Cardiopulmonary exercise test as a tool in surveillance after Fontan operation
Abstract
Fontan patients have significantly decreased exercise tolerance secondary to several factors, most notably, a lack of a subpulmonary pump to augment systemic venous return to the heart and to overcome the pulmonary vascular resistance. Cardiopulmonary exercise testing is an important inexpensive non-invasive tool to monitor for subclinical changes and functional data over time that may portend the need for earlier intervention.
Keywords
INTRODUCTION
The Fontan operation was first performed in the early 1970s to palliate functionally single ventricle patients[1]. It has gone through many iterations and has been fraught with complications such as liver fibrosis, plastic bronchitis, protein-losing enteropathy, and arrhythmia[2]. Subsequent surgical technique modifications and closer monitoring have improved outcomes; however, surveillance of complications continues to be highly variable between institutions.
Patients with Fontan circuits have significantly decreased exercise tolerance secondary to several factors. The absence of a subpulmonary ventricle causes a lack of negative pressure pulling blood back into the heart and driving pressure to overcome the pulmonary vascular resistance with progressive exercise. In addition, these patients have decreased muscle mass, diminished vascular function, and abnormal autonomic regulation that can impede oxygen delivery to the muscles, thereby further decreasing the ability to exercise efficiently[3]. Factors such as depression, deconditioning, chronic illnesses, and arrhythmia further complicate the picture[4,5].
Cardiopulmonary exercise testing (CPET) is an important non-invasive tool to monitor functional measures of the Fontan circuit and serves as adjunct information to guide timing and need for interventions. It is a relatively inexpensive modality to evaluate the Fontan circuit for any significant desaturations, arrhythmia, oxygen delivery and monitor for any decreased function over time.
In this paper, we will discuss the physiology of exercise in the Fontan circulation and the various CPET measures that can be used to follow Fontan function as well as guide intervention in the Fontan patient.
PHYSIOLOGY OF EXERCISE IN THE FONTAN POPULATION
Preload dependency
During exercise in a normal biventricular system, the pulsatile flow of the blood through the pulmonary vasculature stimulates the release of nitric oxide, thereby decreasing pulmonary artery pressures[6-8]. The subpulmonary ventricle produces a negative pressure to augment the systemic venous return to the heart and generates increasing pressure to drive blood through the pulmonary vasculature, thereby increasing cardiac output to allow adequate oxygen delivery with increasing amounts of exertion.
Fontan circuits lack this subpulmonary pump and depend on the negative pressure of inspiration in order to overcome pulmonary artery pressures. Stroke volume is limited by the inability to increasingly drive the blood through the pulmonary vasculature, even in the setting of normal ventricular function and end-diastolic pressure[9]. In addition, there is some energy loss in the Fontan circuit due to the total cavopulmonary connection.
Because of multiple sternotomies, Fontan patients have intrathoracic fibrous adhesions that can decrease chest wall compliance; therefore, they have decreased forced vital capacity (FVC), which also negatively affects their ability to increase preload back to the heart during inspiration[8]. These factors contribute to the relatively decreased cardiac output with increasing exertion compared to biventricular physiology, which contributes to exercise intolerance in Fontan patients at high exertion.
Ventricular compliance and atrioventricular valve regurgitation
Fontan circulation is well tolerated in younger patients; however, as the patient ages, the ventricular compliance decreases secondary to myocardial fibrosis. This then affects ventricular filling and decreases cardiac output and is most evident at higher heart rates because of the decreased filling time of the ventricle. Significant atrioventricular (AV) valve regurgitation further decreases forward flow that can affect cardiac output negatively in a Fontan patient.
Chronotropic incompetence and arrhythmias
Peak heart rate decreases as patients age. Chronotropic incompetence and arrhythmias are well-known complications in the Fontan population. These patients have compromised cardiac output compared to biventricular patients when chronotropic incompetence is present. Arrhythmias, such as atrial tachycardias, are relatively common secondary to previous incisions in the atria creating a substrate for arrhythmias during exercise.
Peripheral vascular dysfunction
Patients with Fontan physiology have reduced endothelial function and autonomic dysregulation, which is deleterious to the aerobic function[10]. The etiology of this is multifactorial. A lifetime of activity restriction and fear of adverse events from exercise leads to decreased muscle mass and poor conditioning. Low skeletal muscle mass causes decreased oxygen extraction and poor conditioning leading to poor oxygen utilization efficiency, thereby further contributing to decreased exercise performance.
Abnormal ventilatory function
Patients with Fontan palliation have abnormal ventilation at both rest and with exercise. The exact cause is not entirely clear; however, it is more than likely due to several factors. Fontan patients have multiple median sternotomies, resulting in decreased chest wall compliance secondary to multiple adhesions. Patients with Fontan circulation also hyperventilate compared to normal two ventricle physiology patients because of systemic cyanosis and increased dead space to tidal volume ratio[11,12].
In the presence of a Fontan fenestration, there is increasing right to left shunt with progressive exercise, thereby exacerbating the Ventilation/Flow (V/Q) mismatch, further compromising the oxygen delivery to muscle and producing decreased exercise capacity.
CARDIOPULMONARY EXERCISE MEASURES
VO2 peak
VO2 peak is the rate at which the patient consumes oxygen at peak exercise and represents the efficiency with which the patient utilizes oxygen. It is a measure of aerobic capacity that has been shown to have prognostic values in adult heart failure patients[13]. Fontan patients have a multitude of reasons for VO2 peak to be decreased, such as decreased preload from a lack of a subpulmonary pump, obstruction of the Fontan circuit, significant AV valve insufficiency, left ventricular outflow obstruction, chronotropic insufficiency, arrhythmias, decreased peripheral vascular function and abnormal ventilatory function.
Numerous studies in Fontan patients have shown decreased VO2 peak of ~50%-60% of expected[14-17]. It has also been shown that VO2 peak declines with age and is also dependent on the morphology of the systemic ventricle, a single right ventricle having decreased VO2 peak over time compared to a single left ventricle[18,19]. A recent metaanalysis by Udholm et al.[20] reports that in the seven studies analyzed, there was universal exercise impairment in Fontan patients with a VO2 peak range of 21.2-27.1 mL/kg/min; however, it was noted that there was no clear consensus of whether VO2 peak itself portends greater risk of hospitalization or cardiac adverse event.
Several studies that analyzed the peak VO2 in Fontan patients as it relates to outcome indicate that decreasing VO2 peak correlates with cardiac adverse events, i.e., death or cardiac surgery[21-23]. An absolute cut-off value remains elusive, however, decreased peak VO2 does correlate with cardiac symptoms and worsening functioning class[24]. Egbe et al.[23] noted that a decline in ≥ 3% per year was the only predictor of a 5-year risk of death or surgery. VO2 peak over time can be a helpful measure to survey for possible functional derangements.
Submaximal measures
Aerobic metabolism is the primary source of energy to sustain exercise during the early phase. With progressive intensity, metabolism shifts from aerobic to anaerobic metabolism. Patients with a Fontan circulation have problems exercising with anaerobic metabolism. It is difficult to sustain high intensity exercise in a Fontan circulation, as there is decreased flow through the pulmonary vasculature due to lack of subpulmonary pump and increased pulmonary vascular resistance, thus diminishing cardiac output with progressive exercise. For these reasons, submaximal measures can also be used to monitor Fontan function over time.
VO2 at anaerobic threshold
Anaerobic threshold (AT) is the point during exercise at which the patient changes from aerobic to anaerobic metabolism. AT is decreased in patients with poor aerobic fitness as well as heart failure patients. While VO2 peaks in Fontan patients are generally decreased, VO2 at the anaerobic threshold is less impaired and is generally ~75% expected as opposed to 65% expected[25].
There is no data to suggest a clear cut-off for significantly increased risk for mortality; however, the lower the AT, the more risk of morbidity and mortality. Fernandes et al.[26] suggested that a cut-off of
Interestingly, some interventions such as pulmonary vasodilators and strength training have shown improvement in the VO2 at AT[3,27]. Therefore, despite a lack of clear cut-off, VO2 at AT is a measure that can be trended over time to assess a Fontan’s function and aerobic fitness in Fontan patients.
Oxygen uptake efficiency slope
Oxygen uptake efficiency slope (OUES) is a submaximal relationship of oxygen consumption and minute ventilation, is calculated from submaximal data, and does not depend on intra/inter observer variability[28,29]. It is calculated using a logarithmic curve using the equation: VO2 = A log10 VE + B, where “A” is the OUES, VE is minute ventilation, and it has been well validated in healthy adults and patients with heart failure[28].
The higher OUES or the steeper the slope, the more efficient the oxygen uptake. It has been shown to strongly predict peak VO2 in Fontan patients and is significantly lower in Fontan patients compared to healthy subjects and other congenital heart disease patients, such as Tetralogy of Fallot[30]. Multiple studies have shown OUES as an excellent predictor of adverse cardiac events in Tetralogy of Fallot patients.
OUES has been validated as an excellent predictor of VO2 peak in Fontan patients. However,
OUES is a promising independent predictor of outcomes in Fontan patients, and further studies need to be performed to validate the usefulness of this measure.
Exercise oscillatory ventilation
Exercise oscillatory ventilation (EOV) is a common measure in adult heart failure patients and has long been established as a poor prognostic indicator in adult heart failure[33-35]. In a study from Japan, it was noted that 58% of their young Fontan patients displayed EOV[36].
However, Muneuchi et al.[36] found that their patients with EOV were typically smaller, younger and had a higher VO2 peak, which they attributed EOV to be a compensatory mechanism to overcome the pulmonary artery pressure. Nathan et al.[24] found that EOV during a CPET for Fontan was a strong independent predictor for non-elective hospitalization, death or cardiac transplant. There was no correlation between VO2 peak and EOV, mostly likely because patients in this study were larger and older. EOV still is a promising submaximal measure to follow in older Fontan patients, although more studies need to be performed.
O2 pulse
O2 pulse is the VO2 at peak divided by heart rate and is a marker of stroke volume. O2 pulse in patients with Fontan’s is lower than biventricular counterparts, largely because of decreased peak VO2[25]. Although higher O2 pulse at peak exercise was associated with higher peak VO2[37], few studies that have reported O2 pulse and have shown no significant correlation with risk of morbidity or mortality[23,26]. Despite these findings, patients in both studies were relatively midterm in their course after their Fontan’s; therefore, it would be difficult to conclude whether changes over a longer period of time would portend a different outcome.
Respiratory efficiency and spirometry
Patients who have undergone staged Fontan have had at least two to three median sternotomies, therefore, have the presence of adhesions in the chest cavity. These adhesions can decrease chest wall compliance and restrict excursion of the chest during inspiration. This negatively affects preload given preload is directly affected by the negative inspiratory pressure and lack of subpulmonary pump. FVC correlates with Fontan mortality[38].
VE/VCO2 is a marker of respiratory insufficiency and can be decreased in Fontan patients. Chen et al.[32] showed that a VE/VCO2 slope ≥ 37 conferred a hazard ratio of 10.77 (p0.023) on univariate analysis for
Heart rate reserve and chronotropic index
Sinus node dysfunction and chronotropic incompetence commonly occur as patients with Fontan circulation age due to incisions at the SVC/RA junction and progressive fibrosis. The peak heart rates on average in a large study in Fontan patients were ~155-165 bpm[25], which is likely because of other physiologic factors of the Fontan circulation, rather than chronotropic incompetence. Metabolic acidosis and cyanosis with progressive exercise in a Fontan patient limit the length and intensity of exercise, thus keeping the patient from achieving a higher heart rate. There are mixed findings on whether HRR and Chronotropic index confers poor outcomes and is likely age-dependent.
CONCLUSION
CPET is an important tool in the surveillance of the Fontan circulation to detect trends in the function that would necessitate intervention. Preload and overcoming pulmonary vascular resistance seem to be the most important determinant of exercise intolerance in the Fontan population. Metabolic measures including VO2 peak, VO2 at anaerobic threshold, oxygen pulse and oxygen uptake efficiency slope and ventilatory efficiency can be followed over time to monitor for subclinical changes and be paired with catheterization, imaging and clinical data to determine need and timing for intervention.
DECLARATIONS
Authors’ contributionsWriting of the manuscript: Wang-Giuffre EW, Doshi UH
Availability of data and materialsNot applicable.
Financial support and sponsorshipNone.
Conflicts of interestBoth authors declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2022.
REFERENCES
2. Syamasundar Rao P. Fontan operation: a comprehensive review. In: S. Firstenberg M, Khan I, editors. Advances in complex valvular disease. IntechOpen; 2021.
3. Cordina RL, O'Meagher S, Karmali A, et al. Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology. Int J Cardiol 2013;168:780-8.
4. McCrindle BW, Williams RV, Mital S, et al. Physical activity levels in children and adolescents are reduced after the Fontan procedure, independent of exercise capacity, and are associated with lower perceived general health. Arch Dis Child 2007;92:509-14.
5. Ong L, Nolan RP, Irvine J, Kovacs AH. Parental overprotection and heart-focused anxiety in adults with congenital heart disease. Int J Behav Med 2011;18:260-7.
6. Argiento P, Chesler N, Mulè M, et al. Exercise stress echocardiography for the study of the pulmonary circulation. Eur Respir J 2010;35:1273-8.
7. Stickland MK, Welsh RC, Petersen SR, et al. Does fitness level modulate the cardiovascular hemodynamic response to exercise? J Appl Physiol (1985) 2006;100:1895-901.
8. Hsia TY, Khambadkone S, Redington AN, Migliavacca F, Deanfield JE, de Leval MR. Effects of respiration and gravity on infradiaphragmatic venous flow in normal and Fontan patients. Circulation 2000;102:III148-53.
9. Gewillig MH, Lundström UR, Bull C, Wyse RK, Deanfield JE. Exercise responses in patients with congenital heart disease after fontan repair: Patterns and determinants of performance. J Am Coll Cardiol 1990;15:1424-32.
10. Lambert E, d’Udekem Y, Cheung M, et al. Sympathetic and vascular dysfunction in adult patients with Fontan circulation. Int J Cardiol 2013;167:1333-8.
11. Driscoll DJ, Staats BA, Heise CT, et al. Functional single ventricle: cardiorespiratory response to exercise. J Am Coll Cardiol 1984;4:337-42.
12. Ohuchi H, Ohashi H, Takasugi H, Yamada O, Yagihara T, Echigo S. Restrictive ventilatory impairment and arterial oxygenation characterize rest and exercise ventilation in patients after fontan operation. Pediatr Cardiol 2004;25:513-21.
13. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778-86.
14. Driscoll DJ, Durongpisitkul K. Exercise testing after the Fontan operation. Pediatr Cardiol 1999;20:57-9; discussion 60.
15. Durongpisitkul K, Driscoll DJ, Mahoney DW, et al. Cardiorespiratory response to exercise after modified Fontan operation: determinants of performance. J Am Coll Cardiol 1997;29:785-90.
16. Harrison DA, Liu P, Walters JE, et al. Cardiopulmonary function in adult patients late after Fontan repair. J Am Coll Cardiol 1995;26:1016-21.
17. Cooper DM, Leu SY, Taylor-Lucas C, Lu K, Galassetti P, Radom-Aizik S. Cardiopulmonary exercise testing in children and adolescents with high body mass index. Pediatr Exerc Sci 2016;28:98-108.
18. Butts RJ, Spencer CT, Jackson L, et al. Estimating equations for cardiopulmonary exercise testing variables in Fontan patients: derivation and validation using a multicenter cross-sectional database. Pediatr Cardiol 2015;36:393-401.
19. Giardini A, Hager A, Pace Napoleone C, Picchio FM. Natural history of exercise capacity after the Fontan operation: a longitudinal study. Ann Thorac Surg 2008;85:818-21.
20. Udholm S, Aldweib N, Hjortdal VE, Veldtman GR. Prognostic power of cardiopulmonary exercise testing in Fontan patients: a systematic review. Open Heart 2018;5:e000812.
21. Cunningham JW, Nathan AS, Rhodes J, Shafer K, Landzberg MJ, Opotowsky AR. Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation. Am Heart J 2017;189:184-92.
22. Diller GP, Giardini A, Dimopoulos K, et al. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J 2010;31:3073-83.
23. Egbe AC, Driscoll DJ, Khan AR, et al. Cardiopulmonary exercise test in adults with prior Fontan operation: the prognostic value of serial testing. Int J Cardiol 2017;235:6-10.
24. Nathan AS, Loukas B, Moko L, et al. Exercise oscillatory ventilation in patients with Fontan physiology. Circ Heart Fail 2015;8:304-11.
25. Goldberg DJ, Avitabile CM, McBride MG, Paridon SM. Exercise capacity in the Fontan circulation. Cardiol Young 2013;23:824-30.
26. Fernandes SM, Alexander ME, Graham DA, et al. Exercise testing identifies patients at increased risk for morbidity and mortality following Fontan surgery. Congenit Heart Dis 2011;6:294-303.
27. Goldberg DJ, Zak V, Goldstein BH, et al. Pediatric Heart Network Investigators. Results of the FUEL trial. Circulation 2020;141:641-51.
28. Baba R, Kubo N, Morotome Y, Iwagaki S. Reproducibility of the oxygen uptake efficiency slope in normal healthy subjects. J Sports Med Phys Fitness 1999;39:202-6.
29. Hollenberg M, Tager IB. Oxygen uptake efficiency slope: an index of exercise performance and cardiopulmonary reserve requiring only submaximal exercise. J Am Coll Cardiol 2000;36:194-201.
30. Bongers BC, Hulzebos HJ, Blank AC, van Brussel M, Takken T. The oxygen uptake efficiency slope in children with congenital heart disease: construct and group validity. Eur J Cardiovasc Prev Rehabil 2011;18:384-92.
31. Giardini A, Specchia S, Gargiulo G, Sangiorgi D, Picchio FM. Accuracy of oxygen uptake efficiency slope in adults with congenital heart disease. Int J Cardiol 2009;133:74-9.
32. Chen CA, Chen SY, Chiu HH, et al. Prognostic value of submaximal exercise data for cardiac morbidity in Fontan patients. Med Sci Sports Exerc 2014;46:10-5.
33. Arena R, Myers J, Abella J, et al. Prognostic value of timing and duration characteristics of exercise oscillatory ventilation in patients with heart failure. J Heart Lung Transplant 2008;27:341-7.
34. Leite JJ, Mansur AJ, de Freitas HF, et al. Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation. J Am Coll Cardiol 2003;41:2175-81.
35. Guazzi M, Raimondo R, Vicenzi M, et al. Exercise oscillatory ventilation may predict sudden cardiac death in heart failure patients. J Am Coll Cardiol 2007;50:299-308.
36. Muneuchi J, Joo K, Yamamura K, et al. Exertional oscillatory ventilation during cardiopulmonary exercise test in Fontan patients with total cavopulmonary connection. Pediatr Cardiol 2009;30:452-7.
37. Paridon SM, Mitchell PD, Colan SD, et al. Pediatric Heart Network Investigators. A cross-sectional study of exercise performance during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol 2008;52:99-107.
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Wang-Giuffre EW, Doshi UH. Cardiopulmonary exercise test as a tool in surveillance after Fontan operation. Vessel Plus 2022;6:29. http://dx.doi.org/10.20517/2574-1209.2021.98
AMA Style
Wang-Giuffre EW, Doshi UH. Cardiopulmonary exercise test as a tool in surveillance after Fontan operation. Vessel Plus. 2022; 6: 29. http://dx.doi.org/10.20517/2574-1209.2021.98
Chicago/Turabian Style
Wang-Giuffre, Elizabeth W., Unnati H. Doshi. 2022. "Cardiopulmonary exercise test as a tool in surveillance after Fontan operation" Vessel Plus. 6: 29. http://dx.doi.org/10.20517/2574-1209.2021.98
ACS Style
Wang-Giuffre, EW.; Doshi UH. Cardiopulmonary exercise test as a tool in surveillance after Fontan operation. Vessel Plus. 2022, 6, 29. http://dx.doi.org/10.20517/2574-1209.2021.98
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