¹Medellin Colombia,  and Nashville, TN

* Update from 1999-05-18-12 Hypoplastic left heart syndrome © Silva www.thefetus.net/

Synonyms: erroneously called aortic atresia[1]^,[2].

Definition: is a group of congenital anomalies characterized by underdevelopment of the aorta, aortic valve, left ventricle, mitral valve and left atrium. It is the congenital heart anomaly that imposes the most severe form of impedance to aortic blood flow in humans2. For several years it has been erroneously called aortic atresia. Aortic atresia is not always synonymous with an underdeveloped left ventricle and about 6% of all patients with aortic atresia will have a normal sized left ventricle2.

This complex combination of cardiac malformations probably results from multiple developmental errors in the early stages of cardiogenesis, and without treatment, invariably proves fatal[3].

History: A group or several patients with hypoplasia of the left ventricular inlet and outflow tract were described by Lev more than 40 years ago. For several years and until 1970 there was no surgical therapy for these children and most of them died during their first month of life. Surgical approaches were than developed by Fontan and Baudet in Bordeaux, France, and than by Norwood and his colleagues in the United States. The first group to try allotransplantation for babies with hypoplastic left heart syndrome was Bailey and his colleagues in Loma Linda, California2.

Incidence: Varies from 1.7- 6.7: 10.000 livebirths according to different studies2.

Prevalence: The most common major congenital anomalies are cardiovascular anomalies, which occur in approximately 8 of 1000 births. The incidence of cardiovascular anomalies at birth is 6.5 times higher than that of chromosomal anomalies, and they are four times as common as neural tube defects. Congenital cardiovascular malformations account for approximately 20% of neonatal deaths and 50% of infant deaths, and are seen four to five times more frequently in still births than in live-born babies[4]. After a three year study that included 875 fetal echocardiograms, Macedo and his group found 4.2% of congenital heart disease and a prevalence of 13.5% of hypoplastic left heart syndrome in this affected group[5].

Etiology: Shokeir (1971) described 13 patients in 5 families with hypoplastic left heart syndrome. Parental consanguinity was present in 3 sibs. In all affected infants, the course of the disease was progressive and fatal. Holmes et al. (1974) found a frequency of the hypoplastic left heart syndrome among sibs most consistent with multifactorial inheritance. The possibility of a subtype with autosomal recessive inheritance remains. In a later study, Brownell and Shokeir (1976) also obtained results most compatible with multifactorial inheritance[6]^,[7],[8].

The etiology of hypoplastic left heart is not precisely known. Autosomal recessive, autosomal dominant and polygenic inheritance have been suggested[9]^,[10]. Multifactorial is the more likely form of transmition9[11].

Morphogenesis and pathogenesis: unknown.

Morphology:

·        Heart – is usually left sided (dextrocardia is uncommon), with a situs solitus atrial arrangement and atrioventricular and ventriculoarterial concordant connections2^,[12],[13].  The apex is usually formed by the right ventricle. The heart is usually enlarged, particularly the right atrium and ventricle. The left anterior descending aorta, which follows the course of the left ventricle, is usually short2.

·        Right atrium – overall enlargement with enlarged atrial appendage2. 10% of the patients with hypoplastic left heart syndrome will have non-patent foramen ovale (intact atrial septum). When aortic and mitral atresias are present, obligatory left-to-right shunting at atrial level is also present.

·        Tricuspid valve – appears normal.

·        Right ventricle – is hypertrophied and dilated, and its infundibular and septal architecture are exaggerated by the hypertrophy2.

·        Pulmonary valve – is usually tricuspid and functionally normal although dysplasia and stenosis have been reported2.

·        Pulmonary artery – the main pulmonary artery trunk is dilated as are the branches2^,12.

·        Ductus arteriosus – usually wide and serves as a conduit to derive flow from the pulmonary artery to the thoracic descending aorta2^,13. In severe cases, retrograde flow from the ductus arteriosus to the ascending aorta serves as the main blood supply to the coronary arteries.

·        Pulmonary veins – usually connect in a normal fashion to a hypoplastic left atrium. Anomalously connected pulmonary veins in association with left hypoplastic left heart syndrome have also been recognized2.

·        Left atrium – hypoplastic.

·        Mitral valve – is either atretic or stenotic almost without exception (95% of patients), and when is patent all its components are abnormal, including a hypoplastic annulus, thickened free valve margins, shortened chordae tendineae and abnormally short and positioned papillary muscles2.

·        Left ventricle – if the mitral and aortic valves are atretic the left ventricle is usually aplastic, absent, and seen as a “remnant” of left ventricle. If the mitral valve is perforate, a thick walled, small cavity is usually present2.

·        Aortic valve – is either atretic (absent or imperforate) or extremely stenotic.

·        Coronary arteries – originate normally.

·        Ascending aorta – exhibits variable degree of hypoplasia, usually severe2^,12^,13. If the aortic outflow tract is patent, the aortic root is usually small, with thickened, dysplasic, or obstructive aortic valve leaflets.

Sonographic findings:

In a study by Stoll et al. the sensitivity of sonographic detection for isolated left heart syndrome was 61.9%. In this study, cardiac defects affecting the size of the ventricles had the highest detection rate[14]. In other studies, sensitivities only reach 36.6% and 37% for prenatal sonographic diagnosis[15]^,[16].

The prenatal diagnostic approach is important for appropriate counseling, time to consider treatment options, and has been associated with fewer adverse perioperative neurologic events (morbidity). It is also important for preventing ductal shock (giving prostaglandin E1 on time) and keeping the patients’ preoperative condition good[17]. However, the mortality rate does not differ between patients who have been diagnosed prenatally and those diagnosed postnatally with sonography15^,[18].

Echocardiography allows assessment of the size and location of the ductus arteriosus, the hemodynamics of the aortic root, the patency and size of the foramen ovale and atrial septal defects, and the presence of ventricular septal defects to help determine whether the surgical intervention is appropriate3.

With 2D echocardiography the greatly enlarged right heart chambers and pulmonary artery, and the grossly underdeveloped left heart chambers and aorta can be readily seen.

The following are the most important sonographic findings[19]^,20:

• A small, thick-walled and hyperechoic left ventricle (figs. 1-2), with weak contractility (fig. 1-2). An absent or minute left ventricle and an anterior mitral leaflet, of 5mm or less, is diagnostic of hypoplastic left heart ventricle.
• Enlarged right ventricle with increased tricuspid valve excursion.
• Absence of the antegrade flow through the aortic valve, and poor aortic valve motion.
• Variable degree of hypoplasia of the ascending aorta (figs. 3-4), which is small or not visible, and small amount of flow through it, only feasible with color or pulsed Doppler (fig 3-4). An aortic root of 5mm or less is consistent with aortic atresia.
• Hypoplasia of the mitral valve with or without measurable flow, and poor mitral valve motion
• Presence of an echogenic bundle where the AV valve should have been (is a typical finding of the mitral or tricuspid atresias).
• In cases of functional left heart hypoplasia the size of the left ventricle, aorta and mitral valves are under the 3^rd percentile but a measurable antegrade flow can be seen through the aorta[20].

A complete sonographic evaluation of the fetus should be done to rule out associated genetic and extracardiac malformations.

Figure 1 : 4-chamber view. The left ventricle is posterior and to the right of the image. Note the size discrepancy between the left and right ventricles. There is also a small pericardial effusion in the atrioventricular groove on the right side of the heart.

Figure 2 : A VSD connects the hypoplastic left ventricle with the right ventricle. This image could be confused with a similar image of endocardial cushion defect. However in a complete form of endocardial cushion defect the AV valve would be seen to bridge the crux the heart, while in a hypoplastic left heart the AV is either normally implanted (if the HLHS results from an aortic obstruction) or will appear as an thick echogenic band if the HLHS result from an inflow obstruction.

Figure 3 : In the "3-vessel" view the "line-dot-dot" configuration of the pulmonary artery, the ascending aorta and the superior vena cava is incomplete. The hypoplastic ascending aorta is missing between the pulmonary artery and the superior vena cava.

Figure 4 : Color Doppler confirms the absence of the ascending aorta (in spite of a large VSD in this case). This configuration may happen in progressive aortic obstruction (aortic stenosis) leading to aortic atresia by the time of birth.

Genetic anomalies: A defect at 11q23.3 has been suggested[21]. Reports of recurrent isolated hypoplastic left heart syndrome have been infrequent, and the genetic basis of this occurrence is not well understood.[22]

Differential diagnosis: The single ventricles, hypoplastic right ventricles and the severe forms of endocardial cushion defect may all appear similar in the 4-chamber view. A careful observation of the position of the atria, AV valves and great vessels often allows the correct diagnosis. Aortic stenosis, coarctation of the aorta, and interruption of the aortic arch (hypoplasia of the isthmic region), which also imposes severe impedance to aortic blood flow, should also be ruled out2.

Associated anomalies: Aside from the cardiac anomalies (mentioned above), extra-cardiac defects are frequently seen associated with hypoplastic left heart, and the most common are two-vessel cord, craniofacial, gastrointestinal, genitourinary, and central nervous system abnormalities22.

The risk of aneuploidy associated with fetal cardiac anomalies is much greater (ranging from 13-32%) than that associated with advanced maternal age4. Blake et al. found a 40% association of karyotype and extracardiac malformations in patients with hypoplastic left heart syndrome[23]. Brackley and his group found an overall frequency of abnormal karyotype in 12% and associated structural anomalies in 21%[24]. Munn and coworkers found similar data (16% and 20% respectively)[25].

Prognosis: The hypoplastic left heart syndrome usually presents during the first week of life with signs of low systemic perfusion secondary to constriction of the ductus arteriosus due to the falling pulmonary vascular resistance. These babies usually tolerate their defect for a few days while the ductus remains widely open. When the ductus constricts, arterial pressure decreases and a severe metabolic acidemia develops12. Hypoplastic left heart syndrome is responsible for 25% of cardiac deaths in the first week of life1. Almost all of the affected infants die within 6 weeks if they are not treated[26]. Several palliative procedures, including atrial septectomy[27], banding of the pulmonary artery[28], and creation of aortopulmonary shunt[29] have been used looking for a better prognosis.

Patients undergoing these procedures either died at some time after the operation or have been followed for a very limited period, therefore long term prognosis is not known[30]. Prognostic factors:

• Integrity of the interatrial septum
• Left ventricular size
• Aortic root diameter
• Integrity of the interventricular septum
• Aortic stenosis with associated mitral valve stenosis and/or endocardial fibroelastosis
• Associated hepatic injury with liver necrosis
• Combination of associated lesions

Recurrence risk: The recurrence risk depends on the etiology, and varies from 0.5% to 25%, being quoted around 2% in most of the cases9. According to Norwood, the recurrence risk is 4% for those families with one affected child and 25% for those with 2 or more affected[31].

Management:  Apart from determining the karyotype and looking for associated anomalies no obstetrical interventions are needed during pregnancy[32]. Prenatal diagnosis is important for pregnancy counseling and for planning the delivery, which is of particular relevance in fetuses with hypoplastic left heart syndrome, due to the severity of this condition and the specialized surgical treatment that is required15^,18. Staged reconstructive surgery has radically altered the prognosis of hypoplastic left heart syndrome. Furthermore, prenatal diagnosis will allow for preventing ductal shock (avoiding closure of the ductus arteriosus) after birth17 which is usually accomplished with the use of prostaglandin E14.

The recent evolution of palliative surgical procedures (modified Norwood procedure, bidirectional cavo-pulmonary shunt, modified Fontan procedure, aortic valvuloplasty and heart transplantation) has increased the survival rate of children with left hypoplastic heart syndrome3. Staged surgical palliation is preferred over cardiac transplantation as the initial therapeutic approach[33].

The overall survival rate after staged surgery varies and rates between 25%-48% have been reported, with a good medium term outcome18^,25.

Reviewer: Alfred Z. Abuhamad, MD

References

[1] Hata T, Hata K, Makihara K, Eda Y, Kitao M. Hypoplastic left heart syndrome: color Doppler flow mapping. Fetus 7467: 1-3, 1991

[2] Freedom RM, Benson LN, SmallhornJF. Neonatal Heart Desease. First Ed. Springer-Verlag, 1992

[3] Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP. Hypoplastic left heart syndrome. Radiographics. 2001 May-Jun;21(3):705-17. Review.

[4] Anandakumar C, Nuruddin M, Wong YC, Chia D Routine screening with fetal echocardiography for prenatal diagnosis of congenital heart disease. Ultrasound Rev Obtet Gynecol. 2002; March;2:50-55

[5] Macedo AJ, Ferreira M, Borges A, Sampaio A, Ferraz F, Sampayo F. Fetal echocardiography. The results of a 3-year study. Acta Med Port. 1993 Nov;6 Suppl 1:I9-13.

[6] Brownell, L. G.; Shokeir, M. H. K. : Inheritance of hypoplastic left heart syndrome (HLHS): further observations. Clin. Genet. 9: 245-249, 1976

[7] Holmes, L. B.; Rose, V.; Child, A. H.; Kratzer, W. : Commentary on the inheritance of the hypoplastic left heart syndrome. Birth Defects Orig. Art. Ser. X(4): 228-230, 1974

[8] Shokeir, M. H. K. : Hypoplastic left heart syndrome: an autosomal recessive disorder. Clin. Genet. 2: 7-14, 1971

[9] Grobman W, Pergament E. Isolated hypoplastic left heart syndrome in three siblings. Obstet Ginecol 88 (4): 673-675, 1996

[10] Shokeir MH: Hypoplastic left heart syndrome: an autosomal recessive disorder. Clin Genet 2:7-14, 1971

[11] Holmes LB, Rose V, Child AH, et al: Commentary on the inheritance of the hypoplastic left heart syndrome. Birth Defects Orig Art Ser X:228-30, 1974

[12] Adams FH,Emmanouilides GC, Riemenschneider TA. Heart Disease in Infants, Children, and Adolescents. Fourth Ed. Williams & Willkins, Baltimore Maryland. 1989

[13] Perloff JK. The Clinical Recognotion of Congenital Heart Disease. Third Ed. Saunders, Philadelphia, PA, 1987

[14] Stoll C, Dott B, Alembik Y, De Geeter B.Evaluation and evolution during time of prenatal diagnosis of congenital heart diseases by routine fetal ultrasonographic examination. Ann Genet. 2002 Jan-Mar;45(1):21-7.

[15] Mahle WT, Clancy RR, McGaurn SP, Goin JE, Clark BJ. Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with the hypoplastic left heart syndrome. Pediatrics. 2001 Jun;107(6):1277-82.

[16] Reis PM, Punch MR, Bove EL, van de Ven CJ. Obstetric management of 219 infants with hypoplastic left heart syndrome. Am J Obstet Gynecol. 1998 Nov;179(5):1150-4.

[17] Satomi G, Yasukochi S, Shimizu T, Takigiku K, Ishii T. Has fetal echocardiography improved the prognosis of congenital heart disease? Comparison of patients with hypoplastic left heart syndrome with and without prenatal diagnosis.Pediatr Int. 1999 Dec;41(6):728-32.

[18] Andrews R, Tulloh R, Sharland G, Simpson J, Rollings S, Baker E, Qureshi S, Rosenthal E, Austin C, Anderson D. Outcome of staged reconstructive surgery for hypoplastic left heart syndrome following antenatal diagnosis. Arch Dis Child. 2001 Dec;85(6):474-7.

[19] Hornberger LK, Need L, Benacerraf BR. Development of significant left and right ventricular hypoplasia in the second and third trimester fetus. J Ultrasound Med. 1996 Sep;15(9):655-9

[20] Hajdu J, Marton T, Toth-Pal E, Szabo I, Machay T, Papp Z. Prenatal diagnosis of left cardiac abnormality. Orv Hetil. 1995 Oct 22;136(43):2333-7. Review.

[21] Guenthard J, Bueler E, Jaeggi E, Wyler F. Possible genes for left heart formation on 11q23.3. Ann. Genet 37: 143-146, 1994.

[22] Grobman W, Pergament E. Isolated hypoplastic left heart syndrome in three siblings. Obstet Gynecol. 1996 Oct;88(4 Pt 2):673-5.

[23] Blake DM, Copel JA, Kleinman CS. Hypoplastic left heart syndrome: prenatal diagnosis, clinical profile and management. Am J Obstet Gynecol. 1991 Sept;165(3): 529-34.

[24] Brackley KJ, Kilby MD, Wright JB, Brawn WJ. Outcome of prenatal diagnosis of hypoplastic left heart syndrome: a case series. Lancet 2000 Sept 30; 356(9236): 1143-7

[25] Munn MB, Brumfield CG, Lau Y, Colvin EV. Prenatally diagnosed hypoplastic left heart syndrome: outcomes after postnatal surgery. J Matern Fetal Med 1999 Jul- Aug; 8(4): 147-50

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

[27] Moodie DS, Gallen WJ, Friedberg DZ. Congenital aortic atresia. Report of long survival and some speculations about surgical approaches. J Thorac Cardiovasc Surg 63:726-31,1972

[28] Doty DB, Knott HW. Hypoplastic left heart syndrome. Experience with an operation to establish functionally normal circulation. J Thorac Cardiovasc Surg 74:624-30,1977.

[29] Behrendt DM, Rochini A. An operation for the hypoplastic left heart syndrome: Preliminary report. Ann Thorac Surg 32:284-88,1981

[30] 2000 Simpson JM. Hypoplastic left heart syndrome. Ultrasound Obstet Gynecol. Apr;15(4):271-8.

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

[32] Reis PM, Punch MR, Bove EL, van de Ven CJ. Obstetric management of 219 infants with hypoplastic left heart syndrome. Am J Obstet Gynecol. 1998 Nov;179(5):1150-4.

[33] Donner RM. Hypoplastic Left Heart Syndrome. Current treatment options in cardiovascular medicine. 2000 Dec;2(6):469-480.