The First Brazilian Cardiovascular Registry of Atrial Fibrillation: Primary Results of the RECALL Study.

BACKGROUND: It is estimated that atrial fibrillation (AF) affects approximately 1.5 million people in Brazil; however, epidemiological data are limited. We sought to evaluate the characteristics, treatment patterns, and clinical outcomes in patients with AF in Brazil by creating the first nationwide prospective registry. METHODS: RECALL was a multicenter, prospective registry that included and followed for 1 year 4,585 patients with AF at 89 sites across Brazil from April 2012 to August 2019. Patient characteristics, concomitant medication use, and clinical outcomes were analyzed using descriptive statistics and multivariable models. RESULTS: Of 4,585 patients enrolled, the median age was 70 (61, 78) years, 46% were women, and 53.8% had permanent AF. Only 4.4% of patients had a history of previous AF ablation and 25.2% had a previous cardioversion. The mean (SD) CHA2DS2-VASc score was 3.2 (1.6); median HAS-BLED score was 2 (2, 3). At baseline, 22% were not on anticoagulants. Of those taking anticoagulants, 62.6% were taking vitamin K antagonists and 37.4% were taking direct oral anticoagulants. The primary reasons for not using an oral anticoagulant were physician judgment (24.6%) and difficulty in controlling (14.7%) or performing (9.9%) INR. Mean (SD) TTR for the study period was 49.5% (27.5). During follow-up, the use of anticoagulants and INR in the therapeutic range increased to 87.1% and 59.1%, respectively. The rates/100 patient-years of death, hospitalization due to AF, AF ablation, cardioversion, stroke, systemic embolism, and major bleeding were 5.76 (5.12-6.47), 15.8 (14.6-17.0), 5.0 (4.4-5.7), 1.8 (1.4-2.2), 2.77 (2.32-3.32), 1.01 (0.75-1.36), and 2.21 (1.81-2.70). Older age, permanent AF, New York Heart Association class III/IV, chronic kidney disease, peripheral arterial disease, stroke, chronic obstructive pulmonary disease, and dementia were independently associated with increased mortality while the use of anticoagulant was associated with lower risk of death. CONCLUSIONS: RECALL represents the largest prospective registry of patients with AF in Latin America. Our findings highlight important gaps in treatment, which can inform clinical practice and guide future interventions to improve the care of these patients.

Use of instant messaging in electrophysiological clinical practice in Latin America: a LAHRS survey.

AIMS: Instant messaging (IM) platforms are a prominent component of telemedicine and a practical tool for sharing clinical data and counselling. Purpose of the survey was to inquire about the use of IM, the platforms used, frequency, recipients, and contents in Latin America region. METHODS AND RESULTS: An online survey was sent to medical community via newsletter and social media channels. The survey consisted in 22 questions, in Spanish and Portuguese, collected on SurveyMonkey. A total of 125 responders from 13 Latin-American countries (79% male, mean age 46.1 ± 9.7 years) completed the survey. Most of the responders declared that they send (88.8%) and receive (97.6%) clinical data through IM apps. Most senders declare that they anonymize clinical data before sending (71.0 ± 38.3%), but that the data received is anonymized only in 51.4 ± 33.5%. The most common tests shared with other physicians were 12-lead electrocardiograms (99.2%), followed by Holter recordings (68.0%) and tracings from electrophysiological studies (63.2%). The majority (55.2%) said that are unaware of legal data protection rules in their countries. CONCLUSIONS: IM apps are used by medical professionals worldwide to share and discuss clinical data and are preferred to many other methods of data sharing and are often used to share many different types of clinical data. They are perceived as a fast and easy way of communication, but medical professionals should be aware of the appropriate use of IM to prevent legal and privacy issues.

European Society of Cardiology quality indicators for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.

To develop a suite of quality indicators (QIs) for the management of patients with ventricular arrhythmias (VA) and the prevention of sudden cardiac death (SCD). The Working Group comprised experts in heart rhythm management including Task Force members of the 2022 European Society of Cardiology (ESC) Clinical Practice Guidelines for the management of patients with VA and the prevention of SCD, members of the European Heart Rhythm Association, international experts, and a patient representative. We followed the ESC methodology for QI development, which involves (i) the identification of the key domains of care for the management of patients with VA and the prevention of SCD by constructing a conceptual framework of care, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. We identified eight domains of care for the management of patients with VA and the prevention of SCD: (i) structural framework, (ii) screening and diagnosis, (iii) risk stratification, (iv) patient education and lifestyle modification, (v) pharmacological treatment, (vi) device therapy, (vii) catheter ablation, and (viii) outcomes, which included 17 main and 4 secondary QIs across these domains. Following a standardized methodology, we developed 21 QIs for the management of patients with VA and the prevention of SCD. The implementation of these QIs will improve the care and outcomes of patients with VA and contribute to the prevention of SCD.

Worldwide sedation strategies for atrial fibrillation ablation: current status and evolution over the last decade.

Catheter ablation for atrial fibrillation (AF) has become one of the most common procedures in the electrophysiology lab with rapidly increasing volumes. Peri-procedural anaesthesia for AF ablation varies between centres, from general anaesthesia to deep or conscious sedation. The aim of this survey was to assess current sedation practices for AF ablation worldwide and its evolution over the last decade. Centres regularly performing AF ablation responded to an online survey. A total of 297 centres participated in the survey. Overall, the median (interquartile range) number of AF ablation procedures increased from 91 (43-200) to 200 (74-350) per year (P < 0.001) between 2010 and 2019. The proportion of cryoablation also increased from 17.0% to 33.2% (P < 0.001). In 2019, the most used sedation technique was general anaesthesia (40.5%), followed by conscious sedation (32.0%) and deep sedation (27.5%). Between 2010 and 2019, the proportion of procedures performed under general anaesthesia (+4.4%; P = 0.02) and deep sedation (+4.8%; P < 0.01) increased, whereas the use of conscious sedation decreased (-9.2%; P < 0.001). The most commonly used hypnotic drugs were propofol and midazolam, whereas the most commonly used opioid drugs were remifentanyl and fentanyl. This worldwide survey shows that the number of AF ablation procedures has more than doubled over the last decade and general anaesthesia remains most commonly used. Studies comparing outcomes between different sedation strategies are needed to guide optimal decision-making.

Cerebral Structure and Function in Stroke-free Patients with Atrial Fibrillation.

OBJECTIVES: Atrial fibrillation (AF) is associated with high risk of dementia and brain atrophy in stroke-free patients, but the mechanisms underlying this association remain unclear. We aimed to examine the brain volume and connectivity of paramount cognitive brain networks in stroke-free patients with AF without dementia. MATERIALS AND METHODS: Twenty-six stroke-free patients with AF and 26 age and sex-matched subjects without AF were submitted to a 3-tesla brain structural and functional MRI. An extensive clinical evaluation excluded stroke, dementia, low cardiac output, carotid stenosis and metabolic diseases without optimal therapy. We used CHA2DS2-VASc score to classify the cardiovascular risk factor burden and a broad neuropsychological battery to assess the cognitive performance. Voxel based morphometry analysis of. structural MRI defined whole-brain gray and white matter volumes. Finally, we used eco-plannar MRI images to compare the differences of functional connectivity of 7 large-scale resting-state networks between AF patients and controls. RESULTS: Taking into account the history of hypertension and heart failure, AF was associated to volume decrease of the right basal frontal lobe and right inferior cerebellum. Decreased connectivity of the ventral Default Mode Network (vDMN) was observed in the AF group. No disruption of connectivity was observed in the executive, visuospatial and salience networks. CONCLUSION: Individuals with AF without stroke or dementia have subtle reduction of gray and white matter, restricted to frontal areas and cerebellum. These patients show decreased vDMN connectivity, without other large-scale brain network disruption.

Default Mode Network Disruption in Stroke-Free Patients with Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a widely accepted risk for causing stroke. However, recent studies show AF as a risk factor for dementia, even without causing stroke. The mechanisms by which dementia develops in stroke-free patients with AF are still poorly understood and the association of AF with abnormal function of brain networks activities, such as the default mode network (DMN), has not been previously studied. We aimed to determine whether, in the absence of stroke and dementia, patients with AF have abnormal resting-state brain networks compared to controls without AF. METHODS: Twenty-one stroke-free patients with AF and 21 age- and sex-matched controls without AF underwent brain functional magnetic resonance imaging acquired at a 3.0 Tesla scanner. During the exam, the subjects were instructed to lie still with eyes closed. At first-level analysis, connectivity of the DMN was obtained for all subjects. Second-level analysis compared the DMN connectivity between AF patients and controls with a general linear model (two-sample t test, p < 0.05, False Discovery Rate corrected, minimum of 50 contiguous voxels). RESULTS: Patients with AF compared with controls showed decreased connectivity in regions of the DMN including the frontal lobe (left medial frontal gyrus, left superior frontal gyrus and anterior cingulate), left angular gyrus, and bilateral precuneus. CONCLUSIONS: Stroke-free patients with AF have evidence of abnormal DMN connectivity. This study adds evidence to the occurrence of cerebral dysfunction in patients with AF.

Expression profile of glucose transport-related genes under chronic and acute exposure to growth hormone in zebrafish.

The brain is a highly demanding organ in terms of energy requirements, and precise regulatory mechanisms must operate to ensure adequate energy delivery to maintain normal neuronal activity. Of the energy-promoting substrates present in the circulation, glucose is preferred by the brain, and as with all other substrates, its utilization depends on the presence of humoral factors such as hormones including growth hormone (GH). Glucose enters the cells though specific transport proteins. Among all transporter families and subtypes described to date, the most studied ones are the glucose transporters (GLUTs). The aim of this study is to determine a possible relationship between GH and GLUTs. Therefore, we evaluated the effect of GH-transgenesis and recombinant GH injections upon GLUT expression in the brain of male zebrafish. Overall, the results demonstrated that increasing the GH concentrations above the normal level, via transgenesis or injection, in the fish may impair energy uptake by the brain. This appeared to occur through downregulation of most of the analyzed GLUTs.

Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

Hypertension is a common cardiovascular risk factor leading to heart failure (HF), coronary artery disease, stroke, peripheral artery disease and chronic renal insufficiency. Hypertensive heart disease can manifest as many cardiac arrhythmias, most commonly being atrial fibrillation (AF). Both supraventricular and ventricular arrhythmias may occur in hypertensive patients, especially in those with left ventricular hypertrophy (LVH) or HF. Also, some of the antihypertensive drugs commonly used to reduce blood pressure, such as thiazide diuretics, may result in electrolyte abnormalities (e.g. hypokalaemia, hypomagnesemia), further contributing to arrhythmias, whereas effective control of blood pressure may prevent the development of the arrhythmias such as AF. In recognizing this close relationship between hypertension and arrhythmias, the European Heart Rhythm Association (EHRA) and the European Society of Cardiology (ESC) Council on Hypertension convened a Task Force, with representation from the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE), with the remit to comprehensively review the available evidence to publish a joint consensus document on hypertension and cardiac arrhythmias, and to provide up-to-date consensus recommendations for use in clinical practice. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and the patient in light of all of the circumstances presented by that patient.

Rationale and design of the First Brazilian Cardiovascular Registry of Atrial Fibrillation: The RECALL study.

BACKGROUND: Atrial fibrillation (AF) is an important and growing public health problem worldwide, but data about its actual prevalence, therapeutic management, and clinical outcomes in middle- to low-income countries are scarce. DESIGN: The First Brazilian Cardiovascular Registry of Atrial Fibrillation (the RECALL study) will assess demographic characteristics and evidence-based practice of a representative sample of patients with AF in Brazil. The prospective, multicenter registry has a planned sample size of around 5,000 patients at approximately 80 sites. Eligibility criteria include age >18 years and permanent, paroxysmal, or persistent AF documented by electrocardiogram, 24-hour Holter monitoring, or device interrogation. Patients will be followed up through 1 year after enrollment. Information on laboratory tests, echocardiographic data, medication use, and clinical outcomes will be obtained. Various aspects of the population will be described, including demographic characteristics; antithrombotic therapies; antiarrhythmic agents; level of control of international normalized ratio (by average time within the therapeutic range) among patients using vitamin K antagonists; rates of warfarin discontinuation; outcomes such as death, stroke, systemic embolism, and major bleeding within 1 year after enrollment in the study; and rates of electrical cardioversion, percutaneous ablation of AF, ablation of the atrioventricular junction, and pacemaker/cardioverter-defibrillator implantation. SUMMARY: RECALL is the first prospective, multicenter registry of AF in Brazil. This study will provide important information about demographics, practice patterns, treatments, and associated outcomes in patients with AF. The results of this registry will also allow Brazilian data to be put in perspective with other AF registries across the world and provide opportunities to improve care of patients with AF in Brazil.

GH indirectly enhances the regeneration of transgenic zebrafish fins through IGF2a and IGF2b.

The somatotropic axis, composed essentially of the growth hormone (GH) and insulin-like growth factors (IGFs), is the main regulator of somatic growth in vertebrates. However, these protein hormones are also involved in various other major physiological processes. Although the importance of IGFs in mechanisms involving tissue regeneration has already been established, little is known regarding the direct effects of GH in these processes. In this study, we used a transgenic zebrafish (Danio rerio) model, which overexpresses GH from the beta-actin constitutive promoter. The regenerative ability of the caudal fin was assessed after repeated amputations, as well as the expression of genes related to the GH/IGF axis. The results revealed that GH overexpression increased the regenerated area of the caudal fin in transgenic fish after the second amputation. Transgenic fish also presented a decrease in gene expression of the GH receptor (ghrb), in opposition to the increased expression of the IGF1 receptors (igf1ra and igf1rb). These results suggest that transgenic fish have a higher sensitivity to IGFs than to GH during fin regeneration. With respect to the different IGFs produced locally, a decrease in igf1a expression and a significant increase in both igf2a and igf2b expression was observed, suggesting that igf1a is not directly involved in fin regeneration. Overall, the results revealed that excess GH enhances fin regeneration in zebrafish through igf2a and igf2b expression, acting indirectly on this major physiological process.

Expression profile of IGF paralog genes in liver and muscle of a GH-transgenic zebrafish.

The objective of this study was to investigate the relationship between IGFs produced in the liver and skeletal muscle with muscle hypertrophy previously observed in a line of GH-transgenic zebrafish. In this sense, we evaluated the expression of genes related to the IGF system in liver and muscle of transgenics, as well as the main intracellular signaling pathways used by GH/IGF axis. Our results showed an increase in expression of igf1a, igf2a, and igf2b genes in the liver. Moreover, there was a decrease in the expression of igf1ra and an increase in muscle igf2r of transgenics, indicating a negative response of muscle tissue with respect to excess circulating IGFs. Muscle IGFs expression analyses revealed a significant increase only for igf2b, accompanied by a parallel induction of igfbp5a gene. The presence of IGFBP5a may potentiate the IGF2 action in muscle cells differentiation. Regarding JAK/STAT-related genes, we observed an alteration in the expression profile of both stat3 and stat5a in transgenic fish liver. No changes were observed in the muscle, suggesting that both tissues respond differently to GH-transgenesis. Western blotting analyses indicated an imbalance between the phosphorylation levels of the proliferative (MEK/ERK) and hypertrophic (PI3K/Akt) pathways, in favor of the latter. In summary, the results of this study suggest that the hypertrophy caused by GH-transgenesis in zebrafish may be due to circulating IGFs produced by the liver, with an important participation of muscle IGF2b. This group of IGFs appears to be favoring the hypertrophic intracellular pathway in muscle tissue of transgenic zebrafish.

OCT4 mutations in human erythroleukemic cells: implications for multiple drug resistance (MDR) phenotype.

The OCT4 transcription factor is a crucial stem cells marker and it has been related to the cancer stem cells concept. Moreover, it has also been associated to the multiple drug resistance (MDR) phenotype. Our first results pointed out a straight relation between OCT4 and ABC transporters in K562-derivative MDR (Lucena) cells. Sequencing of ABC promoters did not reveal any mutation that could explain the differential expression of OCT4 in Lucena cells. Furthermore, sequencing of the homeobox domain region from the OCT4 gene isolated from both cell lines evinced, for the first time, that this transcription factor is a target of mutations and might be related to the MDR phenotype. The encountered mutations implied in several amino acids substitutions in both cell lines. K562 had seven amino acids substituted (three of them exclusive), while Lucena had 13 substitutions (nine of them exclusive). In addition, an in silico search for phosphorylation motifs within the amino acid stretch compared showed that human normal OCT4 has seven potential phosphorylation motifs. However, K562 has lost one phosphorylation motif and Lucena two of them. These findings bring OCT4 as an important target for cancer treatment, especially those resistant to chemotherapy.

Effects of somatotrophic axis (GH/GHR) double transgenesis on structural and molecular aspects of the zebrafish immune system.

The development of growth hormone (GH) transgenic fish has been shown to be a promising method to improve growth rates. However, the role of GH is not restricted only to processes involved in growth. Several others physiological processes, including immune function, are impaired due to GH imbalances. Given the importance of generating GH transgenic organisms for aquaculture purposes, it is necessary to develop strategies to reduce or compensate for the collateral effects of GH. We hypothesized that the generation of double transgenic fish that overexpress GH and growth hormone receptor (GHR) in the skeletal muscle could be a possible alternative to compensate for the deleterious effects of GH on the immune system. Specifically, we hypothesized that increased GHR amounts in the skeletal muscle would be able to reduce the level of circulating GH, attenuating the GH signaling on the immune cells while still increasing the growth rate. To test this hypothesis, we evaluated the size of the immune organs, T cell content in the thymus and head kidney, and expression of immune-related genes in double-transgenic fish. Contrary to our expectations, we found that the overexpression of GHR does not decrease the deleterious effect of GH excess on the size of the thymus and head kidney, and in the content of CD3(+) and CD4(+) cells in the thymus and head kidney. Unexpectedly, the control GHR transgenic group showed similar impairments in immune system parameters. These results indicate that GHR overexpression does not reverse the impairments caused by GH and, in addition, could reinforce the damage to the immune functions in GH transgenic zebrafish.

Food intake and appetite control in a GH-transgenic zebrafish.

The biological actions of growth hormone (GH) are pleiotropic, including growth promotion, energy mobilization, gonadal development, appetite, and social behavior. The regulatory network for GH is complex and includes many central and peripheral endocrine factors as well as that from the environment. It is known that GH transgenesis results in increased growth, food intake, and consequent metabolic rates in fishes. However, the manner in which GH transgenesis alters the energetic metabolism in fishes has not been well explored. In order to elucidate these consequences, we examined the effect of GH overexpression on appetite control mechanisms in a transgenic zebrafish (Danio rerio) model. To this, we analyzed feeding behavior and the expression of the main appetite-related genes in two different feeding periods (fed and fasting) in non-transgenic (NT) and transgenic (T) zebrafish as well as glycaemic parameters of them. Our initial results have shown that NT males and females present the same feeding behavior and expression of main appetite-controlling genes; therefore, the data of both sexes were properly grouped. Following grouped data analyses, we compared the same parameters in NT and T animals. Feeding behavior results have shown that T animals eat significantly more and faster than NT siblings. Gene expression results pointed out that gastrointestinal (GT) cholecystokinin has a substantial contribution to the communication between peripheral and central control of food intake. Brain genes expression analyses revealed that T animals have a down-regulation of two strong and opposite peptides related to food intake: the anorexigenic proopiomelanocortin (pomc) and the orexigenic neuropeptide Y (npy). The down-regulation of pomc in T when compared with NT is an expected result, since the decrease in an anorexigenic factor might keep the transgenic fish hungry. The down-regulation of npy seemed to be contradictory at first, but if we consider the GH's capacity to elevate blood glucose, and that NPY is able to respond to humoral factors like glucose, this down-regulation makes sense. In fact, our last experiment showed that transgenics presented elevated blood glucose levels, confirming that npy might responded to this humoral factor. In conclusion, we have shown that GT responds to feeding status without interference of transgenesis, whereas brain responds to GH transgenesis without any effect of treatment. It is clear that transgenic zebrafish eat more and faster, and it seems that it occurs due to pomc down-regulation, since npy might be under regulation of the humoral factor glucose.

Impairment of the immune system in GH-overexpressing transgenic zebrafish (Danio rerio).

Growth hormone (GH) is an important regulator of immune functions in vertebrates, and it has been intensively reported a series of stimulatory actions of this hormone over on the immune system. Within aquaculture, overexpression of GH has been considered a promising alternative for promoting higher growth rates in organisms of commercial interest. Considering the various pleiotropic effects of GH, there are still few studies that aim to understand the consequences of the excess of GH on the physiological systems. In this context, our goal was to present the effects of the overexpression of GH on immune parameters using a model of zebrafish (Danio rerio) that overexpress this hormone. The results showed that GH transgenic zebrafish had 100% of mortality when immunosuppressed with dexamethasone, revealing a prior weakening of the immune system in this lineage. Morphometric analysis of thymus and head kidney revealed a reduction in the area of these structures in transgenic zebrafish. Moreover, the phenotypic expression of CD3 and CD4 thymocytes was also depreciated in transgenic zebrafish. Furthermore, a decrease was noted in the expression of genes RAG-1 (60%), IKAROS (50%), IL-1ß (55%), CD4 (60%) and CD247 (40%), indicating that development parameters, of innate and acquired immunity, are being harmed. Based on these results, it can be concluded that the excess of GH impairs the immune functions in GH transgenic zebrafish, indicating that the maintenance of normal levels of this hormone is essential for the functioning of immunological activities.

BMP2 rs1005464 is associated with mandibular condyle size variation.

This study aimed to evaluate the association between single nucleotide polymorphisms (SNPs) in endochondral development-related genes and mandibular condyle shape, size, volume, and symmetry traits. Cone-beam Computed Tomographies and genomic DNA from 118 individuals were evaluated (age range: 15-66 years). Data from twelve 3D landmarks on mandibular condyles were submitted to morphometric analyses including Procrustes fit, principal component analysis, and estimation of centroid sizes and fluctuating asymmetry scores. Condylar volumes were additionally measured. Seven SNPs across BMP2, BMP4, RUNX2 and SMAD6 were genotyped. Linear models were fit to evaluate the effect of the SNPs on the mandibular condyles' quantitative traits. Only the association between BMP2 rs1005464 and centroid size remained significant after adjusting to account for the false discovery rate due to multiple testing. Individuals carrying at least one A allele for this SNP showed larger condylar size than common homozygotes GG (ß = 0.043; 95% CI: 0.014-0.071; P value = 0.028). The model including BMP2 rs1005464, age and sex of the participants explained 17% of the variation in condylar size. Shape, volume, and symmetry were not associated with the evaluated SNPs. These results suggest that BMP2 rs1005464 might be associated with variation in the mandibular condyles size.