The Effect of Losartan on Atrial Fibrillation and Pacemaker Dependence in Sick Sinus Syndrome (SSS) Patients Receiving Physiological Pacemaker - A Prospective, Randomized, Multicenter Study in Taiwan

Sick sinus syndrome is a common indication for permanent cardiac pacing in the community. It results from disordered impulse generation within the sinus node or impaired conduction of the impulse to the surrounding atrial tissue, thus leading to the clinical manifestation of bradycardia. In patients with SSS, AF frequently develops after pacemaker implantation,and progresses to persistent AF over long term follow up.

The occurrence of AF have been shown to be an independent predictor for major cardiovascular events in SSS patients receiving physiologic pacing. Recent prospective clinical trials have demonstrated that physiologic pacing mode reduces the risk of AF compared to single chamber ventricular pacing in patients with SSS. However, the effectiveness of physiologic pacing in reducing the incidence of AF in patients with sinus node dysfunction is still incomplete.

One recent clinical study had reported that 68% of SSS patients with a DDDR pacemaker have atrial tachyarrhythmias detected by the pacemaker devices at median 718 days follow-up. Modern pacemakers have diagnostic features that permit the detection and storage of information about the date, time of onset, and duration of multiple, sequential episodes of atrial tachyarrhythmias. Since a high percentage of AF episodes may be asymptomatic, AF "burden" have been used as surrogate end points. Prolonged P wave, shortened refractoriness, or remarkably abnormal conduction disturbances in the presence of prolonged refractoriness limit the effectiveness of standard physiologic pacing in AF prevention. This could explain, at least in part, the tendency of SSS to develop AF as a part of its natural history. Clinical electrophysiology has focused the attention on the electrophysiological and structural properties of the atrial muscle in patients with SSS: shortened and inhomogeneous refractoriness and local and regional conduction slowing, as well as prolonged intra- and inter-atrial conduction disturbances, are well described as increased interstitial fibrosis associated with the genesis of AF.

A growing body of evidences has shown that inhibition of the renin-angiotensin system can prevent the promotion of AF by suppressing the development of atrial fibrosis and structural remodeling. At present, the influence of a treatment target aiming on altered fibrosis and structural substrate in patients with SSS is not yet known. One striking result of the losartan intervention for endpoint reduction in hypertension (LIFE) study was that new-onset AF and associated stroke were significantly reduced by losartan- compared to atenolol-based antihypertensive treatment with similar blood pressure reduction.

The relative risk of new-onset AF in losartan group is 0.67 compared to atenolol group (i.e.; 33% risk reduction) Therefore, there is every reason to believe that blocking the renin-angiotensin pathway with angiotensin II type 1 receptor blockade would have positive influence on AF burden in this clinical setting. Recently, enalapril has been reported to prevent rapid atrial pacing (4 weeks)-induced interstitial fibrosis and fatty degeneration of the sinus node and to improve sinus node function in canine model, supporting the important role of structural changes of sinus node in the regulation of sinus node function. This possibility supporting therapeutic interventions using RAS inhibitors forms an attractive theoretical basis for interventions to reverse SND in such patients.