exercise is an important determinant of health and provides numerous cardiovascular , psychological , and prognostic benefits . the fontan operation , and its refinements , have proved a major success with a majority of patients with univentricular malformations now surviving into adulthood with a good quality of life . however , exercise tolerance is significantly reduced and the factors responsible for this exertional limitation are incompletely understood . this paper aims to provide a unique perspective on the limitations of the fontan circulation by focusing on exercise constraints in a normal biventricular circulation .   rather than describing abnormalities within the components of a fontan circulation , we will focus on highlighting the importance of that which is missing  a prepulmonary pump . popular models of exercise physiology have concentrated on the systemic circulation and the left ventricle ( lv ) as the primary determinant of cardiac output ( co ) augmentation during physical exertion . however , in the healthy subject , there is a large reserve for exercise - induced augmentation of the systemic ventricle and vasculature . we will discuss the evidence supporting the concept that the right ventricle ( rv ) is a determinant of exercise performance and that , in its absence , pulmonary vascular resistance becomes a critical limitation . the recent availability of relatively specific pulmonary vasodilators has given these physiological discussions immediate clinical relevance . the potential benefit of these agents   is consistent with physiological theory and represents an exciting avenue of investigation in fontan patients . exercise performance is defined by the ability of the body 's working muscles to utilize oxygen , and this can be measured by vo2 max on cardiorespiratory testing . it has been demonstrated that the skeletal muscles ' ability to utilize oxygen far exceeds the capacity of the cardiovascular system to deliver oxygen . thus , cardiac output ( co ) becomes the limiting step , and explains 70%85% of the variance in vo2 max with the remainder being determined by peripheral factors such as mitochondrial density which enables greater oxygen extraction . in healthy subjects , co may be expected to increase 3- to 5-fold whilst increases are even greater in athletes . cardiac output is enhanced by ( 1 ) greater preload , ( 2 ) increased heart rate , ( 3 ) increased myocardial contractility , and ( 4 ) reduced afterload during exercise , and both ventricles need to generate the same stroke volume . weak link  by asking which factor is closest to its physiological limit during exercise .   conventional teaching is that it is the lv and its interaction with the systemic circulation which determines cardiac output . however , lv functional measures and measures of systemic vascular tone have not been shown to predict exercise performance as might be expected if they were the limitation of exercise performance [ 1012 ] . preload may be defined as the passive stretch applied to the myocardium prior to the initiation of active contraction . according to the frank - starling mechanism , increases in preload augment cardiac output . the extent to which this mechanism contributes to exercise - induced co augmentation remains a point of debate . studies using radionuclide ventriculography have reported large increases in lv end - diastolic volume during exercise and minimal or no decrease in lv end - systolic volume . warburton et al . [ 13 , 14 ] suggested that this increase in lv preload was the dominant means by which co increased during exercise , especially in well - trained athletes [ 13 , 14 ] .   however , more recent exercise studies using 2d echocardiography [ 3 , 1519 ] and cardiac magnetic resonance ( cmr ) [ 2022 ] have found little or no increase in lv end - diastolic volume and that augmentation of stroke volume is primarily due to decreases in lv end - systolic volume . assimilating these contrasting findings is difficult , but perhaps a reasonable summary may be that enhanced lv preload contributes to , but is not the sole determinant of , exercise - induced increases in stroke volume . accepting the contribution of lv preload in cardiac output augmentation it is often assumed that the lv generates flow which then serves as its own preload with , perhaps , some facilitation from skeletal muscle acting to enhance venous return . with a few notable exceptions [ 46 , 23 ] , the rv and pulmonary circulation have rarely been considered as potential constraints on lv filling in normal exercise physiology . at least in settings where rv afterload is increased , reduced flow in the presystemic circulation can result in reduced lv preload and , thus , cardiac output limitation . [ 20 , 21 ] demonstrated reduced lv filling during exercise in patients with pulmonary hypertension and obstructive airways disease . also , the demonstration of improved exercise tolerance with pulmonary vasodilators provides some indirect affirmation of this concept . it has been shown that sildenafil [ 24 , 25 ] and bosentan   can increase exercise performance at altitude or during hypoxic exercise although no benefit has been demonstrated in normoxic settings . it was concluded by faoro et al .   that the pulmonary circulation provides a limitation to cardiac output when the lack of efficacy of selective pulmonary vasodilators during normoxic exercise may suggest that pulmonary vasodilation is close to maximal in this setting . frequently , exercise intolerance is attributed to diastolic dysfunction , and it is implied that the lv filling impairment is due to pathology of the lv myocardium .   however , it is important to note that it is extremely difficult to differentiate impaired filling due to myocardial stiffness from that due to reduced preload when using noninvasive measures . echocardiographic measures are similar when there is a lack of  push  from reduced preload and when there is a lack of  suck  from lv impairment . described reductions in traditional and novel diastolic measures in patients with pulmonary hypertension despite relatively normal lv function . hart et al . reported measures of diastolic dysfunction which were associated with preload reduction following marathon running . these changes normalized immediately with preload augmentation by leg lifting .   finally , in a large cohort of patients with obstructive pulmonary disease , barr et al . attributed impaired lv filling to preload reduction through increased pulmonary vascular resistance rather than myocardial stiffness resulting from hypoxia or hypertension . afterload can be defined as the myocardial stress achieved during contraction , the major determinants being systolic pressure , cavity size , and wall thickness . decreases in lv afterload serve to increase stroke volume and this has been emphasized as an important source of cardiac output modulation in popular models of exercise physiology . it has even been suggested that the exercise - induced decreases in systemic vascular resistance ( due to vasodilation in skeletal muscle ) is the primary determinant of co augmentation , and that the resultant increases in heart rate and contractility are simply a compensation to maintain systemic blood pressures [ 32 , 33 ] . however , it has been well established that the capacity for peripheral vasodilation far exceeds the capacity for cardiac output augmentation , implying that the limitation to cardiac output is upstream of the peripheral circulation . characterization of rv afterload during exercise is more difficult because its measurement requires invasive pulmonary artery catheterization or echocardiographic estimates , both of which can be challenging during exercise . whilst it is commonly stated that pulmonary artery pressures increase only slightly with exercise [ 35 , 36 ] , multiple studies have reported considerable increases in pulmonary artery pressures [ 4 , 23 , 3742 ] . kovacs et al .   combined data from nearly 200 patients in invasive studies to demonstrate that mean pulmonary artery pressures increased in a linear manner with exercise which explains why relatively high pressures have been measured in those with good exercise tolerance . argiento et al .   described exercise - induced increases in systolic pulmonary artery pressures that frequently exceeded 60  mmhg in healthy subjects whilst bidart et al .   reported even greater increases in athletes . it may be that these increases in pulmonary artery pressures are a result of an inability for the pulmonary vasculature to reduce its resistance sufficiently to compensate for the increased co of exercise . this concept is best summarized by the simplified poiseuille 's relation in which co is proportional to pressure and inversely to resistance . pulmonary vascular resistance is very low at rest and previous studies have suggested that its capacity for reduction is only 20%50% [ 23 , 35 , 43 ] . this represents a marked difference to the systemic circulation where greater reductions in peripheral resistance moderate increases in lv afterload ( see table 1 ) . contractility is an intrinsic property of the myocardium , is load independent , and is most frequently derived from invasive indices such as the slope of the end - systolic pressure volume relation or the preload recruitable stroke work . there are no studies which have assessed and compared lv and rv contractility during exercise in healthy subjects .   at rest , rv measures of mass   and contractility   are one - third to one - fifth those of the lv and this appropriately matches the pressure requirements of each . however , when rv afterload increases , rv contractility may be unable to maintain ventriculo - arterial coupling such that cardiac output declines . macnee   described marked reductions in rv stroke volume ( ~30% ) when pulmonary artery pressures doubled and compared this with only slight decreases in lv stroke volume with physiological increases in mean arterial pressures .   during exercise , morrison et al . used first - pass radionuclide ventriculography and invasive pressure measures to demonstrate a progressive improvement in rv ejection fraction with exercise - induced reductions in pulmonary vascular resistance . however , in comparison with the systemic circulation , increases in pulmonary vascular pressures were relatively greater , and reductions in vascular resistance were less . this would suggest that exercise results in a disproportionate workload for the rv , a concept which is further supported by the demonstration that cardiac fatigue predominantly affects the rv after intense prolonged exercise [ 49 , 50 ] . therefore , there are reasonable grounds to contend that exercise - induced increases in rv load represent a potential for cardiac output limitation .   for cardiac output to be maintained during exercise , the rv must greatly augment its contractility , possibly more so than the lv . as will be discussed , this is problematic for exercise performance when rv function is reduced or absent . heart rate is a major determinant of cardiac output , particularly in the later phases of exercise when stroke volume augmentation plateaus . it is , however , inefficient for the heart rate to increase such that lv filling is impaired . thus , although the factors which determine maximal heart rate during exercise are incompletely understood , it is likely that cardiopulmonary baroreceptor activation contributes to maintaining an appropriate balance between lv preload and heart rate during exercise . in the fontan circulation , the systemic and pulmonary vascular beds are connected in series without the presence of a pre - pulmonary pump to add forward energy to flow through the lungs ( figure 1 ) . typically co in a fontan circulation at rest is decreased to 70% ( range 50%80% ) of normal and an increase in peripheral oxygen utilization compensates for this reduction in oxygen supply . during exercise , oxygen utilization remains normal or supra - normal but maximal co is approximately half that of normal . control of cardiac output in a fontan circulation is complex with a different interplay of contractility , afterload , preload , and heart rate . the implications of exercise on each of these variables will be discussed and contrasted with that already described for normal subjects . there is limited data in which lv filling during exercise has been assessed in the fontan patient . more frequently , studies have assessed the hemodynamic response to low - dose dobutamine as an exercise surrogate . senzaki et al . [ 55 , 56 ] have twice demonstrated limitations in preload reserve in this setting . they demonstrated a significant 25% reduction in lv end - diastolic pressure in the fontan patient whereas there was no change in subjects with normal circulation . using variables derived from ventricular pressure - area hybrid loops , they found that cardiac index was dependent upon preload ( end - diastolic area ) and not contractility ( ventricular elastance ) or afterload ( arterial elastance ) . thus , inadequate preload reserve was implicated in the failure for co to augment with -adrenergic stimulation . robbers - visser et al .   used cmr imaging to provide a volumetric assessment of dobutamine - induced cardiac augmentation in a young group of patients with fontan circulation . they described a modest increase in co which was entirely due to increasing heart rate . stroke volume was unchanged due to the fact that end - diastolic volumes decreased to the same extent as end - systolic volumes . this contrasts with the normal physiological response to dobutamine in which stroke volume increases due to a reduction in end - systolic volume and preserved end - diastolic volumes [ 58 , 59 ] . thus , co limitation in the fontan patient was again attributed to inadequate preload reserve suggesting that the constraint to exercise is  up - stream  of the lv . as discussed previously , measures of impaired filling preload reduction and myocardial relaxation impairment will manifest similarly on non - invasive measures such as echocardiography . in which echocardiographic indices of diastolic dysfunction were demonstrable in 16 of 28 young fontan patients .   however , hemodynamic data performed in a subset of these patients during exercise demonstrated normal lv filling pressures which did not increase with exercise , a finding which is inconsistent with the raised filling pressures expected with diastolic dysfunction [ 61 , 62 ] . rather , these findings again reinforce the concept of preload inadequacy whereby the normal exercise - induced augmentation in lv filling pressures   is absent in the fontan patient . in the fontan patient during exercise , the reduction in systemic vascular resistance is less than in the normal subject . it is likely that this represents a secondary phenomenon which attempts to maintain blood pressure when co augmentation is reduced . this is achieved by an increase in sympathetic vasomotor tone   but is not always sufficient and bp may still fall in the fontan patient during exercise . thus the relatively greater systemic afterload in the fontan patient is a consequence , rather than cause , of reduced output . as described earlier , normal exercise is associated with an increase in stroke volume and pulmonary artery pressures . a pre - pulmonary pump is required to generate the pressure and flow which enables adequate lv filling during exercise .   without a pre - pulmonary pump , and without adequate preload , indirect evidence for our proposition that the pulmonary circulation serves as a limitation to exercise in the fontan patient is provided by the demonstration that exercise tolerance is improved with pulmonary vasodilators . studied the exercise response in 18 fontan patients before and after a single oral dose of sildenafil as compared with a group of 9 control fontan patients . an improvement in vo2 max ( 9.4  5.2% ) and cardiac index ( 10.0  7.2% ) was demonstrable in those who took sildenafil whilst these measures were unchanged in those who did not receive treatment . pulmonary vasodilator therapy warrants further investigation in fontan patients given its potential to address a likely source of limitation to exercise . there is limited evidence to suggest that contractility serves as a limitation to co in the fontan patient , with the exception of those patients with advanced ventricular dysfunction .   as described earlier , senzaki et al . used hybrid measures of ventricular elastance to demonstrate that contractility and contractile reserve were largely preserved in the fontan patient . studies that have suggested reduced systolic performance in the fontan ventricle have frequently based conclusions on measures which are load dependent . furthermore , if abnormalities of the systemic ventricle and the peripheral circulation were a cause of exercise limitation , a benefit in exercise tolerance might be expected with ace inhibitor therapy but this has not been demonstrated . figure 2 summarizes the relative contribution of lv function and pulmonary vascular resistance to exercise - induced increases in cardiac output . in the fontan patient , atrial pacing at increased rates does not result in the augmentation of cardiac output that is seen in normal subjects . rather , there is a proportional reduction in stroke volume which illustrates heart rate has a less direct effect on co than in a normal circulation . during exercise , fontan patients exhibit chronotropic incompetence with a heart rate consistently lower than normal controls , and this has typically been attributed to abnormal reflex control of heart rate or adrenergic dysfunction [ 6771 ] . however , preload inadequacy in the fontan patient may lead to reducing stroke volume if the ventricular filling time decreases with increasing heart rate . thus , it is possible that chronotropic incompetence is an adaptive response to prevent hemodynamic compromise in patients with limited preload , such as in the fontan patient [ 72 , 73 ] . traditional models of exercise physiology have emphasized the performance of the systemic ventricle and systemic circulation .   in the fontan patient with pathology of the systemic ventricle however , in the healthy fontan patient , limitation is defined by upstream factors which determine systemic ventricular filling . inadequate preload reserve has been demonstrated to limit cardiac augmentation caused by ionotropic stimulation and it is likely that this mechanism also explains cardiac limitation during exercise . at rest , pulmonary vascular resistance and pressure are low .   during exercise , increases in flow mandate an increase in pressure unless resistance can fall proportionately . substantial reserve in the systemic circulation moderates pressure increases whilst , in the pulmonary circulation , there is evidence that the capacity for further vasodilation is limited . in a normal biventricular circulation , however , in the fontan patient , there is no rv to provide this work demand and hence flow , lv filling and co are unable to increase normally . treatment regimens are most likely to be efficacious if they address the part of the circulation which serves as the greatest source of limitation . classical heart failure regimens have demonstrated poor efficacy in fontan patients but this may be expected if the systemic circulation is not the primary source of limitation . early results with these agents have offered promise and may prove an important means of improving exercise tolerance .
exercise is an important determinant of health but is significantly reduced in the patient with a univentricular circulation . 
 normal exercise physiology mandates an increase in pulmonary artery pressures which places an increased work demand on the right ventricle ( rv ) .   in a biventricular circulation with pathological increases in pulmonary vascular resistance and/or reductions in rv function , 
 exercise - induced augmentation of cardiac output is limited . 
 left ventricular preload reserve is dependent upon flow through the pulmonary circulation and this requires adequate rv performance . in the fontan patient , the reasons for exercise intolerance are complex . in those patients with myocardial dysfunction or other pathologies of the circulatory components , 
 it is likely that these abnormalities serve as a limitation to cardiac performance during exercise . 
 however , in the healthy fontan patient , it may be the absence of a sub - pulmonary pump which limits normal increases in pulmonary pressures , trans - pulmonary flow requirements and cardiac output . 
 if so , performance will be exquisitely dependent on pulmonary vascular resistance . 
 this provides a potential   explanation as to why pulmonary vasodilators may improve exercise tolerance . 
 as has recently been demonstrated , these agents may offer an important new treatment strategy which directly addresses the physiological limitations in the fontan patient .