Can Zheng

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.

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.

Resetting of the arterial baroreflex increases orthostatic sympathetic activation and prevents postural hypotension in rabbits

Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomized and aortic‐denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP–AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension.

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).

Intravascular parasympathetic cardiac nerve stimulation prevents ventricular arrhythmias during acute myocardial ischemia

Although previous animal studies clearly demonstrated antiarrhythmic effects of vagal stimulation during acute myocardial ischemia, highly invasive nature of vagal stimulation limited its clinical use. Recently, intravascular parasympathetic cardiac nerve stimulation (IPS) has emerged as a novel approach to the cardiac autonomic nervous system. We hypothesized that IPS might prevent ventricular arrhythmias during acute myocardial ischemia. Methods: The IPS (36 V, 10 Hz) was performed in superior vena cava using an expandable electrode-basket catheter. In 18 open-chest dogs, left anterior descending coronary artery ligation was performed without IPS (control group, n = 6), with IPS (IPS group, n = 6) and with IPS and right atrial pacing at 180/min (IPS+P group, n = 6). The ECGs were monitored for 60 min. The incidence and severity of ventricular arrhythmias were analyzed. Results: The IPS significantly decreased the frequency of premature ventricular contractions (control group: 9.1 plusmn 4.6 /min, IPS group: 0.2 plusmn 0.4 /min, IPS+P group: 10.6 plusmn 4.2 /min; p < 0.05). The frequency of ventricular tachycardia was lower in IPS group (0 plusmn 0 /min) than in control group (0.15 plusmn 0.18 /min, p < 0.05) and than in IPS+P group (0.17 plusmn 0.12 /min, p < 0.05). The incidence of ventricular fibrillation was lower in IPS group (0%) than in control group (33.3%) and than in IPS+P group (33.3%). Conclusions: The IPS suppressed ventricular arrhythmias during acute ischemia mainly through its bradycardiac effect. In addition to the conventional pharmacological antiarrhythmic therapy, IPS might be an alternative tool to control ventricular arrhythmias especially in patients with refractory arrhythmias to pharmacological therapy

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.

A sieve electrode as a potential autonomic neural interface for bionic medicine

We examined the applicability of a sieve electrode to the autonomic nervous system as a potential neural interface for bionic medicine. We developed, using a Si-semiconductor process, a sieve electrode having a square diaphragm (1 mm in one side, 12 /spl mu/m in thickness) with 30-81 penetrating square holes (50-100 /spl mu/m in one side). In the first protocol, we implanted the sieve electrode to the vagal nerve in rats. One hundred and twenty days after the implantation, cuff electrodes were attached to the vagal nerve proximal and distal to the sieve electrode under halothane anesthesia. The evoked action potential was recorded from the sieve electrode by nerve stimulation via the cuff electrodes. The evoked action potential was also recorded from the cuff electrodes by nerve stimulation via the sieve electrode. In the second protocol, we implanted the sieve electrode to the renal sympathetic nerve in rabbits. Forty days after the implantation, the spontaneous action potential or sympathetic nerve activity was recorded under pentobarbital anesthesia. In conclusion, we were able to record the evoked and spontaneous action potentials using the sieve electrode. The sieve electrode will provide a useful neural interface for recording and stimulating the autonomic nervous system.

Chronic vagal stimulation decreased vasopressin secretion and sodium ingestion in heart failure rats after myocardial infarction

Chronic vagal stimulation (VS) markedly improved long-term survival in the heart failure rats. We examined the effects of VS on arginine vasopressin (AVP) secretion and salt ingestion in heart failure rats after myocardial infarction (MI). Surviving rats after MI were randomly assigned to two groups. One group was treated with sham stimulation (SS), and the other group was treated with VS. All rats could access water and 1.8% NaCl solution ad libitum. Treatment started at 2 weeks after MI, and continued for 6 weeks. We monitored drinking behavior during treatment. At the end of treatment, we measured hemodynamics and plasma levels of AVP and brain natriuretic peptide (BNP). The plasma AVP and BNP levels were significantly lower in the VS group than the SS group. VS significantly inhibited the ingestion of 1.8% NaCl solution. The normalized biventricular weight of the VS group was significantly lower than that of the SS group. The VS group had significantly lower left ventricular end-diastolic pressure, and higher cardiac index than the SS group. In conclusion, these results suggest that chronic VS regulates the water balance by suppression of plasma AVP level and salt ingestion in the heart failure rats after MI

Less Invasive and Inotrope-Reduction Approach to Automated Closed-Loop Control of Hemodynamics in Decompensated Heart Failure

We have been developing an automated cardiovascular drug infusion system for simultaneous control of arterial pressure (AP), cardiac output (CO), and left atrial pressure (PLA) in decompensated heart failure (HF). In our prototype system, CO and PLA were measured invasively through thoracotomy. Furthermore, the control logic inevitably required use of inotropes to improve hemodynamics, which was not in line with clinical HF guidelines. The goal of this study was to solve these problems and develop a clinically feasible system. We integrated to the system minimally invasive monitors of CO and pulmonary capillary wedge pressure (PCWP, surrogates for PLA) that we developed recently. We also redesigned the control logic to reduce the use of inotrope. We applied the newly developed system to nine dogs with decompensated HF. Once activated, our system started to control the infusion of vasodilator and diuretics in all the animals. Inotrope was not infused in three animals, and infused at minimal doses in six animals that were intolerant of vasodilator infusion alone. Within 50 min, our system controlled AP, CO, and PCWP to their respective targets accurately. Pulmonary artery catheterization confirmed optimization of hemodynamics (AP, from 98 ± 4 to 74 ± 11 mmHg; CO, from 2.2 ± 0.5 to 2.9 ± 0.3 L·min-1·m-2; PCWP, from 27.0 ± 6.6 to 13.8 ± 3.0 mmHg). In a minimally invasive setting while reducing the use of inotrope, our system succeeded in automatically optimizing the overall hemodynamics in canine models of HF. The present results pave the way for clinical application of our automated drug infusion system.