Hypoplastic left Heart Syndrome

Hypoplastic Left Heart Syndrome (HLHS) is a group of congenital malformations characterized by significant underdevelopment of the left side of heart, including: the left ventricle, left atrium, aortic and the mitral valves.

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HLHS occurs in 0.1 to 0.25 per 1000 live births. It accounts for about 4-16% of all congenital heart defects (CHD) and for a quarter of the neonatal deaths related to CHD.1,2,3

The etiology of HLHS is uncertain and considered to be multifactorial and several theories have been proposed in this regard. Poor development of the left ventricle (LV), resulting in diversion of blood flow away from the left heart chambers in early fetal developmental period is one of the proposed theories. This theory suggests the causative factor may be an abnormal atrial septum followed by restriction of normal right-to-left shunting. Conversely, abnormal atrial septum function may be secondary to altered compliance of LV.4
In some cases, aortic stenosis (AS) may be the initial defect that consequently changes LV filling capacity. In the fetus with AS and normal LV length at midgestation, predictors of progression to HLHS later in life are: reversal flow in the aortic arch and foramen ovale, monophasic inflow in mitral valve, and LV abnormal function.5
One of the most debated  issues is congenital coronary fistula and it is not clear whether they are secondary to the elevated intraventricular pressure in the setting of HLHS or they are primary malformation responsible for the hypoplasia of LV.6 

Another explanatory mechanism could be due to simultaneous occurrence of a series of gene-signalled defects in different structures in left side of the heart.

HLHS consists of a spectrum of combined malformations of aortic and mitral valves including aortic and mitral valves atresia, aortic atresia and mitral stenosis, stenosis of both valves, and mitral atresia and aortic stenosis with a ventricular septal defecte.7

The overall frequency of chromosomal abnormalities and associated extracardiac anomalies in HLHS cases is thought to be  about 3-31%.  Almost all fetuses with abnormal karyotypes are confined to cases with associated structural anomalies. The common associated chromosomal abnormalities are Turner syndrome, Trisomy 13 and Trisomy 18.1,3 Aside from the abnormal karyotype, extra-cardiac defects are frequently associated with HLHS, and the most frequent ones are a two-vessel umbilical cord; and gastrointestinal, genitourinary, craniofacial, and central nervous system abnormalities.8 Rarely, chromosome 22q11 deletion can occur. Smith-Lemli-Opitz, Holt-Oram, and the VACTERL are among associated syndromes. 

The risk of recurrence of HLHS depends on the etiology and is roughly about 2% (varies from 0.5% to 25%).
For families with one affected child, the recurrence risk is 4% but the risk increases to 25% for those with ≥2 affected children.9

The four-chamber cardiac view is the main stay of diagnosis and is typically abnormal in HLHS. The most conspicuous finding that targets a fetus  for more advanced evaluation,is the presence of a very small and slit like LV although  it is not always present. Actually, the left ventriclular size can vary (absent, small, normal size, or even dilated), but in all cases the left ventricle is hypokinetic with poor function. The apex is predominantly formed by the right ventricle (RV).
The most common features of HLHS  is a combination of an atretic aortic valve, a hypoplastic and dysplastic mitral valve and a globularly small LV with hypo-contractility and increased echogenicity of endocardium due to endocardial fibroelastosis. Other associated findings are a small left atrium, a paradoxical movement of the flap valve of foramen ovale in four-chamber view, a hypoplastic or nonvisible aortic arch and a prominent pulmonary trunk (implying compensatory dilation of pulmonary artery) in three-vessel view. 10,11,12
In color Doppler evaluation, according to the severity of HLHS, minimal or no flow can be visualized in LV. Increased pressure in the left atrium consequently causes reversal of  flow (left to right) across the foramen ovale. Typically, there is no detectable flow across aortic valve and the aortic isthmus and arch are supplied  by the ductus arteriosus, retrogradely (ductus dependency).4,11,13
Pulsed Doppler assessment of pulmonary venous flow pattern  helps to identify an intact atrial septum and  has been reported in about 19% of cases. [Galindo] Normally, Doppler flow velocity waveforms of pulmonary veins during pregnancy show a pulsatile forward flow in all cardiac cycles. In the presence of left atrial obstruction and during the atrial contraction, pressure in the left atrium is highly increased and as a result, reversal of end-diastolic flow and an increase in pulsatility index are seen in the pulmonary venous wave.14
Tissue Doppler Imaging (TDI) is a well‑known pulsed Doppler tool to assess both systolic and diastolic ventricular functions in children and adults. TDI is also applicable in prenatal assessment of the right ventricular function in HLHS. It often reveals altered RV properties (particularly in diastole), impaired ventricular relaxation (significantly lower peak early (e’) diastolic velocity and E′/A′ ratio), prolonged isovolumetric contraction time(ICT) and increased myocardial performance index (MPI), that may be related to an adaptation to the altered loading situations.7,15.16
Three-dimensional (3D) ultrasonography with different techniques such as tomographic imaging and volume rendering can better demonstrate the cardiac findings such as  the severity of the hypoplastic left chambers, the hypoplastic aortic root and mitral valve annulus. 11 The images obtained by colour Doppler Fetal Intelligent Navigation Echocardiography (FINE) or 5D Heart colour could make an accurate diagnosis of fetal HLHS and associated coarctation of the aorta possible.17
Magnetic resonance imaging (MRI) with ultrafast sequences has an increased role in obstetrics especially when ultrasound imaging is limited such as in the presence of  oligohydramnios and shadowing from bone ossification due to advanced gestation. However, technical difficulties (the effects of fetal blood flow and fetal cardiac and body motion) limit MRI role in fetal cardiac imaging. It has been shown  that MRI with use of steady-state free precession (SSFP) sequences can be used as a second-line approach for the four-chamber view abnormalities( As HLHS) detected by prenatal ultrasound with a sensitivity of 88% and the specificity of 96%.18

HLHS, especially its severe forms, can be detected at first trimester sonography(11-14ws),based on presence of the aforementioned findings, but it is worth-noting that a normal first and even second trimester sonography exam  dose not rule out the development of HLHS later in gestation. In the setting of primary left outflow tract obstruction, evolution to HLHS may occur.2,11 Axt-Fliedner et al., have reported a case of aortic stenosis with normal 4-chamber view in the  first trimester that progressed to HLHS in the  second trimester.19
 

All cardiac abnormalities with diminutive LV, (including severe forms of coarctation of aorta, critical aortic stenosis and less commonly, interruption of the aortic arch) single ventricle and the unbalanced endocardial cushion defect may appear similar in the 4-chamber view.
A careful attention to the atria, AV valves, crux, and great vessels on gray scale and colour Doppler study often leads to the correct diagnosis.
The presence of a narrow LV inflow, normal contractility of LV and a normal right to left shunt at the level of foramen ovale are strongly in favour of coarctation and rule out the presence of HLHS.11
In CHDs with single ventricle, the hypoplastic ventricle should be named. If the dilated ventricle is closer to the sternum it will be concluded that the hypoplastic ventricle is LV.

Based on the last updated ISUOG Practice Guideline for 2nd trimester ultrasound, the screening examination of the fetal heart must include four-chamber and outflow tract views. In HLHS, all of these views are obviously abnormal.20 HLHS is commonly picked up during routine screening due to presence of marked discrepancy between the sizes of two ventricles, visible on four-chamber view.1 A sensitivity of 61.9% is reported for detection of isolated HLHS by screening ultrasonography.21

Following prenatal detection and diagnosis, a detailed fetal cardiac evaluation is indicated. The LV size, severity of mitral valve involvement, shunting characteristics at the level of foramen ovale and any involvement of right side of the heart should be assessed to determine the necessity for in-utero intervention and to disclose the probable final outcome.  A detailed fetal ultrasound exam should be performed to exclude concomitant associated extracardiac defects.

In order to provide the most accurate consultation for the expecting parents and after prenatal diagnosis of HLHS, the prognostic factors should have been clarified. Unfortunately, HLHS still has a poor prognosis, with a total survival rate of less than 40%.1,8
Prognostic factors, that should be defined during fetal echocardiography, are as follows:
•    LV size and function
•    Presence/absence of mitral valve and its size 
•    Size of the aorta and the aortic root
•    Retrograde shunt in transverse aorta
•    The presence of coronary-cameral fistulae (an abnormal connection between coronary artery and LV) in the small left ventricle when mitral valve is patent
•    Restriction of flow across the foramen ovale and its patency
•    Pulmonary venous Doppler flow pattern (indirectly shows the possibility of restriction at the level of the atrial septum)
•    Tricuspid valve flow and RV function
•    Endocardial fibroelastosis
•    Associated anomalies

In these fetuses, patency of the foramen ovale is critical for normal in-utero development. Flow pattern of pulmonary veins in Doppler study is an indirect way to evaluate the patency of the foramen ovale. In 6% of infants with HLHS, a severely restrictive or intact atrial septum is present which results in a high pressure in the left atrium and damage to the developing lung vasculature. There is no symptom during antenatal life but after birth, marked hypoxemia and early demise are noted.14,22 The mortality rate of these children had been reported as high as 62.5%-100% even after implemented  treatments.1,23
In HLHS, the systemic perfusion and aortic flow are ductus dependent, hence, these neonates become symptomatic during the first week of life as a result of constriction of the ductus arteriosus following the fall of vascular resistance in the pulmonary circulation. After ductus constriction, systemic arterial pressure decreases and a severe metabolic acidemia develops. If the affected infants don’t receive appropriate treatment, almost all of them will die within 6 weeks.24
Altered right ventricular function in prenatal life, is influential on the long-term outcome even when palliation staged surgery has been applied. RV functional impairment may offer clues to the development of RV failure in the childhood period. It is accepted  that LV endocardial fibroelastosis is associated with marked impaired RV myocardial function because it adds additional stiffness to the LV.7,15 Hydrops fetalis does not occur in HLHS unless there is a severe tricuspid regurgitation or severe right sided dysfunction. Even in fetuses with normal RV function and no tricuspid regurgitation, the Doppler-derived cardiac output decreases about 20%.4,25
 

Performing a detailed fetal ultrasonography to exclude associated anomalies and karyotyping are required. Serial prenatal evaluations of tricuspid valve and RV function, flow across the foramen ovale, Doppler flow measures of pulmonary veins and assessment of fetal growth rate are recommended in every 4 to 6 weeks because hemodynamic impairment can progress over time.11
In infants with an intact atrial septum, postnatal immediate intervention does not seem to substantially improve the outcome, but the fetal intervention with balloon atrial septoplasty in the early fetal life seems to be helpful in treatment.4 It is reported that the threshold of ≤3 for forward to reverse time-velocity integral ratio in the pulmonary venous Doppler, is a specific indicator for doing emergent in-utero atrial septostomy and a ratio of approximately 1 indicates intact atrial septum.22
If critical aortic stenosis (AS) at 20 weeks of gestation is left untreated, there will be a high chance of evolving to HLHS at birth. In those cases of critical AS with dilated, dysfunctional LV that are accompanied by specific criteria predicting evolution to HLHS. In utero aortic balloon valvuloplasty may promote LV growth and could be performed with relatively high success rates with an acceptable fetal risk. Also this technique has the ability to restore cardiac output and may result in the resolution of hydrops in fetuses with critical AS and hydrops. Patients who survive appear to be ideal candidates for a biventricular outcome.26,27,28
 Prenatal diagnosis is essential for appropriate delivery planning and will prevent ductal shock (closure of the ductus arteriosus) after birth by using prostaglandin E prescription. Furthermore, three-staged reconstructive surgery (Norwood surgery, superior cavo-pulmonary connection and Fontan operation) has dramatically changed the prognosis of these cases and provides up to 90% survival rate (usually 40-61%).1,8 In this surgical approach, the small LV is eliminated from the circulation and the systemic pumping chamber is made by RV.29 With respect to the overall improvement in outcome of this staged protocol during the past years, cardiac transplantation has become less necessary as an extreme treatment option for infants with HLHS.
As survival from cardiac surgery continues to increase, emerging data show a wide range of neurodevelopmental impairments (up to half of them), especially among univentricular conditions such as HLHS. Children who undergo cardiac surgery in the first year after birth are at higher risk for developmental, learning and behavioral problems later in their life. Actually multiple factors can influence neurodevelopment in these children, including associated neurological anomalies, genetic conditions and surgical techniques. Indeed, because of the burden of such impairments, one of the primary outcome measures in clinical decision making for these children should be neurodevelopmental outcomes. 30

 1.   Galindo A, Nieto O, Villagrá S, Grañeras A, Herraiz I, Mendoza A. Hypoplastic left heart syndrome diagnosed in fetal life: associated findings, pregnancy outcome and results of palliative surgery. Ultrasound Obstet Gynecol. 2009 May;33(5):560-6. doi: 10.1002/uog.6355.

2.    Wilkins-Haug LE, Benson CB, Tworetzky W, Marshall AC, Jennings RW, Lock JE. In-utero intervention for hypoplastic left heart syndrome--a perinatologist's perspective. Ultrasound Obstet Gynecol. 2005 Oct;26(5):481-6.

3. Allen RH1, Benson CB, Haug LW. Pregnancy outcome of fetuses with a diagnosis of hypoplastic left ventricle on prenatal sonography. J Ultrasound Med. 2005 Sep;24(9):1199-203.

4. Rychik J. Hypoplastic Left Heart Syndrome. In Fetal Cardiovascular Imaging A Disease-Based Approach, Reychik J, Tian Z. ( eds). Elsevier & Saunders 2012.

5. Mäkikallio K1, McElhinney DB, Levine JC, Marx GR, Colan SD, Marshall AC, Lock JE, Marcus EN, Tworetzky W. Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention. Circulation. 2006 Mar 21;113(11):1401-5. Epub 2006 Mar 13.

6. Paladini D, Caruso G, Sglavo G, Lapadula C, Parisi G, Martinelli P. Hypoplastic left heart syndrome associated with left ventricle-coronary artery-pulmonary artery fistula: prenatal diagnosis and histological correlation. Ultrasound Obstet Gynecol. 2005 Jul;26(1):78-80.

7. Graupner O, Enzensberger C, Wieg L1, Willruth A, Steinhard J, Gembruch U, Doelle , Bahlmann F6, Kawecki A, Degenhardt J, Wolter A, Herrmann J, Axt-Fliedner R; Fetal Cardiac Imaging Research Group Germany. Evaluation of right ventricular function in fetal hypoplastic left heart syndrome by color tissue Doppler imaging. Ultrasound Obstet Gynecol. 2016 Jun;47(6):732-8. doi: 10.1002/uog.14940.

8. Rychik J, Szwast A, Natarajan S, Quartermain M, Donaghue DD, Combs J, Gaynor JW, Gruber PJ, Spray TL, Bebbington M, Johnson MP. Perinatal and early surgical outcome for the fetus with hypoplastic left heart syndrome: a 5-year single institutional experience. Ultrasound Obstet Gynecol. 2010 Oct;36(4):465-70. doi: 10.1002/uog.7674

9. Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia–Hypoplastic left heart syndrome. N Engl J Med 308,23, 1983.

10. Rychik J. Hypoplastic left heart syndrome: From in-utero diagnosis to school age. Seminars in Fetal & Neonatal Medicine (2005) 10, 553-566

11. Abuhamad A, Chaoui R . Aortic Stenosis and Hypoplastic Left Heart Syndrome. In A practical guide to fetal echocardiography, Abuhamad A, Chaoui R. (2nd eds). Lippincot Williams & Wilkins 2010

12. Jeanty P, Chaoui R, Tihonenko I, Grochal F. A Review of Findings in Fetal Cardiac
Section Drawings: Part 1: The 4-Chamber View. J Ultrasound Med 2007; 26:1601–1610

13. Jeanty P, Chaoui R, Tihonenko I, Grochal F. A Review of Findings in Fetal Cardiac
Section Drawings: Part 3: The 3-Vessel-Trachea View and Variants. J Ultrasound Med 2008; 27:109–117

14. Lenz F1, Chaoui R. Changes in pulmonary venous Doppler parameters in fetal cardiac defects. Ultrasound Obstet Gynecol. 2006 Jul;28(1):63-70.

15. Natarajan S, Szwast A, Tian Z, McCann M, Soffer D, Rychik J.Right Ventricular Mechanics in the Fetus with Hypoplastic Left Heart Syndrome. J Am Soc Echocardiogr. 2013 May;26(5):515-20. doi: 10.1016/j.echo.2013.02.001.

16. Vyas HV, Eidem BW, Cetta F, Acharya G, Huhta J, Roberson D, Cuneo B. Myocardial tissue Doppler velocities in fetuses with hypoplastic left heart syndrome. Ann Pediatr Cardiol. 2011 Jul;4(2):129-34. doi: 10.4103/0974-2069.84650.

17. Yeo L, Romero R. Prenatal diagnosis of hypoplastic left heart and coarctation of the aorta with color Doppler FINE. Ultrasound Obstet Gynecol 2017; 50: 543–544. DOI: 10.1002/uog.18889

18. Votino C, Jani J, Damry N, Dessy H, Kang X, Cos T, Divano L, Foulon W, De Mey J, Cannie  M. Magnetic resonance imaging in the normal fetal heart and in congenital heart disease. Ultrasound Obstet Gynecol. 2012 Mar;39(3):322-9. doi: 10.1002/uog.10061. Epub 2012 Feb 8.

19. Axt-Fliedner R, Kreiselmaier P, Schwarze A, Krapp M, Gembruch U. Development of hypoplastic left heart syndrome after diagnosis of aortic stenosis in the first trimester by early echocardiography. Ultrasound Obstet Gynecol. 2006 Jul;28(1):106-9.

20. International Society of Ultrasound in Obstetrics and Gynecology, Carvalho JS, Allan LD, Chaoui R, Copel JA, DeVore GR, Hecher K, Lee W, Munoz H, Paladini D, Tutschek B, Yagel S. ISUOG Practice Guidelines (updated): sonographic screening examination of the fetal heart. Ultrasound Obstet Gynecol. 2013 Mar;41(3):348-59. doi: 10.1002/uog.12403.

21. Stoll C, Dott B, Alembik Y et al. Evaluation and evolution during the time of prenatal diagnosis of congenital heart diseases by routine fetal ultrasonographic examination. Ann Genet 2002;45:21

22. Divanović A, Hor K, Cnota J, Hirsch R, Kinsel-Ziter M, Michelfelder E. Prediction and perinatal management of severely restrictive atrial septum in fetuses with critical left heart obstruction: clinical experience using pulmonary venous Doppler analysis. J Thorac Cardiovasc Surg. 2011 Apr;141(4):988-94. doi: 10.1016/j.jtcvs.2010.09.043. Epub 2010 Dec 3.

23. Michelfelder E, Gomez C, Border W, Gottliebson W, Franklin C. Predictive value of fetal pulmonary venous flow patterns in identifying the need for atrial septoplasty in th newborn with hypoplastic left ventricle. Circulation 2005; 112: 2974–2979.

24. Doty DB. Aortic atresia. J Thorac Cardiovasc Surg 79:462-63,1980

25. Szwast A, Tian Z, McCann M, Donaghue D, Rychik J. Right ventricular performance in the fetus with hypoplastic left heart syndrome. Ann Thorac Surg 2009;87:1214-9.

26. A. Tulzer, W. Arzt and G. Tulzer.  Fetal aortic valvuloplasty may rescue fetuses with critical aortic stenosis and hydrops. Ultrasound Obstet Gynecol 2021; 57: 119–125.
27. A. Tulzer, W. Arzt, R. Gitter, E. Sames-Dolzer, M. Kreuzer, R. Mair, G. Tulzer. Valvuloplasty in 103 fetuses with critical aortic stenosis: outcome and new predictors for postnatal circulation. Ultrasound Obstet Gynecol. 2021 Oct 4.
28. C.N. Vorisek, D. Zurakowski, A. Tamayo, R. Axt-Fliedner, T. Siepmann, I. Friehs. Postnatal outcome in patients with aortic stenosis undergoing fetal aortic valvuloplasty: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2021 Nov 2.

29. Bardo D M E, Frankel D G,  Applegate K E, Murphy D J, Saneto R P. Hypoplastic Left Heart Syndrome. RadioGraphics 2001; 21:705–717

30. Lloyd D F A , Rutherford M A, Simpson J M, Razavi R. The neurodevelopmental implications of hypoplastic left heart syndrome in the fetus. 2017 Mar;27(2):217-223.
 

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