Autosomal recessive hypercholesterolemia: Case report.

INTRODUCTION: Autosomal recessive hypercholesterolemia (ARH; OMIM #603813) is a very rare monogenic disorder affecting less than 1 in 1000,000 people and is characterized by very high levels of low-density lipoprotein cholesterol (LDL-C), leading to aggressive and premature atherosclerotic cardiovascular disease if left untreated. Lowering of LDL-C is the main target of the treatment. We report on a 29-year-old male patient born in nonconsanguineous Lithuanian family homo(hemi-)zygous for LDLRAP1 gene variant causing ARH. This variant is not present in population databases and, to our knowledge, has not been reported in scientific literature before. METHODS AND RESULTS: The earliest clinical sign, noticed at the age of 5 years, was painful and enlarging nodules on Achilles tendons. At the age of 10 years, xanthomas of the metacarpal joint area on both hands emerged. The first lipid panel was performed at the age of 12 years. In accordance with Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolemia (FH), definite FH (type IIA hyperlipoproteinemia) was diagnosed and the treatment with cholestyramine 4 grams per day was initiated. As the patient was 15 years old, direct adsorption of low-density lipoprotein apheresis was started and repeated monthly. At the age of 20 years, along with lipoprotein apheresis, 10 mg of rosuvastatin daily intake was prescribed. At the age of 28 years, the dose of rosuvastatin was increased to 40 mg per day, and 10 mg of ezetimibe daily intake was added. At the age of 28 years, homozygous LDLRAP1 gene variant NM_015627.2:c.488A.C, NP_056442.2:p.(Gln163Pro) causing autosomal recessive hypercholesterolemia was determined by genetic testing. CONCLUSIONS: This case report implies that ARH, being an extremely rare disorder, is a severe disease. As there is limited routine testing, including genetic testing, patients suffering from both this disease and FH may remain undiagnosed. Cascade screening and genetic counseling differ for ARH as compared with FH, as the carrier of a pathogenic variant in the LDLRAP1 gene does not have marked total cholesterol and LDL-C elevations. However, genetic testing of the proband and their relatives is essential to evaluate the risk of development of FH and to provide prognosis as well as adequate, timely treatment. To improve the quality of life of patients with FH and prolong their life expectancy, national registries of FH and wider laboratory and genetic testing are undoubtedly necessary. A national FH screening program was set up in Lithuania, which helps to identify, monitor, and treat subjects with FH

HDAC and HMT inhibitors in combination with conventional therapy: a novel treatment option for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by PML-RARA translocation, which causes the blockage of promyelocyte differentiation. Conventional treatment with Retinoic acid and chemotherapeutics is quite satisfactory. However, there are still patients who relapse or develop resistance to conventional treatment. To propose new possibilities for acute leukemia treatment, we studied the potential of histone deacetylase (HDAC) inhibitor and histone methyl transferase (HMT) inhibitor to enhance conventional therapy in vitro and ex vivo. NB4 and HL60 cell lines were used as an in vitro model; APL patient bone marrow mononuclear cells were used as an ex vivo model. Cell samples were treated with Belinostat (HDAC inhibitor) and 3-Deazaneplanocin A (HMT inhibitor) in combination with conventional treatment (Retinoic acid and Idarubicin). We demonstrated that the combined treatment used in the study had slightly higher effect on cell proliferation inhibition than conventional treatment. Also, enhanced treatment showed stronger effect on induction of apoptosis and on suppression of metabolism. Moreover, the treatment accelerated granulocytic cell differentiation and caused chromatin remodelling (increased H3K14 and H4 acetylation levels). In vitro and ex vivo models showed similar response to the treatment with different combinations of 3-Deazaneplanocin A, Belinostat, Retinoic acid, and Idarubicin. In conclusion, we suggest that 3-Deazaneplanocin A and Belinostat enhanced conventional acute promyelocytic leukemia treatment and could be considered for further investigations for clinical use

Lower than average HDL cholesterol efflux capacity in Lithuanian population.

Background: The aim of our study was to evaluate high-density lipoprotein cholesterol (HDL-C) efflux capacity in healthy controls and patients with severe dyslipidemia. Evaluation of HDL function may be beneficial for better understanding of cardiovascular diseases, as well as for taking actions to minimize residual cardiovascular risk. Methods: During 2016–2017 a total of 93 participants – 48 (51.6%) women and 45 (48.4%) men – were included in this cross-sectional study. Data of 45 (48.4%) participants with severe dyslipidemia (SD) and 48 (51.6%) controls without dyslipidemia was used for statistical analysis. Total lipid panel, concentration of lipoprotein (a) and apolipoproteins were measured, data about cardiovascular risk factors were collected and detailed evaluation of HDL-C quality was performed for all patients. Results: Increased HDL-C concentration was associated with higher ApoA1 (r = 0.866 in controls, r = 0.63 in SD group), ApoA2 (r = 0.41 in controls, r = 0.418 in SD group) and LDL-C concentrations (r = − 0.412 in SD group), lower ApoE (r = − 0.314 in SD group) and TG concentrations (r = − 0.38 in controls, r = − 0.608 in SD group), lower ApoB/ ApoA1 ratio (r = − 0.567 in control group), below average HDL-C efflux capacity (r = − 0.335 in SD group), lower BMI (r = − 0.327 in controls, r = − 0.531 in SD group) and abdominal circumference (r = − 0.309 in women with SD). Below-average HDL-C efflux capacity was found in 67.7% (N = 63) of participants. It was more often found among patients with normal weight or BMI 30–31 kg/m2. HDL-C efflux capacity was inversely associated with HDL-C concentration (r = − 0.228). Conclusion: Abnormal HDL function may be associated with residual cardiovascular risk in Lithuanian populatio

Association of aortic stiffness, carotid intima-media thickness and endothelial function with cardiovascular events in metabolic syndrome subjects

Purpose: The objective of this study was to assess predictive value of various arterial markers for cardiovascular (CV) events in patients with metabolic syndrome (MetS). Materials and methods: A longitudinal study with the follow-up period of 3.9 ± 1.7 years investigated 2728 middle-aged (53.9 ± 6.2 years old, 63% women) MetS subjects without overt CV disease. The study cohort was comprised of the participants of the Lithuanian High Cardiovascular Risk primary prevention program. The baseline assessment included the evaluation of brachial flow-mediated dilatation (FMD), carotid intima-media thickness (cIMT), carotid stiffness index, aortic pulse wave velocity (aPWV), aortic augmentation index (AIx), and cardio-ankle vascular index). The data on the cardiovascular outcome (fatal or non-fatal myocardial infarction or stroke) was collected by using the databases of the two major national registries. Results: Over the follow-up period, 83 (3%) patients had at least one cardiovascular event. In a univariate analysis, occurrence of CV events was associated with the following parameters: higher mean blood pressure, aPWV, AIx and cIMT, and lower FMD (all p  794 mcm had higher CV risk (p  11.1 m/s (p = .023). Meanwhile, in patients with cIMT ≤ 794mcm, the FMD cut-off point of 6.5% further stratified the risk (p = .003). Conclusions: In our prospective study, CV risk in the middle-aged patients with MetS was associated with an increase in cIMT and aPWV, and with a decrease in FMD

Does education degree affect the patient’s attitude towards the treatment after myocardial infarction?

Objectives. To assess the association between education degree and attitude towards the treatment after myocardial infarction (MI). Design and Methods. The participants of this cross-sectional study were 191 (140 men and 51 women) outpatients in a period of 3 months – 5 years after acute MI (mean age 59 ± 9.2 years) from Vilnius University Hospital Santaros Klinikos. All patients were asked to complete two questionnaires: “Quality of Life and Treatment after Myocardial Infarction” and “Cholesterol-lowering Drugs Consumption Peculiarities”. The data was analyzed using the SPSS software. Results. The education degree (a higher (post-secondary education provided by a college or university) vs. a lower (secondary or vocational education) education degree) had similar influence on the patients’ occasional concern (43.2%; n = 35 vs. 52.9%; n = 55, respectively; p = 0.226) and on the frequent concern (25.9%; n = 21 vs. 26.9%; n = 28, respectively; p = 0.226) about MI. Patients with a higher education degree were more likely to identify themselves as the main subjects in MI treatment in comparison with patients that had a lower education degree (30.5%; n = 25 vs. 15.2%; n = 16, respectively, p = 0.033). More educated patients found it easier to follow up the doctor’s treatment plan than less educated patients (23.2%; n = 19 vs. 9.5%; n = 10, respectively; p = 0.035). Conclusions. More educated patients are more likely to follow up the doctor’s treatment plan and see it easier than less educated patients. Thus, more attention should be paid to less educated patients in order to increase their own impact on their post-MI treatmen

Is the coronary artery calcium score the first-line tool for investigating patients with severe hypercholesterolemia?

Background: Coronary artery calcium (CAC) is known as a reliable tool for estimating risk of myocardial infarction, coronary death, all-cause mortality and is even used to evaluate suitable asymptomatic patients. We therefore aimed to evaluate whether CAC scoring can be applied in the algorithm for clinical examination of patients with severe hypercholesterolemia (SH). Methods: During the period of 2016–2017 a total of 213 asymptomatic adults, underwent computed tomography angiography to evaluate their CAC scoring. The sample consisted of 110 patients with SH and 103 age and sex matched controls without dyslipidemia and established cardiovascular disease. Results: In total there were 79 (37.2%) subjects with elevated (≥25th) CAC percentiles. Out of them 47 (59.5%) had SH and 32 (40.5%) did not. CAC score did not differ between groups (SH (+) 140.30 ± 185.72 vs SH (−) 87.84 ± 140.65, p = 0.146), however there was a comparable difference in how the participants of these groups distributed among different percentile groups (p = 0.044). Gender, blood pressure, tabaco use, physical activity, family history of coronary artery disease and diabetes mellitus were not associated with CAC score (p > 0.05). There were no significant correlations between biochemical parameters and CAC percentiles except for increase in lipoprotein(a) (p = 0.038). Achilles tendon pathology, visceral obesity, body mass index and increased waist-hip ratio were not associated with CAC percentiles either (p > 0.05). Conclusions: CAC score is not associated with presence of SH. CAC score is not an appropriate diagnostic tool in the algorithm for clinical examination of patients with SH. Further larger studies are needed to support our findings