Central versus peripheral control of cardiac output in humans: insight from atrial pacing

A major goal of the cardiovascular system is to ensure adequate oxygen (O2) delivery to all body tissues over a wide range of metabolic demands. In healthy exercising individuals, matching of O2 demand and delivery is well preserved from rest to intense sub-maximal exercise (Mortensen et al. 2005). Over this range of exercise intensities, cardiac output () is a major determinant of systemic O2 delivery and increases linearly with the prevailing O2 demand. This is achieved through linear increases in heart rate (HR) while stroke volume (SV) often increases initially and then plateaus. Over the last century, it has been demonstrated that the HR response to increased O2 demand is modulated by multiple regulatory inputs including the sympathetic nervous system as well as the baro-, chemo- and mechano-reflexes. Equally, and systemic O2 delivery are also dependent on the SV response whose control factors include left ventricular filling/preload, afterload, contractility and complex muscle deformation characteristics. Despite our existing understanding of the integrative control of the human cardiovascular response to exercise, the exact interplay between central (cardiac) and peripheral (limb vasodilation) regulatory mechanisms is still unclear. In a recent study published in The Journal of Physiology, Bada et al. (2012) present data from an impressive investigation of cardiovascular function using state-of-the-art methodology to tease out the role of central and peripheral mechanisms involved in control in young individuals. The primary aim of the study was to determine the isolated effect of an increase in HR on , blood pressure and limb and brain perfusion in three conditions: (1) at rest, (2) during low-intensity one-legged knee-extensor exercise (∼24 W) and (3) during femoral arterial ATP infusion at rest (0.5–1.2 μmol min−1) designed to mimick leg hyperaemia observed during the knee-extensor trial. In order to accomplish this aim, Bada et al. employed atrial pacing in healthy males to assess the effect of experimentally increased HR (by up to 54 beats min−1) on systemic, leg and cerebral haemodynamics in all three conditions. The main original findings show that atrial pacing does not increase beyond baseline in any condition. Specifically, was maintained at baseline control levels because the increase in HR was accompanied by a proportional reduction in SV at rest as well as during exercise and femoral arterial ATP infusion-induced hyperaemia. In addition, pacing decreased central venous pressure (CVP) but did not affect leg or cerebral perfusion. On the basis of these results, the authors conclude that the elevation in is determined by increased skeletal muscle O2 demand, vasodilatation and the resulting elevation in blood flow as well as enhanced venous return to the heart. They also suggest that HR and SV respond secondary to the initial peripheral events. The absence of pacing-induced increases in at rest is in line with the previous literature in resting humans (Bergman et al. 2009). Fundamental to this observation is the concomitant decrease in SV, CVP and left ventricular contractility index (dP/dtmax). Bada et al. propose that decreased left ventricular cardiac filling and contractility are involved in the reduced SV with atrial pacing. However, a close analysis of pulmonary capillary wedge pressure (PCWP) at rest suggests that SV may be falling between 100 and 118 beats min−1 while PCWP increased back to baseline level and mean arterial pressure (MAP) is gradually elevated. During exercise and ATP infusion, the reduction in SV with pacing was also consistently associated with a reduced CVP and dP/dtmax but overall maintained MAP and pulmonary arterial mean pressure (PAMP). In line with observations at rest, PCWP decreased with the initial pacing levels (100 to 125 beats min−1) but returned to baseline at the highest pacing level (∼150 beats min−1) despite continuous reduction in CVP, probably reducing cardiac preload albeit without compromising left ventricular filling. Taken together, these data suggest a possible compensatory intervention of the right ventricle to preserve PCWP and point towards a reduction in contractility rather than reduced filling as a potential mechanism for the reduction in SV. How left ventricular contractility is reduced as a result of atrial pacing remains uncertain but might be linked to either sympathetic withdrawal, modified operating point on the Frank–Starling curve and/or a pacing-mediated perturbation of mechanical factors such as intra-ventricular pressure gradients, strain, twist, untwisting and myocardial synchronicity. At the peripheral level, increasing atrial pacing rate did not change leg blood flow or vascular conductance. Together with a preserved LV filling pressure (PCWP) and lower CVP, these results suggest that peripheral vasodilatation was sufficient to maintain left ventricular filling despite a possible shift in central blood volume and lack of muscle pump, thereby supporting the notion that skeletal muscle vasodilatation exerts a potent signalling action in the regulation of (Gonzalez-Alonso et al. 2008). Future directions Bada and colleagues should be commended for attempting to answer a fundamental question in cardiovascular physiology by using scientific methods that have never been employed in exercising humans. Their elegant work suggests that is tightly coupled to factors regulating peripheral blood flow and O2 delivery. Following on from these new data, exciting questions arise for future studies. Instead of artificially modifying HR, cardiovascular regulation could be further explored by manipulating SV, for example, through saline infusion or lower body negative pressure to determine the HR and responses. Another interesting experimental strategy could be to expand on the findings of Bada et al., obtained at sub-maximal cardiovascular and O2 demands (peak = ∼12 l min−1; max O2 uptake not known), by using experimental interventions that challenge the regulation of the cardiovascular system further, either by increasing the exercise intensity, employing a larger muscle mass or increasing HR with higher pacing levels. These approaches seem appropriate as previous work has demonstrated that blood flow to limb muscles can be compromised at high (Mortensen et al. 2005). Stimulation of the cardiovascular system could also be further exacerbated with increases in the duration of the experimental intervention. In their study, Bada et al. used exercise and ATP infusions for quite short durations (∼3 min). Therefore, one might wonder if the lack of skeletal muscle pump would not start to limit venous return with a longer duration of ATP infusion. Whatever the experimental set-up, a major step forward in our understanding of the human cardiovascular regulation is likely to come with combined central and peripheral explorations of the system's responses. As Bada et al. did not perform a direct assessment of cardiac function, a potential intrinsic contribution of the heart to the regulation of cannot be currently ruled out. This idea could now be further explored using novel indicators of cardiac function because a change in SV can be achieved by many different mechanisms such as filling, emptying, mechanical deformation, preload, afterload, twist, suction and timing of myocardial events (Stohr et al. 2012). Technological developments also make it possible to measure peripheral and central adjustments of haemodynamics on a beat-by-beat basis. Such approaches might help to unravel the interaction between the heart and the periphery and, perhaps most critically, to determine the exact sequence of central/peripheral events in the integrative regulation of In summary, the novel results presented by Bada and colleagues demonstrate that the coupling between local skeletal muscle blood flow, venous return and appears to involve mechanisms unrelated to the muscle pump and HR. Their contribution opens exciting new research perspectives to further explore the complex interplay between central (intrinsic cardiac factors) and peripheral (skeletal muscle vasodilation and blood flow) mechanisms in the control of in humans.