Ezetimibe therapy: mechanism of action and clinical update.

The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios

Assessing the effect of statins in lowering the risk of stroke and preventing cerebral ischemia in patients with hypercholesterolemia

Numerous analyses have explored the role of statins in reducing stroke incidence, reducing cerebral ischemia in hypercholesterolemic patients, and preventing ischemic stroke. This paper aims to assess the effect of statins in lowering the risk of stroke and preventing cerebral ischemia in patients with hypercholesterolemia. To achieve this objective, the literature was reviewed, randomized control tests were analyzed, and a systematic review was performed. The risk of developing cerebral ischemia was found to be reduced in hypercholesterolemic patients and patients with a history of cerebrovascular disease. However, it is unknown whether this reduction in incidence is a result of the drug, which reduces low-density lipoprotein levels in the blood, or to statins’ pleotropic effects on the vascular endothelium. Since their discovery, statins have proven to be beneficial in controlling cholesterol blood levels. Moreover, statins have been shown to have pleotropic effects after a certain period of use, one of which is lowering ischemic stroke incidence in hypercholesterolemic patients. Most recently, statins have been found to lower systolic blood pressure. It is not yet clear whether it has a significant effect on mortality or whether or not it is linked to statins

Carotid intima–media thickness (IMT) in patients with severe familial and non-familial hypercholesterolemia: The effect of measurement site on the IMT correlation with traditional cardiovascular risk factors and calcium scores

Background: The carotid intima–media thickness (IMT) measurement may be carried out proximally (pIMT) or distally (dIMT) in relation to the bulb of the common carotid artery which has significant implications on the results and correlation with risk factors. The aim of the study was to compare the pIMT and dIMT in patients with familial hypercholesterolemia confirmed by genetic testing (FH group) and patients with severe non-familial hypercholesterolemia, with negative results of genetic testing (NFH group) and to determine the correlation of results with traditional atherosclerotic risk factors and calcium scores.Methods: A total of 86 FH and 50 NFH patients underwent pIMT and dIMT measurements of both carotid arteries as well as computed tomography (CT) with coronary and thoracic aorta calcium scoring.Results: The meanpIMT of both right and left common carotid artery were significantly higher in patients with FH compared to the NFH group (meanpRIMT 0.721 ± 0.152 vs. 0.644 ± 0.156, p < 0.01, meanpLIMT 0.758 ± 0.173 vs. 0.670 ± 0.110, p < 0.01). Patient age, pre-treatment lowdensity lipoprotein (LDL) cholesterol levels (LDLmax) at baseline and systolic blood pressure were independent predictors of pIMT increases in both carotid arteries. Smoking history, age and LDLmax were independent predictors of dIMT increase. There was a significant correlation between the calcium scores of the ascending aorta, coronary artery and aortic valve and all IMT parameters.Conclusions: The IMT measured proximally better between patients with familial and non-familial hypercholesterolemia. The association between IMT and traditional cardiovascular risk factors varies between measurement sites. IMT values correlate CT calcium scores in all patients with hypercholesterolaemia regardless of genetic etiology

Bile acid synthesis precursors in subjects with genetic hypercholesterolemia negative for LDLR/APOB/PCSK9/APOE mutations. Association with lipids and carotid atherosclerosis

Some oxysterols are precursors of bile acid synthesis and play an important role in cholesterol homeostasis. However, if they are involved in the pathogeny of genetic hypercholesterolemia has not been previously explored. We have studied non-cholesterol sterol markers of cholesterol synthesis (lanosterol and desmosterol) and oxysterols (7a-hydroxy-4-cholesten-3-one, 24S-hydroxycholesterol and 27-hydroxycholesterol) in 200 affected subjects with primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH) and 100 normolipemic controls. All studied oxysterols and cholesterol synthesis markers were significantly higher in affected subjects than controls (P < 0.001). Ratios of oxysterols to total cholesterol were higher in non-FH GH than in controls, although only 24S-hydroxycholesterol showed statistical significance (P < 0.001). Cholesterol synthesis markers had a positive correlation with BMI, triglycerides, cholesterol and apoB in control population. However, these correlations disappeared in non-FH GH with the exception of a weak positive correlation for non-HDL cholesterol and apoB. The same pattern was observed for oxysterols with high positive correlation in controls and absence of correlation for non-FH GH, except non-HDL cholesterol for 24S-hydroxycholesterol and 27-hydroxycholesterol and apoB for 27-hydroxycholesterol. All non-cholesterol sterols had positive correlation among them in patients and in controls. A total of 65 (32.5%) and 35 (17.5%) affected subjects presented values of oxysterols ratios to total cholesterol above the 95th percentile of the normal distribution (24S-hydroxycholesterol and 27-hydroxycholesterol, respectively). Those patients with the highest levels of 24S-hydroxycholesterol associated an increase in the carotid intima media thickness. These results suggest that bile acid metabolism is affected in some patients with primary hypercholesterolemia of genetic origin, negative for mutations in the candidate genes, and may confer a higher cardiovascular risk. Our results confirm that cholesterol synthesis overproduction is a primary defect in non-HF GH and suggest that subjects with non-FH GH show high levels of oxysterols in response to hepatic overproduction of cholesterol

Aorta of young and middle-aged heterozygous familial hypercholesterolemia patients shows no functional or morphological impairment assessed by MRI

In familial hypercholesterolemia (FH) the level of LDL cholesterol is 2–3 times that of the normal population and leads to accelerated atherosclerosis. Improved care for risk factors has decreased cardiovascular mortality of these patients. We studied subclinical atherosclerotic changes with morphologic and functional aortic magnetic resonance imaging (MRI) in FH patients under the age of 50. 39 DNA test-verified heterozygous FH-North Karelia patients, aged 6–48, 28 of them treated with statins, and 25 healthy controls, aged 12 to 50, underwent aortic MRI, carotid ultrasound (US), and risk-factor assessment. No differences in any of the morphologic or functional aortic parameters appeared between patients and controls. Age and gender were independent predictors of the majority of the morphologic and functional measures. Carotid intima-media thickness assessed by US was greater in patients (0.57 mm ± 0.13 vs 0.48 ± 0.13 mm, p = 0.005) as was cholesterol-years score (243 ± 122 vs 137 ± 74, p < 0.001). Patients had thicker intima-media of the common carotid artery and higher cholesterol burden as indicated by their cholesterol-years score. Despite this, no differences existed in morphologic or functional aortic parameters assessed with MRI. The improved care of cardiovascular risk factors, especially statin treatment, may protect the aorta of FH patients. However, larger confirmatory studies are needed

Intima-media thickness correlates with features of metabolic syndrome in young people with a clinical diagnosis of familial hypercholesterolaemia

Background: Familial hypercholesterolaemia (FH) is a monogenic lipid metabolism disorder characterised by markedlyelevated serum low-density lipoprotein (LDL) cholesterol level due to a mutation in the LDL receptor gene. Clinical featuresof FH include premature atherosclerosis and coronary artery disease.Aim: To explore associations between noninvasive markers of atherosclerosis including intima–media thickness (IMT) andpulse wave velocity (PWV) and blood lipids, blood pressure (BP) and obesity in a group of young patients with FH.Methods: Study population included 36 patients aged &lt; 35 years with the diagnosis of FH based on the Simon Broome Register criteria, and their 49 relatives who comprised the control group free of FH.Results: Mean IMT values were higher in FH patients than controls (0.60 ± 0.19 vs. 0.53 ± 0.07 mm, respectively, p &lt; 0.05).Mean body mass index (BMI) and waist circumference were similar in patients and controls. The prevalence of carotid atheroscleroticplaques was significantly higher among FH patients (n = 6) than in controls (n = 1) (21.4% vs. 2.6%, p = 0.012). Arterial hypertension was present in 27.8% of patients with FH and 16.3% of subjects in the control group. Systolic blood pressure (SBP) in FH patients correlated significantly with age (r = 0.35), BMI (r = 0.48) and waist circumference (r = 0.47), and diastolic blood pressure (DBP) correlated with BMI (r = 0.42) and waist circumference (r = 0.41). PWV correlated significantly with age (r = 0.44), SBP (r = 0.63) and DBP (r = 0.52). We did not find any correlations between IMT and serumlipids, BP or obesity indices in FH patients.Conclusions: Our findings show a higher rate of arterial hypertension in young FH patients compared to their relatives freeof FH, with significant associations between BP and indices of obesity and arterial stiffness. Intensive lipid lowering and antihypertensive therapy along with a reduction in central fat may be considered a mandatory treatment strategy in young FH patients to prevent atherosclerosis and increased arterial stiffness.Wstęp: Rodzinna heterozygotyczna hipercholesterolemia (RHH) jest monogenowym zaburzeniem metabolizmu lipidów cechującymsię znacznym podwyższeniem stężenia cholesterolu LDL w wyniku mutacji w genie receptora LDL. RHH występuje z częstością ok.1/500 osób w populacji. W Polsce RHH dotyczy ok. 70 000 chorych, jednak znaczna ich część pozostaje niezdiagnozowana, a osobyz ustalonym rozpoznaniem często nie są leczone lub leczone nieadekwatnie. Charakterystyczne cechy kliniczne RHH obejmują podwyższenie stężenia cholesterolu całkowitego i cholesterolu LDL w surowicy, zmiany skórne o typie żółtaków ścięgien prostowników palców, ścięgna Achillesa, rąbek starczy oraz żółtaki powiek. Najgroźniejszym objawem klinicznym RHH jest przedwczesna miażdżyca naczyń wieńcowych i choroba niedokrwienna serca. Umieralność nieleczonych pacjentów z RHH jest znacznie większaniż osób zdrowych tej samej płci i wieku.Cel: W niniejszym badaniu oceniono związek między grubością błony intima–media (IMT) i prędkością fali tętna, nieinwazyjnymimarkerami miażdżycy naczyń a stężeniem lipidów, ciśnieniem tętniczym krwi i otyłością w grupie młodych pacjentów z RHH.Metody: Badaniem objęto 36 młodych pacjentów z rozpoznaniem RHH na podstawie kryteriów Simon Broome Register, w wieku &lt; 35 lat i ich 49 krewnych bez RHH, stanowiących grupę kontrolną, dobraną pod względem wieku i płci. U wszystkich chorych przeprowadzono wywiad wg standardowego kwestionariusza, obejmujący dane na temat obecności choroby niedokrwiennej serca, chorób układu sercowo-naczyniowego, nałogu palenia tytoniu oraz sposobu leczenia.Wyniki: Średnie wartości IMT były wyższe u osób z RHH niż w grupie kontrolnej: 0,60 ± 0,19 vs. 0,53 ± 0,07 mm (p &lt; 0,05).Średnie wartości wskaźnika masy ciała (BMI) i obwód pasa były podobne w obu grupach. Pacjenci z RHH cechowali się częstszym występowaniem blaszek miażdżycowych (n = 6) niż grupa kontrola (n = 1) (21,4% vs. 2,6%; p = 0,012). Nadciśnienie tętnicze występowało u 27,8% pacjentów z RHH i u 16,3% osób z grupy kontrolnej. Ciśnienie skurczowe u osób z RHH korelowało istotniez wiekiem (r = 0,35), BMI (r = 0,48) i obwodem pasa (r = 0,47), a ciśnienie rozkurczowe z BMI (r = 0,42) i obwodem pasa (r = 0,41).Prędkość fali tętna korelowała istotnie z wiekiem (r = 0,44), ciśnieniem skurczowym (r = 0,63) i rozkurczowym (r = 0,52). Nie zaobserwowano korelacji między IMT a stężeniem lipidów surowicy, ciśnieniem tętniczym lub wskaźnikami otyłości u pacjentów z RHH.Wnioski: Wyniki wskazują, że odsetek osób z nadciśnieniem tętniczym jest wyższy u młodych pacjentów z RHH niż u krewnych bez RHH oraz na obecność silnej korelacji między ciśnieniem tętniczym a wskaźnikami otyłości (takimi jak obwód pasa, BMI, współczynnik pas/biodra) oraz sztywnością naczyń. Intensywne leczenie hipolipemizujące i hipotensyjne, a także zmniejszenie otyłościbrzusznej wydają się ważnymi elementami leczenia młodych pacjentów z RHH w celu prewencji miażdżycy i sztywnienia naczyń

Cardiovascular risk stratification in familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common autosomal-dominant disorder in most European countries. Patients with FH are characterised by a raised level of low-density lipoprotein cholesterol and a high risk of premature coronary heart disease (CHD). Currently there is no consensus regarding the clinical utility to predict future coronary events or testing for the presence of subclinical atherosclerotic disease in asymptomatic patients with FH. Family screening of patients with FH as recommended by the UK National Institute of Health and Care Excellence guideline would result in finding many young individuals with a diagnosis of FH who are clinically asymptomatic. The traditional CHD risk scores, that is, the Framingham score, are insufficient in risk prediction in this group of young individuals. In addition, a better understanding of the genetic aetiology of the FH phenotype and CHD risk in monogenic FH and polygenic hypercholesterolaemia is needed. Non-invasive imaging methods such as carotid intima-media thickness measurement might produce more reliable information in finding high-risk patients with FH. The potential market authorisation of novel therapeutic agents such as PCSK9 monoclonal inhibitors makes it essential to have a better screening programme to prioritise the candidates for treatment with the most severe form of FH and at higher risk of coronary events. The utility of new imaging techniques and new cardiovascular biomarkers remains to be determined in prospective trials

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources

Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management