Author + information
- Received August 29, 2004
- Revision received February 21, 2005
- Accepted March 10, 2005
- Published online October 4, 2005.
- Markus Zarse, MD⁎,
- Jurgita Plisiene, MD†,
- Karl Mischke, MD⁎,
- Thomas Schimpf, MD⁎,
- Christian Knackstedt, MD⁎,
- Felix Gramley, MD⁎,
- Georg Mühlenbruch, MD⁎,
- Mathias Waldmann, MD⁎,
- Michael Schmid, MD⁎,§,
- Nima Hatam, MD⁎,§,
- Jürgen Graf, MD⁎,
- Dirk Schuster, MD⁎,
- Peter Hanrath, MD, FACC⁎,
- Dainius Pauza, PhD‡ and
- Patrick Schauerte, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Prof. Patrick Schauerte, Department of Cardiology, University of Technology, Pauwelsstrasse 30, 52074 Aachen, Germany
Objectives This study was designed to develop a technique to selectively increase the sympathetic tone to the heart by cardiac sympathetic nerve stimulation (SNS).
Background Access to the cardiac sympathetic neurons may allow modulating the adrenergic tone of the heart while avoiding systemic side effects.
Methods Cardiac sympathetic nerves course within neural sleeves along the subclavian artery. Because of this proximity, transvascular SNS was attempted with electrode catheters inside the subclavian artery in 16 pigs.
Results Right/left (R-/L-) SNS (20 Hz) during ventricular pacing at 200/min evoked a >100% increase of left ventricular systolic pressure (baseline: 51 ± 1 mm Hg; L-SNS: 118 ± 26 mm Hg; R-SNS: 116 ± 33 mm Hg; p < 0.001) while systemic vascular resistance remained unchanged. There was a sigmoid dose-response curve with rapid on- and offset of the effect during SNS initiation/cessation. Positive inotropic effects persisted for 12 h of continued SNS (n = 4). Besides positive dromotropic effects, L-SNS/R-SNS yielded a 41% and 77% sinus rate increase, respectively.
Conclusions The neural adrenergic tone to the heart can be selectively increased by catheter stimulation of cardiac efferent sympathetic nerves.
The sympathetic nervous system exerts its effects via humoral and neural pathways. Access to organ-specific autonomic neurons would allow therapeutic modulation of the autonomic tone of a target organ while avoiding undesired systemic side effects observed during pharmacologic sympathetic stimulation or blockade. A selective elevation of the cardiac parasympathetic neural tone has recently been obtained in humans (1). The present study introduces a percutaneous approach for identification and stimulation of sympathetic nerves, which exclusively innervate the heart.
Animal preparation and instrumentation
In 16 pigs (71 ± 6 kg), anesthesia was induced with 400 mg azaperone intramuscularly and maintained by sodium pentobarbital (bolus: 16 mg/kg, infusion: 5 to 20 mg/kg/h) and N2O/O2(Dräger-Sulla-808V/Dräger, Lübeck, Germany). Six surface electrocardiogram limb leads were recorded. After heparinization (1,000 IE/h), multipolar electrode catheters were inserted into the coronary sinus, high right atrium, and right ventricular apex via femoral/jugular veins.
A pigtail catheter was introduced into the left ventricle (LV) (n = 16) and a Swan-Ganz-Catheter (Becton/Dickinson, Sandy, Utah) into the pulmonary artery (n = 6) for pressure recording and calculation of cardiac output and total peripheral resistance (TPR) during sinus rhythm and ventricular pacing at 200/min. The rates of LV systolic pressure increase (end-diastole to peak-systole) and decrease (aortic valve closure to beginning of diastole) were calculated.
The RR, PR, QRS- QT, and QTcintervals were measured in lead II. The intervals between ventricular deflections in proximal and distal coronary sinus electrograms were averaged to calculate local conduction velocity by dividing inter-electrode distance by time.
Effective refractory periods (ERPs) were determined at the high right atrium, interatrial septum/left atrium (proximal/distal coronary sinus), and right ventricular apex (extrastimulus step-size: 2 ms; baseline cycle length: 350 ms). An atrial ERP heterogeneity index (1 · SD/mean · 100%) was calculated.
Sympathetic nerve stimulation (SNS)
Efferent sympathetic cardiac nerves course within neural sleeves (ansae subclaviae) adjacent to both subclavian arteries (2). For SNS, deflectable electrode-catheters (Cordis-Corp., Baldwin Park, California) were introduced into the subclavian arteries via the femoral artery (Fig. 1).Sympathetic nerve stimulation was attempted over the distal electrode pair (20 Hz, 37.5 V, 2-ms pulse duration, Grass-S-88-stimulator/Astro-Med-Inc., West Warwick, Rhode Island). While gently rotating, advancing, or withdrawing the catheter, the SNS site was identified by an arterial pressure increase. After SNS, 5 min elapsed for heart rate and pressure normalization.
In eight pigs, SNS was performed before/after beta1+2-receptor blockade (propranolol, 0.2 mg/kg intravenously). In four pigs, L-SNS at 37.5 V was continued over 12 h during ventricular pacing at 200/min.
Data are expressed as mean values ± 1 SD. Repeated-measures analysis of variance with Dunnett’s post-test was used for repeated measures. The Student ttest was applied for quantitative variables. A p value <0.05 was considered significant.
In all 16 pigs cardiac sympathetic nerves along the subclavian arteries could be identified 1 to 2 cm proximal to the offspring of the thoracic artery within 10 min (Fig. 2).At the effective site the catheter position remained stable throughout the experiment.
Inotropy, chronotropy, and dromotropy
Sympathetic nerve stimulation more than doubled LV systolic pressure (Fig. 3)independent of a concomitant sinus rate increase (Fig. 4).The dose-response curve revealed a sigmoid shape with a quick on-/offset of the inotropic effect within 20 to 30 s after SNS initiation/cessation (Fig. 5).Right-sided/left-sided sympathetic nerve stimulation (R-SNS/L-SNS, respectively) increased cardiac output during sinus rhythm by 60% but did not increase TPR (Table 1).
During R-SNS/L-SNS, a 43%/26% shortening of the sinus cycle length occurred. Likewise, the PR interval declined from 127 ± 17 ms to 107 ± 14/105 ± 9 ms during L-SNS/R-SNS (p < 0.01). All SNS-mediated effects were abolished by propranolol (Table 1).
Depolarization and repolarization
Sympathetic nerve stimulation decreased right ventricular and atrial ERPs without changing atrial ERP heterogeneity (Table 2).Propranolol prevented the ERP shortening. Sympathetic nerve stimulation did not significantly change QTctime but shortened QRS width and increased local ventricular conduction velocity (Table 3).
Programmed stimulation during SNS did not induce ventricular fibrillation. Right-sided SNS at 37.5 V elicited wide QRS tachycardias (cycle length 350/390 ms) in 2 of 16 pigs, which terminated within 30 s after SNS cessation. This cycle length was slightly shorter than the preceding sinus cycle length, consistent with an accelerated idioventricular rhythm. Right-sided SNS (L-SNS) at 37.5 V induced atrial fibrillation (AF) in 5 of 12 (2 of 12) pigs, which dissipated within 60 s after SNS cessation.
Long-term efficacy and safety
Despite a slight decrease of the positive inotropic response during the first 2 h of continued SNS, a more than 90% increase of LV systolic pressure, rate of systolic pressure development, and cardiac output could be maintained for 12 h of SNS, whereas TPR was not significantly altered (Figs. 6A to 6D).
Postmortem inspection of the subclavian arteries revealed no macroscopic thrombus formation (n = 16), but revealed circumscript microscopic superficial endothelial lesion (length 2 to 3 mm) without thrombus or involvement of the lamina elastica interna or tunica media in 3 of 4 animals subjected to 12 h of SNS.
The present study demonstrates how the neural sympathetic tone to the heart can be selectively increased by transvascular electrical neural stimulation. A graded-response augmentation of LV contractile force can thereby be obtained depending on the chosen stimulus intensity. The effect can be maintained for at least 12 h of continued SNS, with a slight decrease of the inotropic response during the first 2 h. Such an initial loss of the pressure response to open-chest SNS has been described before and been attributed to a neuronal inhibition mechanism using nicotinic cholinergic synaptic connections to thoracic autonomic ganglia (3). By contrast, alpha-receptor or muscarinic cholinergic-mediated presynaptic inhibition of neuronal noradrenaline release could be ruled out in these studies, as was postsynaptic beta-receptor desensitization (4).
A concomitant positive chronotropic effect was less pronounced during L-SNS, which is in line with previous observations in open-chest dogs (5,6). The comparable effects of R-SNS or L-SNS on ventricular inotropy and atrial refractoriness may be explained by a concomitant activation of afferent cardiac fibers (7). The contralateral stellate ganglion may thereby also be activated, and the discharge of efferent fibers from the opposite site may be increased (8).
The positive inotropic response increased while the catheter approached the stimulation site with maximal inotropic effects. This supports the hypothesis that the magnitude of effects depended on how close the electrode was to the ansa subclavia. Likewise, the correlation between stimulus strength and inotropic effects may be partly due to an increasing recruitment of nerve fibers in proximity to the stimulation catheter.
There are slight anatomic differences between human and porcine ansae subclaviae: in humans, the right ventral ansa is thin and may consist of two or more slips (9). In pigs, both ventral ansae are thin, with the right ventral ansa connecting to more than one middle cervical ganglion (10). In both species a ventral ansa can be found adjacent to the subclavian artery. This offers the opportunity to functionally identify these nerve structures with the technique described herein despite some anatomic variability.
The 15% decrease of atrial ERP was larger than in open-chest experiments (11). This may be due to intact sympathetic nerves in the present study, which leaves the opportunity of central mediated changes of the cardiac autonomic tone. Different stimulus intensities or ERP determination protocols may also have contributed. However, the SNS-mediated ERP decrease is small compared to parasympathetic stimulation (12). Still, R-SNS elicited AF in almost half of the pigs. Similarly, in baboons arrhythmias are more likely to occur during open-chest R-SNS (2). This is evidence that the sympathetic neural system preferentially contributes to AF by triggering extrasystoles rather than by substantially modifying the atrial electrophysiologic substrate.
Sympathetic nerve stimulation also shortened ventricular ERP and increased conduction velocity, whereas a non-significant QTc-time shortening was noted. This is in line with Ben-David and Zipes (13), and Cardinal et al. (14), but in contrast to Yanowitz et al. (15). Different stimulation intensities rather than species differences may be operative.
Clinical implications have to be considered cautiously, as this is a proof of principle study in animals. Left-sided SNS, however, may be developed as adjunct treatment of acute systolic heart failure because it avoids TPR increases usually obtained during intravenous catecholamine treatment.
Right-sided SNS elicited self-terminating accelerated idioventricular rhythms in 2 of 16 pigs, as has been reported (16). It will be mandatory to assess a possible arrhythmogenicity of SNS in congestive heart failure models and to evaluate whether the SNS response is preserved in circumstances of down-regulated ventricular beta-receptors and reduced cardiac norepinephrine stores. In such circumstances a striking increase in heart rate might occur relative to the inotropic effect.
Furthermore, SNS may stimulate afferent sympathetic nerves, which may not only modify the effects of efferent cardiac sympathetic stimulation, but also cause untoward CNS-mediated effects or sensations of discomfort. Although this would not necessarily preclude a clinical use, as most patients are sedated or anesthetized during severe acute heart failure, further experiments in awake animals with heart failure are necessary until SNS can be applied in humans. Anesthetics might have blunted a baroreflex-mediated vasodilation during the SNS induced pressure increase (17).
Although a preserved positive inotropic effect over 12 h may exert a clinical benefit, it will be important to investigate whether SNS can be maintained longer.
Postmortem inspection revealed minimal microscopic endothelial lesions after prolonged SNS. Because transvascular nerve stimulation does not increase local wall temperature (18), lesions are probably due to catheter pressure against the wall. Similar lesions have been described for coronary angiography catheters (19). Thus, it seems reasonable to expect that the lesions may resolve, which needs to be proven during chronic experiments.
The neural adrenergic tone to the heart can be dynamically and selectively increased by transvascular electrical stimulation of cardiac sympathetic nerves.
- Abbreviations and Acronyms
- atrial fibrillation
- effective refractory period
- left-sided/right-sided sympathetic nerve stimulation
- left ventricle/ventricular
- sympathetic nerve stimulation
- total peripheral resistance
- Received August 29, 2004.
- Revision received February 21, 2005.
- Accepted March 10, 2005.
- American College of Cardiology Foundation
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