Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias

Abstract

Obesity increases the risk of arrhythmias and sudden cardiac death, but the mechanisms are unknown. This study tested the hypothesis that obesity-induced cardiac sympathetic outgrowth and hyperinnervation promotes the development of arrhythmic events. Male Sprague-Dawley rats (250-275 g), fed a high-fat diet (33% kcal/fat), diverged into obesity-resistant (OR) and obesity-prone (OP) groups and were compared with rats fed normal chow (13% kcal/fat; CON). In vitro experiments showed that both OR and OP rats exhibited hyperinnervation of the heart and high sympathetic outgrowth compared with CON rats, even though OR rats are not obese. Despite the hyperinnervation and outgrowth, we showed that, in vivo, OR rats were less susceptible to arrhythmic events after an intravenous epinephrine challenge compared with OP rats. On examining total and stimulus-evoked neurotransmitter levels in an ex vivo system, we demonstrate that atrial acetylcholine content and release were attenuated in OP compared with OR and CON groups. OP rats also expressed elevated atrial norepinephrine content, while norepinephrine release was suppressed. These findings suggest that the consumption of a high-fat diet, even in the absence of overt obesity, stimulates sympathetic outgrowth and hyperinnervation of the heart. However, normalized cardiac parasympathetic nervous system control may protect the heart from arrhythmic events.

Keywords: arrhythmia; autonomic imbalance; neurite outgrowth; obesity.

Fig. 1.

Immunohistochemical quantification of cardiac tyrosine hydroxylase (TH+) nerve fiber density in control (CON), obesity-resistant (OR), and obesity-prone (OP) rats. A: diagram showing the regions of the heart that were analyzed for innervation density of TH+ fibers; 1 and 2, left ventricle (LV); 3 and 4, septum; 5 and 6, right ventricle (RV). B: compared with CON rats (n = 6), the combined sympathetic innervation of the LV and RV was higher in OR (n = 5) and OP (n = 5) rats (P < 0.05). When analyzed separately, hyperinnervation was prominent in the RV (C), but not in the LV (D) or in the septum (E). Representative images are shown at ×40 magnification of TH+ fibers in the RV from a CON (F), OR (G), and OP (H) rat. Scale bar = 50 μm. Values are means ± SE. *P < 0.05 vs. CON.

Fig. 2.

Basal neurite outgrowth in superior cervical ganglia (SCG) explants from CON (n = 3), OR (n = 4), and OP (n = 5) rats. A: average basal sympathetic neurite outgrowth from SCG explants was greater in OR and OP rats compared with CON rats. B–D: photos of SCG explants at time 24 h from a CON, OR, and OP rat, respectively. Values are means ± SE. *P < 0.05 vs. CON.

Fig. 3.

Assessment of arrhythmic events in OR (n = 3) and OP (n = 5) rats. A: the duration of arrhythmic events evoked by intravenous epinephrine were greater in OP compared with OR rats. B: representative arterial pulse pressure trace in an OR and OP rat during an epinephrine challenge. Values are means ± SE. *P < 0.05 vs. OR.

Fig. 4.

HPLC-mass spectrometry quantification of atrial acetylcholine (ACh) content and release. Total atrial ACh content (left) and release (right) were lower in OP rats (n = 7) compared with CON (n = 4) and OR (n = 4) rats. Values are means ± SE. *P < 0.05 vs. CON. †P < 0.05 vs. OR.

Fig. 5.

HPLC-electrochemical detection quantification of atrial norepinephrine (NE) content and release. OP rats (n = 7) exhibited high atrial NE content (top left) but low NE release (top right) compared with CON (n = 4) and OR rats (n = 4). NE content in the LV (bottom left) and RV (bottom right) did not differ between groups. Values are means ± SE. *P < 0.05 vs. CON. †P < 0.05 vs. OR.