Tissue Perfusion Microsphere Analysis
Table 3 lists the results of tissue perfusion studies at baseline and during CPS. Cardiac plexus stimulation increased perfusion over baseline in the skeletal muscle and end-organ samples, including the spleen, liver, and bilateral kidneys (cortex and medulla). Only one skeletal sample (quadriceps femoris muscle) showed a decrease in tissue perfusion. Statistically, however, there were no significant differences in tissue perfusion between baseline and CPS for all samples.
The following are the most significant results of endovascular CPS: (a) a significant and selective increase in LV contractility, and (b) sinus rhythm was maintained with no increase in HR. We demonstrated this endovascular CPS hemodynamic effect in eight of the 12 healthy animals studied. The hemodynamic changes in four animals of the eight animals, however, were not reproducible and, therefore, we did not use their data in this manuscript. Endovascular CPS is highly dependent on electrode placement as it requires stimulation of autonomic cardiac nerves running on the epivascular surface of the great vessels. In contrast to the 100% success rate obtained in our epivascular CPS studies, where we were able to accurately locate and fix stimulation sites,7 percutaneous endovascular stimulation requires blind placement of the electrode and is dependent on fixation at the site of stimulation. Use of relatively crude stimulation catheters with no real fixation method made intravascular fixation at any one given stimulation site a technical challenge. One specific problem encountered was dislodgment of the stimulation catheter when we occluded the IVC to obtain the pressure-volume loops needed to assess changes in myocardial contractility. This issue was corrected in later studies using a vascular balloon occluder. Other difficulties, especially in the early studies, included the fact that the effective points in the site of CPS within the right PA had not been reported and that we had no reliable intravascular fixation method for our stimulation catheters. Development of an electrode grid system with good intravascular fixation methods is critically needed to achieve reliable and reproducible endovascular CPS results. This is a focus of our future studies.
To our knowledge, this is the first detailed study to document enhanced cardiac contractility with essentially no change in HR achieved by endovascular stimulation of both sympathetic and parasympathetic cardiac nerves at the cardiac plexus. Although the endovascular stimulating electrodes were delivered to the PA by a venous intravascular route and would not require an invasive approach in clinical application, in this study, a median sternotomy was performed to record detailed LV function data such as LAP and LV pressure-volume loops using the IVC vascular occluder.
The ability to locate and fix the lead at the optimal endovascular stimulation sites in this acute study in healthy dogs was our biggest challenge. For the animals in which a stable endovascular CPS site was obtained, the data demonstrate a significant and selective increase in LV contractility with no increase in HR, SVR, or PVR. This result is qualitatively and quantitatively similar to the results we had found using epivascular CPS. Hemodynamic indices of cardiac function such as systolic AoP, LVSW, CO, and Ees also showed statistically significant increases. This response suggests a complex concurrent stimulation of parasympathetic nerves (suppressing an increased HR) and sympathetic nerves (increasing contractility). Brack et al13 similarly reported that vagal parasympathetic stimulation has a predominant effect on HR when combined with sympathetic nerve stimulation. These opposing effects were also demonstrated in our previous acute studies, in which epivascular CPS at the right PA produced an increase in AoP, LVSW, and CO by increasing LV contractility while yielding no increase in HR.7
The transient decrease in AoP at the start of endovascular CPS (Fig. 3) is consistent with the different temporal responses documented for parasympathetic and sympathetic stimulation and offers further support for their concurrent stimulation. Immediately after stimulation began, AoP decreased slightly from baseline, then gradually began to increase to levels well above baseline. This fall and rise can be explained by the previously documented 1- to 3-second delay in response to sympathetic nerve stimulation followed by a steady increase in response at a slow 10- to 20-second time constant caused in part by a slower rate of release of the sympathetic neurotransmitter norepinephrine (NE).14,15 In contrast, acetylcholine, the parasympathetic neurotransmitter, acts more quickly than NE, and very soon after the onset of stimulation, acetylcholine will markedly suppress the release of NE from sympathetic nerve terminals. Therefore, the initial response to simultaneous stimulation would be expected to be a parasympathetic-dominant response, supporting that shown in Figure 3.
The endovascular stimulation performed in this study used relatively simple bipolar electrodes or grid-type electrophysiology mapping catheters. As an optimal site for endovascular CPS via the right PA has not been reported previously, much effort was directed at locating optimal stimulation sites. Making this difficult is the fact that individual nerve fibers in the cardiac plexus cannot be identified or isolated anatomically to determine if there is a predominance of either sympathetic or parasympathetic autonomic nerve fibers at any one stimulation site. The true site optimization will not, however, be realized without further development and study of endovascular CPS catheter design, electrode fixation methods, delivery systems, and stimulation parameters.
Comparison to Epivascular CPS
We have previously reported our findings for epivascular CPS in this same series of animals7 and in our discussion above. Epivascular stimulation yielded a reproducible positive hemodynamic response in all (12 of 12) animals studied. Using the endovascular approach, we obtained similar hemodynamic responses in only 66% of the animals and stable electrode fixation and hemodynamics in only half of them. This difference can be explained by the fact that the autonomic nerves at the cardiac plexus run in closer proximity to the epivascular surface of the right PA, providing a much shorter stimulation pathway for the epivascular electrode versus an endovascular electrode placed in the right PA. In addition, the electrode we used was not designed for endovascular CPS, and future CPS development will focus on the design of stimulation electrodes and catheters optimized to the right PA endovascular approach to improve electrode fixation and reproducibility of hemodynamic response.
The optimal endovascular CPS site (ventral surface of right PA wall) and its optimal stimulation voltage (25 ± 13.2 V) reported in this study were also different from that for epivascular CPS at the cranioventral surface of the right PA at a higher optimal stimulation voltage of 37.5 ± 8.9 V. A second effective epivascular stimulation site reported was at the caudoventral surface of the right PA. This epivascular site, however, induced frequent atrial fibrillation because of the fact that the stimulating electrode contacted not only the epivascular right PA surface but also parts of the LA wall. Interestingly, our current study showed that endovascular CPS at the endovascular caudoventral surface of the PA wall produced no arrhythmias. The vessel wall most likely provides sufficient isolation from the LA.
Current Drug and Autonomic Nerve Stimulation Therapy for Autonomic Imbalance
Cardiac function is tightly controlled by the balance between sympathetic and parasympathetic tone. Norepinephrine, the primary sympathetic neurotransmitter, increases HR, conduction velocity, and myocardial contraction and constricts peripheral vessels, whereas the parasympathetic neurotransmitter acetylcholine reduces HR.
The autonomic imbalance recently documented in HF patients shows sympathetic activation and parasympathetic withdrawal and is believed to contribute to the pathogenesis of HF.17 Chronic HF therapy using VNS acts to decrease HR elevated by increased sympathetic tone. These negative chronotropic effects also improve diastolic filling and coronary perfusion and reduce MVO2. Vagal nerve stimulation significantly improved NYHA functional class and LV ejection fraction in its initial clinical trials for patients in NYHA Class II to III HF.17
The therapeutic action of VNS in HF patients is similar to that of beta blockers, which typically produce a decrease in HR and a negative inotropic effect. Careful and appropriate use of beta blockers has proven effective in reducing mortality and improving cardiac function in patients with chronic HF.18 A recent clinical trial of ivabradine (a selective inhibitor of the If current in the sinoatrial node, used to decrease HR without inotropic effects) also ameliorated conditions of patients in NYHA Class II to III HF.19 These negative chronotropic HF therapies target stable chronic HF patients, providing long-term therapeutic effects, but do not provide the significant augmentation of CO needed in end-stage and acute-phase severe HF.
Direct stimulation of the cardiac sympathetic nerves alone has been shown to produce a cardioselective positive inotropic effect without significant effects on systemic vascular tone.5,20,21 Unfortunately, the resulting increase in HR has the same detrimental effects on ventricular filling and myocardial perfusion and the same adverse myocardial ischemic consequences as inotropes caused by the increase in myocardial oxygen demand.
Beta blockers, VNS, and targeted negative chronotropic agents are difficult to apply to more advanced HF patients because of systemic side effects such as arterial hypotension and bradycardia and their limited ability to increase CO.
The ideal therapy to treat advanced HF would increase cardiac contractility, maintain or lower HR (depending on the presence of HF-associated tachycardia), and minimize the increase in MVO2 required to sustain adequate resting systemic pressures and flow. The results of our previous epivascular CPS study and this endovascular CPS study indicate that concurrent excitation of cardiac sympathetic and parasympathetic tone produces a selective increase in LV contractility with no increase in HR.
Limitations to this study include the following. (a) In this acute study, we used a healthy animal model. Evaluation of endovascular CPS in ischemic and cardiomyopathic chronic HF animal models will be needed to fully investigate the potential clinical benefit of this technique in advanced HF. (b) Although an increase in contractility with no change in HR is indicative of dual stimulation, this hypothesis was not validated using adrenergic and cholinergic blockade during CPS. (c) Measuring regional and global MVO2 levels after generating equivalent increases in cardiac contractility for endovascular CPS and then administering dobutamine would have provided a better quantitative measure of any metabolic advantage provided by CPS over inotropes. (d) Catheter mapping methods to determine the effective stimulation points proved unreliable in our open-chest procedures because air between the mapping patch and the catheter made this method ineffective. (e) This study focused only on the effect of CPS on LV function and did not include assessment of right ventricular function. (f) Only one of three electrical stimulation parameters (stimulation voltage) was investigated. (g) A clinical electrophysiology mapping and ablation catheter with a bipolar electrode was used for CPS in this study; use of a dedicated CPS electrode design and electrode fixation methods would have allowed us to expand our investigation into the reliability, reproducibility, and range of cardiac function effects that can be obtained with endovascular CPS. (h) Finally, CPS was applied for only approximately 1 hour in this study. Meyer et al6 and Zarse et al5 have previously reported continuous CANS stimulation for, respectively, 4- and 12-hour periods with sustained effects on ventricular function. These limited-duration studies raise questions about the effects of chronic stimulation, such as the possible loss of cardiac nerve sensitivity to stimulation, depletion of neurotransmitters, and reflex cardiac parasympathetic responses, with sustained cardiac sympathetic stimulation. (i) Because of the small number of animals (n = 4) from which data were obtained, the statistical power of the analysis was insufficient to make definitive conclusions on the parameters where there was no statistical significance.
In contrast to conventional inotropic drugs acting on cardiac sympathetic nerve terminals, endovascular CANS stimulation induced a significant and selective increase in LV contractility with no increase in HR or SVR in the acute healthy dog model. Further studies designed to evaluate endovascular CPS in acute and chronic HF animal models will be needed to determine whether this approach has potential clinical benefits for patients with advanced HF.
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This is an interesting experimental study from Dr. Kobayashi and his colleagues at the Cleveland Clinic. In 12 dogs, they examined the acute changes in cardiac function and hemodynamics in response to endovascular cardiac plexus stimulation. The results of this study weremixed. In one third of the animals, therewas no response. In another one third, the increase in systemic arterial pressure was dependent on electrode placement. In the final one third, there were reproducible and stable increases in aortic pressure. In contrast to conventional inotropic agents, endovascular cardiac plexus stimulation induced increases in left ventricular contractility without increasing the heart rate
The major limitations of this study, which were well acknowledged by the authors, include the small number of animals, the lack of use of adrenergic and cholinergic blockade during stimulation to define the specificity of this response, and the fact that this was an acute study in healthy animals. This is a very preliminary study and difficult to interpret because of the variable physiologic responses. This work does suggest that efforts to optimize electrode placement, improve the reproducibility of endovascular cardiac plexus stimulation, and understand which patients may benefit from this treatment are warranted. Future studies from this group are eagerly anticipated.
Keywords:Copyright © 2012 by the International Society for Minimally Invasive Cardiothoracic Surgery. Unauthorized reproduction of this article is prohibited.
Electrical stimulation; Heart rate; Hemodynamics; Myocardial contraction; Nervous system