Am J Physiol Heart Circ Physiol 291: H2377-H2379, 2006.
First published May 26, 2006; doi:10.1152/ajpheart.00254.2006
0363-6135/06 $8.00
Adverse effects of atrioventricular synchronous right ventricular pacing on left ventricular sympathetic activity, efficiency, and hemodynamic status
Abdul Al-Hesayen and
John D. Parker
Department of Medicine, Division of Cardiology, Mount Sinai and University Health Network Hospitals, University of Toronto, Toronto, Ontario, Canada
Submitted 13 March 2006
; accepted in final form 22 May 2006
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ABSTRACT
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Right ventricular (RV) pacing is now recognized to play a role in the development of heart failure in patients with and without underlying left ventricular (LV) dysfunction. We used the cardiac norepinephrine spillover method to test the hypothesis that RV pacing is associated with cardiac sympathetic activation. We studied 8 patients with normal LV function using temporary right atrial and ventricular pacing wires. All measurements were carried out during a fixed atrial pacing rate. The radiotracer norepinephrine spillover technique was employed to measure total body and cardiac sympathetic activity while changes in LV performance were evaluated with a high-fidelity manometer catheter. Atrioventricular synchronous RV pacing, compared with atrial pacing alone, was associated with a 65% increase in cardiac norepinephrine spillover, an increase in LV end-diastolic pressure, and a reduction in myocardial efficiency. These responses may play a role in the development of heart failure and poor outcomes that are associated with chronic RV pacing.
pacemaker; dyssynchrony; sympathetic activity
IATROGENIC LEFT BUNDLE BRANCH BLOCK (LBBB), caused by right ventricular (RV) pacing, is associated with increased mortality and hospitalization rates in the setting of depressed left ventricular (LV) systolic function (18). Furthermore, iatrogenic LBBB in patients with normal systolic function is associated with the development of impaired cardiac function and an increased risk of heart failure (15). The mechanism(s) of these adverse effects of right ventricular pacing remain uncertain.
Congestive heart failure (CHF) is characterized by generalized and organ-specific activation of the sympathetic nervous system (10). This activation appears to occur early in the course of heart failure development and antedates the activation of other neurohormonal systems (5). An increase in efferent cardiac sympathetic activity precedes the generalized increase in sympathetic nervous system activity and is an independent prognostic marker (11, 14). The impact of RV pacing and the resulting iatrogenic LBBB on cardiac-specific sympathetic activity remains unknown.
Therefore, in patients with normal LV function, we tested the hypothesis that atrioventricular (AV) synchronous RV pacing would be acutely associated with activation of the sympathetic nervous system and a reduction in LV chamber efficiency, as well as adverse effects on LV hemodynamics.
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EXPERIMENTAL PROCEDURES
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We studied eight patients with normal LV function (mean age 63 ± 3 yr; ejection fraction 53 ± 3%). Baseline therapy included angiotensin-converting enzyme inhibitors (n = 5), 
-blockers (n = 5), calcium channel antagonists (n = 2), and lipid-lowering agents (n = 7). The subjects were referred for coronary angiography to investigate a chest pain syndrome. Two subjects had three-vessel disease, one had two-vessel disease, four had single-vessel disease, and one had normal coronary arteries.
All medications were held on the morning of the study. The Mount Sinai Hospital Research Ethics Board for experimentation involving human subjects approved the protocol, and written informed consent was obtained from all participants.
After a diagnostic coronary angiogram without sedation, patients were instrumented with temporary right atrial and ventricular pacing wires. A micromanometer-tipped catheter (Millar Industries) was placed in the LV for monitoring of LV pressures and the first derivative of LV pressure (LV peak +dP/dt). This high-fidelity LV pressure recording was also used to determine the rate of LV isovolumic relaxation according to methods our laboratory has previously described (4). Finally, a coronary sinus thermodilution catheter (type CCS-7U-90B; Webster Laboratories) was placed in the coronary sinus with an antecubital or jugular venous approach. Coronary sinus blood flow measurements were performed in duplicate according to the method of Ganz et al. (6).
Sympathetic activity was estimated by the measurements of cardiac and total body norepinephrine spillover according to the radiotracer technique of Hasking et al. (10). Plasma catecholamine concentrations were measured using high-performance liquid chromatography with electrochemical detection as previously described (1, 2). The biochemical analysis was performed by personnel blinded to patient status.
All measurements were done at a fixed atrial pacing rate (
5 beats/min above the intrinsic sinus rate). Hemodynamics (arterial femoral pressure, LV pressure, LV +dP/dt, and the time constant of isovolumic relaxation, 
) and cardiac norepinephrine spillover (CANESP) were determined at baseline (right atrial pacing with normal AV conduction) after 20 min of RV pacing (DDD with RV capture, iatrogenic LBBB) and 20 min of right atrial pacing (recontrol). The product of mean coronary flow and the arterial versus coronary sinus oxygen saturation difference were calculated to estimate myocardial oxygen consumption (MVO2). Myocardial efficiency was calculated as (LV +dP/dt)/MVO2 (12).
Data are presented as means ± SE, and statistical analysis was done using a repeated-measures ANOVA with a Bonferroni correction for post hoc comparisons. Correlations between hemodynamic and neurochemical measurements were made using simple linear regression.
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RESULTS
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Hemodynamic responses.
Hemodynamic responses are given in Table 1. All patients were in sinus rhythm. The mean PR interval was 191 ± 23 ms, and the QRS duration was 86 ± 4 ms. During AV synchronous RV pacing, the PR was shortened to 143 ± 12 ms and the electrocardiogram exhibited a LBBB pattern with QRS duration of 155 ± 9 ms (P < 0.0001 vs. baseline). RV pacing caused no change in systemic arterial pressure but caused a significant increase in LV end-diastolic pressure (+61 ± 32%, P < 0.02). There were no symptoms or electrocardiographic changes suggestive of ischemia during pacing, and there was no change in coronary sinus lactate levels (0.54 ± 0.10 vs. 0.52 ± 0.12 mmol/l, P = not significant).
Measures of sympathetic activity.
CANESP increased by 65 ± 26% during iatrogenic LBBB (P = 0.015) and returned to baseline during recontrol (Fig. 1). This increase in sympathetic activity was cardiac specific, because RV pacing had no effect on total body norepinephrine spillover (Table 1). Furthermore, this increase in CANESP was significantly related to the increase in QRS duration (Fig. 2).
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Fig. 1. Effects of atrioventricular synchronous right ventricular pacing on cardiac sympathetic activity. CANESP, cardiac norepinephrine spillover; BSL, baseline; LBBB, left bundle branch block (RV pacing); RC, recontrol. *P < 0.05.
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Myocardial contractility, relaxation, and efficiency.
Data regarding myocardial contractility, relaxation, and efficiency are given in Table 1. Iatrogenic LBBB was associated with a slight reduction in LV peak +dP/dt that did not reach statistical significance (–5 ± 3%, P = 0.1). RV pacing caused a significant slowing of isovolumic relaxation (+10 ± 2%, P < 0.004). There was a significant relationship between the decrease in LV peak +dP/dt and the increase in CANESP (r = 0.89, P < 0.02). Similarly, the slowing of ventricular relaxation was significantly correlated with the increase in CANESP (r = 0.92, P < 0.008). Furthermore, iatrogenic LBBB was accompanied by a 9 ± 4% reduction in LV chamber efficiency (P < 0.05) as MVO2 increased while LV peak +dP/dt decreased.
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DISCUSSION
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We observed an increase in cardiac sympathetic activity, a decrease in LV chamber efficiency, slowing of the rate of LV isovolumic relaxation, and a rise in LV end-diastolic pressure in response to AV synchronous RV pacing. Iatrogenic LBBB was associated with a 65% increase in cardiac norepinephrine spillover, an index of efferent cardiac sympathetic nerve activity. The reason for this increase is not entirely clear; however, it would appear that RV pacing stimulates one or more afferent reflexes that increase cardiac sympathetic drive. It is possible that reduced LV contractility and an associated reduction in firing rate of ventricular mechanoreceptors lead to withdrawal of vagal tone and sympathetic excitation, thus providing an explanation for our findings (16, 17). The observed correlation between decreased measures of LV inotropic and lusitropic function during RV pacing and the observed increase in CANESP would be consistent with this hypothesis. This increase does not appear to be mediated by arterial and/or cardiopulmonary baroreflex function, because there was no change in arterial blood pressure and a slight rise in ventricular filling pressure. The cardiac specificity of this response is not surprising given that a number of previous investigations have documented that sympathetic responses can be regionally specific (7).
Sympathetic activation plays a central role in the development and progression of heart failure. Cardiac sympathetic activity is elevated early in the setting of heart failure and has independent prognostic implications (11, 14). The relevance of this specific marker has been recently highlighted by the results of the COMET trial (13). Carvedilol reduced cardiac sympathetic activity and was associated with a survival benefit compared with metoprolol, which has a neutral effect on cardiac sympathetic activity (3).
Our observations complement the findings of Hamdan et al. (8, 9), who documented a reduction in muscle sympathetic nerve activity with biventricular pacing compared with RV pacing or an intraventricular conduction delay in patients with CHF. Our study provides unique data documenting the deleterious effects of iatrogenic LBBB compared with normal conduction on LV function and cardiac sympathetic activity. We have also documented the relationship between changes in QRS duration and cardiac sympathetic activity. Furthermore, we have documented that the sympathetic activation that occurs in response to RV pacing is cardiac specific, a response that is similar to the cardiac-specific sympathetic activation that is observed patients with early LV dysfunction (14).
It is important to recognize some of the limitations of our study. Although we did not measure the chronic effects of RV pacing on these parameters, we hypothesize that the observed effects on cardiac sympathetic activity, measures of LV efficiency, and hemodynamics could provide a mechanistic basis for the observation that RV pacing is associated with worsening of LV function and development of heart failure. These observations may be of particular relevance to those patients with depressed LV function who require RV pacing, because they may be particularly susceptible to these adverse effects. The AV delay had to be reduced to provide ventricular capture during AV synchronous RV pacing. It is not possible from our experimental protocol to define the isolated effect of this electrophysiological change on cardiac sympathetic activity.
In summary, these observations document, for the first time in humans, that RV pacing has adverse effects in patients with normal LV function and intact AV conduction. It is associated with increases in measures of cardiac sympathetic activity, decreases in LV chamber efficiency, and slowing of LV isovolumic relaxation. These findings provide mechanistic information relevant to the clinical observation that RV pacing can have adverse clinical consequences.
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GRANTS
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This study was funded by an operating grant (T-3696) from the Heart and Stroke Foundation of Ontario.
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ACKNOWLEDGMENTS
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We thank the staff of the Cardiovascular Clinical Research Laboratory of Mount Sinai Hospital for help in the completion of these studies.
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FOOTNOTES
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Address for reprint requests and other correspondence: J. D. Parker, Dept. of Medicine, Division of Cardiology, Mount Sinai and Univ. Health Network Hospitals, Univ. of Toronto, 600 Univ. Ave., Suite 1609, Toronto, Ontario, Canada M5G 1X5 (e-mail: jdp{at}ca.inter.net)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Copyright © 2006 by the American Physiological Society.
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ABSTRACT
EXPERIMENTAL PROCEDURES
