Pulmonary vascular disease in Fontan circulation-is there a rationale for pulmonary vasodilator therapies?

Abstract

The Fontan circulation is a palliative concept for patients with univentricular hearts. The central veins are connected directly to the pulmonary arteries (cavo-pulmonary connection) to separate the pulmonary and the systemic circulation. There is no sub-pulmonary ventricle that generates pressure to drive blood through the pulmonary arteries. Pulmonary blood flow is determined by central venous pressure (CVP) and pulmonary vascular resistance (PVR). The capability of the Fontan circulation to compensate for alterations in PVR is limited, as CVP can only be increased within narrow ranges without adverse clinical consequences. Consequently, systemic ventricular preload and cardiac output are dependent on a healthy lung with low PVR. Failure of the Fontan circulation is relatively common. In addition to ventricular dysfunction, maladaptive pulmonary vascular remodeling resulting in increased pulmonary resistance may play a key role. The pathophysiology of the maladaptive vascular processes remains largely unclear and diagnosis of an increased PVR is challenging in Fontan circulation as accurate measurement of pulmonary arterial blood flow is difficult. In the absence of a sub-pulmonary ventricle, pulmonary artery pressure will almost never reach the threshold conventionally used to define pulmonary arterial hypertension. There is a need for markers of pulmonary vascular disease complementary to invasive hemodynamic data in Fontan patients. In order to treat or prevent failure of the Fontan circulation, pathophysiological considerations support the use of pulmonary vasodilators to augment pulmonary blood flow and systemic ventricular preload and lower CVP. However, to date the available trial data have neither yielded enough evidence to support routine use of pulmonary vasodilators in every Fontan patient nor have they been helpful in defining subgroups of patients that might benefit from such therapies. This review discusses potential pathomechanisms of pulmonary vascular disease; it summarizes the current knowledge of the effects and efficacy of pulmonary vasodilator therapy in Fontan patients and tries to outline areas of potential future research on the diagnosis and treatment of pulmonary vascular disease and Fontan failure.

Keywords: Fontan circulation; hypoxia-inducible factor 1; pulmonary hypertension; univentricular heart; vasodilators.

Figure 1

The Fontan circulation. The Fontan procedure serves as a palliative procedure for a variety of complex congenital heart defects with a functional single ventricle. Systemic venous blood from the superior vena cava (SVC) and the inferior vena cava (IVC) drains directly into the left and right pulmonary arteries (LPA and RPA) ①. Pulmonary blood flow is passive and is mainly driven by central venous pressure (CVP) ②. Pulmonary veins (PV) drain the oxygenated blood into the atrium ③. Pulmonary venous return provides filling of the single ventricle. Ventricular preload is dependent upon flow through the pulmonary circulation ④. A patent fenestration in the Fontan tunnel results in a right-to-left shunt on the atrial level, which might improve preload of the ventricle but on the expense of enhanced cyanosis ⑤.

Figure 2

Relation between pulmonary blood flow (PBF), pulmonary vascular resistance (PVR) and central venous pressure (CVP). In theory, there is a strong linear relationship between CVP and transpulmonary gradient (TP). If PVR increases in Fontan patients, the TP will increase if pulmonary blood flow is constant (green line). Changes of CVP in relation to PVR are dependent on PBF. Small increments in PVR can result in a significant reduction of PBF (red line). In extreme cases, CVP can be in a normal range for Fontan patients with low cardiac output despite elevated PVRi.

Figure 3

Model of the mechanisms that likely initiate and maintain pulmonary vascular changes in Fontan patients. Green lines and arrows depict effects that might ameliorate and red lines and arrows effects that likely worsen pulmonary vascular disease in Fontan patients. Possible therapeutic strategies that focus on these mechanisms are highlighted with red boxes on the bottom of the figure.