Oxidative damage is implicated in atrial fibrillation (AF), but antioxidants are ineffective therapeutically. The authors tested the hypothesis that highly reactive lipid dicarbonyl metabolites, or isolevuglandins (IsoLGs), are principal drivers of AF during hypertension. In a hypertensive murine model and stretched atriomyocytes, the dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) prevented IsoLG adducts and preamyloid oligomers (PAOs), and AF susceptibility, whereas the ineffective analog 4-hydroxybenzylamine (4-HOBA) had minimal effect. Natriuretic peptides generated cytotoxic oligomers, a process accelerated by IsoLGs, contributing to atrial PAO formation. These findings support the concept of pre-emptively scavenging reactive downstream oxidative stress mediators as a potential therapeutic approach to prevent AF.
Background: Hypertension is one of the most common risk factors for atrial fibrillation (AF), although the precise cellular and molecular mechanism(s) by which hypertension leads to AF are not well understood. Isolevuglandins (IsoLGs) are highly reactive dicarbonyl products of lipid peroxidation responsible for a major component of oxidative stress-related injury. In a mouse model of hypertension, we recently demonstrated that IsoLGs are elevated in hypertensive mouse atria and that an IsoLG scavenger reduced both IsoLG burden and AF susceptibility. Hypothesis: In this study, we hypothesized that IsoLGs can promote AF by inducing proarrhythmic metabolic and electrophysiologic (EP) changes in atrial cardiomyocytes. Methods and Results: Using standard patch clamp methods, we found significant changes in action potential properties of isolated mouse atrial cardiomyocytes exposed to IsoLGs (1μM, n=15 cells), including elevation of resting membrane potential, shortening of APD and reduction of V max . Acute IsoLG treatment led to a reduction of intracellular ATP production in atrial HL-1 cardiomyocytes, as measured by using a luminescence assay. Employing TMRM and Mitotracker Green staining for confocal and high-throughput screening (HTS) live-cell imaging assays, we also found that IsoLGs decreased mitochondrial membrane potential (compared to control, TMRM fluorescence decreased by 23%, 28%, 36% and 42%, respectively, when exposed to 0.01, 0.1, 0.5 and 1μM concentrations of IsoLG) accompanied by increased apoptosis (Cell Event Caspase-3/7 Green Detection Reagent) in a concentration-dependent manner, suggesting a prolonged mitochondrial transition pore opening. Moreover, cell metabolism assays performed using Agilent’s Seahorse XF96 extracellular flux analyzer revealed that IsoLGs exert a concentration dependent decrease in basal oxygen consumption rate and ATP production in HL-1 atrial cardiomyocytes. Conclusion: Together, these findings indicate that IsoLGs promote proarrhythmic EP and mitochondrial effects in atrial cells and thus may provide a novel therapeutic target for AF.
In summary, many of these patients have achieved a normal working capacity, but as a group there is a statistically significant reduction when compared to healthy children (p < 0.01). There was no significant difference between the group of patients who had their Mustard operation in infancy and later. As yet, there is no suggestion that the older patients, or those with the longest time interval between the operation and the exercise test, have a progressive reduction in working capacity. The decreased working capacity and moderate increase in ventilation suggests restricted cardiac output on exercise. This could be related to the abnormal heart rate response rather than indicating poor ventricular function. Equally, a restricted cardiac output on exercise may be due to inefficiency of atrial transport, tricuspid regurgitation or unmasked pulmonary vascular obstructive disease. Further studies may clarify these points. This study demonstrated that the exercise performance of asymptomatic patients 6-13 years after Mustard's operation was somewhat diminished, compared with a group of normal children. Nevertheless, these patients did lead and enjoy a normal life. Only longitudinal studies may bring the final answer to the important question: How many patients will be alive with normal or near normal exercise tolerance 40-50 years after Mustard's operation? Until such an answer is available, we believe that the Mustard operation should be used in the treatment of TGA, while the alternative techniques are carefully explored.
At the Hospital for Sick Children, London, between Jan. 1965 and Jan. 1980, 98 patients, ranging in age from 22 days to 20.8 years (mean = 29.6 months), with a clinical diagnosis of transposition of the great arteries (TGA) associated with a ventricular septal defect (VSD) found at cardiac catheterization, underwent Mustard procedure at the atrial level, whether or not associated with the VSD closure. Twenty-nine other patients, with irreversible obstructive pulmonary vascular disease in whom a "palliative" Mustard was performed, have been excluded from this report. At operation, in 8 cases, the VSD was found to have closed spontaneously during the interval between the cardiac catheterization and the surgical repair, while, in 13 patients, the VSD was judged to be too small to influence the hemodynamic results and, accordingly, was left open. In 35 cases the VSD was closed with mattress stitches buttressed with dacron pledgets and in 42 patients a dacron patch was used. The defects were accessible through the tricuspid valve in all but 10 cases. There were 24 early deaths (24%) and these did not correlate either with the year of operation or with the age at the time of operation. The mortality rate was higher in the cases who had required previous pulmonary artery banding (37%), than in those who had not (21.5%), but this difference was not statistically significant. The early results were related to the size of the VSD. In the 21 patients in whom the VSD was partially or completely closed, the early mortality was 9.5%.(ABSTRACT TRUNCATED AT 250 WORDS)
TRATAMENTO CIRURGICO E RESULTADOS NA TRANSPOSICAO DOS GRANDES VASOS Pensava-se que a incidencia de cardiopatias congenitas era baixa mas sabe-se actualmente que ocorre em cerca de 1% dos nados-vivos. A transposicao dos grandes vasos (TGV) e uma das mais frequentes cardiopatias congenitas cianosantes e e a mais comum entre as que sao mortais no 1o ano de vida. Neste artigo descrevemos a nossa experiencia com TGV e apresentamos a forma de tratamento que preferimos nas suas diversas variantes anatomicas. TGV – com Septo inter ventricular intacto : Constituem cerca de 50% dos doentes com TGV, e devem a sua sobrevivencia a uma comunicacao interauricular ou a um « foramen ovale » patente. Nelas se poe a indicacao terapeutica primaria de septostomia de Rashkind ao mesmo tempo que se realiza o primeiro cateterismo cardiaco. Se o resultado obtido e bom a crianca e seguida ate a idade de 3 ou 4 meses, altura em que se repete o cateterismo. Entre os 8 e os 12 meses de idade realiza-se entao uma intervencao cirurgica venosa intra cardiaca. Descrevem-se as alternativas de terapeutica cirurgica nestes casos. Mencionam-se os resultados e a mortalidade da operacao de Mustard descritos em varios Centros. Recentemente a operacao de Senning tem de novo passado a usar-se e os resultados obtidos sao favoravelmente comparaveis com os da operacao de Mustard. TGV+Comunicacao inter-ventricular (CIV): Em 25% dos casos de TGV existe uma CIV. Nestes doentes aparece precocemente doenca vascular pulmonar e por isso a operacao correctiva deve ser realizada mais cedo. A mortalidade operatoria em doentes com TGV+CIV e mais elevada do que nas TGV simples. TGV+CIV+Obstrucao da câmara de saida do ventriculo esquerdo : Este conjunto de malformacoes ocorre em 0,67% dos doentes com cardiopatias congenitas. No entanto, em 31%i destes doentes a obstrucao da câmara de saida do ventriculo esquerdo e significativa. As tentativas de resseccao da estenose ventricular esquerda sempre deram mortalidade alta ate que em 1969, Rastelli et aI descreveram a correccao anatomica deste conjunto de lesoes, dirigindo o sangue do ventriculo esquerdo para a aorta atraves da CIV e ligando ventriculo direito a arteria pulmonar por intermedio de um conduto valvulado. TGV+Doenca vascular pulmonar : Depois de se ter considerado esta associacao como sinonimo de inoperabilidade, passaram a obter-se bons resultados operatorios com a tecnica de operacao de Mustard paliativa, descrita por Lindesmith, em que nao se faz o encerramento da CIV. Descrevem-se em seguida os resultados a distância das correccoes cirurgicas das TGV e reveem-se as possibilidades futuras de tecnicas descritas recentemente como a operacao ou de SWITCH arterial.
Between January 1965 and December 1979, in our Unit 53 patients underwent Mustard's operation for TGA, intact ventricular septum and LVOTO. There were 35 males and 18 females, ranging in age from 27 days to 12 years (mean = 26 months) and in weight from 3.7 to 26 kg (mean = 9.6 Kg). Twenty-one infants had undergone previous palliative procedures. The degree of LVOTO was mild in 26 cases, moderate in 10 and severe in 17 patients. In 28 cases no distinct anatomical obstructions were identified. In the other 25 patients the obstruction occurred at various level and it was determined by several anatomical structures. Subvalvular fibromuscular narrowing, redundant mitral valve, valvular stenosis and subvalvular fibrous shelf were the commonest forms encountered. The LVOTO was managed in several different ways. In 28 patients in whom the gradient was judged to be functional, no surgical intervention at the level of the LVOT was attempted. In 8 cases, all operated on at the beginning of this experience, an anatomic obstruction was present but was considered too difficult to be resected and, therefore, was left untreated. In 9 patients the LVOT was inspected either through the pulmonary valve or from below, through a left ventriculotomy. Pulmonary valvotomy was carried out in 5 of these cases, resection of the subvalvular fibrous shelf in 3 and subvalvular fibromuscular tunnel resection in 1. In 6 patients a left ventricle to pulmonary artery conduit was used to bypass the obstruction. A fibromuscular tunnel type of obstruction was present in 5 of these cases, while in one the obstruction was mainly due to a redundant mitral valve.(ABSTRACT TRUNCATED AT 250 WORDS)
Introduction: Inflammation and oxidative stress are linked to multiple risk factors for atrial fibrillation (AF), and to AF itself in the setting of sterile injury (e.g. after catheter ablation or cardiac surgery). However, anti-inflammatory therapies and conventional antioxidants cause adverse effects or are ineffective to prevent AF. Highly reactive mediators of lipid peroxidation such as isolevuglandins (IsoLGs) have been identified as a major component of oxidative stress-related injury. We hypothesized that during AF promoted by cardiac inflammation, a scavenger of IsoLG will decrease AF susceptibility. Methods: We studied mice with a systemic inflammatory phenotype due to deficiency in the lymphocyte adaptor protein ( Lnk -/- ), a negative regulator of cytokine signaling. At weaning, Lnk -/- mice and their wild-type (WT) littermates received either vehicle or a potent IsoLG scavenger, 2-hydroxybenzylamine (2-HOBA), by oral administration. At age 14 weeks, animals underwent transesophageal burst pacing, echocardiography, and tissue harvest or flow cytometry to measure atrial inflammation and IsoLG-adducts. Results: Cardiac histology and echocardiography revealed no major histologic or structural abnormalities in Lnk -/- mice. Nevertheless, Lnk -/- mice demonstrated a significant increase in AF burden compared to WT controls (124.8±43.3 vs 6.8±3 sec, respectively [mean±SEM, n=28, 12; P<0.05]), as well as increased sustained AF (> 30 sec; 48.1% vs 0%; P<0.01]). Leukocyte infiltration was present in the atria of Lnk -/- mice, with a significant increase in CD3, CD19, NK1.1, and CD11b/MHCII positive cells, compared to atria from WT control mice. Furthermore, there was a 2 to 4-fold increase in IsoLG-adducts for Lnk -/- atrial immune cells positive for CD3, CD19, NK1.1 and CD11b/MHCII, compared to cells from WT atria. Lnk -/- mice treated with 2-HOBA had significantly reduced AF burden (4.7±4.5 sec, n=7; P<0.05) with a trend towards reduction in sustained AF (0%, n=7; P=0.057). Conclusions: IsoLGs play a critical role in the pathogenesis of inflammation-mediated AF, and 2-HOBA, a scavenger of IsoLGs, represents a potentially novel therapeutic strategy for AF in this clinical setting.
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