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Background: The "Healthy and Active Fund" involved 17 community-based projects focused on the delivery of physical activity interventions, led by a variety of public and third sector organizations. As a novel, direct approach to capturing impact at this level, these organizations were encouraged to robustly evaluate and monitor their own project's outcomes, with core funds allocated to this process. This study aimed to explore project experiences of planning and completing evaluation activities, to better understand how to support community-based practice improvement., Methods: In-depth semistructured interviews were completed with individuals who had supported their project's evaluation. Reflexive thematic analysis was used to identify key facilitators and barriers associated with evaluation in this context., Results: Across 3 identified themes, participants (N = 15, 12 projects) referred to a need for greater organizational capacity and expertise, familiarity with evaluation methods, partnership-working, inclusivity, and flexibility, particularly when collecting data from project beneficiaries. Overarching program support (eg, case officers) was viewed as a valuable resource that was disrupted by COVID-19. Participants highlighted the resilience of their projects when engaging with evaluation processes and acknowledged wider learning across organization networks as a result of this success., Conclusions: This study shows that projects may benefit from closer support and external expertise for research and evaluation. There is willingness by third sector and public bodies to adopt research and evaluation methods into routine practice, but significant barriers persist. Future programs should continue to support adaptable approaches to evaluation at community-level, to better progress health and well-being goals for diverse populations.

Background & Aims: The effect of lipid-lowering treatment (LLT) on metabolic dysfunction associated steatotic liver disease (MASLD) is unclear. This is relevant for patients with familial hypercholesterolemia (FH) who are on lifelong LLT. We aimed to evaluate the effect of LLT on MASLD indices in this population., Methods: Patients with at least possible diagnosis of FH were included into the Hellenic FH Registry (HELLAS-FH) registry. We analyzed the effect of statin monotherapy, statin/ezetimibe and statin/ezetimibe/proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) on MASLD indices, i.e., original triglyceride-glucose index (TyGO) and triglyceride-glucose index (TyG). We compared changes of TyG and TyGO before any treatment and after at least one year of stable LLT., Results: We included 1289 patients: n = 569 in the statin monotherapy group (mean age = 51 ± 15 years, 52.7 % males), n = 629 in the statin/ezetimibe group (52 ± 14 years, 51.8 %), and n = 91 in the statin/ezetimibe/PCSK9i group (54 ± 13 years, 58.2 %). Compared with baseline, TyGO and TyG decreased significantly following statin monotherapy (8.61 vs 8.49 and 4.65 vs 4.59, respectively, both p < 0.01), statin/ezetimibe (8.59 vs 8.41 and 4.64 vs 4.55, respectively, both p < 0.01) and statin/ezetimibe/PCSK9i (8.79 vs 8.55 and 4.74 vs 4.62, respectively, both p < 0.01). There was no difference regarding the change of TyGO and TyG between groups after adjusting for baseline levels. A greater percentage of patients in the statin/ezetimibe and statin/ezetimibe/PCSK9i groups exhibited TyGO-defined MASLD resolution compared with statin monotherapy (p < 0.05). After adjustment for possible confounders, LLT was significantly associated with MASLD resolution., Conclusions: MASLD indices were significantly improved in all LLT groups in FH patients. Statin/ezetimibe and statin/ezetimibe/PCSK9i were associated with greater TyGO-defined MASLD resolution compared with statin monotherapy., Competing Interests: Conflict of interest CB, CVR, GL, AG, GS, PA, VK, GA, EP, CV, ID, FG, KAP, AA, VK, CK, DA, CA has nothing to declare. IS has given talks, received honoraria, and participated in clinical trials sponsored by MSD, AMGEN, SANOFI. LR has received research grants and honoraria from Amgen, Sanofi-Aventis, Viatris, Novartis, Vianex and Servier. GK has given talks, attended conferences and participated in trials sponsored by Amgen, Angelini, MSD, Lilly, Vianex and Sanofi and has also accepted travel support to conferences from Amgen, Sanofi and MSD. KT has participated in educational, research and advisory activities sponsored by AMGEN, ANGELINI, ASTRA-ZENECA, BAYER, BOEHRINGER-INGELHEIM, ELPEN, LILLY, MSD, MYLAN, NOVO NORDISK, SANOFI and VIANEX. ES has participated in educational and advisory activities sponsored by AstraZeneca, Medtronic, MSD, Sanofi and Servier. VK has given talks and attended conferences sponsored by AstraZeneca, MSD, Sanofi-Aventis, and Vianex. MD has participated in educational, research and advisory activities sponsored by Menarini, Elpen, AstraZeneca, MSD, Bayer, Sanofi, Novartis, and Servier. KS has received honoraria from Amgen. VL has given lectures, attended conferences and participated in trials sponsored by Novo Nordisk, Sanofi-Aventis, Novartis, AstraZeneca, Boehringer-Ingelheim, MSD, GSK, Vianex, Elli Lilly, ELPEN, Mylan and Aegereon. AB has received honoraria from Vianex, Amarin and Sanofi. EL has participated in educational, research and advisory activities sponsored by AstraZeneca, MSD, Lilly, Bayer, Amgen, Sanofi, Boehringer-Ingelheim, Novartis, Novo Nordisk, Valeant and Servier. EZ has received honoraria for lectures from Amgen. Sanofi, MSD, and Astra Zeneca. HM participated in educational, research and consulting activities supported by healthcare companies, including Amgen, AstraZeneca, Boehringer Ingelheim, Elpen, Novartis, Sanofi, Vianex, Ultragenyx, Winmedica. EL has participated in educational, research and advisory activities sponsored by AstraZeneca, MSD, Lilly, Bayer, Amgen, Sanofi, Boehringer-Ingelheim, Novartis, Novo Nordisk, Valeant and Servier. CSM reports grants through his institution from Merck, Massachusetts Life Sciences Center, and Boehringer Ingelheim, has been a shareholder of and has received grants through his institution and personal consulting fees from Coherus Inc. and AltrixBio; he reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Genfit, Lumos, Amgen, Corcept, Aligos, Intercept, 89 Bio, Madrigal, and Regeneron, reports travel support and fees from TMIOA, Elsevier, and the Cardio Metabolic Health Conference. None is related to the work presented herein. ENL has participated in educational, research and advisory activities sponsored by AstraZeneca, MSD, Lilly, Bayer, Amgen, Sanofi, Boehringer Ingelheim, Novartis, Novo Nordisk, Valeant and Servier., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Familial hypercholesterolemia (FH) and obesity are well-established risk factors of atherosclerotic cardiovascular disease (ASCVD). Despite high prevalence, their joint association with ASCVD remains largely unknown., Objective: To investigate the association of obesity with prevalent ASCVD in individuals with heterozygous FH (HeFH) enrolled in the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH)., Methods: FH diagnosis was based on Dutch Lipid Clinic Network (DLCN) criteria. Adults with at least possible FH diagnosis (DLCN score ≥3) and available body mass index (BMI) values were included. Homozygous FH individuals were excluded., Results: 1655 HeFH adults (mean age 51.0 ± 14.4 years, 48.6% female) were included; 378 (22.8%) and 430 (26.0%) were diagnosed with probable and definite FH, respectively. Furthermore, 371 participants (22.4%) had obesity and 761 (46.0%) were overweight. Prevalence of ASCVD risk factors increased progressively with BMI. Prevalence of coronary artery disease (CAD) was 23.4% (3.2% for stroke and 2.7% for peripheral artery disease [PAD]), and increased progressively across BMI groups. After adjusting for traditional ASCVD risk factors and lipid-lowering medication, individuals with obesity had higher odds of established CAD (OR: 1.54, 95% CI: 1.04-2.27, p = 0.036) as well as premature CAD (OR: 1.74, 95% CI: 1.17-2.60, p = 0.009) compared with those with normal BMI. No association was found with stroke or PAD., Conclusions: Over half of adults with HeFH have overweight or obesity. Obesity was independently associated with increased prevalence of CAD in this population., (Copyright © 2024. Published by Elsevier Inc.)

Aims: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals., Methods: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD., Results: Adult patients ( n  = 2156, mean age 50 ± 15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets., Conclusion: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Familial hypercholesterolemia (FH) carries a high risk of atherosclerotic cardiovascular disease (ASCVD). As the population ages, the age-related influence on clinical characteristics and outcomes becomes increasingly pertinent. This cross-sectional analysis from the HELLAS-FH registry aims to explore potential differences in clinical characteristics, treatment, ASCVD, and goal achievement between those younger and older than 65 years with FH., Results: A total of 2273 adults with heterozygous FH (51.4% males) were studied. Elderly FH patients ( n = 349) had a higher prevalence of ASCVD risk factors, such as hypertension (52.1% vs. 20.9%, p < 0.05) and type 2 diabetes (16.9% vs. 6.0%, p < 0.05), compared to younger patients ( n = 1924). They also had a higher prevalence of established ASCVD (38.4% vs. 23.1%, p < 0.001), particularly CAD (33.0% vs. 20.2%, p < 0.001), even after adjusting for major ASCVD risk factors. Elderly patients were more frequently and intensively receiving lipid-lowering treatment than younger ones. Although post-treatment LDL-C levels were lower in elderly than younger patients (125 vs. 146 mg/dL, p < 0.05), both groups had similar attainment of the LDL-C target (3.7% vs. 3.0%)., Conclusions: Elderly FH patients have a higher prevalence of ASCVD, particularly CAD. Despite more aggressive treatment, the achievement of LDL-C targets remains very poor. These results emphasize the importance of early FH diagnosis and treatment in reducing ASCVD.

Aims: To review the barriers and facilitators that cross-sector partners face in promoting physical activity., Methods: We searched Medline, Embase, PsychINFO, ProQuest Central, SCOPUS and SPORTDiscus to identify published records dating from 1986 to August 2021. We searched for public health interventions drawn from partnerships, where the partners worked across sectors and their shared goal was to promote or increase physical activity through partnership approaches. We used the Critical Appraisal Skills Programme UK (CASP) checklist and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool to guide the critical appraisal of included records, and thematic analysis to summarise and synthesise the findings., Results: Findings ( n = 32 articles) described public health interventions ( n = 19) aiming to promote physical activity through cross-sector collaboration and/or partnerships. We identified barriers, facilitators and recommendations in relation to four broad themes: approaching and selecting partners, funding, building capacity and taking joint action., Conclusion: Common challenges that partners face are related to allocating time and resources, and sustaining momentum. Identifying similarities and differences between partners early on and building good relationships, strong momentum and trust can take considerable time. However, these factors may be essential for fruitful collaboration. Boundary spanners in the physical activity system could help translate differences and consolidate common ground between cross-sector partners, accelerating joint leadership and introducing systems thinking., Prospero Registration Number: CRD42020226207.

Familial hypercholesterolemia (FH) and type 2 diabetes mellitus (T2DM) are both associated with a high risk of atherosclerotic cardiovascular disease (ASCVD). Little is known about the prevalence of T2DM and its association with ASCVD risk in FH patients. This was a cross-sectional analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH) including adults with FH (n = 1719, mean age 51.3 ± 14.6 years). Of FH patients, 7.2% had a diagnosis of T2DM. The prevalence of ASCVD, coronary artery disease (CAD), and stroke was higher among subjects with T2DM compared with those without (55.3% vs. 23.3%, 48.8% vs. 20.7%, 8.3% vs. 2.7%, respectively, p < 0.001). When adjusted for age, systolic blood pressure, smoking, body mass index, hypertension, waist circumference, triglyceride levels, high-density lipoprotein cholesterol levels, and gender, T2DM was significantly associated with prevalent ASCVD [OR 2.0 (95% CI 1.2−3.3), p = 0.004]. FH patients with T2DM were more likely to have undergone coronary revascularization than those without (14.2% vs. 4.5% for coronary artery bypass graft, and 23.9% vs. 11.5% for percutaneous coronary intervention, p < 0.001). T2DM is associated with an increased risk for prevalent ASCVD in subjects with FH. This may have implications for risk stratification and treatment intensity in these patients.

Aims: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, such a role in patients with familial hypercholesterolemia (FH) is less documented. The purpose of this study was to evaluate the association between Lp(a) concentrations and ASCVD prevalence in adult patients with FH., Methods: This was a cross-sectional study from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Patients were categorized into 3 tertiles according to Lp(a) levels., Results: A total of 541 adult patients (249 males) with possible/probable/definite FH heterozygous FH (HeFH) were included (mean age 48.5 ± 15.0 years at registration, 40.8 ± 15.9 years at diagnosis). Median (interquartile range) Lp(a) concentrations in the 1st, 2nd and 3rd Lp(a) tertile were 6.4 (3.0-9.7), 22.4 (16.0-29.1) and 77.0 (55.0-102.0) mg/dL, respectively. There was no difference in lipid profile across Lp(a) tertiles. The overall prevalence of ASCVD was 9.4% in the first, 16.1% in the second and 20.6% in the third tertile (p = 0.012 among tertiles). This was also the case for premature ASCVD, with prevalence rates of 8.5, 13.4 and 19.8%, respectively (p = 0.010 among tertiles). A trend for increasing prevalence of coronary artery disease (8.3, 12.2 and 16.1%, respectively; p = 0.076 among tertiles) was also observed. No difference in the prevalence of stroke and peripheral artery disease was found across tertiles., Conclusions: Elevated Lp(a) concentrations are significantly associated with increased prevalence of ASCVD in patients with possible/probable/definite HeFH., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Familial chylomicronemia syndrome (FCS) is a rare inherited disease, mainly due to lipoprotein lipase ( LPL ) gene mutations, leading to lipid abnormalities. Volanesorsen, a second-generation 2'- O -methoxyethyl (2'-MOE) chimeric antisense therapeutic oligonucleotide, can decrease plasma apolipoprotein C3 and triglycerides (TG) levels through LPL-independent pathways. The European Medicines Agency has approved volanesorsen as an adjunct to diet in adult FCS patients with an inadequate response to TG-lowering therapy. Areas covered: Available clinical data on volanesorsen efficacy and safety are presented. Furthermore, we discuss the yearly treatment with volanesorsen of a 21-year-old female FCS patient with LPL mutation. Volanesorsen was well-tolerated and decreased patient's TG levels (from >5000 mg/dL (56 mmol/L) to 350-500 mg/dL (4-5.6 mmol/L)) at 12 months. Lipoprotein apheresis (LA) was stopped and there were no episodes of pancreatitis or abdominal pain. Expert opinion: Severe hypertriglyceridemia can potentially be fatal. Until recently, there was no specific treatment for FCS, apart from hypotriglyceridemic diet, fibrates, omega-3 fatty acids, and LA sessions. Therefore, volanesorsen represents a promising therapeutic solution for these patients. The main side effect of volanesorsen therapy is thrombocytopenia, which should be monitored and treated accordingly. Increasing evidence will further elucidate the clinical implications of volanesorsen use in daily practice.

Background: Cancer outcomes are poor in socioeconomically deprived communities, with low symptom awareness contributing to prolonged help-seeking and advanced disease. Targeted cancer awareness interventions require evaluation., Methods: This is a randomised controlled trial involving adults aged 40+ years recruited in community and healthcare settings in deprived areas of South Yorkshire and South-East Wales., Intervention: personalised behavioural advice facilitated by a trained lay advisor., Control: usual care. Follow-up at two weeks and six months post-randomisation., Primary Outcome: total cancer symptom recognition score two weeks post-randomisation., Results: Two hundred and thirty-four participants were randomised. The difference in total symptom recognition at two weeks [adjusted mean difference (AMD) 0.6, 95% CI: -0.03, 1.17, p = 0.06] was not statistically significant. Intervention participants reported increased symptom recognition (AMD 0.8, 95% CI: 0.18, 1.37, p = 0.01) and earlier intended presentation (AMD -2.0, 95% CI: -3.02, -0.91, p < 0.001) at six months. "Lesser known" symptom recognition was higher in the intervention arm (2 weeks AMD 0.5, 95% CI: 0.03, 0.97 and six months AMD 0.7, 95% CI: 0.16, 1.17). Implementation cost per participant was £91.34, with no significant between-group differences in healthcare resource use post-intervention., Conclusions: Improved symptom recognition and earlier anticipated presentation occurred at longer-term follow-up. The ABACus Health Check is a viable low-cost intervention to increase cancer awareness in socioeconomically deprived communities., Clinical Trial Registration: ISRCTN16872545., (© 2021. The Author(s).)

Aim: We evaluated the lipid-lowering (LL) effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with heterozygous familial hypercholesterolemia (HeFH) treated with LL-drugs and lipoprotein apheresis (LA)., Patients and Methods: The PCSK9i treatment (evolocumab 420 mg/4 weeks, alirocumab 150 mg/2 weeks, or alirocumab 75 mg/2 weeks: 9, 6, and 2 patients, respectively) was initiated in patients with HeFH (n = 17; aged 35-69 years, 10 men, previously treated with statins + ezetimibe ± colesevelam and LA sessions for 2-12 years). A lipid profile was obtained before and immediately after the LA session and before, 1 and 2 months after switching to PCSK9i treatment. The duration of PCSK9i therapy ranged from 3 to 18 months., Results: Median total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels before LA were 268, 198, 46, and 126 mg/dL, respectively, and decreased (at the end of the LA session) to 117, 50, 40, and 51 mg/dL, respectively ( P < .001 for TC and P = .001 for all other comparisons). The median time-averaged LDL-C levels following LA were 155 (121, 176; median [25th, 75th percentile]) mg/dL. Median TC, LDL-C, and TG levels before PCSK9i therapy were 269, 190, and 127 mg/dL and decreased to 152, 100, and 95 mg/dL, respectively ( P = .002, P < .002, and P < .03, respectively). Steady LDL-C levels with PCSK9i treatment were significantly lower compared with time-averaged LDL-C levels following LA (median value: 100 vs 155 mg/dL; P = .008). With PCSK9i, from 13 patients with CHD, 6 (46.1%) patients achieved LDL-C <70 mg/dL, and 2 patients (15.4%) achieved LDL-C <100 mg/dL. Lipoprotein apheresis was discontinued in all patients except for 2 who continued once monthly., Conclusions: PCSK9i can reduce LDL-C more consistently over time compared with a transient decrease following LA in HeFH patients. PCSK9i therapy may reduce the frequency of LA. Larger trials are required to establish the clinical implications of PCSK9i in patients previously on LA.

Background: Recruitment of research participants poses challenges in socioeconomically deprived areas. The Awareness and Beliefs About Cancer (ABACus) phase 3 Randomised Control Trial recruited adult participants from socioeconomically deprived areas using a combined healthcare/community engagement model. We report the strategies used to successfully recruit and retain our trial participant sample., Methods: Community and healthcare settings in areas of high socioeconomic deprivation were identified by lay advisors who recruited participants opportunistically or by appointment. Follow-up was done by telephone or post at 2-weeks and 6-months after recruitment, and all participants were offered financial incentives. Qualitative interviews were conducted with lay advisors regarding their experience and reflections., Results: The lay advisors identified and contacted 107 potential recruitment venues across South and West Yorkshire and South East Wales of which 41.1% (n = 42) were opened for recruitment. A total of 234 participants were recruited, with 91% (n = 212) retention at 2-weeks and 85% (n = 199) at 6-months. Community settings yielded 75% (n = 176) of participants. Participants had a mean age of 61.3 years and 63.3% (n = 148) were female, with 66% (n = 154) resident in the most deprived geographical areas. Lay advisors described recruitment as intensive, although engaging participants was easier in community settings., Conclusions: The ABACus3 trial achieved recruitment and high retention with a population that is often "hard to reach" or entirely missed in health research. Strategies were specifically tailored to engage the venues and adult residents of highly deprived areas. Future studies recruiting adults living in the most deprived areas might benefit from community recruitment and from collaborating with local gatekeepers who are key to engagement. This study adheres to CONSORT guidelines., Trial Registration: Retrospectively registered with ISRCTN ( http://www.isrctn.com/ISRCTN16872545 ) on 12.01.2018.

Aims: The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in patients with homozygous familial hypercholesterolaemia., Methods and Results: In 12 homozygous familial hypercholesterolaemia patients treated with lipid-lowering drugs ± biweekly lipoprotein apheresis sessions (nine patients), daily lomitapide was added. The lipid profile (total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol) before and after lomitapide treatment was evaluated. The follow-up period with lomitapide treatment was 3-24 months (13.8 ± 7.9). The median baseline low-density lipoprotein cholesterol level was 900 mg/dl (348-1070), after lipid-lowering drugs therapy was 383.5 mg/dl (214-866) and after lipid-lowering drugs + time-averaged level was 288 mg/dl (183.7-716.6). The addition of lomitapide lowered low-density lipoprotein cholesterol levels further by 56.8% compared to lipid-lowering drugs alone (mean reduction 262, 95% confidence interval (105.5-418.7), p  = 0.005) and by 54% (mean reduction 182.9, 95% confidence interval (-342 - -23), p  = 0.031) comparing to lipid-lowering drugs + lipoprotein apheresis (time-averaged level). The time-averaged level of low-density lipoprotein cholesterol in lipid-lowering drugs + lipoprotein apheresis patients compared with lipid-lowering drugs + lomitapide was 54% in favour of lomitapide ( p  = 0.031)., Conclusions: Treatment with lomitapide in homozygous familial hypercholesterolaemia patients has a beneficial effect with a constant decrease of low-density lipoprotein cholesterol by 57% compared with classical lipid-lowering therapy and by 54% compared with classical lipid-lowering therapy and time-averaged level of low-density lipoprotein cholesterol.

Rhabdomyolysis (RM), a fortunately rare disease of the striated muscle cells, is a complication of non-traumatic (congenital (glycogen storage disease, discrete mitochondrial myopathies and various muscular dystrophies) or acquired (alcoholic myopathy, systemic diseases, arterial occlusion, viral illness or bacterial sepsis)) and traumatic conditions. Additionally, RM can occur in some individuals under specific circumstances such as toxic substance use and illicit drug abuse. Lipid-lowering drugs in particular are capable of causing RM. This comprehensive review will focus on non-traumatic and non-drug-induced RM. Moreover, the pathology of RM, its clinical manifestation and biochemical effects, and finally its management will be discussed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Termedia & Banach.)

Aims: We evaluated the influence of CETP (rs5882 and rs708272), APOE (rs7412, rs429358) and LPL (rs328) gene polymorphisms on triglyceride (TG) response to oral fat tolerance test (OFTT) meal in patients with well-controlled type 2 diabetes mellitus (T2DM)., Methods: Fifty-one men underwent OFTT and according to postprandial TG response patients were divided into two subgroups (positive [TG ≥ 220 mg/dL, 31 patients] and negative [TG < 220 mg/dL, 20 patients]). All patients were genotyped, and study variants were detected using polymerase chain reaction (PCR) and restricted fragment length polymorphism (RFLP) analysis., Results: Patients with genotype SS of LPL gene compared with genotype SX had more frequently positive response to OFTT (P = .04) and lower high-density lipoprotein cholesterol (HDL-C) concentration (P = .03). Patients with positive response to OFTT and genotype SS of LPL gene compared with genotype SX had lower AUC (area under the curve)-TG, 1744 (368) vs 1887 (807) mg/dL/h, respectively, P = .04. CETP and APOE gene polymorphisms had no influence on postprandial TG response to OFTT., Conclusions: In patients with well-controlled T2DM, LPL but not CETP and APOE gene polymorphisms influenced TG postprandial response. Particularly, S447 allele carriers of LPL gene presented more frequently positive postprandial TG response to OFTT compared with 447X allele carriers. No differences were found between allele carriers of patients with negative response to OFTT in any other studied gene polymorphism., (© 2019 John Wiley & Sons Ltd.)

Fasting and postprandial hypertriglyceridemia have been related to cardiovascular (CV) disease. We describe the design and methods of the Hellenic Postprandial Lipemia Study (HPLS, NCT02163044), a prospective, open-label, randomized, multicentre trial. The study will recruit 900 participants from 8 centers, and aims to determinate the prevalence of abnormal postprandial lipemia in patients at high- and very high-risk for CV disease, the efficacy of statin treatment and other medications on postprandial lipemia, and the interaction between postprandial lipemia and CV risk during a treatment period of 3 years. Participants will be screened in an outpatient lipid clinic setting. METHODS: High- and very high-risk individuals with fasting triglycerides (TGs) <220 mg/dL (2.5 mmol/L) will be included. At baseline visit demographic and clinical characteristics will be recorded. At the first follow-up visit (within 2-4 weeks from baseline), plasma TG concentrations will be measured, following an overnight 12 h fasting period, before and 4 h after ingestion of a commercially available oral fat tolerance test (OFTT) meal. Then a statin will be prescribed. At the second follow-up visit (within 3-5 month from baseline), plasma TG concentrations will be measured again following an overnight 12 h fasting period, before and 4 h after ingestion of OFTT and then patients will be followed annually for 3 years. CONCLUSION: HPLS is the largest trial assessing the effects of statin therapy on postprandial lipemia. Its results will provide useful insight on the prevalence of postprandial lipemia, the efficacy of statins regarding postprandial lipemia and the clinical significance of this effect. Clinical trial registration information The HPLS trial is registered with clinicaltrials.gov (NCT Identifier: NCT02163044)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cancer survival is lower in socioeconomically deprived communities, partly due to low awareness of symptoms, negative beliefs and delayed help-seeking. We developed an interactive health check questionnaire facilitated by trained lay advisors. It entails 29 questions about background, lifestyle and health with tailored behaviour change advice. Personalised results are printed using a traffic light (red/amber/green) system, highlighting areas where action should be taken. This is an individually randomised control trial to test effectiveness of the health check on symptom recognition., Methods: A total 246 participants aged 40+ years will be recruited from community and healthcare settings in socioeconomically deprived areas of Yorkshire and South Wales. Participants will be randomised to receive the health check or standard care (1:1 ratio). Outcome measures include: adapted Awareness and Beliefs about Cancer (primary outcome), brief State Trait Anxiety Inventory, intentions and motivation to adopt recommended health behaviours (early symptom presentation, cancer screening and lifestyle behaviours), adapted Client Service Receipt Inventory, brief medical history/screening and demographic questionnaire at: baseline; 2-weeks; and 6-months post-randomisation. A purposive sample of intervention sessions will be audio-recorded (n = 24) and half will additionally be observed (n = 12). Semi-structured interviews will take place at 2-weeks (n = 30) and 6-months (n = 15-20) post-randomisation. The primary analysis will compare cancer symptom recognition scores between arms at 2-weeks. Secondary analysis will assess cancer beliefs, barriers/time to presentation, screening and lifestyle behaviours, anxiety and costs. A process evaluation will assess intervention fidelity, dose and contamination. The London-Surrey NHS Research Ethics Committee (Ref: 17/LO/1507) approved this trial., Discussion: This is a trial of a theoretically underpinned complex intervention which has undergone phase 1 and 2 development work. The findings will evaluate evidence about the effect of the health check on symptom awareness. Although there are few exclusion criteria there are limitations regarding the population we are able to reach, who may have even higher risks of late diagnosis and poor cancer prognosis. However, the health check has the potential to improve cancer symptom awareness and encourage early help-seeking behaviour in deprived populations, thereby reducing inequalities in longer term cancer outcomes., Trial Registration: Retrospectively registered with ISRCTN (Ref: ISRCTN16872545 ) on 12.01.2018.

Patients with left main (LM) coronary artery disease (CAD) are at the highest risk of cardiovascular events. We evaluated possible gene polymorphisms of tumor protein 53 ( TP53, rs1042522, p.Arg72Pro) that can differentiate LM-CAD from patients with more peripheral CAD (MP-CAD) and healthy participants (control group) in 520 individuals (LM-CAD, n = 175; MP-CAD, n = 185; and control group, n = 160). Patients with LM-CAD had the lowest Arg/Arg genotype frequency (36.0%) compared with the MP-CAD (57.3%) and control groups (61.9%), P < .001 for both comparisons. Similarly, the Arg allele was more frequent in the control group than in patients with MP-CAD (78.8% vs 73.2%; P = .007) and LM-CAD (78.8% vs 64.0%; P < .001). The Arg/Pro genotype was more frequent in the LM-CAD group compared with the MP-CAD and control groups (56.0, 31.9, and 33.8, respectively, P < .001 for both comparisons). Furthermore, the frequency of Arg/Arg genotypes was the lowest in the LM-CAD group compared with the MP-CAD and control groups. Knowing that TP53 is an antioncogene protein that acts as a tumor suppressor and regulator of apoptosis, the lowest frequency of Arg/Arg genotype observed in these high-risk patients may indicate lower protection from the atherosclerosis process. Replication studies are needed to evaluate this association.

Background: The influence of biomarkers in human lifespan has been investigated but with no clear results yet., Materials and Methods: Lipids, Uric Acid (UA), Adiponectin (ADIPOQ), Insulin-like Growth Factor (IGF-1), cholesteryl ester transfer protein (CETP) and angiotensin-converting enzyme (ACE) proteins, as well as CETP , ADIPOQ , insulin-like growth factor binding protein-3 ( IGFBP3 ) and ACE -gene polymorphisms were evaluated in 149 Greek individuals. The Long-Lived Families (LON) (n=84) comprised of 3 generations: long-lived aged ≥90 years (P), offspring (FL1) and their grandchildren (FL2), while the Short-Lived Families (EAD) (n=65) where both parents died <75 years, comprised of 2 generations: middle-aged (FD1) and children (FD2)., Results: Serum CETP and IGF-1 levels were lower, whereas AdipoQ concentrations were higher in P compared with FL1 and FL2 members (CETP: p = 0.03 for both comparisons; IGF-1 p < 0.001 for both comparisons and ADIPOQ: p = 0.001 and p = 0.004, respectively). Furthermore, serum triglycerides, UA and glucose concentrations were higher in FD1 compared with FD2 subjects (p=0.001, 0.02 and ≤0.001, respectively). In FD2 and FL2, CETP levels were lower in individuals with B2B2 compared with B1B1 genotype (p=0.007). Additionally, ACE concentrations were higher in individuals with DD compared with II genotype in both Families (p=0.001). After adjustment for age and gender, CETP levels were lower in P and FL2 individuals with B2B2 compared with the B1B1 genotype (p=0.004 and 0.007, respectively)., Conclusion: Increase serum TGs, UA and GL concentrations were higher in the middle-aged individuals compared with their children in families independently of their lifespan. The serum adiponectin concentration was the highest in the oldest old individuals implying beneficial influence on lifespan. Independently of family's lifespan history, the youngest individuals with CETPB2B2 genotype, compared with individuals with CETPB1B1 genotypes, had lower serum CETP concentrations. The knowledge of the unfavourable gene(s)influencing human lifespan may be helpful in encouraging individuals to follow healthier lifestyle habits and better control their high-risk biomarkers.

Background: Enhanced postprandial lipaemia has been reported in patients with obesity, hypertension, metabolic syndrome and type 2 diabetes mellitus (T2DM). We compared 2 oral fat meal tests (LIPOLD: 149g of fat, 56g of carbohydrates and 11.7g of proteins administrated per 2m2 of body surface) and LIPOTEST: 75g of fat, 25g of carbohydrates and 10g of protein with the addition of 15g common sugar) with regard to changes in triglycerides (TGs) as well as other cardiometabolic parameters between baseline and 4 h after the meals., Methods: We studied 21 men [median age (interquartile range; IQR) = 65 (16) years] with well-controlled T2DM [median glycated haemoglobin (HbA1c) (IQR) = 6.6 (0.9) %]. All participants performed the meals with 1 week interval between the 2 meals., Results: Median (IQR) TG differences in mg/dl were 86 (100) and 46 (60) for LIPOLD and LIPOTEST meals, respectively, whereas the % differences in TGs were 105 (105) and 48 (55), respectively. The differences (in mg/dl and %) between TGs before ingesting the test meal and after 4h were significant for both LIPOLD and LIPOTEST meals (p = 0.003 for mg/dl differences and p = 0.005 for % differences). Patients who had a positive response to the LIPOLD meal (i.e. TGs > 220 mg/dl at 4 h) also had increased postprandial TGs with LIPOTEST. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) correlated with TG differences (in mg/dl) following the LIPOLD meal consumption (Spearman's rho = (+) 0.527, p = 0.02). C-peptide correlated with TG differences (in mg/dl) following the LIPOTEST meal consumption (Spearman's rho = (+) 0.538, p = 0.032). There were no differences in TGs and glucose response postprandially in both testing meals according to body mass index (except for TGs between tertile 21.3-24.5 and 25-26.8 kg/m2, p=0.046, in LPOTEST group) and body surface area., Conclusion: An oral fat tolerance test (OFTT), which contains 75g fat, and represents the everyday habits of Western societies, could provide additional information regarding the postprandial state of the individuals with well-controlled T2DM. The consumption of meals with very high fat content may lead to over diagnosing PPL. TG differences after the consumption of a high fat meal correlated with HOMA-IR. This may be useful to evaluate the role of HOMA-IR in T2DM patients. A standardized the OFTT will help clinicians to better define postprandial TG abnormalities, leading to more appropriate therapeutic options to improve postprandial dysmetabolism., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: We have earlier developed a pharmacogenomic algorithm for acenocoumarol dose prediction in Greek patients that included CYP2C9/VKORC1 genetic information. This study aims at analyzing the potential effect of CYP4F2, CYP2C19, and CYP1A2 gene polymorphisms on acenocoumarol dose requirements and at further improving the Greek-specific pharmacogenomic algorithm., Methods: A total of 205 Greek patients taking acenocoumarol (140 who reached and 65 who did not reach stable dose), participants of acenocoumarol EU-PACT trial, were included in the study. CYP4F2, CYP2C19, and CYP1A2 polymorphisms were genotyped by use of the PCR-RFLP method. All patients were previously genotyped for CYP2C9/VKORC1 polymorphisms., Results: In the pooled sample, CYP4F2, CYP2C19, and CYP1A2 polymorphisms do not affect independently acenocoumarol dose requirements. For CYP4F2, significant effects were found on patients' ability to reach stable dose and on acenocoumarol dose requirements when CYP2C9/VKORC1 sub-phenotypes were analyzed. Specifically, when the patients were stratified according to their CYP2C9/VKORC1 functional bins, in sensitive responders, CYP4F2*3 allele carriers (CYP4F2 *1/*3 and *3/*3 genotypes) were more frequent in the patient group who reached stable dose (p=0.049). Additionally, in CYP2C9 intermediate metabolizers (IMs), after adjusting for age, weight, and VKORC1 genotypes, CYP4F2 genotypes were significantly associated with acenocoumarol stable dose (β: 0.07; 95% CI: 0.006-0.134; p=0.033)., Conclusions: CYP4F2 gene shows a prominent weak association with acenocoumarol dose requirements. Sub-phenotype analysis is potentially important in determining additional gene polymorphisms that are associated with acenocoumarol dose requirements.

Introduction: Genetic factors contribute to the variation of human life span which is believed to be more profound after 85 years of age. The aim of the present study was to evaluate the frequency of 5 gene polymorphisms between nonagenarians, centenarians and average individuals., Material and Methods: Single nucleotide polymorphisms (SNPs) of telomerase reverse transcriptase ( TERT ; rs2736098), insulin-like growth factor-1 binding protein-3 ( IGFBP3 ; A-202C, rs2857744), fork-head box O3A ( FOXO3A ; rs13217795 and rs2764264) factor and adiponectin ( ADIPOQ ; rs2241766) were evaluated in 405 individuals: n = 256 nonagenarians and centenarians (study group) and n = 149 average lifespan individuals (control group aged 18 - < 80 years)., Results: The frequency of women was significantly higher in the study group than the control group (64.5 vs. 49.7%, p = 0.004). Genotypic and allele frequencies did not differ between groups according to gender. However, in men, the frequency of TT genotype of FOXO3A ; rs2764264 was higher in the study group than the control group (45.6 vs. 28.0%, p = 0.05). Overall, the frequency of the C allele of FOXO3A ; rs2764264 was significantly lower in the study group than the control group (3.9 vs. 9.5%, respectively, p = 0.023). Furthermore, in the study group, the T allele was significantly more frequent in the nonagenarians ( n = 239) than the centenarians ( n = 17) in both FOXO3A ; rs13217795 and rs2764264 (64.4 vs. 44.1%, p = 0.018 and 69.7 vs. 50.0%, p = 0.017, respectively)., Conclusions: According to survival status, there is differentiation in the prevalence of both studied FOXO3A gene polymorphisms. The study group had half of the C alleles compared with the control group and centenarians less frequently had the T allele of both FOXO3A gene polymorphisms compared with nonagenarians. No difference was found between groups according to TERT , IGFBP3 and ADIPOQ gene polymorphisms. It seems that some polymorphisms may be significant in prolonging our lifespan. Nevertheless, confirmation in additional study populations is needed.

Aim: To generate and validate a pharmacogenomic-guided (PG) dosing algorithm for acenocoumarol in the Greek population. To compare its performance with other PG algorithms developed for the Greek population., Patients & Methods: A total of 140 Greek patients participants of the EU-PACT trial for acenocoumarol, a randomized clinical trial that prospectively compared the effect of a PG dosing algorithm with a clinical dosing algorithm on the percentage of time within INR therapeutic range, who reached acenocoumarol stable dose were included in the study., Results: CYP2C9 and VKORC1 genotypes, age and weight affected acenocoumarol dose and predicted 53.9% of its variability. EU-PACT PG algorithm overestimated acenocoumarol dose across all different CYP2C9/VKORC1 functional phenotype bins (predicted dose vs stable dose in normal responders 2.31 vs 2.00 mg/day, p = 0.028, in sensitive responders 1.72 vs 1.50 mg/day, p = 0.003, in highly sensitive responders 1.39 vs 1.00 mg/day, p = 0.029). The PG algorithm previously developed for the Greek population overestimated the dose in normal responders (2.51 vs 2.00 mg/day, p < 0.001)., Conclusion: Ethnic-specific dosing algorithm is suggested for better prediction of acenocoumarol dosage requirements in patients of Greek origin.

The limited distribution of lipoprotein (a) (Lp(a)) to humans, Old World primates and to the European hedgehog, has raised considerable interest and speculation regarding its possible physiological role. Lp(a) has variable circulating concentrations (<0.1 - >100 mg/ml) which are highly genetically determined in humans. These characteristics gave rise to several theories concerning the origins and evolution of Lp(a). Lp(a) has a protective role after injury since Lp(a) particles bind to macrophages and platelets membrane receptors, leading to fibrin activation and injury healing. On the other hand, Lp(a) seems to be implicated in the formation of atheromatic plaques but also in cerebrovascular events and stenosis of the aortic valve. The main genetic factor determining plasma Lp(a) levels is the Lp(a) gene (LPA). Most Caucasian people have normal plasma Lp(a) concentrations, but there is important distribution variation according to race. Women seem to have increased Lp(a) levels compared with men, while diabetes mellitus type 2 favours lower plasma Lp(a) levels. Nutrition, hormones and several drugs may also influence circulating Lp(a) levels., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: The present study is on line with our previous studies evaluating the influence of ATP-binding cassette transporter A1 ( ABCA1 ) gene polymorphisms on the lipid variables of Greek student-nurses. The current study was undertaken to (1) estimate the influence of variant(s) such as rs2066715 (V825I), R219K, R1587K, I883M of ABCA1 gene on lipid variables and (2) evaluate the effect of all four ABCA1 polymorphisms on common demographic parameters., Methods: The study population involved 432 unrelated nurses (86 men) who were genotyped for ABCA1 polymorphisms and correlated according to lipid variables [total cholesterol (TC), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) A] and demographic parameters (age, gender, BMI, waist circumference)., Results: According to lipid variables concentration there was no difference between genotypes and alleles of V825I, R219K and I883M polymorphisms. The LDL-C concentration was 13% lower in RR compared with RK genotype (100.7 vs . 113.9 mg/dl, p=0.013) of R1587K gene polymorphism. In regression analysis the effects of age, gender and only R1587K gene polymorphism on LDL-C concentrations were proved significant. Additionally, LDL-C was increased (by 1.29 mg/dl on average) by every year of increase of age. Moreover, females had lower LDL-C concentrations as compared with males., Conclusion: Findings suggested that only R1587K polymorphism of ABCA1 gene was associated with lipid variables, age, and gender of Greek nurses. These findings may be helpful in assessing the risk factors for premature coronary heart disease and distinct individuals with lower/higher atherosclerotic burden.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder, which leads to premature cardiovascular diseases. Microsomal triglyceride transport protein (MTP) inhibitors, such as lomitapide, offer a new therapeutic approach for treating these patients. We evaluated the lipid lowering (LL) efficacy of lomitapide according to several gene variants in MTP. Four clinically and/or molecularly defined HoFH patients were treated with lomitapide in addition to conventional high intensity LL therapy and regular lipoprotein apheresis. Two patients responded to the therapy, with a significant reduction of LDL cholesterol (LDL-C＞50%, hyper-responders). Sequencing of all exonic and intronic flanking regions of the MTP gene in all patients revealed 36 different variants. The hyper-responders to lomitapide shared six common variants: rs17533489, rs79194015, rs745075, rs41275715, rs1491246, and rs17533517, which were not seen in hypo-responders (reduction in LDL-C＜50%). We suggest that in HoFH variants in the MTP gene may impact on the therapeutic response to lomitapide, but this requires further investigation.

Background: Hypertension, one of the most important risk factors for premature cardiovascular disease, is a major worldwide public health problem. Angiotensin-1-converting enzyme (ACE) and angiotensinogen (AGT) gene polymorphisms are thought to be associated with primary hypertension. In the present study, we examined the frequency of these gene polymorphisms in an adult population with and without essential hypertension. Furthermore, we evaluated the effect of ACE and AGT gene polymorphisms on ramipril treatment efficacy in the hypertensive patients., Methods: A total of 166 adults (83 hypertensives and 83 normotensives) were involved in the study and genotyped for AGTM235T (rs699), AGTT174M (rs4762) and ACEI/D (rs1799752) gene polymorphisms., Results: The genotype and allele distribution of the AGTM235T variant significantly differed between hypertensives and normotensives [odds ratio (OR) = 1.57% (T vs M allele), 95% confidence intervals (CIs): 1.01 - 2.44; p=0.045 for hypertensives]. However, none of the 3 studied Simple Nucleotide Polymorphisms were associated with the blood pressure-lowering response to ramipril., Conclusion: These results suggest that AGTM235T gene polymorphism is associated with essential hypertension. However, none of the AGTM235T, AGTT174M and ACEI/D gene polymorphisms influenced ramipril effectiveness.

Objective: In the present study, we evaluated the influence of lipoprotein lipase (LPL) and apolipoprotein (apo) E polymorphisms on lipid concentrations of 178 Greek men of similar age with coronary heart disease (CHD), but varying body mass index (BMI)., Design: Patients were divided according to their BMI (in kg/m²) into three groups: lean (BMI = 20-24.9), overweight (BMI = 25-29.9), and obese (BMI ≥ 30). Polymorphisms of LPL (HindIII, S447X) and apo E (ε2, ε3, ε4), and lipid parameters were studied., Results: There was a negative correlation between BMI and high-density lipoprotein cholesterol (HDL-C) concentration (r = -0.272, p < 0.001), as has already been described. Lean homozygotes for the HindIII(+) allele had higher HDL-C levels compared to lean homozygotes for the HindIII(-) allele (p = 0.012). No correlation was found between S447X or apo E polymorphisms and BMI or plasma lipids in any group. Overweight men with the ε3/ε3 and SS genotypes had higher triglycerides concentration compared with overweight men with ε3/ε3 and SX (p = 0.002)., Conclusions: The HindIII polymorphism alone may influence HDL-C concentration in lean men, in contrast to S447X alone, which has no influence on any lipid parameters. However, the S447X and apo E polymorphisms may have a synergetic effect and alter plasma triglyceride concentration in overweight men.

Identifying the mechanisms that convert a healthy vascular wall to an atherosclerotic wall is of major importance since the consequences may lead to a shortened lifespan. Classical risk factors (age, smoking, obesity, diabetes mellitus, hypertension, and dyslipidemia) may result in the progression of atherosclerotic lesions by processes including inflammation and lipid accumulation. Thus, the evaluation of blood lipids and the full lipid complement produced by cells, organisms, or tissues (lipidomics) is an issue of importance. In this review, we shall describe the recent progress in vascular health research using lipidomic advances. We will begin with an overview of vascular wall biology and lipids, followed by a short analysis of lipidomics. Finally, we shall focus on the clinical implications of lipidomics and studies that have examined lipidomic approaches and vascular health.

In this work, we examined the impact of polymorphism in the cytochrome P450 (CYP) 3A5 gene, CYP3A5*1 (6986A > G, rs 776746), on the reduction in the lipid levels caused by simvastatin and atorvastatin. We studied 350 hyperlipidemic patients who received 10-40 mg of atorvastatin (n = 175) or simvastatin (n = 175) daily. Genotyping for CYP3A5 was done by PCR-RFLP analysis. Differences in the lipid profile before and after treatment were expressed as the % difference. The frequency of CYP3A5polymorphism was 13.4% for heterozygotes and 86.6% for homozygotes. Comparison of the responses to same dose of each drug showed that the highest % difference was associated with total cholesterol (TC) in subjects receiving atorvastatin 40 mg compared with simvastatin 40 mg (p = 0.048). However, comparison of the responses to equivalent doses of atorvastatin vs. simvastatin revealed no difference in the % change in any of the lipid parameters examined. In individuals with the same CYP3A5 genotype, a head to head comparison of the efficacy of the same dose of simvastatin vs. atorvastatin revealed an advantage for atorvastatin. For equivalent doses of atorvastatin vs. simvastatin there was no difference in the % change in any of the lipid parameters examined. Within the same genotype there was a significant difference in the % change related to the drug treatment.

The genetic causes of cholesterol metabolism disorders usually lead to premature atherosclerosis. The most well recognized genetically caused hypercholesterolemia is familial hypercholesterolemia. Although the disease is well known, as the discovery of low-density lipoprotein receptor, the classical treatment with lipid-lowering drugs (statins, fibrates, ezetimibe, colesevelam) is still not adequate and new options are seeking. This review is an attempt to analyze the microsomal transfer protein (MTP) inhibitors as a new approach for treatment of familial hypercholesterolemia, to reviews the literature according to MTP inhibitors and finally to provide original findings., (© 2015 John Wiley & Sons Ltd.)

Background: Interindividual variability exists in statin lipid-lowering response, partially attributed to genetic factors. CYP3A4 intron 6 C>T polymorphism (CYP3A4*22 allele, rs35599367) has been recently identified and was associated with reduced CYP3A4 expression. We analyzed the association of CYP3A4*22 allele with response to atorvastatin and simvastatin., Methods: A total of 416 statin-treated (207 atorvastatin- and 209 simvastatin-treated) adults with primary hypercholesterolemia were included in the study. Total cholesterol and low-density lipoprotein cholesterol were measured at baseline and on 6 months of treatment. CYP3A4*22 allele was analyzed with TaqMan assay., Results: In the entire cohort population, 41 individuals carried CYP3A4*22 allele (18 in atorvastatin and 23 in simvastatin treatment). CYP3A4*22 allele was not associated with lipid-lowering response to atorvastatin or simvastatin. No sex-gene or statin dose-gene interaction was observed in either statin-treated patient cohort., Conclusions: The effect of CYP3A4*22 allele on lipid-lowering response to CYP3A metabolized statins, if present, can potentially be masked by relevant confounding or uncontrolled factors; therefore, further population-driven studies are required.

Plasma lipids are major risk factors for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) and apolipoprotein (apo) E genes are involved in lipoprotein metabolism, thus affecting plasma lipid and lipoproteins levels. Furthermore, such polymorphisms have been associated with susceptibility to CHD and obesity. We evaluated the influence of the gene polymorphisms of CETP TaqIB (B1, B2) and I405V (V, I) and apo E (∊2,∊3,∊4) on lipid levels, according to body mass index (BMI) in Greek men with CHD. The TaqIB (B1, B2) polymorphism affected plasma low-density lipoprotein cholesterol levels in overweight men with CHD, whereas the I405V (V, I) polymorphism affected triglyceride concentrations in normal weight men. No correlation was found between BMI and apo E polymorphisms. Large prospective studies are required to investigate the relationships of CETP and apo E polymorphisms with lipids, BMI, and CHD susceptibility., (© The Author(s) 2014.)

Atherosclerotic Coronary heart disease (CHD) and non-atherosclerotic CHD in individuals less than 50 years of age is considered a "men's case". Undoubtedly, premenopausal women develop atherosclerotic/non-atherosclerotic CHD relatively rarely compared with men. This is attributed mostly to the cardioprotective role of estrogens (mainly estradiol). Nevertheless, there are predisposing conditions, which also make young women vulnerable to develop atherosclerotic/non-atherosclerotic CHD. Women who have classical cardiovascular (CV) risk factors, such as hypertension, diabetes mellitus, smoking, obesity, and dyslipidaemia, are more likely to develop cardiac events, even at a young age. Moreover, there are also other conditions that cause acute coronary syndromes, even in the absence of coronary atheromatic plaques such as myocardial bridge, coronary artery dissection, coronary artery spasm, coronary artery embolism and congenital anomalies of coronary arteries. Also, autoimmune diseases, some of which are more prevalent in women can cause atherosclerotic/ non-atherosclerotic CHD. In this narrative review we have summarized some of the causes that predispose young women to develop atherosclerotic/non-atherosclerotic CHD.

Pharmacogenetics investigates heritable genetic polymorphisms that can effect responses to drug therapy. The main application of pharmacogenetics is genotype-guided dosing of medications and genotype-selection of treatment with the highest efficacy and lowest risk of adverse effects. Cardiovascular disease (CVD) is the leading cause of mortality and morbidity globally. Dyslipidemia is one of the classical risk factors for developing CVD. 3-hydroxy-3-methylglutaryl-coenzyme (HMGCoA) reductase inhibitors called statins are the cornerstones in dyslipidemia treatment. However, there is a broad variation in individual responses to statin treatment. This variation may not only be due to environmental factors such as adherence to treatment, diet and exercise but also due to genetic factors. Many studies have focused on various genetic polymorphisms of genes that are involved in cholesterol metabolism, trying to define their contribution to a potential genotype-guided treatment against dyslipidemia.

Objective: This study is in line with two previous ones from our group. They evaluated the influence of ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms [such as rs2230806 (R219K), rs2230808 (R1587K) and rs4149313 (I883M)] on the human lipid profile (defined as Optimal and Non-Optimal)., Methods: The present study included 447 unrelated young women and men self-reported as being healthy and that attended the University of Nursing of Technological and Educational Institution. All subjects were genotyped and the ABCA1 polymorphisms (R219K, R1587K and I883M) were recorded. According to lipid profile [total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C)] the subjects were separated into those with optimal lipid profile (Optimal Group, n=209) and Non-Optimal Group (n=238)., Results: No statistical differences were observed in the distribution of R219K, R1587K and I883M polymorphisms according to the lipid profile (p>0.05 in all cases). No statistical differences were observed in the distribution of R219K, R1587K and I883M polymorphisms according to sex (p>0.05 in all cases). However, Logistic Regression revealed that subjects with RK (R1587K polymorphism) genotype had 69% increased risk on average of having LDL-C above normal limits as compared with those with RR genotype. Similarly, subjects with K allele (R1587K polymorphism) had 59% increased risk on average of having LDL-C above normal limits compared with those with R allele., Conclusion: These findings suggest that R1587K polymorphism of ABCA1 gene may influence the lipid profile. However, this needs to be confirmed by larger studies.

Interindividual variability exists in statin lipid-lowering response, partially attributed to genetic factors. Organic anion-transporting polypeptide 1B1 (OATP1B1) encoded by SLCO1B1 gene (solute carrier organic anion transporter family member 1B1) facilitates hepatic uptake of simvastatin and atorvastatin. SLCO1B1 polymorphisms are strongly associated with statin-induced myopathy whereas few studies have assessed their effect on statin differential response. In the present study, we analyzed the association of SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms with response to atorvastatin and simvastatin in 386 adults (201 atorvastatin-treated and 185 simvastatin-treated) with primary hypercholesterolemia, all of Greek origin. Total cholesterol and low-density lipoprotein cholesterol were measured at baseline and on 6 months of treatment. Genetic polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A novel RFLP protocol was developed for the simultaneous identification of 388A>G and 411G>A polymorphisms. SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms were not associated with lipid-lowering response to atorvastatin or simvastatin. No sex-gene or statin dose-gene interaction was observed on the effect of the analyzed SLCO1B1 polymorphisms in statin lipid lowering response in either statin-treated patient cohort. Further studies in different populations are required to draw firm conclusion on the potential association of SLCO1B1 polymorphisms with statin lipid-lowering response.

Background and Objective: Inter-individual variability exists in the statin (HMG-CoA reductase inhibitor) lipid-lowering response, which is partially attributed to genetic factors. The polymorphic enzyme P450 oxidoreductase (POR) transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to cytochrome P450 (CYP) 3A enzymes, which metabolize atorvastatin and simvastatin. The POR*28 allele is associated with increased activity of CYP3A enzymes. We analyzed the association of the POR*28 allele with response to atorvastatin and simvastatin., Methods: A total of 207 atorvastatin-treated adults were included in the study. An independent population of 210 simvastatin-treated adults served as a replication cohort. Total cholesterol (TChol) and low-density lipoprotein cholesterol (LDL-C) were measured at baseline and after 6 months of treatment. The POR*28 allele was analyzed with a TaqMan(®) assay., Results: The POR*28 allele was associated with a non-significant trend towards lower percentage mean reduction of TChol (-35.5 % in *1/*1, -33.7 % in *1/*28, and -29.5 % in *28/*28 individuals) and LDL-C (-42.6 % in *1/*1, -41.7 % in *1/*28, and -37.8 % in *28/*28 individuals) in response to atorvastatin. This trend was not observed in the replication cohort of simvastatin-treated patients. No sex-gene interaction was observed regarding the effect of the POR*28 allele on the statin lipid-lowering response in either statin-treated patient cohort., Conclusion: The POR*28 allele was not associated with the lipid-lowering effect of atorvastatin and the results were replicated in an independent simvastatin-treated population. The hypothesized effect of the POR*28 allele on the lipid-lowering response to CYP3A-metabolized statins can potentially be masked by relevant confounding or uncontrolled factors; therefore, further studies in different populations are required.

Single nucleotide polymorphisms of angiotensin-converting enzyme (ACE) such as rs1799752, nuclear factor kappa B (NFkB) such as rs28362491 and cholesteryl ester transport protein (CETP) such as rs708272 (TaqB1) and rs5882 (I405V) were evaluated in nonagenarians, centenarians, and average life span individuals (controls). The study population (n = 307; 190 nonagenarians, 12 centenarians and 105 middle-aged controls) was genotyped for ACE, NFkB, and CETP genetic variants. The age of nonagenarian and centenarian group ranged between 90 and 111 years; centenarians and controls age ranged from 99 to 111, and from 18 to 80 years, respectively. The I carriers of ACE I/D gene were fewer in nonagenarians compared to centenarians (37.6% vs 62.5%, P = .016). The I carriers of ACE gene were more frequent in centenarians compared to controls (62% vs 41%, P = .045). No differences in frequency of common NFkB and CETP genotypes between patients with exceptional longevity and middle-aged patients were observed.

Background: One of the promises of human genetics is individualized therapy. Therefore, we evaluated the impact of CYP3A5 gene polymorphism on the effectiveness of simvastatin (a HMG-CoA reductase inhibitor)., Methods: Patients (n = 191) with hypercholesterolemia were treated with simvastatin for at least 6 months and were genotyped for the CYP3A5 polymorphism., Results: The frequency of CYP3A5 polymorphism was 0.5% for WT (wild-type), 15.6% for HT (heterozygous, expressors) and 83.9% for HM (homozygous, non-expressors). Differences in lipid profile before and after dose-response of simvastatin treatment were described as % difference {[(variable after-variable before)/variable before]*100}. There was a trend towards the decrease of low density lipoprotein cholesterol (LDL-C) in HT individuals who had a -35.2% reduction with a dose of 20 mg simvastatin and HM individuals who had a slightly higher decrease (-37.5%) despite the lower dose of simvastatin (10 mg, p = 0.07). Furthermore, HT genotype individuals had significantly higher than expected (6-8%) LDL-C % difference between 20 and 40 mg of simvastatin (-35.2 vs -49.2%, p = 0.037). In individuals with HM genotype a significant LDL-C % difference was found between 10 and 40 mg of simvastatin (-37.5 vs -48.4%, p = 0.023)., Conclusion: The individuals with HM polymorphism display a trend towards higher LDL-C reductions compared with HT polymorphism. Within the same genotype, differences between doses were also observed. These findings need to be confirmed in larger studies.

We evaluated nuclear factor kappa B {NFkB, rs28362491 [-94ins/delATTG (W/D)]} and angiotensin converting enzyme {ACE; rs1799752 [Ins(I)/Del(D)]} gene polymorphisms and their correlation with thyroid function in patients with heart failure (HF). Peak oxygen uptake (VO(2)) was evaluated (by Weber classification) during a symptom-limited cardiopulmonary exercise test in 194 patients. Thyroid-stimulating hormone, triiodothyronine (T3), thyroxine (T4), and free (F) T3 and FT4 were also measured. According to their cardiovascular (CV) capacity, patients were subdivided into four groups: group A included patients with peak VO(2) >20 ml/kg/min, group B 16-20 ml/kg/min, group C 10-16 ml/kg/min, and group D 6-10 ml/kg/min. Patients were also genotyped for NFkB and ACE genetic variants. T3 was increased and FT3 was decreased for every raise in Weber's classification (p = 0.007 and p = 0.012, respectively). Del carriers had elevated FT3 levels compared with Ins carriers (p = 0.021). Patients with II genotype had elevated T4 levels compared with ID genotype (p = 0.044). Both T4 and FT4 were decreased in D allele carriers (p = 0.007 and p = 0.045, respectively). Thyroid hormones correlated with CV capacity. Associations between the NFkB and ACE gene polymorphisms and thyroid hormones levels were also observed. Further larger studies are required to clarify genes contribution in HF.

Ageing and longevity is unquestioningly complex. Several thoughts and mechanisms of ageing such as pathways involved in oxidative stress, lipid and glucose metabolism, inflammation, DNA damage and repair, growth hormone axis and insulin-like growth factor (GH/IGF), and environmental exposure have been proposed. Also, some theories of ageing were introduced. To date, the most promising leads for longevity are caloric restriction, particularly target of rapamycin (TOR), sirtuins, hexarelin and hormetic responses. This review is an attempt to analyze the mechanisms and theories of ageing and achieving longevity.

Estrogens influence lipid metabolism and body fat distribution in women. Premenopausal women have increased lipoprotein lipase action in abdominal and femoral subcutaneous fat compared with men of the same age. Estrogens may also affect adipose tissue either directly through specific estrogen receptors or indirectly via their effects on other tissues. As adipose tissue produces several cytokines including leptin, adiponectin and interleukin-6, estrogens may alter their levels, thus influencing various biological processes. Lack of estrogens such as in menopause, causes an increase in visceral adiposity, leading to changes in lipid and lipoprotein metabolism. Due to those alterations, postmenopausal women are more prone to coronary heart disease. In this review the influence of estrogens on body mass index, lipid metabolism and some of the therapeutic options will be analyzed.