Update on Sitosterolemia and Atherosclerosis.

PURPOSE OF REVIEW: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. RECENT FINDINGS: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.

Screening of ABCG5 and ABCG8 Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program.

BACKGROUND: Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in ABCG5/ABCG8. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program. METHODS: From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the ABCG5/8 genes. Clinical and laboratory characteristics of affected individuals were determined. RESULTS: Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean ß-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122-521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities. CONCLUSIONS: Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.

Phenotypical, Clinical, and Molecular Aspects of Adults and Children With Homozygous Familial Hypercholesterolemia in Iberoamerica.

OBJECTIVE: Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3±15.8 years, 38.0% males), and 63 children (age 8.8±4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in the LDLR. True HoFH due to LDLR variants had higher total (P=0.015) and LDL (low-density lipoprotein)-cholesterol (P=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (P=0.051) and had a greater frequency of xanthomas (P=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults with LDLR variants. Children who are true HoFH had higher frequency of major cardiovascular events (P=0.02), coronary heart (P=0.013), and aortic/supra-aortic valve diseases (P=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type of LDLR variant. From 118 subjects with LDLR variants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2 LDLR variants, those with at least one null allele were younger (P=0.003) and had a greater frequency of major cardiovascular events (P=0.038) occurring at an earlier age (P=0.001). CONCLUSIONS: There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.

Case report: The efficacy and safety of lomitapide in a homozygous familial hypercholesterolemic child.

We report for the first time the efficiency and safety of a 49-month compassionate use of the microsomal transfer protein inhibitor lomitapide in a child with homozygous familial hypercholesterolemia. On average, 20 mg of lomitapide caused a 37% reduction in low-density lipoprotein cholesterol levels on top of ezetimibe and atorvastatin. The drug was well tolerated with no changes in liver enzymes and occurrence of steatosis on hepatic ultrasound. The patient presented adequate growth and sexual maturation. Nonetheless, there was progression in either subclinical atherosclerotic carotid or aortic valve diseases. Further studies are necessary to test the impact and safety of lomitapide in children with homozygous familial hypercholesterolemia.

Quando e como avaliar o risco cardiovascular global em indivíduos aparentemente normais ­ ou check-up para todos / When and how to assess global cardiovascular risk in apparently normal individuals ­ or check-up for everyone

A prevenção cardiovascular é tema fundamental, pois as doenças cardiovasculares que têm como substrato a aterosclerose, têm grande impacto na morbidade e mortalidade cardiovascular no Brasil e no mundo. Estima-se que 80% dos casos de doença arterial co-ronariana resultam da presença isolada ou em associação a fatores como as dislipidemias, tabagismo, hipertensão arterial, diabetes entre outros. Além disso, biomarcadores como história familiar de aterosclerose precoce, marcadores de inflamação de baixo grau como a proteína C reativa (PCR) e imagem da placa de ateroma (escore de cálcio coronário) ajudam a identificar e reclassificar o risco de doença cardiovascular. Estratégias como check-up cardiovascular ou os dos escores de risco são utilizadas na identificação do indivíduo assintomático com maior risco de desenvolver um evento agudo. O check-upcardiovascular, além de identificar os fatores de risco, inclui exames laboratoriais, testes funcionais e de imagem, o que pode implicar em custos excessivos dos exames que não agregarão valor discriminatório ou de reclassificação do risco cardiovascular. Apesar da escassez de dados, meta-análise recente não observou qualquer diferença na mortali-dade por todas as causas e cardiovascular, quanto à realização ou não dos exames de check-up de rotina. A partir da medicina baseada em evidência, diversos algoritmos foram criados para estratificação, de acordo com a presença dos fatores de risco e calibrados para a população estudada. Esses algoritmos são de simples realização e de baixo custo.A Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose ­ 2017 mantém a recomendação do uso do Escore Global de Risco na avalição inicial de indiví-duos assintomáticos. A revisão sistemática realizada pelo grupo Cochrane, observou que o uso dos escores de risco na prevenção primária tiveram modesto impacto na redução de eventos cardiovasculares, comparados com a não utilização. Além disso, o uso dos escores clínicos reduziu fatores de risco como colesterol elevado e hipertensão arterial, aumentou a prescrição de hipolipemiantes, anti-hipertensivos e AAS, sem evidência de danos e diminuiu a prevalência de tabagismo. Atualmente, ainda há controvérsias sobre quando e como deve ser feita a avaliação do risco cardiovascular. A literatura é clara em dizer que o uso de testes de forma indiscriminada na população não tem boa relação de custo-eficácia. Entretanto, a avaliação do risco cardiovascular pelos escores clínicos de risco pode identificar indivíduos de maior risco que serão beneficiados pela implementação de tratamentos preventivos.

Cardiovascular disease prevention is a key topic as cases with atherosclerosis as an underlying cause have a considerable impact on cardiovascular morbidity and mortality in Brazil and the rest of the world. It is estimated that 80% of coronary artery disease cases result from the individual presence or combination of factors such as dyslipidemias, smo-king, hypertension, diabetes, and others. In addition, biomarkers such as family history of early atherosclerosis, low-grade inflammatory markers such as C-reactive protein (CRP), and atheromatous plaque imaging (coronary calcium score) help identify and reclassify the risk of cardiovascular disease. Strategies such as cardiovascular check-ups or the use of risk scores are used to identify the asymptomatic patient with a higher risk of developing an acute event. Besides identifying risk factors, the cardiovascular check-up also includes laboratory, functional and imaging tests, which may involve excessive costs that will not add discriminatory value or allow the cardiovascular risk to be reclassified. Despite the lack of data, a recent meta-analysis found no difference in all-cause and cardiovascular mortality, whether or not routine check-ups were performed. According to evidence-based medicine, several algorithms have been created for stratification, depending on the presence of risk factors and calibrated for a particular study population. These algorithms are both simple and inexpensive. The Update of the Brazilian Guideline on Dyslipidemia and Atherosclerosis Prevention - 2017 recommends using the Global Risk Score in the initial assessment of asymptomatic individuals. A systematic review conducted by the Cochrane group found that the use of risk scores in primary prevention had a modest impact on the reduction of cardiovascular events compared to non-use. Furthermore, the use of clinical scores reduced risk factors such as high cholesterol and high blood pressure, increased lipid-lowering/antihypertensive drug and aspirin prescriptions, with no evidence of harmful side effects, and reduced the prevalence of smoking. There is still controversy as to when and how to assess cardiovascular risk. The literature is clear in stating that the use of indiscriminate testing in the population is not cost effective. However, the evaluation of cardiovascular risk using clinical risk scores can identify higher risk individuals who will benefit from the implementation of preventive treatments.

Acute pancreatitis secondary to oral contraceptive-induced hypertriglyceridemia: a case report.

Hypertriglyceridemia is the third most common cause of acute pancreatitis. Among the causes that lead to secondary hypertriglyceridemia, the use of contraceptive agents is the main reason to be assessed in young women. We report a case of a 31-year-old woman who had suffered two acute pancreatitis episodes secondary to hypertriglyceridemia. In the investigation, the previous medical team indicated a genetic screening before ruling out all secondary causes. LPL, apo CII and apo AV genes were negative for mutations. In the first appointment with us, the patient reported the use of a contraceptive agent for about 2 years. She was instructed to discontinue the drug. After one year of follow-up, her serum triglycerides are within the normal range and a copper intrauterine device was the method chosen by the patient for contraception.

Importância do diabetes mellitus na estratificação do risco de doença arterial coronária e risco cardiovascular global / Importance of diabetes mellitus in the risk stratification of coronary arterial disease and global cardiovascular risk

O diabetes mellitus é uma doença epidêmica. Os adultos portadores de diabetes têm taxas de doenças cardiovasculares duas a três vezes maiores do que aquelas observadas em adultos não diabéticos. O reconhecimento de que o diabetes é uma doença heterogênea em relação ao risco cardiovascular foi fundamental para a identificação correta dos indivíduos sob maior risco, os quais necessitam de tratamento farmacológico mais intensivo, e daqueles cujo risco é menor, em que o uso de medidas não farmacológicas isoladamente em uma fase inicial é opcional. Ferramentas para estratificação de risco mais precisas, uso apropriado de métodos de rastreamento de isquemia no paciente assintomático e indicação dos métodos de imagem são brevemente revisados neste capítulo. O tratamento de todos os fatores de risco inclui a moderna abordagem do paciente com diabetes, visando a redução de eventos macro e microvasculares. Descritores: Diabetes mellitus; Doença da artéria coronariana; Infarto do miocárdio; Acidente vascular cerebral.

Diabetes mellitus can be considered an epidemic disease. Adults with diabetes have two to three times higher rates of cardiovascular disease than those observed in non-diabetic adults. The recognition that diabetes is a heterogeneous disease in relation to cardiovascular risk was fundamental for the correct identification of individuals at higher risk, who require more intensive pharmacological intervention, and those at lower risk, where the use of non-pharmacological strategies alone in an initial phase is optional. More precise risk stratification tools, the appropriate use of screening methods for tracking ischemia in the asymptomatic patient, and the indication of imaging tests will be summarized in this review. Treatment based on global risk factor control includes the modern approach for the patient with diabetes, aiming at reducing both macro- and microvascular events.

Diretriz brasileira baseada em evidências sobre prevenção de doenças cardiovasculares em pacientes com diabetes: posicionamento da Sociedade Brasileira de Diabetes (SBD), da Sociedade Brasileira de Cardiologia (SBC) e da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) / Brazilian evidence-based guideline on cardiovascular disease prevention in patients with diabetes: positioning of the Brazilian Society of Diabetes (SBD), the Brazilian Society of Cardiology (SBC) and the Brazilian Society of Endocrinology and Metabology (SBEM)

Resumo Fundamentação: desde o primeiro posicionamento da Sociedade Brasileira de Diabetes (SBD) sobre diabetes e prevenção cardiovascular, em 2014,1 importantes estudos têm sido publicados na área de prevenção cardiovascular e tratamento do diabetes,2 os quais contribuíram para a evolução na prevenção primária e secundária nos pacientes com diabetes. Ferramentas de estratificação de risco mais precisas, novos fármacos hipolipemiantes e novos antidiabéticos com efeitos cardiovasculares e redução da mortalidade, são parte desta nova abordagem para os pacientes com diabetes. O reconhecimento de que o diabetes é uma doença heterogênea foi fundamental, sendo claramente demonstrado que nem todos os pacientes diabéticos pertencem a categorias de risco alto ou muito alto. Um porcentual elevado é composto por pacientes jovens, sem os fatores de risco clássicos, os quais podem ser classificados adequadamente em categorias de risco intermediário ou mesmo em baixo risco cardiovascular. O presente posicionamento revisa as melhores evidências atualmente disponíveis e propõe uma abordagem prática, baseada em risco, para o tratamento de pacientes com diabetes. Estruturação: perante este desafio e reconhecendo a natureza multifacetada da doença, a SBD uniu-se à Sociedade Brasileira de Cardiologia (SBC) e à Sociedade Brasileira de Endocrinologia e Metabolismo (SBEM), e formou um painel de especialistas, constituído por 28 cardiologistas e endocrinologistas, para revisar as melhores evidências disponíveis e elaborar uma diretriz contendo recomendações práticas para a estratificação de risco e prevenção da Doença Cardiovascular (DVC) no Diabetes Melito (DM). As principais inovações incluem: (1) considerações do impacto de novos hipolipemiantes e das novas medicações antidiabéticas no risco cardiovascular; (2) uma abordagem prática, baseada em fator de risco, para orientar o uso das estatinas, incluindo novas definições das metas da Lipoproteína de Baixa Densidade-colesterol (LDL-colesterol) e colesterol não Lipoproteína de Alta Densidade HDL; (3) uma abordagem baseada em evidências, para avaliar a isquemia miocárdica silenciosa (IMS) e a aterosclerose subclínica em pacientes com diabetes; (4) as abordagens mais atuais para o tratamento da hipertensão; e (5) recomendação de atualizações para o uso de terapia antiplaquetária. Esperamos que esta diretriz auxilie os médicos no cuidado dedicado aos pacientes com diabetes. Métodos: inicialmente, os membros do painel foram divididos em sete subcomitês para definirem os tópicos principais que necessitavam de uma posição atualizada das sociedades. Os membros do painel pesquisaram e buscaram no PubMed estudos clínicos randomizados e metanálises de estudos clínicos e estudos observacionais de boa qualidade, publicados entre 1997 e 2017, usando termos MeSH: [diabetes], [diabetes tipo 2], [doença cardiovascular], [estratificação de risco cardiovascular] [doença arterial coronária], [rastreamento], [isquemia silenciosa], [estatinas], [hipertensão], [ácido acetilsalicílico]. Estudos observacionais de baixa qualidade, metanálises com alta heterogeneidade e estudos transversais não foram incluídos, embora talvez tenham impactado no Nível de Evidência indicado. A opinião de especialistas foi usada quando os resultados das buscas não eram satisfatórios para um item específico. É importante salientar que este posicionamento não teve a intenção de incluir uma revisão sistemática rigorosa. Um manuscrito preliminar, destacando recomendações de graus e níveis de evidência (Quadro 1), foi esboçado. Este passo levou a várias discussões entre os membros dos subcomitês, que revisaram os achados e fizeram novas sugestões. O manuscrito foi, então, revisto pelo autor líder, encarregado da padronização do texto e da inclusão de pequenas alterações, sendo submetido à apreciação mais detalhada pelos membros dos comitês, buscando uma posição de consenso. Depois desta fase, o manuscrito foi enviado para a banca editorial e edição final, sendo encaminhado para publicação. Quadro 1 Graus de recomendações e níveis de evidências adotados nesta revisão Grau de recomendação Classe I A evidência é conclusiva ou, se não, existe consenso de que o procedimento ou tratamento é seguro e eficaz Classe II Há evidências contraditórias ou opiniões divergentes sobre segurança, eficácia, ou utilidade do tratamento ou procedimento Classe IIa As opiniões são favoráveis ao tratamento ou procedimento. A maioria dos especialistas aprova Classe IIb A eficácia é bem menos estabelecida, e as opiniões são divergentes Classe III Há evidências ou consenso de que o tratamento ou procedimento não é útil, eficaz, ou pode ser prejudicial Níveis de Evidência A Múltiplos estudos clínicos randomizados concordantes e bem elaborados ou metanálises robustas de estudos clínicos randomizados B Dados de metanálises menos robustas, um único estudo clínico randomizado ou estudos observacionais C Opinião dos especialistas

Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM).

BACKGROUND: Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes. MAIN BODY: The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy. CONCLUSIONS: Diabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub-clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk.

Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil.

BACKGROUND AND AIMS: There is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. METHODS: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. RESULTS: Overall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704-0.784) and 0.730 (95% CI: 0.687-0.774), respectively, p=0.014. CONCLUSIONS: In our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.