RESUMO
Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and elderly. Most adjuvants are formulated with injectable vaccines. However, an intranasal route of vaccination may induce mucosal and systemic immune responses for enhancing protective immunity in individuals and be easier to administer compared to injectable vaccines. In this study, a next generation of broadly-reactive influenza hemagglutinin (HA) vaccines were developed using the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology. These HA vaccines were formulated with Mastoparan 7 (M7-NH2) mast cell degranulating peptide adjuvant and administered intranasally to determine vaccine-induced seroconversion of antibodies against a panel of influenza viruses and protection following infection with H1N1 and H3N2 viruses in mice. Mice vaccinated intranasally with M7-NH2-adjuvanted COBRA HA vaccines had high HAIs against a panel of H1N1 and H3N2 influenza viruses and were protected against both morbidity and mortality, with reduced viral lung titers, following challenge with an H1N1 influenza virus. Additionally, M7-NH2 adjuvanted COBRA HA vaccines induced Th2 skewed immune responses with robust IgG and isotype antibodies in the serum and mucosal lung lavages. Overall, this intranasally delivered M7-NH2 -adjuvanted COBRA HA vaccine provides effective protection against drifted H1N1 and H3N2 viruses.
Assuntos
Adjuvantes Imunológicos , Administração Intranasal , Anticorpos Antivirais , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Animais , Camundongos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/imunologia , Feminino , Camundongos Endogâmicos BALB C , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Adjuvantes de Vacinas/administração & dosagemRESUMO
AIMS: Heart failure (HF) elicits a pro-inflammatory state, which is associated with impaired clinical outcomes, but no anti-inflammatory therapies have demonstrated a clinical benefit yet. Inflammatory pathways related with the interleukin-1 axis are overactivated during episodes of acute HF. Colchicine, an anti-inflammatory drug with proven benefits in acute pericarditis and ischaemic heart disease, may target this inflammatory response. This study aims to assess the efficacy of colchicine in acute HF patients. METHODS: COLICA is a multicentre, randomized, double-blind, placebo-controlled trial enrolling 278 patients across 12 sites. Patients presenting with acute HF, clinical evidence of congestion requiring ≥40 mg of intravenous furosemide and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >900 pg/ml, are eligible for participation. Patients are enrolled irrespective of left ventricular ejection fraction, HF type (new-onset or not) and setting (hospital or outpatient clinic). Patients are randomized 1:1 within the first 24 h of presentation to either placebo or colchicine, with an initial loading dose of 2 mg followed by 0.5 mg every 12 h for 8 weeks (reduced dose if <70 kg, >75 years old, or glomerular filtration rate <50 ml/min/1.73 m2). The primary efficacy endpoint is the time-averaged proportional change in NT-proBNP concentrations from baseline to week 8. Key secondary and exploratory outcomes include symptoms, diuretic use, worsening HF episodes, related biomarkers of cardiac stress and inflammation, total and cardiovascular readmissions, mortality and safety events. CONCLUSION: COLICA will be the first randomized trial testing the efficacy and safety of colchicine for acute HF.
RESUMO
Adjuvants enhance immune responses stimulated by vaccines. To date, many seasonal influenza vaccines are not formulated with an adjuvant. In the present study, the adjuvant Advax-SM™ was combined with next generation, broadly reactive influenza hemagglutinin (HA) vaccines that were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. Advax-SM™ is a novel adjuvant comprising inulin polysaccharide and CpG55.2, a TLR9 agonist. COBRA HA vaccines were combined with Advax-SM™ or a comparator squalene emulsion (SE) adjuvant and administered to mice intramuscularly. Mice vaccinated with Advax-SM™ adjuvanted COBRA HA vaccines had increased serum levels of anti-influenza IgG and IgA, high hemagglutination inhibition activity against a panel of H1N1 and H3N2 influenza viruses, and increased anti-influenza antibody secreting cells isolated from spleens. COBRA HA plus Advax-SM™ immunized mice were protected against both morbidity and mortality following viral challenge and, at postmortem, had no detectable lung viral titers or lung inflammation. Overall, the Advax-SM™-adjuvanted COBRA HA formulation provided effective protection against drifted H1N1 and H3N2 influenza viruses.
RESUMO
A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.
Assuntos
Cricetulus , Canal de Sódio Disparado por Voltagem NAV1.5 , Linhagem , Penetrância , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Humanos , Animais , Células CHO , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Espanha , Mutação com Perda de Função , Fenótipo , MutaçãoRESUMO
INTRODUCTION AND OBJECTIVES: Most of the complications associated with acute and symptomatic bradyarrhythmia (ASB) occur in the time from diagnosis to permanent pacemaker implantation (PPI). We aimed to evaluate the outcomes of an urgent 24/7 PPI service (PPI-24/7) for patients with ASB. METHODS: A total of 664 patients undergoing first-time PPI for ASB were prospectively assessed during 2 periods of identical length (18 months): 341 patients who underwent the procedure during working hours only (PPI-WH), and 323 patients who underwent the procedure after the implementation of the PPI-24/7 service. The primary safety endpoint was established as the cumulative 180-day incidence of complications related to the index arrhythmia and device implant. The primary efficacy endpoint was determined as the average number of hospital stays per patient. RESULTS: The PPI-24/7 period was associated with a significant shortening of the time from diagnosis to implantation (median [interquartile range]): 3hours [2-6] vs 16 [5-21]). The cumulative incidence of patients with complications at 180 days was lower in the PPI-24/7 period: 9% vs 17% (adjusted odds ratio, 0.5; P=.002), due to a significant reduction in preimplant complications: 2.5% vs 12% (P <.001). The average number of hospital stays was reduced by 2 per patient in the PPI-24/7 period (nonparametric P <.001). PPI-24/7 implants performed outside working hours (n=178) were safe, with a 180-day cumulative incidence in procedure-related complications of 3.9%. CONCLUSIONS: Among patients with ASB, PPI-24/7 was associated with a significant reduction in patient morbidity and efficient hospital resource use.
RESUMO
Calcific aortic valve disease (CAVD) and coronary artery disease (CAD) are related cardiovascular diseases in which common mechanisms lead to tissue calcification. Oxidative stress plays a key role in these diseases and there is also evidence that the redox state of serum albumin exerts a significant influence on these conditions. To further explore this issue, we used multimarker scores (OxyScore and AntioxyScore) to assess the global oxidative status in patients with CAVD, with and without CAD, also evaluating their plasma thiol levels. In addition, valvular interstitial cells were treated with reduced, oxidized, and native albumin to study how this protein and its modifications affect cell calcification. The differences we found suggest that oxidative status is distinct in CAVD and CAD, with differences in redox markers and thiol levels. Importantly, the in vitro interstitial cell model revealed that modified albumin affects cell calcification, accelerating this process. Hence, we show here the importance of the redox system in the development of CAVD, emphasizing the relevance of multimarker scores, while also offering evidence of how the redox state of albumin influences vascular calcification. These data highlight the relevance of understanding the overall redox processes involved in these diseases, opening the door to new studies on antioxidants as potential therapies for these patients.
RESUMO
Aim: This study aimed to evaluate the capacity of a genetic risk score (GRS) for coronary artery disease (CAD) independent of classical cardiovascular risk factors to assess the risk of recurrence in patients with first myocardial infarction. The secondary aim was to determine the predictive value of this GRS. Methods: We performed a meta-analysis of individual data from three studies, namely, a prospective study including 75 patients aged <55 years, a prospective study including 184 patients with a mean age of 60.5 years, and a case-control study (77 cases and 160 controls) nested in a cohort of patients with first myocardial infarction. A GRS including 12 CAD genetic variants independent of classical cardiovascular risk factors was developed. The outcome was a composite of cardiovascular mortality and recurrent acute coronary syndrome. Results: The GRS was associated with a higher risk of recurrence [hazard ratio = 1.24; 95% confidence interval (CI): 1.04-1.47]. The inclusion of the GRS in the clinical model did not increase the model's discriminative capacity (change in C-statistic/area under the curve: 0.009; 95% CI: -0.007 to 0.025) but improved its reclassification (continuous net reclassification index: 0.29; 95% CI: 0.08-0.51). Conclusion: The GRS for CAD, independent of classical cardiovascular risk factors, was associated with a higher risk of recurrence in patients with first myocardial infarction. The predictive capacity of this GRS identified a subgroup of high-risk patients who could benefit from intensive preventive strategies.
RESUMO
AIMS: Same-day discharge (SDD) is feasible after pulmonary vein isolation (PVI). We aim to compare prospectively cryoballoon (CRYO) vs. radiofrequency (RF) ablation in a systematic SDD programme. METHODS AND RESULTS: We prospectively analysed the 617 scheduled PVI performed consecutively at our institution (n = 377 CRYO, n = 240 RF) from 1 April 2019 to 31 December 2022 within a systematic programme of SDD. The feasibility of SDD, the 10-day incidence of urgent/unplanned medical care after discharge (UUC-10), and the cost per procedure due to hospital resource use were studied. The 100 procedures performed during the previous year, in which patients were systematically hospitalized, were used as a control group. Same-day discharge was achieved in 585/617 (95%) procedures, with a significant trend towards a higher monthly SDD rate from 2019 to 2022 (P = 0.03). The frequency of SDD was similar in CRYO (356/377; 94%) vs. RF (229/240; 95%). After SDD, the UUC-10 was 66/585 (11.3%), being similar for CRYO (41/356; 11.5%) and RF (25/229; 10.9%); P = 0.8 (log-rank test). Of these, 10 patients were re-hospitalized, with an identical rate in CRYO-treated (6/356; 1.7%) and RF-treated (4/229; 1.7%) patients and owing to similar causes (4 haematomas, 4 pericarditis, and 2 symptomatic sinus node dysfunction). Same-day discharge was associated with an average savings per procedure of 63% (P < 0.001), but no differences were found between the CRYO and RF (P = 0.8). CONCLUSION: In a systematic SDD programme, feasibility (95%, increasing over time), safety (11% UUC-10, 1.7% re-hospitalizations), and savings (63% per procedure) were similar for CRYO and RF ablation procedures.
Assuntos
Técnicas de Ablação , Veias Pulmonares , Ablação por Radiofrequência , Humanos , Alta do Paciente , Veias Pulmonares/cirurgia , HospitalizaçãoRESUMO
BACKGROUND: Disease progression in patients with mild-to-moderate aortic stenosis is heterogenous and requires periodic echocardiographic examinations to evaluate severity. OBJECTIVES: This study sought to explore the use of machine learning to optimize aortic stenosis echocardiographic surveillance automatically. METHODS: The study investigators trained, validated, and externally applied a machine learning model to predict whether a patient with mild-to-moderate aortic stenosis will develop severe valvular disease at 1, 2, or 3 years. Demographic and echocardiographic patient data to develop the model were obtained from a tertiary hospital consisting of 4,633 echocardiograms from 1,638 consecutive patients. The external cohort was obtained from an independent tertiary hospital, consisting of 4,531 echocardiograms from 1,533 patients. Echocardiographic surveillance timing results were compared with the European and American guidelines echocardiographic follow-up recommendations. RESULTS: In internal validation, the model discriminated severe from nonsevere aortic stenosis development with an area under the receiver-operating characteristic curve (AUC-ROC) of 0.90, 0.92, and 0.92 for the 1-, 2-, or 3-year interval, respectively. In external application, the model showed an AUC-ROC of 0.85, 0.85, and 0.85, for the 1-, 2-, or 3-year interval. A simulated application of the model in the external validation cohort resulted in savings of 49% and 13% of unnecessary echocardiographic examinations per year compared with European and American guideline recommendations, respectively. CONCLUSIONS: Machine learning provides real-time, automated, personalized timing of next echocardiographic follow-up examination for patients with mild-to-moderate aortic stenosis. Compared with European and American guidelines, the model reduces the number of patient examinations.
Assuntos
Estenose da Valva Aórtica , Humanos , Seguimentos , Valor Preditivo dos Testes , Estenose da Valva Aórtica/diagnóstico por imagem , Ecocardiografia/métodos , Progressão da Doença , Índice de Gravidade de Doença , Valva Aórtica/diagnóstico por imagemRESUMO
Background: Determining the mechanism of supraventricular tachycardias with prolongedP ventriculoatrial (VA) intervals is sometimes a challenge. Our objective is to analyse the determinants, time course and diagnostic accuracy (atypical atrioventricular nodal reentrant tachycardias [AVNRT] versus orthodromic reentrant tachycardias through an accessory pathway [ORT]) of spontaneous VA intervals variation in patients with narrow QRS tachycardias and prolonged VA. Methods: A total of 156 induced tachycardias were studied (44 with atypical AVNRT and 112 with ORT). Two sets of 10 measurements were performed for each patientafter tachycardia induction and one minute later. VA and VV intervals were determined. Results: The difference between the longest and the shortest VA interval (Dif-VA) correlates significantly with the diagnosis of atypical AVNRT (C coefficient = 0.95 and 0.85 after induction and at one minute, respectively; p < 0.001). A Dif-VA ≥ 15 ms presents a sensitivity and specificity for atypical AVNRT of 50% and 99%, respectively after induction, and of 27% and 100% one minute later. We found a robust and significant correlation between the fluctuations of VV and VA intervals in atypical AVNRTs (Coefficient Rho: 0.56 and 0.76, after induction and at one minute, respectively; p < 0.001 for both) but not in ORTs. Conclusions: The analysis of VA interval variability after induction and one minute later correctly discriminates atypical AVNRT from ORT in almost all cases.
RESUMO
INTRODUCTION AND OBJECTIVES: Dual antiplatelet therapy (DAPT) duration after ST-segment elevation myocardial infarction (STEMI) remains a matter of debate. METHODS: We analyzed the effect of DAPT on 5-year all-cause mortality, cardiovascular mortality, and cardiovascular readmission or mortality in a cohort of 1-year survivor STEMI patients. RESULTS: A total of 3107 patients with the diagnosis of STEMI were included: 93% of them were discharged on DAPT, a therapy that persisted in 275 high-risk patients at 5 years. Cardiovascular mortality in patients on single antiplatelet therapy vs DAPT at 5 years was 1.4% vs 3.6% (P <.01), respectively, whereas noncardiovascular mortality was 3.3% vs 5.8% (P=.049) at 5 years. Cardiovascular readmission or mortality in patients with single antiplatelet therapy vs DAPT was 11.4% vs 46.5% (P <.001). Extended DAPT was independently associated with worse 5-year all-cause mortality (HR, 2.16; 95%CI, 1.40-3.33), cardiovascular mortality (HR, 2.83; 95%CI, 1.37-5.84), and cardiovascular readmission or mortality (HR, 5.20; 95%CI, 3.96-6.82). These findings were confirmed in propensity score matching and inverse probability weighting analyses. CONCLUSIONS: Our results suggest the hypothesis that, in 1-year STEMI survivors, extending DAPT up to 5 years in high-risk patients does not improve their long-term prognosis.
Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Resultado do Tratamento , Intervenção Coronária Percutânea/métodosRESUMO
Ischemic heart disease (IHD) and type-2 diabetes mellitus (T2DM) remain major health problems worldwide and commonly coexist in individuals. Gut microbial metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), have been linked to cardiovascular and metabolic diseases. Previous studies have reported dysbiosis in the gut microbiota of these patients and the prebiotic effects of some components of the Mediterranean diet. Essential oil emulsions of savory (Satureja hortensis), parsley (Petroselinum crispum) and rosemary (Rosmarinus officinalis) were assessed as nutraceuticals and prebiotics in IHD and T2DM. Humanized mice harboring gut microbiota derived from that of patients with IHD and T2DM were supplemented with L-carnitine and orally treated with essential oil emulsions for 40 days. We assessed the effects on gut microbiota composition and abundance, microbial metabolites and plasma markers of cardiovascular disease, inflammation and oxidative stress. Our results showed that essential oil emulsions in mice supplemented with L-carnitine have prebiotic effects on beneficial commensal bacteria, mainly Lactobacillus genus. There was a decrease in plasma TMAO and an increase in fecal SCFAs levels in mice treated with parsley and rosemary essential oils. Thrombomodulin levels were increased in mice treated with savory and parsley essential oils. While mice treated with parsley and rosemary essential oils showed a decrease in plasma cytokines (INFÉ£, TNFα, IL-12p70 and IL-22); savory essential oil was associated with increased levels of chemokines (CXCL1, CCL2 and CCL11). Finally, there was a decrease in protein carbonyls and pentosidine according to the essential oil emulsion. These results suggest that changes in the gut microbiota induced by essential oils of parsley, savory and rosemary as prebiotics could differentially regulate cardiovascular and metabolic factors, which highlights the potential of these nutraceuticals for reducing IHD risk in patients affected by T2DM.
Assuntos
Diabetes Mellitus Tipo 2 , Dieta Mediterrânea , Microbioma Gastrointestinal , Isquemia Miocárdica , Óleos Voláteis , Rosmarinus , Camundongos , Animais , Prebióticos , Emulsões/farmacologia , Ácidos Graxos Voláteis/metabolismo , Óleos Voláteis/farmacologia , Carnitina/farmacologiaRESUMO
Cardiogenic shock (CS) is a condition associated with high morbidity and mortality. Our study aimed to perform a risk score for in-hospital mortality that allows for stratifying the risk of death in patients with CS.This is a retrospective analysis, which included 135 patients from a Spanish university hospital between 2011 and 2020. The Santiago Shock Score (S3) was created using clinical, analytical, and echocardiographic variables obtained at the time of admission.The in-hospital mortality rate was 41.5%, and acute coronary syndrome (ACS) was the responsible cause of shock in 60.7% of patients. Mitral regurgitation grade III-IV, age, ACS etiology, NT-proBNP, blood hemoglobin, and lactate at admission were included in the score. The S3 had good accuracy for predicting in-hospital mortality area under the receiver operating characteristic curve (AUC) 0.85 (95% confidence interval (CI) 0.78-0.90), higher than the AUC of the CardShock score, which was 0.74 (95% CI 0.66-0.83). Predictive power in a cohort of 131 patients with profound CS was similar to that of CardShock with an AUC of 0.601 (95% CI 0.496-0.706) versus an AUC of 0.558 (95% CI 0.453-0.664). Three risk categories were created according to the S3: low (scores 0-6), intermediate (scores 7-10), and high (scores 11-16) risks, with an observed mortality of 12.9%, 49.1%, and 87.5% respectively (P < 0.001).The S3 score had excellent predictive power for in-hospital mortality in patients with nonprofound CS. It could aid the initial risk stratification of patients and thus, guide treatment and clinical decision making in patients with CS.
Assuntos
Síndrome Coronariana Aguda , Choque Cardiogênico , Humanos , Choque Cardiogênico/terapia , Mortalidade Hospitalar , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/diagnóstico , PrognósticoRESUMO
SARS-Cov2 is currently causing a persistent Covid-19 pandemic, which poses a risk of causing long-term cardiovascular sequels in the population. The viral mechanism of cell infection through the angiotensin 2 converter enzyme receptor and the limited antiviral innate immune response are the suspected causes for a more frequent cardiovascular damage in SARS-Cov2 infection. Knowledge of: the appearance during acute infection of other cardiac conditions beyond the classical myocarditis and pericarditis), the long-term cardiac manifestations (persistent Covid-19), and the increased incidence of myocarditis and pericarditis after vaccination; it is of special interest in order to offer our patients best practices based on current scientific evidence.
El SARS-Cov2 está causando actualmente una pandemia sostenida de Covid-19, con el riesgo de causar secuelas cardíacas a largo plazo en la población. El temor que el SARS-Cov2 cause un daño miocárdico mayor que otros virus convencionales se basa en su mecanismo de infección de células humanas a través del receptor de la enzima convertidora de la angiotensina 2 y las defensas antivirales innatas hasta ahora reducidas contra un nuevo virus. El conocimiento de: la aparición durante la infección aguda de otras afectaciones cardiacas además de las clásicas miocarditis y pericarditis, las manifestaciones cardiacas observadas a largo plazo (Covid-19 persistente) y, la incidencia incrementada de miocarditis y pericarditis tras la vacunación; resulta de especial interés a fin de ofrecer a nuestros pacientes la mejor atención posible basada en la evidencia científica actual.