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Am J Physiol Heart Circ Physiol 291: H2647-H2652, 2006. First published July 14, 2006; doi:10.1152/ajpheart.00373.2006
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Sympathetic control after cardiac resynchronization therapy: responders versus nonresponders

Boutaïna Najem,1 Philippe Unger,1,* Nicolas Preumont,1,* Jean-Luc Jansens,1 Anne Houssière,1 Atul Pathak,1 Olivier Xhaet,1 Laurence Gabriel,3 Alain Friart,2 Luc De Roy,3 Jean-Luc Vandenbossche,4 and Philippe van de Borne1

1Department of Cardiology and Cardiac Surgery, Erasme Hospital, Brussels; 2Department of Cardiology, Centre Hospitalier Universitaire de Tivoli, La Louvière; 3Department of Cardiology, Universite Catholique de Louvain, Mont-Godinne Hospital, Mont-Godinne; and 4Department of Cardiology, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium

Submitted 8 April 2006 ; accepted in final form 27 June 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Cardiac resynchronization therapy (CRT) decreases muscle sympathetic nerve activity (MSNA) in patients with severe congestive heart failure (CHF) and cardiac asynchrony. Whether this affects equally patients who clinically respond or not to CRT is unknown. We tested the hypothesis that the favorable effects of CRT on MSNA disappear on CRT interruption only in those who respond to CRT. Twenty-three consecutive CHF patients participated in the study, among whom 16 presented a symptomatic improvement by one or more New York Heart Association (NYHA) functional classes 15 ± 5 mo after CRT (responders), and seven had not improved after 12 ± 4 mo of CRT (nonresponders). MSNA and echocardiographic recordings were obtained in random order during atrio-right ventricular pacing (ARV), without stimulation in patients who were not pacemaker dependent (OFF, n = 17), and during atrio-biventricular pacing (BIV). Responders had a longer 6-min walking distance, a lower NYHA class and brain natriuretic peptide levels, and a better quality of life than did nonresponders (all P < 0.05). MSNA increased by 25 ± 7% in the responders, whereas it remained unchanged in the nonresponders, when shifting from the BIV mode to a nonsynchronous condition (ARV and OFF modes) (P < 0.01). Cardiac output decreased by 0.7 ± 0.2 l/min in the responders but did not change when shifting from the BIV mode to the nonsynchronous pacing mode in the nonresponders (P < 0.01). In conclusion, reversible sympathoinhibition is a marker of the clinical response to CRT.

sympathetic nervous system; heart failure; muscle sympathetic nerve activity

SYMPATHETIC ACTIVATION is a key component of the physiopathology of chronic congestive heart failure (CHF) (12, 14, 25). This sympathetic overactivity is directly related to the severity of heart failure and is implicated in the poor prognosis of the disease (9). One of the major aims of the therapeutic approach in heart failure is to reduce sympathetic overactivity while improving cardiac hemodynamics and functional capacity (15, 19, 32).

Cardiac resynchronization therapy (CRT) by atrio-biventricular pacing (BIV) improves symptoms, quality of life, exercise tolerance, and prognosis of patients with drug-refractory CHF and left bundle branch block (1, 5, 7, 8).

Biventricular pacing reduces muscle sympathetic nerve activity (MSNA) compared with atrio-right ventricular pacing (ARV) (24) and right atrial pacing (22) in the acute setting. These beneficial effects persist up to 6 mo after resynchronization therapy (21, 28).

However, it is not yet known whether the clinical response to CRT is related to the MSNA inhibitory effects of this therapy. This is of importance because a significant proportion of patients who appear to be ideal candidates for CRT do not show the expected clinical benefits (4). Factors responsible for this relatively high prevalence of nonresponders are not clear (3). Unknown, also, is whether the favorable MSNA effects of CRT persist during even longer follow-up periods.

We tested the hypothesis that long-term sympathoinhibition induced by CRT is acutely reversible when the pacemaker is switched to a nonsynchronous condition (NSC) [i.e., to a conventional ARV mode and pacing cessation (OFF mode)] and that this occurs only in those who respond to CRT by an improved New York Heart Association (NYHA) functional class. This would indicate that persistent MSNA inhibition after CRT is a marker of the clinical response to this therapy.

In CHF patients treated by CRT, we determined MSNA, clinical variables, and noninvasive cardiac hemodynamics during BIV pacing, ARV pacing, and, if the patient was not pacemaker dependent, in the OFF mode.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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The study was approved by the Ethical Committee of the Erasme Hospital, Brussels. Each subject signed an informed consent before inclusion in the study.

Subjects. The responder status to CRT was determined before the experimental recording session. All had undergone a careful determination of their NYHA functional class by their cardiologist before CRT. NYHA functional class before CRT was retrospectively determined in the medical record of the patient by the referring cardiologist. NYHA functional class at the time of the study was determined by the same referring cardiologist (P. Unger, N. Preumont, A. Friart, L. De Roy, and J.-L. Vandenbossche). Thus assessments of NYHA classes were fully independent of the investigators (B. Najem, A. Houssière, A. Pathak, O. Xhaet, L. Gabriel, and P. van de Borne) and blinded to the recordings of the study. A nonresponder patient to CRT was defined prospectively as a patient who had not decreased his or her NYHA functional class at the time of the study (31). A patient who presented a symptomatic improvement by one or more NYHA functional classes at the time of the study was defined as a responder.

Sixteen patients responded to CRT (4 women). In seven patients (1 woman), NYHA functional class did not change (n = 5) or worsened (n = 2) 12 ± 4 mo after CRT.

In all patients, indication for CRT was drug-refractory CHF (NYHA functional class >II) in the presence of a left bundle branch block with a QRS duration >120 ms, a left ventricular ejection fraction assessed by echocardiography <35%, a left ventricular end-diastolic diameter >55 mm, interventricular asynchrony (difference between aortic and pulmonary preejection time delay >40 ms, interventricular mechanical delay). In six patients, the left bundle branch block was induced by a conventional atrio-right ventricular pacemaker that was upgraded to a biventricular pacemaker. In these pacemaker-dependent patients, the OFF mode was not performed.

Measurements. Multiunit recordings of postganglionic MSNA were obtained in all patients with a unipolar tungsten electrode inserted selectively into a nerve fascicle of the right or left peroneal nerve, posterior to the fibular head (28). After obtaining 10 min of an acceptable recording of MSNA during BIV pacing, we performed, in random order, recordings during 10 min of ARV pacing, 10 min in OFF mode, and 10 min of BIV pacing. The OFF mode was recorded only in 17 patients who were not pacemaker dependent (11 responders and 6 nonresponders). MSNA recordings were acquired and analyzed on a MacLab 8/s data acquisition system (ADInstruments, Castle Hill, NSW, Australia).

During the study protocol, we also recorded heart rate (Siemens Medical, ECG Monitoring, Erlangen, Germany), oscillometric blood pressure measurements every 2 min with a Physiocontrol Colin BP-880 sphygmomanometer (Colin Press Mate, Colin, Komaki City, Japan) and continuous oxygen saturation determinations (Nellcor N-100 C pulse oxymeter, Pleasanton, CA).

Blood samples for plasma norepinephrine were obtained in 10 patients in each mode during the MSNA recording in carefully standardized supine resting conditions. Samples were collected in prechilled heparinized tubes (10 ml), immediately placed on ice, and then centrifuged at 4°C. Norepinephrine levels were assayed by high-performance liquid chromatography (17).

A blood sample was also taken in all patients to determine brain natriuretic peptide (BNP) plasma concentrations by the triage BNP levels point-of-care test (Biosite Diagnostics, San Diego, CA).

An electrocardiogram (Hewlett-Packard XLS electrocardiograph, Palo Alto, CA) was recorded in the three modes to determine the QRS axis and duration.

Standard echocardiography, including Doppler measurement (Vivid 7, General Electric, Horten, Norway), was performed in patients according to the American Society of Echocardiography recommendations (16). Measurements were performed in the three modes in the same order as in the MSNA recordings. The echocardiographist was blinded according to the pacemaker stimulation mode. Three consecutive beats were measured and averaged. Left ventricular end-diastolic and end-systolic volumes were measured by the biplane Simpson method and were used for left ventricular ejection fraction determinations. Aortic and pulmonary preejection times were derived from continuous-wave Doppler measurements, allowing calculation of interventricular mechanical delay. Doppler echocardiography allowed measurements of cardiac output at the level of the left ventricular outflow tract. The rate of pressure rise in systole (dP/dt) was estimated from the continuous-wave Doppler mitral regurgitation (16).

All patients underwent a functional evaluation by a 6-min walking test conducted according to Bittner (6). All completed the self-administered Minnesota Living with Heart Failure questionnaire for scoring quality of life on a scale from 0 (best) to 105 (worst).

Sympathetic nerve traffic analysis. Sympathetic bursts were identified by careful inspection of the voltage neurogram by a trained observer (B. Najem) blinded to the pacemaker stimulation mode and clinical status of patients. Sympathetic activity was expressed as burst frequency per minute and bursts per 100 heartbeats. The amplitude of each burst was determined. Integrated sympathetic activity was calculated as burst frequency multiplied by mean burst amplitude and expressed as the percentage from BIV value. Burst frequency permits comparison of sympathetic nerve activity between patients, whereas both burst frequency and percentage of change in integrated sympathetic activity were used to assess the effects of a change in pacemaker stimulation mode.

Statistical analysis. Analysis of all recordings was fully blinded to the pacemaker stimulation mode and clinical status of patients. Results are expressed as means ± SE. Comparisons of patient characteristics, hemodynamics, and sympathetic activity between responders and nonresponders were made with unpaired two-tailed Student t-tests, whereas comparisons of nominal data were made with a {chi}2-test. The link between norepinephrine concentration and MSNA was assessed by a correlation analysis. Significance was assumed at P < 0.05. Comparisons of changes from BIV pacing to NSC (i.e., conventional ARV mode and OFF mode) between responders and nonresponders were made with an ANOVA, with pacing mode and responder status as factors. Bonferroni contrasts were made a posteriori (4 contrasts, significance assumed at P < 0.0125).


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Patient characteristics. Responders and nonresponders did not differ in age, sex, body mass index, postimplantation delay, and medical treatment (Table 1). In the responders, there were nine patients with ischemic cardiomyopathy, two patients who previously had surgery for valvular heart disease, and five patients with idiopathic cardiomyopathy. In the nonresponders, three patients had ischemic heart disease and four patients had idiopathic cardiomyopathy (P = 0.40).


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  		Table 1. Patient characteristics

 
Comparisons between responders and nonresponders before changes in the pacing modes. Responders had a better clinical status than that of nonresponders, with a longer 6-min walking distance, a better quality of life, and lower levels of BNP (Table 2). In the responders, two patients were in NYHA class I, 13 were in class II, and one was in class III (this patient was in class IV before CRT). In the nonresponders, all patients were in NYHA class III (P < 0.001). Blood pressure, heart rate, left ventricular ejection fraction, and cardiac index did not differ between both groups.


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  		Table 2. Comparison of hemodynamic and sympathetic parameters between responders and nonresponders during BIV pacing before changing the pacing modes

 
MSNA (normalized for heart rate) tended to be lower in the responders than in the nonresponders (P = 0.06), and plasma norepinephrine levels did not differ.

Our observation of a longer 6-min walking distance, a better quality of life, and lower levels of BNP is consistent with the improved NYHA functional class in the responders.

Effects of switching biventricular pacing into a NSC (ARV and OFF) on sympathetic and hemodynamic parameters. MSNA amplitude increased only in the responders when biventricular pacing was switched to a NSC (+25 ± 7% vs. –5 ± 4%, respectively, in the responders and nonresponders) (Table 3 and Figure 1; P < 0.01). A similar, albeit not significant, trend was observed for MSNA burst frequency/100 heartbeats. Blood pressure did not change in responders when switching to a NSC, whereas it decreased in the nonresponders (P < 0.01). Cardiac output decreased by 0.7 ± 0.2 l/min when shifting from the BIV to a NSC in the responders (P < 0.01) but did not change in the nonresponders. The decrease in dP/dt and diastole duration and the increase in interventricular delay after switching to NSC were comparable in responders and nonresponders.


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  		Table 3. Effect of switching to a nonsynchronous mode (BIV and ARV) on hemodynamic and sympathetic parameters

 

Figure 1
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  		Fig. 1. Representative recordings of ECG and neurogram during three pacing modes [atrio-biventricular pacing (BIV); without stimulation (OFF); and atrio-right ventricular pacing (ARV)] in a patient who responded to cardiac resynchronization therapy by a reduction in New York Heart Association class from III to I. Muscle sympathetic nerve activity (MSNA) was higher during the OFF and ARV pacing modes than in the BIV mode.

 
Correlation between MSNA and norepinephrine levels in each mode. The MSNA in each mode was related to norepinephrine levels in the same mode and taken during the MSNA recording (Figure 2; n = 10 patients, r = +0.7, P < 0.0001).


Figure 2
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  		Fig. 2. Correlation analysis between sympathetic activity (MSNA) and plasma norepinephrine during BIV, OFF (if not pacemaker dependent), and ARV pacing in 10 patients. MSNA is related to norepinephrine levels during the different pacing modes.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The main new findings of our study are that 1) sympathoinhibition induced by chronic CRT is acutely reversible when patients are shifted from a synchronous to a NSC; 2) this is observed only in patients who are clinically improved by CRT, even more than a year after initiation of the therapy; and 3) MSNA is positively correlated to norepinephrine levels and reflects overall sympathetic activity in CRT patients.

We are not aware of previous studies on the effects of the responder status to CRT on MSNA. This is also, to the best of our knowledge, the first study to assess effects of different programming modes on sympathetic activity more than a year after CRT.

Our study provides direct evidence that reversible sympathoinhibition is a marker of the clinical response to CRT. Biventricular pacing interruption induced an acute and marked increase in MSNA only in those who improved their NYHA functional class with CRT. This was not due to a pacemaker rate dependency in the responders, because the pacing was stopped only in those who were not pacemaker dependent. Differences in sympathetic reactivity on changes in the pacing mode did not translate, however, into clear-cut reductions in sympathetic burst frequency during BIV pacing in the responders (P = 0.06). There are several possible reasons for the apparent discrepancy between more marked acute increases in MSNA on loss of synchrony and lack of marked MSNA inhibition during chronic synchronous pacing in the responders. First, sympathetic activation involves both increases in burst amplitude and frequency in multiunit recordings (13, 22, 24, 33, 34, 36). Burst frequency, which is used for comparisons of multiunit recordings between subjects (26, 28, 29, 35), is less sensitive to modifications in sympathetic drive than changes in integrated burst activity, which is used for comparisons of changes within an experimental recording (22, 24, 33, 34, 36, 37). Second, it may be that responders to CRT preserve the ability to show acute changes in MSNA, whereas a somewhat more saturated MSNA may have less reserve to further increase sympathetic nerve traffic in the nonresponders (26). Third, baroreceptors are important regulators of acute changes in MSNA but may be less involved in the tonic regulation in baseline MSNA (27). Thus preservation of the acute ability to modify MSNA may not necessarily translate into sustained reductions in mean baseline sympathetic drive.

More functional baroreceptors, which sense changes in cardiac and arterial pressures, could have contributed to differences in MSNA reactivity in our patients (20). In the nonresponders, switching to the NSC induced an acute decrease in blood pressure without any significant effect on MSNA, suggesting that arterial baroreceptors were impaired in those patients.

Preservation of MSNA reactivity in responders may have clinical implications. The magnitude of sympathoexcitation is an important determinant of the hemodynamic outcome of ventricular tachycardia (23). The late recovery of blood pressure during ventricular tachycardia is related to the magnitude of early sympathetic responses (23). The larger sympathetic response when BIV pacing is stopped may explain why blood pressure remained unchanged in the responders but decreased in the nonresponders. Preservation of sympathetic homeostatic mechanisms in CRT patients may thus also prove beneficial during acute conditions such as cardiac arrhythmias (23).

Plasma norepinephrine did not differ between the responders and the nonresponders in our study. This has also been reported after 10 wk of successful cardiac resynchronization as well as in a study where patients were randomized to 3 mo of CRT-on or CRT-off therapy (2, 21). Similar findings have been observed in several conditions where lower MSNA did not translate into reduced plasma norepinephrine concentrations (21, 35). This could be explained by the limited reproducibility of plasma norepinephrine measurement (18) as well as by modifications in norepinephrine clearance in CHF patients (10). MSNA recordings provided more relevant insights into sympathetic regulation during sudden modifications in CRT pacing than plasma norepinephrine in our study. Norepinephrine is, however, an important prognostic factor inversely correlated with survival in CHF (9). The positive correlation between MSNA and norepinephrine underscores the clinical and prognostic relevance of our sympathetic nerve traffic recordings after CRT.

Limitations of the study. Our study has several limitations. First, the study was cross-sectional and included no pre-CRT baseline measurements. Second, previous studies on MSNA and CRT therapy included between 11 and 15 patients. Although a larger number of patients participated in our study, only a small group of seven patients were nonresponders. Third, although severe heart failure was likely the main mechanism for altered autonomic control in our study, we cannot exclude a limited contribution of aging on our findings in the nonresponders. Our study also has several strengths. Responders and nonresponders did not differ in several parameters known to affect MSNA, such as body mass index (29), sex (30), and medical therapy (11). Moreover, only patients who were not pacemaker dependent were switched to an OFF mode. This allowed us to rule out a contribution of pacemaker dependency on our findings when patients were in the OFF mode. Finally, the sequence of the pacing modes was randomized and recordings were analyzed in a blinded fashion.

In conclusion, our study provides direct evidence that reversible sympathoinhibition is a marker of the clinical response to CRT.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by the Erasme Foundation (to B. Najem and O. Xhaet), the Belgian National Fund of Research (to A. Houssière and P. van de Borne), the Emile Saucez-René Van Poucke Foundation (to P. van de Borne), the David and Alice Van Buuren Foundation (to P. van de Borne), and Fonds pour la Chirurgie Cardiaque, Belgium (to P. Unger, J.-L. Jansens, and P. van de Borne).


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. Najem, Dept. of Cardiology, Erasme Hospital, 808 route de Lennik, 1070 Brussels, Belgium (e-mail: bnajem{at}ulb.ac.be)

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.

* P. Unger and N. Preumont contributed equally to this work. Back


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