Marcio H. Miname

Uric acid: A marker of increased cardiovascular risk.

The relationship between uric acid and cardiovascular disease has been known since the 19th century, after that many authors reported the classical association of gout, hypertension, obesity and cardiovascular disease. With the exception of specific genetic defects in purine metabolism, increased uric acid is generally associated with important risk factors for atherosclerosis like hypertension, abdominal obesity, insulin resistance, the metabolic syndrome and renal failure. Studies have clearly shown an association between increased uric acid concentrations with oxidative stress, endothelial dysfunction, inflammation, subclinical atherosclerosis and an increased risk of cardiovascular events. Increased uric acid levels are independent markers of cardiovascular disease risk. Prospective studies are necessary to show that reduction of uric acid levels prevent cardiovascular events.

Phosphate Binder Impact on Bone Remodeling and Coronary Calcification – Results from the BRiC Study

Backgroundand Aims: Calcium-containing phosphate binders have been shown to increase the progression of vascular calcification in hemodialysis patients. This is a prospective study that compares the effects of calcium acetate and sevelamer on coronary calcification (CAC) and bone histology. Methods: 101 hemodialysis patients were randomized for each phosphate binder and submitted to multislice coronary tomographies and bone biopsies at entry and 12 months. Results: The 71 patients who concluded the study had similar baseline characteristics. On follow-up, the sevelamer group had higher levels of intact parathyroid hormone (498 ± 352 vs. 326 ± 236 pg/ml, p = 0.017), bone alkaline phosphatase (38 ± 24 vs. 28 ± 15 U/l, p = 0.03) and deoxypyridinoline (135 ± 107 vs. 89 ± 71 nmol/l, p = 0.03) and lower LDL cholesterol (74 ± 21 vs. 91 ± 28 mg/dl, p = 0.015). Phosphorus (5.8 ± 1.0 vs. 6 ± 1.0 mg/dl, p = 0.47) and calcium (1.27 ± 0.07 vs. 1.23 ± 0.08 mmol/l, p = 0.68) levels did not differ between groups. CAC progression (35 vs. 24%, p = 0.94) and bone histological diagnosis at baseline and 12 months were similar in both groups. Patients of the sevelamer group with a high turnover at baseline had an increase in bone resorption (eroded surface, ES/BS = 9.0 ± 5.9 vs. 13.1 ± 9.5%, p = 0.05), whereas patients of both groups with low turnover at baseline had an improvement in bone formation rate (BFR/BS = 0.015 ± 0.016 vs. 0.062 ± 0.078, p = 0.003 for calcium and 0.017 ± 0.016 vs. 0.071 ± 0.084 μm3/μm2/day, p = 0.010 for sevelamer). Conclusions: There was no difference in CAC progression or changes in bone remodeling between the calcium and the sevelamer groups.

Association of Changes in Bone Remodeling and Coronary Calcification in Hemodialysis Patients: A Prospective Study

BACKGROUND Vascular calcification is common and constitutes a prognostic marker of mortality in the hemodialysis population. Derangements of mineral metabolism may influence its development. The aim of this study is to prospectively evaluate the association between bone remodeling disorders and progression of coronary artery calcification (CAC) in hemodialysis patients. STUDY DESIGN Cohort study nested within a randomized controlled trial. SETTING & PARTICIPANTS 64 stable hemodialysis patients. PREDICTOR Bone-related laboratory parameters and bone histomorphometric characteristics at baseline and after 1 year of follow-up. OUTCOMES Progression of CAC assessed by means of coronary multislice tomography at baseline and after 1 year of follow-up. Baseline calcification score of 30 Agatston units or greater was defined as calcification. Change in calcification score of 15% or greater was defined as progression. RESULTS Of 64 patients, 38 (60%) of the patients had CAC and 26 (40%) did not [corrected]. Participants without CAC at baseline were younger (P < 0.001), mainly men (P = 0.03) and nonwhite (P = 0.003), and had lower serum osteoprotegerin levels (P = 0.003) and higher trabecular bone volume (P = 0.001). Age (P = 0.003; beta coefficient = 1.107; 95% confidence interval [CI], 1.036 to 1.183) and trabecular bone volume (P = 0.006; beta coefficient = 0.828; 95% CI, 0.723 to 0.948) were predictors for CAC development. Of 38 participants who had calcification at baseline, 26 (68%) had CAC progression in 1 year. Progressors had lower bone-specific alkaline phosphatase (P = 0.03) and deoxypyridinoline levels (P = 0.02) on follow-up, and low turnover was mainly diagnosed at the 12-month bone biopsy (P = 0.04). Low-turnover bone status at the 12-month bone biopsy was the only independent predictor for CAC progression (P = 0.04; beta coefficient = 4.5; 95% CI, 1.04 to 19.39). According to bone histological examination, nonprogressors with initially high turnover (n = 5) subsequently had decreased bone formation rate (P = 0.03), and those initially with low turnover (n = 7) subsequently had increased bone formation rate (P = 0.003) and osteoid volume (P = 0.001). LIMITATIONS Relatively small population, absence of patients with severe hyperparathyroidism, short observational period. CONCLUSIONS Lower trabecular bone volume was associated with CAC development, whereas improvement in bone turnover was associated with lower CAC progression in patients with high- and low-turnover bone disorders. Because CAC is implicated in cardiovascular mortality, bone derangements may constitute a modifiable mortality risk factor in hemodialysis patients.

Relation between visceral fat and coronary artery disease evaluated by multidetector computed tomography

Visceral abdominal fat has been associated to cardiovascular risk factors and coronary artery disease (CAD). Computed tomography (CT) coronary angiography is an emerging technology allowing detection of both obstructive and nonobstructive CAD adding information to clinical risk stratification. The aim of this study was to evaluate the association between CAD and adiposity measurements assessed clinically and by CT. We prospectively evaluated 125 consecutive subjects (57% men, age 56.0+/-12 years) referred to perform CT angiography. Clinical and laboratory variables were determined and CT angiography and abdominal CT were performed in a 64-slice scanner. CAD was defined as any plaque calcified or not detected by CT angiography. Visceral and subcutaneous adiposity areas were determined at different intervertebral levels. CT angiography detected CAD in 70 (56%) subjects, and no association was found with usual anthropometric adiposity measurements (waist and hip circumferences and body mass index). Otherwise, CT visceral fat areas (VFA) were significantly related to CAD. VFA T12-L1 values > or =145cm(2) had an odds ratio of 2.85 (95% CI 1.30-6.26) and VFA L4-L5 > or =150cm(2) had a 2.87-fold (95% CI 1.31-6.30) CAD risk. The multivariate analysis determined age and VFA T12-L1 as the only independent variables associated to CAD. Visceral fat assessed by CT is an independent marker of CAD determined by CT angiography.

Evaluation of subclinical atherosclerosis by computed tomography coronary angiography and its association with risk factors in familial hypercholesterolemia

BACKGROUND Increasing age and cholesterol levels, male gender, and family history of early coronary heart disease (CHD) are associated with early onset of CHD in familial hypercholesterolemia (FH). OBJECTIVE Assess subclinical atherosclerosis by computed tomography coronary angiography (CTCA) and its association with clinical and laboratorial parameters in asymptomatic FH subjects. METHODS 102 FH subjects (36% male, 45 ± 13 years, LDL-c 280 ± 54 mg/dL) and 35 controls (40% male, 46 ± 12 years, LDL-c 103 ± 18 mg/dL) were submitted to CTCA. Plaques were divided into calcified, mixed and non-calcified; luminal stenosis was characterized as >50% obstruction. RESULTS FH had a greater atherosclerotic burden represented by higher number of patients with: plaques (48% vs. 14%, p=0.0005), stenosis (19% vs. 3%, p=0.015), segments with plaques (2.05 ± 2.85 vs.0.43 ± 1.33, p=0.0016) and calcium scores (55 ± 129 vs. 38 ± 140, p=0.0028). After multivariate analysis, determinants of plaque presence were increasing age (OR=2.06, for age change of 10 years, CI95%: 1.38-3.07, p<0.001) and total cholesterol (OR=1.86, for cholesterol change by 1 standard deviation, CI95%: 1.09-3.15, p=0.027). Coronary calcium score was associated with the presence of stenosis (OR=1.54; CI95%: 1.27-1.86, p<0.001, for doubling the calcium score). Male gender was directly associated with the presence of non-calcified plaques (OR: 15.45, CI95% 1.72-138.23, p=0.014) and inversely with calcified plaques (OR=0.21, CI95%: 0.05-0.84, p=0.027). Family history of early CHD was associated with the presence of mixed plaques (OR=4.90, CI95%: 1.32-18.21, p=0.018). CONCLUSIONS Patients with FH had an increased burden of coronary atherosclerosis by CTCA. The burden of atherosclerosis and individual plaque subtypes differed with the presence of other associated risk factors, with age and cholesterol being most important. A coronary calcium score of zero ruled out obstructive disease in this higher risk population.

Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon −2, Q[−2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small α-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow α migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large α-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II α-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.

Familial hypercholesterolemia in Brazil: Cascade screening program, clinical and genetic aspects

BACKGROUND There is little knowledge about familial hypercholesterolemia in Brazil. This study presents the first results of genetic cascade screening performed in the city of Sao Paulo. MATERIAL AND METHODS Two-hundred and forty-eight suspected index cases were initially included. DNA was extracted from peripheral blood and the complete coding sequence of low-density lipoprotein receptor, exon 7 of proprotein convertase subtilisin/kexin type 9 gene and part of exon 26 of apolipoprotein B genes were sequenced. Multiplex Ligation-dependent Probe Amplification was performed on cases where a causal mutation was not identified through sequencing. After the identification of a causal mutation screening in first-degree relatives was pursued. RESULTS From 248 index cases, a mutation was found in 125 individuals (50.4%). 394 relatives were included in the cascade screening program and a mutation was identified in 59.4%. Seventy different causal mutations in the low-density lipoprotein receptor gene (97.2%) and 2 in the apolipoprotein B gene (2.8%) were found. No mutations were encountered in the proprotein convertase subtilisin/kexin type 9 gene. Mutations in exons 14 and 4 were the most prevalent and, 10 cases of true homozygotes (8 index cases and 2 relatives) and 1 compound heterozygote were identified. The most frequent mutation found was of Lebanese origin, the p.(Cys681*) mutation in exon 14 (8.5%). CONCLUSION Genetic familial hypercholesterolemia cascade screening is feasible in Brazil and leads to identification of a mutation in approximately half of the index cases with higher rates of success in their relatives.

Severe Periodontitis Is Associated With Diastolic Blood Pressure Elevation in Individuals With Heterozygous Familial Hypercholesterolemia: A Pilot Study

BACKGROUND This pilot study evaluates the association of severe periodontitis with pulse wave velocity (PWV), carotid artery intima-medial thickness (IMT), and clinical, metabolic, and atherogenic inflammatory markers in 79 subjects with heterozygous familial hypercholesterolemia (hFH). All subjects were free of previous vascular disease manifestations. METHODS The body mass index (in kilograms per square meter), plasma lipids, glucose, C-reactive protein, and white blood cell counts were evaluated. After full-mouth periodontal examinations, patients were categorized into the severe periodontitis group (SPG) or non-severe periodontitis group (NSPG). RESULTS The SPG showed significantly higher values of cholesterol-year scores, triglycerides, glucose, PWV, IMT, and diastolic blood pressure (DBP) (P ≤0.05) than the NSPG. After adjustment for traditional risk factors for atherosclerosis, only the association between severe periodontitis and DBP (odds ratio: 3.1; 95% CI: 1.1 to 8.5; P = 0.03) was confirmed. CONCLUSION In individuals with hFH, severe periodontitis was associated with a higher DBP, which suggests that severe periodontitis, itself, may contribute to the increased cardiovascular risk profile in this population.

Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein–deficiency states

Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels <10 mg/dL in the absence of severe hypertriglyceridemia or liver disease) and to provide information about coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If apolipoprotein (Apo) A-I is not present in plasma, then three forms of ApoA-I deficiency, all with premature CHD,and normal low-density lipoprotein (LDL) cholesterol levels have been described: ApoA-I/C-III/A-IV deficiency with fat malabsorption, ApoA-I/C-III deficiency with planar xanthomas, and ApoA-I deficiency with planar and tubero-eruptive xanthomas (pictured in this review for the first time). If ApoA-I is present in plasma at a concentration <10 mg/dL, with LDL cholesterol that is about 50% of normal and mild hypertriglyceridemia, a possible diagnosis is Tangier disease due to mutations at the adenosine triphosphate binding cassette protein A1 (ABCA1) gene locus. These patients may develop premature CHD and peripheral neuropathy, and have evidence of cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma ApoA-I levels <40 mg/dL, moderate hypertriglyceridemia, and decreased LDL cholesterol, and the finding that most of the cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and splenomegaly, and are at increased risk of developing renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk.

Defective functionality of HDL particles in familial apoA-I deficiency: relevance of alterations in HDL lipidome and proteome

To evaluate functional and compositional properties of HDL in subjects from a kindred of genetic apoA-I deficiency, two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2, Q[-2]X, were recruited together with age- and sex-matched healthy controls (n = 11). Homozygotes displayed undetectable plasma levels of apoA-I and reduced levels of HDL-cholesterol (HDL-C) and apoC-III (5.4% and 42.6% of controls, respectively). Heterozygotes displayed low HDL-C (21 ± 9 mg/dl), low apoA-I (79 ± 24 mg/dl), normal LDL-cholesterol (132 ± 25 mg/dl), and elevated TG (130 ± 45 mg/dl) levels. Cholesterol efflux capacity of ultracentrifugally isolated HDL subpopulations was reduced (up to −25%, P < 0.01, on a glycerophospholipid [GP] basis) in heterozygotes versus controls. Small, dense HDL3 and total HDL from heterozygotes exhibited diminished antioxidative activity (up to −48%, P < 0.001 on a total mass basis) versus controls. HDL subpopulations from both homozygotes and heterozygotes displayed altered chemical composition, with depletion in apoA-I, GP, and cholesteryl ester; enrichment in apoA-II, free cholesterol, and TG; and altered phosphosphingolipidome. The defective atheroprotective activities of HDL were correlated with altered lipid and apo composition. These data reveal that atheroprotective activities of HDL particles are impaired in homozygous and heterozygous apoA-I deficiency and are intimately related to marked alterations in protein and lipid composition.