Abstract
We aimed to determine the effects of the oral direct renin inhibitor aliskiren on in vivo oxidative stress in atrial fibrillation (AF) patients. In this study, 150 mg oral direct renin inhibitor aliskiren was administered once daily to 12 permanent AF patients. Aliskiren significantly reduced urinary excretion of the oxidative stress biomarker 8-iso-prostglandin F2α and serum levels of matrix metalloproteinase-2(MMP-2). We concluded that aliskiren reduces in vivo oxidative stress and serum MMP-2 levels in patients with permanent AF.
Keywords: Atrial fibrillation, Free radicals, Matrix metalloproteinase
1. Introduction
Activation of the renin–angiotensin–aldosterone system (RAAS) in the atrial tissue is a point of concern in patients with atrial fibrillation (AF), since increased generation of angiotensin II activates NADPH oxidase and enhances oxidative stress in vivo in these individuals [1,2]. Enhanced oxidative stress in turn activates matrix metalloproteinases (MMPs) [3], which are key enzymes in atrial remodeling [4,5]. The serum MMP-2 content was reported to be an independent predictor of post-ablation AF recurrence [6]. The oral direct renin inhibitor aliskiren is expected to block the RAAS completely when supplemented in treatment with conventional RAAS inhibitors, since addition of aliskiren was found to reduce in vivo oxidative stress and albuminuria in hypertensive diabetic patients with chronic kidney disease [7]. The aim of this study was to determine the effects of aliskiren on in vivo oxidative stress in AF patients.
2. Materials and methods
2.1. Patients and study protocol
Informed consent was obtained from each patient for participation in this study, which was approved by the Institutional Ethics Committee of Higashi-osaka City General Hospital on January 26, 2012. Enrolled were 12 patients (8 men and 4 women; mean age, 72.8 years) with permanent AF and hypertension who visited our outpatient clinic from October 2010 to June 2012. Inclusion criteria were (1) plasma levels of brain-type natriuretic peptide (BNP) >100 pg/mL on at least two occasions prior to enrollment; (2) no episodes of admission because of chronic heart failure (CHF) worsening; and (3) non-smoking status. CHF was treated using conventional medicines, including angiotensin-converting enzyme inhibitor, β-blockers, angiotensin II receptor blockers, diuretics, and mineral corticoid receptor antagonists. An optimal dose of warfarin was also prescribed. Excluded criteria were as described elsewhere [8]. Lastly, 150 mg aliskiren once daily was administered for at least 3 months. The conventional medicines were not changed during the protocol. Immediately before and 3 months after aliskiren administration, blood and urine were sampled for biochemical measurements.
To assess the normal range of urinary excretion of 8-iso-prostaglandin F2α (8-iso-PG-F2α), a reliable biomarker of in vivo oxidative stress, 23 subjects who visited our Health Screening Department were selected. None of these subjects had AF, hypertension, diabetes mellitus, dyslipidemia, or history of heart failure and none were current smokers (14 men and 9 women; mean age, 53±14 years).
2.2. Biochemical measurements
Immunoreactive 8-iso-PGF2α was measured in urine by using an enzyme immunoassay kit, as described previously (Cayman Chemical, Ann Arbor, MI, USA) [8]. Commercially available kits were used to measure plasma BNP, serum MMP-2, plasma renin activity, and serum aldosterone [8].
2.3. Statistical analyses
Data were expressed as mean±standard deviation. The differences between pre- and post-aliskiren administration were analyzed using Student׳s t-test. Differences between the AF patients and the normal control group were analyzed using the unpaired Student׳s t-test. P<0.05 was considered significant.
3. Results
Aliskiren reduced urinary 8-iso-PG-F2α excretion (340±137 to 285±97 g/mg creatinine, P=0.02). Urinary 8-iso-PGF2α excretion after aliskiren administration in the AF group was similar to that in the normal control group (229±76 pg/mg creatinine; n=23; Table 1). Aliskiren reduced serum MMP-2 levels (1305±421 vs. 1158±323 ng/mL, P=0.04) but not plasma BNP (243±137 vs. 230±161 pg/mL) or aldosterone levels (8.2±3.6 vs. 8.8±3.1 ng/dL) (Table 1). Echocardiographic parameters, including the dimensions of the left atrium and ventricle, remained unaltered during the study protocol (data not shown).
Table 1.
Biochemical parameters.
| Aliskiren |
P value | ||
|---|---|---|---|
| Pre | Post | ||
| Urinary 8-iso-PG-F2α (pg/mg creatinine) | 340±137 | 285±97 | 0.02 |
| Serum MMP-2 (ng/mL) | 1305±421 | 1158±323 | 0.04 |
| Plasma BNP (pg/mL) | 243±137 | 230±161 | n.s. |
| Systolic BP (mmHg) | 138.8±21.6 | 128.3±19.2 | 0.07 |
| Serum creatinine (mg/dL) | 0.88±0.20 | 0.95±0.27 | n.s. |
| Serum K (meq/L) | 4.13±0.39 | 4.05±0.32 | n.s. |
| Plasma renin activity (ng mL−1 h−1) | 1.85±2.40 | 1.62±2.18 | 0.07 |
| Plasma aldosterone content (ng/dL) | 8.2±3.6 | 8.8±3.1 | n.s. |
4. Discussion
Aliskiren reduced in vivo oxidative stress and serum MMP-2 levels in patients with permanent AF, although it did not alter the symptoms of CHF or plasma BNP levels. Further, these biochemical markers seemed to have no association with echocardiographic parameters. One of the reasons for this lack of an association might be the irreversible atrial remodeling occurring in permanent AF.
This study had some limitations. First, we did not measure myocardial MMP-2 activity but serum MMP-2 levels. MMP-2 activity in tissue might better reflect atrial remodeling. Second, we did not measure the biomarkers in a placebo-controlled group. To determine whether aliskiren affects atrial remodeling, further investigation is necessary with a larger population of not only permanent but also paroxysmal AF patients and a longer observation period.
5. Conclusions
Aliskiren reduced in vivo oxidative stress and serum MMP-2 levels in patients with permanent AF.
Disclosure of conflict of interest
None.
Acknowledgments
This work was supported by a research grant from Higashi-osaka City General Hospital to Dr. Yoshiyuki Kijima.
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