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1.  Hypotheses, rationale, design, and methods for prognostic evaluation in type 2 diabetic patients with angiographically normal coronary arteries. The MASS IV-DM Trial 
The MASS IV-DM Trial is a large project from a single institution, the Heart Institute (InCor), University of São Paulo Medical School, Brazil to study ventricular function and coronary arteries in patients with type 2 diabetes mellitus.
The study will enroll 600 patients with type 2 diabetes who have angiographically normal ventricular function and coronary arteries. The goal of the MASS IV-DM Trial is to achieve a long-term evaluation of the development of coronary atherosclerosis by using angiograms and coronary-artery calcium scan by electron-beam computed tomography at baseline and after 5 years of follow-up. In addition, the incidence of major cardiovascular events, the dysfunction of various organs involved in this disease, particularly microalbuminuria and renal function, will be analyzed through clinical evaluation. In addition, an effort will be made to investigate in depth the presence of major cardiovascular risk factors, especially the biochemical profile, metabolic syndrome inflammatory activity, oxidative stress, endothelial function, prothrombotic factors, and profibrinolytic and platelet activity. An evaluation will be made of the polymorphism as a determinant of disease and its possible role in the genesis of micro- and macrovascular damage.
The MASS IV-DM trial is designed to include diabetic patients with clinically suspected myocardial ischemia in whom conventional angiography shows angiographically normal coronary arteries. The result of extensive investigation including angiographic follow-up by several methods, vascular reactivity, pro-thrombotic mechanisms, genetic and biochemical studies may facilitate the understanding of so-called micro- and macrovascular disease of DM.
PMCID: PMC2956708  PMID: 20920271
2.  Hypotheses, rationale, design, and methods for prognostic evaluation of cardiac biomarker elevation after percutaneous and surgical revascularization in the absence of manifest myocardial infarction. A comparative analysis of biomarkers and cardiac magnetic resonance. The MASS-V Trial 
Although the release of cardiac biomarkers after percutaneous (PCI) or surgical revascularization (CABG) is common, its prognostic significance is not known. Questions remain about the mechanisms and degree of correlation between the release, the volume of myocardial tissue loss, and the long-term significance. Delayed-enhancement of cardiac magnetic resonance (CMR) consistently quantifies areas of irreversible myocardial injury. To investigate the quantitative relationship between irreversible injury and cardiac biomarkers, we will evaluate the extent of irreversible injury in patients undergoing PCI and CABG and relate it to postprocedural modifications in cardiac biomarkers and long-term prognosis.
The study will include 150 patients with multivessel coronary artery disease (CAD) with left ventricle ejection fraction (LVEF) and a formal indication for CABG; 50 patients will undergo CABG with cardiopulmonary bypass (CPB); 50 patients with the same arterial and ventricular condition indicated for myocardial revascularization will undergo CABG without CPB; and another 50 patients with CAD and preserved ventricular function will undergo PCI using stents. All patients will undergo CMR before and after surgery or PCI. We will also evaluate the release of cardiac markers of necrosis immediately before and after each procedure. Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and systolic left ventricle dysfunction assessed by CMR.
The MASS-V Trial aims to establish reliable values for parameters of enzyme markers of myocardial necrosis in the absence of manifest myocardial infarction after mechanical interventions. The establishments of these indices have diagnostic value and clinical prognosis and therefore require relevant and different therapeutic measures. In daily practice, the inappropriate use of these necrosis markers has led to misdiagnosis and therefore wrong treatment. The appearance of a more sensitive tool such as CMR provides an unprecedented diagnostic accuracy of myocardial damage when correlated with necrosis enzyme markers. We aim to correlate laboratory data with imaging, thereby establishing more refined data on the presence or absence of irreversible myocardial injury after the procedure, either percutaneous or surgical, and this, with or without the use of cardiopulmonary bypass.
PMCID: PMC3468382  PMID: 22898311
Cardiopulmonary bypass; Necrosis markers; Myocardial infarction; PCI; CABG
3.  A population-based study of the stratum corneum moisture 
The stratum corneum (SC) has important functions as a bound-water modulator and a primary barrier of the human skin from the external environment. However, no large epidemiological study has quantified the relative importance of different exposures with regard to these functional properties. In this study, we have studied a large sample of individuals from the Brazilian population in order to understand the different relationships between the properties of SC and a number of demographic and self-perceived variables.
One thousand three hundred and thirty-nine individuals from a rural Brazilian population, who were participants of a family-based study, were submitted to a cross-sectional examination of the SC moisture by capacitance using the Corneometer® CM820 and investigated regarding environmental exposures, cosmetic use, and other physiological and epidemiological measurements. Self-perception-scaled questions about skin conditions were also applied.
We found significant associations between SC moisture and sex, age, high sun exposure, and sunscreen use frequency (P<0.025). In specific studied sites, self-reported race and obesity were also found to show significant effects. Dry skin self-perception was also found to be highly correlated with the objective measurement of the skin. Other environmental effects on SC moisture are also reported.
PMCID: PMC4845893  PMID: 27143945
investigative dermatology; stratum corneum moisture; Corneometer; sun exposure; familial data modeling
4.  Impact of Exhaled Breath Acetone in the Prognosis of Patients with Heart Failure with Reduced Ejection Fraction (HFrEF). One Year of Clinical Follow-up 
PLoS ONE  2016;11(12):e0168790.
The identification of new biomarkers of heart failure (HF) could help in its treatment. Previously, our group studied 89 patients with HF and showed that exhaled breath acetone (EBA) is a new noninvasive biomarker of HF diagnosis. However, there is no data about the relevance of EBA as a biomarker of prognosis.
To evaluate whether EBA could give prognostic information in patients with heart failure with reduced ejection fraction (HFrEF).
After breath collection and analysis by gas chromatography-mass spectrometry and by spectrophotometry, the 89 patients referred before were followed by one year. Study physicians, blind to the results of cardiac biomarker testing, ascertained vital status of each study participant at 12 months.
The composite endpoint death and heart transplantation (HT) were observed in 35 patients (39.3%): 29 patients (32.6%) died and 6 (6.7%) were submitted to HT within 12 months after study enrollment. High levels of EBA (≥3.7μg/L, 50th percentile) were associated with a progressively worse prognosis in 12-month follow-up (log-rank = 11.06, p = 0.001). Concentrations of EBA above 3.7μg/L increased the risk of death or HT in 3.26 times (HR = 3.26, 95%CI = 1.56–6.80, p = 0.002) within 12 months. In a multivariable cox regression model, the independent predictors of all-cause mortality were systolic blood pressure, respiratory rate and EBA levels.
High EBA levels could be associated to poor prognosis in HFrEF patients.
PMCID: PMC5193433  PMID: 28030609
5.  Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range – study protocol for a randomized controlled trial 
Time in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (<50%) are associated with greater risk of thromboembolic and bleeding events. Recently, we developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (<50%) from a tertiary cardiovascular hospital.
This study is a randomized controlled trial in patients (n = 300) with atrial fibrillation with TTR < 50%, based on the last three INR values. At the first consultation, patients will be randomized into two groups: TA group (traditional anticoagulation) and PA group (pharmacogenetic anticoagulation). For the first group, the physician will adjust the dose according to current INR value and, for the second group, a pharmacogenetic algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient’s INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School.
This randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients.
Trial registration, NCT02592980. Registered on 29 October 2015.
PMCID: PMC5112885  PMID: 27855643
Warfarin; Algorithm; Pharmacogenetic; Pharmacoeconomy; Polymorphisms
6.  Genomic ancestry as a predictor of haemodynamic profile in heart failure 
Open Heart  2016;3(2):e000434.
The aim of this study is to assess the association between genetic ancestry, self-declared race and haemodynamic parameters in patients with chronic heart failure (HF).
Observational, cross-sectional study. Eligible participants were aged between 18 and 80 years; ejection fraction was ≤50%. Patients underwent genetic analysis of ancestry informative markers, echocardiography and impedance cardiography (ICG). Race was determined by self-classification into two groups: white and non-white. Genomic ancestry was estimated using a panel of 101 348 polymorphic markers and three continental reference populations (European, African and Native American).
Our study included 362 patients with HF between August 2012 and August 2014. 123 patients with HF declared themselves as white and 234 patients declared themselves as non-white. No statistically significant differences were found regarding the ICG parameters according to self-declared race. The Amerindian ancestry was positively correlated with systolic time ratio (r=0.109, p<0.05). The thoracic fluid content index (r=0.124. p<0.05), E wave peak (r=0.127. p<0.05) and E/e′ ratio (r=0.197. p<0.01) were correlated positively with African ancestry. In multiple linear regression, African ancestry remained associated with the E/e′ ratio, even after adjustment to risk factors.
The African genetic ancestry was associated with worse parameters of diastolic function; the Amerindian ancestry correlated with a worse pattern of ventricular contractility, while self-declared colour was not helpful to infer haemodynamic profiles in HF.
Trials registration number
PMCID: PMC4975862  PMID: 27547430
7.  Effects of aging on the effectiveness of smoking cessation medication 
Oncotarget  2016;7(21):30032-30036.
Considering the pharmacokinetic and pharmacodynamic aspects of different medications, it is plausible that the age of a smoker could affect the half-life of these drugs. The aim of this study was to compare the effectiveness of smoking cessation drugs (nicotine replacement therapy, bupropion, and varenicline) used either in isolation or in combination in adults under and over 60 years of age.
Data were collected from 940 Brazilian patients participating in a smoking cessation program. Participants were prescribed smoking cessation medication to be used for at least 12 weeks and were followed for 52 weeks.
Cessation rates were significantly different among younger and older participants who were using nicotine replacement therapy (NRT) alone. Being over 60 years of age was significantly associated with increased cessation success among those who used NRT alone (OR 2.34, 95% CI: 1.36 to 4.04, p = 0.002). The effectiveness of varenicline and bupropion were not significantly different according to age groups.
Using age as a predictor for tailoring smoking cessation drugs might potentially lead to a more individualized prescription of smoking cessation therapy. These results should be tested in randomized controlled trials.
PMCID: PMC5058661  PMID: 27166253
nicotine replacement therapy; varenicline; bupropion; smoking cessation; aging; Gerotarget
8.  Genomic African and Native American Ancestry and Chagas Disease: The Bambui (Brazil) Epigen Cohort Study of Aging 
PLoS Neglected Tropical Diseases  2016;10(5):e0004724.
The influence of genetic ancestry on Trypanosoma cruzi infection and Chagas disease outcomes is unknown.
Methodology/Principal Findings
We used 370,539 Single Nucleotide Polymorphisms (SNPs) to examine the association between individual proportions of African, European and Native American genomic ancestry with T. cruzi infection and related outcomes in 1,341 participants (aged ≥ 60 years) of the Bambui (Brazil) population-based cohort study of aging. Potential confounding variables included sociodemographic characteristics and an array of health measures. The prevalence of T. cruzi infection was 37.5% and 56.3% of those infected had a major ECG abnormality. Baseline T. cruzi infection was correlated with higher levels of African and Native American ancestry, which in turn were strongly associated with poor socioeconomic circumstances. Cardiomyopathy in infected persons was not significantly associated with African or Native American ancestry levels. Infected persons with a major ECG abnormality were at increased risk of 15-year mortality relative to their counterparts with no such abnormalities (adjusted hazard ratio = 1.80; 95% 1.41, 2.32). African and Native American ancestry levels had no significant effect modifying this association.
Our findings indicate that African and Native American ancestry have no influence on the presence of major ECG abnormalities and had no influence on the ability of an ECG abnormality to predict mortality in older people infected with T. cruzi. In contrast, our results revealed a strong and independent association between prevalent T. cruzi infection and higher levels of African and Native American ancestry. Whether this association is a consequence of genetic background or differential exposure to infection remains to be determined.
Author Summary
Chagas disease (ChD), which is caused by the protozoan Trypanosoma cruzi, affects approximately 8 million people worldwide. ChD is known as a neglected tropical disease. The disease is endemic in South and Central American countries, and is an emerging issue in North America and Europe. This study examined, for the first time, the association between genomic ancestry and T. cruzi infection, Chagasic cardiomyopathy and its ability to predict long term mortality. Our results show that persons with higher levels of African and Native American ancestries (and the reverse for European ancestry) are more likely to be infected with T. cruzi. However, genomic ancestry had no effect on either Chagasic cardiomyopathy or on its ability to predict mortality. Whether the association between T. cruzi infection and genomic ancestry is a consequence of genetic susceptibility or differential exposure to infection due to poor socioeconomic circumstances over the life course, remains to be determined.
PMCID: PMC4868305  PMID: 27182885
9.  Influence of smoking cessation drugs on blood pressure and heart rate in patients with cardiovascular disease or high risk score: real life setting 
Smoking is the most important reversible cardiovascular risk factor. It is well established that quitting smoking reduces coronary events. However, on several occasions, the cardiovascular safety of smoking cessation drugs has been questioned. Our goal is to evaluate the effects of smoking cessation drugs on blood pressure and heart rate in patients from a smoking cessation service in a cardiology hospital.
We examined the PAF database (Smoking Cessation Assistance Program database) between January 2008 and March 2014. We analyzed data from 900 patients who were compliant with the treatment (50.5 % male, average age 53 ± 17 years). The most frequent clinical diagnoses were coronary artery disease (25.2 %), hypertension (57.2 %), and diabetes (13.4 %). Blood pressure, heart rate, and carbon monoxide (CO) concentration in exhaled air were analyzed at consecutive visits during the first 45 days of treatment (mean visits - 3). Analysis of repeated measures was used for the statistical analysis (p < 0.05).
Two hundred seventy one patients used nicotine replacement therapy (NRT) alone, 81 used bupropion alone, 154 used varenicline alone, 283 used NRT plus bupropion and 111 used bupropion plus varenicline. For all smoking cessation drugs, used alone or in combination, no increase occurred in the average value of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). Significant reductions in CO concentrations occurred in all smoking cessation drug groups.
Smoking cessation drugs used in monotherapy or in combined regimens did not influence systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) in this group of patients during the observation period.
PMCID: PMC4700597  PMID: 26728720
Smoking cessation; Nicotine replacement therapy; Bupropion; Varenicline; Cardiovascular disease; Hypertension
10.  Smoking and Female Sex: Independent Predictors of Human Vascular Smooth Muscle Cells Stiffening 
PLoS ONE  2015;10(12):e0145062.
Recent evidence shows the rigidity of vascular smooth muscle cells (VSMC) contributes to vascular mechanics. Arterial rigidity is an independent cardiovascular risk factor whose associated modifications in VSMC viscoelasticity have never been investigated. This study’s objective was to evaluate if the arterial rigidity risk factors aging, African ancestry, female sex, smoking and diabetes mellitus are associated with VMSC stiffening in an experimental model using a human derived vascular smooth muscle primary cell line repository.
Eighty patients subjected to coronary artery bypass surgery were enrolled. VSMCs were extracted from internal thoracic artery fragments and mechanically evaluated using Optical Magnetic Twisting Cytometry assay. The obtained mechanical variables were correlated with the clinical variables: age, gender, African ancestry, smoking and diabetes mellitus.
The mechanical variables Gr, G’r and G”r had a normal distribution, demonstrating an inter-individual variability of VSMC viscoelasticity, which has never been reported before. Female sex and smoking were independently associated with VSMC stiffening: Gr (apparent cell stiffness) p = 0.022 and p = 0.018, R2 0.164; G’r (elastic modulus) p = 0.019 and p = 0.009, R2 0.184 and G”r (dissipative modulus) p = 0.011 and p = 0.66, R2 0.141.
Female sex and smoking are independent predictors of VSMC stiffening. This pro-rigidity effect represents an important element for understanding the vascular rigidity observed in post-menopausal females and smokers, as well as a potential therapeutic target to be explored in the future. There is a significant inter-individual variation of VSMC viscoelasticity, which is slightly modulated by clinical variables and probably relies on molecular factors.
PMCID: PMC4678027  PMID: 26661469
11.  Glycemic control and arterial stiffness in a Brazilian rural population: Baependi Heart Study 
Increased arterial stiffness predicts morbidity and mortality, independently of other cardiovascular risk factors, and glycemic control impairments are related to higher vascular stiffness. The aim of this study was to evaluate the association between HbA1c levels and increased arterial stiffness in a Brazilian rural population.
For this study were selected 1675 individuals (both genders and aged over 18 years) resident in the municipality of Baependi, a city located in the Southeast of Brazil. HbA1c levels were determined by HPLC. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior).
HbA1c levels were associated with an increased PWV. This was more relevant for the third tertile of age. In addition, logistic regression multivariate model including age, blood pressure, gender, BMI and fasting glucose showed that the elevation of a single unit percentage of HbA1c represented an increase of 54 % in the odds of increased arterial stiffness [OR 1.54 (95 % CI 1.01–2.17)]. Both, HbA1c and fasting glucose showed higher discriminatory power in the risk assessment for increased arterial stiffness in the non-diabetic when compared to the diabetic group (AUC of HbA1c = 0.71 vs 0.57, p = 0.02; AUC of fasting glucose = 0.66 vs 0.45, p = 0.0007, respectively).
Our findings indicate that a increase in HbA1c levels is associated with increased arterial stiffness and that both, HbA1c and fasting glucose, presented higher discriminatory power in the risk assessment for increased arterial stiffness in the non-diabetic group as compared to diabetic individuals.
PMCID: PMC4595065  PMID: 26445602
HbA1c; Arterial stiffness; Glycemic control
12.  One-year Mortality after an Acute Coronary Event and its Clinical Predictors: The ERICO Study 
Information about post-acute coronary syndrome (ACS) survival have been mostly short-term findings or based on specialized, cardiology referral centers.
To describe one-year case-fatality rates in the Strategy of Registry of Acute Coronary Syndrome (ERICO) cohort, and to study baseline characteristics as predictors.
We analyzed data from 964 ERICO participants enrolled from February 2009 to December 2012. We assessed vital status by telephone contact and official death certificate searches. The cause of death was determined according to the official death certificates. We used log-rank tests to compare the probabilities of survival across subgroups. We built crude and adjusted (for age, sex and ACS subtype) Cox regression models to study if the ACS subtype or baseline characteristics were independent predictors of all-cause or cardiovascular mortality.
We identified 110 deaths in the cohort (case-fatality rate, 12.0%). Age [Hazard ratio (HR) = 2.04 per 10 year increase; 95% confidence interval (95%CI) = 1.75–2.38], non-ST elevation myocardial infarction (HR = 3.82 ; 95%CI = 2.21–6.60) or ST elevation myocardial infarction (HR = 2.59; 95%CI = 1.38–4.89) diagnoses, and diabetes (HR = 1.78; 95%CI = 1.20‑2.63) were significant risk factors for all-cause mortality in the adjusted models. We found similar results for cardiovascular mortality. A previous coronary artery disease diagnosis was also an independent predictor of all-cause mortality (HR = 1.61; 95%CI = 1.04–2.50), but not for cardiovascular mortality.
We found an overall one-year mortality rate of 12.0% in a sample of post-ACS patients in a community, non-specialized hospital in São Paulo, Brazil. Age, ACS subtype, and diabetes were independent predictors of poor one‑year survival for overall and cardiovascular-related causes.
PMCID: PMC4523288  PMID: 25993485
Acute Coronary Syndrome/mortality; Risk Factors; Prognosis; Lethality; Cohort Studies
13.  ACTN3 R577X polymorphism and long-term survival in patients with chronic heart failure 
Previous studies have shown the occurrence of actinin-3 deficiency in the presence of the R577X polymorphism in the ACTN3 gene. Our hypothesis is that this deficiency, by interfering with the function of skeletal muscle fiber, can result in a worse prognosis in patients with chronic heart failure.
A prospective cohort study was conducted from 2002 to 2004. The eligibility criteria included diagnosis of chronic heart failure stage C from different etiologies. We excluded all patients with concomitant disease that could be related to poor prognosis. ACTN3 rs1815739 (R577X) polymorphism was detected by high resolution melting analysis. Survival curves were calculated with the Kaplan-Meier method and evaluated with the log-rank statistic. The relationship between the baseline variables and the composite end-point of all-cause death was assessed using a Cox proportional hazards survival model.
A total of 463 patients were included in this study. The frequency of the ACTN3 577X variant allele was 39.0%. The LVEF mean was 45.6 ± 18.7% and the most common etiology of this study was hypertensive. After a follow-up of five years, 239 (51.6%) patients met the pre-defined endpoint. Survival curves showed higher mortality in patients carrying RX or XX genotypes compared with patients carrying RR genotype (p = 0.01).
R577X polymorphism in the ACTN3 gene was independently associated with worse survival in patients with chronic heart failure. Further studies are necessary to ensure its use as a marker of prognosis for this syndrome.
PMCID: PMC4113663  PMID: 25059829
ACTN3; R577X; Polymorphism; Heart failure
14.  Clinical predictors of a positive genetic test in hypertrophic cardiomyopathy in the Brazilian population 
Hypertrophic cardiomyopathy is a genetic autosomal dominant disease characterized by left ventricular hypertrophy. The molecular diagnosis is important but still expensive. This work aimed to find clinical predictors of a positive genetic test in a Brazilian tertiary centre cohort of index cases with HCM.
In the study were included patients with HCM clinical diagnosis. For genotype x phenotype comparison we have evaluated echocardiographic, electrocardiographic, and nuclear magnetic resonance measures. All patients answered a questionnaire about familial history of HCM and/or sudden death. β-myosin heavy chain, myosin binding protein C, and troponin T genes were sequenced for genetic diagnosis.
The variables related to a higher probability of a positive genetic test were familial history of HCM, higher mean heart frequency, presence of NSVT and lower age. Probabilities of having a positive molecular genetic test were calculated from the final multivariate logistic regression model and were used to identify those with a higher probability of a positive molecular diagnosis.
We developed an easy and fast screening method that takes into account only clinical data that can help to select the patients with a high probability of positive genetic results from molecular sequencing of Brazilian HCM patients.
PMCID: PMC3995628  PMID: 24625281
Genetics; MYH7; MYBPC3; TNNT2; Molecular; Screening
15.  Hypertrophic Cardiomyopathy: How do Mutations Lead to Disease? 
Arquivos brasileiros de cardiologia  2014;102(3):295-304.
Hypertrophic cardiomyopathy (HCM) is the most common monogenic genetic cardiac disease, with an estimated prevalence of 1:500 in the general population. Clinically, HCM is characterized by hypertrophy of the left ventricle (LV) walls, especially the septum, usually asymmetric, in the absence of any cardiac or systemic disease that leads to a secondary hypertrophy. The clinical course of the disease has a large inter- and intrafamilial heterogeneity, ranging from mild symptoms of heart failure late in life to the onset of sudden cardiac death at a young age and is caused by a mutation in one of the genes that encode a protein from the sarcomere, Z-disc or intracellular calcium modulators. Although many genes and mutations are already known to cause HCM, the molecular pathways that lead to the phenotype are still unclear. This review focus on the molecular mechanisms of HCM, the pathways from mutation to clinical phenotype and how the disease's genotype correlates with phenotype.
PMCID: PMC3987320  PMID: 24714796
Cardiomyopathy, Hypertrophic; Phenotype; Genotype; Genes; Sarcomers
16.  Subcutaneous Tissue Thickness is an Independent Predictor of Image Noise in Cardiac CT 
Few data on the definition of simple robust parameters to predict image noise in cardiac computed tomography (CT) exist.
To evaluate the value of a simple measure of subcutaneous tissue as a predictor of image noise in cardiac CT.
86 patients underwent prospective ECG-gated coronary computed tomographic angiography (CTA) and coronary calcium scoring (CAC) with 120 kV and 150 mA. The image quality was objectively measured by the image noise in the aorta in the cardiac CTA, and low noise was defined as noise < 30HU. The chest anteroposterior diameter and lateral width, the image noise in the aorta and the skin-sternum (SS) thickness were measured as predictors of cardiac CTA noise. The association of the predictors and image noise was performed by using Pearson correlation.
The mean radiation dose was 3.5 ± 1.5 mSv. The mean image noise in CT was 36.3 ± 8.5 HU, and the mean image noise in non-contrast scan was 17.7 ± 4.4 HU. All predictors were independently associated with cardiac CTA noise. The best predictors were SS thickness, with a correlation of 0.70 (p < 0.001), and noise in the non-contrast images, with a correlation of 0.73 (p < 0.001). When evaluating the ability to predict low image noise, the areas under the ROC curve for the non-contrast noise and for the SS thickness were 0.837 and 0.864, respectively.
Both SS thickness and CAC noise are simple accurate predictors of cardiac CTA image noise. Those parameters can be incorporated in standard CT protocols to adequately adjust radiation exposure.
PMCID: PMC3987400  PMID: 24173136
Sternum / radiation effects; Radiation injuries; Computed tomography; Artifacts
17.  Polymorphism in the Alpha Cardiac Muscle Actin 1 Gene Is Associated to Susceptibility to Chronic Inflammatory Cardiomyopathy 
PLoS ONE  2013;8(12):e83446.
Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to a life-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infected individuals progress to CCC while the others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin (ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1 gene in CCC pathogenesis.
Methods and Results
We conducted a proteomic and genetic study on a Brazilian study population. The genetic study was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and the replication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower in myocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping a case-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1 gene identified rs640249 SNP, located at the 5’ region, as associated to CCC. Associations are borderline after correction for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype. Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in the promoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replication cohort will be useful.
Genetic variations at the ACTC1 gene may contribute to progression to chronic Chagas Cardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1 promoter regions.
PMCID: PMC3868584  PMID: 24367596
18.  Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways 
BMC Infectious Diseases  2013;13:587.
Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.
Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.
The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.
Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.
PMCID: PMC3866603  PMID: 24330528
Chagas disease; Susceptibility; CCR5; CCL2; TIRAP
19.  Investigation of Genetic Disturbances in Oxygen Sensing and Erythropoietin Signaling Pathways in Cases of Idiopathic Erythrocytosis 
Background. Idiopathic erythrocytosis is the term reserved for cases with unexplained origins of abnormally increased hemoglobin after initial investigation. Extensive molecular investigation of genes associated with oxygen sensing and erythropoietin signaling pathways, in those cases, usually involves sequencing all of their exons and it may be time consuming. Aim. To perform a strategy for molecular investigation of patients with idiopathic erythrocytosis regarding oxygen sensing and erythropoietin signaling pathways. Methods. Samples of patients with idiopathic erythrocytosis were evaluated for the EPOR, VHL, PHD2, and HIF-2α genes using bidirectional sequencing of their hotspots. Results. One case was associated with HIF-2α mutation. Sequencing did not identify any pathogenic mutation in 4 of 5 cases studied in any of the studied genes. Three known nonpathogenic polymorphisms were found (VHL p.P25L, rs35460768; HIF-2α p.N636N, rs35606117; HIF-2α p.P579P, rs184760160). Conclusion. Extensive molecular investigation of cases considered as idiopathic erythrocytosis does not frequently change the treatment of the patient. However, we propose a complementary molecular investigation of those cases comprising genes associated with erythrocytosis phenotype to meet both academic and genetic counseling purposes.
PMCID: PMC3864166  PMID: 24363938
20.  Butyrylcholinesterase Genetic Variants: Association with Cocaine Dependence and Related Phenotypes 
PLoS ONE  2013;8(11):e80505.
The search for genetic vulnerability factors in cocaine dependence has focused on the role that neuroplasticity plays in addiction. However, like many other drugs, the ability of an individual to metabolize cocaine can also influence susceptibility to dependence. Butyrylcholinesterase (BChE) metabolizes cocaine, and genetic variants of the BChE gene (BCHE) alter its catalytic activity. Therefore, we hypothesize that cocaine users with polymorphisms in BCHE can show diverse addictive behaviors due to differences in effective plasma concentrations of cocaine. Those polymorphisms might also influence users to prefer one of the two main preparations (crack or powder cocaine), despite having equal access to both. The present work investigates polymorphisms in BCHE and if those genetic variants constitute risk factors for cocaine dependence and for crack cocaine use.
A total of 1,436 individuals (698 cocaine-dependent patients and 738 controls) were genotyped for three single nucleotide polymorphisms (SNPs) in BCHE: rs1803274, rs4263329, and rs4680662.
For rs4263329, a nominal difference was found between cases and controls. For rs1803274 (the functional SNP), a statistically significant difference was found between patients who used crack cocaine exclusively and those who used only powder cocaine (P = 0.027; OR = 4.36; 95% CI = 1.18–16.04). Allele frequencies and genotypes related to other markers did not differ between cases and controls or between the two cocaine subgroups.
Our findings suggest that the AA genotype of rs1803274 is a risk factor for crack cocaine use, which is more addictive than powder cocaine use. Further studies are needed in order to confirm this preliminary result and clarify the role of BCHE and its variants in cocaine dependence.
PMCID: PMC3842332  PMID: 24312228
21.  Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population 
Independent of other cardiovascular (CV) risk factors, increased arterial stiffness has been established as a predictor of morbidity and mortality. The main aim of this study was to investigate the impact of diabetes on arterial stiffness in a representative sample of an urban Brazilian population plus Amerindians.
A total of 1,415 individuals from the general population were randomly selected plus 588 Amerindians from a native community in Brazil. In addition, a sub-sample of 380 individuals from the general population had 5-year follow-up data. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior, Colson; Garges les Gonesses, France) and increased arterial stiffness was defined as PWV ≥ 12 m/s.
In the overall group, diabetic individuals had higher frequencies of increased arterial stiffness and hypertension. They also had higher values of PWV, body mass index, total cholesterol, triglycerides, systolic and diastolic blood pressures compared to non-diabetic individuals (p < 0.01). In an analysis stratified by hypertension, PWV values and increased arterial stiffness frequency were higher in diabetic individuals in both groups (hypertensive and non-hypertensive) (p < 0.05). Furthermore, higher risk for increased arterial stiffness was observed in the diabetic individuals from the overall group (OR = 2.27; CI = 1.47-3.52, p < 0.001) and from the hypertensive group (OR = 2.70; CI = 1.58-4.75, p < 0.001), adjusted for covariates. Regarding the ethnic stratification, diabetic individuals from Amerindian, White, and Mulatto (mixed-race) groups had higher PWV values and a greater frequency of increased arterial stiffness compared to non-diabetic individuals. Both diabetic and non-diabetic individuals had higher PWV values after 5 years. There was no significant difference in the 5-year PWV progression in diabetic compared to non-diabetic individuals.
These results confirm, in a sample of Brazilian population, that the presence of diabetes is associated with increased arterial stiffness and it may contribute in part to increased cardiovascular risk in diabetic patients.
PMCID: PMC3765236  PMID: 23965633
Arterial stiffness; Diabetes mellitus; Hypertension; Brazilian population
22.  Higher incidence of death in multi-vessel coronary artery disease patients associated with polymorphisms in chromosome 9p21 
We investigated whether 9p21 polymorphisms are associated with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease (CAD) and preserved left ventricular function.
The participants of the MASS II were genotyped for 9p21 polymorphisms (rs10757274, rs2383206, rs10757278 and rs1333049). Survival curves were calculated with the Kaplan–Meier method and compared with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, death from cardiac causes and myocardial infarction using a Cox proportional hazards survival model.
We observed significant differences between patients within each polymorphism genotype group for baseline characteristics. The frequency of diabetes was lower in patients carrying GG genotype for rs10757274, rs2383206 and rs10757278 (29.4%, 32.8%, 32.0%) compared to patients carrying AA or AG genotypes (49.1% and 39.2%, p = 0.01; 52.4% and 40.1%, p = 0.01; 47.8% and 37.9%, p = 0.04; respectively).
Significant differences in genotype frequencies between double and triple vessel disease patients were observed for the rs10757274, rs10757278 and rs1333049. Finally, there was a higher incidence of overall mortality in patients with the GG genotype for rs2383206 compared to patients with AA and AG genotypes (19.5%, 11.9%, 11.0%, respectively; p = 0.04). Moreover, the rs2383206 was still significantly associated with a 1.75-fold increased risk of overall mortality (p = 0.02) even after adjustment of a Cox multivariate model for age, previous myocardial infarction, diabetes, smoking and type of coronary anatomy.
Our data are in accordance to previous evidence that chromosome 9p21 genetic variation may constitute a genetic modulator in the cardiovascular system in different scenarios. In patients with established CAD, we observed an association between the rs2383206 and higher incidence of overall mortality and death from cardiac causes in patients with multi-vessel CAD.
PMCID: PMC3469382  PMID: 22856518
Coronary artery disease; Polymorphism; Genetics; Chromosome 9p21
23.  Survival Analysis of Patients with Heart Failure: Implications of Time-Varying Regression Effects in Modeling Mortality 
PLoS ONE  2012;7(6):e37392.
Several models have been designed to predict survival of patients with heart failure. These, while available and widely used for both stratifying and deciding upon different treatment options on the individual level, have several limitations. Specifically, some clinical variables that may influence prognosis may have an influence that change over time. Statistical models that include such characteristic may help in evaluating prognosis. The aim of the present study was to analyze and quantify the impact of modeling heart failure survival allowing for covariates with time-varying effects known to be independent predictors of overall mortality in this clinical setting.
Survival data from an inception cohort of five hundred patients diagnosed with heart failure functional class III and IV between 2002 and 2004 and followed-up to 2006 were analyzed by using the proportional hazards Cox model and variations of the Cox’s model and also of the Aalen’s additive model.
Principal Findings
One-hundred and eighty eight (188) patients died during follow-up. For patients under study, age, serum sodium, hemoglobin, serum creatinine, and left ventricular ejection fraction were significantly associated with mortality. Evidence of time-varying effect was suggested for the last three. Both high hemoglobin and high LV ejection fraction were associated with a reduced risk of dying with a stronger initial effect. High creatinine, associated with an increased risk of dying, also presented an initial stronger effect. The impact of age and sodium were constant over time.
The current study points to the importance of evaluating covariates with time-varying effects in heart failure models. The analysis performed suggests that variations of Cox and Aalen models constitute a valuable tool for identifying these variables. The implementation of covariates with time-varying effects into heart failure prognostication models may reduce bias and increase the specificity of such models.
PMCID: PMC3371034  PMID: 22715367
24.  Non-HFE hemochromatosis 
Hereditary hemochromatosis (HH) is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH), hepcidin (HAMP, type 2B juvenile HH), transferrin receptor 2 (TFR2, type 3 HH) and ferroportin (SLC40A1, type 4 HH). The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.
PMCID: PMC3460409  PMID: 23049448
Hemochromatosis; Iron overload; Iron metabolism disorders
25.  Genetics and cardiovascular system: influence of human genetic variants on vascular function 
Genes & Nutrition  2010;6(1):55-62.
Candidate gene association studies in cardiovascular diseases have provided evidence on the molecular basis of phenotypic differences between individuals. The comprehension of how inherited genetic variants are able to affect protein functions has increased the knowledge of how genes interact with environment in order to modulate a particular phenotype. Although it is known that the human genome contains more than 10 million SNPs, only a minor part of them are supposed to be functional. A causative SNP in a particular gene may confer a small to moderate effect in complex phenotypes, such as functions important to cardiovascular homeostasis. This paper is a selective review of the literature on the evidence for interactions between vascular function and naturally occurring genetic variants in endothelial nitric oxide synthase (eNOS) and beta-2 adrenergic receptor (ADRB2), two genes among those influencing vascular phenotype and examples for which there is a strong evidence base. eNOS and ADRB2 will be characterized, as well as the mechanisms by which the enzyme and the receptor work to control vascular responses will be described. Understanding the molecular mechanisms underlying gene-mediated vascular function and their modification by genetic variants is expected to result in a better comprehension about individual’s phenotypic differences.
PMCID: PMC3040801  PMID: 21437030
Genetic; Genetic variant; Polymorphism; Vascular function; Gene-environment interaction; Phenotype

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