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Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications

Abstract

Hypertension is one of the most important risk factors associated with atrial fibrillation (AF) and increased the risk of cardiovascular events in patients with AF. However, the pathophysiological link between hypertension and AF is unclear. Nevertheless, this can be explained by the hemodynamic changes of the left atrium secondary to long standing hypertension, resulting in elevated left atrium pressure and subsequently left atrial enlargement. Moreover, the activation of renin–angiotensin–aldosterone system (RAAS) activation in patients with hypertension induces left atrial fibrosis and conduction block in the left atrium, resulting in the development of AF. Accordingly, recent studies have shown that effective blockage of RAAS by angiotensin converting enzyme inhibitors or angiotensin receptor antagonist may be effective in both primary and secondary prevention of AF in patients with hypertension, although with controversies. In addition, optimal antithrombotic therapy, blood pressure control as well as rate control for AF are key to the management of patients with AF.

Introduction

Hypertension is the most common coexisting cardiovascular diseases in patients who have atrial fibrillation (AF).1, 2 Both hypertension3 and AF4 have increased frequency with the ageing population worldwide, and are associated with increased cardiovascular events. They are important risk factors for stroke, heart failure and overall mortality.5, 6, 7 On the other hand, hypertension is one of the important risk factors for the occurrence of AF,8 and increased the risk of stroke and cardiovascular mortality in patients with AF.9, 10 Compare with other risk factors for AF, hypertension appears to be responsible for more AF than any other risk factor because of its high prevalence. However, the pathophysiological link between AF and hypertension remains unclear. Moreover, it is also unclear whether treatment of hypertension prevents AF or reduces the risk of AF related complications. The purpose of this article is to review the epidemiology, underlying mechanisms and therapeutic implications of AF in hypertensive patients. A systematic literature search for full-text papers in the English language was performed using MEDLINE, Embase and the Cochrane library through to July 2011. In the search phrases used, the following terms were used: ‘atrial fibrillation’, ‘hypertension’, ‘epidemiology’, ‘pathophysiology’ and ‘treatment’. Papers selected and cited in this review were based on the authors’ view on the relevance to the manuscript. In addition, abstracts from international cardiovascular meetings were studied to identify unpublished studies.

Epidemiology

Clinical studies suggest that at least 1% of the overall population suffered from AF.11 The prevalence of AF increases with age, and up to 10% of population will develop AF by the age of 75.12, 13 According to Framingham Heart Study, the lifetime risk for the development of AF was up to 25% at the age of 40.14 Because of the ageing population, the total number of patients with AF is expected to increase by 2–3 times within the coming 20–30 years.15 Although hypertension alone only confers a relatively modest risk of AF (relative risk: 1.4–2.1) as compared with the valvular heart disease (relative risk: 2.2–8.3) and congestive heart failure (relative risk: 6.1–17.5),16 hypertension independently accounts for more AF cases than any other risk factor because of its high prevalence (1 billion individuals worldwide). In the Framingham Heart Study, cigarette smoking, diabetes mellitus, hypertension and coronary artery disease together explained 44% and 58% of occurrence of AF in men and women, respectively. Furthermore, hypertension alone account for 14% of the AF burden in both men and women, and was one of the independent predictor for new-onset AF.8 Recently, the Atherosclerosis Risk in Communities study also confirmed that common cardiovascular risk factors include cigarette smoking, diabetes mellitus, elevated blood pressure (BP), overweight/obesity, and prior cardiac disease contributed to 57% of incident AF.17 Among these risk factors, elevated or borderline BP explained 20–25% of AF, and was the most important contributor to the burden of AF. Indeed, in clinical survey studies of patients with AF, hypertension is found in up to 60–80% of patients.1, 2 Furthermore, hypertension is frequently associated with other structural heart diseases that lead to AF.

Moreover, there are differences in the relationship between the risk of AF and individual BP component. For the prediction of incident AF, systolic BP was better than diastolic BP.18, 19, 20 Nevertheless, diastolic BP also provided incremental prediction beyond the effect of systolic BP.20 These findings suggest that pulse pressure and thus arterial stiffness may be even more important for prediction of AF than either systolic or diastolic BP alone.19 Furthermore, there is no evidence of a threshold BP level below which the risk of AF was not increased as even BP values considered as normal are still associated with an increased risk of incident AF. In women health study,20 subjects with systolic or diastolic BP values between 130–139 mm Hg and 85–89 mm Hg had a 28% and 53% increase in risk compared with those had systolic or diastolic BP below 120 mm Hg or 65 mm Hg, respectively.

Pathophysiology

Despite the close link between hypertension and AF, the underlying pathophysiology of AF in patients with hypertension remains unclear. In spontaneous hypertensive rats, the presence of atrial fibrosis was associated with inducibility of atrial tachycardia.21 Similarly, in a large animal model of young onset hypertension, increased atrial fibrosis with cellular hypertrophy and apoptosis were associated with increased stability of AF.22 These animal studies demonstrated that hypertension induced AF structural substrate and increased the susceptibility for AF. Nevertheless, the underlying mechanisms by which hypertension induce atrial structural remodeling remains unclear. Two major mechanisms have been proposed to explain the development of AF in hypertension: hemodynamic changes in atria due to hypertension, and activation of renin—angiotensin–aldosterone system (RAAS, Figure 1).

Figure 1
figure1

Potential pathogenic mechanisms linking hypertension and atrial fibrillation.

Hemodynamic changes in atria

In the setting of long-standing hypertension, the excessive afterload imposing onto the left ventricle leads to progressive thickening of the left ventricular wall with left ventricular hypertrophy (LVH). The increased left ventricular stiffness and the left ventricular diastolic and systolic dysfunction accompanying the development of LVH inevitably raise left atrial pressure.23 This chronic atrial stretch results in progressive left atrial enlargement with decreased atrial contractility and increased atrial compliance. In Framingham Heart Study, the duration of elevated BP as well as the level of systolic BP were associated with the development of left atrial dilatation.24 Moreover, diastolic dysfunction,25, 26 left atrial enlargement and mechanical function, 27 and LVH 28 are all important predictors for the development of AF in patients with hypertension. On the other hand, the development of AF in hypertensive patients with left ventricular diastolic and/or systolic dysfunction can further worsen the left atrial enlargement, and thus increased the risk of AF recurrence. Moreover, chronic atrial stretch may further induce atrial structural and electrophysiological changes, and thus act as substrates for AF.23

RAAS activation

Emerging evidences suggest that activation of RAAS not only have an important role in the pathophysiology of hypertension, but also contribute to the development of AF. Experimental studies29, 30 demonstrated that angiotensin II induce atrial fibrosis and hypertrophy, changes in expression of ion channels, gap junction and calcium handling, as well as increased oxidative stress and inflammation. Angiotensin II induces the proliferation of fibroblast and accumulation of extracellular matrix protein by activating mitogen-activated-protein kinase. These changes can lead to atrial hypertrophy and fibrosis, which act as atrial substrates for reentry due to the development of conduction block.29 In spontaneous hypertensive rat model, angiotensin II induced interstitial fibrosis and thus conducted blocking in the left atrium.31

In addition, angiotensin II also exerts direct cellular electrophysiological effects on cardiomyocytes that favor the development of AF.32 Experimental studies have shown that angiotensin II modulate the expression of multiple ion channels, including the L-type and T-type calcium current (ICa, T, ICa, L),33, 34 the rapid and slow component of the delayed rectifier potassium currents (IKs, IKr),35 and the transient outward potassium current (Ito).36 These changes in the expression of ion channels as well as alteration of calcium handling in atrial cardiomyocytes can promote the development of AF.37 Furthermore, increased oxidative stress and inflammation induced by RAAS activation have also been implicated in the pathogenesis of AF.20, 38 Therefore, multiple mechanisms may account for the pathophysiological link between activation of RAAS and AF. Indeed, in animal models of AF, blockade of RAAS with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor antagonists (ARB) attenuated some of these pathophysiological changes and prevent the development of AF.19, 20

Therapeutic implications

As discussed above, the close link between the pathophysiology of hypertension and AF offers the opportunities for therapeutic intervention to prevent AF in hypertensive patients. Recent data from Atherosclerosis Risk in Communities study also suggested that suboptimal BP control is one of the most important risk factors for new onset AF.17 Effective control of hypertension per se may be one of the most important factors for AF prevention via reduction of left atrial enlargement and LVH.39, 40, 41 On the other hand, it is well known that despite comparable BP lowering effects, antihypertensive agents, which block RAAS appear to be more effective in regression of LVH.42 Moreover, in view of the potential implication of the activation of RAAS in the mechanism of AF as well the experimental evidence of protective effects of RAAS blockade, many studies have been focused on the potential benefit of ACEI or ARB for primary and secondary prevention of AF in patients with hypertension.

Primary prevention of AF with RAAS inhibition

Table 1 summaries the results of clinical studies on the effects of ACEI or ARB for primary prevention of AF. In CAPPP trial,43 captopril was compared with diuretics and/or beta-blocker; and in the STOP-2 trial,44 enalapril or lisinopril were compared with beta-blocker, diuretic and/or calcium channel blocker in patients with essential hypertension. In both studies, there was no significant reduction in the new occurrence of AF over followup period of >5 years. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),45 treatment with lisinopril had a similar incidence of new-onset AF as compared with diuretic or calcium channel blocker. On the other hand, a retrospective analysis from a USA drug administration database46 suggested that ACEI decreased the risk of AF by 15% over 4.5 years of followup as compared with calcium channel blocker.

Table 1 Hypertension trials reporting new-onset AF (primary prevention)

In contrast, more recent clinical trials on ARBs showed more consistent benefit effects for AF prevention. In the Losartan Intervention For EndPoint reduction in hypertension (LIFE study),47 9193 patients with hypertension and electrocardiographic evidences of LVH were randomized to receive losartan or atenolol. In the secondary analysis with new-onset AF as secondary end point, treatment with losartan had a 33% reduction in incidence of AF (3.5% versus 5.3%, P<0.001) compared with atenolol. In the Valsartan Antihypertensive Long-term Use Evaluation Trial (VALUE), treatment with valsartan-based regimen had a 16% reduction in new-onset AF as compared with amlodipine-based regimen.48 In these two studies, the prevention of AF appears to be beyond the BP control. Furthermore, a nested case-control study in UK also demonstrated that treatment with ACEIs-based and ARBs-based regimen was associated with a 25–29% reduction in AF compared with calcium channel blockers-based regimen.49

Several meta-analyses30 have been performed to investigate the effects of ACEIs and ARBs for AF prevention in patients with different cardiovascular diseases. These analyses mainly included clinical trials as mentioned above and most of them did not show significant reduction of AF with ACEIs and ARBs for primary prevention of AF. However, it is important to note that there was significant heterogeneity in those clinical trials, in term of study population and method for AF monitoring. In those early ACEIs studies,43, 44 the lack of detail AF monitoring and enrollment of young and low-risk patients in the CAPPP trial might account for their lack of benefit to prevent AF. On the other hand, it remains unclear whether ARBs are superior to ACEIs for AF prevention in patients with hypertension. In meta-analyses, overall benefit for AF prevention was similar between ACEIs and ARBs, but data on direct comparison is not available.50 A comparison between results from LIFE versus VALUE suggested that hypertensive patients with LVH seem to be more benefited from ARB for AF prevention.

In summary, a stronger evidence for prevention of AF by RAAS blockade with ACEIs or ARB was seen in hypertensive patients with LVH. Indeed, recent European Society of Cardiology guidelines9 recommends that ACEIs and ARBs should be considered for prevention of new-onset AF in patients with hypertension, particularly with LVH (Class IIa, level B). In patients with uncomplicated hypertension, an optimal BP control to prevent LVH and left atrial enlargement with effective antihypertensive drugs rather than specific class of agents appear to be more important to prevent further development of AF.

Secondary prevention with RAAS inhibition

Currently, there are very limited data to support the use of ACEIs or ARBs for secondary prevention of AF in patients with hypertension. There is no randomized controlled study on the use of ACEI or ARB for secondary prevention of AF primarily in patients with hypertension (Table 2). In patients with persistent AF, the use of enalapril51 or irbesartan52 in addition to amiodarone reduced the risk of AF recurrence over amiodarone alone after electrical and/or pharmacological cardioversion. On the other hand, the use of ACEIs53 or candesartan54 alone without antiarrhythmic agents failed to reduce the risk of AF recurrence after cardioversion. However, in these studies, <50% of patients had hypertension. The Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca Atrial Fibrillation (GISSI-AF)55 was the largest secondary prevention study involving 1442 patients with either paroxysmal or recently cardioverted persistent AF. In this study, up to 85% of patients had hypertension, and there was no significant reduction in AF recurrence between patients randomized to valsartan versus placebo group.

Table 2 Hypertension trials reporting AF recurrence (secondary prevention)

In hypertensive patients and paroxysmal AF with or without prior cardioversion, three open-labeled studies56, 57, 58 demonstrated that ACEIs- or ARBs-based treatment in addition to the use of antiarrhythmic agents reduced the risk of AF recurrence (Table 2). In another study,59 the beneficial effects of RAAS blockade with valsartan or ramipril over amlodipine in hypertensive patients with paroxysmal AF persisted even in the absence of concurrent antiarrhythmic drug. In these studies, there were no significant differences in the BP control between patients assigned to ACEIs- or ARBs-based therapy as compared with other antihypertensive agents, mainly calcium channel blockers, suggesting the beneficial effects of ACEIs and ARBs on AF prevention were beyond their BP lowering effect.

In contrast, several studies had failed to show any benefit with ACEIs or ARBs for prevention of paroxysmal AF in hypertensive patients (Table 2). In two retrospective analyses, ACEls and ARBs in addition to antiarrhythmic agents neither prevent progression to permanent AF60 or AF recurrence.61 Recently, the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) II study62 also demonstrated no reduction in the AF recurrence with candesartan as compared with amlodipine as monitored by daily transtelephonic ECG recording in 318 hypertensive patients with paroxysmal AF. Furthermore, the preliminary data of the prospective, randomized study—Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF)—30, 63 showed that olmesartan did not prevent AF in the absence of anitarrhythmic agents as compared with placebo. In this study, 43% of patients had hypertension but without LVH. Moreover, in the Atrial Fibrillation Clopidogrel Trials with Irbesartan for prevention of Vascular Events-Irbesartan (ACTIVE I) trial, in paroxysmal atrial fibrillation patients (n=1730), who were in sinus rhythm on enrollment, treatment with irbesartan did not reduce the risk of AF recurrence.64 Overall, these studies suggested that neither ACEIs nor ARBs therapy alone prevent arrhythmic recurrence in hypertensive patients with paroxysmal AF or those with persistent AF after cardioversion. It is possible that ACEIs and ARBs cannot prevent progression of AF in those who have significant atrial remodeling.

Treatment of AF in patients with hypertension

In addition to prevent onset or progression of AF in hypertensive patients with antihypertensive agents and RAAS blockade, optimal antithrombotic therapy as well as treatment of AF are also important to reduce mortality and morbidity of AF in patients with hypertension.

Anticoagulation therapy

The development of AF in hypertensive patients is one of the important risk factor for stroke and thromboembolism.9 However, the risk of stroke associated with AF is not homogeneous and increase with the presence of other stroke risk factors. As a result, different stroke risk stratification schemas have been created based on those risk factors in which hypertension is being the most common one. The most commonly used schema recommended by various guidelines is the congestive heart failure, hypertension, age >75, diabetes mellitus and prior stroke or TIA [CHADS2] score, and then the more recently CHA2DS2-VASc score, which was designed to be complementary to the CHADS2 score.9, 65, 66 In general, those guidelines recommended that ‘moderate-high risk’ patients be treated with oral anticoagulation (OAC) whereas ‘low risk’ AF patients be treated with aspirin or nothing. Based on the new CHA2DS2-VASc score, the majority of hypertensive patients with AF should be treated with OAC provided that their bleeding risk is acceptable.9

One of the most important risk factors for bleeding, in particular intracranial hemorrhage, in patients treated with OAC therapy is uncontrolled hypertension.67 Therefore, optimal BP control is needed to minimise the risk of bleeding in hypertensive patients treated with OAC therapy. Furthermore, analysis from the Stroke Prevention using an ORal Thrombin Inhibitor in Atrial Fibrillation Trial (SPORTIF) has demonstrated that level of systolic BP correlated with the risk of the systemic thromboembolism and stroke in patients with non-valvular AF.68 Recent retrospective analysis also showed that hypertensive patients who achieved target BP control (<130/80 mm Hg) had a lower ischemic stroke (0.9% versus 3.1% per year, P=0.01), but similar bleeding risk compared with those not achieving target BP.69 These studies highlighted the importance of achieving optimal BP control in hypertensive patients with AF to maximize the benefit of OAC therapy for stroke prevention.

Rate control and antiarrhythmic agents

A review of the randomized trials comparing rate versus rhythm control in patients with AF have failed to demonstrate any difference in all-cause and cardiovascular mortality and stroke rate between rate control versus rhythm control in patients with AF.9 In those studies, a significant proportion of patients had hypertension. Based on these observations, some clinical guideline70, 71 recommended that an initial rate control strategy should be considered in patients with hypertension. In general, β-blockers and/or non-dihydropyridine calcium channels blocker can be used for both ventricular rate as well as BP control in hypertensive patients with AF.

On the other hand, rhythm control should be used in those who have failed rate control and significant symptoms. For the choice of antiarrhythmic agents for maintenance of sinus rhythm, latest clinical guidelines9, 71, 72 recommend that flecainide, propafenone, sotalol and dronedarone can be used as first-line agents in hypertensive patients without significant LVH. In those hypertensive patients with significant LVH, the optimal antiarrhythmic agents remain unclear. Although some guideline9 suggests that dronedarone can be used before amiodarone, the other guideline72 only recommends amiodarone in view of potential higher proarrhythmic risk of other antiarrhythmic agents in patients with LVH.

Monitoring of BP

Current treatment of hypertension relies on the clinic BP measurement. Indeed, recent study has shown a substantial difference between mean home and clinic BP (up to 10 mm Hg lower in mean home BP), which may affect clinician's treatment decision.73, 74 In addition, BP varies constantly throughout the day. Instability of BP may reflect increase arterial stiffness and surge of BP increases risk of stroke, although not directly related to new-onset AF.75 As a result, variability of BP has an important role in the progression of end-organ damage and cardiovascular events.76 Studies are needed to define the optimal BP monitoring treatment target in patients with hypertension.

Conclusions

Hypertension is the most common attributed risk factor for the increasing burden of AF in the population. Both clinical and experimental studies have demonstrated a close link between the pathophysiology between AF and hypertension. Although optimal BP control with antihypertensive agents in hypertensive patients may potentially reduce the risk of AF, the promise of RAAS blockade with ACEIs and ARBs for primary and secondary prevention of AF remains unclear. Further randomized studies are needed to define the optimal antihypertensive agents for prevention of AF recurrence and progression. Finally, both optimal use of OAC as well as BP control are required to prevent stroke and minimize the bleeding complications in hypertensive patients with AF.

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Lau, YF., Yiu, KH., Siu, CW. et al. Hypertension and atrial fibrillation: epidemiology, pathophysiology and therapeutic implications. J Hum Hypertens 26, 563–569 (2012). https://doi.org/10.1038/jhh.2011.105

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Keywords

  • atrial fibrillation
  • renin–angiotensin–aldosterone system
  • prevention

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