Background: Observational studies suggested that residual risk of cardiovascular events after LDL (low-density lipoprotein) cholesterol lowering may be linked to remnant cholesterol (RC). We conducted a large-scale Mendelian randomization study to investigate the causal role of RC to predict coronary artery disease (CAD), myocardial infarction (MI), and stroke risk. Methods: We extracted single-nucleotide polymorphisms for RC and LDL from large-scale genome-wide association databases. We estimated the genetic association with outcomes from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics), the Metastroke consortium, as well as the GLGC (Global Lipids Genetics Consortium). Genetic variants were used as instruments, thereby minimizing residual confounding and reverse causation biases of observational studies. Results: By leveraging data from a combined sample of 958 434 participants, we found evidence for a significant causal effect of RC on the risk of CAD (odds ratio [OR], 1.51 per SD unit increase in RC [95% CI, 1.42–1.60]; P =5.3×10 ^-5 ), MI (OR, 1.57 [95% CI, 1.21–2.05]; P =9.5×10 ^-4 ), and stroke (OR, 1.23 [95% CI, 1.12–1.35]; P =3.72×10 ^-6 ). There was no evidence of pleiotropy. The effect of RC on CAD and MI remained consistent after accounting for the effects of RC-associated genetic variants on LDL cholesterol: OR, 1.49 (95% CI, 1.37–1.61) for CAD and OR, 1.80 (95% CI, 1.70–19.1) for MI without a meaningful indirect effect exerted on these outcomes via the LDL cholesterol mediator. Conclusions: This large-scale Mendelian randomization study showed a robust genetic causal association between RC and cardiovascular outcomes. The effect on CAD and MI is independent of LDL cholesterol. Early screening for RC along with long-term inhibition of RC should be the focus of future therapeutic interventions.

Background: Polycystic Ovary Syndrome (PCOS) is the most common endocrine-metabolic disorder affecting health and quality of life of those affected across the lifespan. We currently have limited evidence-based data on the experience of those living with PCOS in the health care system including diagnosis, health concerns and disease management. The aim of this study was to assess the perceptions of health status, health care experience and disease management support in those affected by PCOS in Alberta, Canada. Methods: An online questionnaire was completed via REDCap by individuals self-reporting a diagnosis of PCOS. Question categories included demographics, symptoms of PCOS and time to confirm a diagnosis, follow-up care, health concerns, and information resources. Descriptive statistics were used and thematic analyses was applied to open-response questions. Results: Responses from 194 participants living in Canada (93% in Alberta) were included. The average age was 34 ± 8 years and BMI was 35 ± 9. Menstrual irregularity was identified in 84% of respondents as the first symptom noticed and the primary reason for seeking a medical consultation. A PCOS diagnosis occurred on average 4.3 years following awareness of first symptoms and required consultation with more than one primary care provider for 57% of respondents. Half (53%) of respondents reported not receiving a referral to specialists for follow-up care and 70% were not informed about long-term health morbidity such as diabetes or cardiovascular disease. Most respondents (82%) did their own research about PCOS using on-line sources, academic literature and advice from peer support. The participant themes from open questions for improving health care included more resources and support, increased and reliable information, better education and training for clinicians, timely diagnosis, prompt referrals to specialists, and generally more compassion and empathy to the challenges faced by those managing their disease. Conclusion: Our findings highlight the health concerns and challenges in health care for those with PCOS. In Alberta, Canada we have identified major gaps in health care including a timely diagnosis, follow up care and supports, and multidisciplinary care. This evidence-based data can be used to inform development of pathways to improve the health care experience in those affected by PCOS.

Polycystic ovary syndrome (PCOS) is the most common metabolic-endocrine disorder impacting the health and quality of life of women over the lifespan. Evidence-based data on the scope of adverse health outcomes in those affected by PCOS is critical to improve healthcare and quality of life in this population. The aim of this study was to determine the prevalence of adverse health outcomes in those with PCOS compared to age-matched controls. We conducted a retrospective observational case-control study in those diagnosed with PCOS and age-matched controls using the Alberta Health Services Health Analytics database and the International Classification of Diseases, for the period from 2002-2018 in Alberta, Canada. The cohort consisted of n = 16,531 exposed PCOS cases and n = 49,335 age-matched un-exposed controls. The prevalences of hypertension, renal disease, gastrointestinal disease, eating disorders, mental illness, depression-anxiety, rheumatoid arthritis, respiratory infections, and all malignancies were 20%-40% (P < 0.0001) higher in those with PCOS, compared to controls. The prevalence of obesity, dyslipidemia, nonalcoholic fatty liver disease, and type 2 diabetes was 2-3 fold higher in those with PCOS (P < 0.001). Cardiovascular, cerebrovascular, and peripheral vascular disease were 30%-50% higher, and they occurred 3-4 years earlier in those with PCOS (P < 0.0001); a 2-fold higher prevalence of dementia occurred in those with PCOS, compared to controls. These findings provide evidence that PCOS is associated with a higher prevalence of morbidities over the lifespan, and the potential scope of the healthcare burden in women affected by PCOS.

There is increasing interest in the potential chronic beneficial effects of dietaryn-3 PUFA on the metabolic syndrome (MetS) and associated cardiovascular complications. We have recently established that increased dietaryn-3 PUFA has a profound acute benefit on fasting lipids and the postprandial pro-inflammatory response in the JCR:LA-cprat, a model of the MetS. However, it is unclear to what extent chronic dietaryn-3 PUFA intervention can modulate the progression of end-stage metabolic and vascular complications. The present study aimed to determine the chronic effects of dietaryn-3 PUFA supplementation on fasting and non-fasting dyslipidaemia, insulin resistance and vascular complications in the JCR:LA-cprodent model. JCR:LA-cprats were fed an isoenergetic lipid-balanced diet supplemented with 5 %n-3 PUFA (w/w) of the total fat (fish oil-derived EPA/DHA) for 16 weeks. Fasting and non-fasting (postprandial) plasma lipid profile was assessed. Hepatic and adipose tissue was probed for the expression of lipogenic proteins (acyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1 (SREBP-1)), while the activity of Jun N-terminal kinase (JNK) was assessed via Western blot to target phosphorylated JNK protein in primary enterocytes. The frequency of myocardial lesions was assessed by haematoxylin and eosin staining. Increased dietaryn-3 PUFA improved both the fasting and postprandial lipid profiles (TAG, cholesterol and apoB48) in the JCR:LA-cprat, potentially via the down-regulation of the hepatic or adipose tissue expression of lipogenic enzymes (ACC, FAS and SREBP-1). Rats fed the 5 %n-3 PUFA diet had lower (58·2 %;P < 0·01) enterocytic phosphorylated JNK protein and secreted less cholesterol (30 %;P < 0·05) into mesenteric lymph compared with the control. The chronic metabolic benefits of dietaryn-3 PUFA may underlie the potential to reduce vascular complications during the MetS, including the observed reduction in the frequency (approximately 80 %) of late-stage 3 myocardial lesions.

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder affecting females across the lifespan. Eating disorders (EDs) are psychiatric conditions that may impact the development of PCOS and comorbidities including obesity, metabolic syndrome, and type 2 diabetes. The aim of this scoping review was to determine the prevalence of EDs and disordered eating, and to review the etiology of EDs in PCOS. The review was conducted using search terms addressing PCOS, EDs, and disordered eating in databases, including PubMed, Scopus, PsycINFO, and CINAHL. Structured interviews, self-administered questionnaires, chart review, or self-reported diagnosis were used to identify EDs in 38 studies included in the review. The prevalence of any ED in those with PCOS ranged from 0% to 62%. Those with PCOS were 3-6-fold more likely to have an ED and higher odds ratios (ORs) of an elevated ED score compared with controls. In those with PCOS, 30% had a higher OR of bulimia nervosa and binge ED was 3-fold higher compared with controls. Studies were limited on anorexia nervosa and other specified feeding or ED (such as night eating syndrome) and these were not reported to be higher in PCOS. To our knowledge, no studies reported on avoidant/restrictive food intake disorder, rumination disorder, or pica in PCOS. Studies showed strong associations between overweight, body dissatisfaction, and disordered eating in PCOS. The etiologic development of EDs in PCOS remains unclear; however, psychological, metabolic, hypothalamic, and genetic factors are implicated. The prevalence of any ED in PCOS varied because of the use of different diagnostic and screening tools. Screening of all individuals with PCOS for EDs is recommended and high-quality studies on the prevalence, pathogenesis of specific EDs, relationship to comorbidities, and effective interventions to treat ED in those with PCOS are needed.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease involved in the regulation of LDL receptor (LDLR) expression and apolipopr