Increasingly end-organ injury is being demonstrated late after institution of the Fontan circulation, particularly liver fibrosis and cirrhosis. The exact mechanisms for these late phenomena remain largely elusive. Hypothesizing that exercise induces precipitous systemic venous hypertension and insufficient cardiac output for the exercise demand, that is, a possible mechanism for end-organ injury, we sought to demonstrate the dynamic exercise responses in systemic venous perfusion (SVP) and concurrent end-organ perfusion. Ten stable Fontan patients and 9 control subjects underwent incremental cycle ergometry–based cardiopulmonary exercise testing. SVP was monitored in the right upper limb, and regional tissue oxygen saturation was monitored in the brain and kidney using near-infrared spectroscopy. SVP rose profoundly in concert with workload in the Fontan group, described by the regression equation 15.97 + 0.073 watts per mm Hg. In contrast, SVP did not change in healthy controls. Regional renal (p <0.01) and cerebral tissue saturations (p <0.001) were significantly lower and decrease more rapidly in Fontan patients. We conclude that in a stable group of adult patients with Fontan circulation, high-intensity exercise was associated with systemic venous hypertension and reduced systemic oxygen delivery. This physiological substrate has the potential to contribute to end-organ injury.
The Fontan operation has transformed outcomes for children born with single ventricle physiology. This circulation separates pulmonary and systemic venous return, minimizes systemic desaturation, and volume offloads the single systemic ventricle at the cost of placing 2 arteriolar capillary resistor beds in series (arterial and pulmonary capillary) downstream from single ventricular action. This presents the single ventricle with an enormous total afterload. The venous bed is subject to obligatory hypertension. Gravitational hydrostasis contributes to diminished venous conductance as does the terminal location of the pulmonary vascular bed in the venous circulation. Intermittent or sustained venous hypertension and diminished cardiac output may contribute to liver damage in Fontan patients. There is also growing evidence that hepatic fibrosis can be induced by liver stiffness and cyclical uniaxial strain pressure strain. Very few data exist however describing the characteristics of venous pressure responses to exercise in Fontan patients. In this investigation, we sought to demonstrate (1) exercise-induced changes in systemic venous perfusion (SVP) and (2) regional renal and cerebral oxygenation during exercise to examine pathophysiological changes in end-organ oxygen delivery that may contribute to liver and or other organ injury.
Methods
The South Central National Research Ethics Service Committee granted ethical approval and Southampton University Hospitals National Health Service Trust (RHM CAR0437) gave local Trust Research and Development approval. Ten consecutive stable Fontan patients were recruited using the Southampton Congenital Cardiac Database. Patients were excluded if they had uncontrolled arrhythmias or heart failure, were being evaluated for surgical or catheter based intervention, or had associated known systemic venous thrombosis. All patients had previous cardiac catheterization on clinical grounds and pathway obstruction was excluded. Nine healthy age- and gender-matched control participants were recruited.
Ventilation and gas exchange and arterial saturation earlobe pulse oximetry were prospectively measured during rest and exercise using a metabolic cart (Geratherm Respiratory GmbH with Blue Cherry software; Love Medical Ltd, Manchester, United Kingdom). The equipment was calibrated and operated to the standards specified in the American Thoracic Society/American College of Chest Physicians (2003) guidelines. Participants initially sat at rest on an electromagnetically braked cycle ergometer (Ergoline 2000) for 3 minutes (baseline phase), followed by 3 minutes of unloaded cycling and then performed a ramp incremental to intolerance (exercise phase). Exercise duration was targeted to range from 8 to 12 minutes and power output incrementation individualized accordingly. Power output for Fontan patients was increased at 10 to 15 W/minute depending on the patient’s reported and assessed physical ability. The ramp incremental was 30 W/minute for controls. In all participants, a cadence of 60 rpm was maintained throughout. At volitional intolerance, the power output was immediately reduced to zero, and cardiopulmonary variables were monitored for at least 5 minutes (recovery phase).
NIRS (near-infrared spectroscopy) was measured using an Adult Equanox Advance Sensor (Model 8004CA; Nonin, Plymouth) connected to a conversion box (7600 PA Oximeter; Nonin). NIRS was used to measure regional cerebral (StO 2 -C; left frontal lobe) and renal (StO 2 -R; left lumbar region, directly over the left kidney, confirmed by ultrasound) tissue oxygen saturation every minute during the rest, exercise, and recovery phases.
A 16-18 Gauge cannula was inserted in a large left antecubital vein before the exercise test. The cannula was connected to a venous pressure manometer through a transducer set. The transducer was individually flushed, deaired, calibrated, and “zeroed” to atmospheric pressure at the level of the right atrium. To ensure measurement reliability, the pressure trace was evaluated during a Valsalva maneuver, with proximal occlusion of the axillary vein and while raising and lowering the arm. At all times during exercise, the transducer was kept at the midright atrial level, and care was taken to ensure the arm was kept relaxed and extended. A baseline SVP reading was obtained at rest, and the pressure was monitored continuously, and recorded every minute, until a return to baseline after exercise. Recordings were only used when a phasic waveform was demonstrable. Peripheral upper limb venous pressure in Fontan patients reflects pulmonary artery pressure and is concordant with central venous pressures.
Statistical analysis was performed with R version 2.4.122 and MedCalc 10.1.2.0 (MedCalc Software, Mariakerke, Belgium). For all analyses, a probability value <0.05 was used as the criterion for statistical significance. All values are presented as mean ± SD or median for nonnormally distributed variables. Categorical variables are presented as frequencies and percentages. Exercise gas exchange and ventilatory variables were analyzed and presented at the following defined points: at rest, unloaded cycling, 20, 40, 50, 60, 80, 100, and 120 W. Comparison between Fontan patients and control subjects was performed using an unpaired Student t test. Changes in physiological variables with exercise were assessed by random mixed-effects models using the R nlme package. Association between physiological variables during exercise and laboratory serology was assessed using nonparametric correlation (Spearman’s Rho).
Results
There were 8 male and 2 female Fontan subjects (n = 10), with a mean age of 26.4 years, range 19 to 31 years. Their underlying anatomic diagnoses included:
- 1.
Double inlet left ventricle (n = 2) with D-transposition of the great arteries and aortic coarctation, with extra cardiac Fontan connections.
- 2.
Pulmonary atresia (n = 1) with intact septum and a lateral tunnel Fontan.
- 3.
Tricuspid atresia (n = 7) with normally related great vessels. Of these, 4 had previously had extra cardiac revision of an atriopulmonary Fontan, one had a primary lateral tunnel, and the other had an unrevised atriopulmonary Fontan connection, and one had a homograft connection between the right atrium and a diminutive right ventricle. Nine age- and gender-matched controls ranged from 22 to 25 years (p = 0.25 for age).
Fontan patients had significantly lower peak power output (119 ± 36 vs 267 ± 73 W, p = 0.022), estimated lactate threshold (0.95 ± 0.30 vs 1.59 ± 0.48 L/minute, p = 0.003), peak oxygen uptake (21 ± 8 vs 35 ± 8 ml/kg/minute, p = 0.001), and had a greater ventilatory equivalent for CO 2 at lactate threshold (V E /VCO 2 : 34.9 ± 1.7 vs 23.4 ± 2.7, p <0.001) compared with control subjects.
SVP was significantly greater in Fontan patients at rest (14 ± 4 vs 6 ± 2 mm Hg, p <0.0001), during unloaded exercise (16 ± 4 vs 7 ± 3 mm Hg, p = 0.0001), and at peak exercise (25 ± 6 vs 9 ± 3 mm Hg, p <0.0001). SVP increased abruptly at exercise onset in both Fontan and control participants, but unlike the control, SVP continued to increase progressively during exercise in Fontan. The rate of the exercise-induced SVP increase was significantly greater in Fontan than control (0.087 ± 0.045 vs 0.006 ± 0.011 mm Hg/W, p = 0.0001; Figures 1 and 2 ).
Resting StO 2 -C (76 ± 4% vs 66 ± 7%, p = 0.001) and StO 2 -R (79 ± 9% vs 65 ± 9%,p = 0.001) were lower in Fontan patients than controls ( Figure 3 ): both decreased during exercise more rapidly in Fontans than controls (peak StO 2 -C 74 ± 6% vs 55 ± 6%; peak StO 2 -R 70 ± 6% vs 48 ± 10%).This significantly lower S t O 2 values in Fontans were sustained into the recovery period (p <0.02). StO 2 -C decrease significantly from mid to peak exercise in Fontan patients but not in controls. Although arterial saturation at rest (by pulse oximetry) was greater in controls than Fontan (99 ± 1% vs 93 ± 6%, p = 0.01), exercise-induced arterial desaturation was not significant in Fontan (−3 ± 5%, p = 0.26) or controls (−1 ± 1%, p = 0.09), and was not different between groups (p = 0.15). Three Fontan patients had desaturation at rest because of venovenous collateralization.
