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Guyton removed the heart from its pedestal in cardiovascular physiology by arguing that cardiac output is primarily regulated by the peripheral vasculature. This is counterintuitive, as modulating heart rate would appear to be the most obvious means of regulating cardiac output. In this Review, we visit recent and classic advances in comparative physiology in light of this concept. Although most vertebrates increase heart rate when oxygen demands rise (e.g. during activity or warming), experimental evidence suggests that this tachycardia is neither necessary nor sufficient to drive a change in cardiac output (i.e. systemic blood flow, Q\u0307sys) under most circumstances. Instead, Q\u0307sys is determined by the interplay between vascular conductance (resistance) and capacitance (which is mainly determined by the venous circulation), with a limited and variable contribution from heart function (myocardial inotropy). This pattern prevails across vertebrates; however, we also highlight the unique adaptations that have evolved in certain vertebrate groups to regulate venous return during diving bradycardia (i.e. inferior caval sphincters in diving mammals and atrial smooth muscle in turtles). Going forward, future investigation of cardiovascular responses to altered metabolic rate should pay equal consideration to the factors influencing venous return and cardiac filling as to the factors dictating cardiac function and heart rate.<\/jats:p>","DOI":"10.1242\/jeb.215335","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T16:55:12Z","timestamp":1582217712000},"source":"Crossref","is-referenced-by-count":44,"title":["What determines systemic blood flow in vertebrates?"],"prefix":"10.1242","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3782-1641","authenticated-orcid":false,"given":"William","family":"Joyce","sequence":"first","affiliation":[{"name":"Zoophysiology, Department of Bioscience, Aarhus University, 8000 Aarhus C, Denmark"},{"name":"Department of Biology, University of Ottawa, 30 Marie Curie, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Wang","sequence":"additional","affiliation":[{"name":"Zoophysiology, Department of Bioscience, Aarhus University, 8000 Aarhus C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,2,20]]},"reference":[{"key":"2021042623245675600_JEB215335C1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1242\/jeb.00742","article-title":"Intrinsic autoregulation of cardiac output in rainbow trout (Oncorhynchus mykiss) at different heart rates","volume":"207","author":"Altimiras","year":"2004","journal-title":"J. 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