Francisco Antonio Helfenstein Fonseca

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 (n = 35) with sex-matched and age-matched healthy controls (n = 33). 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%, P = 0.045). In addition, endothelial microparticles concentration was higher in HIV-infected individuals (1963 vs. 436 microparticles/&mgr;l platelet-poor plasma, P = 0.003), 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; P = 0.03]. 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.

Risk factors, biochemical markers, and genetic polymorphisms in early coronary artery disease

OBJECTIVE To assess the risk factors, lipid and apolipoprotein profile, hemostasis variables, and polymorphisms of the apolipoprotein AI-CIII gene in early coronary artery disease (CAD). METHODS Case-control study with 112 patients in each group controlled by sex and age. After clinical evaluation and nutritional instruction, blood samples were collected for biochemical assays and genetic study. RESULTS Familial history of early CAD (64 vs 39%), arterial hypertension (69 vs 36%), diabetes mellitus (25 vs 3%), and previous smoking (71 vs 46%) were more prevalent in the case group (p<0.001). Hypertension and diabetes were independent risk factors. Early CAD was characterized by higher serum levels of total cholesterol (235 +/-6 vs 209 +/- 4 mg/dL), of LDL-c (154 +/- 5 vs 135 +/- 4 mg/dL), triglycerides (205 +/- 12 vs 143 +/- 9 mg/dL), and apolipoprotein B (129 +/- 3 vs 105 +/- 3 mg/dL), and lower serum levels of HDL-c (40 +/- 1 vs 46 +/- 1 mg/dL) and apolipoprotein AI (134 +/- 2 vs 146 +/- 2mg/dL) [p<0.01], in addition to an elevation in fibrinogen and D-dimer (p<0.02). The simultaneous presence of the rare alleles of the APO AI-CIII genes in early CAD are associated with hypertriglyceridemia (p=0.03). CONCLUSION Of the classical risk factors, hypertension and diabetes mellitus were independently associated with early CAD. In addition to an unfavorable lipid profile, an increase in the thrombotic risk was identified in this population. An additive effect of the APO AI-CIII genes was observed in triglyceride levels.

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.

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.

I Posicionamento Brasileiro sobre Combinação de Fármacos Anti-Hipertensivos

Arterial hypertension (AH) is a highly prevalent disease, and is a major cardiovascular (CV) risk factor1; therefore, achieving blood pressure (BP) control goals as soon as possible is paramount to reduce that risk2. That means that approximately 70% of hypertensive individuals will need antihypertensive drug combination3, and up to 30% of hypertensive individuals are estimated to use four or more drugs to achieve BP control4. Thus, drug combination is currently described as an important strategy to manage AH, providing effective and safe BP reduction. Drug choice is based on effective BP reduction and CV outcomes. Despite the existence of a significant number of drugs to treat AH, their control rates are still very low, contributing to the high CV morbidity and mortality rates observed in Brazil and worldwide1,2. According to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Hypertension Optimal Treatment (HOT) Study, only 26% and 33% of the patients, respectively, could control their BP with monotherapy, while in the Losartan Intervention for Endpoints Reduction (LIFE) Study, 90% of the patients needed combined therapy for that purpose3 . Drug combination is mainly aimed at increasing antihypertensive efficacy, with fewer adverse events. It is worth noting the importance of considering therapy adherence. The pathophysiology of AH involves multiple factors and mechanisms, making its control difficult when only one drug is used, because counterregulatory mechanisms that attenuate the antihypertensive effect of the drug can occur. The association of drugs with different mechanisms of action has a greater impact on BP reduction as long as there is pharmacokinetic compatibility and no disparity of effects and properties3-5. Thus, the choice of the drugs to be combined should contemplate two aspects: synergism of the mechanisms of action and opposition to counterregulatory mechanisms triggered after the beginning of therapy with a certain drug. The desired antihypertensive efficacy is more likely to be achieved by using lower doses of the drugs involved. Thus, fewer adverse events are observed, with no loss of antihypertensive drug potency3-5. Another important aspect is that drugs should be preferably combined in a single galenic presentation, facilitating their administration, and assuring lower cost, with a consequent improvement in treatment adherence2,6.

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.

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.

Rare Presentation of Dercum's Disease in a Child with Abnormalities in Lipoprotein Metabolism

DOI: 10.5935/abc.20180191 Adiposis dolorosa, or Dercum’s disease, is a subcutaneous accumulation of fat in the body accompanied by intense, chronic, and symmetrical pain, often disabling, and usually not responsive to conventional analgesics. It was first described by Dercum, recognized as a separate disease in 1892,1 and further reported by White in 1899.2 Termed in the literature Dercum’s disease, Morbus Dercum, lipomatosis dolorosa, adiposalgia, adiposis dolorosa, and adipose tissue rheumatism, this condition is more prevalent in young women, aged 35 to 50 years, and affects preferably those in the post-menopause phase.1-3 Adiposis dolorosa can also occur in multiple familial lipomatosis, a condition associated with multiple lipomas.4 Other symptoms and signs include psychiatric (depression, anxiety, sleep disturbances, memory and concentration impairment), cardiovascular (tachycardia), pulmonary (shortness of breath), rheumatological (fatigue, weakness, joint and muscle aches) and gastrointestinal (bloating, constipation) disorders.3

Behavior of Blood Pressure Variables in Children and Adolescents with Duchenne Muscular Dystrophy

BACKGROUND Duchenne muscular dystrophy is an X-chromosome-linked genetic disorder (locus Xp21). Involvement of the cardiovascular system is characterized by fibrous degeneration/replacement of myocytes with consequent ventricular hypertrophy and arterial hypertension. OBJECTIVE To assess, by using 24-hour ambulatory blood pressure monitoring, the behavior of blood pressure variables in children and adolescents with a confirmed diagnosis of Duchenne muscular dystrophy. METHODS Prospective observational cohort study, which selected 46 patients followed up on an outpatient basis, divided according to age groups. Blood pressure was classified according to the age percentile. The monitoring interpretation includes systolic and diastolic blood pressure means, systolic and diastolic blood pressure loads, and nocturnal dipping. The blood pressure means were calculated for the 24-hour, wakefulness and sleep periods. Nocturnal dipping was defined as a drop in blood pressure means during sleep greater than 10%. The significance level adopted was p < 0.05. RESULTS Nocturnal dipping for systolic blood pressure was present in 29.9% of the participants. Approximately 53% of them had attenuated nocturnal dipping, and 15%, reverse nocturnal dipping. The age groups of 9-11 years and 6-8 years had the greatest percentage of attenuation, 19.1% and 14.9%, respectively. Regarding diastolic blood pressure, nocturnal dipping was identified in 53.2% of the children, being extreme in 27.7% of those in the age group of 6-11 years. CONCLUSIONS The early diagnosis of blood pressure changes can allow the appropriate and specific therapy, aimed at increasing the life expectancy of patients with Duchenne muscular dystrophy.