Heart Transplantation in a 14-Year-Old Boy in the Presence of Severe Out-of-Proportion Pulmonary Hypertension due to Restrictive Left Heart Disease: A Case Report

A 14-year-old boy after balloon valvuloplasty of severe aortic valve stenosis in the neonatal period was referred for heart-lung transplantation because of high grade pulmonary hypertension and left heart dysfunction due to endocardial fibroelastosis with severe mitral insufficiency. After heart catheterization, hemodynamic parameters were invasively monitored: a course of levosimendan and initiation of diuretics led to a decrease of pulmonary capillary wedge pressure (from maximum 35 to 24 mmHg). Instead of an expected decrease, mean pulmonary artery pressures (mPAP) increased up to 80 mmHg with increasing transpulmonary pressure gradient (TPG) up to 55 mmHg. Oral bosentan and intravenous epoprostenol then led to a ~50% decrease of mPAP (TPG between 16 and 22 mmHg). The boy was listed solely for heart transplantation which was successfully accomplished 1 month later.


Case
year-old boy presented with the history of severe aortic valve stenosis; he had undergone successful balloon valvuloplasty at the age of 3 days. He was on followup elsewhere and was reportedly in stable clinical condition for 13 years, performing alpine skiing, cross country running, and mountain biking. He reportedly had normal systolic left heart function in the presence of left ventricular endocardial fibroelastosis (EFE) without signs of elevated right ventricular pressure on echocardiography. Neither heart catheterization nor cardiopulmonary exercise testing was performed. At the age of 14 years, he complained of fatigue during cycling and hiking for the first time. On echocardiography at that time severe mitral valve regurgitation and a markedly enlarged left atrium were seen besides the well-known mild aortic valve stenosis/regurgitation and endocardial fibroelastosis. Tricuspid valve regurgitation was demonstrated with a maximum velocity of 5.28 m/sec presuming a systolic pulmonary artery pressure of 111 mmHg ( Figure 1).

Case Reports in Cardiology
The Swan Ganz catheter was removed 6 days later, and the patient was listed for heart transplantation. He remained stable on bosentan, epoprostenol, and diuretics until a donor heart became available. Heart transplantation was then successfully performed after 28 days on the waiting list. Perioperatively the patient received NO 20 ppm. Bosentan and epoprostenol were stopped on the first postoperative day and oral sildenafil 3 × 10 mg/d was initiated. The patient was weaned from NO two days after transplantation. His perioperative course was completely uneventful with a cardiac index of 2.5-3.5 l/min/m 2 , a PCWP of 12 mmHG, and mPAP of 30 mmHg immediately after transplantation. Heart catheterization three weeks later revealed normal PCWP (6 mmHg), mPAP (19 mmHg), PVRI (3.5 WU × m 2 ), and TPG (13 mmHg) ( Table 1). Four weeks after heart transplantation, sildenafil was stopped and the patient was discharged home.
Gross examination of the explanted heart showed globular enlargement and an extensive endocardial fibroelastosis of the left ventricle with involvement of the aortic and mitral valves, the papillary muscles, and chordae tendineae ( Figure 4).

Discussion
Pulmonary hypertension (PH), secondary to structural or functional left heart disease in children, represents a delicate clinical condition where treatment options are often limited. The presence of endocardial fibroelastosis (Figure 4) in congenital aortic valve stenosis carries a poor prognosis; it is not correlated with the amount of aortic valve stenosis before or after intervention [2]. Reich et al. describe an incidence of 13.8% of EFE in long-term results of 269 patients after percutaneous balloon valvuloplasty [3]. It is thought that this fibroelastosis is a consequence of persistent pressure overload or decreased flow in the ventricle being present in early infancy and even in the fetus. Decreased diastolic function with preserved systolic function is present; therefore, diagnosis by means of echocardiography often is difficult. Left ventricular diastolic dysfunction leads to high filling pressures and enlargement of the left atrium. Pulmonary capillary wedge pressure rises, which leads to an increase in mPAP. This form of pulmonary hypertension is classified as pulmonary hypertension owing to left heart disease (group 2, Dana Point Classification) [4] characterized by an increased PCWP and a diastolic pulmonary artery pressure gradient of ≥10 mmHg. The TPG is calculated as the difference between the mean PA pressure and PCWP. By definition, it is flowindependent and thus may better reflect resistance to flow across the pulmonary bed. It is assumed that a TPG of around 15 mmHg is acceptable for heart transplantation, although there is no accurate definition yet. We and others consider pulmonary hypertension to be inadequately high to left heart disease when the mPAP is severely elevated in the presence of moderately elevated PCWP or LVEDP (≥22 mmHg) and a TPG of 18-20 mmHg [5]. These patients have a poor outcome after heart transplantation alone [6]; thus, a combined heartlung transplantation is considered to be the only surgical option.
Medical treatment of pulmonary hypertension by advanced therapies without treating the underlying left heart disease can lead to severe pulmonary congestion [7]. Therefore, it is mandatory to test vasoreactivity of the pulmonary artery bed prior to therapy. The reversibility of increased PVR or TPG under pharmacologic testing is supposed to indicate a decreased probability of right ventricular failure/death after transplantation [8]. It has been shown that, for example, in patients with mitral stenosis, surgical or interventional decompression of the left atrium with a concomitant rapid decrease in the LA and PCWP is followed by a marked decrease in PA pressure. Lower TPG eventually resulted in normalization of the pulmonary artery pressure [9].
What is remarkable in this case is the substantial and somewhat unexpected increase of pulmonary artery pressure after improvement of left ventricular restrictive kinetics by diuretics and levosimendan. At that point, we felt safe enough to initiate pulmonary vasodilative therapy in order to lower PVR.
The positive inotropic action of levosimendan is due to its binding to troponin C which facilitates the interaction between actin and myosin filaments without changes in intracellular Ca++ ion concentrations [10,11]. Because of its calcium sensitizing mechanism levosimendan leads even to a shorter isovolumic relaxation time [12]. In addition, the drug produces peripheral, coronary [13], and pulmonary vasodilation by opening ATP-sensitive potassium channels [14]. These mechanisms lead to an improved myocardial contractility and a better diastolic function of both the left and the right heart without increasing myocardial oxygen consumption. Improved right heart function and a previously "hidden" precapillary pulmonary vasoconstriction might have increased PAP and PVRI. A decrease in PAP and PVRI [15] and in filling pressures of the right ventricle [16], like in this case by vasodilating agents, could result in an increased contractility and mechanical effectiveness of the right ventricle [17,18].
After consultation of several centers with superb expertise, surgical options like resection of EFE and mitral valve plasty as well as extra corporal mechanical support by means of left ventricular assist device were omitted in our patient and heart transplantation was considered as the therapeutic strategy with most favorable prognostic outcome for this young boy.
Diuretics and levosimendan led to a substantial improvement of diastolic left heart function. Our own experience of beneficial effects of pulmonary vascular dilative medical therapy with bosentan in patients with heart failure with a normal ejection fraction with PVH and right ventricular failure [19] led us to consider the application of an endothelin-1-receptor antagonist in this case. In addition a therapy with epoprostenol, of which beneficial effects on reversibility of pulmonary hypertension in congestive heart failure prior to cardiac transplantation are known, was started [8,[20][21][22].
The pursued stepwise increase of epoprostenol from the initial dose of 2 ng/kg/min could not be carried out due to systemic hypotension (RR < 100/60 mmHg), most probably because of synergistic vasodilative effects of both drugs on the systemic vasculature. Therefore we consider bosentan as the main acting drug on the pulmonary vascular bed in this case.

Conclusion
Invasive monitoring of therapeutic effects on left heart function and pulmonary vasoreactivity is mandatory before deciding on heart or heart lung transplantation in patients with pulmonary hypertension owing to left heart disease.