Imaging associations enhance the understanding of ECG abnormalities in male Brazilian football players: findings from the B-Pro Foot ECG study.

OBJECTIVES: To evaluate the prevalence of abnormal ECG findings and their association with imaging results in male Brazilian football players. METHODS: The 'B-Pro Foot ECG' is a multicentre observational study conducted in 82 Brazilian professional clubs. It analysed 6125 players aged 15-35 years (2496 white, 2004 mixed-race and 1625 black individuals) who underwent cardiovascular screening from 2002 to 2023. All ECGs were reviewed by two experienced cardiologists in the athlete's care. Those with abnormal findings underwent further investigations, including a transthoracic echocardiogram (TTE). Cardiac magnetic resonance (CMR) was subsequently performed based on TTE findings or clinical suspicion. RESULTS: In total, 180 (3%) players had abnormal ECGs and 176 (98%) showed normal TTE results. Athletes aged 26-35 years had a higher prevalence of abnormal ECGs than younger athletes (15-25 years). Black players had a higher prevalence of T-wave inversion (TWI) in the inferior leads than white players (2.6% vs 1.4%; p=0.005), as well as in V5 (2.9%) and V6 (2.1%) compared with white (1.2% and 1.0%; p<0.001) and mixed-race (1.5% and 1.2%; p<0.05) players, respectively. TTE parameters were similar across ethnicities. However, four out of 75 players with inferolateral TWI showed abnormal TTEs and CMR findings consistent with cardiomyopathies. CMR also showed cardiomyopathies or myocarditis in four players with inferolateral TWI and normal TTEs. In total, nine (0.1%) athletes were diagnosed with cardiac diseases and were followed for 40±30 months, with no cardiac events documented. CONCLUSION: This study found a 3% prevalence of abnormal ECGs in male Brazilian football players. Inferolateral TWI was associated with cardiac pathologies confirmed by CMR, even in athletes with a normal TTE.

Efficacy of six exercise-based interventions for individuals undergoing hemodialysis: a network meta-analysis of randomized clinical trials.

BACKGROUND: Evidence comparing different exercise modalities in individuals undergoing hemodialysis remains incipient. Our aim was to conduct a systematic review and network meta-analysis of randomized clinical trials to compare and synthesize the efficacy of five different intradialytic exercise modalities and home-based training in this population. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Studies were searched in PubMed/MEDLINE, Cochrane Library, Embase, Cinahl, and Scopus from their inception to 19 September 2022. We used traditional random-effects models and Bayesian network meta-analysis models. The risk of bias was assessed using the RoB v.2.0 tool, and the assessment of confidence in the results through the Confidence in Network Meta-Analysis (CINeMA) tool. RESULTS: Seventy-eight studies involving 3326 participants were included. Our network meta-analysis showed that combined training was the intervention with the best performance to increase VO2 peak [mean difference (MD) = 3.94 ml/kg/min; 95% credible interval (CrI), 2.38 to 5.76] and to reduce diastolic blood pressure (MD = -5.19 mmHg; 95%CrI, -9.35 to -0.96) compared to the usual care group. Inspiratory muscle training was the intervention that most improved the 6-minute walk test distance (MD = 70.97 m; 95%CrI, 18.09 to 129.87). C-reactive protein decreased in resistance training (MD = -2.6 mg/l; 95%CrI, -4.97 to -0.33) and aerobic training (MD = -1.4 mg/l; 95%CrI, -3.15 to -0.06). Kt/V improved in aerobic training (MD = 0.11; 95%CrI, 0.02 to 0.18), and SF-36 physical functioning outcomes improved in resistance training (MD = 10.66 points; 95%Crl, 1.91 to 20.22). No intradialytic exercise modality was superior to others or comparable with home-based training in improving the evaluated outcomes. Subgroup analysis revealed that exercise interventions >12 weeks improved functional capacity more than interventions ≤12 weeks, and that combined training reduces diastolic blood pressure only after 12 weeks of follow-up. Furthermore, our results suggest that moderate or moderate-to-vigorous intensity training leads to more pronounced improvements in functional capacity, whereas mild or mild-to-moderate intensity training does not have the same effect. In this review, most of the included studies were assessed as having some concern, which resulted in a low to very low level of confidence in the overall findings. CONCLUSIONS: Both intradialytic training and home-based training can promote benefits for individuals undergoing hemodialysis, with no evidence of the superiority of either training modality over the other.

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

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: SGLT2 inhibitors, sodium-glucose co-transporter-2 inhibitors, SGLT2i, heart failure, and heart failure with reduced ejection fraction. 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.

Genetics, Dyslipidemia, and Cardiovascular Disease: New Insights.

PURPOSE OF REVIEW: The cardiovascular (CV) risk related to lipid disorders is well established and is based on a robust body of evidence from well-designed randomized clinical trials, as well as prospective observational studies. In the last two decades, significant advances have been made in understanding the genetic basis of dyslipidemias. The present review is intended as a comprehensive discussion of current knowledge about the genetics and pathophysiology of disorders that predispose to dyslipidemia. We also focus on issues related to statins and the proprotein convertase subtilisin/kexin type 9 (PCSK9) and some of its polymorphisms, as well as new cholesterol-lowering medications, including PCSK9 inhibitors. RECENT FINDING: Cholesterol is essential for the proper functioning of several body systems. However, dyslipidemia-especially elevated low-density lipoprotein (LDL-c) and triglyceride levels, as well as reduced lipoprotein lipase activity-is associated with an increased risk of coronary artery disease (CAD). High-density lipoprotein (HDL-c), however, seems to play a role as a risk marker rather than as a causal factor of the disease, as suggested by Mendelian randomization studies. Several polymorphisms in the lipoprotein lipase locus have been described and are associated with variations in the activity of this enzyme, producing high concentrations of triglycerides and increased risk of CAD. Dyslipidemia, especially increased LDL-c and triglyceride levels, continues to play a significant role in CV risk. The combination of genetic testing and counseling is important in the management of patients with dyslipidemia of genetic etiology. Strategies focused on primary prevention can offer an opportunity to reduce CV events.

The impact of high-intensity inspiratory muscle training on exercise capacity and inspiratory muscle strength in heart failure with reduced ejection fraction: a systematic review and meta-analysis.

OBJECTIVE:: Inspiratory muscle training (IMT) improves prognostic clinical variables in patients with heart failure. However, the optimal intensity for increasing those outcomes remains unclear. Thus, we aimed to determine whether high-intensity inspiratory muscle training (HIIMT) improves exercise capacity and respiratory muscle strength in patients with heart failure with reduced ejection fraction (HFrEF). METHODS:: We searched for randomized controlled clinical trials at MEDLINE, the Cochrane Central Register of Controlled Trials, the Physiotherapy Evidence Database, SciELO and CINAHL from the earliest date available to May 2018. Primary studies on HIIMT against low-intensity IMT or sham-IMT that evaluated exercise capacity and inspiratory muscle strength were included. Two independent reviewers evaluated the eligibility of studies retrieved from the databases. Disagreements were resolved by discussion or by a third reviewer. Weighted mean difference (WMD), standardized mean difference (SMD) and 95% confidence interval (CI) were estimated by random effect models. RESULTS:: Five studies met the eligibility criteria (138 patients). HIIMT improved VO2peak (WMD 2.65 mL kg-1 min-1; 95% CI: 2.2 to 3.1 mL kg-1 min-1), walking tests (SMD 1.71; 95% CI: 0.83 to 2.59) and maximal inspiratory pressure (WMD 16.63 cmH2O; 95% CI: 10.34 to 22.91 cmH2O). The estimate for potential risks of adverse events was not performed because of the low prevalence of reports in primary studies. CONCLUSION:: HIIMT seems to be a useful strategy for improving exercise capacity and inspiratory muscle strength in HFrEF patients.

Polygenic Risk Scores: The Next Step for Improved Risk Stratification in Coronary Artery Disease? / Escores de Risco Poligênico: O Próximo Passo para Melhorar a Estratificação de Risco na Doença Arterial Coronariana?

Despite significant advances in the management of coronary artery disease (CAD) and reductions in annual mortality rates in recent decades, this disease remains the leading cause of death worldwide. Consequently, there is an ongoing need for efforts to address this situation. Current clinical algorithms to identify at-risk patients are particularly inaccurate in moderate-risk individuals. For this reason, the need for ancillary tests has been suggested, including predictive genetic screening. As genetic studies rapidly expand and genomic data becomes more accessible, numerous genetic risk scores have been proposed to identify and evaluate an individual's susceptibility to developing diseases, including CAD. The field of genetics has indeed made substantial contributions to risk prediction, particularly in cases where children have parents with premature CAD, resulting in an increased risk of up to 75%. The polygenic risk scores (PRSs) have emerged as a potentially valuable tool for understanding and stratifying an individual's genetic risk. The PRS is calculated as a weighted sum of single-nucleotide variants present throughout the human genome, identifiable through genome-wide association studies, and associated with various cardiometabolic diseases. The use of PRSs holds promise, as it enables the development of personalized strategies for preventing or diagnosing specific pathologies early. Furthermore, it can complement existing clinical scores, increasing the accuracy of individual risk prediction. Consequently, the application of PRSs has the potential to impact the costs and adverse outcomes associated with CAD positively. This narrative review provides an overview of the role of PRSs in the context of CAD.

Apesar dos avanços significativos no tratamento da doença arterial coronariana (DAC) e das reduções nas taxas de mortalidade anuais nas últimas décadas, a DAC continua sendo a principal causa de morte no mundo. Consequentemente, há uma necessidade contínua de esforços para abordar essa situação. Os algoritmos clínicos atuais para identificar pacientes em risco são particularmente imprecisos para indivíduos de risco moderado. Por esse motivo, foi sugerido que são necessários testes auxiliares, incluindo triagem genética preditiva. À medida que os estudos genéticos se expandem rapidamente e os dados genômicos se tornam mais acessíveis, diversos escores de risco genético têm sido propostos para identificar e avaliar a suscetibilidade de um indivíduo ao desenvolvimento de doenças, incluindo a DAC. De fato, o campo da genética tem contribuído substancialmente para a previsão de risco, particularmente nos casos em que as crianças têm genitores com DAC prematura, resultando em um risco aumentado de até 75%. Os escores de risco poligênico (PRSs, do inglês polygenic risk scores) surgiram como uma ferramenta potencialmente valiosa para compreender e estratificar o risco genético de um indivíduo. O PRS é calculado como uma soma ponderada de variantes de nucleotídeo único presentes em todo o genoma humano, identificáveis por meio de estudos de associação genômica ampla, e associadas a várias doenças cardiometabólicas. O uso dos PRSs é promissor, pois permite o desenvolvimento de estratégias personalizadas para prevenir ou diagnosticar patologias específicas de forma precoce. Ademais, seu uso é capaz de complementar os escores clínicos existentes, aumentando a precisão da previsão de risco individual. Consequentemente, a aplicação dos PRSs tem o potencial de impactar positivamente os custos e os desfechos adversos associados à DAC. A presente revisão narrativa oferece uma visão ampla do papel dos PRSs no contexto da DAC.

Dysregulated microRNAs in type 2 diabetes and breast cancer: Potential associated molecular mechanisms.

Type 2 diabetes (T2D) is a multifaceted and heterogeneous syndrome associated with complications such as hypertension, coronary artery disease, and notably, breast cancer (BC). The connection between T2D and BC is established through processes that involve insulin resistance, inflammation and other factors. Despite this comprehension the specific cellular and molecular mechanisms linking T2D to BC, especially through microRNAs (miRNAs), remain elusive. miRNAs are regulators of gene expression at the post-transcriptional level and have the function of regulating target genes by modulating various signaling pathways and biological processes. However, the signaling pathways and biological processes regulated by miRNAs that are associated with T2D and BC have not yet been elucidated. This review aims to identify dysregulated miRNAs in both T2D and BC, exploring potential signaling pathways and biological processes that collectively contribute to the development of BC.

Effects of intradialytic inspiratory muscle training at different intensities on diaphragm thickness and functional capacity: clinical trial protocol in patients undergoing haemodialysis.

INTRODUCTION: Patients with end-stage renal disease (ESRD) undergoing haemodialysis (HD) commonly present with a sedentary behaviour and reduced functional capacity, factors that can compromise their prognosis. Intradialytic inspiratory muscle training (IMT) can increase respiratory muscle strength and, consequently, improve functional capacity, besides being easy to apply, cheap and performed in a supervised setting. However, few studies show the effects of this type of training applied at different intensities in this population. This study aims to compare the effects of IMT at different intensities in adults with ESRD undergoing HD. METHODS AND ANALYSIS: A randomised, double-blind, sham-controlled trial will be conducted on 36 subjects randomly allocated into three groups: IMT at intensities of 30% or 50% of maximal inspiratory pressure (intervention groups), or 10% of maximal inspiratory pressure (sham-IMT). All the interventions will be supervised and performed three times per week, for 12 weeks, totalling 36 sessions. The primary outcomes are the 6-minute walk test, diaphragm thickness and the response of VO2peak post-intervention. Respiratory muscle strength, 24-hour ambulatory blood pressure measurement and the Kidney Disease Quality of Life 36-item short form survey will be evaluated as secondary outcomes. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committee of the Hospital de Clínicas de Porto Alegre (ID: 2020-0458). The results of this study will be disseminated by conference presentations and peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04660383.

Thiazide diuretics alone or combined with potassium-sparing diuretics to treat hypertension: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The magnitude of blood pressure (BP)-lowering effects and decrease of the adverse effects of thiazide diuretics provided by potassium-sparing diuretics remain uncertain. The aim of this study was to compare the BP-lowering efficacy and the incidence of adverse effects of high (T+) and low-dose (T-) thiazide diuretics, alone or combined with high (PS+) or low-dose (PS-) potassium-sparing diuretics in patients with primary hypertension. METHODS: A systematic literature search was performed in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, Scopus and LILACS. Randomized double-blind placebo or active-controlled trials (RCT) with 3 weeks to 1 year of follow-up were included. Sample size, mean and standard deviation from baseline, follow-up and change from baseline values were extracted by two independent reviewers. Pairwise random effect models and Bayesian network meta-analysis models were used to compare the effects of treatments. The risk of bias in individual studies was assessed using the Rob 1.0 tool. The primary outcome was the mean difference in office SBP. Secondary outcomes were the mean difference in biochemical parameters and the incidence of nonmelanoma skin cancer. RESULTS: Two hundred and seventy-six double-blind RCTs involving 58 807 participants (mean age: 55 years; 45% women) were included. All treatment groups were more effective than placebo in lowering BP, with mean differences (MDs) of change from baseline ranging from -7.66 mmHg [95% credible interval (95% CrI), -8.53 to -6.79] for T- to -12.77 mmHg (95% CrI, -15.22 to -10.31) for T+PS-. T+ alone or combined with potassium-sparing was more effective in reducing BP than T-. The surface under the cumulative ranking curve (SUCRA) estimated ranking showed that the best effectiveness in lowering SBP was found for T+PS- (0.69), T+PS+ (0.65) and T+ (0.54). Compared with placebo, all treatments (except T-PS-) were associated with more potassium reduction and T+ compared with all other treatments and T- when compared with T-PS-. Compared with placebo, all active treatments (except T+PS+) showed higher elevations of uric acid. The increase of plasma glucose promoted by thiazides alone was reduced by potassium-sparing agents. CONCLUSION: Thiazides with potassium-sparing diuretics are associated with increased BP-lowering efficacy compared with thiazides alone while minimizing hypokalaemia and hyperglycaemia. These findings demonstrate that thiazide and potassium-sparing diuretic combination is preferable to thiazide alone in treating hypertension.

Prevalence and diagnostic significance of de-novo 12-lead ECG changes after COVID-19 infection in elite soccer players.

BACKGROUND AND AIM: The efficacy of pre-COVID-19 and post-COVID-19 infection 12-lead ECGs for identifying athletes with myopericarditis has never been reported. We aimed to assess the prevalence and significance of de-novo ECG changes following COVID-19 infection. METHODS: In this multicentre observational study, between March 2020 and May 2022, we evaluated consecutive athletes with COVID-19 infection. Athletes exhibiting de-novo ECG changes underwent cardiovascular magnetic resonance (CMR) scans. One club mandated CMR scans for all players (n=30) following COVID-19 infection, despite the absence of cardiac symptoms or de-novo ECG changes. RESULTS: 511 soccer players (median age 21 years, IQR 18-26 years) were included. 17 (3%) athletes demonstrated de-novo ECG changes, which included reduction in T-wave amplitude in the inferior and lateral leads (n=5), inferior leads (n=4) and lateral leads (n=4); inferior T-wave inversion (n=7); and ST-segment depression (n=2). 15 (88%) athletes with de-novo ECG changes revealed evidence of inflammatory cardiac sequelae. All 30 athletes who underwent a mandatory CMR scan had normal findings. Athletes revealing de-novo ECG changes had a higher prevalence of cardiac symptoms (71% vs 12%, p<0.0001) and longer median symptom duration (5 days, IQR 3-10) compared with athletes without de-novo ECG changes (2 days, IQR 1-3, p<0.001). Among athletes without cardiac symptoms, the additional yield of de-novo ECG changes to detect cardiac inflammation was 20%. CONCLUSIONS: 3% of athletes demonstrated de-novo ECG changes post COVID-19 infection, of which 88% were diagnosed with cardiac inflammation. Most affected athletes exhibited cardiac symptoms; however, de-novo ECG changes contributed to a diagnosis of cardiac inflammation in 20% of athletes without cardiac symptoms.

Effects of Physical Exercise on Cardiometabolic Biomarkers and Inflammatory Markers in Children: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The prevalence of obesity among children as well as the beneficial effects of physical exercise (PE) on weight loss has been determined by modulating the secretory factors of adipose tissue. PE has also been shown to have beneficial effects on obesity. OBJECTIVE: The objective of this systematic review and meta-analysis was to investigate the effects of physical exercise (PE) on adiponectin and other important health markers in children. DATA SOURCES: We searched 6 electronic databases (PubMed/Medline, Embase, Cochrane Library, Cinahl, Scopus, and Web of Science) and Google Scholar for randomized controlled trials from inception to December 15, 2021. We used random-effects models to estimate weighted mean difference (WMD) with 95% confidence intervals (CI). STUDY SELECTION: Fourteen studies were included (N = 468 participants; mean age: 14 years). RESULTS: In general, PE increased adiponectin (WMD: 0.91 µg/mL; 95% CI, 0.27 to 1.55, p = 0.005), high-density lipoprotein cholesterol (HDL-C) (WMD: 1.01 mg/dL; 95% CI, 0.33 to 1.69, p = 0.004), and VO2max (WMD: 2.52 mL.kg.min; 95% CI, 1.41 to 3.62, p = 0.00,001). The levels of c-reactive protein (WMD: -0.37 mg/L; 95% CI, -0.57 to -0.17, p = 0.0003), insulin (WMD: -4.61 µIU/ml; 95% CI, -5.46 to -3.76, p = 0.00,001), fasting glucose (WMD: -5.11 mg/dL; 95% CI, -7.88 to -2.34, p = 0.0003), and insulin resistance index (WMD: -1.44; 95% CI, -1.92 to -0.96, p = 0.00,001), decreased significantly. CONCLUSION: Our study showed that PE may increase the level of adiponectin, HDL-C, and VO2max in children.

Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future.

Type 2 diabetes mellitus (T2DM) is associated with high cardiovascular morbidity and mortality, and cardiovascular diseases are the leading causes of death and disability in people with T2DM. Unfortunately, therapies strictly aimed at glycemic control have poorly contributed to a significant reduction in the risk of cardiovascular events. On the other hand, randomized controlled trials have shown that five glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and one exendin-based GLP-1 RA reduced atherosclerotic cardiovascular events in patients with diabetes at high cardiovascular risk. Furthermore, a meta-analysis including these six agents showed a reduction in major adverse cardiovascular events as well as all-cause mortality compared with placebo, regardless of structural homology. Evidence has also shown that some drugs in this class have beneficial effects on renal outcomes, such as preventing the onset of macroalbuminuria. In addition to lowering blood pressure, these drugs also favorably impacted on body weight in large randomized controlled trials as in real-world studies, a result considered a priority in T2DM management; these and other factors may justify the benefits of GLP-1 RAs upon the cardiovascular system, regardless of glycemic control. Finally, studies showed safety with a low risk of hypoglycemia and no increase in pancreatitis events. Given these benefits, GLP-1 RAs were preferentially endorsed in the guidelines of the European and American societies for patients with these conditions. This narrative review provides a current and comprehensive overview of GLP-1 RAs as cardiovascular and renal protective agents, far beyond their use as glucose-lowering drugs, supporting their effectiveness in treating patients with T2DM at high cardiovascular risk.

Thiazide diuretics alone or in combination with a potassium-sparing diuretic on blood pressure-lowering in patients with primary hypertension: protocol for a systematic review and network meta-analysis.

BACKGROUND: The use of thiazide (T) diuretics for the treatment of hypertension may be associated with adverse metabolic effects, which can be minimized by combining thiazides with potassium-sparing (PS) diuretics. The additional blood pressure (BP)-lowering effect provided by the addition of a PS diuretic is unclear. Due to a large number of drugs in the T diuretics class, and the possible difference between them, there is a need to identify the best available evidence for health decision-making. This systematic review with network meta-analysis aims to compare the antihypertensive efficacy of T diuretics alone or in combination with a PS diuretic in patients with primary hypertension, as well as the safety of such drugs through the measurement of drug-related adverse events. METHODS: A comprehensive electronic search will be conducted in six electronic bibliographic databases (PubMed/MEDLINE, Cochrane Library, Embase, Web of Science, Scopus, Lilacs), a registration database ( ClinicalTrials.gov ), and Educational Resources Information Center (ERIC [ProQuest]), published from inception to the date of the search. The search will be updated towards the end of the review. A hand search of the reference sections of the included studies and cited studies will also be performed. In case of missing data, authors will be contacted by e-mail or academic social networking sites whenever possible. To be included in the review, studies must be double-blind randomized controlled trials evaluating T diuretics alone or in combination with PS diuretics in patients with primary hypertension. The primary outcome measure will be office BP. Ambulatory BP monitoring (ABPM), non-melanoma skin cancer, major adverse cardiovascular events, laboratory parameters, and the number of withdrawals will be included as secondary outcomes. The results will be quantitatively summarized using differences between the mean change from baseline or differences between means for quantitative outcomes and relative risk for dichotomous outcomes. Results will be presented as mean or relative risk with credible intervals through a league table. The treatments will also be ranked using the surface under the cumulative ranking curve method. The risk of bias will be assessed through the RoB 1.0 tool. DISCUSSION: To the best of our knowledge, this review will be the first to synthesize currently available evidence on the antihypertensive efficacy of different T diuretics alone or in combination with PS diuretics in adults with hypertension. The goals of hypertension treatment are to control high BP and to reduce associated cardiovascular morbidity and mortality, using the most appropriate therapy. Thiazides are widely used for pharmacological treatment due to their demonstrated effectiveness in reducing BP, favorable safety profile, and low cost. The results of this study will provide evidence regarding the best therapeutic strategies with T and PS diuretics, evidencing interventions with better antihypertensive efficacy and safety profile. TRIAL REGISTRATION: This systematic review and network meta-analysis was prospectively registered at the PROSPERO database ( CRD42018118492 ).

Renin-Angiotensin-Aldosterone System Inhibitors in COVID-19: A Review.

Among the multiple uncertainties surrounding the novel coronavirus disease (COVID-19) pandemic, a research letter published in The Lancet implicated drugs that antagonize the renin-angiotensin-aldosterone system (RAAS) in an unfavorable prognosis of COVID-19. This report prompted investigations to identify mechanisms by which blocking angiotensin-converting enzyme 2 (ACE2) could lead to serious consequences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The possible association between RAAS inhibitors use and unfavorable prognosis in this disease may have been biased by the presence of underlying cardiovascular diseases. As the number of COVID-19 cases has increased worldwide, it has now become possible to investigate the association between RAAS inhibitors and unfavorable prognosis in larger cohorts. Observational studies and one randomized clinical trial failed to identify any consistent association between the use of these drugs and unfavorable prognosis in COVID-19. In view of the accumulated clinical evidence, several scientific societies recommend that treatment with RAAS inhibitors should not be discontinued in patients diagnosed with COVID-19 (unless contraindicated). This recommendation should be followed by clinicians and patients.

Advances with lipid-lowering drugs for pediatric patients with familial hypercholesterolemia.

INTRODUCTION: Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated LDL-cholesterol (LDL-C) and early onset of atherosclerosis. AREAS COVERED: The authors provide an overview of the pediatric FH scenario, with emphasis on the role of statins as the preferred pharmacological therapy, discussing their potential benefits, as well as adverse effects, and the remaining uncertainties about their use in this population. They also comment on other lipid-lowering therapies. EXPERT OPINION: Statin therapy is recommended after the ages of 8-10 years old for heterozygous FH patients and can reduce LDL-C by 24-50% depending on drug type and dosage. For more severe cases, higher doses and adjuvant therapies like ezetimibe may be necessary and treatment should be started at diagnosis, as is the case of homozygous FH. Statins reduce progression of subclinical vascular disease and may reduce early cardiovascular events. The available evidence indicates safety of statins in children with no apparent harms related to growth, sexual maturation, steroid hormones, glucose levels, cognitive function, or muscle and liver problems, in comparison with placebo. Newer treatments like lomitapide, PCSK9 inhibitors, bempedoic acid and evinacumab need to be adequately evaluated in pediatric FH patients with more severe dyslipidemia.

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

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.

Direct-Acting Oral Anticoagulants in Atrial Fibrillation: What's New in the Literature.

Atrial fibrillation (AF) is considered the most common sustained cardiac arrhythmia, and it is associated with a significant risk of adverse events, especially ischemic stroke. Oral anticoagulation is the cornerstone for stroke prevention in AF; for many years, only vitamin K antagonists were used for this purpose, with an absolute risk reduction >60%. However, these agents have limitations, such as narrow therapeutic margins and drug-food and drug-drug interactions. More recently, 4 direct-acting oral anticoagulants (DOACs)-non-vitamin K antagonists-have become available for patients with AF: dabigatran, rivaroxaban, apixaban, and edoxaban. In addition to a comparable efficacy to warfarin in large randomized controlled trials, DOACs were found to promote a lower risk of intracranial bleeding. The strategic dosage and lack of need for periodic prothrombin-time testing make their use attractive, especially for primary or secondary prevention of stroke in older adults. Furthermore, among patients with AF presenting with acute coronary syndrome or undergoing percutaneous coronary intervention, apixaban is associated with a reduction in serious bleeding events when compared with warfarin. On the other hand, there is no evidence of benefit of DOACs in patients with mechanical prosthetic valves or moderate/severe mitral stenosis. Furthermore, the suitability of DOACs in patients with liver disease is still poorly understood, and their safety in patients requiring renal replacement therapy remains uncertain. This review provides an overview of the main trials of DOACs, their pharmacology and safety profile, clinical implications, and best indications in light of the current evidence.

COVID-19: Updated Data and its Relation to the Cardiovascular System. / COVID-19: Dados Atualizados e sua Relação Com o Sistema Cardiovascular.

In December 2019, a new human coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) by the World Health Organization, emerged in the city of Wuhan, China. Spreading globally, it is now considered pandemic, with approximately 3 million cases worldwide at the end of April. Its symptoms include fever, cough, and headache, but the main one is shortness of breath. In turn, it is believed that there is a relationship between COVID-19 and damage to the heart muscle, and hypertensive and diabetic patients, for example, seem to have worse prognosis. Therefore, COVID-19 may worsen in individuals with underlying adverse conditions, and a not negligible number of patients hospitalized with this virus had cardiovascular or cerebrovascular diseases. Systemic inflammatory response and immune system disorders during disease progression may be behind this association. In addition, the virus uses angiotensin-converting enzyme (ACE) receptors, more precisely ACE2, to penetrate the cell; therefore, the use of ACE inhibitor drugs and angiotensin receptor blockers could cause an increase in these receptors, thus facilitating the entry of the virus into the cell. There is, however, no scientific evidence to support the interruption of these drugs. Since they are fundamental for certain chronic diseases, the risk and benefit of their withdrawal in this scenario should be carefully weighed. Finally, cardiologists and health professionals should be aware of the risks of infection and protect themselves as much as possible, sleeping properly and avoiding long working hours.

Em dezembro de 2019, um novo coronavírus humano, chamado síndrome respiratória aguda grave do coronavírus 2 (SARS-CoV-2) ou nomeado doença de coronavírus (COVID-19) pela Organização Mundial da Saúde, surgiu na cidade de Wuhan, China. Difundido globalmente, é atualmente considerado pandêmico, com aproximadamente 3 milhões de casos no mundo no final de abril. Seus sintomas incluem febre, tosse, dor de cabeça e falta de ar, esse último considerado o sintoma principal. Por sua vez, acredita-se que haja uma relação entre o COVID-19 e danos ao músculo cardíaco, e pacientes com hipertensão e diabetes, por exemplo, parecem apresentar prognóstico pior. Portanto, o COVID-19 pode piorar em indivíduos com condições adversas subjacentes. Um número não negligenciável de pacientes internados com este vírus tinham doenças cardiovasculares ou cerebrovasculares. A resposta inflamatória sistêmica e distúrbios do sistema imunológico durante a progressão da doença podem estar por trás dessa associação. Além disso, o vírus usa os receptores da enzima conversora da angiotensina (ECA), mais especificamente da ECA2, para penetrar nas células; portanto, o uso de fármacos inibidores de ECA e bloqueadores de receptores de angiotensina pode causar um aumento nestes receptores, assim facilitando a entrada do vírus na célula. No entanto, não há evidências científicas que apóiem a interrupção desses medicamentos. Considerando que são fundamentais para o manejo de certas doenças crônicas, os riscos e benefícios da sua retirada devem ser cuidadosamente ponderados neste cenário. Finalmente, cardiologistas e profissionais de saúde devem estar cientes dos riscos de infecção e se proteger o máximo possível, dormindo adequadamente e evitando longos turnos de trabalho.

Digoxin in Atrial Fibrillation: An Old Topic Revisited.

Digoxin has been used for more than 50 years in patients with Atrial Fibrillation (AF), with the goal of Controlling Heart Rate (HR) and restoring sinus rhythm. In the last two decades, several studies have correlated therapeutic use of digoxin with increased mortality. However, such studies have potential biases that cannot be disregarded, mainly because they are cross-sectional experiments or post-hoc analyses of Randomized Controlled Trials (RCTs). Despite uncertainties regarding the safety of digoxin in this setting, it remains one of the most prescribed drugs for AF worldwide. On the other hand, the absence of any RCTs designed to evaluate mortality makes a definitive conclusion more difficult to reach; therefore, this medication must be used with care. In this review, we explored the therapeutic use of digoxin in the context of AF, discussed mortality data by means of critical analysis in the light of the best available evidence, and position ourselves in relation to more rigorous control of serum levels of this drug in daily practice.

Exercise training modalities for heart transplant recipients: a systematic review and network meta-analysis protocol.

INTRODUCTION: Heart transplantation is the gold standard treatment for selected patients with end-stage heart failure. Although this procedure can improve quality and prolong life expectancy, several of these patients persist with decreased exercise tolerance. Evidence suggests that exercise training can bring multifactorial benefits to heart transplant (HTx) recipients. However, it is unclear that exercise modality should be preferred. Therefore, the aim of this systematic review and network meta-analysis is to compare the efficacy and safety of different training modalities in HTx recipients. METHODS AND ANALYSIS: We will perform a comprehensive literature search in PubMed/MEDLINE, Embase, The Cochrane Library, CINAHL, Scopus, SportDISCUS, Web of Science Core Collection and PEDro from inception until November 2020. Two registries (ClinicalTrials.gov and REBEC) will also be searched for potential results in unpublished studies. There will be no restriction on language, date of publication, publication status or sample size. We will include randomised controlled trials enrolling adult HTx recipients with the presence of at least one exercise training group, which might be compared with another training modality and/or a non-exercise control group for a minimum of 4 weeks of intervention. The primary outcomes will be peak oxygen consumption and occurrence of adverse events. As secondary outcomes, the interaction between pulmonary ventilation, pulmonary perfusion and cardiac output, oxygen uptake efficiency slope, heart rate response, oxygen pulse, peak blood pressure and peak subjective perception of effort. In addition, we will evaluate the 6 min walking distance, health-related quality of life, endothelial function, muscle strength, body fat percentage and lean mass. Risk of bias will be assessed using the Cochrane RoB V.2.0 tool, and we plan to use the Confidence in Network Meta-Analysis tool to assess confidence in the results. All materials (raw data, processed data, statistical code and outputs) will be shared in a public repository. ETHICS AND DISSEMINATION: Given the nature of this study, no ethical approval will be required. We believe that the findings of this study may show which is the most efficacious and safe physical training modality for HTx recipients. The completed systematic review and network meta-analysis will be submitted to a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020191192.