Nonantiarrhythmic drug therapy for atrial fibrillation

doi:10.1016/j.hrthm.2006.12.027

Heart Rhythm

Volume 4, Issue 3, Supplement, March 2007, Pages S88-S90

https://doi.org/10.1016/j.hrthm.2006.12.027 Get rights and content

Recent studies have begun to elucidate the molecular mechanisms that promote the generation and progressive nature of atrial fibrillation. Evidence from both experimental and clinical investigations has implicated an important role for the renin-angiotensin-aldosterone system, inflammation, and oxidative stress, with data that suggest a potential beneficial effect for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, antiinflammatory agents, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), and omega-3 polyunsaturated fatty acids. In addition, compounds that increase gap junctional conductance or that block 5-hydroxytryptamine-4 receptors have also shown promise in the experimental setting. Large-scale, prospective clinical trials will clarify the utility of these new therapeutic approaches to prevent atrial fibrillation in specific clinical settings.

Section snippets

Intracellular calcium

As in ventricular fibrillation, it is probable that AF causes intracellular Ca⁺⁺ overload, which promotes transcriptional regulation.1, 2 Although L-type Ca⁺⁺ channel blockers prevent short-term AT remodeling, they are not effective at suppressing long-term remodeling or AF recurrence.² Mibefradil, which preferentially blocks T-type Ca⁺⁺ channels, reduces remodeling in prolonged AT, but this drug is no longer marketed in the United States, which precludes clinical trials.²

The RAAS

Multiple studies support a role for RAAS activation in animal models and humans with AF.1, 2, 3, 7, 9, 10, 11 Stimulation of the RAAS promotes fibrosis and adverse ventricular remodeling as well as inflammation and oxidative stress. In addition, angiotensin II–mediated left ventricular (LV) hypertrophy creates adverse hemodynamic effects that increase atrial wall stress, further promoting AF susceptibility. Components of the RAAS (including angiotensin II and aldosterone) can be synthesized

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The importance of the neutrophil-to-lymphocyte ratio in patients with hypertrophic cardiomyopathy
2017, Revista Portuguesa de Cardiologia
Citation Excerpt :
The precise mechanism of this inflammatory pathway remains unknown; systemic inflammation can lead to infiltration of the myocardium with inflammatory cells, and this condition may cause irregular interstitial fibrosis in atrial and ventricular tissue. Relationships have been demonstrated between the development of atrial fibrillation and interleukin 8, interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) levels, and increased white blood cell (WBC) count.14 Leukocytes release pro-inflammatory cytokines, such as tumor necrosis factor-alpha, IL-6, and C-reactive protein, and can activate neutrophils to release a variety of proteolytic enzymes such as myeloperoxidase, acid phosphatase, and elastase, which facilitate increased tissue destruction and can lead to direct deleterious effects on the myocardium, resulting in irregular fibrous thickening and the formation of arrhythmia foci in the ventricles.15
Previous studies have demonstrated the predictive value of the neutrophil-to-lymphocyte ratio (NLR) in many cardiovascular disorders. The aim of this study was to assess whether NLR is associated with echocardiographic or electrocardiographic parameters, or with predicted five-year risk of sudden cardiac death (SCD), in patients with hypertrophic cardiomyopathy (HCM).
This prospective observational study included 74 controls and 97 HCM patients. Three years of follow-up results for HCM patients were evaluated.
NLR was significantly higher in patients with fragmented QRS, ventricular tachycardia, and presyncope than in those without (p=0.031, 0.030, and 0.020, respectively). NLR was significantly higher in patients whose predicted five-year risk of SCD was more than 6% and whose corrected QT interval was greater than 440 ms (p=0.022 and 0.001, respectively). It was also significantly higher in patients whose left ventricular ejection fraction (LVEF) was <60% than in those with LVEF >60% (p=0.017).
NLR was significantly higher in patients with HCM compared to the control group. A high NLR is associated with a higher five-year risk of SCD in patients with HCM.
Estudos prévios demonstraram o valor preditivo da relação neutrófilos/linfócitos (RNL) em muitas alterações cardiovasculares. O objetivo deste estudo foi avaliar se a RNL está associada a parâmetros ecocardiográficos ou eletrocardiográficos, ou com o score de risco de morte súbita cardíaca (MSC) a cinco anos em doentes com miocardiopatia hipertrófica (MCH).
Este estudo prospetivo observacional incluiu 74 controlos e 97 doentes com MCH. Foram avaliados os resultados dos doentes com MCH ao longo de três anos de seguimento.
O valor da RNL foi significativamente superior nos doentes com QRS fragmentado, com taquicardia ventricular e com pré-síncope do que nos que não revelaram esses sinais (valores p: 0,031, 0,030, 0,020, respetivamente). O valor RNL foi estatística e significativamente superior nos doentes com risco de MSC previsível a cinco anos superior a 6%, e com um intervalo QT corrigido superior a 440 ms (valores p: 0,022, 0,001, respetivamente). O valor da RNL foi significativamente superior nos doentes com fração de ejeção (FE) < 60% do que nos doentes com FE > 60% (valor p = 0,017).
A RNL foi significativamente superior nos doentes com MCH quando comparada com o grupo controlo. Uma RNL alta está associada a um score de risco de MSC elevado aos cinco anos em doentes com MCH.
Usefulness of neutrophil/lymphocyte ratio as a predictor of atrial fibrillation: A meta-analysis
2015, Archives of Medical Research
Citation Excerpt :
This involvement is evidenced by the infiltration of inflammatory cells and interstitial fibrosis found in atrial tissue from AF patients. The presence of a relationship between AF development and interleukin 8 (IL-8), interleukin 6 (IL-6), increased WBC count, hs-CRP has been shown (22–24). White blood cell (WBC) count and its subtypes have been found as markers of inflammation in various cardiovascular diseases.
Current evidence suggests that a high neutrophil/lymphocyte ratio (NLR) may increase the risk of atrial fibrillation (AF), but this association is still uncertain. The aim of the comprehensive meta-analysis was to evaluate the potential association between NLR and the risk of AF.
We conducted a systematic literature search using electronic databases (PubMed, Ovid, Embase, Cochrane Database and Web of Science) to identify the studies reporting the association between NLR and risk of AF. We searched the literature published January 2015 or earlier. We used both fixed-effects and random-effects models to calculate the overall effect estimate. An I² >50% indicates at least moderate statistical heterogeneity. A sensitivity analysis and subgroup analysis were performed to find the origin of heterogeneity.
We retrieved 11 studies involving a total of 2,766 participants. The combined odds ratio (OR) of incident AF for baseline NLR level was 1.25 (95% confidence interval [CI] 1.16–1.35) with significant heterogeneity across studies (I² = 82.7%, p <0.01) and for the post-NLR level (following CABG, RFCA and cardioversion) was 1.518 (95% CI 1.076–2.142) with significant heterogeneity across studies (I² = 93.7%, p = 0.017). We also showed an association between AF recurrence following CABG, RFCA and cardioversion and baseline NLR level (OR 1.517, 95% CI 1.108–2.079) with significant heterogeneity across studies (I² = 86.8%, p <0.01).
Our comprehensive meta-analysis suggests that the high level of NLR, whether baseline or postsurgery/procedure, is associated with the increased risk of AF recurrence/occurrence.
Is it possible to prevent atrial firrillation and its complications?
2012, Revista Medica Clinica Las Condes
La Fibrilación Auricular es una arritmia frecuente, es la causa de un número importante de accidentes cerebro-vasculares, y tiene una incidencia y prevalencia que aumenta con la edad, lo que se está constituyendo en un problema de salud pública. Existen medidas terapéuticas farmacológicas y no farmacológicas que podrían prevenir esta arritmia. Se revisa la clasificación de la FA, los factores de riesgo relacionados con la ocurrencia de la FA y el rol de fármacos como los inhibidores del sistema renina-angiotensina- aldosterona, inhibidores de aldosterona, estatinas, ácidos grasos omega 3 y beta bloqueadores en la prevención primaria y secundaria de esta arritmia. Además, se revisan los criterios para estratificar el riesgo embólico y el rol de la warfarina y de los nuevos anticoagulantes en prevenir el trombo-embolismo.
Atrial fibrillation is a common arrhythmia, is the cause of a significant number of strokes, and it has an incidence and prevalence that increases with age, which is being a public health problem. There are pharmacological and non pharmacological therapeutic tools that could prevent this arrhythmia. We review the classification of AF, the risk factors related to the occurrence of AF and the role of drugs as inhibitors of the renin-angiotensin-aldosterone, aldosterone inhibitors, statins, omega-3 fatty acids and beta blockers in primary and secondary prevention of this arrhythmia. It also reviewed the criteria to stratify the embolic risk and the role of warfarin and new anticoagulants in the prevention of thromboembolism.
Non-antiarrhythmic drug therapy for the prevention of atrial fibrillation?
2010, Annales de Cardiologie et d'Angeiologie
L’absence de bénéfice net avec les stratégies de contrôle du rythme sur celui de la fréquence cardiaque en cas de fibrillation auriculaire (FA) pourrait être liée aux effets indésirables des anti-arythmiques classiques. Parallèlement à la recherche pour améliorer l’efficacité et la sécurité d’emploi d’anti-arythmiques conventionnels, des thérapeutiques ciblant les substrats anatomiques ou le remodelage auriculaire en amont des aspects électriques de la FA ont été proposées comme nouvelle approche de traitement pharmacologique. Ces traitements potentiels de la FA incluent des classes différentes comme les inhibiteurs de l’enzyme de conversion de l’angiotensine (IEC), les antagonistes des récepteurs à l’angiotensine 2 (ARA2), les statines, les acides gras poly insaturés ou les corticostéroïdes. Sur la base de données expérimentales, des études cliniques ont apporté des informations sur le potentiel de ces traitements sur différentes populations de patients. En cas d’insuffisance cardiaque ou d’hypertension, les résultats paraissent suffisants pour justifier l’utilisation des IEC ou des ARA2 afin de diminuer le risque de FA, en plus du bénéfice clinique déjà établi par ailleurs. De même, il est probable que l’utilisation de statines lorsqu’elles ont une indication reconnue soit associée à un bénéfice en terme de prévention de la FA. Néanmoins, dans la plupart des situations cliniques, ces données semblent insuffisantes pour justifier des modifications thérapeutiques individuelles majeures et des grands essais contrôlés randomisés avec des critères d’évaluation pertinents restent nécessaires. Leurs résultats permettraient de mieux comprendre certains des mécanismes complexes aboutissant à la FA et de mieux quantifier le rapport bénéfice/risque de ces nouvelles approches thérapeutiques.
In atrial fibrillation (AF), the absence of a clear benefit of a rhythm-control strategy over a rate-control strategy seen in recent trials may be due to the fact that many of the usual antiarrhythmic strategy have significant weaknesses. Besides research efforts to improve the efficacy and safety of conventional antiarrhythmic agents, therapies directed ‘upstream’of the electrical aspects of AF, towards the underlying anatomical substrate and atrial remodelling, have been proposed as new pharmacological therapeutic approaches. Potential upstream therapies for AF comprise a variety of agents such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), statins, N-3 polyunsaturated fatty acids and steroids. On the basis of experimental data, clinical studies have provided information on the potential of upstream therapy for the prevention of AF across a broad spectrum of cardiovascular patient groups. In patients with heart failure or hypertension, data are sufficient to support the use of ACEI or ARB as treatment that may decrease the risk of AF beyond their other beneficial effects. Similarly, it is highly possible that the use of statin in patients with a recognized indication may be associated with a benefit against AF. However, in most clinical settings, the evidence appears to be insufficient to drive changes in therapy management per se, and large-scale, randomized controlled trials with adequately defined endpoints are still needed. The results from these trials may help to understand the complex mechanisms that lead to AF, and may clarify the benefit-to-risk ratio of these new therapeutic approaches.
Use of vitamins C and E as a prophylactic therapy to prevent postoperative atrial fibrillation
2010, International Journal of Cardiology
Oxidative stress has been strongly involved in the underlying mechanism of atrial fibrillation, particularly in the arrhythmia occurring in patients undergoing cardiac surgery with extracorporeal circulation (postoperative atrial fibrillation). The ischemia/reperfusion injury thus occurring in the myocardial tissue contributes to the development of tissue remodeling, thought to be responsible for the functional heart impairment. Consequently, structural changes due to the cardiac tissue biomolecules attack by reactive oxygen and/or nitrogen species could account for functional changes in ion channels, transporters, membrane conductance, cytosolic transduction signals, and other events, all associated with the occurrence of arrhythmic consequences. The lack of success and significant side effects of anti-arrhythmic drugs have given rise to attempts aimed to develop alternative novel pharmacologic treatments. On this line, the biological properties of the antioxidant vitamins C and E suggest that they could decrease the vulnerability of the heart to the oxidative damage. Nevertheless, very few studies to assess their anti-arrhythmic effects have been reported in humans. The clinical and experimental evidence supporting the view that the pharmacological use of antioxidant vitamins could contribute to prevent postoperative atrial fibrillation is presented.
Levosimendan May Prevent Postoperative Atrial Fibrillation Through Anti-inflammatory and Antioxidant Modulation
2009, Journal of Cardiothoracic and Vascular Anesthesia

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Nonantiarrhythmic drug therapy for atrial fibrillation

Section snippets

Intracellular calcium

The RAAS

Prog Cardiovasc Dis

Prog Cardiovasc Dis

Pharmacol Ther

Heart Rhythm

J Mol Cell Cardiol

Am Heart J

AM Heart J

J Am Coll Cardiol

Heart Rhythm

J Am Coll Cardiol

J Am Coll Cardiol

Int J Cardiol

J Thorac Cardiovasc Surg

Prog Lipid Res

Drug therapy for atrial fibrillation: where do we go from here?

Nat Rev Drug Discov

Pharmacological prevention of atrial tachycardia induced atrial remodeling as a potential therapeutic strategy

Pacing Clin Electrophysiol

Mechanisms of atrial remodeling and clinical relevance

Curr Opin Cardiol