I appreciate Joyce and Wang's review of the determinants of blood flow in vertebrates (Joyce and Wang, 2020), featuring Guyton's model of the systemic circulation.

Although I do not dispute that Guyton's view ‘provides important insight into cardiovascular regulation’, some of the arguments supporting Guyton's ‘venous return’ model (GM) (as defined by their Eqn 1), as well as other arguments addressing the position of those who have criticized GM, require clarification.

From the outset, the authors seem to be confusing the heart's function as a pump (i.e. to generate flow) with heart performance regulation by the systemic vasculature (i.e. the vascular properties that determine cardiac output, CO). CO (which equals systemic flow) always equals ventricular stroke volume (SV) multiplied by ventricular stroke rate (SR): (1)SR=1/T, where T is the period (the time interval between beats), yielding CO with units of volume per unit of time (i.e. volume flow rate). This means that Eqn 1 does not establish ‘priority’ between SV and SR; CO will at all times be (SV×SR), whether SV or SR is under regulation.

In this regard, Joyce and Wang's points about SR are ambiguous. Indeed, SR regulation is complex, but SR does not ‘regulate’ CO; rather, it determines it (by Eqn 1). That is not to say that CO should vary in direct proportion to SR (as shown in their Fig. 1), as CO also depends on SV.

Secondly, SV is a function of ventricular preload (according to Starling's ‘law of the heart’ – which is not a ‘concept’ but rather the mathematical function by which the ventricles operate), and preload is determined by the physical properties of the vascular circuitry (volume, resistance and capacitance).

Misinterpretation of this basic mechanism of heart–vasculature interaction at the level of the filling side of the heart has led to the establishment of a false dichotomy whereby either the heart or the vasculature is considered ‘primary’ in CO regulation (Magder, 2006; Henderson, et al., 2010; Furst and O'Leary, 2016).

However, even Starling's and Guyton's classical experiments are not mutually exclusive, but complementary: the former related cardiac filling (measured as right atrial pressure, P_ra, and set via an artificial blood reservoir) with CO in the isolated heart (yielding the function known as Starling's law), and the latter related CO (measured as the steady-state systemic flow set by an artificial pump) with cardiac filling (measured as P_ra) in the isolated vasculature (Guyton's law).

As Brengelmann emphasized (Brengelmann, 2003; Brengelmann, 2019), Guyton's ‘important insight into cardiovascular regulation’ was that of counterpoising the two functions of the respective ‘open-loop’ subsystems yielding an input–output relationship (P_ra:CO and CO:P_ra) that dictates the stability of the closed-loop cardiovascular system (via negative feedback interaction), which is simultaneously consistent with heart and vascular properties, and of overlaying the two functional relationships (as in Fig. 2 of Joyce and Wang, 2020), with the consequence of plotting one of them ‘backwards’ (i.e. the independent variable on the ordinate and the dependent variable on the abscissa).

Unfortunately, the model represented by Joyce and Wang's Eqn 1 (and the related notions about the ‘mean systemic pressure’, and the ‘stressed’ and ‘unstressed’ vascular volumes explained in their review), is what transcended instead.

In addition, critics of GM have never conceived such a polarized, or ‘biased’, view of heart and vascular function, nor have they neglected the role of the vasculature in CO modulation. As a matter of fact, each one of the landmark papers by critics of this model (Grodins et al., 1960; Levy, 1979; Tyberg, 2002; Brengelmann, 2003; Reddi and Carpenter, 2005; Beard and Feigl, 2011; Brengelmann, 2019) is about vascular function and properties, and their interaction with the heart. Their focus has never been ‘cardio-centric’ in this regard.

Turning to comparative physiology, Loring B. Rowell consistently reviewed the subject of CO regulation in quadrupeds and bipeds and highlighted that the main difference between species is primarily due to two specific vascular properties; namely, the total capacitance (determined by size and compliance, both larger in humans) and, more importantly, volume distribution relative to heart level. While upright humans have approximately 80% of their total blood volume below heart level and in compliant venous vessels, quadrupeds have the same proportion at or above heart level.

This poses a crucial difference in blood volume distribution and therefore the volume available for cardiac filling (i.e. preload). Only in this way could CO be considered more ‘SR related’ in quadrupeds than in humans as heart preload is only slightly affected by postural and hemodynamic changes. In other words, cardiac preload (and, therefore, SV) depends on the pattern of blood volume distribution, which is virtually fixed in quadrupeds. Finally, as an outsider in the field of comparative physiology, I must refrain from commenting on specifics about blood flow and oxygen delivery regulation in various species of vertebrates. But I doubt that blood flow, like any other fluid flow, would somehow violate the principle of conservation of energy, as GM implies (Brengelmann, 2019).

Understanding that the heart (or any pump-like organ in the circulatory system) is the source of mechanical energy for steady-state blood flow does not reflect a biased focus but is in accordance with universal laws of thermodynamics.