Use Of Cholesterol-lowering Drugs Research Articles

Sex-specific plasma-proteome of incident coronary artery disease

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by a Leiden University Medical Center MD/PhD research grant to V.Q. Sier and Dr. R. Noordam is supported by an innovation grant from the Dutch Heart Foundation. Purpose The onset and symptomatology of coronary artery disease (CAD) are different for men and women, yet insights into sex-specific biological mechanisms causing CAD are limited. To increase insight in the onset of CAD in men and women, we performed a sex-specific proteome-wide association analysis using data from a large cohort of middle-aged participants from the UK Biobank. Methods Associations between 2,923 plasma proteins and CAD incidence (angina pectoris, acute myocardial ischemia, chronic myocardial ischemia) were examined in European-ancestry participants from the UK Biobank who were free of CAD at baseline. Plasma samples were collected at baseline (2006-2010), and CAD incidence was monitored continuously for a median (interquartile range) follow-up of 5,013 (4775-5251) days. Using Cox proportional hazard modelling, the associations between CAD incidence and plasma protein levels were examined, adjusted for age, sex, body mass index, socioeconomic status, type 2 diabetes mellitus, and cholesterol-lowering and insulin drug use at baseline. The Metascape portal was employed for pathway analyses to identify (sex-specific) biological pathways. Results In a total sample comprising 40,829 individuals (55% women, mean age (sd) 56.9 (8.10)), featuring 3,155 incident CAD cases, our sex-combined model demonstrated significant associations between 93 proteins and hazard for CAD. Pathway analyses identified early plasma proteomic changes related to cytokine-cytokine receptor interactions (p=3.42e-17), matrix remodelling (p=9.24e-14, p=1.08 e-9), regulation of innate and adaptive immune cells (p=1.92e-12, p=3.88e-9), and angiogenesis (p=5.34e-9). Stratification by sex revealed distinct sex-specific proteomic patterns linked to CAD incidence, with 10 female-specific and 49 male-specific significant proteins. Through interaction analyses, we demonstrated that 8 proteins were distinctly associated with a significant increased hazard in women, while 20 proteins were significantly associated with increased hazard for CAD in men. Pathway analyses identified a significant female-specific relation between CAD incidence and matrix remodelling (p=9.72e-15, p=3.19e-13), angiogenesis/hypoxia (p=1.41e-12), and inflammatory signalling (p=7.18e-10, p=8.01e-10) pathways, whereas male-specific top pathways related to inflammatory signalling (p=9.58e-25), matrix remodelling (p=1.22e-17), and immune cell response/recruitment (p=3.08e-16, p=8.34e-12). Conclusion Using large-scale association analyses of proteomics data with CAD, we identified sex-specific proteomic profiles. Distinct patterns in more angiogenic (women) and more immune cell response (men) profiles were found. These findings contribute novel insights to the development of CAD, potentially guiding future sex-specific research and clinical strategies for disease prevention.Proteome-wide analysis for CAD incidence

Untargeted Lipidomic Profiling Reveals Lysophosphatidylcholine and Ceramide as Atherosclerotic Risk Factors in apolipoprotein E Knockout Mice.

Despite the availability and use of numerous cholesterol-lowering drugs, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality globally. Many researchers have focused their effort on identifying modified lipoproteins. However, lipid moieties such as lysophosphatidylcholine (LPC) and ceramide (CER) contribute to atherogenic events. LPC and CER both cause endothelial mitochondrial dysfunction, leading to fatty acid and triglyceride (TG) accumulation. In addition, they cause immune cells to differentiate into proinflammatory phenotypes. To uncover alternative therapeutic approaches other than cholesterol- and TG-lowering medications, we conducted untargeted lipidomic investigations to assess the alteration of lipid profiles in apolipoprotein E knockout (apoE-/-) mouse model, with or without feeding a high-fat diet (HFD). Results indicated that, in addition to hypercholesterolemia and hyperlipidemia, LPC levels were two to four times higher in apoE-/- mice compared to wild-type mice in C57BL/6 background, regardless of whether they were 8 or 16 weeks old. Sphingomyelin (SM) and CER were elevated three- to five-fold in apoE-/- mice both at the basal level and after 16 weeks when compared to wild-type mice. After HFD treatment, the difference in CER levels elevated more than ten-fold. Considering the atherogenic properties of LPC and CER, they may also contribute to the early onset of atherosclerosis in apoE-/- mice. In summary, the HFD-fed apoE-/- mouse shows elevated LPC and CER contents and is a suitable model for developing LPC- and CER-lowering therapies.

Incidence of erectile dysfunction treatment after radical prostatectomy by Statin use in Finnish Nationwide Cohort Study

Background Erectile dysfunction (ED) is common after radical prostatectomy (RP) due to cavernous nerve damage. Risk of ED is also affected by vascular function. Statins prevent vascular events but their association with post-prostatectomy ED is unclear. We explored the likelihood of starting ED treatment after RP by statin use at the population level. Methods The study cohort included 14,295 prostate cancer (PCa) patients with no ED treatment prior to diagnosis of PCa treated with RP in Finland during 1995–2013. Information on use of cholesterol-lowering drugs and ED medication during 1995–2014 and penile prosthesis implantation during 1996–2014 were gathered from national registries. Risk of ED treatment initiation after RP was analyzed by pre-diagnostic and post-diagnostic statin and non-statin cholesterol lowering (NSCL) drug use with Cox regression model. Results Pre-diagnostic statin use or NSCL drug use overall had no association with risk of ED treatment initiation after RP. Post-diagnostic statin use was associated with a slightly increased risk of initiation of any ED treatment (HR = 1.07; 95% CI = 1.01–1.14). Patients with the longest duration of post-diagnostic statin use had a significantly decreased risk of PDE5 inhibitor initiation compared to non-users (HR = 0.43; 95% CI = 0.20–0.94). Among patients with no cardiovascular comorbidities, pre-diagnostic statin users had a significantly increased risk of initiation of injectable ED drugs (HR = 1.27; 95% CI = 1.04–1.55), however, no association with risk of any other ED treatment was observed. Conclusion Statin users have a slightly increased risk of ED treatment initiation after RP, which probably reflects the effect of the underlying vascular insufficiency.

Outcomes of Screening for Prostate Cancer Among Men Who Use Statins

Prostate-specific antigen (PSA) screening for prostate cancer has resulted in a slight reduction in prostate cancer mortality but also a concomitant overdiagnosis of low-risk tumors. Prostate-specific antigen levels are affected by use of cholesterol-lowering statin drugs, but the association of statin use with PSA screening performance is unknown. To investigate whether statin use was associated with outcomes of a randomized PSA-based prostate cancer screening intervention. This post hoc subgroup analysis of a cohort from a population-based randomized clinical trial used data from the population-based Finnish Randomized Study of Prostate Cancer Screening, which randomized men to PSA screening or routine care from March 1, 1996, to December 31, 1999, with follow-up continuing until December 31, 2015. The population included all men aged 55 to 67 years at baseline and residing in the Tampere or Helsinki districts of Finland. Information on statin purchases from 1996 to 2009 was obtained from a national prescription registry. Eligible men were identified from the population registry of Finland. Prevalent prostate cancer cases at baseline were excluded. Data were analyzed from January 1, 2019 to March 31, 2021. Three invitations for PSA screening at 4-year intervals from 1996 to 2007 vs routine care. Risk for prostate cancer overall, high-risk disease, and prostate cancer mortality in the screening group vs the control group as an intention-to-treat analysis. The analysis was stratified by statin use. The study comprised 78 606 men (median age, 59 years [range, 55-67 years]) with statin purchase data available. Although PSA screening was associated with increased prostate cancer incidence among statin nonusers (screening vs control, 11.2 vs 8.6 per 1000 person-years); rate ratio [RR], 1.31; 95% CI, 1.24-1.38), no similar increase in incidence was observed among statin users (6.9 vs 5.9 per 1000 person-years; RR, 1.02; 95% CI, 0.95-1.10; P < .001 for interaction). Incidence of low-risk (Gleason score 6) and localized tumors was lower among statin users, whereas detection of tumors with a Gleason score of 8 to 10 was similar. Screening was associated with a lower incidence of metastatic tumors regardless of statin use. In this post hoc subgroup analysis of a cohort from a population-based randomized clinical trial, PSA screening among statin users was associated with a decreased incidence of advanced prostate cancer that was similar among statin nonusers, but with less increase in detection of low-grade localized tumors in statin users than in nonusers. These findings suggest that statin use does not materially compromise benefits of PSA-based screening.

Associations Between Intake of Fermented Dairy Products and Blood Lipid Concentrations Are Affected by Fat Content and Dairy Matrix - The Tromsø Study: Tromsø7.

Introduction: Dairy fat is rich in saturated fatty acids known to increase serum low-density lipoprotein cholesterol (LDL-C) concentration, an important risk factor for cardiovascular disease (CVD). However, intake of fermented dairy products has been associated with reduced CVD risk in observational studies. How intakes of different fermented dairy products are associated with blood lipid concentrations may provide a possible explanation for the suggested reduced CVD risk.Aim: To examine the associations between different types of fermented dairy products, with various fat contents and dairy matrix structures, and blood lipid concentrations in a general population.Methods: In 11,377 women and men aged between 40-99 participating in the population-based Tromsø Study 2015-2016, multivariable linear regression was used to examine associations between total intake of fermented dairy products, intake of yogurt (including regular-fat, low-fat, and semi-solid yogurt), cheese (including regular-fat and low-fat), and liquid fermented dairy, and serum concentrations of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Dietary data was collected using a validated food frequency questionnaire. Analyses were adjusted for potential confounding factors, and cheese intake analyses were stratified by self-reported use of cholesterol-lowering drugs.Results: Cheese intake was positively associated with HDL-C [regression coefficient 0.02 mmol/l (95 % CI 0.01, 0.03)], and inversely associated with LDL-C [regression coefficient−0.03 mmol/l (95 % CI−0.04,−0.01)] and triglycerides [relative change −1.34 % (95 % CI: −2.29 %, −0.37 %)] per 25 g/day among non-users of cholesterol-lowering drugs, while no associations were found among users. Total intake of fermented dairy was inversely associated with triglycerides [relative change −1.11 % (95 % CI: −1.96 %, −0.24 %)] per 250 g/day, while no associations were found for yogurt intake. Intake of low-fat cheese was more favorably associated with blood lipids compared to regular-fat cheese, and semi-solid yogurt was inversely associated with LDL-C and triglycerides, while intake of liquid fermented dairy was not associated with any of the blood lipids.Conclusion: This study highlights the importance of investigating specific types of dairy products separately, based on fat content and dairy matrix, when examining effects on blood lipid concentrations, and stratifying statistical models by use of cholesterol-lowering drugs when relevant.

Cholesterol lowering drug use and breast cancer survival: the Multiethnic Cohort Study

PurposePrior studies conducted primarily in white populations have suggested that pre-diagnostic cholesterol lowering drugs (CLDs) improved survival among women with breast cancer (BC). However, this association had not been well characterized in diverse racial/ethnic populations. We investigated whether pre-diagnostic CLD use is associated with all-cause and BC-specific mortality among female BC cases of the Multiethnic Cohort (MEC).MethodsCLD use was ascertained through questionnaires administered in 2003–2008. A total of 1448 incident BC cases were identified by linkage to SEER cancer registries in Hawaii and California from 2003 to 2014. Multivariable Cox regression was conducted to estimate hazard ratios (HR) and 95% confidence intervals (CI) of the associations of pre-diagnostic CLD use with all-cause and BC-specific mortality, adjusting for tumor characteristics, first course of treatment, health behaviors, co-morbidities, and demographics. Subgroup analyses by stage and hormone receptor status were conducted for all-cause mortality.ResultsThere were 224 all-cause and 87 BC-specific deaths among the 1448 BC cases during a median follow-up of 4.5 years after diagnosis. Women with BC who ever used CLDs had a 27% lower hazard of all-cause mortality (HR 0.73, 95% CI 0.54–0.98) and 17% lower hazard of BC-specific mortality (HR 0.83, 95% CI 0.49–1.39) compared to never users. CLD use reduced mortality among women with advanced-stage tumors and hormone receptor-positive breast tumors (HR 0.54 95% CI 0.33–0.90; HR 0.69, 95% CI 0.48–0.99, respectively).ConclusionThese findings demonstrate an improved survival associated with CLD use prior to diagnosis in a multiethnic population of women with BC.

A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth

Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC.

Consumption and market share of cholesterol-lowering drugs in high-risk patients before and after the release of the 2013 ACC/AHA cholesterol guidelines: a retrospective observational study

ObjectiveWe examined the use of cholesterol-lowering drugs in Taiwan in high-risk patients before and after the release of the 2013 American College of Cardiology and the American Heart Association (ACC/AHA)...

Pre-diagnostic plasma lipid levels and the risk of amyotrophic lateral sclerosis

Objective To assess whether pre-diagnostic lipid levels are associated with Amyotrophic lateral sclerosis (ALS) risk. Methods: We conducted a matched case-control study nested in five large prospective US cohorts (the Nurses’ Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the Women’s Health Initiative), and identified 275 individuals who developed ALS during follow-up and had provided blood samples before disease diagnosis. For each ALS case, we randomly selected two controls who were alive at the time of the case diagnosis and matched on cohort, birth year (±1 year), sex, race/ethnicity, fasting status, and time of blood draw. We measured total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels in the plasma samples, and used conditional logistic regression to estimate associations between lipid levels and ALS risk. Results: Higher levels of HDL-C were associated with higher ALS risk in an analysis adjusted for the matching factors (risk ratio [RR] Q4 vs. Q1: 1.78, 95% confidence interval [CI]: 1.18–2.69, p trend: 0.007). The estimate remained similar in a multivariable analysis additionally adjusted for body mass index, physical activity, smoking, alcohol intake, plasma urate levels, and use of cholesterol-lowering drugs (RR Q4 vs. Q1: 1.71, 95% CI: 1.07–2.73, p trend: 0.02). Plasma levels of TC, LDL-C, and TG were not associated with ALS risk. Conclusions: Higher pre-diagnostic HDL-C levels, but not levels of other lipids, were associated with a higher risk of ALS.

Abstract 428: The role of Mig-6 as a tumor suppressor in metastatic and recurrent endometrial cancer

Abstract Endometrial cancer is the most common gynecologic malignancy with an estimated 63,230 new cases in 2018. Although early-stage and low grade endometrioid endometrial cancers (EEC) generally exhibit a favorable prognosis, 10-15% of tumors recur within 5 years with poor treatment outcomes and low survival rates. Therefore, there is an urgent obligation to explore the mechanism of tumor metastasis and recurrence to further elucidate the progression of EEC. Mitogen inducible gene 6 (MIG-6) plays a tumor suppressor role in endometrial cancer. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced EEC. However, how MIG-6 suppresses tumorigenesis and metastasis in EEC is unclear. We have developed a genetically engineered mouse model for metastatic and recurrent EEC that implicates coexistent Pten and Mig-6 mutations in EEC. We also added a double-fluorescent Cre reporter to our EEC mouse model to distinguish EEC from surrounding normal tissues. In Pgrcre/+Rosa26mTmG mice, the Pgr-positive uterine cells express GFP, while Pgr-negative cells express membrane-targeted tandem dimer Tomato. The ablation of both Mig-6 and Pten in the uterus (Pgrcre/+Mig-6f/fPtenf/f; Mig-6d/dPtend/d) dramatically accelerated the development of EEC compared to single ablation of either gene. Importantly, Pten mutation is not sufficient for distant metastasis, but mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. After hysterectomy at stage I of EEC, 62% of Mig-6d/dPtend/d mice (5/8) developed recurrence of EEC in the abdomen and lung. Cholesterol metabolism plays a significant role in cancer metastasis, and Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis. The ingenuity pathway analysis revealed that cholesterol biosynthesis was the most significantly changed pathway in the endometrial hyperplasia from 2-week-old Mig-6d/dPtend/d mice compared with Ptend/d mice. We found 67 and 18 significantly increased or decreased transcripts, respectively, that are related cholesterol biosynthesis. HMG-coA reductase inhibitors, commonly known as statins, account for the great majority of cholesterol-lowering drug use. However, little is known about the association between statin use and incidence of most types of cancers. To determine the effect of statins on tumorigenesis of EEC in Mig-6d/dPtend/d mice, the mutant mice were treated with atorvastatin (10mg/kg/day oral administration) or vehicle for 2 months. Treatment with statins significantly reduced development and progression of EEC in Mig-6d/dPtend/d mice compared to the vehicle group. Our results demonstrate that Mig-6 suppresses metastasis and recurrence in EEC with Pten mutation by inhibiting cholesterol biosynthesis. Research reported in this publication was supported by The Mary Kay Foundation 2019 research grant. Citation Format: Tae Hoon Kim, Ryan M. Marquardt, Russell R. Broaddus, Jae-Wook Jeong. The role of Mig-6 as a tumor suppressor in metastatic and recurrent endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 428.

Associations between peroxisome proliferator-activated receptor γ (PPAR-γ) polymorphisms and serum lipids: Two cross-sectional studies of community-dwelling adults.

Dyslipidemia is a well-established risk factor for cardiovascular disease. Experimental studies have reported that peroxisome proliferator-activated receptor γ (PPAR-γ) regulates adipocyte differentiation, lipid storage, and glucose metabolism. Therefore, we examined the associations between PPAR-γ polymorphisms (rs1801282, rs3856806, rs12497191, rs1151999, and rs1152003) and serum lipids in two cross-sectional studies. In the Shizuoka area of the Japan Multi-Institutional Collaborative Cohort Study, we examined 4,952 participants (3,356 men and 1,596 women) in a baseline survey and 2,245 participants (1,550 men and 695 women) in a second survey 5years later. Outcome measures were the prevalence of dyslipidemia (low-density lipoprotein-cholesterol [LDL-C]≥140mg/dl, high-density lipoprotein-cholesterol<40mg/dl, triglycerides≥150mg/dl, and/or use of cholesterol-lowering drugs) and the prevalence of high LDL-C (LDL-C≥140mg/dl and/or use of cholesterol-lowering drugs). Multivariate odds ratios (ORs) were estimated by using unconditional logistic regression models. A total of 2,114 and 1,431 individuals (42.7% and 28.9%) had dyslipidemia and high LDL-C in the baseline survey, respectively, as did 933 and 716 (41.6% and 31.9%), respectively, in the second survey. In the baseline study, compared with major allele homozygotes, minor allele homozygotes of rs3856806 and rs12497191 had a 42% (OR, 0.58; 95% confidence interval (CI), 0.39-0.85) and 23% (OR, 0.77; 95% CI, 0.60-0.99) lower risk of dyslipidemia, respectively, after adjustment for potential confounding factors. In addition, minor allele homozygotes of rs3856806 had a 45% (OR, 0.55; 95% CI, 0.35-0.86) lower risk of high LDL-C. Similar risk reductions were found in the second survey. In conclusion, rs3856806 and rs12497191 polymorphisms may be related to a lower risk of dyslipidemia and high LDL-C.

A register-based SAH study in Japan: high incidence rate and recent decline trend based on lifestyle.

Japan has been reported to have the highest (and increasing) incidence of subarachnoid hemorrhage (SAH) in the world. However, there has never been a report on the nationwide incidence rate and recent trends for SAH in Japan. In this register-based study, the authors aimed to clarify the estimated nationwide SAH incidence rate and the recent trend in SAH incidence in Japan and the reasons for any changes in this trend. The authors compiled data from the Japanese Ministry of Health, Labour and Welfare and from the records of the Japan Neurosurgical Society. They reviewed the age-standardized nationwide SAH mortality rate, the estimated age-standardized SAH incidence rate according to the age-standardized SAH mortality rate, and the estimated crude SAH incidence rate, including the 95% confidence intervals, from 2003 to 2015. The trends in the number of treatments for unruptured and ruptured cerebral aneurysms, as well as the prevalence of hypertension, current smoking status, and use of cholesterol-lowering drugs, were assessed. The estimated treatment rate for unruptured cerebral aneurysms (UCAs) was also calculated along with the 95% confidence interval. The estimated age-standardized nationwide SAH incidence rate significantly declined from 31.34 cases (95% CI 31.32-31.34) to 27.63 (95% CI 27.59-27.63; decrease by 11.8%) per 100,000 person-years. This decline was based on the 2010 population as the reference from 2003 through 2015 and a case-fatality rate of SAH that was assumed to decrease by 1% annually from 44% in 2003 to 32% in 2015. According to sensitivity analysis, the change rate of the estimated age-standardized SAH incidence rate ranged from -56.69% to 23.27%, with a mean of -30.91% (SD 20.52%), and there were decline trends in 92% of all trends. The estimated nationwide crude SAH incidence rate also showed a significant decline from 23.79 (95% CI 23.78-23.79) to 20.25 (95% CI 20.24-20.25; decrease by 14.9%) per 100,000 person-years. The trend in treatment numbers for UCAs increased significantly (p < 0.0001) from 2003 through 2015; however, the estimated treatment rate for UCAs was only 0.19 (95% CI 0.19-0.20) to 0.51 (95% CI 0.50-0.51) among all UCA patients. The prevalence of hypertension (males, p = 0.0003; females, p < 0.0001) and current smoking status (males, p < 0.0001; females, p = 0.0002) declined significantly from 2003 through 2015, while the use of cholesterol-lowering drugs increased significantly (males, p < 0.0001; females, p = 0.0005) during the same period. The estimated nationwide SAH incidence rate in Japan was higher than rates in other countries, although it has declined recently. An improving lifestyle may have contributed to the declining rate of SAH incidence in Japan.

Abstract WMP92: High Nationwide Incidence and Decline Trend of Subarachnoid Hemorrhage From Register-based Study in Japan

Background and Purpose: There has never been a report of the nationwide incidence rate and the recent trend of subarachnoid hemorrhage (SAH) in Japan. This study aimed to clarify the age-standardized nationwide incidence rate and recent trend of SAH in Japan and reasons for recent changes in this trend. Methods: We compiled data from the Japan Neurosurgical Society and records from the Ministry of Health, Labor, and Welfare in Japan. We reviewed the age-standardized mortality rate and estimated crude incidence rate of SAH including the 95% confidence interval (CI) from 2002 to 2017. The trend in treatment numbers of unruptured cerebral aneurysms (UCAs), ruptured cerebral aneurysms, the estimated treatment rate of UCAs with 95% CI, and the prevalence of hypertension, current smoking and use of cholesterol-lowering drugs were assessed. Results: Based on the 2010 population as a reference, the age-standardized nationwide SAH mortality rate significantly declined from 13.91 (95%CI:13.90-13.91) to 8.12 (8.12-8.13) by 41.7% per 100,000 person-years from 2002 through 2017. The estimated crude incidence rate of SAH excluding conservative survivors per 100,000 also showed a significant decline from 25.41 (25.40-25.42) to 21.35 (21.34-21.36) by 16.0 % and from 23.89 (23.88-23.89) to 20.05 (20.04-20.05) by 16.1% , if the in-hospital mortality was 10% and 20%, respectively. The prevalence of hypertension and current smoking declined significantly (p&lt;0.05) and use of cholesterol-lowering drugs increased significantly (p&lt;0.05) during the same period. Conclusions: The nationwide incidence rate of SAH in Japan was higher than in other countries. However, the declining trend of SAH was shown in this study. Improving lifestyle might contribute to reducing the incidence of SAH in Japan.

Impact of a cardiovascular disease risk screening result on preventive behaviour in asymptomatic participants of the ROBINSCA trial

A teachable moment for preventive behavioural change can occur when asymptomatic individuals receive their cardiovascular disease screening result. This study investigated prevention-seeking behaviour and compliance with preventive treatment of participants of the population-based Risk Or Benefit IN Screening for CArdiovascular disease (ROBINSCA) trial after receiving a screening result. Asymptomatic Dutch individuals (n = 43,447) were randomly assigned (1:1:1) to screening for cardiovascular disease by either traditional risk assessment (intervention arm A), or determining the amount of coronary artery calcification (intervention arm B), or to usual care (control arm). A random sample (n = 600) of ROBINSCA participants with a screening result (arms A and B) received an online questionnaire (in 2017) to measure the impact of a cardiovascular disease screening result in low and increased (arm A: risk > 10%; arm B: Agatston ≥ 100) risk groups. Of all respondents (438/600; 73%) 63.5% were men and the mean age ( ± standard deviation) was 63.8 ± 6.9 years. Individuals with an increased coronary artery calcification score consulted their general practitioner more often compared to increased risk individuals from arm A: 140/149 (94%) and 86/137 (62.8%), respectively (P < 0.001). Current use of blood pressure and cholesterol-lowering drugs was significantly higher in the increased coronary artery calcification score group (108/140; 77.1%), compared to the group with an increased traditional risk (35/80, 43.8%; P < 0.001). Self-reported compliance was high (98.1-100%). Receiving the screening result might be a teachable moment that can enhance cardiovascular disease prevention-seeking behaviour through consulting a general practitioner and high compliance with preventive treatment. The impact of the screening result was more profound in the increased coronary artery calcification score group. Trial registration number: NTR6471.

Abstract 182: Adverse Pregnancy Outcomes and Cardiovascular Disease in the Mother: The Women’s Health Initiative (WHI)

Background: Adverse pregnancy outcomes (APOs) occur in up to 15% of all pregnancies, and are associated with an increased risk of long-term atherosclerotic cardiovascular disease (ASCVD) in the mother. However, it is unclear if this association is independent of standard ASCVD risk factors or is present in multiethnic populations with adjudicated CVD events. Methods: Participants in the Women’s Health Initiative were asked to complete a retrospective survey in 2017 about APOs, [gestational diabetes, birthweight &lt; 5 pounds, birth weight &gt; 9 pounds, delivery &gt; 3 weeks pre-term, and hypertensive disorder of pregnancy (gestational hypertension or preeclampsia)]. Cox models were used to assess the hazard for developing incident ASCVD (defined as adjudicated stroke, myocardial infarction, peripheral artery disease, coronary revascularization). Follow up began at the baseline study exam. Hazard ratios were assessed using the Cox model. Two primary models were employed for each individual APO: 1) univariate, and 2) adjusted for the baseline ASCVD risk factors of age, smoking, use of cholesterol lowering drugs, hypertension and diabetes. Results: The 50,679 respondents were 89.1% White, 5.2% Black, 2.4% Hispanic, 2.1% Asian-Pacific Islander, and 1.2% Other race. There were 12,499 (25%) women who reported an APO: 1041 (2.1%) had gestational diabetes, 6282 (12.4%) had low birth weight, 2970 (5.9%) had high birth weight, 7365 (14.5%) had a premature birth, and 3238 (6.4%) had preeclampsia or gestational hypertension. Over 1,020,899 person-years of follow up, 3569 (7.0%) adjudicated CVD events occurred. In univariate models, each APO was associated with ASCVD (Figure). In multivariable models adjusting for standard risk factors, all APOs were associated with a significantly increased risk of CVD (Figure), with the exception of high birth weight. There was no significant effect modification by race on these associations. Conclusion: Adverse pregnancy outcomes were associated with increased risk of late ASCVD in a multiethnic population of post-menopausal women, independent of ASCVD risk factors. Associations between APO and ASCVD were consistent across racial groups. APOs should be considered in CVD risk assessment in women.

The effects of cholesterol lowering drugs on vitamin D status in familial hypercholesterolemia patients

Background: Familial high blood cholesterol (hypercholesterolemia) is a common disease that involves many complications for patients. The aim of this study is to investigate the effects of cholesterol-lowering drugs (Gemfibrozil and Atorvastatin) on the level of serum Vitamin D. Materials and methods: In this study, the 25-hydroxy vitamin D levels were evaluated in 65 women between 30-55 years of age. After receiving drug information of patients, cholesterol-lowering medication; Gemfibrozil and Atorvastatin were prescribed by a specialist, then vitamin D and cholesterol levels were measured following 9 month treatment. Also 30 patients consumed vitamin D supplements plus medicine regularly. Results: In the first stage, vitamin D levels in subjects are quite normal but their cholesterol levels were higher than normal. In the second stage, vitamin D levels were measured after 9 months use of Gemfibrozil and Atorvastatin. Accordingly, cholesterol levels decreased significantly due to the use of blood cholesterol-lowering drugs (p=0.021). Also, in this stage the level of vitamin D showed a severe and significant reduction (p=0.041). However, there were no significant reductions in vitamin D in 30 women who consumed vitamin D supplements plus medicine (p=0.073). Conclusion: It seems that taking cholesterol-lowering medicines have reduced the amount of vitamin D. With long-term use of medications, bone diseases such as osteoporosis can be predicted in these individuals. Therefore, taking supplements and food rich in vitamin D during the use of these drugs is recommended.

Lifestyle Change Alone Sufficient to Lower Cholesterol in Male Patient With Moderately Elevated Cholesterol: A Case Report.

Background. Cardiovascular disease is a major cause of deaths. Elevated cholesterol levels to above the normal reference range is a major risk factor for developing cardiovascular disease. Current guidelines recommend the use of cholesterol-lowering drugs to lower cholesterol levels to within the normal reference range. However, the American Heart Association further recommends a change in lifestyle in managing cholesterol levels. Thus, cholesterol-lowering drugs may not be needed if a lifestyle-change alone is sufficient in lowering cholesterol levels to within normal ranges. Unfortunately, limited examples exist in academic literature to illustrate the effectiveness of lifestyle change alone in lowering of cholesterol levels. Case report. We report a case of a 33-year-old man, with moderately elevated cholesterol levels and a family history of cardiovascular disease. Method. The man followed an altered healthy fat diet accompanied with moderate exercise for 6 weeks, without the addition of cholesterol-lowering agents. Results. At the 6-week follow-up, he was able to decrease his total cholesterol by 40.25% and low-density lipid cholesterol by 52.8%, to within normal ranges. The cholesterol levels remained within normal ranges after 6 months. Conclusion. This case illustrates that in some individuals, lifestyle change alone is sufficient to lower moderately elevated cholesterol levels.

Abstract 997: The cholesterol metabolite 27-hydroxycholesterol promotes breast cancer progression by affecting immune responses

Abstract With upwards of 90% of mortalities associated with breast cancer being attributed to metastasis, there is an urgent need to better understand what drives this stage of disease. In this regard, it has been reported that an elevated concentration of circulating cholesterol is an independent risk factor for breast cancer recurrence. Supporting the relationship between cholesterol and breast cancer progression, the use of cholesterol lowering drugs (statins) has been demonstrated to improve recurrence-free survival. These clinical observations suggest that cholesterol influences the metastatic progression of breast cancer. Therefore, in this study we directly tested the impact of cholesterol on breast cancer metastasis, and interrogated the downstream mechanisms by which it may be doing so. In strong support of our hypothesis, increased metastasis was observed when mice were placed on a high cholesterol diet. These findings highlighted recent work by us and others demonstrating that the primary metabolite, 27-hydroxycholesterol (27HC), was able to modulate the activities of two hormone receptors: the estrogen and the liver X receptors. Thus, we pursued a series of experiments to determine whether 27HC was responsible for the metastatic actions of cholesterol. 27HC is synthesized from cholesterol by the enzyme CYP27A1. The genetic ablation of CYP27A1 completely attenuated the effects of a high cholesterol diet, implicating 27HC as a primary mediator of cholesterol. Treatment with exogenous 27HC robustly increased metastasis. Importantly, genetic or pharmacologic inhibition of CYP27A1 also reduced the basal metastatic burden, indicating that this enzyme may be a suitable target for the prevention and/or treatment of metastatic breast cancer. Intriguingly, we found that the pro-metastatic effects of 27HC also required the presence of myeloid cells, which was demonstrated by their ablation using clodronate-loaded liposomes. In the absence of myeloid cells, the ability of 27HC to promote metastasis was dramatically reduced. Whilst interrogating the distal metastatic site, we found that this oxysterol enriched Ly6G+/CD11b+ polymorphonuclear-neutrophils (PMNs) and γδ T cells. The induction of metastasis by 27HC was lost in models where either PMNs or γδ T cells were ablated. We further demonstrate that 27HC treatment results in a decrease in cytotoxic CD8+ T cells, suggesting that the net result of the 27HC enriched γδ T cells and PMNs is local immune suppression. Collectively, our results demonstrate that cholesterol increases metastasis via the actions of its metabolite 27HC, which exerts its effects through γδ T cells and PMNs to suppress acquired immunity. Since 27HC acts on the host environment to promote breast cancer progression, these results strongly support the immediate translational potential of targeting the 27HC pathway for the prevention and treatment of metastasis. Citation Format: Amy E. Baek, Sisi He, Hannah B. McDowell, Erik R. Nelson. The cholesterol metabolite 27-hydroxycholesterol promotes breast cancer progression by affecting immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 997.

MTOR Inhibition and Cardiovascular Diseases: Dyslipidemia and Atherosclerosis.

Inhibitors of the mechanistic target of rapamycin (mTOR) have unique antiatherosclerotic effects, such as depletion of plaque macrophages, induction of autophagy, and activation of cholesterol efflux. However, a common side effect of their use is dyslipidemia, a well-known risk factor for atherosclerosis. Indeed, mTOR inhibitors prevent lipid storage, increase low-density lipoprotein cholesterol levels, and activate lipolysis. Although the net effect of mTOR inhibition seems favorable, the use of cholesterol lowering drugs to manage dyslipidemia remains the most recommended strategy.

Effects of cholesterol, C-reactive protein, and interleukin-6 on prostate cancer risk in a population of African ancestry.

To investigate the association between serum cholesterol and prostate cancer and whether any effect may be mediated through inflammatory markers. Data from a case-control study of 40-80years old Jamaicanmale patients (229 cases; 252 controls) were used. Cases had incident histologically-confirmed prostate cancer and controls were men with normal digital rectal examination and prostate-specific antigen (PSA)<4μg/Lorfree: total PSA>0.15 obtained from the same clinic. Total and HDL cholesterol, interleukin-6 (IL-6), and C-reactive protein (CRP) were measured from a non-fasting sample. Multivariable logistic regression models were used to evaluate the associations between these factors and prostate cancer, adjusting for age, body mass index, waist circumference, family history of prostate cancer, diabetes, hypertension, use of cholesterol-lowering drugs, and smoking. Total cholesterol [Mean (cases, 4.71±1.07; controls, 4.64±1.07mmol/L)], CRP [median (cases, 2.11; controls, 2.09µg/ml)], and IL-6: [median (cases, 3.34; controls, 3.24pg/ml)] did not differ by PCA status. Higher total cholesterol was associated with an increased risk of low-grade disease after adjusting for potential confounders [multivariable-adjusted OR (95% CI): tertile 2: 3.32(1.66, 6.45), tertile 3: 2.14(1.07, 4.32)]. Total cholesterol was unrelated to overall prostate cancer or high-grade disease. There was no significant association between HDL cholesterol or any of the inflammatory markers with prostate cancer. Increasing total cholesterol but not inflammatory markers were associated with low-grade prostate cancer in Caribbean men.