Canadian Contributions to Exercise Physiology: A focus on cardiovascular function

October 13, 2017

The Canadian Society for Exercise Physiology will be celebrating its 50th anniversary in 2017. A signature initiative is a celebration of the contributions of Canadian researchers to exercise physiology over the past 50 years. The objective is to highlight significant Canadian contributors and their contributions to exercise physiology, health and fitness, nutrition and gold standard publications globally as well as provide insights on future research directions in these areas. These achievements have been organized into a series of short historical communiqués on prominent Canadian contributors and will be published on a monthly basis.

Canadian Contributions to Exercise Physiology: A focus on cardiovascular function

Maureen J. MacDonald1 and Patrick G. McPhee2

1Department of Kinesiology, McMaster University

2School of Rehabilitation Science,McMaster University

Introduction

The cardiovascular system is comprised of the heart, arteries, veins, capillaries and blood. This dynamic system includes complex interactions of mechanical, neural and humoral factors in both the central and peripheral arteries in response to short- and long-term changes via external stimuli. Alterations to the cardiovascular system, via structural and functional adaptations, play essential roles especially when the system is faced with physiological stresses such as physical activity and exercise training.

Many Canadian researchers have made significant contributions to the advancement of knowledge surrounding cardiovascular function, thereby leading to novel strategies to assess, understand, and influence the cardiovascular system as it relates to various stimuli including exercise, disease, and aging. This short synopsis will highlight the advancements in knowledge related to cardiovascular function made by Canadian

researchers with specific considerations for the understanding of the impact of varying exercise intensities and training modalities on cardiovascular function.

Cardiovascular function and blood flow

Prominent early research contributions to the understanding of cardiovascular function made by Canadians included determinations of the role of blood flow in limiting maximal metabolic rate. Jack Barclay performed this seminal investigation and discovered that maximal skeletal muscle metabolic rate and contractile performance were limited by blood flow in the canine gastrocnemius muscle (Barclay, 1975). Barclay would later confirm this finding in the mid 1980s via an oxygen delivery-independent blood flow effect on skeletal muscle fatigue (Barclay, 1986). It was discovered that increased blood flow, or hyperperfusion, of the stimulated muscles decreased fatigue by a mechanism independent of increased oxygen delivery. This led Barclay to question the mechanism responsible. At a similar time, Norman Gledhill wrote an interesting piece on the influence of changing blood volume on aerobic performance (Gledhill, 1985). The idea was that changes in blood volume could affect maximal aerobic performance through changes in cardiac output, and alterations in hemoglobin concentration could affect arterial oxygen content. In 1991, Barclay postulated that free radicals contributed to fatigue in oxidative skeletal muscle, suggesting perhaps that increases in blood flow could sequester free radicals (Barclay, 1991), while increases in blood volume and hemoglobin concentration would increase the amount of oxygen available for the exercising muscle (Gledhill, 1985).

These early studies examining the links between skeletal muscle blood flow and metabolic rate have provided the foundation for many interesting and impactful lines of research. In 1996, Richard Hughson led a series of studies examining the impact of muscle blood flow increases on muscle oxygen uptake at the onset of exercise (Hughson,1996). In the same year, trainees of Hughson, Michael Tschakovsky and Kevin Shoemaker, published research on the effect of vasodilation as it contributed to immediate exercise in humans and day-to-day repeatability of measuring forearm blood flow via ultrasonography during exercise, respectively (Tschakovsky, 1996; Shoemaker, 1996). Not only were Canadians interested in blood flow patterns of exercising skeletal muscle, but Marc Poulin examined the importance of cross-sectional area and blood flow patterns of the middle cerebral artery under reduced oxygen and increased carbon dioxide exposures (Poulin, 1996).

A year later, in 1997, Shoemaker added to Barclay’s findings about mechanisms related to blood flow to the exercising musculature (Shoemaker,1997). From this study it was discovered that neither acetylcholine nor nitric oxide were essential to the magnitude of the exercise response, as blood flow to the exercising forearm was unaffected when both substrates were blocked; however brachial artery diameter remained the same. Only resting blood flow was affected by the blocking of acetylcholine and nitric oxide. This led Shoemaker to conclude that a different cholinergic mechanism may be responsible for maintaining the hyperemic response during exercise. At the microvascular level, Coral Murrant was investigating the effects of both oxygen and nitric oxide on the intracellular oxidant status of skeletal muscle (Murrant, 1999). Murrant also employed advanced in situ animal models to examine muscle metabolism and muscle blood flow at the microvascular level during muscle contraction (Murrant, 2000).

Important findings from Murrant’s publications indicate that capillaries are capable of responding to stimuli in their immediate environment and are able to communicate with arterioles in close proximity. In the early 21st century, Kyra Pyke and supervisor Michael Tschakovsky examined the impact of controlling blood flow rates on the dilatory response of the brachial artery (Pyke, 2004). From this study they discovered the importance of controlling the shear rate stimulus when examining endothelial-dependent flow-mediated vasodilation between groups who differ in baseline brachial artery diameter. Again in 2004, Tschakovsky tested the hypothesis that rapid arterial vasodilation was proportional to contraction intensity at the onset of forearm exercise (Tschakovsky, 2004).

The results of these studies showed that immediate increases in forearm blood flow were proportional to contraction intensity from 5 to 70% of maximal voluntary contraction during the forearm exercise. The results of these detailed stimulus response studies supported the existence of a fast-acting vasodilatory mechanism once forearm exercise was initiated. It is evident that the early work of Barclay initiated a line of research where Canadian researchers continue to advance the knowledge about relationships between blood flow patterns and oxygen utilization in skeletal muscle as well as blood flow patterns and cerebrovascular function.

Cardiovascular function in clinical populations

Around the same time Canadians began to examine the effects of blood flow patterns on skeletal muscle, other researchers were interested in investigating cardiovascular function in various populations (i.e. clinical, aging). David Cunningham led a study in which he had unfit women (mean age 31 years) participate in a 9-week exercise training program and a subsequent 52-week program. Stroke volume increased by 28% while

exercising at 80% of maximal oxygen consumption after the 9-week program with peripheral adaptations occurring during the longer (i.e. 52-week) program (Cunningham, 1975). Shortly after, Donald Paterson, with David Cunningham and Norman Jones, examined the effects of exercise training on cardiovascular function in individuals who previously had experienced a myocardial infarction (Paterson, 1979). The patients performing high intensity exercise training experienced training-related increases in maximal oxygen uptake and stroke volume and reductions in heart rate at each work level in comparison to those in the low intensity training group. Paterson also published a seminal review of the effects of aging on the cardiorespiratory system (Paterson, 1992) in which he concluded that, despite the losses in absolute exercise capacity

inherent with aging, the ability to sustain a high intensity of aerobic exercise relative to age is preserved and that cardiorespiratory training in older men and women is effective in increasing maximal oxygen consumption. Scott Thomas, in 1993, examined cardiac output and left ventricular function in

response to exercise in older men (Thomas, 1993). In contrast to previous research in older participants, Thomas and colleagues found only small losses in cardiovascular response and left ventricular performance during light through strenuous exercise. Jack Goodman investigated the central and peripheral adaptations in post-coronary artery bypass surgery patients following twelve weeks of exercise training (Goodman, 1999). These findings suggested a significant improvement in maximal oxygen consumption after training accompanied by an increase in ejection fraction. Fast-forwarding to the 21st century, Canadian researchers including Victoria Claydon, Philip Millar, Mark Haykowsky, Darren Warburton, Don McKenzie and Cheri McGowan continued to investigate the role of cardiovascular function in various clinical populations; these included heart failure patients (Haykowsky, 2007), hypertensives (McGowan, 2006; Millar 2007), patients receiving transplants (Warburton, 2004), patients with chronic obstructive pulmonary disease (McKenzie, 2003) and patients with syncope (Claydon, 2004).

Cardiovascular function and exercise

The combination of cardiovascular function and exercise training has been a topic of interest for many Canadian researchers for many years. Within this topic is the ongoing debate of whether stroke volume plateaus during exercise of increasing intensity. This idea was attributed mostly to a decrease in the diastolic filling time as a result of increasing heart rate that occurs during increasing exercise intensity. Gledhill and colleagues were the first to acknowledge a difference in the stroke volume response to exercise between trained and untrained individuals (Gledhill, 1994). They proposed that enhanced diastolic filling with enhanced myocardial contractility were responsible for the increased stroke volume in trained persons. Gledhill also found that ventricular ejection times were longer, diastolic filling times were shorter, and blood volumes were higher in trained individuals compared to untrained (Gledhill, 1994). Warburton also added to this debate, discovering that stroke volume was elevated after plasma volume expansion, proposing that blood volume has an impact on the stroke volume response to exercise (Warburton, 1999).

In 1985, Norman Jones led studies that compared single-breath and carbon dioxide rebreathing techniques when examining cardiac output during exercise (Inman, 1985). Jones and colleagues discovered that the single-breath method significantly underestimated cardiac output values when compared to carbon dioxide rebreathing (Inman, 1985). Robert McKelvie, with Jones, followed this research by measuring cardiac output in non steady-state exercise with the carbon dioxide rebreathing technique (McKelvie, 1987). The work conducted in 1987 validated the carbon dioxide rebreathing method as an accurate and reproducible technique to measure cardiac output during progressive exercise tests with similar values at comparable oxygen consumption to those obtained in the steady-state. Much more research was performed in this area towards the beginning of the 21st century; for example Marc Poulin used ultrasound to assess blood flow of the cerebral artery during exercise in humans (Poulin, 1999).

Other Canadian researchers who have contributed to significant advances in the area of exercise and cardiovascular function include Robert Boushel, Darren Warburton, Mark Rakobowchuk, Darren Delorey and Michael Strickland. Specifically, Robert Boushel and colleagues were the first to use near-infrared spectroscopy (NIRS) in combination with tracer indocyanine green (ICG) to measure regional tissue blood flow (i.e. in calf muscle) during exercise in humans (Boushel, 2000). It was concluded that this technique (NIRS + ICG) might be useful for determining regional blood flow due to its highly spatial and temporal resolution.

Warburton and colleagues, in 2004, examined the effects of 12 weeks of either interval versus continuous exercise training on cardiorespiratory function and training-induced blood volume (i.e. hypervolemia) on aerobic power and left ventricular function. They concluded that 12 weeks of either modality of exercise resulted in similar improvements in aerobic power and left ventricular function, with training-induced hypervolemia accounting for nearly 50% of the changes in aerobic power after training (Warburton, 2004).

Again, comparing two different training modalities, Mark Rakobowchuk, under the supervision of Maureen MacDonald, looked at the effects of 6 weeks of sprint interval versus traditional endurance training on improving peripheral arterial stiffness and popliteal artery flow-mediated dilation in healthy humans. This study found that both low-volume sprint interval training (4-6 30 second “all-out” Wingate tests, 3 days/week) and high-volume endurance training (40-60 minutes of cycling at 65% of peak oxygen uptake, 5 days/week) resulted in similar improvements in peripheral arterial structure and function (Rakobowchuk, 2008). Michael Strickland, under the supervision of Mark Haykowsky, investigated whether fitness level affected the cardiovascular response to exercise. Healthy male participants were categorized into either low or high aerobic power groups. It was discovered that, compared to the less fit group, subjects with higher aerobic power had lower left ventricular filling pressures during exercise, suggesting superior diastolic function and compliance (Strickland, 2006). Darren Delorey, with Kevin Shoemaker and John Kowalchuk and under the supervision of Don Paterson, examined the effect of hypoxia on pulmonary oxygen uptake, leg blood flow and muscle deoxygenation during knee extension exercise. It was discovered that leg blood flow was 35% higher during a hypoxic state, resulting in a similar leg oxygen delivery between hypoxic and normoxic states.

Therefore it was concluded that oxygen delivery was not responsible for decreased oxygen uptake during the onset of exercise during hypoxia (Delorey, 2004). Thus, Canadian researchers have made significant advancements in the field of cardiovascular function and its relationship to exercise and different training modalities.

Contributions by these Canadian scientists to the advancement of research in the area of cardiovascular function during exercise and with exercise training are well documented. Equally important are the continuing contributions of their trainees to this dynamic field of research.

References

Barclay JK, Stainsby WN. The role of blood flow in limiting maximal metabolic rate in muscle. Medicine and science in sports. 1974 Dec;7(2):116-9.

Barclay JK. A delivery-independent blood flow effect on skeletal muscle fatigue. Journal of Applied Physiology. 1986 Sep 1;61(3):1084-90.

Gledhill N. The influence of altered blood volume and oxygen transport capacity on aerobic performance. Exercise and sport sciences reviews. 1985 Jan 1;13(1):75-94.

Barclay JK, Hansel M. Free radicals may contribute to oxidative skeletal muscle fatigue. Canadian journal of physiology and pharmacology. 1991 Feb 1;69(2):279-84.

Hughson RL, Shoemaker JK, Tschakovsky ME, Kowalchuk JM. Dependence of muscle Vo2 on blood flow dynamics at onset of forearm exercise. Journal of Applied Physiology. 1996 Oct 1;81(4):1619-26.

Tschakovsky ME, Shoemaker JK, Hughson RL. Vasodilation and muscle pump contribution toimmediate exercise hyperemia. American Journal of Physiology-Heart and Circulatory Physiology. 1996 Oct 1;271(4):H1697-701.

Shoemaker JK, Pozeg ZI, Hughson RL. Forearm blood flow by Doppler ultrasound during test and exercise: tests of day-to-day repeatability. Medicine and science in sports and exercise. 1996 Sep;28(9):1144-9.

Poulin MJ, Robbins PA. Indexes of flow and cross-sectional area of the middle cerebral artery using Doppler ultrasound during hypoxia and hypercapnia in humans. Stroke. 1996 Dec 1;27(12):2244-50.

Shoemaker JK, Halliwill JR, Hughson RL, Joyner MJ. Contributions of acetylcholine and nitric oxide to forearm blood flow at exercise onset and recovery. American Journal of Physiology-Heart and Circulatory Physiology. 1997 Nov 1;273(5):H2388-95.

Murrant CL, Andrade FH, Reid MB. Exogenous reactive oxygen and nitric oxide alter

intracellular oxidant status of skeletal muscle fibres. Acta physiologica

Scandinavica. 1999 Jun;166(2):111-21.Murrant CL, Sarelius IH. Coupling of muscle metabolism and muscle blood flow in capillary units during contraction. Acta physiologica Scandinavica. 2000 Apr 1;168(4):531-41.

Pyke KE, Dwyer EM, Tschakovsky ME. Impact of controlling shear rate on flow-mediated dilation responses in the brachial artery of humans. Journal of Applied Physiology. 2004 Aug 1;97(2):499-508.

Tschakovsky ME, Rogers AM, Pyke KE, Saunders NR, Glenn N, Lee SJ, Weissgerber T, Dwyer EM. Immediate exercise hyperemia in humans is contraction intensity dependent: evidence for rapid vasodilation. Journal of Applied Physiology. 2004 Feb 1;96(2):639-44.

Cunningham DA, Hill JS. Effect of training on cardiovascular response to exercise in women. Journal of Applied Physiology. 1975 Dec 1;39(6):891-5.

Paterson DH, Shephard RJ, Cunningham D, Jones NL, Andrew G. Effects of physical training on cardiovascular function following myocardial infarction. Journal of Applied Physiology. 1979 Sep 1;47(3):482-9.

Paterson DH. Effects of ageing on the cardiorespiratory system. Canadian journal of sport sciences. 1992 Sep;17(3):171-7.

Thomas SG, Paterson DH, Cunningham DA, McLellan DG, Kostuk WJ. Cardiac output and left ventricular function in response to exercise in older men. Canadian journal of physiology and pharmacology. 1993 Feb 1;71(2):136-44.

Goodman JM, Pallandi DV, Reading JR, Plyley MJ, Liu PP, Kavanagh T. Central and peripheral adaptations after 12 weeks of exercise training in post-coronary artery bypass surgery patients. Journal of Cardiopulmonary Rehabilitation and Prevention. 1999 May 1;19(3):144-50.

Haykowsky MJ, Liang Y, Pechter D, Jones LW, McAlister FA, Clark AM. A meta-analysis of the effect of exercise training on left ventricular remodeling in heart failure patients: the benefit depends on the type of training performed. Journal of the American College of Cardiology. 2007 Jun 19;49(24):2329-36.

McGowan CL, Levy AS, Millar PJ, Guzman JC, Morillo CA, McCartney N, MacDonald MJ. Acute vascular responses to isometric handgrip exercise and effects of training in persons medicated for hypertension. American Journal of Physiology-Heart and Circulatory Physiology. 2006 Oct 1;291(4):H1797-802.

Millar PJ, Bray SR, McGowan CL, MacDonald MJ, McCartney N. Effects of isometric handgrip training among people medicated for hypertension: a multilevel analysis. Blood Pressure Monitoring. 2007 Oct 1;12(5):307-14.

Warburton DE, Sheel AW, Hodges AN, Stewart IB, Yoshida EM, Levy RD, McKenzie DC. Effects of upper extremity exercise training on peak aerobic and anaerobic fitness in patients after transplantation. The American journal of cardiology. 2004 Apr 1;93(7):939-43.

McKenzie DK, Frith PA, Burdon JG, Town GI. The COPDX Plan: Australian and New Zealand guidelines for the management of chronic obstructive pulmonary disease 2003. Med J Aust. 2003 Mar 17;178(6 Suppl):S1-40.

Claydon VE, Hainsworth R. Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope. Hypertension. 2004 Apr 1;43(4):809-13.

Gledhill N, Cox D, Jamnik R. Endurance athletes’ stroke volume does not plateau: major advantage is diastolic function. Medicine and science in sports and exercise. 1994 Sep;26(9):1116-21.

Warburton DE, Gledhill NO, Jamnik VK, Krip BR, Card NO. Induced hypervolemia, cardiac function, VO2max, and performance of elite cyclists. Medicine and science in sports and exercise. 1999 Jun;31(6):800-8.

Inman MD, Hughson RL, Jones NL. Comparison of cardiac output during exercise by single-breath and CO2-rebreathing methods. Journal of applied physiology. 1985Apr 1;58(4):1372-7.

McKelvie RS, Heigenhauser GJ, Jones NL. Measurement of cardiac output by CO2 rebreathing in unsteady state exercise. CHEST Journal. 1987 Nov 1;92(5):777-82.

Poulin MJ, Syed RJ, Robbins PA. Assessments of flow by transcranial Doppler ultrasound in the middle cerebral artery during exercise in humans. Journal of Applied Physiology. 1999 May 1;86(5):1632-7.

Boushel R, Langberg H, Olesen J, Nowak M, Simonsen L, Bülow J, Kjær M. Regional blood flow during exercise in humans measured by near-infrared spectroscopy and indocyanine green. Journal of Applied Physiology. 2000 Nov 1;89(5):1868-78.

Warburton DE, Haykowsky MJ, Quinney HA, Blackmore DE, Teo KK, Taylor DA, McGavock JO, Humen DP. Blood volume expansion and cardiorespiratory function: effects of training modality. Medicine and science in sports and exercise. 2004 Jun;36(6):991-1000.

Rakobowchuk M, Tanguay S, Burgomaster KA, Howarth KR, Gibala MJ, MacDonald MJ. Sprint interval and traditional endurance training induce similar improvements in peripheral arterial stiffness and flow-mediated dilation in healthy humans. American Journal of Physiology-Regulatory, Integrative and ComparativePhysiology. 2008 Jul 1;295(1):R236-42.

Stickland MK, Welsh RC, Petersen SR, Tyberg JV, Anderson WD, Jones RL, Taylor DA, Bouffard M, Haykowsky MJ. Does fitness level modulate the cardiovascular hemodynamic response to exercise?. Journal of applied physiology. 2006 Jun 1;100(6):1895-901.

DeLorey DS, Shaw CN, Shoemaker JK, Kowalchuk JM, Paterson DH. The effect of hypoxia on pulmonary O2 uptake, leg blood flow and muscle deoxygenation during single‐leg knee‐extension exercise. Experimental physiology. 2004 May 1;89(3):293-302.