination) in all individuals, correlation was only observed in those who were aspirin insensitive after ingestion of the combination. CONCLUSIONS: Co-administration of aspirin and fish oil may reduce platelet aggregation more than aspirin alone in adults with diabetes mellitus.

Our expanding view of platelet functions and its clinical implications.

Platelets are the primary cell mediator of thrombosis. A deficiency of platelets can result in severe bleeding defects. "Overactive" platelets contribute to life-threatening outcomes in diseases such as heart attack, stroke, and cancer. The use of platelet inhibitors for thrombosis prevention must therefore seek a delicate balance between inhibiting platelet activation and an associated increased bleeding risk. There are currently few platelet inhibitors clinically available, making the search for novel anti-platelet drug targets a major research priority. Several newly identified pathways of platelet activation may hold hope in this area. In addition, important roles for platelets beyond hemostasis have been discovered. Platelets have recently been described as mediators of diverse inflammatory diseases such as arthritis, hepatitis, malaria, and atherosclerosis. This has heightened the need to broaden our understanding of platelet functions and platelet-derived inflammatory mediators. It has also heightened interest in a continued search for new platelet inhibitors and presents new opportunities for platelet inhibitors to be used in a wide array of disease treatment strategies.

Parenteral fish oil-associated burr cell anemia.

We report the development of burr cell anemia in an infant with short bowel syndrome who received parenteral fish oil (Omegaven, Fresenius-Kabi, Graz, Austria) after development of total parenteral nutrition-associated liver disease. Parenteral fish oil was discontinued, and the burr cell anemia disappeared, suggesting that parenteral fish oil might be associated with hemolytic anemia.

EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls.

BACKGROUND: Increased blood levels of the omega-3 fatty acids (FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been inversely associated with risk for sudden cardiac death, but their relationship with acute coronary syndromes (ACS) is unclear. OBJECTIVE: We hypothesized that the EPA+DHA content of blood cell membranes, as a percent of total FAs, is reduced in ACS patients relative to matched controls. METHODS: We measured the content of EPA+DHA in 768 ACS patients and 768 age-, sex- and race-matched controls. The association with ACS case status of blood cell EPA+DHA [both by a 1 unit change and by category (low, <4%; intermediate 4.1-7.9%; and high, > or =8%)] was assessed using multivariate conditional logistic regression models adjusting for matching variables and smoking status, alcohol use, diabetes, body mass index, serum lipids, education, family history of coronary artery disease, personal histories of myocardial infarction and hypertension, and statin, aspirin, and other antiplatelet drug use. RESULTS: The combined groups had a mean age of 61+/-12 years, 66% were male, and 92% were Caucasian. The EPA+DHA content was 20% lower in cases than controls (3.4+/-1.6 vs. 4.25+/-2.0%, p<0.001). The multivariable-adjusted odds for case status was 0.77 (95% CI 0.70 to 0.85, p<0.001) for a 1 unit increase in EPA+DHA content. Compared with the lowest EPA+DHA group, the odds ratio for an ACS event was 0.58 (95% CI 0.42-0.80), in the intermediate EPA+DHA group and was 0.31 (95% CI 0.14-0.67; p for trend <0.0001) in the highest EPA+DHA group. CONCLUSIONS: Odds for ACS case status increased incrementally as the EPA+DHA content decreased suggesting that low EPA+DHA may be associated with increased risk for ACS.

Determinants of Blood Cell Omega-3 Fatty Acid Content.

BACKGROUND: Although red blood cell eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) content (the Omega-3 Index) predicts cardiovascular death, the factors determining the Index are unknown. METHODS: In 704 outpatients, we undertook an investigation of the clinical determinants of the Index. RESULTS: Factors associated with the Index in decreasing order were: EPA+DHA supplement use, fish consumption frequency, triglyceride level, age, high cholesterol history, and smoking. These factors explained 59% of Index variability, with capsules/fish intake together accounting for 47%. The Index increased by 13% (p< 0.0001) for each serving level increase in fish intake and EPA+DHA supplementation correlated with a 58% increase (p< 0.0001) regardless of background fish intake (p=0.25; test for interaction). A 100 mg/dL decrease in serum triglycerides was associated with a 15% higher (p<0.0001) Index. CONCLUSIONS: The intake of EPA+DHA-rich foods and supplements principally determined the Omega-3 Index, but explained only about half of the variability.