Novel Therapeutic Targets in the Management of Atrial Fibrillation
Novel Therapeutic Targets in the Management of Atrial Fibrillation
On the basis of the established relationship of RAAS, atrial fibrosis and AF, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been investigated in the context of primary and secondary AF prevention. Li et al. investigated the mechanistic effect of ACEIs on atrial remodeling in a canine ventricular tachypacing (VTP)-induced CHF model and observed that the administration of enalapril was associated with a significant decrease in tissue concentration of Ang II and also reduced the expression of the phosphorylated form of ERK. The administration of enalapril was also associated with attenuation of atrial fibrosis and conduction heterogeneity. Similar experiments by Shi et al. also investigated the role of enalapril in attenuation of atrial fibrosis in a VTP-induced CHF canine model. Atrial fibrosis was estimated with left atrium (LA) functional area shortening (FAS) (measured on transthoracic as systolic area – diastolic area/systolic area × 100), and AF inducibility was measured by the effective refractory period (ERP) and AF duration. The treatment with enalapril was observed with attenuation of atrial fibrosis which further correlated with histological evidence as well as echocardiographic measurement of FAS. Another study, by Saygili et al., observed that, in cultured atrial myocytes exposed to stretch, treatment with the ARB losartan prevented stretch-induced and consequently angiotensinmediated atrial hypertrophy. In addition, losartan also attenuated stretch-induced alterations in IK1, IKur, and Ito density and thereby prevented stretch-induced decreases in action potential duration (APD).
In addition to these salutatory effects of ACEIs/ARBs on atrial fibrosis, Chen et al. demonstrated that these agents also mitigated local Ang II-induced automaticity in isolated rabbit pulmonary vein tissue preparations and isolated cardiomyocytes. Further investigations by Shetty and DelGrande also observed that the ARBs irbesartan and valsartan reduced local Ang II-mediated norepinephrine spillover in rat atria, and thereby led to a decrease in conduction heterogeneity and inducibility of AF. Endothelial dysfunction also has a pertinent role in the pathogenesis of AF; an increased expression of adhesion molecules mediated by Ang II has been demonstrated in the fibrillating atria. Goette et al. used a rapid atrial pacing model in pigs to show treatment with ACEIs abrogated the increased expression of adhesion molecules, further supporting the role of ACE inhibition in mitigating the endothelial dysfunction.
A recently published meta-analysis of 14 clinical trials including 92,817 patients demonstrated that RAAS inhibition with an ACEI was associated with a modest decrease in the incidence of new-onset AF as compared with conventional therapy or placebo [relative risk (RR) 0.79, 95 % confidence interval (CI) 0.62–1.00, p = 0.05]. ARBs showed a similar effect in reduction of AF (RR 0.78, 95 %CI 0.66–0.92, p = 0.009). The authors of this meta-analysis acknowledged that although there was a modest degree of benefit of RAAS inhibition in the prevention of AF, the overall quality of evidence of these findings was low.
Data from the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study further support the benefit of RAAS antagonism for prevention of AF. The LIFE investigators showed that, despite similar reductions in blood pressure, patients in the losartan arm had a lower incidence of new-onset AF than patients in the atenolol arm (6.8 vs. 10.1 per 1,000 patient-years; RR 0.67, 95 % CI 0.55–0.83, p<0.001). Further analyses from this study also showed that a greater degree of regression of left ventricular hypertrophy (LVH) with the use of losartan as compared with atenolol might also be responsible for prevention of AF. A greater degree of LVH regression might contribute to greater improvement in left atrial hemodynamics and dilatation. These additional mechanisms also seem pertinent in the beneficial effects of losartan in the LIFE study. Similarly, in a broad CHF patient population, candesartan was found to be more effective in prevention of new-onset AF as compared with placebo [5.55 % patients developed new-onset AF in the candesartan arm vs. 6.74 % in the placebo arm; odds ratio (OR) 0.81, 95 % CI 0.66–0.99, p = 0.048] in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial.
Contrary to these beneficial effects of ACE inhibition particularly for prevention of new-onset AF, the results of the Gruppo Italiano per lo Studio della Sopravvivenzanell'Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial showed that valsartan did not reduce the recurrence rates for AF in patients with pre-existing cardiovascular diseases. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-I) trial investigated the impact of irbesartan on a composite of adverse cardiovascular events (stroke, MI, death from vascular causes as the primary outcome). The rate of this outcome was observed to be similar for both irbesartan and placebo [5.4 % per 100 patient-years in each; hazard ratio (HR) with irbesartan 0.99, 95 % CI 0.91–1.08, p = 0.85]. The use of irbesartan also did not have a significant effect in reducing the rate of hospitalization due to heart failure in this study. The Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) trial aimed to investigate the impact of olmesartan on the AF burden (measured by transtelephonic electrocardiograms) in patients with paroxysmal AF without any coexisting structural heart disease. During a 12-month follow-up period, the use of olmesartan was not observed to have any beneficial effect in decreasing AF burden (p = 0.77). Similarly, the secondary outcomes of the trial (quality of life, time to develop persistent AF, and rate of cardiovascular hospitalizations) were also not affected by the use of olmesartan as compared with placebo.
The lack of clinically beneficial effects with the use of ARBs for prevention of AF suppression was further substantiated by the results of the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II). In this open-labeled randomized trial, symptomatic and asymptomatic recurrences of AF episodes were assessed in patients with paroxysmal AF who received either candesartan or amlodipine. At a follow-up period of 1-year, the frequency of total AF was 2.1 ? 3.8 days/month in the candesartan group as compared with 2.4 ± 4.4 days/month in the amlodipine group, p = 0.51. The use of candesartan was also not found to have a significant effect on the frequency of cardiovascular events, left atrial dimensions and subsequent development of persistent AF.
Therapeutic Interventions Targeting the Renin-angiotensin-aldosterone System
On the basis of the established relationship of RAAS, atrial fibrosis and AF, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been investigated in the context of primary and secondary AF prevention. Li et al. investigated the mechanistic effect of ACEIs on atrial remodeling in a canine ventricular tachypacing (VTP)-induced CHF model and observed that the administration of enalapril was associated with a significant decrease in tissue concentration of Ang II and also reduced the expression of the phosphorylated form of ERK. The administration of enalapril was also associated with attenuation of atrial fibrosis and conduction heterogeneity. Similar experiments by Shi et al. also investigated the role of enalapril in attenuation of atrial fibrosis in a VTP-induced CHF canine model. Atrial fibrosis was estimated with left atrium (LA) functional area shortening (FAS) (measured on transthoracic as systolic area – diastolic area/systolic area × 100), and AF inducibility was measured by the effective refractory period (ERP) and AF duration. The treatment with enalapril was observed with attenuation of atrial fibrosis which further correlated with histological evidence as well as echocardiographic measurement of FAS. Another study, by Saygili et al., observed that, in cultured atrial myocytes exposed to stretch, treatment with the ARB losartan prevented stretch-induced and consequently angiotensinmediated atrial hypertrophy. In addition, losartan also attenuated stretch-induced alterations in IK1, IKur, and Ito density and thereby prevented stretch-induced decreases in action potential duration (APD).
In addition to these salutatory effects of ACEIs/ARBs on atrial fibrosis, Chen et al. demonstrated that these agents also mitigated local Ang II-induced automaticity in isolated rabbit pulmonary vein tissue preparations and isolated cardiomyocytes. Further investigations by Shetty and DelGrande also observed that the ARBs irbesartan and valsartan reduced local Ang II-mediated norepinephrine spillover in rat atria, and thereby led to a decrease in conduction heterogeneity and inducibility of AF. Endothelial dysfunction also has a pertinent role in the pathogenesis of AF; an increased expression of adhesion molecules mediated by Ang II has been demonstrated in the fibrillating atria. Goette et al. used a rapid atrial pacing model in pigs to show treatment with ACEIs abrogated the increased expression of adhesion molecules, further supporting the role of ACE inhibition in mitigating the endothelial dysfunction.
Clinical Studies
A recently published meta-analysis of 14 clinical trials including 92,817 patients demonstrated that RAAS inhibition with an ACEI was associated with a modest decrease in the incidence of new-onset AF as compared with conventional therapy or placebo [relative risk (RR) 0.79, 95 % confidence interval (CI) 0.62–1.00, p = 0.05]. ARBs showed a similar effect in reduction of AF (RR 0.78, 95 %CI 0.66–0.92, p = 0.009). The authors of this meta-analysis acknowledged that although there was a modest degree of benefit of RAAS inhibition in the prevention of AF, the overall quality of evidence of these findings was low.
Data from the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study further support the benefit of RAAS antagonism for prevention of AF. The LIFE investigators showed that, despite similar reductions in blood pressure, patients in the losartan arm had a lower incidence of new-onset AF than patients in the atenolol arm (6.8 vs. 10.1 per 1,000 patient-years; RR 0.67, 95 % CI 0.55–0.83, p<0.001). Further analyses from this study also showed that a greater degree of regression of left ventricular hypertrophy (LVH) with the use of losartan as compared with atenolol might also be responsible for prevention of AF. A greater degree of LVH regression might contribute to greater improvement in left atrial hemodynamics and dilatation. These additional mechanisms also seem pertinent in the beneficial effects of losartan in the LIFE study. Similarly, in a broad CHF patient population, candesartan was found to be more effective in prevention of new-onset AF as compared with placebo [5.55 % patients developed new-onset AF in the candesartan arm vs. 6.74 % in the placebo arm; odds ratio (OR) 0.81, 95 % CI 0.66–0.99, p = 0.048] in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial.
Contrary to these beneficial effects of ACE inhibition particularly for prevention of new-onset AF, the results of the Gruppo Italiano per lo Studio della Sopravvivenzanell'Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial showed that valsartan did not reduce the recurrence rates for AF in patients with pre-existing cardiovascular diseases. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-I) trial investigated the impact of irbesartan on a composite of adverse cardiovascular events (stroke, MI, death from vascular causes as the primary outcome). The rate of this outcome was observed to be similar for both irbesartan and placebo [5.4 % per 100 patient-years in each; hazard ratio (HR) with irbesartan 0.99, 95 % CI 0.91–1.08, p = 0.85]. The use of irbesartan also did not have a significant effect in reducing the rate of hospitalization due to heart failure in this study. The Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) trial aimed to investigate the impact of olmesartan on the AF burden (measured by transtelephonic electrocardiograms) in patients with paroxysmal AF without any coexisting structural heart disease. During a 12-month follow-up period, the use of olmesartan was not observed to have any beneficial effect in decreasing AF burden (p = 0.77). Similarly, the secondary outcomes of the trial (quality of life, time to develop persistent AF, and rate of cardiovascular hospitalizations) were also not affected by the use of olmesartan as compared with placebo.
The lack of clinically beneficial effects with the use of ARBs for prevention of AF suppression was further substantiated by the results of the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II). In this open-labeled randomized trial, symptomatic and asymptomatic recurrences of AF episodes were assessed in patients with paroxysmal AF who received either candesartan or amlodipine. At a follow-up period of 1-year, the frequency of total AF was 2.1 ? 3.8 days/month in the candesartan group as compared with 2.4 ± 4.4 days/month in the amlodipine group, p = 0.51. The use of candesartan was also not found to have a significant effect on the frequency of cardiovascular events, left atrial dimensions and subsequent development of persistent AF.
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