In their recent Review, Joyce and Wang (2020) advance the thesis that focusing on cardiac output (CO) as the main source of oxygen convection across the vertebrate classes is ‘misleading and inherently biases our focus towards the heart’. This adds to an ever-growing body of evidence against the pressure–propulsion (P–P) paradigm upheld by adherents of the cardiocentric view of the circulation (Brengelmann, 2019). The ongoing debate regarding whether the heart or the peripheral circulation is the principal controller of CO has reached the point of diminishing returns and is clearly beyond resolve. A historical analysis of circulation models and a review of the literature on the subject suggest that the problem lies with the deeply ingrained P–P circulation model (Furst, 2020a). The proposed evolutionary–developmental model of circulation (Alexander, 2017) can settle these issues by simply rephrasing the question; namely, what is the primary phenomenon – flow or pressure?

Numerous studies on embryo hearts involving heart rate and flow perturbation, such as those utilizing changes in ambient or local (sinus venosus) temperature and electrical pacing (Furst, 2020b), point to metabolic rate as the common denominator which determines flow. While it has been assumed for over a century that the valveless embryo heart impels the blood by means of peristaltic contractions, as is the case in hollow muscular organs such as the ureter or the gut, a landmark study by Forouhar et al. (2006) demonstrated that the rate of flow in the zebrafish heart exceeds the velocity of the peristaltic wave which supposedly propels it (Forouhar et al., 2006). The discovery prompted a lively response amongst the embryonic cardiovascular physiologists (Männer et al., 2010); however, because of the narrowly specialized fields, the debate failed to reach wider circles and remains unresolved. Considering that the early embryonic circulation still lacks the basement membrane and endothelial lining, it is conceivable that a pressure-driven system would be self-defeating on account of seepage of plasma through the porous vascular wall.

Developmental anatomy of the cardiovascular system offers further proof for the precedence of flow over pressure. For example, the lancelet (Branchiostoma lanceolatum), a primitive vertebrate, has no heart but nevertheless has a vigorous circulation. Its vessels, too, lack endothelial lining and there is little reason to suppose that the contractile elements at the base of the branchial arches, the bulibulli, provide propulsive force to the circulating hemolymph (Rähr, 1981). In fishes, the S-shaped, single-ventricle heart is placed in the venous limb of the circuit, before the gills, which, paradoxically, are perfused at higher pressures than the systemic vascular beds. As noted by Joyce and Wang (2020), the determination of systemic and pulmonary flows by pressure gradients is compounded in amphibians and reptiles where a single-ventricle heart supposedly drives the systemic and pulmonary circulations in parallel, hence limiting their analysis to the systemic circulation. The problem has long been recognized in clinical practice (Marik et al., 2008), where the estimation of central venous and pulmonary artery occlusion pressures has been largely superseded by a less invasive (and more expedient) sonographic hemodynamic assessment.

If the blood circulates before the functional maturity of the heart and the metabolic rate controls the amount of flow, what then is the function of the heart? By tersest definition, summed in the original formulation of Starling's law, the heart ‘ejects all of the blood it receives’ and by regulating the function of the valves, it plays a pivotal role in the distribution of blood between the low- and high-pressure vascular compartments. The heart therefore functions as an impedance pump which converts kinetic energy of the autonomously moving blood into pressure (Furst, 2015).

Phylogenetically, the development of the heart reflects major vertebrate evolutionary transitions from the near-weightlessness in water to terrestrial gravity, reflected in the metamorphosis from a two-chamber (fishes) to a three- (amphibians) or four-chamber organ. With the change from gill to lung ventilation and the emergence of endothermy, the pressure in the arterial limb of the circuit gradually increases to reach mean values of about 80 mmHg across the mammalian species. It nearly doubles in value in birds, which have higher metabolic rates and larger hearts than mammals with similar body mass, as well as higher resting stroke volume and cardiac output (Grubb, 1983).

The notion that the blood is an inert fluid in need of ‘pushing’ or ‘pulling’ is at the core of the mechanistic view of the circulation (Fuchs, 2001) and in need of revision. The intrinsic property of blood (and the heart) is movement in response to metabolic demands of the tissues. Over the past three decades the field of microvascular research has become ‘the great new frontier’ with seminal discoveries such as the active role of the red blood cell ATP in tissue oxygenation (conducted vasodilation), the multifaceted roles of NO and of reactive oxygen species in the feed-forward control of tissue perfusion, to name a few. The problem, therefore, is systemic and lies with the interpretation of the data to fit the P–P model, rather than focusing on the actual phenomena, which support the opposite; namely, that flow precedes pressure.

In conclusion, the authors ought to be congratulated for their up-to-date, comprehensive review of factors that determine systemic blood flow in vertebrates and for bringing attention to the ongoing debate on this fundamental issue in cardiovascular physiology.

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