Hypoplastic left heart syndrome (HLHS) is a rare congenital heart disease that is characterized by the presentation of left ventricular (LV) inlet and outflow tract hypoplasia; it was first described by Lev in 1952 and termed “HLHS” by Noonan and Nadas [
Twenty-five fetuses with LV hypoplasia, mitral stenosis or atresia, or aortic stenosis or atresia and 25 gestational age-matched normal controls were evaluated by prenatal echocardiography at Xinqiao Hospital, Chongqing, between February 1, 2006, and December, 31, 2012. We did not include fetuses with exclusive coarctation of the aorta (CoA). Through the kind efforts of the dedicated families who signed the donation agreements, 12 formalin-fixed heart specimens from HLHS fetuses (gestational age 23.9–34.3 weeks; 11 voluntary terminations of pregnancy and 1 fetal death in utero) and 6 normal control heart specimens (gestational age 22.6–32.1 weeks; inevitable abortion) were obtained from the Department of Pathology at Xinqiao Hospital. These specimens were suitable for both macroscopic and microscopic study. Sections of the LV myocardium and the aortic walls were labeled using hematoxylin and eosin (HE), Masson’s trichrome, and elastic van Gieson (EVG) stains. Each section was examined by two independent pathologists. In instances where there was a discrepancy, the specimens were reevaluated by both pathologists and by a third pathologist to reach a consensus. Follow-ups in the antenatal and postpartum periods were performed for six live births; they included clinical interventions and changes in echocardiographic characteristics. Another seven cases were lost to follow-up. This study was performed in accordance with a protocol that was approved by the Xinqiao Hospital Committee for Clinical Investigations.
All fetal patients underwent at least 1 detailed prenatal echocardiogram, and 6 neonates received echo examinations each month following birth. Echocardiography was performed using a Philips IE33 unit (Philips Healthcare, Bothell, WA, USA), equipped with the latest version of QLAB analysis software, with S8-3, C5-1 probe, and X5-1 matrix probe. Multiple parameters, including cardiovascular anatomic structure and Doppler blood flow, were assessed. Specifically, the anatomic assessment included the measurement of the following structures, in accordance with the cardiac segmental approach: left atrial (LA) and right atrial (RA) dimensions, LV and right ventricular (RV) end-diastolic width diameters, and ascending aorta (AA) and pulmonary trunk (PT) diameters. The mitral valve (MV) was described as either anatomically normal or abnormal. Mitral valve stenosis (MS) was defined as a pathologically decreased diameter of the mitral valve annulus, where color Doppler imaging demonstrated minimal forward flow across the mitral valve. The diameter of the foramen ovale (FO) was also recorded. Cardiac Doppler evaluation included measurements of the MV and the tricuspid valve (TV) flow patterns, the MV and TV color Doppler regurgitant jet areas, and the velocities and flow patterns in the AA and PT. The direction of FO flow was further described. Real time three-dimensional echocardiography (RT-3DE) was used to measure RV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), cardiac output (CO), and ejection fraction (EF). All direct measurements were performed by a single experienced investigator. The investigator was blinded to the patient information when measuring these parameters.
When performing autopsies, the right atrial appendage and RV were opened along the lateral wall to the RV apex and along the interventricular septum to the pulmonary valve. The left side of the heart was similarly opened according to the path of blood flow [
The data are primarily presented in a descriptive fashion due to the small number of fetuses and infants included in our study. Statistical analyses were performed using a sample
Twenty-five fetuses with HLHS, whose mothers underwent prenatal echocardiography at a gestational age of
Clinical characteristics and follow-up data of the 6 fetuses who were born alive.
Fetus | GA at presentation (weeks) | GA at birth (weeks) | Gender | Postnatal intervention or traumatic examination | Follow-up |
---|---|---|---|---|---|
1 (twin 1) | 32.4 | 38.6 | Male | None | Death at 18 days |
2 (twin 1) | 32.4 | 38.6 | Male | Pericardium patch widened operation in CoA | Death at 135 days (1 week after the operation) |
3 (twin 2) | 31.9 | 38.7 | Male | None | Alive, 6 months |
4 | 26.7 | 39.4 | Male | Selective angiocardiography catheter | Death at 126 days (1 day after angiocardiography) |
5 (twin 3) | 34.6 | 38.2 | Male | None | Alive, 5 months |
6 | 28.9 | 39.1 | Male | CT angiography | Death at 89 days (1 week after CT angiography) |
GA: gestational age; CoA: coarctation of the aorta.
The results of two-dimensional and Doppler echocardiography performed on 18 fetuses with HLHS during the follow-up period are summarized in Table
Echocardiographic details of fetuses with HLHS in follow-up (
FO ( |
|
Normal | 5 |
Restrictive | 8 |
Intact | 5 |
MV ( |
|
Stenosis | 11 |
Atresia | 7 |
RV/LV diameter ratio | 2.44 (1.33 to 6.25) |
AV ( |
|
Stenosis | 14 |
Atresia | 4 |
AO/PA diameter ratio | 0.49 (0.24 to 0.69) |
Values are presented as number (
FO: foramen ovale; LV: left ventricular; RV: right ventricular; TV: tricuspid valve.
Comparison of RV volume and RV function parameters between HLHS (
Groups | GA (weeks) | RV EDV (mL) | RV ESV (mL) | RV SV (mL) | RV CO (mL/min) | RV EF (%) |
---|---|---|---|---|---|---|
HLHS ( |
28.0 ± 7.1 | 3.92 ± 1.29 |
1.55 ± 0.68 |
2.42 ± 0.56 |
352.41 ± 116.86 |
60.93 ± 4.58 |
Controls ( |
27.5 ± 2.9 | 3.36 ± 1.51 | 1.23 ± 0.51 | 2.11 ± 0.87 | 325.35 ± 130.15 | 61.65 ± 4.36 |
GA: gestational age; RV: right ventricular; HLHS: hypoplastic left heart syndrome; EDV: end-diastolic volume; ESV: end-systolic volume; SV: stroke volume; CO: cardiac output; EF: ejection fraction.
HLHS fetal echocardiogram images at 33 weeks of gestation. Fetal echocardiogram in a 4-chamber view, demonstrating that both the end-diastolic length and the diameter of left ventricle (LV) decreased (a) as compared with the normal heart in same gestational age (b), while the right ventricle (RV) diameter increased (a), resulting in a notably higher diameter ratio of the RV to LV. M mode echocardiogram image showed the poor contractility of LV (c, white arrow) as compared with the normal heart (d, white arrow). LV: left ventricle; RV: right ventricle; and LVPW: left ventricular posterior wall.
Six fetuses had either mild or severe left ventricular outflow tract (LVOT) obstruction. During the postnatal follow-up of the infants, one presented with progressive biventricular hypertrophy within a short period of time after birth (from 6 mm to 12 mm over three months) (Figures
Infant echocardiogram images at 125 days. Echocardiogram in a left ventricular long axis view, demonstrating severe left ventricular outflow tract (LVOT) obstruction and biventricular hypertrophy (a). Doppler color flow image, displaying turbulence flow through LVOT (b, green arrow). Doppler color flow image in the suprasternal long axis view of the aortic arch, demonstrating low velocity laminar flow through the coarctation of the DAO (c, red arrow). AO: aorta; LA: left atrium; LV: left ventricle; RV: right ventricle; LVOT: left ventricular outflow tract; AOA: aortic arch; and DAO: descending aortic.
Histomorphological and histopathological examinations of fetuses with HLHS were performed in the 12 induced cases. Among the autopsy specimens, 12 displayed a decreased ratio of the diameter of the aortic (AO) to the diameter of the pulmonary artery (PA) (Figure
HLHS fetal autopsy heart specimen at 33.1 weeks of gestation. An autopsy heart specimen at 33.1 weeks gestation demonstrating decreased ratio of the diameter of the AO to that of the PA (a), severely underdeveloped LV and left atrial appendages in comparison with RV and right atrial appendages, with left superior vena cava (b), and aortic valve dysplasia, as well as an abnormal mitral valve along with shortened chordae and basal displacement of the papillary muscles, with the old clot deposition (c). A normal autopsy heart specimen at 33.5 weeks gestation as contrast (d). AO: aorta; RSVC: right superior vena cava; RAA: right atrial appendages; PA: pulmonary artery; LAA: left atrial appendages; RV: right ventricular; LSVC: left superior vena cava; LV: left ventricular; AV: aortic valve; and MV: mitral valve.
Histological abnormalities of left ventricular myocardium as compared with normal. Histological abnormalities from the LV myocardium of HLHS specimens presented with grade 3 fibrosis (a, b) compared to normal controls (c, d). Hematoxylin and eosin staining (a and c). Masson staining (b and d). Magnification ×10 (the bottom left of a, b, c, and d) and Magnification ×20 (the upper right of a, b, c, and d). HE: Hematoxylin and Eosin.
Aortic wall histopathology. Histological abnormalities from the aortic wall of HLHS specimens presented with fibrosis and elastic fragmentation (a and b) compared with normal controls (c and d). Masson staining (a and c). Elastic van Gieson staining (b and d). Magnification ×10 (the bottom left of a, b, c, and d) and magnification ×20 (the upper right of a, b, c, and d). EVG: elastic van Gieson.
HLHS has been recognized as a congenital heart disease with a high mortality rate following birth. However, little is known about the histopathological features of the aorta and LV myocardium during the fetal stages of the disease. This study reports the histopathological features of HLHS specimens from patients who presented with severe LV dysplasia, aortic stenosis or aortic atresia, mitral stenosis or mitral atresia, restrictive or intact atrial septum, and CoA. We hypothesized that these abnormalities might be a complex set of defects that should be considered as a distinct clinical entity.
A small proportion of infants with HLHS have either an intact or a restrictive atrial septum. Their neonatal mortality is particularly high, even following successful atrial decompression [
However, the best timing for intervention and the possible feasibility of such a maneuver in a fetus remain speculative at this time. The favorable consequences, however, appear to increase the chances of successful postnatal biventricular physiology. Disappointingly, intervention during the second trimester has not been shown to improve the growth and development of LV dimensions [
Normal cardiac morphogenesis requires blood-flow directed remodeling in addition to intrinsic patterning. Blood-flow directed remodeling contributes to the secondary development and differentiation of structures as a result of the effects of shear stress and the dynamics of blood flow within the structures [
Cellular proliferation (hyperplasia) is confirmed to be an obligatory process during embryogenesis. In contrast, the developing human heart mainly results from cardiomyocyte hypertrophy and not from hyperplasia. Therefore, at some point during heart development, the ventricular muscle may undergo a switch in potential from hyperplasia to hypertrophy. This switch in myogenic potential may have important implications for ventricular remodeling in neonates with LVOT obstruction [
In some congenital heart diseases, in addition to abnormal cardiac anatomy, myocardial histopathological changes can be discerned at an early developmental stage during the fetal period; such changes include noncompaction, fibrosis, and endocardial fibroelastosis (EFE) [
Because of severe left ventricular dysfunction being unable to maintain the circulation of blood perfusion in neonates with HLHS, RV is actually functional single ventricle and assumes the pulmonary circulation and blood circulation spring function. Therefore, an accurate assessment of right ventricular function in fetuses with HLHS would have given a more meaningful message on prenatal counseling, intrauterine intervention surgical treatment options, and prognosis after birth. Our results displayed that the RV volume, SV, and CO in HLHS fetuses were increased compared with the gestational age-matched normal controls, which indicates the compensated contraction of right ventricle. The RV EF showed no significant difference between HLHS fetuses and the controls. RV EF reflects the percentage of RV SV accounted for RV EDV. RV SV increases with the increase of RV EDV; both of them adapt to each other, thus leading to RV EF values remaining within a certain range of fluctuations in HLHS fetuses. Natarajan et al. showed that fetuses with endocardial fibroelastosis (EFE) of the left ventricle and HLHS presented with marked abnormal RV myocardial function by lower tricuspid
Despite significant improvements in medical resources and therapies, the lifespan of patients with HLHS remains short. We hypothesized that the changes in cardiac function in these patients may be related to cardiac pathological changes. Cardiac morphogenesis and myocardial tissue structure changed significantly during the fetal period and in the first years after birth. Some related studies have reported the ultrasound and MRI characteristics of patients with HLHS, but few histopathological observations have been reported. With the support of the patients and Xinqiao Hospital, we were able to observe preliminary histopathological features in these patients. However, our case series contains only a limited number of patients. Large histopathological studies that include the right ventricle and pulmonary artery in HLHS specimens are needed to further understand the pathophysiologic features of HLHS patients.
In addition to severe anatomical deformity, distinct histological abnormalities in the LV myocardium and aortic wall were identified in the fetuses with HLHS. These changes suggest that structural abnormalities of the heart may be intrinsic in HLHS. RV function damage may potentially exist.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Yan Jiang and Yali Xu contributed equally to this work.
This research was supported by the clinical research funds of Xinqiao Hospital, Third Military Medical University, Chongqing, China (no. 2015YLC10 and no. 2011XLC43).