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Aims Home-based interventions for heart failure ( HF) patients might be particularly effective in middle-income countries, where social, cultural, and economic constraints limit the effectiveness of HF treatment outside the hospital environment. Methods and results HELEN-II was a randomized clinical trial conducted in Brazil designed to evaluate the clinical efficacy of a nurse-based strategy, started after discharge following an acute decompensated HF ( ADHF) admission. HELEN-II compares the efficacy of home visits and telephone reinforcement ( n = 123) with that of the conventional strategy, which is based on medical follow-up ( n = 129). The primary outcome was a composite endpoint of a first visit to the emergency department (≤24 h), a hospital readmission (>24 h), or all-cause death, assessed during the first 6 months of follow-up. Most enrolled subjects were middle-aged (62 ± 13 years) males (63%) in NYHA functional class II-III (84%) with severe LV dysfunction (mean LVEF 29.6 ± 9%). The primary composite endpoint was decreased by 27% in the interventional group (relative risk 0.73; 95% confidence interval 0.54-0.99; P = 0.049). At the end of follow-up, the rate of use of the standard-of-care HF medications was similar in both groups, except for the higher use of furosemide in the interventional group. Also, HF knowledge and self-care were significantly increased in the interventional group. Conclusions A post-discharge, nurse-led management strategy significantly decreases the morbidity of ADHF patients in the public health system of a developing middle-income country. Trial registration NCT01213875 [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Warfarin is an oral anticoagulant widely used for thromboembolic disease prophylaxis. The pharmacokinetics and pharmacodynamics of this drug vary with environmental and genetic factors. Several algorithms including genetic and non-genetic factors have been developed for different populations. These investigations have shown that polymorphisms in CYP2C9 and VKORC1 genes are related to warfarin dose variation. WHAT THIS STUDY ADDS • This study confirms that CYP2C9 and VKORC1 genes are the main predictors of warfarin dose, but there are other genes with smaller effects that can improve the algorithm for better dose prediction. • This study observed for the first time an effect of the F2 gene on warfarin dose prediction. • The inclusion for the first time of co-medication with amlodipine, carbamazepine, β-adrenoceptor blockers and diuretics refined the construction of an algorithm for dose prediction. AIMS To investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose-response and develop a model including genetic and non-genetic factors for warfarin dose prediction needed for each patient. METHODS A total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for −1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5'-nuclease assays. RESULTS The CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, −1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed. CONCLUSION The model suggested has one of the highest coefficients of determination among those described in the literature. [ABSTRACT FROM AUTHOR]

• Patients vaccinated against COVID-19 may become infected with SARS-CoV-2. • Severe heart failure can be identified after myocarditis caused by SARS-CoV-2. • Severe cardiac sequelae may be associated with reinfection and COVID-19 vaccination. Cardiac involvement in COVID-19 can range from mild damage to severe myocarditis. The precise mechanism by which COVID-19 causes myocardial injury is still unknown. Myocarditis following administration of COVID-19 vaccines, especially those based on mRNA, has also been described. However, no reports of heart failure following reinfection with SARS-CoV-2 in patients immunized with an inactivated vaccine have been identified. The patient was a 47-year-old male construction worker of African descent, with type II diabetes and a history of infection by SARS-CoV-2 in December 2020 and May 2021, confirmed by RT-PCR. He received two doses of an inactivated vaccine against COVID-19. Between the two COVID-19 episodes with positive RT-PCR, he had two episodes of bacterial lung infection. After the second episode of SARS-CoV-2 infection, he was diagnosed with severe heart failure as a sequela of myocarditis. It is essential to perform a thorough follow-up after infection with SARS-CoV-2 since, even with proper immunization, it is possible that the patient was reinfected and suffered severe cardiac sequelae as a consequence. The hypothesis of an etiology associated with the use of an inactivated vaccine against COVID-19, with a potential immune enhancement mechanism following reinfection with SARS-CoV-2, cannot be rejected. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) is an unpredictable and common mode of death in patients with heart failure (HF). Alterations in calcium handling may lead to malignant arrhythmias, resulting in SCD, and variants in calcium signaling-related genes have a significant association with SCD. Therefore, the aim of the present retrospective cohort study was to investigate the association of Ser96Ala [histidine-rich calcium-binding protein (HRC)], Ser49Gly [β1-adrenergic receptor (ADRB1)], Arg389Gly (ADRB1) and Gly1886Ser [ryanodine receptor 2 (RYR2)] polymorphisms with serious arrhythmic events and overall mortality in patients with HF with reduced left ventricular ejection fraction of non-ischemic etiology. In total, 136 patients with HF underwent physical examination, routine laboratory tests, non-invasive assessment of cardiac function and an invasive electrophysiological study. The primary outcome was the occurrence of serious arrhythmic events, set as either SCD or appropriate implantable cardioverter-defibrillator (ICD) therapy, and the secondary outcome was all-cause death. During a median follow-up of 37 months, arrhythmic events occurred in 26 patients (19%) and 41 patients (30%) died. Patients carrying the Ser allele of the Ser96Ala polymorphism in HRC had worse survival than those with the Ala/Ala genotype (log-rank P=0.043). Despite the difference in survival time, the Ala/Ala genotype was not associated with all-cause death in the regression analysis [unadjusted hazard ratio (HR)=0.17; 95% CI, 0.02-1.21]. Regarding the Ser49Gly and Arg389Gly polymorphisms in ADRB1, homozygosity for the major alleles at both sites (Ser49Ser and Arg389Arg) was associated with a two-fold increased risk of all-cause death compared with the other genotype combinations (unadjusted HR=1.98; 95% CI, 1.02-3.82). However, this association was lost after controlling for clinical covariates. No association was observed for the Gly1886Ser polymorphism in RYR2. Overall, the present findings are concurrent with the hypothesis that the Ser96Ala (HRC), Ser49Gly (ADRB1) and Arg389Gly (ADRB1) polymorphisms may be associated with HF prognosis. In particular, the Ser96Ala polymorphism might aid in risk stratification and patient selection for ICD implantation. [ABSTRACT FROM AUTHOR]

Circulating advanced glycation end products (AGE) and their receptor, RAGE, are increased after a myocardial infarction (MI) episode and seem to be associated with worse prognosis in patients. Despite the increasing importance of these molecules in the course of cardiac diseases, they have never been characterized in an animal model of MI. Thus, the aim of this study was to characterize AGE formation and RAGE expression in plasma and cardiac tissue during cardiac remodeling after MI in rats. Adult male Wistar rats were randomized to receive sham surgery (n = 15) or MI induction (n = 14) by left anterior descending coronary artery ligation. The MI group was stratified into two subgroups based on postoperative left ventricular ejection fraction: low (MIlowEF) and intermediate (MIintermEF). Echocardiography findings and plasma levels of AGEs, protein carbonyl, and free amines were assessed at baseline and 2, 30, and 120 days postoperatively. At the end of follow-up, the heart was harvested for AGE and RAGE evaluation. No differences were observed in AGE formation in plasma, except for a decrease in absorbance in MIlowEF at the end of follow-up. A decrease in yellowish-brown AGEs in heart homogenate was found, which was confirmed by immunodetection of N-ε-carboxymethyl-lysine. No differences could be seen in plasma RAGE levels among the groups, despite an increase in MI groups over the time. However, MI animals presented an increase of 50% in heart RAGE at the end of the follow-up. Despite the inflammatory and oxidative profile of experimental MI in rats, there was no increase in plasma AGE or RAGE levels. However, AGE levels in cardiac tissue declined. Thus, we suggest that the rat MI model should be employed with caution when studying the AGE-RAGE signaling axis or anti-AGE drugs for not reflecting previous clinical findings. [ABSTRACT FROM AUTHOR]

Aims MicroRNAs (miRs) regulate processes involved in both cardiac remodeling and obesity. We investigated if the expression of selected miRs in patients with heart failure (HF) is influenced by the presence of obesity. Methods In this case–control study, we compared plasma levels of miR-21, -130b, -221, -423-5p, and the -221/-130b ratio in 57 age- and gender-matched subjects: 40 HF patients (20 obese HF and 20 lean HF) and 17 lean healthy controls. Body composition was estimated by bioelectrical impedance analysis. MiRs were measured by quantitative reverse transcription-PCR. Bioinformatics analysis was performed based on miRs findings to predict their putative targets and investigate their biological function. Results HF was associated with increased miR-423-5p levels in both lean and obese patients ( P < 0.05 vs. controls) without differences between HF groups. MiR-130b levels were reduced in obese HF patients compared with HF lean ( P = 0.036) and controls ( P = 0.025). MiR-221 levels were non-significantly increased in obese HF patients. MiR-21 levels were not different among the groups. MiR-221/-130b ratio was increased in obese HF patients, and was positively associated with body fat percentage ( r = 0.43; P = 0.002), body mass index ( r = 0.44; P = 0.002), and waist circumference ( r = 0.40; P = 0.020). Computational prediction of target genes followed by functional enrichment analysis indicated a relevant role of miR-130b and miR-221 in modulating the expression of genes associated to cardiovascular and endocrine diseases, and suggested their influence in important signaling mechanisms and in numerous processes related to the circulatory and endocrine systems. Conclusions In HF patients, the presence of obesity is associated with a differential expression of selected miRs and the miR-221/-130b ratio had significant correlations with adiposity parameters. Computational target prediction analysis identified several interrelated pathways targeted by miR-130b and miR-221 with a known relationship with endocrine and cardiovascular diseases, representing potential mechanisms to be further validated. [ABSTRACT FROM AUTHOR]

There is a very well known correlation between diabetes and cardiovascular disease but many health care professionals are just concerned with glycemic control, ignoring the paramount importance of controlling other risk factors involved in the pathogenesis of serious cardiovascular diseases. This Position Statement from the Brazilian Diabetes Society was developed to promote increased awareness in relation to six crucial topics dealing with diabetes and cardiovascular disease: Glicemic Control, Cardiovascular Risk Stratification and Screening Coronary Artery Disease, Treatment of Dyslipidemia, Hypertension, Antiplatelet Therapy and Myocardial Revascularization. The issue of what would be the best algorithm for the use of statins in diabetic patients received a special attention and a new Brazilian algorithm was developed by our editorial committee. This document contains 38 recommendations which were classified by their levels of evidence (A, B, C and D). The Editorial Committee included 22 specialists with recognized expertise in diabetes and cardiology. [ABSTRACT FROM AUTHOR]

Context: Matrix metalloproteinases are involved in atherosclerosis and plaque vulnerability. Objective: To investigate serum levels and genetic polymorphisms of matrix metalloproteinases (MMPs) -1, -3 and -9 in patients submitted to carotid endarterectomy. Methods: Genetic polymorphisms were evaluated using polymerase chain reaction (PCR-RFLP); serum levels were measured using ELISA; histological sections were stained with Picrosirius Red to analyze the fibrous cap thickness, lipid core and collagen content and with hematoxylin--eosin to detect the presence of intraplaque hemorrhage. Results: MMP-9 serum levels were significantly higher in patients with a thinner fibrous cap ( p = 0.033) or acute or recent intraplaque hemorrhage ( p = 0.008) on histology, as well as in patients with previous stroke ( p = 0.009) or peripheral vascular disease ( p = 0.049). No consistent associations were observed between different MMP genotypes and fibrous cap thickness, lipid core, collagen content or intraplaque hemorrhage. Conclusions: MMP-9 serum levels were consistently associated with markers of carotid atherosclerosis and lesion vulnerability, whereas specific MMP genotypes were not. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Evaluating myocardial infarct (MI) size prior to intervention is fundamental to ensure accurate results in experimental studies. However, this assessment is performed at late time points. We aimed to evaluate whether measuring plasma cardiac troponin I (cTnI) and performing echocardiographic assessment at earlier time points can predict the occurrence of MI and infarct size. Main methods: Male Wistar rats were subjected to MI (n=40) or sham surgery (n=11). cTnI levels were measured 2 and 8h after MI. Echocardiographic evaluations were performed at 48h and 14days post-MI. After 14days, the animals were euthanized, and the hearts were removed and paraffin-embedded for Sirius red staining. Key findings: cTnI plasma levels increased in the MI group relative to the sham group at 2h after MI (7.2±9.4ng/mL vs. 2.3±1.0ng/mL; p<0.01) with a further increase at 8h after MI (22.2±13.5ng/mL vs. 1.5±1.7ng/mL; p<0.001). cTnI levels (8h) and echocardiographic outcomes correlated with histological infarct size 14days after MI (r=0.74, p<0.001 and r=0.84, p<0.001, respectively), but only echocardiography could confidently identify small, medium, and large infarcts. Additionally, using a cutoff value of 4.8ng/mL we achieved 100% specificity and 91% sensitivity in detecting MI. Significance: A cutoff value of 4.8ng/mL for cTnI could be used as early as 8h after MI to accurately identify infarct in this model, whereas echocardiographic images taken 48h after MI predicted the infarcted area 14days after MI. [Copyright &y& Elsevier]

Abstract: Objective: Exercise therapy in heart failure (HF) patients is considered safe and has demonstrated modest reduction in hospitalization rates and death in recent trials. Previous cost-effectiveness analysis described favorable results considering long-term supervised exercise intervention and significant effectiveness of exercise therapy; however, these evidences are now no longer supported. To evaluate the cost-effectiveness of supervised exercise therapy in HF patients under the perspective of the Brazilian Public Healthcare System. Methods: We developed a Markov model to evaluate the incremental cost-effectiveness ratio of supervised exercise therapy compared to standard treatment in patients with New York Heart Association HF class II and III. Effectiveness was evaluated in quality-adjusted life years in a 10-year time horizon. We searched PUBMED for published clinical trials to estimate effectiveness, mortality, hospitalization, and utilities data. Treatment costs were obtained from published cohort updated to 2008 values. Exercise therapy intervention costs were obtained from a rehabilitation center. Model robustness was assessed through Monte Carlo simulation and sensitivity analysis. Cost were expressed as international dollars, applying the purchasing-power-parity conversion rate. Results: Exercise therapy showed small reduction in hospitalization and mortality at a low cost, an incremental cost-effectiveness ratio of Int$26,462/quality-adjusted life year. Results were more sensitive to exercise therapy costs, standard treatment total costs, exercise therapy effectiveness, and medications costs. Considering a willingness-to-pay of Int$27,500, 55% of the trials fell below this value in the Monte Carlo simulation. Conclusions: In a Brazilian scenario, exercise therapy shows reasonable cost-effectiveness ratio, despite current evidence of limited benefit of this intervention. [Copyright &y& Elsevier]

Abstract: Background and purpose: To investigate early vascular changes related to carotid atherosclerotic injury post-radiation therapy (RT), we studied carotid intima–media thickness (IMT) and vascular cellular adhesion molecule (VCAM)-1 at two time-points after RT and compared local and remote irradiation effects in patients with head and neck (HNC) and prostate cancer (PC), respectively. Material and methods: We prospectively studied patients beginning RT for HNC or PC, performing carotid ultrasound before RT, early after and six months after treatment to measure carotid IMT. Blood samples were simultaneously collected to study VCAM-1 by ELISA. Results: We studied 19 patients with HNC and 24 with PC. Patients with HNC were younger (55±10years) than PC patients (68±8years). Early post-RT only HNC patients had an increase in IMT compared to baseline measurements (0.73±0.04mm vs. 0.80±0.05mm, p =0.029). On the other hand, VCAM-1 levels decreased in PC patients, remaining unchanged in HNC patients. Late post-RT (six months from previous assessment), neither IMT nor VCAM-1 values changed in both groups. Conclusion: Local and remote RT seem to exert differential early effects regarding vascular-related changes: (1) local RT seems to affect vascular structure and increase IMT and (2) RT for PC is associated with reduction in VCAM levels, suggesting systemic modulation of cancer-related factors. [Copyright &y& Elsevier]

Abstract: Aims: Bone marrow cell (BMC) therapy is thought to exert beneficial effects on the infarcted heart. We assessed cardiac function and its correlation with redox status and inflammation in cardiac tissue early post-AMI in rats treated with BMC. Main methods: Male Wistar rats (8-week-old) were randomized into four groups: Sham-operated (S); AMI; S+treatment (ST) and AMI+treatment (AMIT). Therapy with BMC was carried out immediately post-experimental left anterior coronary artery ligation induced-AMI, and assessments made 48h later. Cardiac function and morphometrics were evaluated by echocardiographyc parameters in vivo. Cardiac tissue tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured by Western Blot. Oxidative stress parameters including reduced (GSH) and oxidized (GSSG) glutathione ratio, hydrogen peroxide level, lipid and protein oxidation, superoxide dismutase, catalase and glutathione peroxidase activities were measured spectrophotometrically. Key findings: Ejection fraction was lower in infarcted groups and did not improve in BMC-treated animals: AMI (51±5%) vs. S (74±7%) and AMIT (56±10%) vs. ST groups (73±3%). Both TNF-α and IL-6 myocardial expression increased post-AMI and were reduced following BMC therapy. Nonetheless, there was a decrease in GSH/GSSG ratio in infarcted groups which was greater in BMC-treated groups: AMI (8.21±3.8) vs. S (14.61±3.4) and AMIT (2.1±0.7) vs. ST (4.7±1.5). Significance: The data suggest that BMC promoted a redox status favorable to the oxidation of the pro-inflammatory cytokines in the myocardium, exerting an anti-inflammatory-like effect. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To identify factors related to NT-proBNP levels in systemic sclerosis (SSc). Design and methods: NT-proBNP was measured in 119 patients with SSc and 20 controls. Patients with transtricuspid gradient (TG) ≥36mmHg or ≥31mmHg plus dyspnea were considered to have suspected systemic sclerosis-associated pulmonary arterial hypertension (SScPAH). Results: Increasing age, NYHA functional class, skin score, history of systemic arterial hypertension (SAH), anticentromere antibodies, diastolic dysfunction, reduced pulmonary diffusing capacity, and TG were positively associated with NT-proBNP. In multivariable linear regression, TG, age, and SAH were independently associated to NT-proBNP levels. An ROC curve analysis (with an area under the curve of 0.89, 95% CI: 0.83–0.95) suggested a cutoff of 157.8pg/mL to identify patients with suspected SScPAH, presenting a sensitivity of 100% (78.1–100) and specificity of 72.3% (62.3–80.5). Conclusions: NT-proBNP levels are related to clinical and laboratory abnormalities in SSc. The results indicate that NT-proBNP may be a useful tool in the evaluation of SScPAH. [Copyright &y& Elsevier]

Background: Several studies have demonstrated the effectiveness and cost-effectiveness of implantable cardioverter-defibrillators (ICDs) in chronic heart failure (CHF) patients. Despite its widespread use in developing countries, limited data exist on its cost-effectiveness in these settings. Objective: To evaluate the cost-effectiveness of ICD in CHF patients under the perspective of the Brazilian Public Healthcare System (PHS). Methods: We developed a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) of ICD compared with conventional therapy in patients with CHF and New York Heart Association class II and III. Effectiveness was evaluated in quality-adjusted life years (QALYs) and time horizon was 20 years. We searched MEDLINE for clinical trials and cohort studies to estimate data from effectiveness, complications, mortality, and utilities. Costs from the PHS were retrieved from national administrative databases. The model's robustness was assessed through Monte Carlo simulation and one-way sensitivity analysis. Costs were expressed as international dollars, applying the purchasing power parity conversion rate (PPP US$). Results: ICD therapy was more costly and more effective, with incremental cost-effectiveness estimates of PPP US$ 50,345/QALY. Results were more sensitive to costs related to the device, generator replacement frequency and ICD effectiveness. In a simulation resembling the MADIT-I population survival and ICD benefit, the ICER was PPP US$ 17,494/QALY and PPP US$ 15,394/life years. Conclusions: In a Brazilian scenario, where ICD cost is proportionally more elevated than in developed countries, ICD therapy was associated with a high cost-effectiveness ratio. The results were more favorable for a patient subgroup at increased risk of sudden death. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 38 year-old male who was admitted to the emergency room with fever and hemoptysis in the last 3 weeks.