Current treatments for congestive heart failure (HF) include surgical, interventional, and pharmacologic therapies; however, the number of patients with congestive HF has reached more than 5 million in the United States, with another half million new patients each year. Direct costs of treatment are approximately $20 billion annually, as 78% of patients with congestive HF are hospitalized at least twice per year.1,2 These statistics indicate that current therapies for advanced HF fall short of achieving acceptable treatment in many patients and that additional advanced therapies are needed to reduce the resulting morbidity and mortality that are often devastating and costly.
Recently, modulation of cardiac function by electrical stimulation of either parasympathetic or sympathetic cardiac nerves has drawn widespread interest as a novel method of HF treatment. Initial results of clinical trials of parasympathetic vagal nerve stimulation (VNS) in patients diagnosed with New York Heart Association (NYHA) Class II to III HF have been encouraging.3,4 Efforts to increase vagal control are believed to counteract the increased sympathetic tone often associated with chronic HF, resulting in improved cardiac autonomic balance in these patients. Vagal nerve stimulation, however, acts primarily to decrease heart rate (HR) and cannot provide acute functional improvement of cardiac output (CO) in the end-stage patient with low CO.
In a porcine study, direct stimulation of cardiac sympathetic nerves has been shown to increase adrenergic tone in the heart.5 Also, continuous stimulation of the cardiac autonomic nervous system (CANS) for 4-hour6 and 12-hour5 periods had sustained inotropic effects on ventricular function. However, selective sympathetic cardiac nerve stimulation significantly increases HR, which is linearly related to myocardial oxygen consumption (MVO2), contributing to myocardial ischemia in the setting of coronary artery occlusion or spasm.
The cardiac plexus lies in the adventitia of the great vessels between the ascending aorta and the pulmonary artery (PA) and is traversed by both postganglionic sympathetic and preganglionic parasympathetic cardiac autonomic nerves. Our preliminary data indicated that epivascular cardiac plexus stimulation (CPS) induced significant and selective increases in left ventricular (LV) contractility and CO with no increase in HR.7 These results suggest a potential therapeutic use of concurrent electrical stimulation of parasympathetic and sympathetic cardiac nerves to regulate the autonomic control of cardiac function. Although our epivascular results were more reproducible, most likely because of closer access to the nerves running within the adventitia of the great vessels, this method requires invasive access to the thoracic cavity to reach the epivascular surfaces of the PA. An endovascular CPS approach via venous access would be less invasive than surgical access to epivascular surfaces, and the stimulating lead could easily be removed; however, the efficacy of endovascular CPS has never been tested. The aim of this study was to assess the effects of acute endovascular CPS on HR, LV contractility, and hemodynamics in healthy dogs.
Animal and Surgical Preparation
This protocol was reviewed and approved by the Institutional Animal Care and Use Committee for compliance with federal and institutional guidelines for humane treatment of research animals.
In 12 mongrel dogs (female; n = 10; average body weight, 26.0 ± 2.3 kg), anesthesia was induced with intravenous propofol (200 mg) and maintained with isoflurane (1.5%–2.5%). Electrocardiographic leads were attached to the extremities, and 8F sheath introducers were inserted into the left carotid artery and left jugular vein via the cut-down method. A fluid-filled line was connected to the carotid sheath for aortic pressure (AoP) monitoring. Heparin (3000 U) was administered intravenously for a target activated clotting time of 250 to 350 seconds. A 14F sheath introducer was inserted into the right femoral vein for delivery of the stimulation catheters.
Through a median sternotomy, the pericardium was opened, and a left atrial pressure (LAP) line was inserted directly into the left atrium (LA). Umbilical tape and/or a vascular occluder (OC24HD; In Vivo Metric, Healdsburg, CA USA) was passed around the inferior vena cava (IVC) to create IVC occlusions during LV pressure-volume measurements to be made later in the procedure. Under fluoroscopy, a Millar conductance catheter with dual microtip pressure sensors (model SPC-562; Millar Instruments, Inc, Houston, TX USA) was deployed into the left ventricle via the carotid arterial sheath, and a Swan-Ganz catheter was deployed into the PA via the jugular venous sheath.
Under fluoroscopy, a guide wire was deployed from the femoral vein sheath introducer into the PA to place a 90-cm 10F vascular sheath. The stimulation catheter was deployed at the right PA via this sheath. A straight bipolar 7F catheter (Livewire; St. Jude Medical, St. Paul, MN USA) was used in the first three cases (Figs. 1; 2A, B); we chose to change to the multisensor Constellation Full Contact Mapping 8F catheter (Boston Scientific, Natick, MA USA) in the remaining nine cases (Figs. 1; 2C, D). The stimulation catheters were connected to an external nerve stimulator (Grass SD9 stimulator; Astro-Med, Inc, West Warwick, RI USA).
The Livewire catheter has four electrodes: a single distal anode and three proximal electrodes acting as the cathode. The Constellation catheter consists of a grid of eight splines, each of which holds eight electrodes. The anatomical position of each wire and electrode was determined by fluoroscopic markers located on the eight wires. One of the electrodes in one of the stimulation wires was used as the return anode and connected directly to the stimulator (negative) terminal. The stimulator (positive) cathode terminal was connected to up to 10 selected electrode segments from the array of 64 possible connectors via a switch box. Using this configuration, we were able to quickly switch between 10 active (cathode) electrode segments to find the optimal electrode to be paired with the single anodal electrode for augmenting cardiac function. The stimulation frequency and pulse width were fixed at 20 Hz and 4 milliseconds, respectively; the stimulation voltage was varied in the range of 15 to 60 V.
Initial studies focused on finding the optimal stimulation sites based on the cardiac and hemodynamic response and the absence of adverse events. The optimal stimulation voltage for each experiment was selected to be the voltage that produced a 20% to 35% increase in mean AoP. The sensitivity and variability of cardiac and hemodynamic responses to the anatomical site of stimulation at the cardiac plexus and to any displacement of the electrode from the experimentally obtained optimal site were also recorded.
Hemodynamic Data Acquisition
A Millar conductance catheter was used to record AoP, LV pressure (LVP), and LV volume. The LVP and LV volume measurements were used to produce LV pressure-volume measurements via a Leycom 5DF system (Cardiodynamics, Leiden, Netherlands). The PA pressure and central venous pressure was measured by a Swan-Ganz catheter. The LAP was measured by a fluid-filled line placed in the LA. The CO was measured by a bolus injection of saline given through the Swan-Ganz catheter or by a continuous CO PA catheter and Vigilance Monitor (Edwards Lifesciences, Irvine, CA USA). The CO data were used to calculate stroke volume and systemic (SVR) and pulmonary vascular resistance (PVR) values.
All hemodynamic data were recorded digitally at a sample rate of 200 Hz using a PowerLab data acquisition system (AD Instruments Pty Ltd, Bella Vista, NSW Australia) and saved as Excel data files. The following physiologic parameters were derived via data analyses of each data sampling period using a custom Visual Basic program acting on the Excel data files: HR, stroke volume, maximum and minimum rate of change of LVP (dP/dtmax, dP/dtmin), SVR, PVR, LV stroke work (LVSW), end-systolic elastance (Ees),8 effective arterial elastance,9 preload recruitable stroke work,10 and the slope of the dP/dtmax–end-diastolic volume relationship.11 Mechanical efficiency was calculated as the ratio of stroke work divided by pressure-volume area.
All LV pressure-volume relationship data were recorded with the ventilator off to eliminate respiratory artifacts. Analysis of LV pressure-volume relationships to assess cardiac function requires the recording of LV pressure-volume loops over multiple cardiac cycles under various preload conditions. This condition was accomplished by a transient occlusion of the venous return to the right side of the heart at the IVC, with subsequent decreasing preload to the left ventricle. Occlusion of the IVC was achieved by using umbilical tape as a tie or by the balloon vascular occluder.
Tissue Perfusion Analysis via Microsphere Injection
To determine changes in regional blood flow to cardiac and end-organ tissues under CANS stimulation, a colored microsphere injection technique was used.12 A 6-mL bolus containing 6 million microspheres (mean diameter, 15 μm; BioPAL, Inc, Worcester, MA USA) was injected rapidly (in a few seconds) into the LA during the steady-state condition. Different types of microspheres (lanthanum and holmium) were used to evaluate each baseline and CANS application phase of the studies. With each microsphere injection, a reference sample of arterial blood was also withdrawn through a syringe pump from the left carotid artery according to the microsphere manufacturer’s standard methods. The withdrawal rate was fixed at 10 mL/min, and the sample was collected for 2 minutes, resulting in a collection of 20 mL of reference blood.
After the animals were killed, tissue specimens were taken from the biceps brachii muscle, quadriceps femoris muscle, spleen, liver, and bilateral kidneys. Both the tissue and blood samples taken were processed by dehydration for 48 hours in a vacuum oven at 60°C. All tissue and blood samples were then sent to a commercial laboratory (BioPAL), where the sample microsphere content was determined for tissue perfusion calculations in milliliters per minute per gram of tissue.
Data are expressed as mean ± SD. For all data, a paired t test was used to analyze data obtained at baseline and at the corresponding stimulation phases. A value of P < 0.05 was considered statistically significant.
Optimal CPS Stimulation Sites
Of the 12 dogs receiving endovascular CPS, four dogs showed no response to stimulation and four dogs showed a positive hemodynamic response similar to our epivascular CPS findings; however, this response was difficult to sustain because it was significantly affected by small movements of the catheter in the PA. In the remaining four dogs, we saw a very reproducible stimulation response that allowed us to record the detailed hemodynamic measurements presented here. The hemodynamic chart recording in Figure 3 is an example of the reproducible increase in AoP at baseline and during stimulation. A paradoxical transient (10 seconds) decrease in the mean AoP from baseline immediately after turning stimulation on was followed by a sustained increase in AoP for the remaining duration of stimulation.
As noted above, the cardiac plexus lies chiefly in the adventitia of the great vessels in the concavity of the aortic arch, in front of the right PA. We found that endovascular stimulation was only effective in the right PA and not in the main or left PA. The optimal right PA endovascular stimulation point was at the anterior wall of the right PA (Fig. 4). The stimulation voltage was varied in the range of 15 to 60 V (average, 33.8 ± 20.5 V), with an average optimal stimulation voltage of 25 ± 13.2 V. Despite the high stimulus voltages, there was no obvious macroscopic injury to the endovascular surface of the PA at necropsy.
Data are shown for the four dogs that showed a stable reproducible response to endovascular CPS. Table 1 shows the average prestimulation (baseline) cardiac and hemodynamic data compared with those recorded during CPS using the optimal stimulation voltage. The data reveal marked and statistically significant positive inotropic changes in the following cardiac indices with stimulation, indicating an increase in cardiac contractility with no significant changes in HR (from 110 ± 13 beats/min to 111 ± 9 beats/min, P = 0.106). Cardiac output increased from 2.3 ± 1.0 L/min to 3.6 ± 0.6 L/min (P = 0.03), along with systolic AoP and LVP, LV dP/dtmax, and LVSW (P < 0.02 for all parameters). Stimulation also increased Ees (from 0.7 ± 0.2 mm Hg/mL to 0.9 ± 0.2 mm Hg/mL, P = 0.03) and preload recruitable stroke work (from 21.8 ± 5.5 mm Hg to 36.6 ± 6.5 mm Hg, P = 0.03), indicating an increase in LV contractility. Hemodynamic parameters unchanged by stimulation included central venous pressure and PA pressure (both P > 0.1), as well as SVR (from 2178 ± 870 dyne·s·cm−5 to 1600 ± 474 dyne·s·cm−5, P = 0.3) and PVR (from 258 ± 95 dyne·s·cm−5 to 142 ± 33 dyne·s·cm−5, P = 0.07). The increase in LAP of 1.3 mm Hg was statistically significant (P = 0.04).
Table 2 compares the average echocardiographic variables for all four dogs at baseline versus during endovascular CPS. Left ventricular ejection fraction increased from 46.5% ± 10.0% to 56.3% ± 5.9%, but this rise was not statistically significant. All other parameters were not statistically significant. Figure 5 plots the percent change in the main hemodynamic and echocardiographic parameters after CPS.
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.
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