Congenital heart disease is the most common birth defect with an estimated incidence of 1 in 100 live births (1). Functionally univentricular heart defects represent the most severe end of the spectrum of congenital heart disease, characterized by a severely underdeveloped ventricle that is unable to drive the systemic or pulmonary circulation. Many underlying diagnoses can be present, including patients with an underdeveloped right ventricle (e.g., tricuspid atresia) or an underdeveloped left ventricle (e.g., hypoplastic left heart syndrome). The Fontan operation is the palliative treatment of choice for single ventricle patients, by connecting both caval veins directly to the pulmonary arteries (PAs), also called the total cavopulmonary connection (TCPC) (2). Via this procedure, the venous inflow connections to the heart are rerouted, excluding the hypoplastic ventricle from the circulation, whereas the other ventricle will serve as systemic ventricle. Without the interposition of a subpulmonary ventricle, the pulmonary circulation in Fontan patients is a low-energy, passive circulation that is dependent on elevated systemic venous pressure to drive pulmonary blood flow toward the single ventricle. The Fontan circulation is thus characterized by chronically elevated central venous pressure with reduced cardiac output due to chronic preload deprivation of the single ventricle (3). Although the Fontan circulation has led to survival into adulthood >90%, significant morbidity is present including a reduced quality of life, exercise capacity and the occurrence of liver fibrosis/cirrhosis or protein losing enteropathy (4).

Because of the vulnerable state of the Fontan physiology and its dependence on favorable hemodynamics, regular evaluation of flow within the Fontan circulation is recommended for early detection of (subclinical) complications (4). Currently, echocardiography and magnetic resonance imaging (MRI) are the imaging modalities of choice to evaluate TCPC flow, but differently incorporate the effect of respiration on flow rates. Since respiration importantly influences TCPC flow (5–7), knowledge about the effect of respiration on blood flow and how flow measurements and flow-related clinical parameters are affected by different MRI protocols is therefore important for clinicians taking care of Fontan patients.

In this review, blood flow characteristics as influenced by the cardiac and respiratory cycle at multiple locations within the TCPC are discussed. The effect of not/partially incorporating the influence of the respiratory cycle in conventional MRI flow imaging will be described. Finally, the importance of including respiration-resolved flow measurements in advanced computational fluid dynamic (CFD) modeling of TCPC hemodynamics (e.g., wall shear stress, energy loss) is outlined.

Nowadays, the Fontan circulation is created using two techniques. The lateral tunnel technique connects the IVC to the PA via an intra-atrial patch (thus including part of the right atrium in the Fontan tunnel) (2). The extracardiac conduit technique (8) connects the IVC with the PA via a rigid Goretex conduit outside the heart. Conventionally, the term “TCPC” is considered to cover the area consisting of the Fontan tunnel (both the lateral tunnel and extracardiac conduit technique, above the entry of the HVs), the SVC, and both right- and left PAs. Thus, most papers use the terminology “IVC” when assessing flow in the Fontan tunnel (9–11). In this review, as depicted in Figure 1, the term “IVC” is used for the subhepatic IVC (below the entry of the HVs), and “Fontan tunnel” for the suprahepatic IVC (above the entry of the HVs) to make a clear distinction between these locations within the TCPC.

In the normal biventricular circulation, systemic venous return toward the right atrium is determined by the ratio of the pressure gradient between (1) the mean systemic filling pressure and right atrial pressure and (2) the venous vascular resistance (12). Consequently, a change in one of these parameters is needed to affect venous return and, as a consequence of the Frank-Starling mechanism, thereby affects preload leading to altered cardiac output. For example, factors that increase systemic filling pressure (e.g., augmented blood volume or vasomotor tone) can alter systemic venous return by increasing the pressure gradient promoting venous return (12, 13).

In the Fontan circulation, systemic venous return and thus pulmonary blood flow to the single ventricle is therefore determined by the ratio of (1) the pressure gradient between the mean systemic filling pressure and the atrium, and (2) the venous vascular resistance and the total resistance in the Fontan circuit, constituting of the serial TCPC resistance and pulmonary vascular resistance (3, 14). In general, four components have been described in literature that can affect flow rates in the TCPC, including alterations in blood flow along the cardiac cycle (15), the respiratory cycle, flow alterations because of peripheral muscular pump activity during lower-leg exercise (14, 16), and by gravitational forces, leading to decreased inferior systemic venous flow rates at the upright vs. the supine position (17). All these factors influence TCPC flow by altering the venous pressure gradient from the systemic veins toward the atrium. For example, central venous pressure has been shown to be raised to 20–30 mmHg during lower-leg exercise by the contribution of the peripheral muscle pump, thereby effectively raising the pressure gradient and thus pulmonary blood flow in Fontan patients (3, 18).

Unique to the Fontan circulation where the systemic venous return and pulmonary circulation are fully bypassed from the single ventricle, only minor alterations in blood flow occur along the cardiac cycle, with in general increased flow during systole and early diastole (early filling), with decreased flow during late diastole (atrial contraction) (15). In Fontan patients, however, the effect of respiration on venous return and pulmonary blood flow pulsatility is much more pronounced. This is predominantly caused by a change in intrathoracic pressures (i.e., intrapleural and pericardial pressures), leading to a change in atrial pressures, and a change in abdominal pressure, thereby effectively changing the pressure gradient from the inferior vena cava and hepatic veins, via the pulmonary arteries and pulmonary vascular bed, to the atrium. For this reason, mechanical ventilation using positive end-expiratory pressure has been shown to reduce cardiac output in Fontan patients (19), with significantly increased pulmonary blood flow and cardiac output when negative pressure ventilation is applied (19, 20). Additionally, it also explains reduced caval flow rates during the Valsalva maneuver, as increased intrathoracic pressures during Valsalva lead to a decreased pressure gradient and thus venous return (21).

Of note, it is currently not known if changes in PVR during respiration also have effect on the change in blood flow during respiration. In healthy persons, PVR is lowest around functional residual capacity, with an increase in PVR at total lung capacity or residual volume (22). To date, no studies have studied possible changes in PVR during normal respiration in Fontan patients.

The minor effect of the cardiac cycle on blood flow pulsatility is in contrast to a normal biventricular circulation, where a rise in pulmonary artery pressure during systole results in significant pulmonary blood flow alterations during the cardiac cycle, with a much less pronounced influence of respiration. Because of its relevance to blood flow imaging, flow dynamics along the cardiac and respiratory cycle are the subject of this review.

An important differentiation must be made between net forward flow and flow pulsatility within the TCPC. It is a common belief that part of the venous return in Fontan patients is dependent on energy provided by respiration (9, 17). Hsia et al. (17) used doppler echocardiography to define the percentage of respiration-dependent flow as follows: Qinsp-QexpQinsp+Qexp, where Q_insp and Q_exp are the flow rates during inspiration and expiration, respectively. Based on this parameter, ~30, 14, and 55% of Fontan tunnel flow, subhepatic IVC and HV flow is respiration-dependent, respectively (30). In comparison, in healthy controls respiration-dependent flow in the subhepatic IVC, HVs, and suprahepatic IVC were 11, 25, and 15%, respectively. Therefore, it has been suggested that a significant percentage of specifically Fontan tunnel and HV net forward flow is dependent on respiration as a driving force. However, although inspiration does actively increase flow rates compared to breath-holding conditions due to a decrease in intrathoracic pressure and atrial pressure augmenting the transpulmonary pressure gradient, it must be emphasized that expiration also leads to decreased flow rates, thereby mostly countering the effect of inspiration. Consequently, defining the respiration-dependency of flow using inspiration and expiration flow rates is not ideal. In fact, respiration has only a significant influence on the net forward flow if the increased flow volume during inspiration (i.e., inspiratory flow rate ^* duration of inspiration) outweighs the decreased flow volume during expiration, compared to a breath-hold condition. Indeed, Wei et al. (11) demonstrated that respiration did not significantly affect net forward flow rates (difference on average <0.1 L/min/m²) by comparing 2D real-time MRI acquired under both free-breathing and breath-hold conditions in the SVC, Fontan tunnel and aorta. Recently, Gabbert et al. also stressed the limited influence of respiration on net forward flow in the Fontan tunnel (7). In line with these findings, net forward flow was not affected by forced breathing conditions or after a 6 week inspiratory muscle training program (5, 31). Initiation of hyperventilation (representing the ventilatory pump) in addition to zero resistance exercise (representing the muscle pump) did also not result in significantly higher blood flow rates (16). Thus, it must be concluded that respiration is not an important driving force for net forward flow in the TCPC.

However, these studies clearly showed a significant increase in pulsatility (flow variations along the cardiac and/or respiratory cycle) caused by respiration, with high variability between the different vessels of the TCPC (5, 7, 11). Various parameters have been used to assess blood flow pulsatility along the respiratory cycle, of which the inspiratory-to-expiratory flow ratio (mean inspiratory flow rate divided by mean expiratory flow rate, Q_insp/Q_exp) is most commonly used.

Fontan tunnel flow represents ~65–70% of total systemic venous return (9, 32). Many studies consistently show the pronounced effect of respiration on Fontan tunnel flow rates (5, 9–11, 30, 33), with a 70–90% higher flow rate during inspiration compared to the entire respiratory cycle, significantly more pronounced compared to a 20% increase observed in healthy controls (5, 9). Other studies demonstrate similar findings by reporting a Q_insp/Q_exp of 1.6–3.0 (11, 34, 35). By dividing 2D real-time flow MRI measurements of the Fontan tunnel into components along the respiratory and cardiac cycle, it was shown that respiration-derived pulsatility was 2.8-times the pulsatility along the cardiac cycle. This was the opposite in healthy controls, where pulsatility along the cardiac cycle was 2.5-times the pulsatility along the respiratory cycle at the level of the suprahepatic IVC (Figure 2) (7). As opposed to its effect on net forward flow, normal and forced breathing significantly increases blood flow pulsatility in Fontan patients, further illustrating that respiration rather than the cardiac cycle is the major contributor of flow pulsatility in the Fontan tunnel (Figure 2) (5, 7, 11).

The Fontan tunnel receives blood from both the subhepatic IVC and HVs, which contribute on average 62 and 38%, respectively, to total Fontan tunnel flow (6, 17, 35–38). The study of flow dynamics in this area is of great importance, as the splanchnic venous return plays an important role in the pathophysiology of liver cirrhosis and protein-losing enteropathy. Using (invasive) doppler echocardiography, Q_insp/Q_exp in the subhepatic IVC was 1.3–1.6 (17, 35), not significantly different from healthy controls (Q_insp/Q_exp 1.2) (6, 17, 36, 37). Thus, respiration has a much less pronounced influence at the subhepatic IVC compared to the Fontan tunnel, indicating that most of the respiratory-derived pulsatilty in the Fontan tunnel must be explained by the HV flow contribution.

Respiration indeed strongly influenced HV flow in Fontan patients (Q_insp/Q_exp 2.9–4.4), significantly higher compared to healthy controls (Q_insp/Q_exp 1.7) (17, 35). The important increase in HV flow during inspiration is explained by the liver acting as a reservoir of blood with high venous capacitance, from which both the increased extra- to intra-thoracic venous pressure gradient, as well as the direct pressure of the diaphragmatic descent on the liver, can draw blood toward the Fontan tunnel during inspiration (39). Presence of a fenestration was associated with a significantly higher inspiratory-to-expiratory fraction; 4.4 vs. 3.0 (36). Since central venous pressure is lowered by the presence of a fenestration between the Fontan tunnel and the atrium, the decreased afterload for HV flow likely causes the increased flow rates during inspiration. Importantly, plication of the diaphragm in Fontan patients with a diaphragm paresis does not fully restore normal respiratory mechanics, evidenced by a significantly smaller inspiratory-to-expiratory ratio of HV flow; 2.3 vs. 3.2 (37). However, respiration likely also does not affect net forward HV flow, in line with observations in the Fontan tunnel. This might explain why Fontan patients with a diaphragm paresis have similar cardiac index and exercise capacity compared to patients with a normal functioning diaphragm (40).

Studies on the influence of respiration on SVC flow, contributing ~35% of total systemic venous return, have been conflicting (Q_insp/Q_exp 1.0–1.9) (5, 9, 11, 35). Wei et al. reported an inspiratory-to-expiratory ratio of 1.9 in the SVC, higher compared to the fraction of 1.6 they observed in the Fontan tunnel (11). This is in strong contrast to a previous study using 2D real-time flow MRI, which did not find an effect of breathing on SVC flow rates, in line with observations in healthy controls (5, 9). It remains the question from which vascular region with high venous capacitance (analog to the HVs providing most of the pulsatility observed in the Fontan tunnel) blood would be drawn toward the SVC during inspiration.

In normal subjects, aortic flow rate or ventricular stroke volume only slightly increase during expiration and decreases during inspiration, opposite to systemic venous return. Compared to mean aortic flow rates, flow rates are 0–6% higher at (end)-expiration and 1–6% lower at (end)-inspiration (5). A similar, modest effect of respiration on aortic flow has been observed in Fontan patients, ranging from a 7% increase during expiration, to a 4% decrease during inspiration (5, 9). Therefore, since systemic venous flow (predominantly HV and Fontan tunnel flow) rates are markedly raised during inspiration while aortic flow rates are not, the pulmonary circulation and lungs act as a reservoir with a large inspiratory capacity, releasing blood toward the single ventricle during expiration (9). In contrast to the systemic venous part of the Fontan circulation, respiration thus has a minimal influence on pulsatility in the aorta, which is primarily caused by the cardiac contraction. An example of flow rates during free breathing and under breath-hold conditions in the subhepatic IVC, HVs, Fontan tunnel and aorta are shown in Figure 3. An overview of the influence of respiration on flow rates and a schematic representation are presented in Table 1 and Figure 4.

Currently, the influence of respiration on flow rates under exercise conditions in Fontan patients has only been investigated in the Fontan tunnel, SVC and aorta. During lower-leg exercise conditions, the predominance of inspiratory flow augmentation in the Fontan tunnel seems to become less pronounced. Hjortdal et al. found a mean inspiratory fraction (Q_insp/Q_{average respiratory cycle}) decrease from 1.9 in rest, to 1.4 under 1 W/kg lower-leg exercise conditions. Peripheral muscle contractions were responsible for an almost 3-fold increase in expiratory flow rates, while inspiratory flow rates only increased by 1.6-fold (10). Of interest, Cordina et al. also showed predominantly increased expiratory flow rates in rest in patients after 20 weeks of peripheral muscle resistance training. The increased flow rates are explained by the presence of increased peripheral muscle mass leading to reduced venous compliance, thereby presumably increasing systemic filling pressures leading to increased preload and cardiac output (21). The reason why the muscle pump predominantly increases expiratory flow rates compared to inspiratory flow rates, thereby leading to reduced “respiratory dependence,” remains incompletely understood. Although speculative, there may be a limit in the venous capacity in the inspiratory phase, leading to a diminished response to increased filling pressures caused by the muscle pump.

In conclusion, in contrast to the healthy circulation, respiration is the main source of blood flow pulsatility in the TCPC, whereas cardiac contraction mostly drives the net forward flow rate. Consequently, conventional ECG-gated PC-MRI acquisitions (i.e., 2D flow MRI and 4D flow MRI) can be used for measurements of clinical parameters based on net forward flow.

Inclusion of respiratory pulsatility in state-of-the-art patient-specific CFD models are recommended for evaluation of detailed, time-resolved hemodynamic metrics (e.g., wall shear stress and viscous energy loss rate), continuing to provide important insights for clinicians in the functioning of the TCPC.

SW performed the initial literature review. FR drafted the first manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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