Genetic connection with response to antiarrhythmic drugs

NASHVILLE, TENNESSEE. There is increasing evidence that the renin-angiotensin-aldosterone system (RAAS) is involved in atrial fibrillation. (NOTE: This has been discussed in the Conference Room – Sessions 2 and 26). There is also recent evidence that the angiotensin-converting enzyme (ACE) has at least three common genetic variations (DD, II and ID) that can affect its blood level and activity. Thus, the DD variation increases ACE activity by 50%, while the ID variation increases it by 25%. This increase in activity has been associated with an elevated risk of experiencing a heart attack or suffering cardiac arrest.

Researchers at Vanderbilt University set out to determine if variations in the ACE gene could account for some of the differences experienced by afibbers in response to treatment with common antiarrhythmic drugs. Their study included 213 AF patients (34% were lone afibbers and 41% had hypertension). All patients measured their symptomatic afib burden (duration x frequency x score for severity) before and after being treated with an antiarrhythmic. If their burden decreased by 75% or more, then they were classified as responders. If their burden did not change or reduced by less than 75%, then they were classified as non-responders, and another drug was tried. The frequency of the three polymorphisms of the ACE gene was 25% for the DD mutation, 30% for the II variation, and 45% for the ID variation. Thus, at least 60% of the study participants had one or two D alleles (gene versions) corresponding to higher levels and increased activity of the ACE when compared to the activity of II ACE.

The response to common class I and III antiarrhythmics (flecainide, propafenone, sotalol) in lone afibbers was 95% in patients with the II allele, 59% in those with the ID allele, and 53% in those with the DD genotype (amiodarone efficacy was not affected by genotype). Put it another way, 31% of study participants did not derive benefit because of an unfavourable variation in their ACE gene. So it is clear that in a fair number of cases a lone afibber will not be able to find an antiarrhythmic that works for them simply because of their genetic make-up. The researchers speculate that patients with one or two D alleles might benefit from adding an ACE inhibitor to their antiarrhythmic in order to compensate for the increased activity of their ACE gene.

Darbar, D, et al. ACE I/D polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation. Heart Rhythm, Vol. 4, June 2007, pp: 743-49

Editor’s comment: It is indeed welcome to see the continuing interest in linking the RAAS to lone atrial fibrillation. I am personally convinced that there is a strong link for many afibbers (including myself). However, until it is sorted out afibbers who have experienced no luck with propafenone (Rythmol) or flecainide (Tambocor) may consider asking their prescribing physician if they could run a trial with an ACE inhibitor in addition to their antiarrhythmic – lisinopril (Zestril, Prinivin) at 10 mg/day may be a good start. Of course, an even better approach would be to be tested for the ACE gene variations before adding an inhibitor, but for most afibbers this would probably be difficult to arrange.
Conference Room Session 2
Conference Room Session 26