Publications by authors named "Raul D Santos"

334 Publications

Familial hypercholesterolemia and COVID-19: A menacing but treatable vasculopathic condition.

Atheroscler Plus 2021 Sep 8;43:3-6. Epub 2021 Aug 8.

Wihuri Research Institute, Helsinki, Finland.

SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a long-term follow-up of individualized therapies in FH patients is warranted.
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http://dx.doi.org/10.1016/j.athplu.2021.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349422PMC
September 2021

Physical Activity and HDL-C: Are There Gender Differences in the Dose-response Effect?

Arq Bras Cardiol 2021 09;117(3):501-502

Unidade Clínica de Lípides do Instituto do Coração (InCor) - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, SP - Brasil.

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http://dx.doi.org/10.36660/abc.20210551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462943PMC
September 2021

The Effects of Statin Dose, Lipophilicity, and Combination of Statins plus Ezetimibe on Circulating Oxidized Low-Density Lipoprotein Levels: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Mediators Inflamm 2021 4;2021:9661752. Epub 2021 Sep 4.

Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Elevated plasma low-density lipoprotein cholesterol (LDL-C) is the main risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the drugs of choice for decreasing LDL-C and are used for the prevention and management of ASCVD. Guidelines recommend that subjects with high and very high ASCVD risk should be treated with high-intensity statins or a combination of high-intensity statins and ezetimibe. The lipophilicity or hydrophilicity (solubility) of statins is considered to be important for at least some of their LDL-C lowering independent pleiotropic effects. Oxidative modification of LDL (ox-LDL) is considered to be the most important atherogenic modification of LDL and is supposed to play a crucial role in atherogenesis and ASCVD outcomes.

Objective: The aim of this systematic review and meta-analysis was to find out what are the effects of statin intensity, lipophilicity, and combination of statins plus ezetimibe on ox-LDL.

Methods: PubMed, Scopus, Embase, and Web of Science were searched from inception to February 5, 2021, for randomized controlled trials (RCTs). Two independent and blinded authors evaluated eligibility by screening the titles and abstracts of the studies. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias.

Results: Among the 1427 published studies identified by a systematic databases search, 20 RCTs were finally included in the systematic review and meta-analysis. A total of 1874 patients are included in this meta-analysis. This meta-analysis suggests that high-intensity statin treatment is associated with a significant decrease in circulating concentrations of ox-LDL when compared with low-to-moderate treatment (SMD: -0.675, 95% CI: -0.994, -0.357, < 0.001; : 55.93%). There was no difference concerning ox-LDL concentration between treatments with hydrophilic and lipophilic statins (SMD: -0.129, 95% CI: -0.330, -0.071, = 0.206; : 45.3%), but there was a significant reduction in circulating concentrations of ox-LDL associated with statin plus ezetimibe combination therapy when compared with statin monotherapy (SMD: -0.220, 95% CI: -0.369, -0.071, = 0.004; : 0%).

Conclusion: High-dose statin or combination of statins with ezetmibe reduces plasma ox-LDL in comparison low-to-moderate intensity statin therapy alone. Statin lipophilicity is not associated with reduction in ox-LDL plasma concentrations.
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http://dx.doi.org/10.1155/2021/9661752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437664PMC
September 2021

Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review.

Int J Mol Sci 2021 Aug 29;22(17). Epub 2021 Aug 29.

Department of Basic Medical Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, United Arab Emirates.

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy. It is characterized by an unexplained non-dilated hypertrophy of the left ventricle with a conserved or elevated ejection fraction. It is a genetically heterogeneous disease largely caused by variants of genes encoding for cardiac sarcomere proteins, including , , , , , , , and . Preclinical evidence indicates that the enhanced calcium sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric variations but may also result from secondary mutation-driven alterations. Long non-coding RNAs (lncRNAs) are a large class of transcripts ≥200 nucleotides in length that do not encode proteins. Compared to coding mRNAs, most lncRNAs are not as well-annotated and their functions are greatly unexplored. Nevertheless, increasing evidence shows that lncRNAs are involved in a variety of biological processes and diseases including HCM. Accumulating evidence has indicated that lncRNAs are dysregulated in HCM, and closely related to sarcomere construction, calcium channeling and homeostasis of mitochondria. In this review, we have summarized the known regulatory and functional roles of lncRNAs in HCM.
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http://dx.doi.org/10.3390/ijms22179378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430576PMC
August 2021

Incidence and associated factors of type 2 diabetes mellitus onset in the Brazilian HIV/AIDS cohort study.

Braz J Infect Dis 2021 Jul-Aug;25(4):101608. Epub 2021 Aug 31.

Department and Division of Infectious and Parasitic Diseases, Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil. Electronic address:

Background: People living with HIV (PLH) under combined antiretroviral therapy (cART) are at risk of developing type 2 diabetes mellitus (T2DM).

Objective: We examined the incidence of T2DM, associated factors and mean time to outcome in PLH under cART.

Method: Data for this multicenter cohort study were obtained from PLH aged over 18, who started cART in 13 Brazilian sites from 2003 to 2013. Factors associated with incident T2DM were evaluated by Cox multiple regression models.

Results: A total of 6724 patients (30,997.93 person-years) were followed from January 2003 to December 2016. A T2DM incidence rate of 17.3/1000 person-years (95%CI 15.8-18.8) was observed. Incidence of isolated hypertriglyceridemia and impaired fasting glucose (IFG) were 84.3 (95%CI 81.1-87.6) and 14.5/1000 person-years (95%CI 13.2-15.9), respectively. Mean time to T2DM onset was 10.5 years (95%CI 10.3-10.6). Variables associated with incident T2DM were age 40-50 [Hazard Ratio (HR) 1.7, 95%CI 1.4-2.1] and ≥ 50 years (HR 2.4, 95%CI 1.9-3.1); obesity (HR 2.1, 95%CI 1.6-2.8); abnormal triglyceride/HDL-cholesterol ratio (HR 1.8, 95%CI 1.51-2.2). IFG predicted T2DM (HR 2.6, 95%CI 1.7-2.5) and occurred on average 3.3 years before diabetes onset. Exposure to stavudine for ≥ 2 years was independently associated with incident T2DM [HR 1.6, 95%CI 1.0-2.2).

Conclusion: Brazilian PLH under cART are at significant risk of developing T2DM and share risk factors for diabetes onset with the general population, such as older age, obesity, and having metabolic abnormalities at baseline. Moreover, stavudine use was independently associated with incident T2DM. Identifying PLH at a higher risk of T2DM can help caretakers trigger health promotion and establish specific targets for implementation of preventive measures.
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http://dx.doi.org/10.1016/j.bjid.2021.101608DOI Listing
October 2021

Updates on genetics and molecular biology.

Curr Opin Lipidol 2021 Oct;32(5):333-334

Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital.

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http://dx.doi.org/10.1097/MOL.0000000000000772DOI Listing
October 2021

Reference values for the triglyceride to high-density lipoprotein ratio and its association with cardiometabolic diseases in a mixed adult population: The ELSA-Brasil study.

J Clin Lipidol 2021 Jul 29. Epub 2021 Jul 29.

Department of Pathophysiology, Montes Claros State University (UNIMONTES), Montes Claros, MG, Brazil. Electronic address:

Background: Among several lipid ratios available, the triglyceride/HDL-cholesterol (TG/HDL-C) may detect individuals at risk of cardiometabolic diseases. However, its reference values for different ethnicities are not well established.

Objective: To define sex- and ethnicity-specific reference values for TG/HDL-C ratio in a large sample of healthy multiethnic adults and test its association with cardiometabolic conditions.

Methods: An apparently healthy sample (n = 2,472), aged 35-74, free of major cardiovascular risk factors, was used to generate the reference values for the TG/HDL-C. Exclusion criteria were diabetes, elevated blood pressure, obesity, hypercholesterolemia, severe hypertriglyceridemia, and smoking history. Cut-offs based on the reference values were tested in the whole ELSA Brasil study (n = 13,245), stratified by sex and ethnicity, to identify cardiometabolic conditions.

Results: TG/HDL-C ratio was higher in men than women, and did not change significantly with age, regardless of sex and ethnicity. Also, black individuals showed lower levels of TG/HDL-C as compared to other ethnic groups. ROC curve showed that the cut-off based on the 75th percentile displayed better sensitivities and specificities for men and women, regardless of ethnicity. Also, the sex- and ethnicity-specific cut-offs based on the 75th percentile were significantly associated with all tested cardiometabolic conditions (hypertension, diabetes, obesity, metabolic syndrome, and insulin resistance). Also, we observed that the use of a single sex-specific cut-off (men: 2.6; women: 1.7) could be used for the different ethnicities with good reliability.

Conclusion: The defined TG/HDL-C cut-offs (men: 2.6; women: 1.7) are reliable and showed good clinical applicability to detect cardiometabolic conditions in a multiethnic population.
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http://dx.doi.org/10.1016/j.jacl.2021.07.005DOI Listing
July 2021

The risk of cardiometabolic disorders in lean non-alcoholic fatty liver disease: A longitudinal study.

Am J Prev Cardiol 2020 Dec 20;4:100097. Epub 2020 Oct 20.

Houston Methodist, Debakey Heart and Vascular Institute, Houston, TX, USA.

Background: Recent studies suggest that non-alcoholic fatty liver disease (NAFLD) in lean (BMI<25 ​kg/m) individuals presents a distinct phenotype. We sought to determine the cardiometabolic consequences of lean NAFLD in a population cohort of relatively young asymptomatic individuals who participated in a voluntary routine health promotion evaluation in Brazil.

Methods: We analyzed data in our population collected from 2004 to 2016. Medical and demographic history, anthropometric measures, and fasting blood samples were obtained. Participants had ultrasonography to assess for fatty liver. We defined NAFLD as fatty liver in individuals scoring below 8 on the alcohol use disorders identification test (AUDIT). We included data from 9137 individuals who had complete data at baseline and at follow-up.

Results: The prevalence of lean NAFLD in our cohort was 3.8%. Over the median follow-up period of 2.4 years (range 0.5-9.9 years), lean individuals had 74% (HR: 1.74 (1.39-2.18)) and 67% (1.67 (1.29-2.15)) greater risk of developing elevated BP and elevated glucose, and nearly 3 times the risk of atherogenic dyslipidemia (HR: 2.98 (2.10-4.24)) compared to lean individuals without NAFLD. Lean NAFLD individuals also had higher risk of developing elevated glucose (HR: 1.37 (1.07-1.75)) and atherogenic dyslipidemia (1.46 (1.05-2.01)) compared to non-lean individuals without NAFLD. However, there was no significant difference in the risk of elevated BP, elevated glucose or atherogenic dyslipidemia between lean NAFLD and non-lean individuals with NAFLD in fully adjusted models.

Conclusion: Lean NAFLD is not metabolically benign. Further cardiovascular risk stratification and appropriate preventive measures should be considered in lean individuals who present with NAFLD.
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http://dx.doi.org/10.1016/j.ajpc.2020.100097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315654PMC
December 2020

Coronary Artery Calcification and Risk Stratification in Familial Hypercholesterolemia: Moving Forward But Not There Yet.

JACC Cardiovasc Imaging 2021 Jul 7. Epub 2021 Jul 7.

Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jcmg.2021.06.013DOI Listing
July 2021

From the President of the International Atherosclerosis Society: The Iraqi Lipid Clinics Network.

J Clin Lipidol 2021 May 7. Epub 2021 May 7.

International Atherosclerosis Society. Electronic address:

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http://dx.doi.org/10.1016/j.jacl.2021.04.012DOI Listing
May 2021

Latin American Consensus on management of residual cardiometabolic risk. A consensus paper prepared by the Latin American Academy for the Study of Lipids and Cardiometabolic Risk (ALALIP) endorsed by the Inter-American Society of Cardiology (IASC), the International Atherosclerosis Society (IAS), and the Pan-American College of Endothelium (PACE).

Arch Cardiol Mex 2021 06 29. Epub 2021 Jun 29.

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Womens' Hospital, Harvard Medical School, Boston, MA, USA.

Background: Hypertension, hyperglycemia, dyslipidemia, overweight, obesity, and tobacco (smoking, chewing, and vaping), together with a pro-inflammatory and procoagulant state, are the main risk factors related to atherosclerotic cardiovascular disease.

Objective And Methods: A group of experts from the Americas, based on their clinical expertise in cardiology, cardiovascular prevention, and cardiometabolic (CM) diseases, joined together to develop these practical recommendations for the optimal evaluation and treatment of residual CM risk factors in Latin America, using a modified Delphi methodology (details in electronic TSI) to generate a comprehensive CM risk reduction guideline, and through personalized medicine and patient-centered decision, considering the cost-benefit ratio The process was well defined to avoid conflicts of interest that could bias the discussion and recommendations.

Results: Residual risk reduction should consider therapeutic options adapted to specific patient needs, based on five treatment objectives: triglyceride-rich lipoproteins, inflammation, impaired glucose metabolism, high blood pressure, and prothrombotic status. Comprehensive control of all CM risk factors should be a priority to deal with this important public health problem and prevent premature deaths. The recommendations in this paper address the evidence-based treatment of CM risk and are intended for clinical application in Latin American countries.
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http://dx.doi.org/10.24875/ACM.21000005DOI Listing
June 2021

The Role of RNA-Targeted Therapeutics to Reduce ASCVD Risk: What Have We Learned Recently?

Curr Atheroscler Rep 2021 Jun 19;23(8):40. Epub 2021 Jun 19.

Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Av. Dr. Enéas C. Aguiar 44 CEP, São Paulo, SP, -05403-900, Brazil.

Purpose Of Review: To discuss advances on the RNA-targeted therapies to treat dyslipidemia with the aim of reducing atherosclerotic cardiovascular disease (ASCVD).

Recent Findings: Genetic studies have paved the way for therapies that reduce translation of proteins that play causal roles in dyslipidemia and atherosclerosis like proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B-100 (apoB), apolipoprotein(a) [apo(a)], apolipoprotein C3 (apoC3), and angiopoietin-like 3 (ANGPTL3). Either antisense oligonucleotide (ASO) therapies and small interfering RNA (siRNA) molecules inhibit protein synthesis and consequently improve dyslipidemia. Most of these molecules contain N-acetylgalactosamine (GalNAc) moieties that have high specificity for hepatocytes and therefore reduce concentration in other tissues. Inclisiran, an siRNA for PCSK9, has shown robust LDL-C reductions, with good tolerability, in severe forms of hypercholesterolemia as well as in high cardiovascular disease patients with injections every 3 to 6 months. Pelacarsen is an ASO against apolipoprotein(a) that reduces Lp(a) up to 80% with good tolerability. Either inclisiran or pelacarsen is being tested to show it can prevent ASCVD. AMG 890, an siRNA compound aimed at reducing apo(a) synthesis, is also under investigation. Volanesorsen is an ASO against apoC3 that reduces triglyceride levels up to 70% and is being tested in severe hypertriglyceridemic patients. Vupanorsen is an ASO against ANGPTL3 that reduced triglyceride levels 36-53% among moderate hypertriglyceridemic individuals. Interestingly, it also reduces ApoC3 and non-HDL cholesterol and apoB; however, it lowers HDL cholesterol. RNA-targeted therapies are being extensively tested for dyslipidemia treatment with promising results.
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http://dx.doi.org/10.1007/s11883-021-00936-1DOI Listing
June 2021

Glycated Hemoglobin to Detect Subclinical Atherosclerosis in People Without Diabetes.

J Am Coll Cardiol 2021 Jun;77(22):2792-2795

Department of Medicine and Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, Texas, USA.

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http://dx.doi.org/10.1016/j.jacc.2021.04.018DOI Listing
June 2021

Beyond Statins and PCSK9 Inhibitors: Updates in Management of Familial and Refractory Hypercholesterolemias.

Curr Cardiol Rep 2021 06 3;23(7):83. Epub 2021 Jun 3.

Heart Institute-InCor, University of Sao Paulo Medical School Hospital, Av. Dr Enéas C. Aguiar 44, São Paulo, SP, 05403-900, Brazil.

Purpose Of Review: Elevation in apolipoprotein B-containing lipoproteins in the blood is a cause of atherosclerosis. Statins have changed the preventive cardiology scenario, and more recently monoclonal proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors were added as robust agents to further reduce pro-atherogenic lipoproteins and therefore prevent cardiovascular events. However, despite this many dyslipidemic individuals persist with inadequate LDL-C levels and still at risk. The purpose of this review was to discuss current status and describe advances in therapies beyond statins and monoclonal PCSK9 inhibitors.

Recent Findings: Ezetimibe and lomitapide have been used for many years to further reduce LDL-C and longer term data reinforce their safety. Bempedoic acid, an inhibitor of adenosine triphosphate-citrate lyase, has been shown to add LDL-C reduction on top of statins and ezetimibe, furthermore it may be an alternative for statin intolerant patients. Inclisiran is a small interfering ribonucleic acid inhibitor that reduces the hepatic production of PCSK9 that induces robust LDL-C lowering, similar to monoclonal antibodies, with the advantage of 2 or 3 injections per year. So far, no safety signs were seen with its use. Evinacumab, a monoclonal antibody that binds angiopoietin-like protein 3 (ANGPTL3), induces robust LDL-C lowering in either homozygous familial hypercholesterolemia or severe hypercholesterolemia patients with good tolerability. Many high-risk individuals persist with elevated LDL-C, newer medications further lower LDL-C on top of standard lipid-lowering therapies and are well tolerated. Ongoing clinical trials may prove if these novel medications will reduce cardiovascular events with safety.
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http://dx.doi.org/10.1007/s11886-021-01514-2DOI Listing
June 2021

Vitamin C and primary prevention of cardiovascular disease: the case for Mendelian randomization.

Authors:
Raul D Santos

Eur J Prev Cardiol 2021 May 31. Epub 2021 May 31.

Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Av. Dr. Enéas C. Aguiar 44, CEP 05403-900 Sao Paulo, Brazil.

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http://dx.doi.org/10.1093/eurjpc/zwab089DOI Listing
May 2021

Adherence to a Mediterranean diet, dyslipidemia and inflammation in familial hypercholesterolemia.

Nutr Metab Cardiovasc Dis 2021 06 19;31(7):2014-2022. Epub 2021 Apr 19.

Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, Brazil. Electronic address:

Background And Aims: Familial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH. This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP).

Methods And Results: In this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135-250) and 161 (133-193) mg/dL; 141 (109-181) and 103 (88-134) mg/dL; and 1.6 (0.8-4.0) and 0.8 (0.4-1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies.

Conclusions: Higher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH.
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http://dx.doi.org/10.1016/j.numecd.2021.04.006DOI Listing
June 2021

Plasma proprotein convertase subtilisin/kexin type 9 concentration and recurrent cardiovascular events in patients with familial hypercholesterolemia.

Eur J Prev Cardiol 2021 04;28(3):272-279

State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital and National Center for Cardiovascular Diseases, China.

Aims: Familial hypercholesterolemia patients are characterized by early onset of coronary artery calcification and atherosclerosis, and high incidence of cardiovascular events. Plasma proprotein convertase subtilisin/kexin type 9 was reported to be a predictor for cardiovascular risk in the general population. However, its prognostic value for predicting recurrent cardiovascular events in familial hypercholesterolemia patients remains undetermined.

Methods: A total of 249 patients with molecularly and/or clinically (Dutch Lipid Clinic Network score > 6) defined familial hypercholesterolemia who had experienced a first cardiovascular event were consecutively included and plasma proprotein convertase subtilisin/kexin type 9 concentrations were measured by enzyme-linked immunosorbent assay. Coronary artery calcification was measured using Agatston method and coronary severity was assessed by Gensini score, respectively. All patients received standard lipid-lowering therapy and were followed-up for recurrent cardiovascular events. Univariate and multivariate regression and Cox analyses was used to calculate hazard ratios with 95% confidence interval.

Results: Circulating proprotein convertase subtilisin/kexin type 9 concentrations were positively associated with coronary artery calcification scores and Gensini score by both univariate and multivariate analyses. During a mean follow-up of 43 ± 19 months, 29 (11.51%) recurrent cardiovascular events occurred. Kaplan-Meier analysis showed that patients with the highest proprotein convertase subtilisin/kexin type 9 levels had the lowest event-free survival time. Multivariable Cox regression analysis revealed that proprotein convertase subtilisin/kexin type 9 was independently associated with recurrent cardiovascular events (hazard ratio: 1.45, 95% confidence interval: 1.11-1.88). The combination of proprotein convertase subtilisin/kexin type 9 to Cox prediction model led to an enhanced predictive value for recurrent cardiovascular events.

Conclusions: Increased level of proprotein convertase subtilisin/kexin type 9 was a significant risk factor of atherosclerosis and independently predicted future recurrent cardiovascular events in familial hypercholesterolemia patients receiving standard lipid-lowering treatment.
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http://dx.doi.org/10.1177/2047487319880985DOI Listing
April 2021

COVID-19 and Thromboinflammation: Is There a Role for Statins?

Clinics (Sao Paulo) 2021;76:e2518. Epub 2021 Mar 24.

Programa de Pos-Graduacao em Cardiologia e Ciencias Cardiovasculares, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BR.

The novel coronavirus disease (COVID-19) showed increased morbidity and mortality rates and worse prognosis in individuals with underlying chronic diseases, especially cardiovascular disease and its risk factors, such as hypertension, diabetes, and obesity. There is also evidence of possible links among COVID-19, myocardial infarction, and stroke. Emerging evidence suggests a pro-inflammatory milieu and hypercoagulable state in patients with this infection. Despite anticoagulation, a large proportion of patients requiring intensive care may develop life-threatening thrombotic complications. Indeed, the levels of some markers of hemostatic activation, such as D-dimer, are commonly elevated in COVID-19, indicating potential risk of deep vein thrombosis and pulmonary thromboembolism. In this review, we critically examine and discuss aspects of hypercoagulability and inflammation in COVID-19 and the possible benefits of statins in this scenario, with emphasis on their underlying molecular mechanisms. Moreover, we present recommendations on the use of antiviral drugs in combination with statins.
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http://dx.doi.org/10.6061/clinics/2021/e2518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955154PMC
April 2021

Branched-chain amino acids predict incident diabetes in the Brazilian Longitudinal Study of Adult Health - ELSA-Brasil.

Diabetes Res Clin Pract 2021 Apr 10;174:108747. Epub 2021 Mar 10.

Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, Av. Lineu Prestes 2565 - 4° floor, CEP: 05508-000 São Paulo, SP, Brazil; Centro de Pesquisa do Hospital Universitário, Universidade de São Paulo, Av. Lineu Prestes 2565, 3rd floor, CEP 05508-000 São Paulo, SP, Brazil. Electronic address:

Aims: To evaluate the role of branch chain amino acid (BCAA) concentrations as a predictor for incident type 2 diabetes (DM).

Methods: Participants from ELSA-Brasil without diabetes at baseline and followed for 3.9 ± 0.6 years were included in the analysis. The determinations of BCAA (valine, leucine, isoleucine) were performed by proton nuclear magnetic resonance spectroscopy. Cardiometabolic profile and incidence of DM were evaluated according to quartiles of BCAA at baseline, stratified by sex.

Results: From 3,828 participants (56% female, 50.5 ± 8.7 years) 299 (8.5%) were diagnosed with DM. For both sexes, a worsening of cardiometabolic profile was observed across increasing BCAA quartiles. In survival analysis, incidence rates of DM for the entire period were highest in participants in the third and fourth quartile of BCAA (log Rank analysis < 0.001 for both sexes). In Cox regression analysis, for men, the HR (95%CI) for risk of DM was 2.24 (1.24-4.03) for those from the fourth quartile of BCAA, while in women it was 1.94 (1.07-3.50), comparing to first quartile of BCAA after adjustments for age, BMI, physical activity, family history of DM, pre-diabetes, blood pressure, total cholesterol and HOMA-IR.

Conclusions: Higher levels of BCAA were independently predictors of DM.
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http://dx.doi.org/10.1016/j.diabres.2021.108747DOI Listing
April 2021

Lipid Lowering Drugs: Present Status and Future Developments.

Curr Atheroscler Rep 2021 03 10;23(5):17. Epub 2021 Mar 10.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Purpose Of Review: Based on the recent data of the DA VINCI study, it is clear that, besides utilization of statins, there is a need to increase non-statin lipid lowering approaches to reduce the cardiovascular burden in patients at highest risk.

Recent Findings: For hypercholesterolemia, the small synthetic molecule bempedoic acid has the added benefit of selective liver activation, whereas inclisiran, a hepatic inhibitor of the PCSK9 synthesis, has comparable effects with PCSK9 monoclonal antibodies. For hypertriglyceridemia, cardiovascular benefit has been achieved by the use of icosapent ethyl, whereas results with pemafibrate, a selective agonist of PPAR-α, are eagerly awaited. In the era of RNA-based therapies, new options are offered to dramatically reduce levels of lipoprotein(a) (APO(a)L) and of triglycerides (ANGPTL3L and APOCIII-L). Despite the demonstrated benefits of statins, a large number of patients still remain at significant risk because of inadequate LDL-C reduction or elevated blood triglyceride-rich lipoproteins or lipoprotein(a). The area of lipid modulating agents is still ripe with ideas and major novelties are to be awaited in the next few years.
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http://dx.doi.org/10.1007/s11883-021-00918-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946696PMC
March 2021

EUROASPIRE V and uncontrolled risk factors in primary prevention: Atherosclerotic cardiovascular disease in the making.

Authors:
Raul D Santos

Eur J Prev Cardiol 2020 Apr 2. Epub 2020 Apr 2.

Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Brazil.

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http://dx.doi.org/10.1177/2047487320915662DOI Listing
April 2020

Statins and COVID-19: To Suspend or Not to Suspend? That is the Question!

Arq Bras Cardiol 2021 Jan;116(1):147-152

Unidade Clínica de Lípides, Instituto do Coração (InCor), Hospital da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brasil.

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http://dx.doi.org/10.36660/abc.20200949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159509PMC
January 2021

Cardiovascular Risk Misperception and Low Awareness of Familial Hypercholesterolemia in Individuals with Severe Hypercholesterolemia.

Arq Bras Cardiol 2021 03;116(4):706-712

Hospital Israelita Albert Einstein , São Paulo , SP - Brasil.

Background: Individuals with severe hypercholesterolemia are at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). Many of them have familial hypercholesterolemia (FH).

Objectives: To assess from a patient perspective the degree of awareness about severe hypercholesterolemia, especially FH, ASCVD risk perception, cascade screening performance, and treatment of individuals participating in a routine health evaluation program.

Methods: From a database of 70,000 Brazilian individuals evaluated between 2006 and 2016, 1,987 (2.8%) met the inclusion criteria (age ≥ 18 years and LDL-C ≥ 190 mg/dL or ≥ 160 mg/dL, respectively, if not in use of statins or on statin therapy). Two-hundred individuals were randomly invited to complete an extensive questionnaire. FH was diagnosed if suspected by the attending physician.

Results: Although 97% of the sample (age 48±9 years; 16% women; 95% college/university education; 88% primary prevention; LDL-C 209±47 mg/dL) had severe hypercholesterolemia, only 18% and 29.5% believed to be at high ASCVD risk and reported knowledge of their recommended LDL-C goal, respectively. Fifty-eight percent reported being informed that high cholesterol could be a family disease, 24.5% (n = 49) had ever heard about FH, and merely 14% (n = 29) had been previously identified as suspected of having FH (age at FH diagnosis 35±12 years; 79% and 31% diagnosed, respectively, > 30 and > 40 years old). Only 2.5% underwent genetic tests, 17% underwent cascade screening, and 17% were not in use of pharmacological treatment.

Conclusions: An important gap in risk perception, cholesterol management, and aspects related to FH was encountered in individuals with severe hypercholesterolemia. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0).
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http://dx.doi.org/10.36660/abc.20190516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121404PMC
March 2021

Addressing Gaps in Racial/Ethnic Representation in Familial Hypercholesterolemia Registries: Implications and Recommendations for Equitable Access to Research and Care.

Circ Cardiovasc Qual Outcomes 2021 02 29;14(2):e007306. Epub 2021 Jan 29.

Division of Cardiovascular Prevention & Wellness, Houston Methodist DeBakey Heart & Vascular Center, Houston, TX (K.N.).

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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.007306DOI Listing
February 2021

LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial.

Atherosclerosis 2021 03 12;320:1-9. Epub 2021 Jan 12.

Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.

Background And Aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype.

Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype.

Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH).

Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.01.003DOI Listing
March 2021

Familial hypercholesterolemia and cardiovascular disease in older individuals.

Atherosclerosis 2021 02 19;318:32-37. Epub 2020 Dec 19.

Heart Institute (InCor), University of São Paulo, Medical School Hospital (FMUSP), Sao Paulo, Brazil; Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo, Brazil. Electronic address:

Background And Aims: Familial hypercholesterolemia (FH) is characterized by high LDL-cholesterol (LDL-C) and early atherosclerotic cardiovascular disease (ASCVD). With a lipid lowering therapy (LLT), most individuals with FH may have a longer ASCVD-free survival. However, there is scant data about older individuals with FH.

Methods: We compared characteristics of genetically defined FH older individuals with age-matched non-FH counterparts.

Results: From 4111 genotyped individuals, 462 older than 60 years were included (198 positive and 264 negative for FH variants). There were no differences regarding median age [%25; 75%] 66.0 (62.0; 71.0) and 66.0 (62.2; 71.0) years, p = 0.68 for FH and non-FH, respectively. In both groups, there was a higher frequency of females, however, there were more males in the FH group 37.4% vs. 24.2%, p = 0.002. No differences were seen between FH and non-FH in LLT use: 88.5% vs. 91.5%, p = 0.29. Despite a longer LLT duration in FH patients (with 11.0 (7.0; 20.0) vs. 7.0 (3.0; 13.0) years, p < 0.001), treatment was started late in both groups: at 54.0 (47.0; 61.0) and 59.0 (52.0; 64.0) years, p < 0.001, in FH and non-FH, respectively. FH had greater frequencies of previous and early ASCVD (40.9% vs. 27.3%, p = 0.002, and 22.2% vs. 9.0%, p < 0.001). In FH, male sex [HR (95%CI)] 2.67 (1.50-4.73), p = 0.001, and LLT onset age 0.96 (0.93-0.99), p = 0.009, were independently associated with ASCVD.

Conclusions: Among hypercholesterolemic older individuals participating in a cascade screening program, the genetic diagnosis of FH was associated with higher ASCVD rates, emphasizing the relevance of a monogenic defect as the cause of long-lasting hypercholesterolemia and ASCVD risk, particularly in men.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.012DOI Listing
February 2021

Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia. Reply.

N Engl J Med 2021 01;384(1):84-85

University of São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.1056/NEJMc2032399DOI Listing
January 2021

The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Heart Failure, Regardless of Diabetes Status: Focus on Cardiovascular Disease.

Ann Pharmacother 2021 10 5;55(10):1267-1275. Epub 2021 Jan 5.

Postgraduate Program in Cardiology and Cardiovascular Sciences, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul School of Medicine, Porto Alegre, RS, Brazil.

Objective: To provide clinical guidance and an overview of the available data on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence of type 2 diabetes mellitus (T2DM).

Data Sources: We searched the MEDLINE database via PubMed (from January 2015 to November 2020) for the following key terms: , and .

Study Selection And Data Extraction: To be included in the review, the articles needed to assess the effects of SGLT2 inhibitors in the heart failure (HF) scenario.

Data Synthesis: There is consistent evidence that SGLT2 inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization in patients with HFrEF, even in the absence of T2DM. On May 5, 2020, the U.S. Food and Drug Administration approved dapagliflozin for adults with HFrEF, regardless of the presence of T2DM, even in those patients on standard therapy, including an angiotensin receptor/neprilysin inhibitor.

Relevance To Patient Care And Clinical Practice: The SGLT2 inhibitors are well tolerated, and their once-daily dosing without the need for adjustments is convenient. These drugs can be considered a major breakthrough in pharmacotherapy for HF, providing physicians with a new treatment approach to reduce major clinical outcomes.

Conclusions: SGLT2 inhibitor therapy reduces CV death and hospitalizations in HFrEF patients regardless of T2DM. The decision to prescribe this class of drugs should not be determined by glycemic status.
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http://dx.doi.org/10.1177/1060028020985111DOI Listing
October 2021

The Finnish Diabetes Risk Score (FINDRISC), incident diabetes and low-grade inflammation.

Diabetes Res Clin Pract 2021 Jan 23;171:108558. Epub 2020 Nov 23.

Hospital Israelita Albert Einstein, São Paulo, SP, Brazil; Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil.

Aims: The FINDRISC was created to predict the development of type 2 diabetes mellitus (T2DM). Since T2DM associates with inflammation we evaluated if the FINDRISC could predict either current or incident T2DM, and elevated high sensitivity C-reactive protein (hs-CRP).

Methods: 41,880 people (age 41.9 ± 9.7 years; 31% female) evaluated between 2008 and 2016 were included. First, the cross-sectional association between the FINDRISC with presence of either T2DM or hs-CRP ≥ 2.0 mg/L was tested. After a 5 ± 3 years follow-up we tested the score predictive value for incident T2DM and inflammation in respectively 10,559 individuals without diabetes and in a subset of 2,816 individuals having no elevated hs-CRP at baseline.

Results: In the cross sectional analysis the FINDRISC was associated with both T2DM (OR 1.24, 95% CI: 1.23-1.26, P < 0.001) and inflammation (OR 1.10, 95% CI: 1.09-1.11, P < 0.001) per FINDRISC unit, as well as in longitudinal analyses (OR 1.17, 95% CI: 1.14-1.20, P < 0.001; and OR 1.04, 95% CI: 1.02-1.07, P < 0.001; respectively, per FINDRISC unit). The C-statistic for incident T2DM and inflammation was 0.79 (95% CI 0.77-0.82) and 0.55 (95% CI 0.53-0.58), respectively.

Conclusion: The FINDRISC shows good discrimination for incident T2DM but less for inflammation.
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http://dx.doi.org/10.1016/j.diabres.2020.108558DOI Listing
January 2021

Unfavorable Triglyceride-rich Particle Profile in Subclinical Thyroid Disease: A Cross-sectional Analysis of ELSA-Brasil.

Endocrinology 2021 02;162(2)

Center for Clinical and Epidemiological Research, Hospital Universitário, Universidade de Sao Paulo, São Paulo, São Paulo, Brazil.

Subclinical thyroid disorders have been associated with atherosclerosis and increased cardiovascular risk. As triglyceride-rich lipoprotein particles (TRLPs) have recently emerged as a casual factor for atherogenesis, the aim of this study was to evaluate the relationship between subclinical hypo- and hyperthyroidism and TRLP subfractions. We selected 5066 participants from the ELSA-Brasil cohort with available data of thyroid function and lipid profile measured by nuclear magnetic resonance (NMR) spectroscopy. Individuals were divided into 3 groups by baseline thyroid function (subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism). Triglyceride-rich lipoprotein particle subfractions were analyzed through NMR spectroscopy. To examine the association between TRLP subfractions and thyroid function, we conducted univariate and multivariate linear regression models adjusted for demographic characteristics, body mass index, diabetes, smoking status, and alcohol use. Of 3304 individuals, 54% were women, with a mean age of 50.6 ± 8.7 years, 51% white, and 53% with at least a college education. Of these individuals, 92% were euthyroid, whereas 6.8% had subclinical hypothyroidism and 1.2% had subclinical hyperthyroidism. The univariate linear regression showed that very small TRLPs (P = 0.026) and very large TRLPs (P = 0.008) were statistically increased in subclinical hypothyroidism when compared with euthyroidism. In subclinical hyperthyroidism, there was a reduction in total TRLPs (P = 0.003), seemingly driven by reduced very small TRLPs (P = 0.067). The findings were confirmed when adjusted for demographic characteristics, as well as comorbidities. This study suggests that subclinical hypothyroidism is associated with very small and very large TRLPs, which are related to an unfavorable atherogenic profile. Subclinical hyperthyroidism is associated to lower very small TRLPs.
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http://dx.doi.org/10.1210/endocr/bqaa205DOI Listing
February 2021
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