Background specific heart rate parameters notably associate with variable risks of cardiovascular disease and mortal-ity, however, to date there are no readily available blood tests associated with these parameters. Because of the estab-lished parasympathetic contributions towards cardiac regulation, we challenged the working hypothesis that serum acetylcholinesterase (AChE) activity is involved. Methods A total of 403 Healthy men and women were included in the study and underwent treadmill exercise testing. Prior to exercise testing the subject’s serum AChE activity levels were assessed by measuring rates of acetylthiocholine hydrolysis. Results In male subjects AChE activity was positively cor-related to resting heart rate (r = 0.210, p = 0.001). Complementing this observation, AChE activity was negatively correlated to the exercise-induced heart rate increase (r = –0.181, p = 0.005) and to heart rate recovery at 1, 2 and 5 minutes following cessation of exercise (r = –0.150, p = 0.022; r = –0.157, p = 0.016; r = –0.176, p = 0.008 respec-tively). This indicated that lower than average AChE activities, which presumably reflect increased peripheral ACh levels, might be correlated to favorable heart rate parameters. Similar observations were made in female subjects, ex-cept for lack of correlation to their resting heart rate. Additionally, we observed that we were able to stratify subjects into two groups of significantly different AChE activity (p = 0.001) based on a cut point of heart rate recovery below 20 beats one minute after cessation of exercise. Conclusion In asymptomatic individuals lower than average AChE activity is associated with favorable indices of exercise-inducible heart rate increase as well as heart rate recovery. Future studies will be needed to evaluate the added prognostic significance gained by implementing this marker into routine practice.
KeywordsExerciseNervous SystemAutonomicHeart Rate
P. J. Schwartz, M. T. La Rovere and E. Vanoli, “Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification,” Circulation, Vol. 85, No. S1, 1992, pp. 77-91.
P. J. Schwartz, “The Autonomic Nervous System and Sudden Death,” European Heart Journal, Vol. 19, 1998, pp. F72-F80.
M. T. La Rovere, G. D. Pinna, S. H. Hohnloser, F. I. Marcus, A. Mortara, R. Nohara, J. T. Bigger, A. J. Camm and P. J. Schwartz, “Baroreflex Sensitivity and Heart Rate Variability in the Identification of Patients at Risk for Life-Threatening Arrhythmias: Implications for Clinical Trials,” Circulation, Vol. 103, No. 16, 2001, pp. 2072- 2077.
X. Jouven, J. P. Empana, P. J. Schwartz, M. Desnos, D. Courbon and P. Ducimetiere, “Heart-Rate Profile during Exercise as a Predictor of Sudden Death,” New England Journal of Medicine, Vol. 352, No. 19, 2005, pp. 1951- 1958. doi:10.1056/NEJMoa043012
C. R. Cole, E. H. Blackstone, F. J. Pashkow, C. E. Snader, M. S. Lauer, “Heart-Rate Recovery Immediately after Exercise as a Predictor of Mortality,” New England Journal of Medicine, Vol. 341, No. 18, 1999, pp. 1351-1357. doi:10.1056/NEJM199910283411804
N. J. Leeper, F. E. Dewey, E. A. Ashley, M. Sandri, S. Y. Tan, D. Hadley, J. Myers and V. Froelicher, “Prognostic Value of Heart Rate Increase at Onset of Exercise Testing,” Circulation, Vol. 115, No. 4, 2007, pp. 468-474. doi:10.1161/CIRCULATIONAHA.106.666388
Y. Loewenstein-Lichtenstein, M. Schwarz, D. Glick, B. Norgaard-Pedersen, H. Zakut and H. Soreq, “Genetic predisposition to adverse consequences of anti-cholinesterases in ‘atypical’ BCHE carriers,” Nature Medicine, Vol. 1, No. 10, 1995, pp. 1082-1085. doi:10.1038/nm1095-1082
Y. Kakinuma, M. Ando, M. Kuwabara, R. G. Katare, K. Okudela, M. Kobayashi and T. Sato, “Acetylcholine from Vagal Stimulation Protects Cardiomyocytes against Ischemia and Hypoxia Involving Additive Non-Hypoxic Induction of Hif-1alpha,” FEBS Letters, Vol. 579, No. 10, 2005, pp. 2111-2118. doi:10.1016/j.febslet.2005.02.065
M. Ando, R. G. Katare, Y. Kakinuma, D. Zhang, F. Yamasaki, K. Muramoto and T. Sato, “Efferent Vagal Nerve Stimulation Protects Heart against Ischemia-Induced Arrhythmias by Preserving Connexin43 Protein,” Circulation, Vol. 112, No. 2, 2005, pp. 164-170. doi:10.1161/CIRCULATIONAHA.104.525493
T. A. Dewland, A. S. Androne, F. A. Lee, R. J. Lampert and S. D. Katz, “Effect of Acetylcholinesterase Inhibition with Pyridostigmine on Cardiac Parasympathetic Function in Sedentary Adults and Trained Athletes,” American Journal of Physiology and Heart Circulation Physiology, Vol. 293, No. 1, 2007, pp. 86-92. doi:10.1152/ajpheart.01339.2006
A. S. Androne, K. Hryniewicz, R. Goldsmith and A. Arwady, S. D. Katz, “Acetylcholinesterase Inhibition with Pyridostigmine Improves Heart Rate Recovery after Maximal Exercise in Patients with Chronic Heart Failure,” Heart, Vol. 89, No. 8, 2003, pp. 854-858. doi:10.1136/heart.89.8.854
K. Ofek, K. S. Krabbe, T. Evron, M. Debecco, A. R. Nielsen, H. Brunnsgaad, R. Yirmiya, H. Soreq and B. K. Pedersen, “Cholinergic Status Modulations in Human Volunteers under Acute Inflammation,” Journal of Molecular Medicine, Vol. 85, No. 11, 2007, pp. 1239-1251. doi:10.1007/s00109-007-0226-x
A. Steinvil, A. Shirom, S. Melamed, S. Toker, D. Justo, N. Saar, I. Shapira, S. Berliner and O. Rogowski, “Relation of Educational Level to Inflammation-Sensitive Biomarker Level,” American Journal of Cardiology, Vol. 102, No. 8, 2008, pp. 1034-1039. doi:10.1016/j.amjcard.2008.05.055
O. Rogowski, S. Toker, I. Shapira, S. Melamed, A. Shirom, D. Zeltser and S. Berliner, “Values of High-Sensitivity C-Reactive Protein in Each Month of the Year in Apparently Healthy Individuals,” American Journal of Cardiology, Vol. 95, No. 1, 2005, pp. 152-155. doi:10.1016/j.amjcard.2004.08.086
“Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III),” JAMA, Vol. 285, No. 19, 2001, pp. 2486-2497.
P. M. Rautaharju, R. J. Prineas, W. J. Eifler, C. D. Furberg, J. D. Neaton, R. S. Crow, J. Stamler and J. A. Cutler, “Prognostic Value of Exercise Electrocardiogram in Men at High Risk of Future Coronary Heart Disease: Multiple Risk Factor Intervention Trial Experience,” Journal of the American College of Cardiology, Vol. 8, No. 1, 1986, pp. 1-10. doi:10.1016/S0735-1097(86)80084-5
A. Berson, M. Knobloch, M. Hanan, S. Diamant, M. Sharoni, D. Schuppli, B. C. Geyer, R. Ravid, T. S. Mor, R. M. Nitsch and H. Soreq, “Changes in Readthrough Acetylcholinesterase Expression Modulate Amyloid-Beta Pathology,” Brain, Vol. 131, No. Pt1, 2008, pp. 109-119.
A. Gilboa-Geffen, P. P. Lacoste, L. Soreq, G. Cizeron-Clairac, R. Le Panse, F. Truffault, I. Shaked, H. Soreq and S. Berrih-Aknin, “The Thymic Theme of Acetylcholinesterase Splice Variants in Myasthenia Gravis,” Blood, Vol. 109, No. 10, 2007, pp. 4383-4391. doi:10.1182/blood-2006-07-033373
M. K. Lahiri, P. J. Kannankeril, J. J. Goldberger, “Assessment of Autonomic Function in Cardiovascular Disease: Physiological Basis and Prognostic Implications,” Journal of the American College of Cardiology, Vol. 51, No. 18, 2008, pp. 1725-1733. doi:10.1016/j.jacc.2008.01.038
Adabag AS, Grandits GA, Prineas RJ, Crow RS, Bloomfield HE, Neaton JD. Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men. American Journal of Cardiology 2008; 101(10):1437-1443. doi:10.1016/j.amjcard.2008.01.021
R. Arena, M. Guazzi, J. Myers and M. A. Peberdy, “Prognostic Value of Heart Rate Recovery in Patients with Heart Failure,” American Heart Journal, Vol. 151, No. 4, 2006, pp. 851-857. doi:10.1016/j.ahj.2005.09.012
K. P. Savonen, V. Kiviniemi, J. A. Laukkanen, T. A. Lakka, T. H. Rauramaa, J. T. Salonen and R. Rauramaa, “Chronotropic Incompetence and Mortality in Middle-Aged Men with Known or Suspected Coronary Heart Disease,” European Heart Journal, Vol. 29, No. 15, 2008, pp. 1896-1902. doi:10.1093/eurheartj/ehn269
D. Robertson, G. A. Johnson, R. M. Robertson, A. S. Nies, D. G. Shand and J. A. Oates, “Comparative Assessment of Stimuli That Release Neuronal and Adrenomedullary Catecholamines in Man,” Circulation, Vol. 59, No. 4, 1979, pp. 637-643.
V. Oberhauser, E. Schwertfeger, T. Rutz, F. Beyersdorf and L. C. Rump, “Acetylcholine Release in Human Heart Atrium: Influence of Muscarinic Autoreceptors, Diabetes, and Age,” Circulation, Vol. 103, No. 12, 2001, pp. 1638-1643.
D. P. Vivekananthan, E. H. Blackstone, C. E. Pothier and M. S. Lauer, “Heart Rate Recovery after Exercise is a Predictor of Mortality, Independent of the Angiographic Severity of Coronary Disease,” Journal of the American College of Cardiology, Vol. 42, No. 5, 2003, pp. 831-838. doi:10.1016/S0735-1097(03)00833-7
B. Aijaz, R. W. Squires, R. J. Thomas, B. D. Johnson and T. G. Allison, “Predictive Value of Heart Rate Recovery and Peak Oxygen Consumption for Long-Term Mortality in Patients with Coronary Heart Disease,” American Journal of Cardiology, Vol. 103, No. 12, 2009, pp. 1641-1646. doi:10.1016/j.amjcard.2009.02.013
L. R. Davrath, S. Akselrod, I. Pinhas, E. Toledo, A. Beck, D. Elian and M. Scheinowitz, “Evaluation of Autonomic Function Underlying Slow Postexercise Heart Rate Recovery,” Medical Science Sports Exercise, Vol. 38, No. 12, 2006, pp. 2095-2101. doi:10.1249/01.mss.0000235360.24308.c7
A. P. Morise, “Heart Rate Recovery: Predictor of Risk Today and Target of Therapy Tomorrow?” Circulation, Vol. 110, No. 18, 2004, pp. 2778-2780. doi:10.1161/01.CIR.0000147615.62634.48
P. Kligfield, A. McCormick, A. Chai, A. Jacobson, P. Feuerstadt and S. C. Hao, “Effect of Age and Gender on Heart Rate Recovery after Submaximal Exercise during Cardiac Rehabilitation in Patients with Angina Pectoris, Recent Acute Myocardial Infarction, or Coronary Bypass Surgery,” American Journal of Cardiology, Vol. 92, No. 5, 2003, pp. 600-603. doi:10.1016/S0002-9149(03)00733-1
J. Myers, D. Hadley, U. Oswald, K. Bruner, W. Kottman, L. Hsu and P. Dubach, “Effects of Exercise Training on Heart Rate Recovery in Patients with Chronic Heart Failure,” American Heart Journal, Vol. 153, No. 6, 2007, pp. 1056-1063. doi:10.1016/j.ahj.2007.02.038
E. H. Sklan, A. Lowenthal, M. Korner, Y. Ritov, D. M. Landers, T. Rankinen, C. Bouchard, A. S. Leon, T. Rice, D. C. Rao, J. H. Wilmore, J. S. Skinner and H. Soreq, “Acetylcholinesterase/Paraoxonase Genotype and Expression Predict Anxiety Scores in Health, Risk Factors, Exercise Training, and Genetics Study,” Proceedings of the National Academy of Sciences USA, Vol. 101, No. 15, 2004, pp. 5512-5517. doi:10.1073/pnas.0307659101
B. Bryk, L. BenMoyal-Segal, E. Podoly, O. Livnah, A. Eisenkraft, S. Luria, A. Cohen, Y. Yehezkelli, A. Hourvitz and H. Soreq, “Inherited and Acquired Interactions between Ache and Pon1 Polymorphisms Modulate Plasma Acetylcholinesterase and Paraoxonase Activities,” Journal of Neurochemistry, Vol. 92, No. 5, 2005, pp. 1216-1227. doi:10.1111/j.1471-4159.2004.02959.x
C. Guimaraes-Sternberg, A. Meerson, I. Shaked and H. Soreq, “MicroRNA Modulation of Megakaryoblast Fate Involves Cholinergic Signaling,” Leukocyte Research, Vol. 30, No. 5, 2006, pp. 583-595. doi:10.1016/j.leukres.2005.09.005
I. Shaked, A. Meerson, Y. Wolf, R. Avni, D. Greenberg, A. Gilboa-Geffen and H. Soreq, “MicroRNA-132 Potentiates Cholinergic Anti-Inflammatory Signaling by Targeting Acetylcholinesterase,” Immunity, Vol. 31, No. 6, 2010, pp. 965-73. doi:10.1016/j.immuni.2009.09.019