Rachel AUDO1, Jérome Thireau2, Louis Rauzier3, Marie Barozet1, JACQUES MOREL4, Patrice Bideaux3, alain Lacampagne2 and Claire Daien5, 1CHU Montpellier, Montpellier, France, 2PhyMedExp INSERM U1046, Montpellier, France, 3PhyMedExp U1046, Montpellier, France, 4Protocole thérapeutique immuno-rhumatologie, Montpellier, France, 5University Hospital, Montpellier, France
Background/Purpose: Rheumatoid arthritis (RA) is associated with a high risk of cardiovascular (CV) risks, including accelerated atherosclerosis, left ventricular hypertrophy and decreased heart rate variability (HRV). HRV decrease reflects the inability of the autonomic nervous system (ANS) to adapt cardiac function and lower HRV is associated with a higher risk of CV events. Autonomic dysfunction is observed in RA with a prevalence as high as 60–80% and precedes apparition of symptoms. Given that gut microbiota (GM) dysbiosis also occurs before disease and inflammation in subjects who will develop RA, and that activity of vagus nerve can be modulated by the GM, we hypothesized that GM impairs the ANS balance in RA.
Methods: we investigated whether fecal microbiota transplantation (FMT) of RA patients modulates the electrocardiographic profile, the HRV and cardiac function (echocardiography) compared to FMT of healthy subjects (age-and-sex-matched controls). Using electrocardiogram (ECG) acquired by telemetry, we characterized the impact of FMT on sympathetic and/or vagal outflow using temporal- and spectral-domain analyses of HRV. High resolution echocardiography allowed us to assess both cardiac structural and contractile function. In parallel, FMT consequences on intestinal barrier permeability, the pro- or anti-inflammatory immune cells and early markers of atherosclerosis were evaluated to related potential modification to inflammatory profile.
Results: Heart Rate Variability (HRV) analysis showed that FMT from RA patients altered the ANS activity in mice, reproducing a defect of vagal tone. Indeed, in mice with fecal transfer of RA microbiota (RA-FMT), we observed an increase of heart rate, only during resting time (444.82(±20.07) bpm vs 477.12(±30), p=0.0001, n=34/group). This tachycardia results from a reduction of HRV reflecting altered ANS activity with a decrease in SDNN index (SDNN 23.88±9.97 vs 10.22±4.05 ms, p< 0.0001, n=34/group). Time domain and spectral domain analyses of HRV confirmed a decrease in the parasympathetic activity resulting in a drop of sympathovagal balance. These alterations are independent of cardiac structural, of contractile modifications and of any remodeling of cardiac muscarinic or adrenergic signaling pathway. In addition, this vagal tone dysfunction was independent of inflammation as RA FMT did not induce major immune dysfunction or change in the aortic expression of early markers of atherosclerosis (VCAM and ICAM).
Conclusion: We demonstrated that for the first time that the MI of RA patients contributes to autonomic dysfunction, independently of the inflammatory status, and without structural or contractile modification of the heart. This opens new therapeutic perspectives, such as dietary modifications, for example with the addition of fibre or the use of probiotics, to prevent autonomic dysfunction and CV risk in RA.
R. AUDO: None; J. Thireau: None; L. Rauzier: None; M. Barozet: None; J. MOREL: None; P. Bideaux: None; a. Lacampagne: None; C. Daien: None.
