Angiotensin II Antagonists
P. VERDECCHIA, F. ANGELI, M. G. SARDONE, R. GATTOBIGIO
Introduction
Atrial fibrillation (AF) is a common cardiac disorder that may lead to signifi- cant morbidity and mortality. Its incidence in the general population is increasing; projections in the US population suggest that more than 5.6 mil- lion Americans (50% of whom will be 80 years of age or more) will have AF by the year 2050 [1, 2].
Although much remains to be known about the basic pathophysiological mechanisms underlying the disorder, several clinical factors have been iden- tified as potential predictors of AF. The most important risk factors for AF are age, male sex, hypertension, thyrotoxicosis, smoking, diabetes, left ven- tricular (LV) hypertrophy, left atrial enlargement, valvular and coronary heart disease, congestive heart failure, and stroke. In the Framingham Heart Study, hypertension and diabetes were the sole cardiovascular risk factors to be predictive of AF after controlling for age and other predisposing condi- tions. The role of hypertension as risk factor for AF is established but still incompletely known. In the Manitoba follow-up study, the prevalence of hypertension was 53% and the risk of AF was 1.42 times higher in hyperten- sive subjects than in normotensives [2]. Because of its high prevalence in the population, hypertension independently accounts for more AF cases than any other risk factor. However, despite its leading importance as a highly prevalent and modifiable risk factor, few data are available regarding predic- tors and outcome of AF in large populations of subjects with essential hyper- tension free of coexisting valvular or coronary heart disease, congestive heart failure, hyperthyroidism, or other predisposing conditions.
Ospedale R. Silvestrini, Dipartimento Malattie Cardiovascolari, Perugia, Italy
Predictors and Outcome of Atrial Fibrillation
Among the general population, congestive heart failure and rheumatic heart disease are the most powerful predictive precursors of AF, with relative risks in excess of about six-fold [3–5]. Data from the Framingham Heart Study suggest that another predictor of AF is hypertensive heart disease, which usually is the most common antecedent disease, largely because of its fre- quency in the general population [4]. Among the common risk factors for cardiovascular disease, diabetes and ECG evidence of left ventricular hyper- trophy (LVH) are related to the occurrence of AF [6].
Recently, an analysis of the PIUMA study (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale) identified some predictors and outcome of AF in large populations of subjects with essential hypertension who were free of coexisting valvular or coronary heart disease, congestive heart failure, or hyperthyroidism at entry into the registry [7]. Overall, 2482 initially untreated subjects in sinus rhythm were followed for up to 16 years. Age and LV mass at echocardiography were the sole independent predictors of AF. Age, LV mass, and left atrial diameter were independent predictors of chronic AF (Fig. 1).
Fig. 1.Five-year age-adjusted risk of chronic atrial fibrillation in hypertension (data from the PIUMA study) according to left atrial diameter and left ventricular mass
One of the fundamental clinical complications of AF is thromboembolic stroke. In the PIUMA study, during a mean follow-up of 6 years an ischaemic stroke occurred in 12.1% of hypertensive subjects with paroxysmal and 30% of hypertensive subjects with chronic AF [7]. Notably, none of the subjects who were receiving warfarin experienced stroke during the course of the follow-up.
These data underline the clinical usefulness of LV mass and atrial diame- ter as detected by echocardiography to identify the subset of hypertensive subjects who are at increased risk of developing AF and its chronicisation. In agreement with data from randomised studies, the PIUMA results suggest a more liberal use of warfarin for prevention of stroke in hypertensive subjects with chronic and perhaps paroxysmal AF. Interestingly, recent evidence sug- gests that anticoagulation with warfarin is the only therapy with a proven efficacy in reducing mortality among patients with AF.
Furthermore, suppression of AF has not been shown to reduce the risk of stroke in high-risk patients [8], and recent data suggest that only 50–60% of the strokes in high-risk AF patients are cardioembolic when a high propor- tion of the patients are anticoagulated with warfarin (unpublished data, D.
Sherman, 2004).
Atrial Fibrillation and Antihypertensive Treatment
The direct association between essential hypertension and AF suggests that blood pressure lowering treatment might contribute to reducing the inci- dence and complications of AF. A recent overview [8] described a hypotheti- cal construct of the mechanisms whereby hypertension and vascular disease may increase the risk of stroke in patients with AF. Briefly, hypertension, LVH, and diastolic dysfunction may lead to atrial stretch and dilatation, with atrial electric remodelling and increased probability of AF and left atrial thrombus formation.
Figure 2 depicts some interrelationships in hypertension and the patho- genesis of stroke in AF. In this setting, interference with the renin–angiotensin system may be a novel approach to interrupt the vicious circle leading to AF.
Indeed, emerging data from randomised controlled studies are providing new information about the prevention of AF in specific clinical contexts. For example, in the TRACE [9] and SOLVD studies [10] treatment with ACE inhibitors sig- nificantly reduced the incidence of AF in patients with left ventricular dys- function.
Angiotensin Receptor Blockers and Risk of Atrial Fibrillation
A relatively small study of 186 patients with paroxysmal AF showed that those treated with amiodarone and an angiotensin receptor blocker (ARB) had a lower 2-month recurrence rate and a longer time to first AF recurrence than did those treated with amiodarone alone [11].
In the Losartan Intervention For End-point reduction (LIFE) study [12], the hypothesis that the ARB losartan may be better than atenolol in reducing the risk of new-onset AF in hypertensive patients with ECG-documented LVH was tested. Briefly, 8804 patients with hypertension and ECG-docu- mented LVH who did not have AF at enrolment were randomly assigned to once-daily losartan-based or atenolol-based antihypertensive therapy and followed for at least 4 (mean 4.9) years. During follow-up, new-onset AF occurred in 179 patients given losartan (8.2 per 1000 person-years of follow- up) and 252 patients treated with atenolol (11.7 per 1000 person-years of fol- low-up) [relative risk 0.75 (95% CI 0.58 to 0.85), p < 0.001] (Fig. 3). After adjustment for Framingham risk score and ECG LV mass by Sokolow-Lyon and Cornell voltage duration criteria, the relative risk of new-onset AF was 0.72 (95% CI 0.59 to 0.89; p < 0.001). An identical relative (0.72; 95% CI 0.59 to 0.89; p = 0.003) was found after adjustment for all potential predictors (age, male gender, potassium, creatinine, and log UACR). It remains to be clarified to what extent the reduction in the risk of stroke provided by losar- tan is mediated by prevention of AF.
Fig. 2.Relationships between hypertension, pathogenesis of stroke, and atrial fibrillation (data from [8])
Conclusions
Although lowering the blood pressure stands out as the fundamental mecha- nism for preventing any complication of hypertension, recent data suggest that ARBs might play an important and perhaps independent contribution in the prevention of AF. By inhibiting the effects of angiotensin II, ARBs reduce both blood pressure and myocardial fibrosis, with important potential impli- cations for atrial and ventricular electric remodelling and atrial pressure and stretch. The LIFE study has shown the beneficial effect of losartan in reduc- ing the risk of AF in hypertensive subjects in sinus rhythm. Further studies should clarify to what extent this effect applies to other ARBs.
References
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0 6 12 18 24 30 36 42 48 54 60 66 0
1 2 3 4 5 6 7 8
Losartan Atenolol
Time (months) Proportionofpatients withfirstevent(%)
Fig. 3.Cumulative incidence of new-onset atrial fibrillation in the LIFE study among patients assigned to atenolol and losartan
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