Not so fast: intrinsic heart rate vs. β-adrenergic responsiveness in the aging human heart

Abstract

INVITED EDITORIALSNot so fast: intrinsic heart rate vs. β-adrenergic responsiveness in the aging human heartMichael J. JoynerMichael J. JoynerPublished Online:01 Jul 2008https://doi.org/10.1152/japplphysiol.90645.2008This is the final version - click for previous versionMoreSectionsPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat two of the fundamental observations associated with the cardiovascular responses to exercise are that heart rate increases with exercise but that maximum heart rate declines with aging. This decline in maximum heart rate with aging has a number of important consequences, including its major contribution to the decline in maximal oxygen uptake and maximum exercise capacity seen with advancing age (5, 10). In fact, among highly trained older subjects, the decline in maximal oxygen uptake with aging is due almost exclusively to the decline in maximum heart rate and the associated reduction in peak cardiac output and oxygen delivery to the active muscles (4).In a study in the Journal of Applied Physiology, Christou and Seals (1) tested hypotheses related to 1) the contribution of changes in intrinsic heart rate, the heart rate seen in the absence of ongoing sympathetic or parasympathetic influences on the heart; and 2) the ability of the heart to respond to β-adrenergic stimulation. They reasoned that heart rate might decline with aging either because of a decline in intrinsic heart rate or because of a loss of β-adrenergic sensitivity, or both. The key finding of the study is that both mechanisms contribute to the decline in maximum heart rate with age but that a decline in intrinsic heart rate is the more dominant factor.The physiological mechanisms that contribute to these findings include age-related changes in sinoatrial node function that likely relate to changes in pacemaker cell function and also changes in either β-adrenergic receptor number or signaling (or both). From a functional perspective, the age-related decline in maximum heart rate appears to be among the least modifiable physiological changes with aging and thus the most consistent contributor to the decline in peak or maximum exercise capacity with aging. Because this decrease in maximum heart rate contributes so importantly to the decline in maximal oxygen uptake and work capacity with aging, it also has implications for independence and quality of life. Additionally, there do not appear to be any easy ways to increase intrinsic heart rate and perhaps boost maximal exercise capacity in older adults.These findings are also part of a larger story about how the autonomic nervous system changes with aging and the potential influence of these changes on exercise capacity in humans. While maximum heart rate is declining, there is an upward drift in baseline efferent sympathetic nerve activity (9). At the same time, α-adrenergic vasoconstrictor responsiveness is declining so the net vasoconstrictor effects of the increased efferent sympathetic nerve traffic is blunted at rest (2, 8). In this context, analogous questions concerning intrinsic heart rate and baseline sympathetic traffic emerge, and a key question is what drives the upward drift in sympathetic outflow with aging? How much of this rise in sympathetic outflow is due to intrinsic changes in the cells responsible for central sympathetic pattern generation vs. the effects of altered baroreflex function or other potentially inhibitory influences?As noted above, the ability of α-adrenergic receptors to cause vasoconstriction in resting muscles is blunted with aging. Like their β-adrenergic cousins on the heart, is this due to changes in receptor signaling or receptor number effects (or both)? Paradoxically, the ability of α-adrenergic receptors to cause vasoconstriction in exercising muscles is augmented with aging in a way that likely limits peak muscle blood flow so that it can be matched to the reduced cardiac output seen with aging (3, 6, 7). So, unlike the β-adrenergic receptors, the α-adrenergic receptors seem to “work better” with exercise in aging humans. Why?In addition to answering important specific questions and raising new hypotheses, the observations of Christou and Seals (1) are also important for a number of general reasons. First, the autonomic nervous system is perhaps the most important defender of homeostasis, and questions about how this system changes with aging are therefore of fundamental intellectual importance. Second, many common comorbid conditions seen in older people have associated autonomic effects that amplify normal age-related changes in autonomic function, and ultimately a dysfunctional situation can emerge. In this way, responses that are adaptive with normal aging can “go too far” and become pathophysiological when coupled with disease. In the case of the changes in heart rate, it is easy to speculate how disease on top of normal changes might contribute to cardiac arrhythmias. In the case of sympathetic outflow, it is also easy to speculate how pathophysiology on top of normal aging might contribute to the emergence of hypertension at rest and marked reductions in active muscle blood flow during exercise. Third, all sorts of age-related changes have and will be demonstrated in adrenergic receptor function, pacemaker cells, ion channels, and related reductionist signaling pathways. While these changes might explain some or all of the physiological responses above, only the paintbrush of integrative physiology will permit a full and clear picture of how they fit together to affect the functional capacity of humans to be painted. In this context, Christou and Seals (1) have painted a very clear picture of a fundamental biological phenomenon.REFERENCES1 Christou DD, Seals R. Decreased maximal heart rate with aging is related to reduced β-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate. J Appl Physiol (May 15, 2008). doi:10.1152/japplphysiol.90401.2008.Link | ISI | Google Scholar2 Dinenno FA, Dietz NM, Joyner MJ. Aging and forearm postjunctional alpha-adrenergic vasoconstriction in healthy men. Circulation 106: 1349–1354, 2002.Crossref | PubMed | ISI | Google Scholar3 Dinenno FA, Masuki S, Joyner MJ. Impaired modulation of sympathetic alpha-adrenergic vasoconstriction in contracting forearm muscle of ageing men. J Physiol 567: 311–321, 2005.Crossref | PubMed | ISI | Google Scholar4 Heath GW, Hagberg JM, Ehsani AA, Holloszy JO. A physiological comparison of young and older endurance athletes. J Appl Physiol 51: 634–640, 1981.Link | ISI | Google Scholar5 Holloszy JO, Kohrt Exercise WM. In: Handbook of Physiology: Aging. Bethesda, MD: Am. Physiol Soc, 1995, sect. 11, chapt. 24, p. 633–666.Google Scholar6 Koch DW, Leuenberger UA, Proctor DN. Augmented leg vasoconstriction in dynamically exercising older men during acute sympathetic stimulation. J Physiol 551: 337–344, 2003.Crossref | PubMed | ISI | Google Scholar7 Proctor DN, Shen PH, Dietz NM, Eickhoff TJ, Lawler LA, Ebersold EJ, Loeffler DL, Joyner MJ. Reduced leg blood flow during dynamic exercise in older endurance-trained men. J Appl Physiol 85: 68–75, 1998.Link | ISI | Google Scholar8 Smith EG, Voyles WF, Kirby BS, Markwald RR, Dinenno FA. Ageing and leg postjunctional alpha-adrenergic vasoconstrictor responsiveness in healthy men. J Physiol 582: 63–71, 2007.Crossref | PubMed | ISI | Google Scholar9 Sundlof G, Wallin BG. Human muscle nerve sympathetic activity at rest: relationship to blood pressure, and age. J Physiol 274: 621–637, 1978.Crossref | PubMed | ISI | Google Scholar10 Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol 37: 153–156, 2001.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: M. J. Joyner, Dept. of Anesthesiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByUse of antiarrhythmic drugs in elderly patientsJournal of Geriatric Cardiology, Vol. 8, No. 3Validity, accuracy, and repeatability of monitoring variablesNew practice guidelines for perioperative beta blockade from the United States and Europe: incremental progress or a necessary evil?4 February 2010 | Canadian Journal of Anesthesia/Journal canadien d'anesthésie, Vol. 57, No. 4How Environmental Agents Influence the Aging ProcessBiomolecules and Therapeutics, Vol. 17, No. 2 More from this issue > Volume 105Issue 1July 2008Pages 3-4 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.90645.2008PubMed18483159History Published online 1 July 2008 Published in print 1 July 2008 Metrics