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.

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 population.

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.

Achilles tendon ultrasonography - A useful screening tool for cardiovascular risk estimation in patients with severe hypercholesterolemia.

BACKGROUND AND AIMS: Achilles tendon lesions have long been associated with genetic defects in lipid metabolism and increased risk of cardiovascular diseases (CVD). With this study we aimed to evaluate the usefulness of Achilles tendon ultrasonography in identifying people at greater risk among subjects with severe hypercholesterolemia (SH) in a high-risk population. METHODS: During the period of 2016-2017 a total of 213 participants were enrolled in this case-control study. Data of 110 patients with SH and 103 age and sex matched controls without dyslipidaeplemia and established CVD was collected. RESULTS: Achilles tendinopathy (AT) was present in 42.7% of subjects with SH and in 29.1% of controls (p = 0.039). Stronger association between SH and AT was seen in women - 24.1% vs 2.0% (p = 0.001). SH increased odds of AT by 1.815 (95% CI, 1.028-3.206). Prevalence of AT was higher in males despite presence (SH+) or absence (SH-) of severe hypercholesterolemia (SH+ 60.7% vs 24.1%, SH- 55.8% vs 2.0%, p < 0.001). AT was associated with higher proportion of subjects exceeding normal mean values of TC (80.5% vs 52.9%, p = 0.001), LDL-C (76.6% vs 52.2%), TG (54.5% vs. 22.1%), ApoB (57.1% vs 22.2%), ApoE (44.0% vs 22.4%) levels and ApoB/ApoA ratio (46.1% vs 21.5%) (p = 0.001) and family history of premature coronary heart disease (CHD). CONCLUSIONS: AT is more prevalent among subjects with SH and is associated with higher levels of TC, TG, LDL-C, ApoB, ApoE, ApoB/ApoA ratio, family history of premature CHD. SH increases the odds of developing AT.

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 < .05). In Cox proportional hazard regression analysis, the occurrence of CV event was associated with an increase in aPWV (HR 1.29, 95% CI 1.04-1.60, p = .019), AIx (HR 1.53, 95% CI 1.16-2.02, p = .003), and cIMT (HR 1.31, 95% CI 1.14-1.50, p < .001), and with the decrease in FMD (HR 0.83, 95% CI 0.71-0.97, p = .016) even after the adjustment for age, gender, and common cardiometabolic risk factors. In a two-level survival trees analysis, we established that patients with cIMT > 794 mcm had higher CV risk (p < .001) and their prognosis was further compromised by aPWV > 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.

Lipid profile evaluation and severe hypercholesterolaemia screening in the middle-aged population according to nationwide primary prevention programme in Lithuania.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is a major cause of premature death in Lithuania where abnormal lipid levels are very common among middle-aged adults. The aim of this study was to evaluate lipid profile in middle-aged Lithuanians and perform population-based severe hypercholesterolaemia (SH) screening. METHODS: This study included men aged 40-54 and women aged 50-64 years without overt CVD, participating in the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention programme during the period 2009-2016. Lipidograms of 92,373 adults (58.4% women and 41.6% men) included in the database were analysed and screening for SH was performed. RESULTS: The mean levels of total cholesterol, LDL cholesterol (LDL-C) and triglycerides (TG) among participants were 6.08 mmol/l, 3.87 mmol/l, and 1.59 mmol/l, respectively. Any type of dyslipidaemia was present in 89.7%, and severe dyslipidaemia in 13.4% of the study population. 80.2% of adults without overt CVD had LDL-C ≥3 mmol/l. SH (LDL-C ≥6 mmol/l) was detected in 3.2% of study participants. Prevalence of SH decreased from 2.91% to 2.82% during the period 2009-2016 (p for trend = 0.003). LDL-C ≥6.5 mmol/l was observed in 1.5% of subjects while both LDL-C ≥6.5 mmol/l, and TG ≤ 1.7 mmol/l was found in 0.6% of subjects. CONCLUSIONS: SH was present in 3.2% of the middle-aged population without overt CVD. Slightly decreasing prevalence of SH was observed during the period 2009-2016 in Lithuania. Likely phenotypic familial hypercholesterolaemia was observed in 1.5% of middle-aged Lithuanians. Further clinical and genetic evaluation of people with SH is needed to detect familial forms of SH.

Cardiovascular risk assessment of dyslipidemic middle-aged adults without overt cardiovascular disease over the period of 2009-2016 in Lithuania.

BACKGROUND: Cardiovascular mortality in Lithuania is extremely high and abnormal lipid levels are very common among Lithuanian adults. Dyslipidemia is one of the main independent risk factors for cardiovascular diseases (CVD) leading to high absolute CVD risk. The aim of this study was to assess CVD risk in dyslipidemic middle-aged subjects. METHODS: During the period of 2009-2016 a total of 92,373 people (58.4% women and 41.6% men) were evaluated. This study included men aged 40-54 and women aged 50-64 without overt CVD. RESULTS: Any type of dyslipidemia was present in 89.7% of all study population. 7.5% of dyslipidemic patients did not have any other conventional risk factors. Three and more risk factors were detected in 60.1% of dyslipidemic subjects. All analyzed risk factors, except smoking, were more common in dyslipidemic adults compared to subjects without dyslipidemia: arterial hypertension (55.8% vs. 43.3%, p < 0.001), diabetes (11.1% vs. 7.3%, p < 0.001), abdominal obesity (45.3% vs. 30.2%, p < 0.001), BMI ≥30 kg/m2 (35.8% vs. 23.7%, p < 0.001), metabolic syndrome (34.0% vs. 9.2%, p < 0.001), family history of coronary heart disease (26.3% vs. 23.1%, p < 0.001), unbalanced diet (62.5% vs. 52.9%, p < 0.001) and insufficient physical activity (52.0% vs. 44.2%, p < 0.001). The prevalence of all evaluated risk factors, except smoking, increased with age. Average SCORE index was 1.87 in all study population, while dyslipidemic subjects had higher SCORE compared to control group (1.95 vs 1.20, p < 0.001). CONCLUSIONS: Almost two thirds of dyslipidemic middle-aged Lithuanian adults without overt cardiovascular disease had three or more other CVD risk factors, which synergistically increase absolute risk of CVD. The average 10-year risk of CVD death in patients with dyslipidemia was 1.95%. The importance of managing dyslipidemia as well as other risk factors in order to reduce burden of cardiovascular disease in Lithuania is evident.

Cardiovascular risk profile of patients with atherogenic dyslipidemia in middle age Lithuanian population.

BACKGROUND: Atherogenic dyslipidemia (AD) is a blood serum lipid profile abnormality characterized by elevation of triglycerides and reduced levels of high density lipoprotein cholesterol (HDL-C). It is associated with residual cardiovascular risk. This study evaluated and compared the risk profiles of patients with hypertriglyceridemia, low-HDL-C levels or AD, in order to understand, which lipid profile is associated with greater risk. METHODS: During the period of 2009-2016 a population of 92,373 Lithuanian adults (men 40-54 years old and women 50-64 years old) without overt cardiovascular disease were analyzed. Data of 25,746 patients (68.6% women and 31.4% men) with hypertriglyceridemia and/or low HDL-C low levels were collected and used for further statistical analysis. RESULTS: Participants with AD tend to have more unfavorable risk profile than participants with hypertriglyceridemia or low-HDL-C. AD tends to cluster with other atherogenic risk factors, such as arterial hypertension [odds ratio (OR) 1.96, 95% confidence intervals (CI) 1.87-2.01], smoking [OR 1.20, 95% CI 1.14-1.27], diabetes mellitus [OR 2.74, 95% CI 2.58-2.90], obesity [OR 2.92, 95% CI 2.78-3.10], metabolic syndrome [OR 22.27, 95% CI 20.69-23.97], unbalanced diet [OR 1,59, 95% CI 1.51-1.68], low physical activity [OR 1.80, 95% CI 1.71-1,89], CHD history in first degree relatives [OR 1.18, 95% CI 1.12-1.25] and total number of risk factors [OR 1.47, 95% CI 1.38-1.57]. CONCLUSION: AD is associated with more unfavorable cardiovascular risk profile than hypertriglyceridemia or low-HDL cholesterol levels. Once identified AD should require additional medical attention since it is an important factor of residual cardiovascular risk.

Aortic stiffness is an independent determinant of left ventricular diastolic dysfunction in metabolic syndrome patients.

BACKGROUND: We aimed to evaluate the relationship between arterial stiffness and left ventricular diastolic dysfunction (LVDD) in metabolic syndrome (MetS) patients. METHODS: A cross-sectional study was conducted in 1208 subjects without overt atherosclerotic disease. According to the cardiac ultrasound, patients were divided into two groups: with LVDD (LVDD+, n = 1119) and without LVDD (LVDD-, n = 89). Arterial stiffness parameters [carotid-femoral pulse wave velocity (cfPWV) and aortic augmentation index (AIxHR75)] were assessed by applanation tonometry. RESULTS: In comparison to LVDD-, LVDD + patients were older (55 ± 6 vs 51 ± 6 years, p < 0.001), and had higher cfPWV (8.8 ± 1.6 vs 7.9 ± 1.34 m/s, p < 0.001), AIxHR75 (24.7 ± 10.2 vs 19.7 ± 10, p < 0.001), mean arterial pressure (108 ± 12 vs 101 ± 10 mmHg, p < 0.001), heart rate (66 ± 10 vs 61 ± 9 bpm, p < 0.001), left ventricular mass index (LVMI) (109 ± 24 vs 97 ± 22, p < 0.001) and body mass index (BMI) (32 ± 5 vs 30 ± 4 kg/m(2), p < 0.001). We found significant correlations between cfPWV, AIxHR75 and the ratio of early to late transmitral velocities (E/A) (rcfPWV = -0.19, rAIxHR75 = -0.15, p < 0.001), early diastolic mitral annular velocity (E') (rcfPWV = -0.25, rAIxHR75 = -0.18, p < 0.05) and E/E' ratio (rcfPWV = 0.17, rAIxHR75 = 0.14, p < 0.001). Univariate analysis revealed that the presence of LVDD is associated with age [odds ratio (OR) 1.84], BMI (OR 1.63), waist circumference (WC) (OR 1.52), cfPWV (OR 2.18), AIxHR75 (OR 1.55), mean aortic blood pressure (OR 1.94), aortic pulse pressure (OR 1.78), mean common carotid artery intima-media thickness (OR 1.16), heart rate (OR 1.4) and LVMI (OR 1.79) (all p < 0.05). After performing stepwise multiple logistic regression analysis, only cfPWV and BMI or WC remained significant predictors of the presence of LVDD (p < 0.05). CONCLUSION: cfPWV is a significant determinant of LVDD in subjects with MetS.