Over 50 years ago, John Wahren and Lennart Jorfeldt published a manuscript in Clinical Science where they detailed a series of studies of leg blood flow during exercise. They used a novel approach to indicator dye dilution: continuous arterial infusions of dye using venous samples. This technique allowed them to describe for the first time the fundamental relationships between large muscle group exercise, muscle blood flow, and pulmonary and muscle oxygen uptake. They also defined mechanical efficiency, a key measurement of muscle function. This paper formed the basis for research into muscle blood flow and exercise in health and disease and continued to be cited by modern research. In this commentary, we describe the innovations they made, the key observations that came out of their results, and the importance of this manuscript to current research.
In 1653, William Harvey published ‘The Anatomical Exercises of Doctor William Harvey Professor of Physics and Physicians to the King's Majesty, Concerning the Motion of the Heart and Blood’ confirming hypotheses he published 25 years earlier on the circulation of blood flowing in ‘separate loops’ of arteries and veins in distinct pulmonary and systemic systems. Dr Harvey’s experiments, were the first to describe the use of arterial and venous infusions to determine the function of systemic circulation and laid the foundation for research on the circulation of blood. Since these early studies, the methodology used to conduct investigations on the physiology of circulation and blood flow, particularly when coupled with the use of infusions have advanced considerably and are now core techniques used to further our understanding of physiology in general and blood flow distribution specifically.
Despite Dr Harvey’s initial discoveries, it wasn’t for another 300 years, in 1971, that a major step forward in this area was made through a pivotal paper describing the use of a continuous infusion indicator-dilution technique to measure human leg blood flow at rest and during exercise, published in this journal . This paper by Jorfeldt and Wahren laid the foundation for our ability to accurately quantify blood flow distribution to working muscle. The continuous infusion methodology described by these authors has significantly expanded our understanding of peripheral hemodynamics allowing for significant advances in the science of human performance, consequences of chronic disease, and impact of medical interventions and therapeutic strategies on blood flow dynamics.
At the time of this seminal publication, several methodologies to measure blood flow were actively in use, each with their own set of benefits and limitations. For example, strain gauge plethysmography was used primarily to measure of blood flow to the forearm and calf vascular beds at rest to study the pressure/flow relationship and the impact of changes in vascular resistance and conductance. While a clear benefit of this technique is its non-invasive nature, accurate and reproducible measurements during the dynamic exercising condition remained challenging due to the need for stable plethysmograph tracings [2,3]. In fact, strain gauge plethysmography recorded during steady state cycle exercise overestimated blood flow to the forearm by nearly double [2,3]. Single bolus indicator techniques emerged as a more stable method of measurement using various infusates including 133Xenon, indocyanine green dye, and chilled saline, all of which allowed for the direct measurement of blood flow in the arterial system both at rest and during exercise. While widely used at the time, the validity of this technique is based on the assumption that a single bolus of indicator uniformly disperses prior to the point of sampling. However, a variety of vascular bed circulation times makes it difficult to distinguish the primary circulation of the indicator from the recirculation thus causing significant potential for measurement error and wide standard deviations across individuals [3,4]. These limitations were made even worse during the exercise condition due to variable circulation time and thus inadequate mixing of bolus with circulating blood [3,4].
When Jorfeldt and Wahren performed their work, continuous infusion indicator-dilution methods for the measurement of blood flow were relatively new and primarily used to measure cardiac output . A few studies had been done using continuous infusion indicator-dilution in relatively small, stable vascular beds such as the forearm and only in the resting state. The pioneering work by Jorfeldt and Wahren provided the necessary validation in large vascular beds during dynamic exercise to drive this technique forward for use across a wide range of healthy populations, rest and exercise conditions, ages, sexes, and medical comorbidities and chronic conditions.
Novel ideas introduced
The manuscript by Jorfeldt and Wahren introduced several important ideas that continue to be relevant to studies of blood flow during exercise. Specifically, their results demonstrated that measurement of blood flow using the continuous infusion indicator dilution with venous sampling during exercise was feasible and produced accurate, reproducible results. In their study, the authors compared sampling of infusions of dye into the femoral artery from both the artery distal to the infusion and also from two different sites in the femoral vein. In each participant, results using blood samples from the two femoral venous catheters agreed within the expected error of measurement both at rest and during all workloads of exercise ranging from rest to 1200 kpm/min. In comparison, the measurements from the femoral artery did not agree with the venous measurements in most participants both at rest and during exercise. The authors concluded that the measurements from the venous circulation distal to the muscle bed(s) of interest resulted in a more precise quantification of blood flow to the working group of muscles due to better mixing of infusate. This paper thus validated a novel technique that has been invaluable for exercise studies of blood flow.
Mechanical efficiency as described by Jorfeldt and Wahren, highlights the fundamental relationship between the mechanical work encountered by the muscle and the oxygen uptake needed to accomplish that work. This understanding subsequently formed the basis for a new line of scientific inquiry into skeletal muscle efficiency during dynamic exercise in humans. As such, discoveries in this area have advanced our understanding of the importance of muscle efficiency for athletic performance, ageing, and in chronic disease and continue to be debated today [6,7]. The fundamental ability to reliably measure blood flow to working muscle and expand upon the relationship between physiologic work, blood flow distribution, oxygen uptake in the lungs, and oxygen utilization at the muscle continues to be the basis for studies on the physiology of exercise in health and disease (Figure 1) .
Regional distribution of cardiac output during various intensities of exercise expressed as percent of maximal oxygen consumption
This influential paper by Jorfeldt and Wahren ushered in a new wave of advances in our understanding of the capacities of human exercise performance across the health disease spectrum. As an example, in 1985, Anderson and Saltin demonstrated the close relationship between locomotor muscle blood flow, local vasodilation induced hyperemia, and arterial perfusion pressure during exercise in highly trained athletes . Using a constant venous infusion thermodilution approach, based on the technique and validation detailed by Jorfeldt and Wahren, these authors were able to demonstrate that, even at the single muscle group level, blood flow delivery increases linearly with increasing workload directly proportional to the increase in cardiac output without reaching an apparent limit. At the time, these findings confirmed the unproven conventional wisdom that maximal pulmonary oxygen uptake was limited by the central circulation (cardiac output). While speculation remains on the underlying mechanistic triggers contributing to this coordinated shift in blood flow distribution, it is clear that this technique has played a key role in our understanding of human performance.
In contrast, this technique has also allowed us to develop a new understanding of blood flow distribution in patients with chronic disease and end-organ failure. For example, it has been speculated that patients with chronic heart failure (HF) develop multisystem abnormalities, which contribute to symptoms of fatigue and dyspnea and lead to the hallmark signature of reduced functional capacity and exercise intolerance. In this light, Olson and colleagues examined the impact of reducing the exercise ventilatory demand on shifts in blood flow distribution in the setting of a limited ability to augment cardiac output during exercise . These authors found that, as HF patients exercise, they reach a cardiac output limit which dictates the absolute volume of blood available for distribution systemically to organ systems in need. Moreover, in the face of competing demands, and the central circulations limited ability to adequately supply both the respiratory muscles and the locomotor muscles with oxygenated blood flow, they demonstrated that blood flow to the working locomotor muscles during exercise increased ∼40% when oxygen demand of the respiratory muscles was curtailed via positive inspiratory pressure support. This novel finding showed a previously unrecognized competition between vascular beds in the periphery when the central circulation was unable to increase cardiac output to meet these competing demands. Similarly, Broxterman and colleagues studied the impact of both convective and diffusive oxygen delivery to the skeletal muscle during exercise in patients with chronic obstructive lung disease. These authors used the thermodilution technique validated by Jorfeldt and Wahren to describe significant peripheral impairments experienced by this patient group during dynamic exercise . These authors found that patients with chronic obstructive pulmonary disease demonstrate significant impairment in both convective and diffusive delivery of oxygen to skeletal muscle contributing to exercise impairment. Thus, the ability to measure blood flow directly, during dynamic exercise, has significantly advanced our understanding of exercise induced symptoms and the physiological limitations on exercise tolerance in patients with chronic diseases.
Future directions of the field
While advances in medicine and science are often incremental, the ability to accurately measure blood flow to specific organ beds of interest and in particular the skeletal muscle during exercise is most certainly an important scientific achievement. And, while indicator dilution remains the gold standard, there is still no ideal technique for blood flow measurement. Indicator dilution is highly invasive, occlusion plethysmography cannot be used during dynamic exercise, and doppler ultrasound is highly user dependent and measures only blood velocity in major conducting vessels . As this area of investigation moves forward, continued progress will depend on the ability to develop equally accurate and reproducible techniques, which are less invasive and more accessible to scientists and clinicians. This type of advancement will allow more rapid assessment of changes in blood flow in an acute setting, which will help to close a large gap in our understanding of blood flow distribution across the spectrum of comorbidities and foster a deeper appreciation of the physiologic consequences and adaptations to a variety of chronic conditions.
The authors declare that there are no competing interests associated with the manuscript.
CRediT Author Contribution
Thomas P. Olson: Conceptualization, Writing—original draft, Writing—review & editing. Joshua R. Smith: Writing—original draft, Writing—review & editing. Timothy B. Curry: Writing—original draft, Writing—review & editing.