Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure

A S Androne; K Hryniewicz; R Goldsmith; A Arwady; S D Katz

doi:10.1136/heart.89.8.854

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Cardiovascular medicine

Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure

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Pyridostigmine in CHF: Author's Response to Dr. Nobrega
Stuart D. Katz
Published on: 23 November 2015
Cholinergic stimulation in chronic heart failure: modifiyng predictors of risk
Antonio C.L. Nobrega
Published on: 23 November 2015

Published on: 23 November 2015
Pyridostigmine in CHF: Author's Response to Dr. Nobrega
- Stuart D. Katz, Associate Professor of Medicine
Dear Editor
We greatly appreciate Dr Nobrega’s interest in our recent publication on the acute effects of pyridostigmine on post-exercise heart rate recovery in patients with chronic heart failure.[1]
In accord with our published submaximal exercise data at anaerobic threshold, our more complete analysis of submaximal exercise demonstrated no differences between the effects of pyridostigmine 30 mg and pl...
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Dear Editor
We greatly appreciate Dr Nobrega’s interest in our recent publication on the acute effects of pyridostigmine on post-exercise heart rate recovery in patients with chronic heart failure.[1]
In accord with our published submaximal exercise data at anaerobic threshold, our more complete analysis of submaximal exercise demonstrated no differences between the effects of pyridostigmine 30 mg and placebo on heart rate, oxygen consumption, or oxygen pulse at work rates corresponding to 25-50% of maximal oxygen uptake. Contrary findings during submaximal exercise or mental stress cited by Dr Nobrega may be attributable to differences in the study populations, confounding effects of background medications, or dose of pyridostigmine.[2,3] Indeed, in two of the studies cited by Dr Nobrega, 30mg of pyridostigmine did not change heart rate during submaximal exercise or mental stress in normal subjects.[4,5] We chose to administer 30 mg of pyridostigmine to our heart failure subjects as higher doses have been associated with mild cholinergic side effects in normal subjects.[5,6]
A recent publication on the effects of pyridostigmine on heart rate variability in chronic heart failure patients was not available at the time of our manuscript submission.[7] We agree that our study and the recent publication by Dr Nobrega and colleagues together provide preliminary evidence to suggest that cholinesterase inhibition with pyridostigmine may be a promising new therapeutic modality in patients with chronic heart failure.[1,7] Additional work is needed to determine the optimal dose, formulation, and longer-term safety profile of cholinesterase inhibition in chronic heart failure.
References
(1) Androne AS, Hryniewicz K, Goldsmith R, Arwady A, Katz SD. Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure. Heart 2003;89(8):854-8.
(2) Kawada T, Sugimachi M, Shishido T, Miyano H, Sato T, Yoshimura R, et al. Simultaneous identification of static and dynamic vagosympathetic interactions in regulating heart rate. Am J Physiol 1999;276(3 Pt 2):R782-9. (3) Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, et al. Cholinesterase affects dynamic transduction properties from vagal stimulation to heart rate. Am J Physiol 1998;275(2 Pt 2):R541-7.
(4) Nobrega AC, Carvalho AC, Santos KB, Soares PP. Cholinergic stimulation with pyridostigmine blunts the cardiac responses to mental stress. Clin Auton Res 1999;9(1):11-6.
(5) Serra SM, Costa RV, Bastos BG, Santos KB, Ramalho SH, da Nobrega AC. Exercise stress testing in healthy subjects during cholinergic stimulation after a single dose of pyridostigmine. Arq Bras Cardiol 2001;76(4):279-84.
(6) Sant'anna ID, de Sousa EB, de Moraes AV, Loures DL, Mesquita ET, da Nobrega AC. Cardiac function during mental stress: cholinergic modulation with pyridostigmine in healthy subjects. Clin Sci (Lond) 2003;105(2):161-5.
(7) Behling A, Moraes RS, Rohde LE, Ferlin EL, Nobrega AC, Ribeiro JP. Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure. Am Heart J 2003;146(3):494-500.
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Conflict of Interest:
None declared.
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Published on: 23 November 2015
Cholinergic stimulation in chronic heart failure: modifiyng predictors of risk
- Antonio C.L. Nobrega, Physician and Researcher
Dear Editor
The article by Androne et al.[1] describing the improvement in heart rate recovery after maximal exercise in patients with chronic heart failure when treated with pyridostigmine, supports the recent concept that cholinergic stimulation may have a protective role in cardiovascular disease.[2] We have prompted to investigate this possibility, since depressed heart rate variability[3] and baroref...
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Dear Editor
The article by Androne et al.[1] describing the improvement in heart rate recovery after maximal exercise in patients with chronic heart failure when treated with pyridostigmine, supports the recent concept that cholinergic stimulation may have a protective role in cardiovascular disease.[2] We have prompted to investigate this possibility, since depressed heart rate variability[3] and baroreflex sensitivity,[4] both used as indices of parasympathetic function, has been shown to be independent risk markers for death in chronic heart failure.
We have described previously several aspects of the oral administration of pyridostigmine bromide, an indirect cholinomimetic agent, in healthy volunteers, such as the effect on heart rate variability [5] and the response to physical [6] and mental stress.[7,8] Contrary to the statement by Andone et al,[1] we have demonstrated that pyridostigmine did blunt the heart rate response to physical exercise, an effect previous reported by others,[9] and to mental stress. Our unpublished data with patients with chronic heart failure during exercise reveal that pyridostigmine causes submaximal bradycardia and increased oxygen pulse, a variable calculated by the ratio between oxygen uptake and heart rate that is proportional to stroke volume, suggesting an improvement in cardiac dynamics during physical effort. Unfortunately, our findings could not be compared to those by Androne et al.[1] in this respect, since they did not report data on oxygen pulse.
We have just published [10] results from a ramdomized, double-blind, cross-over study where pyridostigmine reduced ventricular ectopic activity and increased heart rate variability in patients with chronic heart failure. This study together with that of Androne (1) may not contitute enough evidence to support the proposal for large-scale clinical trials to test the hypothesis that selective enhancement of parasympathetic activity will improve outcome,[11] but do certainly point to a new and promising perspective concening the therapeutic management of patients with chronic heart failure.
References
(1) Androne AS, Hryniewicz K, Goldsmith R, Arwady A, Katz SD. Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure. Heart 2003;89(8):854-8.
(2) Nobrega ACL, Castro RRT. Parasympathetic dysfunction as a risk factor in myocardial infarction: what is the treatment? Am Heart J 2000;140(4):E23
(3) Nolan J, Batin PD, Andrews R, et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK- heart). Circulation 1998;98(15):1510-6.
(4) Mortara A, La Rovere MT, Pinna GD, et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 1997;96(10):3450-8.
(5) Nobrega AC, dos Reis AF, Moraes RS, Bastos BG, Ferlin EL, Ribeiro JP. Enhancement of heart rate variability by cholinergic stimulation with pyridostigmine in healthy subjects. Clin Auton Res 2001;11(1):11-7.
(6) Serra SM, Costa RV, Bastos BG, Santos KB, Ramalho SH, da Nobrega AC. Exercise stress testing in healthy subjects during cholinergic stimulation after a single dose of pyridostigmine. Arq Bras Cardiol 2001;76(4):279-84
(7) Nobrega AC, Carvalho AC, Santos KB, Soares PP. Cholinergic stimulation with pyridostigmine blunts the cardiac responses to mental stress. Clin Auton Res 1999;9(1):11-6.
(8) Sant'anna ID, Sousa EB, Moraes AV, Loures DL, Mesquita ET, Nobrega AC. Cardiac function during mental stress: cholinergic modulation with pyridostigmine in healthy subjects. Clin Sci (Lond) 2003;105(2):161- 5.
(9) Wenger B, Quigley MD, Kolka MA. Seven-day pyridostigmine adminstration and thermoregulation during rest and exercise in dry heat. Aviat Space Environ Med 1993;64(10):905-11.
(10) Behling A, Moraes RS, Rohde LE, Ferlin EL, Nobrega ACL, Ribeiro JP. Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure. Am Heart J 2003;146(3):494-500.
(11) Sueta CA. Heart rate variability in chronic heart failure: target for therapy? Am Heart J 2003;146(3):385-7.
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Conflict of Interest:
None declared.
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