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While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating \u03b2-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate\u2013sensitive hyperpolarization\u2013activated current (I\n            <jats:sub>f<\/jats:sub>\n            ) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate\u2013dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.\n          <\/jats:p>","DOI":"10.1161\/circresaha.123.323250","type":"journal-article","created":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T14:00:46Z","timestamp":1715263246000},"page":"1348-1378","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Pacemaker Channels and the Chronotropic Response in Health and Disease"],"prefix":"10.1161","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0343-0068","authenticated-orcid":true,"given":"Konstantin","family":"Hennis","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center Munich, Walter Brendel Centre of Experimental Medicine, Faculty of Medicine (K.H., C.P., C.W.-S.), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3621-8402","authenticated-orcid":true,"given":"Chiara","family":"Piantoni","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center Munich, Walter Brendel Centre of Experimental Medicine, Faculty of Medicine (K.H., C.P., C.W.-S.), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Biel","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research (M.B., S.F.), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Germany (M.B., S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6994-8401","authenticated-orcid":true,"given":"Stefanie","family":"Fenske","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research (M.B., S.F.), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Germany (M.B., S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7514-2367","authenticated-orcid":true,"given":"Christian","family":"Wahl-Schott","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center Munich, Walter Brendel Centre of Experimental Medicine, Faculty of Medicine (K.H., C.P., C.W.-S.), Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2011.00086"},{"key":"e_1_3_3_3_2","first-page":"172","article-title":"The form and nature of the muscular connections between the primary divisions of the vertebrate heart.","volume":"41","author":"Keith A","year":"1907","unstructured":"Keith, A, Flack, M. 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