Autonomic Modulation of Atrial Fibrillation

Abstract

The autonomic nervous system plays a vital role in cardiac arrhythmias, including atrial fibrillation (AF). Therefore, reducing the sympathetic tone via neuromodulation methods may be helpful in AF control. Myocardial ischemia is associated with increased sympathetic tone and incidence of AF. It is an excellent disease model to understand the neural mechanisms of AF and the effects of neuromodulation. This review summarizes the relationship between autonomic nervous system and AF and reviews methods and mechanisms of neuromodulation. This review proposes that noninvasive or minimally invasive neuromodulation methods will be most useful in the future management of AF.

Keywords: neuECG; neuroremodeling; skin sympathetic nerve activity; stellate ganglion; sympathetic nerve activity.

Graphical abstract

Figure 1

A Method to Objectively Determine the SKNA Bursts (A) The proportion of average skin sympathetic nerve activity (aSKNA) recorded every 60 seconds. The aSKNA indicated 2 Gaussian distributions. The burst threshold is indicated by red dotted line, which was calculated as the mean representing lower amplitude plus 3× SD. (B) Actual recordings of the SKNA in lead I in 30-second window. These recordings correspond to points a (sinus), b (sinus), and c (atrial fibrillation [AF]) in A. Small SKNA discharges occurred regularly in a. Large SKNA bursts were observed irregularly in b and c. (C) Heart rate (black line) and aSKNA from lead I (blue) and plotted over time. The immediate recurrence of atrial fibrillation (IRAF) was defined as a reinitiation (recurrence) of AF within 1 minute after the termination of a prior AF episode. IRAF is indicated by red while other AF episodes are orange (non-IRAF). The large and frequent SKNA bursts occurred during AF. There were smaller bursts of nerve activities associated with sinus rate acceleration. The binary time series graph shows the SKNA burst (black) versus nonbursting period (white), indicating SKNA bursts preceded the AF clustering episodes. From Kusayama et al with permission. bpm = beats/min.

Figure 2

SKNA Bursts and Nonsustained Ventricular Arrhythmia in a Patient With STEMI (Top) The blue arrows indicate the nerve bursts. (Middle) The red arrows indicate the corresponding electrocardiogram (ECG) changes. (Bottom) The green arrows indicate the corresponding heart rate changes. The first nerve activity induced a burst of atrial tachycardia and heart rate acceleration. The second nerve activity induced a nonsustained ventricular tachycardia (3 beats). The third nerve activity induced a longer nonsustained ventricular tachycardia episode (20 beats). From Huang et al with permission. STEMI = ST-segment elevation myocardial infarction; other abbreviations as in Figure 1.

Figure 3

Histology of the Left SG in a Dog With Bilateral RDN (A,B) Masson trichrome staining of the SG. The black arrow indicates injured ganglion cells with pyknotic nuclei and contracted cytoplasm (B). (C,D) Tyrosine hydroxylase (TH) staining of the SG. The black arrowhead points to TH-negative ganglion cells (D). (E,F) The stellate ganglion (SG) with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and TH double staining from the yellow box area (C) by confocal microscopy. TUNEL (green) positive ganglion cells were observed. Some TUNEL-positive ganglion cells had pyknotic cytoplasm and stained negative for TH (F). From Tsai et al with permission. RDN = renal denervation.

Figure 4

Immunofluorescence Microscopy Images of the Brainstem at Level 1 in a Bilateral RD Dog (A) Confocal microscope image of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining of the entire left half of the brainstem by combining images taken with 10× objective. The TUNEL positivity (green) was mostly distributed in the medial half of the brainstem. (B) Schematic of TUNEL positivity (dark blue cross) in different color-coded structures. (C) TUNEL and glial fibrillary acidic protein (GFAP) double staining in high TUNEL-positivity area of A (red box). Green indicates positive TUNEL stain, red indicates positive GFAP stain, and blue is the 4′,6-diamidino-2-phenylindole stain of the nuclei. An arrowhead points to a TUNEL-positive neuron and an arrow points to a TUNEL-positive glial cell. There was high level of glial reaction as indicated by the strongly positive GFAP staining. (D) The same staining of the white box area in A. There were no TUNEL-positive or GFAP-positive cells in that region. (E) The percentage of TUNEL-positive neurons in “damaged area” and “nondamaged area” in bilateral renal denervation dogs. The percentage of TUNEL-positive neuron cells significantly increased in “damaged area.” ([A] Scanning and merging of 100× images; [C,D] 800×). From Tsai et al with permission. CN V = trigeminal nerve.

Figure 5

RDN After MI (A) The protocol of renal denervation (RDN) and myocardial infarction (MI) creation in protocols 1 (MI only) and 2 (MI+RDN). In the MI group, we created MI and followed for 8 weeks. In the RDN group, the dogs had MI followed by RDN at week 4 and were followed for an additional 8 weeks. Week 0 is the week immediately after MI. (B) RDN on integrated stellate ganglion nerve activity (iSGNA) over time, showing RDN reduced the iSGNA. (C) The affects of RDN on RR interval ratio compared with week 0. The RDN group had an accelerated RR ratio lengthening (slowing of heart rate) compared to the MI-only group.

Figure 6

Effects of RDN on ATs (A, B) The onset and termination of atrial tachyarrhythmias (ATs), respectively. A long episode of stellate ganglion nerve activity (SGNA) preceded the onset of AT. Termination of SGNA was coincidental with the termination of AT. The superior left ganglionated plexi nerve activity (SLGPNA) activity was stable before the onset of AT, but then increased only after the onset of AT (perhaps as a reaction to AT) along with a large burst of SGNA. These findings suggest that the arrhythmia itself evokes a substantial change in autonomic activity. With regard to termination, it is possible that cessation of SGNA or SLGPNA led to termination of AT. However, it is also possible that the AT termination resulted in reduction of nerve activity. (C,D) The AT episodes and the AT duration during the study in the MI+RDN group. Note that RDN reduced both the AT episodes and duration. ∗P < 0.05 vs week 0; †P < 0.05 vs week 2; ‡P < 0.05 vs week 4. ScNA = subcutaneous nerve activity; other abbreviations as in Figures 1 to 3, and 5.

Central Illustration

Autonomic Modulations of Atrial Fibrillation