LUIZ APARECIDO BORTOLOTTO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cardio-Pneumologia, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina - Médico
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conferenceObject Improvement of the Adipokines Profile and Insulin Resistance in Metabolic Syndrome Patients Induced by Galantamine Activation of Cholinergic Pathway(2016) SANGALETI, Carine Teles; COSTA, Fernando Oliveira; MORAES, Tercio Lemos; IRIGOYEN, Maria Claudia; BORTOLOTTO, Luiz Aparecido Teles; LOPES, Heno Ferreira; PAVLOV, Valentin; TRACEY, Kevin; CONSOLIM-COLOMBO, Fernanda MarcianoconferenceObject Pre-implantation interlead EKG heterogeneity is superior to QRS complex duration in predicting mechanical super-response and survival in patients receiving cardiac resynchronization therapy(2020) BORTOLOTTO, A. L.; VERRIER, R. L.; NEARING, B. D.; MARUM, A. A.; SILVA, B. Araujo; PEDREIRA, G.; SILVA, F. Tessarolo; MEDEIROS, S. A.; SROUBEK, J.; ZIMETBAUM, P.; CHANG, J. D.- Incident Coronary Calcium Score in Patients With OSA With and Without Excessive Sleepiness Brazilian Longitudinal Study of Adult Health(2024) MIRANDA, Erique Jose Farias Peixoto de; MAZZOTTI, Diego R.; SANTOS, Ronaldo B.; SOUZA, Silvana P.; PARISE, Barbara K.; GIATTI, Soraya; AIELO, Aline N.; CUNHA, Lorenna F.; SILVA, Wagner A.; BORTOLOTTO, Luiz A.; LORENZI-FILHO, Geraldo; LOTUFO, Paulo A.; BENSENOR, Isabela M.; BITTENCOURT, Marcio S.; DRAGER, Luciano F.BACKGROUND: Uncertainty exists about the impact of OSA and its phenotypes on cardio-vascular disease. RESEARCH QUESTION: Are OSA and clinical features such as daytime sleepiness associated with incident subclinical coronary atherosclerosis? STUDY DESIGN AND METHODS: In this prospective community-based cohort study, we administered a sleepiness questionnaire, actigraphy, and home sleep studies at baseline. Coronary artery calcium (CAC; 64-slice multidetector CT scan imaging) was measured at two different time points throughout the study (baseline, between 2010 and 2014, and follow-up, between 2016 and 2018). Incidence of subclinical atherosclerosis was defined as baseline CAC of 0 followed by CAC of > 0 at a 5-year follow-up visit. The association of incident CAC outcome was assessed using logistic regression. Stratified analyses based on excessive daytime sleepiness (EDS) were performed. RESULTS: We analyzed 1,956 participants with available CAC scores at baseline (mean age, 49 +/- 8 years; 57.9% female; 32.4% with OSA). In covariate-adjusted analyses (n = 1,247; mean follow-up, 5.1 +/- 0.9 years), we found a significant association between OSA and incidence of subclinical atherosclerosis (OR, 1.26; 95% CI, 1.06-1.48), with stronger effects among those reporting EDS (OR, 1.66; 95% CI, 1.30-2.12; P = .028 for interaction). Interestingly, EDS per se was not associated with any CAC outcome. An exploratory analysis of the square root of CAC progression (baseline CAC > 0 followed by a numerical increase in scores at follow-up; n = 319) showed a positive association for both OSA (beta = 1.084; 95% CI, 0.032-2.136; P = .043) and OSA with EDS (beta = 1.651; 95% CI, 0.208-3.094; P = .025). INTERPRETATION: OSA, particularly with EDS, predicts the incidence and progression of CAC. These results support biological plausibility for the increased cardiovascular risk observed among patients with OSA with excessive sleepiness.
conferenceObject Clinical Features and Penetrance of Pheochromocytoma in a Large Family with a Germline TMEM127 Mutation(2014) LOURENCO, Delmar Muniz; TOLEDO, Rodrigo A.; SEKIYA, Tomoko; LUCON, Marmo; CASTRO, C. C.; BORTOLOTTO, L. A.; TOLEDO, Sergio P. A.; DAHIA, Patricia L.- Effect of fructooligosaccharide on endothelial function in CKD patients: a randomized controlled trial(2022) ARMANI, Rachel G.; CARVALHO, Aluizio B.; I, Christiane Ramos; HONG, Valeria; BORTOLOTTO, Luiz A.; CASSIOLATO, Jose Luiz; OLIVEIRA, Natacha F.; CIESLAROVA, Zuzana; LAGO, Claudimir L. do; KLASSEN, Aline; CUPPARI, Lilian; RAJ, Dominic S.; CANZIANI, Maria Eugenia F.Background. Microbiota-derived uremic toxins have been associated with inflammation that could corroborate with endothelial dysfunction (ED) and increase cardiovascular risk in patients with chronic kidney disease (CKD). This trial aimed to evaluate the effect of the prebiotic fructooligosaccharide (FOS) on endothelial function and arterial stiffness in nondialysis CKD patients. Methods. In a double-blind controlled trial, 46 nondiabetic CKD patients were randomized to receive 12 g/day of FOS or placebo (maltodextrin) for 3 months. Total p-cresyl sulfate (PCS) and indoxyl sulfate by high-performance liquid chromatography, urinary trimethylamine N-oxide by mass spectrometry, C-reactive protein, interleukin-6 (IL-6), serum nitric oxide and stroma-derived factor-1 alfa were measured at baseline and at the end of follow-up; endothelial function was assessed through flow-mediated dilatation (FMD) and arterial stiffness by pulse wave velocity (PWV). Results. The mean (+/- standard deviation) age of the study participants was 57.6 +/- 14.4 years, with an estimated glomerular filtration rate of 21.3 +/- 7.3 mL/min/1.73 m(2). During the follow-up, regarding the inflammatory markers and uremic toxins, there was a significant decrease in IL-6 levels (3.4 +/- 2.1 pg/mL versus 2.6 +/- 1.4 pg/mL; P = 0.04) and a trend toward PCS reduction (55.4 +/- 38.1 mg/L versus 43.1 +/- 32.4 mg/L, P = 0.07) only in the prebiotic group. Comparing both groups, there was no difference in FMD and PWV. In an exploratory analysis, including a less severe ED group of patients (FMD >= 2.2% at baseline), FMD remained stable in the prebiotic group, while it decreased in the placebo group (group effect P = 0.135; time effect P = 0.012; interaction P = 0.002). Conclusions. The prebiotic FOS lowered circulating levels of IL-6 in CKD patients and preserved endothelial function only in those with less damaged endothelium. No effect of FOS in arterial stiffness was observed.
- The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial(2021) SANGALETI, Carine Teles; KATAYAMA, Keyla Yukari; ANGELIS, Katia De; MORAES, Tercio Lemos de; ARAUJO, Amanda Aparecida; LOPES, Heno F.; CAMACHO, Cleber; BORTOLOTTO, Luiz Aparecido; MICHELINI, Lisete Compagno; IRIGOYEN, Maria Claudia; OLOFSSON, Peder S.; BARNABY, Douglas P.; TRACEY, Kevin J.; PAVLOV, Valentin A.; COLOMBO, Fernanda Marciano ConsolimBackground: The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS. Trial Design and Methods: The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n = 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment. Results: Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39-2.92], P = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34-1.51], P = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46-1.07], P = 0.05], and systemic nitrite levels [log scale 0.83 mu mol/mg protein, [95% CI 0.57-1.20], P = 0.04] compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment. Conclusion: Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.
- Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism(2021) RASSI-CRUZ, Marcela; MARIA, Andrea G.; FAUCZ, Fabio R.; LONDON, Edra; VILELA, Leticia A. P.; SANTANA, Lucas S.; BENEDETTI, Anna Flavia F.; GOLDBAUM, Tatiana S.; TANNO, Fabio Y.; SROUGI, Vitor; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; LERARIO, Antonio M.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; MENDONCA, Berenice B.; ZERBINI, Maria Claudia N.; STRATAKIS, Constantine A.; ALMEIDA, Madson Q.Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of gene tic etiologies of PA.
- Three-Year Outcomes of Bariatric Surgery in Patients With Obesity and Hypertension A Randomized Clinical Trial(2020) SCHIAVON, Carlos A.; BHATT, Deepak L.; IKEOKA, Dimas; V, Eliana Santucci; SANTOS, Renato Nakagawa; DAMIANI, Lucas P.; OLIVEIRA, Juliana D.; V, Rachel Helena Machado; HALPERN, Helio; MONTEIRO, Frederico L. J.; NOUJAIM, Patricia M.; V, Ricardo Cohen; SOUZA, Marcio G. de; AMODEO, Celso; BORTOLOTTO, Luiz A.; BERWANGER, Otavio; CAVALCANTI, Alexandre B.; DRAGER, Luciano F.Background: Midterm effects of bariatric surgery on patients with obesity and hypertension remain uncertain. Objective: To determine the 3-year effects of Roux-en-Y gastric bypass (RYGB) on blood pressure (BP) compared with medical therapy (MT) alone. Design: Randomized clinical trial. (ClinicalTrials.gov: NCT01784848) Setting: Investigator-initiated study at Heart Hospital (HCor), Sao Paulo, Brazil. Participants: Patients with hypertension receiving at least 2 medications at maximum doses or more than 2 medications at moderate doses and with a body mass index (BMI) between 30.0 and 39.9 kg/m(2) were randomly assigned (1:1 ratio). Intervention: RYGB plus MT or MT alone. Measurements: The primary outcome was at least a 30% reduction in total number of antihypertensive medications while maintaining BP less than 140/90 mm Hg. Key secondary outcomes were number of antihypertensive medications, hypertension remission, and BP control according to current guidelines (<130/80 mm Hg). Results: Among 100 patients (76% female; mean BMI, 36.9 kg/m(2) [SD, 2.7]), 88% from the RYGB group and 80% from the MT group completed follow-up. At 3 years, the primary outcome occurred in 73% of patients from the RYGB group compared with 11% of patients from the MT group (relative risk, 6.52 [95% CI, 2.50 to 17.03]; P < 0.001). Of the randomly assigned participants, 35% and 31% from the RYGB group and 2% and 0% from the MT group achieved BP less than 140/90 mm Hg and less than 130/80 mm Hg without medications, respectively. Median (interquartile range) number of medications in the RYGB and MT groups at 3 years was 1 (0 to 2) and 3 (2.8 to 4), respectively (P < 0.001). Total weight loss was 27.8% and -0.1% in the RYGB and MT groups, respectively. In the RYGB group, 13 patients developed hypovitaminosis B-12 and 2 patients required reoperation. Limitation: Single-center, nonblinded trial. Conclusion: RYGB is an effective strategy for midterm BP control and hypertension remission, with fewer medications required in patients with hypertension and obesity.
conferenceObject Penetrance of TMEM127-related pheochromocytoma in a six-generation family(2014) TOLEDO, S. P. A.; LOURENCO JR., D. M.; SEKIYA, T.; LUCON, A. M.; BAENA, R. C.; CASTRO, C. C.; BORTOLOTTO, L. A.; ZERBINI, M. C. N.; SIQUEIRA, S. A. C.; TOLEDO, R. A.; DAHIA, P. L. M.- The impact of metabolic syndrome on metabolic, proinflammatory and prothrombotic markers according to the presence of high blood pressure criterion(2013) GIL, Juliana S.; DRAGER, Luciano F.; GUERRA-RICCIO, Grazia M.; MOSTARDA, Cristiano; IRIGOYEN, Maria C.; COSTA-HONG, Valeria; BORTOLOTTO, Luiz A.; EGAN, Brent M.; LOPES, Heno F.OBJECTIVES: We explored whether high blood pressure is associated with metabolic, inflammatory and prothrombotic dysregulation in patients with metabolic syndrome. METHODS: We evaluated 135 consecutive overweight/obese patients. From this group, we selected 75 patients who were not under the regular use of medications for metabolic syndrome as defined by the current Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults criteria. The patients were divided into metabolic syndrome with and without high blood pressure criteria (>= 130/>= 85 mmHg). RESULTS: Compared to the 45 metabolic syndrome patients without high blood pressure, the 30 patients with metabolic syndrome and high blood pressure had significantly higher glucose, insulin, homeostasis model assessment insulin resistance index, total cholesterol, low-density lipoprotein-cholesterol, triglycerides, uric acid and creatinine values; in contrast, these patients had significantly lower high-density lipoprotein-cholesterol values. Metabolic syndrome patients with high blood pressure also had significantly higher levels of retinol-binding protein 4, plasminogen activator inhibitor 1, interleukin 6 and monocyte chemoattractant protein 1 and lower levels of adiponectin. Moreover, patients with metabolic syndrome and high blood pressure had increased surrogate markers of sympathetic activity and decreased baroreflex sensitivity. Logistic regression analysis showed that high-density lipoprotein, retinol-binding protein 4 and plasminogen activator inhibitor-1 levels were independently associated with metabolic syndrome patients with high blood pressure. There is a strong trend for an independent association between metabolic syndrome patients with high blood pressure and glucose levels. CONCLUSIONS: High blood pressure, which may be related to the autonomic dysfunction, is associated with metabolic, inflammatory and prothrombotic dysregulation in patients with metabolic syndrome.