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European Journal of Heart Failure 2005 7(5):878-881; doi:10.1016/j.ejheart.2004.10.012
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© 2004 European Society of Cardiology

Vagal heart rate responses to chronic beta-blockade in human heart failure relate to cardiac norepinephrine spillover

Toshihiko Kubo1, John D. Parker, Eduardo R. Azevedo, Deborah J. Atchison, Gary E. Newton, Peter Picton and John S. Floras*

Division of Cardiology, Mount Sinai Hospital and University Health Network Department of Medicine University of Toronto, 600 University Avenue Suite 1614, Toronto, Ontario, Canada, M5G 1X5

* Corresponding author. Tel.: +1 416 586 8704; fax: +1 416 586 8702. E-mial address: john.floras{at}utoronto.ca


   Abstract
Top
 Notes
 Abstract
1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 
We have documented a pre-junctional β-2 adrenoceptor mediated reduction in cardiac norepinephrine spillover (CNES) in heart failure patients receiving chronic β-blockade. Our present objective was to ascertain the consequence of this decrease for vagal heart rate (HR) regulation by determining CNES, arterial baroreflex sensitivity for HR (BRS) and arterial baroreflex modulation of muscle sympathetic nerve activity (MSNA) before and upon 4 months of β-blockade with either carvedilol or metoprolol. In 19 heart failure patients in sinus rhythm (age: 55±2 [mean±S.E.]; ejection fraction: 20±2%), β-blockade increased BRS from 4.8±0.9 to 7.9±1.3 ms/mm Hg (P<0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=–0.52; n=16, P<0.05). Chronic β-blockade in heart failure augments reflex vagal control of HR at an efferent site of interaction involving blockade of cardiac sympathetic pre-junctional β-2 adrenoceptors that facilitate NE release.

Key Words: Adrenergic receptor blockers • Autonomic nervous system • Baroreflex • Heart rate variability • Receptors, adrenergic, beta • Sympathetic nervous system

Received May 10, 2004; Revised August 4, 2004; Accepted October 14, 2004


   1. Background
Top
 Notes
 Abstract
 1. Background
2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 
In the recently published randomized Carvedilol Or Metoprolol European Trial (COMET) heart failure trial, carvedilol (mean dose 42 mg/day) demonstrated superiority over metoprolol tartrate (mean dose 85 mg/day) with respect to cardiovascular death, a therapeutic benefit evident within 6 months [1]. The considerable commentary generated by this observation has thus far focused on issues of drug formulation and dosing, and on the different post-junctional β-adrenoceptors blocked by these antagonists. The potential contribution of augmented parasympathetic tone to this difference in event rates has received less attention. Reductions in indices of parasympathetic modulation of heart rate (HR), including arterial baroreflex sensitivity for HR (BRS) and vagal contributions to tonic HR variability (HRV) identify heart failure patients at increased risk of premature death [2,3]. Because increased cardiac sympathetic activity attenuates parasympathetic influences at several sites of action, the possibility that β-blockade improves vagal modulation of HR merits consideration.

We have previously investigated the effects of metoprolol and carvedilol on a variety of autonomic variables in patients with congestive heart failure (CHF) [4]. The primary endpoint of that study was the impact of non-selective versus β-1 selective blockade on cardiac norepinephrine spillover (CNES). Although carvedilol significantly reduced CNES while metoprolol did not, analysis of the individual data demonstrated a relatively broad spectrum of treatment effects. As such, these data provided an opportunity to explore, in patients with CHF, the impact of changes in cardiac sympathetic activity on indices of tonic and reflex parasympathetic tone.


   2. Aims
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 Notes
 Abstract
 1. Background
 2. Aims
3. Methods
 4. Results
 5. Conclusion
 References
 
We reasoned that if chronic β-blockade in CHF resulted in less NE released from cardiac sympathetic nerves to counter the action of acetylcholine at the sinus node, reflex vagal HR modulation should increase. Our present objective was to test this hypothesis.


   3. Methods
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Methods
4. Results
 5. Conclusion
 References
 
Our published trial involved 36 patients with stable Class II or III ischaemic and non-ischaemic CHF, who provided written informed consent following Institutional Ethics Review that conformed with the principles outlined in the 1964 Declaration of Helsinki. Subjects were randomly allocated carvedilol or metoprolol tartrate, and restudied after 4 months [4]. The present analysis excluded patients with atrial fibrillation or frequent ventricular ectopy, those who died, or chose not to be restudied. Paired BRS data were available for blinded analysis in 19 subjects (mean age, 55±2 years [mean±S.E.], left ventricular ejection fraction 20±1%, 15 NYHA Class II; 9 with ischemic cardiomyopathy), of whom 11 received carvedilol (mean dose 47±3 mg/day) and 8 metoprolol (mean dose 72±11 mg/day). Of these, 16 (10 on carvedilol, mean 46 mg/day, and 6 receiving metoprolol, mean 62 mg/day) consented to a second CNES study. Every patient received either an angiotensin-converting enzyme inhibitor or receptor blocker, and the proportion receiving digoxin (7/19) was similar in the two groups.

Methods for deriving CNES, using standard radiotracer methodology, and muscle sympathetic nerve activity (MSNA) have been previously published [4]. MSNA, lead II of the electrocardiogram and blood pressure (BP) tracing (Ohmeda 2300 Finapres, Englewood, CO) were recorded during quiet supine rest and digitized for power spectral analysis [5]. Patients were then randomly allocated metoprolol or carvedilol. All pre-existing drug treatment was maintained, and this 2-day protocol was replicated after 4 months of β-blockade.

Arterial BRS was estimated using the systolic BP and R–R interval sequence method. For each subject, the mean value for those slopes with highly correlated sequences (r>0.85) was used to represent spontaneous BRS for HR. The variability of HR, BP and MSNA was calculated by fast Fourier transformation according to previously reported methods [5]. Conventional spectral bands were derived: very low frequency (VLF), 0.0098–0.05 Hz; low frequency (LF), 0.05–0.15 Hz; and high frequency (HF), 0.15–0.50 Hz, with total power (TP) representing the sum of power within these three bands. The HR ratio HF/TP was used to estimate vagal contributions to total spectral power. The gain of the transfer function from the input variable (BP) to the output variable (MSNA) was calculated to determine arterial baroreflex regulation of MSNA. Power in the cross-spectrum of BP and MNSA was divided by power in the auto-spectrum of BP. Average values for gain and coherence across these three frequency bands were then calculated, according to methods described previously in detail [5].

All variables of interest were determined prior to unblinding of the investigators. When data were distributed normally, paired t-tests and linear regression analyses were used for within-group comparisons of pre and β-blockade values. Wilcoxon's rank sum test or log10 transformation was applied when tests of normality failed. P<0.05 was required for significance.


   4. Results
Top
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 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
5. Conclusion
 References
 
Overall (n=19), β-blockade had no effect on either systolic or diastolic BP (120±6/67±3 vs. 122±6/71±2 mm Hg at baseline). β-Blockade reduced HR from 74±3 to 61±2 beats/min (P<0.001), and increased the gain of the arterial baroreceptor reflex regulation of HR (BRS) (from 4.8±0.9 to 7.9±1.3 ms/mm Hg; n=19, P<0.005; Fig. 1, left panel), but had no effect on the arterial baroreflex modulation of MSNA (Fig. 1, right panel). Increases in BRS with β-blockade were inversely related to changes in CNES (r=–0.52; n=16; P=0.041; Fig. 2).


Figure 1
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  		Fig. 1 Gain of arterial baroreflex regulation of heart rate (HR) (BRS) is increased significantly by 4 months of β-adrenoceptor blockade (*P<0.005) (left panel). If the arterial baroreflex regulation of HR was increased by an effect of β-blockade on an afferent or central component of the baroreflex arc, a concordant increase in the arterial baroreflex regulation of muscle sympathetic nerve activity (MSNA) would be anticipated. The right panel illustrates gains of transfer functions between variability of blood pressure (BP) as the input variable, and variability of muscle sympathetic nerve activity (MSNA) as the output variable (i.e., arterial baroreflex regulation of MSNA, as described in greater detail in Ref. [5]) within each of the very low, low and high frequency spectral bands. Note that β-blockade had no effect on the arterial baroreflex modulation of MSNA at any frequency band, an observation consistent with the concept that its augmentation of the arterial baroreflex regulation of HR (left panel) occurred at an efferent site. Values are means±S.E. Open bars, before treatment; hatched bars, 4 months after treatment. VLF, very low frequency, 0–0.05 Hz; LF, low frequency, 0.05–0.15 Hz; HF, high frequency, 0.15–0.5 Hz.

 


Figure 2
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  		Fig. 2 Changes in cardiac norepinephrine spillover (CNES) and changes in the gain of the spontaneous baroreflex sensitivity (BRS) for heart rate after 4 months of β-adrenoceptor blockade (n=16) (r=–0.52; P=0.041). Metoprolol-treated patients appear in open circles, carvedilol-treated patients in closed circles.

 
Because mean values for cardiac NE spillover decreased specifically in the 10 carvedilol-treated subjects (from 203±35 to 139±27 pmol/min; P<0.05), we elected to investigate further the potential relationship between CNES and parasympathetic tone in this subgroup. Consistent with our primary hypothesis, the BRS of carvedilol-treated patients increased from 3.8±1.2 to 7.5±1.9 ms/mm Hg, (P<0.001), HF HR spectral power rose from 47±20 to 112±39 ms2 (P=0.026) and the HRV HF/TP ratio doubled, from 0.09±0.02 to 0.18±0.04 (P=0.015), whereas MSNA (42.2±5.1 vs. 49.6±5.1 bursts/min; P=0.25) and the arterial baroreflex modulation of MSNA were unchanged.


   5. Conclusion
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
References
 
The impact of sympathetic activation and vagal withdrawal on sudden cardiac death, and disease progression in heart failure has been extensively documented [6]. Placebo-controlled trials have demonstrated the symptomatic, hemodynamic and mortality benefits of long-term β-blockade for patients with heart failure. However, thus far, the few observations regarding the effects of β-blockade on BRS or HR variability in CHF patients have been inconsistent, and potential mechanisms by which β-blockade might increase vagal HR modulation were not studied.

In the present investigation, involving similar doses and preparations as in the COMET study [1], chronic β-blockade augmented reflex vagal modulation of HR, but had no effect on the arterial baroreflex modulation of MSNA. As well, increases in BRS were related to reductions in CNES. Our findings are therefore best explained by an efferent mechanism, i.e., withdrawal of the inhibitory effects of excess cardiac NE release on vagal modulation of sino-atrial discharge, rather than by augmentation of afferent or central components of the baroreflex arc. In some patients with well-compensated heart failure, characterized by only mild or moderate sympathetic activation, post-junctional β-1 blockade may be sufficient to counter cardiac adrenergic suppression of vagal HR modulation, and thereby increase sino-atrial responsiveness to parasympathetic nerve firing. In the present analysis, these vagal effects of chronic β-blockade were most evident in those subjects allocated carvedilol, which decreased CNES and increased both BRS and vagal HRV. These latter observations suggest an important role for blockade of facilitatory pre-junctional β-2 adrenoceptors upon cardiac adrenergic nerve terminals in mediating autonomic responses associated with favourable outcome in patients with chronic heart failure, and provide insight into a hitherto unappreciated mechanism to explain the mortality differences between carvedilol and metoprolol tartrate reported in the COMET trial.


   Acknowledgements
 
The present analysis was supported by Heart and Stroke Foundation of Ontario (HSFO) Operating Grants T4050 and T3696. Dr. Kubo's Department of Medicine Fellowship was supplemented by unrestricted post-doctoral support from Merck Frosst, SmithKline Beecham and Roche Pharmaceuticals. Dr. Azevedo held an AstraZeneca/Heart and Stroke Scientific Research Corporation of Canada (HSFC) Research Fellowship. Dr. Newton held a HSFC Research Scholarship Award. Drs. Parker and Floras are HSFO Career Investigators.


   Notes
Top
 Notes
Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 
1 Current address: Matsuyama Red Cross Hospital, Masuyama Ehime 790-0826, Japan. Back


   References
Top
 Notes
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 

  1. Poole-Wilson P.A., Swedberg K., Cleland J.G., Di Lenarda A., Hanrath P., Komajda M., et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet (2003) 362:7–13.[CrossRef][Web of Science][Medline]
  2. Mortara A., La Rovere M.T., Pinna G.D., Prpa A., Maestri R., Febo O., et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation (1997) 96:3450–3458.[Abstract/Free Full Text]
  3. Ponikowski P., Anker S.D., Chua T.P., Szelemej R., Piepoli M., Adamopoulos S., et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am. J. Cardiol. (1997) 79:1645–1650.[CrossRef][Web of Science][Medline]
  4. Azevedo E.R., Kubo T., Mak S., Al-Hesayen A., Schofield A., Allan R., et al. Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity. Circulation (2001) 104:2194–2199.[Abstract/Free Full Text]
  5. Ando S., Dajani H.R., Floras J.S. Frequency domain characteristics of muscle sympathetic nerve activity in heart failure and healthy humans. Am. J. Physiol. (1997) 273:R205–R212. (Regulatory Integrative Comp. Physiol. 42).[Web of Science][Medline]
  6. La Rovere M.T., Pinna G.D., Hohnloser S.H., Marcus F.L., Mortara A., Nohara R., et al. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation (2001) 103:2072–2077.[Abstract/Free Full Text]

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