Maria Cristina de Oliveira Izar

Imbalance between endothelial progenitors cells and microparticles in HIV-infected patients naive for antiretroviral therapy.

Background:Cardiovascular events have been reported among HIV-infected patients following antiretroviral therapy. However, the role of HIV itself in determining vascular damage is less described. Chronic inflammatory state might impair some regulatory endothelium properties leading to its activation, apoptosis or erosion. Objectives:To evaluate the balance between endothelial progenitor cells and microparticles in HIV-infected antiretroviral drug-naive patients. Design:A case–control study comparing HIV-infected patients (nu200a=u200a35) with sex-matched and age-matched healthy controls (nu200a=u200a33). Methods:Endothelial progenitor cells populations expressing CD34+, CD133+ and KDR+ were quantified by flow cytometry. Endothelial-derived microparticles, expressing CD51+, and platelet-derived microparticles, expressing CD31+/CD42+, were also measured. Endothelial function was estimated by flow-mediated dilation. Results:Lower percentages of endothelial progenitor cells (CD34+/KDR+) were observed in HIV-infected individuals compared with controls (0.02 vs. 0.09%, Pu200a=u200a0.045). In addition, endothelial microparticles concentration was higher in HIV-infected individuals (1963 vs. 436u200amicroparticles/&mgr;l platelet-poor plasma, Pu200a=u200a0.003), with similar number of platelet-derived microparticles among groups. Furthermore, flow-mediated dilation was lower among HIV-infected individuals compared with controls [mean (SEM): 10 (1) and 16% (2), respectively; Pu200a=u200a0.03]. Conclusion:Our findings suggest an imbalance between endothelial progenitor cells mobilization and endothelial apoptosis. The alteration in the turnover of endothelial cells may contribute to cardiovascular events in HIV-infected patients.

Association of lipoprotein lipase D9N polymorphism with myocardial infarction in type 2 diabetes: the genetics, outcomes, and lipids in type 2 diabetes (GOLD) study.

The association of polymorphisms affecting lipid metabolism with the risk of myocardial infarction (MI) in type 2 diabetes mellitus was investigated. The Genetics, Outcomes and Lipids in type 2 Diabetes (GOLD) Study is a prospective, multicenter study, conducted on 990 patients presenting diabetes and MI (n=386), or diabetes without previous manifestation of stroke, peripheral or coronary arterial disease (n=604), recruited from 27 institutions in Brazil. APO A1 (A/G -75 and C/T +83) and APO C3 (C/G 3UTR) non-coding sequences, CETP (Taq 1B), LPL (D9N), APO E (epsilon2, epsilon3, epsilon4,), PON-1 (Q192R), and two LCAT variants Arg(147)-->Trp and Tyr(171)-->Stop were tested by PCR-RFLP. There was a higher prevalence of LPL DN genotype (19% vs.12%, p=0.03) and a higher frequency of the N allele (11% vs. 7%) among subjects with MI when compared to controls, with an odds ratio of MI for carriers of 9N allele of 2.46 (95% CI=1.79-3.39, p<0.0001). This association was present in men and women, in non-smokers and in hypertensive patients. A logistic regression model including gender, duration of diabetes, systolic blood pressure, HDL-C, left ventricle hypertrophy and D9N polymorphism showed that the latter still remained significantly associated with MI (OR=1.50, 95% CI=1.02-2.25, p=0.049). These findings suggest that D9N polymorphism can be a useful risk marker for myocardial infarction and that further potential candidate genes should be screened for exploratory analysis and for future therapeutic intervention in diabetes.

Chronic endothelial dysfunction after oversized coronary balloon angioplasty in pigs: a 12-week follow-up of coronary vasoreactivity in vivo and in vitro

Previous studies have reported the development of vasoconstriction immediately after invasive coronary interventions. Other studies in animals have demonstrated that using oversized balloon angioplasty, vasospasm can be suppressed, even in the presence of endothelial denudation due to important structural alteration in vascular smooth muscle. The regenerated endothelium also appears to be impaired chronically by selective attenuation of in vitro endothelial dependent relaxation related to pertussis toxin-sensitive G proteins. The purpose of this investigation was to verify in vivo and in vitro vasoreactivity to bradykinin (BK) and serotonin (5-hydroxytryptamine; 5-HT) (endothelial dependent agonists) as well as to nitroglycerin (NTG) (exogenous nitric oxide donor) at different times after oversized balloon angioplasty intervention ranging from 1 h to 12 weeks, in normal porcine coronary arteries. BK-induced vasodilatation in vivo was impaired acutely, but it was restored after 4 weeks. Serotonin caused vasoconstriction in vivo that was significantly augmented after 12 weeks. Conversely, endothelium-dependent vasodilatation in vitro to BK and 5-HT remained attenuated during the whole period of follow-up. Finally, relaxation elicited by NTG was reduced in the in vivo experiment until the first week after the procedure. Histological analysis showed severe arterial injury, and complete recovery of endothelial coverage after 4 weeks. In conclusion, this experiment supports evidence for the occurrence of the acute attenuation of vasoresponsiveness and chronic endothelial dysfunction following overstretching coronary balloon angioplasty. Abnormal remodeling associated with the severity of injury may contribute to chronic endothelial dysfunction. Differences found between in vivo and in vitro studies also suggest that multiple endogenous influences present in the former can attenuate the greater endothelial dysfunction demonstrated by endothelial assessment in vitro.

High glucose levels abolish antiatherosclerotic benefits of ACE inhibition in alloxan-induced diabetes in rabbits.

Renin-angiotensin system activation is recognized to play an important role in atherosclerosis. This study aimed to verify the antiatherosclerotic effects of ACE inhibition on an experimental model of diabetes and hypercholesterolemia. Diabetes was induced in New Zealand male rabbits with a single dose of alloxan (100 mg/kg, IV), and, according to plasma glucose levels obtained after 1 week, the animals were divided into 2 groups (≥250 mg/dL or <250 mg/dL). Each group was randomly assigned to receive or not quinapril (30 mg/d) added to a 0.5% cholesterol-enriched diet. Animals with high glucose levels at 1 week and that remained high after 12 weeks presented higher triglyceride levels (P < 0.02 versus basal). Those initially hyperglycemic but presenting <250 mg/dL glucose at the end of study formed an additional group. Plasma ACE activity was lower in quinapril-treated animals (P < 0.01 versus untreated groups). However, aorta intima/media ratio and intima area were lower only in the subgroups of quinapril-treated animals with low glucose levels (P < 0.05). Our results support the hypothesis that high plasma glucose may abolish the antiatherosclerotic effect of ACE inhibitors.

Positioning about the Flexibility of Fasting for Lipid Profiling

Arq Bras Cardiol. 2017; 108(3):195-197 Positioning about the Flexibility of Fasting for Lipid Profiling Marileia Scartezini,1 Carlos Eduardo dos Santos Ferreira,2 Maria Cristina Oliveira Izar,3 Marcello Bertoluci,4 Sergio Vencio,5 Gustavo Aguiar Campana,2 Nairo Massakazu Sumita,2 Luiz Fernando Barcelos,1 André A. Faludi,3 Raul D. Santos,3, Marcus Vinícius Bolívar Malachias,3 Jerolino Lopes Aquino,1 César Alex de Oliveira Galoro,2 Cleide Sabino,4 Maria Helane Costa Gurgel,4 Luiz Alberto Andreotti Turatti,5 Alexandre Hohl,4 Tania Leme da Rocha Martinez3 Sociedade Brasileira de Análises Clínicas (SBAC),1 Rio de Janeiro, RJ; Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial (SBPC/ ML),2 Rio de Janeiro, RJ; Sociedade Brasileira de Cardiologia (SBC),3 Rio de Janeiro, RJ; Sociedade Brasileira de Endocrinologia e Metabologia (SBEM),4 Rio de Janeiro, RJ; Sociedade Brasileira de Diabetes (SBD),5 São Paulo, SP – Brazil

I posicionamento brasileiro em hipertensão arterial e diabetes mellitus

The association between AH and DM was first described in the 70s, observed in both sexes and at any age range. The prevalence of hypertension is two to three-fold higher in diabetics than in the general population5, and about 70% of diabetics are hypertensive3,6. A meta-analysis of 102 prospective studies and 698,782 individuals showed that the presence of DM increases by two-fold the risk of coronary artery disease (CAD), cerebrovascular accident (CVA) and CV death. According to this meta-analysis, 10% of CV deaths in developed countries can be attributed to the presence of DM7.

Genetic screening for homozygous and heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a common inherited disorder that results in premature atherosclerosis. Diagnosis of FH is suspected on the basis of clinical criteria, but confirmation requires genetic testing. In the era of statins, early diagnosis and initiation of treatment can modify disease progression and outcomes. Therefore, cascade screening with a combination of lipid concentration measurements and DNA testing should be used to identify relatives of index cases with a clinical diagnosis of FH. Autosomal dominant FH is related to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Genetic screening of the LDLR gene is challenging to achieve at a feasible cost, especially in people who do not have a founder effect. Nucleotide sequencing of all exons and flanking splicing regions in combination with multiplex ligation probe amplification to detect large insertions or deletions is considered the gold-standard approach to screen for LDLR mutations. Alternatively, the cDNA can be sequenced; however, this procedure is not suitable for use in large populations, because of the need of RNA extraction. Multiplex analysis can be appropriate for population with founder effects or a low number of different mutations. Finally, there are many techniques for a mutation scanning approach, which have some benefits over sequencing, and also with the potential for detecting known and novel mutations. Familial defective Apo B is amenable to genetic diagnosis by screening for a few mutations. Recently, gain-of-function mutations in PCSK9 gene have been demonstrated to cause FH phenotype. Strategies for population screening, cost-effectiveness of genetic screening, ethical aspects, and insurance policies are discussed and need implementation worldwide.

Statin-associated muscle symptoms: position paper from the Luso-Latin American Consortium.

Abstract In the last two decades, statin therapy has proved to be the most potent isolated therapy for attenuation of cardiovascular risk. Its frequent use has been seen as one of the most important elements for the reduction of cardiovascular mortality in developed countries. However, the recurrent incidence of muscle symptoms in statin users raised the possibility of causal association, leading to a disease entity known as statin associated muscle symptoms (SAMS). Mechanistic studies and clinical trials, specifically designed for the study of SAMS have allowed a deeper understanding of the natural history and accurate incidence. This set of information becomes essential to avoid an unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents overdiagnosis and an inadequate suspension of one of the most powerful prevention strategies of our times. In this context, the Luso-Latin American Consortium gathered all available information on the subject and presents them in detail in this document as the basis for the identification and management of SAMS.

Counterpoint: Flexibilization of Fasting for Laboratory Determination of the Lipid Profile in Brazil: Science or Convenience?

Some imprecision due to low or high triglycerides in calculating LDL-cholesterol may affect cardiovascular risk assessment, the definition of a therapeutic target, and the need to intensify the treatment.5,6 Accurate results require triglyceride levels below 400 mg/dL, but above 100 mg/dL the calculated LDL-c starts to be underestimated, when compared to ultracentrifugation measurements. Another limitation to the use of the formula is that samples must not contain beta-VLDL, as in the case of type III hyperlipoproteinemia. When one of these conditions are not satisfied, the equation cannot be used due to imprecision.5-7

Predictors of Family Recruitment in a Program of Genetic Cascade Screening for Familial Hypercholesterolemia

DOI: 10.5935/abc.20180193 Familial hypercholesterolemia (FH) is a common inherited disease affecting lipid metabolism; it is associated with lifelong exposure to high levels of LDL-cholesterol, and premature atherosclerotic cardiovascular disease. FH imposes an enormous burden on patients and their relatives, due to years of life lost, and particularly, for not being diagnosed as an entity.1 In spite of the high LDL-cholesterol and even after an atherosclerotic event, a large proportion of individuals with FH remains undiagnosed.2,3 Criteria for diagnosing FH are based on clinical findings, family history, LDL-cholesterol levels, and genetic testing (Simon Broome or Dutch Lipid Clinic Network), or on the LDL-cholesterol levels alone (US MED PED).4 However, FH phenotypes can vary, and the lack of physical signs (15-30% of patients with genetic diagnosis of FH present xanthomas or corneal arcus, and 5% have xanthelasma) can contribute for the underdiagnosis of FH. 5-7 Genetic testing using a panel that includes FH-causing genes (LDLR, APOB, PCSK9, and LDLRAP-1) is the best approach to identify probands.1,4 When cascade screening is proposed to a family with a confirmed genetic case of FH, the costs for this screening program are much lower and are considered a cost-effective intervention, enabling early diagnosis and treatment of the affected relatives. One problem with cascade screening is how to have a high proportion of relatives adhering to the screening program.8-11 Silva-Souza, et al.,12 in the article entitled Predictors of Family Recruitment in a Program of Genetic Cascade Screening for Familial Hypercholesterolemia identified the best predictors of genetic family screening, using characteristics derived from their probands.12 From January 2011 to July 2015, 183 probands (confirmed for FH by genetic testing) had their 1st degree family members recruited for the cascade program. The response variable was the number of relatives that adhered to the recruitment.13 Study variables were derived from clinical and socioeconomic characteristics of the index cases. A linear negative binomial regression model was used to test predictors. Reference origin from the site of cascade screening vs. tertiary prevention, LDL-cholesterol in the proband, and family history were independent predictors for a higher number of recruited subjects.