Meihua Li

Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats

Background—Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Methods and Results—Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1±5.9 versus 23.5±4.2 mm Hg, P <0.05) and higher maximum dp/dt of left ventricular pressure (4152±237 versus 2987±192 mm Hg/s, P <0.05) than the untreated rats. Improvement of cardiac pumping function was accompanied by a decrease in normalized biventricular weight (2.75±0.25 versus 3.14±0.22 g/kg, P <0.01). Although the 140-day survival of the untreated group was only half, vagal stimulation markedly improved the survival rate (86% versus 50%, P =0.008). Vagal stimulation therapy achieved a 73% reduction in a relative risk ratio of death. Conclusions—Vagal nerve stimulation markedly improved the long-term survival of CHF rats through the prevention of pumping failure and cardiac remodeling.

Open-loop dynamic and static characteristics of the carotid sinus baroreflex in rats with chronic heart failure after myocardial infarction

We estimated open-loop dynamic characteristics of the carotid sinus baroreflex in normal control rats and chronic heart failure (CHF) rats after myocardial infarction. First, the neural arc transfer function from carotid sinus pressure to splanchnic sympathetic nerve activity (SNA) and its corresponding step response were examined. Although the steady-state response was attenuated in CHF, the negative peak response and the time to peak did not change significantly, suggesting preserved neural arc dynamic characteristics. Next, the peripheral arc transfer function from SNA to arterial pressure (AP) and its corresponding step response were examined. The steady-state response and the initial slope were reduced in CHF, suggesting impaired end-organ responses. In a simulation study based on the dynamic and static characteristics, the percent recovery of AP was reduced progressively as the size of disturbance increased in CHF, suggesting that a reserve for AP buffering is lost in CHF despite relatively maintained baseline AP.

Early Short-Term Vagal Nerve Stimulation Attenuates Cardiac Remodeling After Reperfused Myocardial Infarction

BACKGROUND Vagal nerve stimulation (VS) has been suggested to be an effective adjunct to reperfusion therapy in myocardial infarction (MI). However, the effect of VS on left ventricular (LV) remodeling after reperfused MI has not been examined. METHODS AND RESULTS We investigated the effects of early, brief VS on acute inflammatory reactions (study 1) and chronic LV remodeling (study 2) in a rabbit model of reperfused MI. In study 1, rabbits were subjected to 60-minute coronary artery occlusion followed by reperfusion alone (MI, n = 8) or treated with 24-hour VS (MI-VS, n = 8). At 24 hours after ischemia-reperfusion, MI-VS rabbits showed significantly decreased myocardial infiltration of neutrophils and reduced myocardial expressions of tumor necrosis factor-alpha and matrix metalloproteinase-8 and -9, compared with MI rabbits. Myocardial expression of interleukin-6 was not affected by VS. In study 2, rabbits were subjected to coronary occlusion and reperfusion alone (n = 16) or treated with VS for 3 days (n = 14). At 8 weeks after ischemia-reperfusion, MI-VS rabbits showed significantly improved LV dysfunction and dilatation, and significantly reduced infarct size, infarct wall thinning, and LV weight compared with MI rabbits. CONCLUSION Early, short-term VS attenuates LV remodeling after reperfused MI, which may be associated with suppression of acute inflammatory reactions.

High-frequency dominant depression of peripheral vagal control of heart rate in rats with chronic heart failure.

To examine whether dynamic characteristics of the peripheral vagal control of heart rate (HR) are altered in chronic heart failure (CHF).

Detection of endogenous acetylcholine release during brief ischemia in the rabbit ventricle: A possible trigger for ischemic preconditioning

AIMS To examine endogenous acetylcholine (ACh) release in the rabbit left ventricle during acute ischemia, ischemic preconditioning and electrical vagal stimulation. MAIN METHODS We measured myocardial interstitial ACh levels in the rabbit left ventricle using a cardiac microdialysis technique. In Protocol 1 (n=6), the left circumflex coronary artery (LCX) was occluded for 30min and reperfused for 30min. In Protocol 2 (n=5), the LCX was temporarily occluded for 5min. Ten minutes later, the LCX was occluded for 30min and reperfused for 30min. In Protocol 3 (n=5), bilateral efferent vagal nerves were stimulated at 20Hz and 40Hz (10V, 1-ms pulse duration). KEY FINDINGS In Protocol 1, a 30-min coronary occlusion increased the ACh level from 0.39+/-0.15 to 7.0+/-2.2nM (mean+/-SE, P<0.01). In Protocol 2, a 5-min coronary occlusion increased the ACh level from 0.33+/-0.07 to 0.75+/-0.11nM (P<0.05). The ACh level returned to 0.48+/-0.10nM during the interval. After that, a 30-min coronary occlusion increased the ACh level to 2.4+/-0.49nM (P<0.01). In Protocol 3, vagal stimulation at 20Hz and 40Hz increased the ACh level from 0.29+/-0.06 to 1.23+/-0.48 (P<0.05) and 2.44+/-1.13nM (P<0.01), respectively. SIGNIFICANCE Acute ischemia significantly increased the ACh levels in the rabbit left ventricle, which appeared to exceed the vagal stimulation-induced ACh release. Brief ischemia as short as 5min can also increase the ACh level, suggesting that endogenous ACh release can be a trigger for ischemic preconditioning.

Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release

AIMS To evaluate vagal stimulation-mediated myocardial protection against ischemia and reperfusion in in vivo ischemic myocardium. MAIN METHODS We measured myocardial interstitial myoglobin levels in the ischemic region using a cardiac microdialysis technique in anesthetized and vagotomized cats. We occluded the left anterior descending coronary artery (LAD) for 60 min and reperfused it for 60 min (VX group, n = 6). The effects of bilateral vagal stimulation (10 V, 5 Hz, 1-ms pulse duration), initiated immediately after LAD occlusion, were examined (VS group, n = 6). To examine the involvement of phosphatidylinositol 3-kinase (PI3K), vagal stimulation was performed after pretreatment with a PI3K inhibitor wortmannin (0.6 mg/kg, i.v.) (VS-W group, n = 6). To examine the contribution of bradycardia, vagal stimulation was performed with fixed-rate ventricular pacing (VS-P group, n = 6). KEY FINDINGS The average myoglobin level during the ischemic period was 1170+/-141 in VX (in ng/ml, mean+/-SE), which was significantly attenuated in VS (466+/-87, P<0.05) and VS-W (613+/-124, P<0.05) but not in VS-P (953+/-203). Reperfusion increased the myoglobin level to 2500+/-544 in VX, whereas it was suppressed in VS (824+/-213, P<0.05) and VS-W (948+/-315, P<0.05) but not in VS-P (1710+/-253). SIGNIFICANCE Vagal stimulation, initiated immediately after LAD occlusion, attenuated the myocardial injury. Moreover, bradycardia, independent of PI3K pathway, plays a significant role in vagally induced cardioprotection during acute myocardial ischemia.

Contrasting effects of moderate vagal stimulation on heart rate and carotid sinus baroreflex-mediated sympathetic arterial pressure regulation in rats

AIMS To examine whether moderate efferent vagal nerve stimulation (VNS) attenuates the carotid sinus baroreflex-mediated arterial pressure (AP) regulation via its antagonism to the sympathetic system. MAIN METHODS Carotid sinus baroreceptor regions were isolated from the systemic circulation in eight anesthetized and vagotomized rats. A staircase-wise input was imposed on carotid sinus pressure (CSP) with or without efferent VNS (20Hz, 2ms, 1-4V), while the responses in AP, heart rate (HR), and splanchnic sympathetic nerve activity (SNA) were measured. KEY FINDINGS A multiple linear regression analysis indicated that VNS decreased the minimum HR in the CSP-HR relationship by 58.2±4.9 beats/min (P<0.01) from its reference value of 387.0±5.8 beats/min. Although VNS significantly decreased an intercept of the SNA-AP relationship, it did not affect parameters of the CSP-AP relationship or the CSP-SNA relationship significantly. The operating-point AP of the baroreflex was decreased by 2.8±1.0mmHg (P<0.01) during VNS, which was less than 3% of the reference value of 117.7±1.2mmHg. SIGNIFICANCE VNS, at an intensity of decreasing HR by approximately 13%, does not acutely attenuate the baroreflex-mediated sympathetic AP regulation.

Chronic vagal nerve stimulation improves baroreflex neural arc function in heart failure rats.

We tested whether 6-wk vagal stimulation (VS) treatment improved open-loop baroreflex function in rats after myocardial infarction (MI). The following three groups of Sprague-Dawley rats were examined: normal control (NC, n = 9), MI with no treatment (MI-NT, n = 8), and MI treated with VS (MI-VS, n = 7). Under anesthesia, a stepwise input ranging from 60 to 180 mmHg was imposed on isolated carotid sinus baroreceptor regions, while the responses in splanchnic sympathetic nerve activity (SNA) and arterial pressure (AP) were measured. The response range of percent SNA was greater in the MI-VS than in the MI-NT group (63.8 ± 4.9% vs. 33.1 ± 3.8%, P < 0.01). The slope of the AP response to percent SNA was not different between the MI-VS and MI-NT groups (0.611 ± 0.076 vs. 0.781 ± 0.057 mmHg/%). The difference in the response range of AP between the MI-VS and MI-NT groups did not reach statistical significance (40.7 ± 6.2 vs. 26.4 ± 3.5 mmHg). In conclusion, the 6-wk VS treatment significantly improved the baroreflex control of SNA, but the effect was limited for the baroreflex total-loop function due to the lack of significant improvement in the AP response to percent SNA.

Adding the acetylcholinesterase inhibitor, donepezil, to losartan treatment markedly improves long‐term survival in rats with chronic heart failure

Modulation of vagal tone using electrical vagal nerve stimulation or pharmacological acetylcholinesterase inhibition by donepezil exerts beneficial effects in an animal model of chronic heart failure (CHF). Considering different treatment mechanisms underlying renin–angiotensin system (RAS) suppression and parasympathetic activation, we hypothesized that parasympathetic activation together with RAS inhibition could attenuate CHF progression. To test this hypothesis, we investigated the therapeutic effects of a combination of donepezil and losartan in CHF rats with extensive myocardial infarction (MI).

Electrical Acupuncture Modifies Autonomic Balance by Resetting the Neural Arc of Arterial Baroreflex System

Contribution of abnormal cardiovascular regulation to the maintenance and progression of heart failure has been repeatedly demonstrated. Besides the current therapeutic modalities, development of an additional therapeutic strategy is needed. We have been developing a bionic system, an artificial device designed for integration into native physiological systems. By communicating with the physiological regulatory system, we tried to not only restore lost function but also correct abnormal function. We have already shown that modification of autonomic balance by direct electrical vagal stimulation has inhibited cardiac remodeling, and improved survival in rats. Because the benefit of the correction of autonomic balance would be greatly enhanced if available by a less invasive method, we examined the possibility of modifying the autonomic balance by electrical acupuncture. The results indicated that electrical acupuncture resets the neural arc of the arterial baroreflex (SNA response range decreases from 144.0plusmn35.0 to 112.6plusmn9.2, p<0.005) and is able to attenuate sympathetic nerve activity.