ACTN3R577X polymorphism and long-term survival in patients with chronic heart failure

Abstract Background Previous studies have shown the occurrence of actinin-3 deficiency in the presence of the R577X polymorphism in the ACTN3 gene. Our hypothesis is that this deficiency, by interfering with the function of skeletal muscle fiber, can result in a worse prognosis in patients with chronic heart failure. Methods A prospective cohort study was conducted from 2002 to 2004. The eligibility criteria included diagnosis of chronic heart failure stage C from different etiologies. We excluded all patients with concomitant disease that could be related to poor prognosis. ACTN3 rs1815739 (R577X) polymorphism was detected by high resolution melting analysis. Survival curves were calculated with the Kaplan-Meier method and evaluated with the log-rank statistic. The relationship between the baseline variables and the composite end-point of all-cause death was assessed using a Cox proportional hazards survival model. Results A total of 463 patients were included in this study. The frequency of the ACTN3 577X variant allele was 39.0%. The LVEF mean was 45.6 ± 18.7% and the most common etiology of this study was hypertensive. After a follow-up of five years, 239 (51.6%) patients met the pre-defined endpoint. Survival curves showed higher mortality in patients carrying RX or XX genotypes compared with patients carrying RR genotype (p = 0.01). Conclusion R577X polymorphism in the ACTN3 gene was independently associated with worse survival in patients with chronic heart failure. Further studies are necessary to ensure its use as a marker of prognosis for this syndrome

Incremental value of B-type natriuretic peptide for early risk prediction of infective endocarditis

SummaryBackgroundEarly and accurate risk prediction is an unmet clinical need in patients with infective endocarditis (IE). The aim of this study was to determine the value of B-type natriuretic peptide (BNP) levels obtained on admission for the prediction of in-hospital death in IE patients.MethodsBetween 2009 and 2011, consecutive patients with IE diagnosed using the revised Duke criteria and admitted to the emergency department were evaluated prospectively. BNP levels were measured on admission. Death during hospitalization was the primary endpoint.ResultsAmong 104 consecutive patients with IE and with available BNP levels, 34 (32.7%) died in hospital. BNP levels were significantly higher in patients who died as compared to survivors (709.0 pg/ml vs. 177.5 pg/ml, p<0.001). The accuracy of BNP to predict death as quantified by the area under the receiver operating characteristics curve was 0.826 (95% confidence interval (CI) 0.747–0.905). The value of BNP was additive to that provided by clinical, microbiological, and echocardiography assessment. On multivariate analysis, new heart failure (hazard ratio (HR) 2.02, 95% CI 1.15–3.57, p=0.015), sepsis (HR 2.10, 95% CI 1.25–3.55, p=0.005), Staphylococcus aureus endocarditis (HR 2.67, 95% CI 1.60–4.45, p<0.001), left ventricular ejection fraction ≤55% (HR 1.63, 95% CI 1.00–2.65, p=0.047), and BNP (HR 1.04, 95% CI 1.02–1.06, p<0.001) were independent predictors of in-hospital mortality.ConclusionAmong patients with IE, BNP levels obtained on admission provide incremental value for early and accurate risk prediction

Biomarkers for prediction of mortality in left-sided infective endocarditis

Background: Evidence regarding biomarkers for risk prediction in patients with infective endocarditis (IE) is limited. We aimed to investigate the value of a panel of biomarkers for the prediction of in-hospital mortality in patients with IE. Methods: Between 2016 and 2018, consecutive IE patients admitted to the emergency department were prospectively included. Blood concentrations of nine biomarkers were measured at admission (D0) and on the seventh day (D7) of antibiotic therapy: C-reactive protein (CRP), sensitive troponin I (s-cTnI), procalcitonin, B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin 6 (IL6), tumor necrosis factor α (TNF-α), proadrenomedullin, alpha-1-acid glycoprotein, and galectin 3. The primary endpoint was in-hospital mortality. Results: Among 97 patients, 56% underwent cardiac surgery, and in-hospital mortality was 27%. At admission, six biomarkers were independent predictors of in-hospital mortality: s-cTnI (OR 3.4; 95%CI 1.8–6.4; P < 0.001), BNP (OR 2.7; 95%CI 1.4–5.1; P = 0.002), IL-6 (OR 2.06; 95%CI 1.3–3.7; P = 0.019), procalcitonin (OR 1.9; 95%CI 1.1–3.2; P = 0.018), TNF-α (OR 1.8; 95%CI 1.1–2.9; P = 0.019), and CRP (OR 1.8; 95%CI 1.0–3.3; P = 0.037). At admission, S-cTnI provided the highest accuracy for predicting mortality (area under the ROC curve: s-cTnI 0.812, BNP 0.727, IL-6 0.734, procalcitonin 0.684, TNF-α 0.675, CRP 0.670). After 7 days of antibiotic therapy, BNP and inflammatory biomarkers improved their performance (s-cTnI 0.814, BNP 0.823, IL-6 0.695, procalcitonin 0.802, TNF-α 0.554, CRP 0.759). Conclusion: S-cTnI concentration measured at admission had the highest accuracy for mortality prediction in patients with IE

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Dementia in Latin America : paving the way towards a regional action plan

Regional challenges faced by Latin American and Caribbean countries (LACs) to fight dementia, such as heterogeneity, diversity, political instabilities, and socioeconomic disparities, can be addressed more effectively grounded in a collaborative setting based on the open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking and translational research) and align them to current global strategies to translate regional knowledge into actions with transformative power. Then, by characterizing genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions and mapping these to the above challenges, we provide the basic mosaics of knowledge that will pave the way towards a KtAF. We describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Evaluation of probability of death in patients with infective endocarditis

Foram estudados 300 episódios de endocardite infecciosa (EI) em 288 pacientes acompanhados no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de outubro de 1978 a agosto de 1986, com o intuito de avaliar a probabilidade de óbito e assim identificar os pacientes sob maior risco de evolução desfavorável. As idades dos pacientes variaram entre 0,2 a 78 (média de 30, desvio padrão de 16,06) anos, correspondentes a pacientes do sexo masculino em 185 (62%) episódios e feminino em 115 (38%). Procedeu-se a análise univariada (testes de qui quadrado e exato de Fischer, análise de variância) para se identificar variáveis cujas distribuições diferissem quanto a mortalidade, para em seguida realizar a análise multivariada com o emprego de regressão logística, a fim de estimar a probabilidade de óbito. Para isso, foi desenvolvido um modelo estatístico e aplicado a casuística e, a casos hipotéticos, para o estudo conceitual. Não houve diferença de distribuição significativa quanto a mortalidade em relação a idade, sexo, tempo decorrido entre o início dos sintomas e a hospitalização, presença de antecedente de manipulação possível de induzir a bacteriemia, informação de lesão cutânea na história clínica, uso prévio de antimicrobiano, presença de petéquias, esplenomegalia, dimensão da área cardíaca na radiografia de tórax, presença de vegetação no ecocardiograma, duração da antibioticoterapia pre-operatória, portadores de aneurisma micótico, embolia arterial sistêmica, infecção em câmaras cardíacas direitas em relação à infecção de câmaras cardíacas esquerdas, infecção em prótese valvar antes ou depois de quatro meses de seu implante, infecção em prótese aórtica em relação à infecção de prótese mitral, prótese única em relação à dupla prótese, velocidade de eritrossedimentação, taxa de hemoglobina no sangue, taxas de gamaglobulina e creatinina séricas. Houve diferença significativa quanto à mortalidade considerando-se o estado cardíaco anterior à EI, a localização da EI, os agentes etiológicos, a alteração no exame do fundo de olho, o número de complicações, a taxa de mucoproteína e albumina séricas e a taxa de leucócitos do sangue, os portadores de infecção em prótese valvar em relação à infecção em estrutura natural. Na análise multivariada foram empregados o estado cardíaco anterior à EI (portadores de valvopatia, de prótese valvar cardíaca, de cardiopatias congênitas, e pacientes sem evidência de cardiopatia prévia), o agente etiológico [estreptococos, Staphylococcus aureus, outras bactérias (incluindo-se as bactérias gram-negativas, gram-positivas excetuando-se os estreptococos e os estafilococos, e os Staphylococcus epidermis) e os portadores de EI com hemoculturas negativas], a presença ou ausência de complicações e as taxas de leucócitos do sangue, de mucoproteína e de albumina séricas. O modelo estatístico desenvolvido, que incorporou informações do estado cardíaco anterior à EI, do agente etiológico, das complicações e da taxa de leucócitos do sangue, era aplicável a 229 episódios e permitiu prever adequadamente 158 entre 173 evoluções de pacientes que receberam alta hospitalar e 27 entre 56 evoluções de enfermos que faleceram; estimar como alta hospitalar 29 pacientes que faleceram e como óbito 15 pacientes que receberam alta hospitalar, classificando corretamente 185 dos 229 episódios. Aplicado a pacientes hipotéticos dos diferentes subgrupos considerados na análise o modelo demonstra, com base em nossa experiência, que a probabilidade de óbito será maior nos portadores de prótese valvar cardíaca, endocardite por microorganismos agrupados como \"outras bactérias\" (bactérias gram-negativas, Staphylococcus epidermidis, e outras bactérias gram positivas excetuando-se estafilococos e estreptococos) e por Staphylococcus aureus, na presença de complicações. À presença de complicações foi a variável que exerceu maior influência na probabilidade de óbito; a sua ausência minimiza sobremaneira essa probabilidade qualquer que seja o estado cardíaco anterior à EI e o agente etiológico. Nossos dados permitem sugerir que considerando de modo simultâneo e conjunto o estado cardíaco anterior à EI, o agente etiológico, a presença ou ausência de complicações e a taxa de leucócitos do sangue contribuem na avaliação prognóstica em portadores de EI. Entre essas variáveis, a participação da presença de complicações e a mais ressaltada. Na ausência de complicações a probabilidade de óbito reduz-se acentuadamente.In order to assess the probability of death in the course of infective endocarditis we studied 300 episodes involving 288 patients, followed from October 1978 up to August 1986. The ages ranged from 0.2 to 78 (mean 30, standard deviation 16.06) years; 185 (62%) episodes occurred in male patients and 115 (38%) in female patients. As a first step we tested several variables against mortality through univariated analysis (chi square test, Fisher\'s exact test, analysis of variance). The variables showing significant differences in the univariated test were then submitted to multivariate analysis (logistic regression), to develop a statistical model to assess the contribution of each of the selected variable to the probability expression and to identify the probability of death for each patient. There was no significant difference in mortality related to age, sex, time elapsed between onset of symptoms and hospital admission, previous manipulation usually associated with bacteremia, information of cutaneous lesions, previous antimicrobial therapy, petechiae, splenomegaly, cardiac dimensions on chest roentgenogram, vegetations detected on echocardiogram, pre operative antibiotic therapy, presence of my cotic aneurysm, arterial embolism, right sided vs. left sided endocarditis, erythrocyte sedimentation rate, blood hemoglobin, serum gama globulin, serum creatinin, early prosthetic valve infection vs. late prosthetic valve infection, prosthetic aortic valve vs. prosthetic mitral valve, single prosthesis vs. two prosthesis. There was significant difference in mortality related to cardiac status before the endocarditis, etiologic agent, fundoscopic abnormality on indirect ophtalmoscopy, frequency of complications. serum mucoprotein, serum albumin, blood leukocyte count, prosthetic valve endocarditis in relation to native valve endocarditis. The model developed through logistic regression included the cardiac status before the endocarditis (valvular heart disease, congenital heart disease, prosthetic heart valves or no known heart disease}, etiologic agent (streptococci, Staphylococcus aureus, other bacteria, negative blood cultures), presence of complications, blood leukocyte count. The model could be applied to 229 episodes. It detected correctly the evolution in 185 of 229 episodes, and identified 158 in 173 patients discharged from the hospital as well as 27 in 56 patients who died. There was also prevision for hospital discharge in 29 patients who died and for death in 15 patients discharged from the hospital. The probability of death is higher in patients with prosthetic heart valve, when the etiologic agent is the Staphylococcus aureus and the group of gram negative bacteria, gram positive bacteria other than streptococci and staphylococci and Staphylococcus epidermis, in the presence of complications. In conclusion, the informations provided by cardiac status before the endocarditis, etiologic agent, presence or absence of complications and blood leukocyte count may be useful in the assessment of the outcome of patients with infective endocarditis

Evaluation of probability of death in patients with infective endocarditis

Foram estudados 300 episódios de endocardite infecciosa (EI) em 288 pacientes acompanhados no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de outubro de 1978 a agosto de 1986, com o intuito de avaliar a probabilidade de óbito e assim identificar os pacientes sob maior risco de evolução desfavorável. As idades dos pacientes variaram entre 0,2 a 78 (média de 30, desvio padrão de 16,06) anos, correspondentes a pacientes do sexo masculino em 185 (62%) episódios e feminino em 115 (38%). Procedeu-se a análise univariada (testes de qui quadrado e exato de Fischer, análise de variância) para se identificar variáveis cujas distribuições diferissem quanto a mortalidade, para em seguida realizar a análise multivariada com o emprego de regressão logística, a fim de estimar a probabilidade de óbito. Para isso, foi desenvolvido um modelo estatístico e aplicado a casuística e, a casos hipotéticos, para o estudo conceitual. Não houve diferença de distribuição significativa quanto a mortalidade em relação a idade, sexo, tempo decorrido entre o início dos sintomas e a hospitalização, presença de antecedente de manipulação possível de induzir a bacteriemia, informação de lesão cutânea na história clínica, uso prévio de antimicrobiano, presença de petéquias, esplenomegalia, dimensão da área cardíaca na radiografia de tórax, presença de vegetação no ecocardiograma, duração da antibioticoterapia pre-operatória, portadores de aneurisma micótico, embolia arterial sistêmica, infecção em câmaras cardíacas direitas em relação à infecção de câmaras cardíacas esquerdas, infecção em prótese valvar antes ou depois de quatro meses de seu implante, infecção em prótese aórtica em relação à infecção de prótese mitral, prótese única em relação à dupla prótese, velocidade de eritrossedimentação, taxa de hemoglobina no sangue, taxas de gamaglobulina e creatinina séricas. Houve diferença significativa quanto à mortalidade considerando-se o estado cardíaco anterior à EI, a localização da EI, os agentes etiológicos, a alteração no exame do fundo de olho, o número de complicações, a taxa de mucoproteína e albumina séricas e a taxa de leucócitos do sangue, os portadores de infecção em prótese valvar em relação à infecção em estrutura natural. Na análise multivariada foram empregados o estado cardíaco anterior à EI (portadores de valvopatia, de prótese valvar cardíaca, de cardiopatias congênitas, e pacientes sem evidência de cardiopatia prévia), o agente etiológico [estreptococos, Staphylococcus aureus, outras bactérias (incluindo-se as bactérias gram-negativas, gram-positivas excetuando-se os estreptococos e os estafilococos, e os Staphylococcus epidermis) e os portadores de EI com hemoculturas negativas], a presença ou ausência de complicações e as taxas de leucócitos do sangue, de mucoproteína e de albumina séricas. O modelo estatístico desenvolvido, que incorporou informações do estado cardíaco anterior à EI, do agente etiológico, das complicações e da taxa de leucócitos do sangue, era aplicável a 229 episódios e permitiu prever adequadamente 158 entre 173 evoluções de pacientes que receberam alta hospitalar e 27 entre 56 evoluções de enfermos que faleceram; estimar como alta hospitalar 29 pacientes que faleceram e como óbito 15 pacientes que receberam alta hospitalar, classificando corretamente 185 dos 229 episódios. Aplicado a pacientes hipotéticos dos diferentes subgrupos considerados na análise o modelo demonstra, com base em nossa experiência, que a probabilidade de óbito será maior nos portadores de prótese valvar cardíaca, endocardite por microorganismos agrupados como \"outras bactérias\" (bactérias gram-negativas, Staphylococcus epidermidis, e outras bactérias gram positivas excetuando-se estafilococos e estreptococos) e por Staphylococcus aureus, na presença de complicações. À presença de complicações foi a variável que exerceu maior influência na probabilidade de óbito; a sua ausência minimiza sobremaneira essa probabilidade qualquer que seja o estado cardíaco anterior à EI e o agente etiológico. Nossos dados permitem sugerir que considerando de modo simultâneo e conjunto o estado cardíaco anterior à EI, o agente etiológico, a presença ou ausência de complicações e a taxa de leucócitos do sangue contribuem na avaliação prognóstica em portadores de EI. Entre essas variáveis, a participação da presença de complicações e a mais ressaltada. Na ausência de complicações a probabilidade de óbito reduz-se acentuadamente.In order to assess the probability of death in the course of infective endocarditis we studied 300 episodes involving 288 patients, followed from October 1978 up to August 1986. The ages ranged from 0.2 to 78 (mean 30, standard deviation 16.06) years; 185 (62%) episodes occurred in male patients and 115 (38%) in female patients. As a first step we tested several variables against mortality through univariated analysis (chi square test, Fisher\'s exact test, analysis of variance). The variables showing significant differences in the univariated test were then submitted to multivariate analysis (logistic regression), to develop a statistical model to assess the contribution of each of the selected variable to the probability expression and to identify the probability of death for each patient. There was no significant difference in mortality related to age, sex, time elapsed between onset of symptoms and hospital admission, previous manipulation usually associated with bacteremia, information of cutaneous lesions, previous antimicrobial therapy, petechiae, splenomegaly, cardiac dimensions on chest roentgenogram, vegetations detected on echocardiogram, pre operative antibiotic therapy, presence of my cotic aneurysm, arterial embolism, right sided vs. left sided endocarditis, erythrocyte sedimentation rate, blood hemoglobin, serum gama globulin, serum creatinin, early prosthetic valve infection vs. late prosthetic valve infection, prosthetic aortic valve vs. prosthetic mitral valve, single prosthesis vs. two prosthesis. There was significant difference in mortality related to cardiac status before the endocarditis, etiologic agent, fundoscopic abnormality on indirect ophtalmoscopy, frequency of complications. serum mucoprotein, serum albumin, blood leukocyte count, prosthetic valve endocarditis in relation to native valve endocarditis. The model developed through logistic regression included the cardiac status before the endocarditis (valvular heart disease, congenital heart disease, prosthetic heart valves or no known heart disease}, etiologic agent (streptococci, Staphylococcus aureus, other bacteria, negative blood cultures), presence of complications, blood leukocyte count. The model could be applied to 229 episodes. It detected correctly the evolution in 185 of 229 episodes, and identified 158 in 173 patients discharged from the hospital as well as 27 in 56 patients who died. There was also prevision for hospital discharge in 29 patients who died and for death in 15 patients discharged from the hospital. The probability of death is higher in patients with prosthetic heart valve, when the etiologic agent is the Staphylococcus aureus and the group of gram negative bacteria, gram positive bacteria other than streptococci and staphylococci and Staphylococcus epidermis, in the presence of complications. In conclusion, the informations provided by cardiac status before the endocarditis, etiologic agent, presence or absence of complications and blood leukocyte count may be useful in the assessment of the outcome of patients with infective endocarditis