Elsevier

Heart Rhythm

Volume 4, Issue 6, June 2007, Pages 743-749
Heart Rhythm

Original-clinical genetic
Polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation

https://doi.org/10.1016/j.hrthm.2007.02.006Get rights and content

Background

The angiotensin-converting enzyme (ACE) deletion allele, ACE D, is associated with increased ACE activity and adverse outcomes in cardiovascular disease. Although activation of the renin-angiotensin-aldosterone system (RAAS) now appears to play a role in the pathophysiology of atrial fibrillation (AF), it remains to be determined if ACE genotype impacts response to conventional AAD therapy in patients with AF.

Objectives

The purpose of this study was to investigate whether response to antiarrhythmic drug (AAD) therapy in patients with AF is modulated by the ACE I/D polymorphism.

Methods

We studied 213 patients (147 men, 66 women; ages 52 ± 15 years) prospectively enrolled in the Vanderbilt AF Registry. AAD therapy outcome was defined prospectively as response if there was a ≥75% reduction in symptomatic AF burden or nonresponse if AF burden was unchanged, necessitating a change in drugs or therapy.

Results

Lone AF (age <65 years, no identifiable cause) was present in 72 (34%) patients, whereas hypertension was the most common underlying disease in the remaining 141 (41%). AF was paroxysmal in 170 (80%) and persistent in 43 (20%). The frequencies of the DD, ID, and II genotypes were in Hardy-Weinberg equilibrium. Lone AF and DD/ID genotypes were highly significant predictors of failure of drug therapy (P <.005). In patients with lone AF, failure of drug response was 5%, 41%, and 47% in patients with II, ID, and DD genotypes, respectively, (P <.005, II vs. ID/DD).

Conclusions

These results provide further evidence for a role of RAAS activation in the pathophysiology of AF and point to a potential role for stratification of therapeutic approaches by ACE genotype.

Introduction

Progress in understanding molecular mechanisms in atrial fibrillation (AF) supports the idea that variability in response to drug therapy may reflect differences in disease mechanisms1; that is, it is entirely possible that response to AF is highly heterogeneous because the arrhythmia itself is not a single pathophysiologic entity but rather represents a final common arrhythmia response to a variety of disease pathways that culminate in AF. Indeed, work by our own group and other investigators increasingly supports the idea that AF risk includes a prominent familial component.2, 3, 4, 5, 6, 7 Further, the last several years have also seen increasing evidence that activation of pathways not traditionally linked to arrhythmias may be intimately involved in the development of AF.8, 9, 10, 11 One “nontraditional” AF risk factor is renin-angiotensin-aldosterone system (RAAS) activation. Retrospective analyses suggest that angiotensin-converting enzyme (ACE) inhibitor therapy is associated with a lower incidence of AF, and a placebo-controlled trial found a similar beneficial effect of adding the angiotensin receptor blocker (ARB) irbesartan to amiodarone.12 Additionally, a case-control study of 250 Taiwanese subjects with AF and 250 controls identified polymorphisms in this pathway as risk factors for AF, although predictors of drug response were not evaluated.13

Antiarrhythmic drugs (AADs) continue to remain a cornerstone of treatment for patients with symptomatic AF, although even the most effective of drugs has a recurrence rate of 30%–50% over a year. Further, predicting response to AAD therapy in individual patients also remains highly problematic. The role of genetic heterogeneity in modulating efficacy of AADs in patients with AF, however, has thus far not been explored.

The ACE gene contains a polymorphism based on the presence (insertion [I]) or absence (deletion [D]) of a 287-bp intronic DNA segment, resulting in three genotypes (DD and II homozygotes and ID heterozygotes).14, 15 The frequency of the ACE DD genotype has been reported to be increased in patients with myocardial infarction,16 dilated cardiomyopathy,17 and sudden death.18 In addition, a pharmacogenetic interaction of the ACE I/D polymorphism with beta-blocker and ACE inhibitor therapy has also recently been demonstrated.19, 20 Subjects with the ACE DD genotype have higher plasma concentration of ACE,14 higher cardiac ACE concentration,21 and increased renal ACE mRNA expression.22 Thus subjects with the D allele may be exposed to higher angiotensin II levels than those with the I allele. Myocardial fibrosis is strongly correlated with RAAS activation, especially angiotensin II and aldosterone,23 and chronic exposure to high levels of circulating and/or tissue angiotensin may predispose to both left ventricular hypertrophy and myocardial fibrosis. Since circulating and tissue ACE levels are higher in patients with the D allele,14, 21 we hypothesized that patients with the DD or ID genotype may have reduced response to conventional AADs compared with patients with the II genotype. Thus, the aim of this study was to investigate whether response to AAD therapy in patients with AF is modulated by the ACE I/D polymorphism.

Section snippets

Study population

The study was performed in patients prospectively enrolled in the Vanderbilt AF Registry, which is made up of a clinical and a genetic registry. Inclusion criteria include age >18 years, a documented history of AF or atrial flutter, and attempted maintenance of sinus rhythm with at least one conventional AAD. Patients with a history of AF that was associated only with cardiac surgery were excluded from this study. At enrollment into the registry, a detailed medical and drug history is obtained

Clinical characteristics

A total of 213 (51% of the entire AF Registry population) enrolled over a 30-month period were eligible for this study. The reasons for exclusion from this analysis included no trial of AAD for maintenance of sinus rhythm, that is, rate control strategy for management of AF, inadequate or incomplete assessment of symptomatic AF burden before initiation of therapy, and discontinuation of AAD therapy due to adverse effects. The demographic and baseline clinical characteristics of the study

Discussion

This study demonstrates a pharmacogenetic interaction between the ACE I/D polymorphism and efficacy of AAD therapy in patients with lone AF. Further, it provides additional evidence for the increasingly important role of RAAS activation in the pathophysiology of AF. Of the 3–5 million Americans with AF,33 it is estimated that ∼750,000 (10%–15%) have lone AF.34 This means that approximately 450,000 patients with lone AF will have the ACE DD genotype. These findings suggest that this genetic

References (58)

  • D. Levy et al.

    Echocardiographic criteria for left ventricular hypertrophy: the Framingham Heart Study

    Am J Cardiol

    (1987)
  • J.L. Houghton et al.

    Relations among impaired coronary flow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensive patients without obstructive coronary artery disease

    J Am Coll Cardiol

    (1990)
  • C.G. Brilla et al.

    Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone

    J Mol Cell Cardiol

    (1994)
  • A. Goette et al.

    Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation

    J Am Coll Cardiol

    (2000)
  • K. Kumagai et al.

    Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation

    J Am Coll Cardiol

    (2003)
  • A.G. Gharavi et al.

    Deletion polymorphism of the angiotensin-converting enzyme gene is independently associated with left ventricular mass and geometric remodeling in systemic hypertension

    Am J Cardiol

    (1996)
  • S. Nattel

    New ideas about atrial fibrillation 50 years on

    Nature

    (2002)
  • R. Brugada et al.

    Identification of a genetic locus for familial atrial fibrillation

    N Engl J Med

    (1997)
  • Y.H. Chen et al.

    KCNQ1 gain-of-function mutation in familial atrial fibrillation

    Science

    (2003)
  • P.T. Ellinor et al.

    Locus for atrial fibrillation maps to chromosome 6q14-16

    Circulation

    (2003)
  • C.S. Fox et al.

    Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring

    JAMA

    (2004)
  • C.A. Carnes et al.

    Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation

    Circ Res

    (2001)
  • M.K. Chung et al.

    C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation

    Circulation

    (2001)
  • J. Dernellis et al.

    C-reactive protein and paroxysmal atrial fibrillation: evidence of the implication of an inflammatory process in paroxysmal atrial fibrillation

    Acta Cardiol

    (2001)
  • J. Dernellis et al.

    Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation

    Eur Heart J

    (2004)
  • A.H. Madrid et al.

    Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study

    Circulation

    (2002)
  • C.T. Tsai et al.

    Renin-angiotensin system gene polymorphisms and atrial fibrillation

    Circulation

    (2004)
  • B. Rigat et al.

    An insertion/deletion polymorphism in the angiotensin I–converting enzyme gene accounting for half the variance of serum enzyme levels

    J Clin Invest

    (1990)
  • B. Rigat et al.

    PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1)

    Nucleic Acids Res

    (1992)
  • Cited by (88)

    • Pharmacogenomics testing: An overview

      2023, Pharmacogenomics: from Discovery to Clinical Implementation
    • Rhythm control in atrial fibrillation

      2016, The Lancet
      Citation Excerpt :

      As a result, there are increased efforts to identify drug targets that can reverse or slow the atrial remodelling that promotes atrial fibrillation.31,32 Another important opportunity to improve pharmacological rhythm control is pharmacogenetic guidance.33 The GENETIC-AF trial (NCT01970501) is evaluating whether or not genotype directed β-blocker therapy with bucindolol can provide effective rhythm control without conventional membrane active antiarrhythmic medication.

    View all citing articles on Scopus

    This work was supported by National Institutes of Health award nos. HL075266 (to DD) and HL65962 (to DMR).

    View full text