Abstract

Background: This study aims to assess the characteristics, results and prognosis of patients with endocardial fibroelastosis secondary to critical aortic stenosis.

Methods: The study included 22 newborns (17 boys, 5 girls; mean age 7.5 days; range 0 to 28 days) having endocardial fibroelastosis associated with critical aortic stenosis between January 2008 and July 2014. Patients’ demographic, echocardiographic and cardiac catheterization, and angiography findings were reviewed.

Results: Patients’ mean weight at presentation was 3.3 kg (range 2 to 4.8 kg). Left ventricular systolic dysfunction with varying degrees (ejection fraction <55%) was present in 90% of the patients. Mean ejection fraction and fractional shortening were 34±13% and 17±6.5%, respectively. All patients were performed balloon aortic valvuloplasty. Peak-to-peak aortic valvular gradients before and after valvuloplasty were 56±23 and 22±15 mmHg, respectively. Early mortality rate was 31%.

Conclusion: Mortality rate is high in newborns with endocardial fibroelastosis associated with critical aortic stenosis. Identifying the patients whose chance of survival is higher with univentricular paliation rather than valvotomy or valvuloplasty may provide superior early results.

Endocardial fibroelastosis (EFE) is a rare disease that mainly involves the left ventricle, and it is characterized by the endomyocardial proliferation of collagen and elastic fibers, ventricular hypertrophy, and diffuse thickening of the endocardium.[1-3] The disease can be primary (i.e., not associated with any structural heart defect) or secondary to various congenital heart disease, with the latter being far more common. Secondary EFE occurs in association with underlying cardiovascular anomalies that lead to persistent, increased ventricular wall tension along with an inability to meet the increased myocardial oxygen demands. The secondary form most notably occurs as a frequent complication of congenital aortic stenosis, for example hypoplastic left heart syndrome (HLHS), coarctation of the aorta, congenital mitral stenosis, or coronary artery anomalies.[3] In addition, the presence of EFE in patients with congenital aortic stenosis is known to be associated with increased mortality and left ventricular dysfunction.[1,4,5] In this report, we describe the characteristics and results of our patients with EFE associated with neonatal critical aortic stenosis.

Methods

Forty-six newborn patients [(17 boys, 5 girls; mean age 7.5 days; range 0 to 28 days); median weight at presentation 3.3 kg (range 2.0-4.8 kg)] who were diagnosed with EFE related to critical aortic stenosis and biventricular circulation and who underwent a neonatal balloon aortic valvuloplasty at our center between January 2008 and July 2014 were identified from the hospital medical records and cardiac catheterization database and included in this study. Those with HLHS and univentricular circulation were excluded. All of the patients underwent initial percutaneous transcatheter balloon dilation of the aortic valve using the technique previously described by Justo et al.[6] The patients’ demographic characteristics, clinical status before the intervention and at the last follow-up, procedural characteristics and hemodynamic conditions, and outcomes were obtained from their records. Furthermore, the echocardiographic findings, such as the increased endocardial echo-brightness, poor contractility, and globular shape of the left ventricle, were suggestive of EFE.

Statistical analysis
Frequency, mean ± standard deviation (SD), or the median with minimum and maximum were used to present the data, as appropriate, and all analyses were carried out using the IBM SPSS Statistics for Windows, version 21.0 software program (IBM Corporation, Armonk, NY, USA).

Results

Of the 46 patients in our study, 22 (48%) had varying degrees of EFE, and their demographic, clinical, and echocardiographic results along with their catheterization and angiographic findings are given in Table 1. All of the patients were at term, and a fetal diagnosis of the aortic stenosis was made in four (18.2%) of them. Of the 22 patients, 72% (n=16) presented with low cardiac output or heart failure symptoms, 31% (n=7) had multiorgan dysfunction, and 50% (n=11) were mechanically ventilated before and during the cardiac catheterization.

Table 1: The patients’ demographic, clinical, echocardiographic, catheterization, and angiographic findings

The most common site for EFE was the papillary muscles of the mitral valve (90%) while involvement of the left ventricular posterior wall and the interventricular septum were seen in 36% (n=8) and 27% (n=6) of the patients respectively (Figure 1). At admission, varying degrees of left ventricular systolic dysfunction [ejection fraction (EF) <55%] were present in 90% of the patients (n=20), and the mean EF and fractional shortening (FS) were 34±13% and 17±6.5% respectively. Echocardiography also revealed a systolic peak-to-peak aortic valvular gradient of 43.7±18.5 mmHg (range 20-75). In addition, all of the patients underwent a balloon valvuloplasty on a trial basis. During the cardiac catheterization and angiography, the mean left ventricular end-systolic and end-diastolic pressures were 114±33 and 8.6±6.4 respectively while the mean systolic peak-to-peak aortic valvular gradient by pullback was 56±23 mmHg. However, after the aortic balloon valvuloplasty, the mean gradient decreased to 22±15 mmHg.

Figure 1: Parasternal four chamber echocardiographic view showing the endocardial fibroelastosis involving the papillary muscles of the mitral valve.

Six of the 22 patients (27%) died during their initial hospital stays because of severe left heart dysfunction and heart failure, with five (23%) succumbing after the balloon aortic valvuloplasty and one (4.5%) during a valvotomy. Additionally, one (4.5%) died two months after being discharged because of aspiration pneumonia. Surgical intervention was performed on three (14%) patients. One of these underwent an aortic valvotomy while another developed an aortic intimal flap after being catheterized. The other pateint had an operation for an associated coarctation of the aorta. The mean follow-up time for the 15 survivors was 38±20 months. In addition, one patient also underwent a dilated cardiomyopathy (4.5%). The survivors also underwent a follow-up echocardiogram that showed aortic valve insufficiency in the majority of the patients, with it being classified as moderate-to-severe in five (33.3%) of these.

Discussion

Critical neonatal aortic stenosis results in severe left ventricular hypertension (HT), left ventricular hypertrophy, and finally endothelial disruption represented as EFE. This disease is thought to occur as a result of high left ventricular pressure that leads to subendocardial ischemia. Then the endocardial smooth muscle cells proliferate and turn into fibroblasts, which produce collagen and elastine under myocardial stress. This fibroelastic reaction occurs mostly during the fetal period but it does continue to a lesser extent in the postnatal period through infancy.[2,7-9] Furthermore, smaller left ventricular size, progressive hypertrophy of the left ventricular wall, and greater hyperechogenicity of the endocardium can be seen as the gestational age increases, and the endocardial thickening gives rise to a decrease in left ventricular compliance, impaired diastolic function, and global hypokinesia.[5,10]

Endocardial fibroelastosis is characterized by an opaque, pearly-white thickening caused by the proliferation of collagen and elastic fibers. It occurs initially in the subendocardial region and rarely extends to the subepicardial region. A diagnosis of EFE via echocardiography may be made on the basis of the increased echodensity of the endocardium and the poor contractility of the ventricle.[2,5,11] Sharland et al.[2] demonstrated the correlation between the echocardiographic diagnosis of EFE and the postmortem findings in patients with aortic valve anomalies. In addition, Stranzinger et al.[11] demonstrated that magnetic resonance imaging (MRI) that features perfusion and myocardial delayed enhancement can be useful for establishing the diagnosis. Moreover, the involvement of the myocardium can be diffuse or patchy, with the most common site being the papillary muscles.[3] This was also the preferred location in our patients.

In newborns with severe aortic stenosis, heart failure that is resistant to medical treatment creates a problem that usually necessitates an emergency valvuloplasty or a valvotomy. Furthermore, several studies have found an association between the higher mortality rates in these patients and the small size of the left ventricles as well as the presence of EFE.[1,5,10]

Aortic balloon valvuloplasties and surgical valvotomies offer similar short- and mid-term palliation. However, balloon valvuloplasty patients have higher reintervention rates but shorter hospital and ICU stays and reduced immediate morbidity. They also have less severe aortic regurgitation.[12-15] In our study, all of the patients initially underwent the balloon valvuloplasty procedure, which was deemed to be effective in 86.3% of the patients (n=19) with respect to the decreased pressure gradient. However, in two of the patients, a second valvuloplasty was required at the postprocedural first and second months respectively.

Our study included patients with critical aortic stenosis as well as biventricular circulation and varying degrees of EFE. Despite the high success rate associated with the valvuloplasties in our patients, the overall early mortality rate was 31% (n=7). However, it was only 8.3% (2/24) for those without EFE. Other studies have reported similar early mortality rates for surgical valvotomies and balloon valvuloplasties in patients with critical aortic stenosis, with rates ranging between 10 and 20%.[13-15]

In a study by McCrindle et al.,[13] the early mortality rates after surgical and transcatheter interventions for neonatal critical aortic stenosis with biventricular circulation were 18% and 11% respectively, and McElhinley et al.,[14] reported that the early mortality rate after an aortic balloon valvuloplasty was 14%. In this study, 11 of the patients underwent conversion to a functionally univentricular circulation, but five of these died in the early postoperative period.

Only four of the 22 patients in our study had a prenatal diagnosis of EFE and aortic stenosis, and these were referred to our hospital late in the pregnancy. Even though we performed an early postnatal aortic balloon valvuloplasty on our patients, six died during the neonatal period.

It has been shown that in utero left heart obstructive lesions are associated with the development or progression of left heart hypoplasia, which may in turn influence the postnatal outcome.[8,9] In several studies, the use of fetal aortic balloon valvuloplasties has been effective in preventing midgestational aortic stenosis from developing into HLHS and EFE in a subset of patients.[10,16-18] However, this procedure must be performed before significant left heart hypoplasia occurs and should not be carried out on fetuses with aortic stenosis that will not progress to HLHS. McElhinley et al.[5] reported that fetal EFE severity corresponded with some indices related to left heart size, geometry, and function as well as the probability of a postnatal biventricular outcome. In their study, they used a four-point grading system and found a significantly higher maximum instantaneous aortic stenosis gradient, an increase in left ventricular pressure with less globular left ventricular geometry, and a significantly higher time-indexed increase in the left ventricular end-diastolic volume from the pre-intervention stage to the late gestation period in patients with grade 1 EFE versus those with more severe EFE.

In a study by Mäkikallio et al.,[19] of the 23 patients diagnosed with aortic stenosis who had a normal left ventricular length at ≤ the 30th gestational week without fetal intervention, only six had biventricular circulation. In addition, they found that a retrograde flow in the transverse aortic arch, left-to-right shunting across the foramen ovale, a monophasic mitral inflow, and significant left ventricular dysfunction were risk factors for the progression to HLHS.

Patients who have biventricular circulation after a fetal valvuloplasty frequently have diastolic dysfunction.[1,10] Infact, Friedman et al.[10] determined that the more extensive the EFE in a patient, the worse the diastolic dysfunction.

Furthermore, Hickey et al.[20] analyzed the risk of reintervention in patients who underwent a biventricular repair to treat neonatal critical aortic stenosis along with the effects of this reintervention on the survival of 139 neonates and found that 15 required reintervention within 30 days of the index biventricular procedure. Moreover, there was a 60% mortality rate associated with these patients versus a rate of 27% for those who underwent an index univentricular repair technique. Hence, they concluded that early intervention implies a poor prognosis and might reflect incorrect management decisions such as choosing the univentricular rather than the biventricular approach.

Our study had some limitations. Not only was it retrospective in nature, but it lacked some important echocardiographic indices, such as the z-scores of the left heart structures. However, we believe we still accomplished our goal, which was to emphasize the high mortality rate in cases with critical arotic stenosis and EFE in spite of technically successful interventions.

Conclusion

The presence of EFE is known to be related with an increase in mortality and morbidity in patients with critical aortic stenosis, and we observed this to be true in our study. Thus, identifying those patients with a better chance of survival after receiving univentricular palliation versus undergoing a valvotomy or valvuloplasty could lead to better early results.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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