1

Hypoplastic left heart syndrome- experience from the

two largest autopsy studies in Serbia

Sofija Glumaca,,Slavisa Djuricic b, Jovan B. Radojevica, Stefan Konstadinovicc, Nebojsa Prijovica,

Jovan D. Vasiljevica

a
Institute of Pathology, School of Medicine, University of Belgrade,
b
Institute for Health Protection of Mather and Child, Belgrade,
c
Cinical Research, PhD studies, Medical School, University of Novi Sad

Short title: Hipoplastic left heart syndrome- autopsy study

Address for correspondence:

Jovan D. Vasiljevic,MD, PhD, FRCPath

Institute of Pathology, Medical School, University of Belgrade
Dr. Subotica 1,
11000 – Belgrade,
Serbia
Phone: +38163254377
E-mail: [email protected]
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Abstract

Background:Hypoplastic left heart syndromeis characterized by several cardiac

abnormalities, mainly by very small left ventricle. The aim of this work was to investigate the

frequency of hypoplastic left heart syndrome among other congenital heart diseases, to analyze

the gender, age, association with other congenital heart defects, as well as pathohistological

changes in the heart and the lungs in these autopsied cases.

Methods: The data were obtained by retrospective analysis of 2593 autopsy protocols

Archive for congenital heart defects Institute of Pathology, School of Medicine, University of

Belgrade, and the autopsy protocol Institute for Health Protection of Mother and Child ,, Dr

Vukan Cupic '' for the period from 1990 to 2014. The analysis used descriptive and analytical

statistically methods.

Results: From a total of 2.593 autopsied cases of CHD, hypoplastic left heart syndrome

was reported in 59 cases, which would represent 2.27% of the total number of CHD autopsies in

the period from 1990 to 2014 year. HLHS is significantly more common in males (p

<0.01).Highly statistically shown that the findings in the aorta in the form of hypoplasia of the

aorta and the aortic arch was the most frequent (p <0.01). Heart failure was the most common

immediate cause of death as demonstrated by highly statistically significant (p <0.01).

Endocardial fibroelastosis was more often present in children with hypoplastic left heart

syndrome (p <0.01).

Conclusion: In our study was observed increased occurrence of malformations in male

patients, but the longer survival was observed in females.

Key words: Hypoplastic left heart syndrome, autopsy, Cardiopatology, Congenital heart

diseases.
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Background

Hypoplastic left heart syndrome (HLHS) is a serious congenital heart defect, and is

manifested by underdevelopment of the left ventricle, aortic or mitral stenosis or atresia, and

hypoplasia of the ascending aorta. Without surgical treatment, HLHS has a high mortality in the

first month of life [1]. Hypoplastic left heart syndrome is characterized by several other cardiac

abnormalities. Anomalies that are included in this syndrome are hypoplasia or

underdevelopment of the left ventricle, atresia or hypoplasia of the aortic valvula, atresia or

hypoplasia of the mitral valve, and aortic atresia or hypoplasia. Because of these defects, the

heart is unable to maintain the systemic circulation [2].

The incidence of HLHS in live births is 0.1 to 0.25 / 1,000 cases [3, 4]. In the larger

study, which included fetuses from spontaneous abortion incidence was 5% [5].

In earlier studies have shown that there is a heightened immune reaction to growth

factors of the heart, and therefore you are changed , in terms of the slow growth of the heart [6 ]

. In addition to recent studies that have been done on this topic is also shown that mutations in

the gene MTHFR 677TT, which is correlated with low concentrations of folate leads to the

occurrence of neural tube defects and phenomena HLHS [7] .

There are a large number of classifications that link to HLHS. The classification to be

used in this paper is the classification of the Tchervenkov[8].

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Methods

Data were obtained retrospective analysis of autopsy protocols Archive for congenital

heart defectsInstitute of Pathology , School of Medicine, University of Belgrade and autopsy

protocols of the Institute for Health Protection of Mother and Child ,, Dr Vukan Cupic '' for the

period from 1990 to 2014 year. In this period were done a total of 2,593 CHD autopsies.

Hypoplastic left heart syndrome was reported in 59 cases, representing 2.27 % of the total

number of autopsies for the period from 1990 to 2014 year.

The aim of this work was to investigate the frequency of hypo plastic left heart syndrome

the population, by gender, age limit up to which these patients are living, association with other

congenital heart defects, as well as histopathological changes in the heart and the lungs in

these patients.

Pathological and morphological analysis of autopsy cases with CHD was performed by

modified Rokitansky technique.

The database was created in Microsoft Office Excel. All the data obtained were analyzed by

appropriate statistical methods: measures of central tendency (mean, standard deviation); χ2 -

test, Mann-Whitney test, T-test, Spearman correlation test. The analysis used statistical

software SPSS version 17.0.

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Results

From a total of 2,593 autopsied CHD cases, HLHS was reported in 59 cases, which

would represent 2.27% of the total number of autopsies in the period from 1990 to 2014 year.

HSLS is found in male children in 41/59 (69.5%), while the incidence of females was

smaller and was 18/59 (30.5%). HSLS is significantly more common in male children (χ2 =

8.966, p = 0.003). (Table 1.)

Patients lived from 1 to 60 days. Survival was on average 8.32 ± 12,031 days. The

largest number of cases has lived 4 days. Longer survival was present in female patients who

lived an average of 9.39 ± 8.00 days, compared to the men's cases who lived 7.85 ± 13.5 days

(Mann-Whitney U = 244, p = 0.038). (Table 1.)

Findings of the aortic valve was normal in 6/59 (10.2%) patients, aortic valve stenos is

occurred in 18/59 (30.5%) patients, aortic valve artesian occurred with the frequency of 35/59

(59.3 %) cases. Significantly more there aortic valve artesian in relation to other entities (χ2 =

23.474, p = 0.0001, DF = 2).Observing morphology cusp of the aortic valve, aortic valve findings

was normal in 44/59 (74.6%) cases, biveral aortic valve occurred in 9/59 (15.2%) cases,

hyperplasia of the aortic valve occurred in 6/59 (10.2%) cases. The largest number of cases had

normal results on aortic valve repair (χ2 = 43.745, p = 0.001, DF = 2). (Table 2.)

Findings of the mitral valve was normal in 27/59 (45.8%) cases, mitral valve stenos is

occurred in 17/59 (28.8%) cases, artesian of the mitral orifice occurred in 15/59 (25.4%) cases.

Looking morphology leaflet of the mitral valve, in 53/59 (89.8%) cases finding the mitral valve

was normal, while the mitral valve hyperplasia occurred in 6/59 (10.2%) cases. Highly

statistically shown that finding the cusps of the mitral valve was normal (χ2 = 37,441, p =

0.0001). (Table 3.)

Looking at the changes in the aorta and the aortic arch, they were frequent. Hipoplasia

of the ascending aorta occurred in 20/59 (33.9%) cases, hipoplasia of the aorta and aortic arch
 6

occurred in 32/59 (54.2%) autopsied cases. Coarctation of the aortic arch occurred in 6/59

(10.2%), aortic arch interruption occurred in 1/59 (1.7%) cases. Highly statistically shown that

finding on the aorta in the form of hipoplasia of the aorta and aortic arch was the most common

(χ2 = 16.145, p = 0.0003, DF = 2). (Figure 1.)

The left ventricle was hipoplastic in 50/59 (84.7%) cases and rudimentary in 9/59

(15.3%) cases. Significantly high statistical been shown to be the left ventricle was hipoplastic

(χ2 = 28.492, p = 0.0001). (Figure 2.)

ASD was associated with HLHS in 18/59 (30.5%) cases. VSD was associated in 8/59

(13.6%) cases.PDA was present in 37/59 (62.7%) cases. The association PDA with HLHS is

statistically significant (χ2 = 3.814, p <0.05) .PFO visited 27/59 (45.8%) cases. (Figure 3.)

Number of communication varied from one to three of communication, a

communication had 31/59 (52.5%), two communication was present in 25/59 (42.4%), while

3/59 (5.1%) cases had 3 communications. Most of the cases had one communication as shown

highly statistically (χ2 = 20.774, p = 0.0001, DF = 2). (Figure 4.)

There was a positive correlation between the number of communications and PDA (ρ

= 0.424, p = 0.001), VSD (ρ = 0.369, p = 0.004) and PFO (ρ = 0.317, p = 0.014).

Findings of the pulmonary veins was normal in the majority of cases, 53/59 (89.8%),

hypoplasia of the pulmonary veins occurred in 4/59 (6.8%) cases, and anomalous compound is

contacted with the lowest incidence of 2/59 (3.4%) cases. (Table 4.)

Dilatation of the right ventricle occurred in 19/59 (32.2%) cases, hypertrophy of the

right ventricle was found in 8/59 (13.6%) autopsied cases, while the hypertrophy and dilatation

of the right ventricle occurred most often in the 32 / 59 (54.2%) cases. Hypertrophy and

dilatation of the right ventricle were most often associated as shown statistical highly significant

(χ2 = 16.145, p = 0.0003, DF = 2). (Figure 5.)

The immediate cause of death in most cases was cardiac insufficiency in 47/59

(79.7%) cases. Other causes of death were renalfailure in 4/59 (6.8%), sepsis 4/59 (6.8%)
 7

cases, and pulmonary causes in 4/59 (6.8%) cases. Heart failure was the most common

immediate cause of death shown highly statistically significant (χ2 = 20.763, p = 0.0001).

(Figure 6.)

Histopathologic findings of the heart in 26/59 (44.1%) were normal.

Endocardialfibroelastosisoccurred in 25/59 (42.4%) cases. Endocardialfibroelastosis was more

often present in children with hypo plastic left heart syndrome, given that the expected value is

less than 1% (χ2 = 585.391, p <0.001). Hypertrophy occurred in 4/59 (6.8%) cases, ischemic

changes have occurred in 3/59 (5.1%) cases, interstitial fibrosis occurred in 1/59 (1.7%) cases.

(Figure 7.)

Histopathological evaluation of the lungs, it was observed that the aspiration of

amniotic fluid occurred in 18/59 (30.5%) cases, diffuse alveolar damage occurred in 13/59

(22%) cases. Lung atelectasis occurred in 13/59 (22%) cases, bronchopneumonia occurred in

11/59 (18.6%) autopsied cases. Pulmonary edema occurred in 3/59 (5.1%) and emphysema in

1/59 (1.7%) cases. (Figure 8.)

Histopathological findings of the blood vessels of the lungs was normal in 34/59

(57.6%) cases. Hypertrophy of the media of blood vessels occurred in 14/59 (23.7%) cases, and

micro thrombosis pulmonary veins occurred in 11/59 (18.6%) cases. (Figure 9.)
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Discussion

HLHS port is very rare group of anomalies of the cardiovascular system. 2593 cases

autopsied, the HLHS is reported in 59 cases, or 2.27%, which is agreed with a number of

studies [9].

In our results, the observed increased incidence of defects in the male population,

which stood at 69.5%, which is also described in a number of studies [2,3,10-17].

Survival was on average 8.32 days, which is consistent with other studies in which the

average survival of patients was 8.2 days [18]. In our work, we have shown that female patients

had longer survival period in relation to the survival of male patients.

Aortic valve atresia occurred in 59.3% of cases, making it the highest-anomaly within

this syndrome, which supports the findings of other studies [19]. The incidence of bivelaraortic

valve amounted to 15.3% of the cases, which shows that this anomaly is more frequent in our

reserch compared to other studies [20].The association mitral stenosis with aortic atresia

estuary occurred in 28.5% of cases.

Hypoplasia of the ascending aorta occurred in 33.9% of cases, while hypoplasia

ascendant aorta and aortic arch appeared in most cases 54.2%, which is consistent with other

studies [21-23]. Coarctation of the aorta was associated in 10.2% of cases with this syndrome,

which is in favor of other studies [21-23]. Findings of the mitral valve was normal in 45.8% of

cases, and numerous studies have shown that the longer survival in these findings [20,24].

Hypoplasia of the left ventricle occurred in 84.7% of cases.

ASD was associated with HSLS in 30.5% of cases, and earlier studies have shown an

association of faults with the extended period of life [25]. PDA was associated with HLHS

62.9%, while the largest number of cases had only one communication 52.5% of cases. PFO

was present in 45.8% of cases.

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There was a positive correlation between the number of communications and the

emergence of persistent ductusarteriosus, ventricular septal defect and perforating foramen

ovale, and previous studies have shown that in such cases observed longer survival [26,27].

Findings of the pulmonary veins in most cases, 89.8% were normal, other studies

have shown that in cases who had normal results on pulmonary veins observed longer survival.

Finding the right ventricle was the most frequently amended in the form of combined

dilatation and hypertrophy of the right ventricle, in 54.2% of cases. Previous research has

shown that changing the size of the right ventricle has a stake in the longer survival of patients.

In most cases, the immediate cause of death was heart failure, which occurred in 79.7% of

cases. This result is consistent with previous studies [26,27].

Histopathologic findings of the heart was normal in 44.1% of cases, while

endocardialfibroelastosiswas present in 42.1% of cases, which represents a high percentage of

histopathological changes in hypoplastic left heart syndrome, this result is consistent with other

studies [28].

Histopathologic findings of the lungs is varied, the most common finding, which

appears aspiration of amniotic fluid, which occurred in 30.5% of cases, followed by lung

atelectasis and diffuse alveolar damage, which occurred in 22% of cases.

Histopathologic findings of the blood vessels of the lungs was normal in 57.6% of

cases, microthrombosis pulmonary veins occurred in 18.6% of cases, while the hypertrophy of

the media of blood vessels alveolar-capillary membrane occurred in 23.7% of cases. Our results

corroborate the literature where it is described that patients with hypoplastic left heart syndrome

often have positive findings on blood vessels alveolar-capillary membrane [29].

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Conclusion

In this study we evaluated the prevalence of HLHS among other CHD in CHD

autopsies for period from 1990. to 2014. year , the incidence between the sexes, the length of

survival of patients who are suffering from this CHD, these CHD association with other CHD, as

well as histopathologic changes at the level of the heart and lungs. This study included 59 cases

with HLHS.

From our results we can conclude that this CHD is very rare, and if not surgically

rehabilitate the prompt death occurs. We observed increased occurrence of these

malformations in male patients, but the longer survival was observed in female patients.

Endocardial fibroelastosis was most common histopathologic finding. The most common

immediate cause of death was cardiac failure.

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Abbreviations

HLHS:Hypoplastic left heart syndrome

CHD:Congenital heart disease

ASD: Atrial septal defect

VSD: Ventricular septal defect

PDA: Persistent ductusarteriosus

PFO: Patent foramen ovale

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Declarations

Acknowledgements

We thank to CardiopatologyReserch Office, Institute of Patology, School of Medicine at the

University of Belgrade.

Competing interests

The authors declare that they have no competing interests.

Authors’ Contributions

SG, SDj and JR performed the data collection. JDV designed the study and performed the

analysis. JR, NP, SG drafted the manuscript. All authors read and approved the final

manuscript.
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Tables

Table 1. Comparison of the frequency of hypoplastic left heart syndrome and survival in male
and female patients.

Male patients Female patients

Number of patients n=41 n=18
Frequency (%) 69,5% * 30,5%
Survival (days) 7,85±13,5 a * 9,39±8,00

*
p < 0,01vs female patients
a
Results are presented as mean ± standard deviation
 18

Table 2.Comparison of findings of the aortic valve.

Finding Frequency (%)

Normal finding 10,2
Morphology of the valve Stenosis 30,5
Atresia 59,3*
Normal finding 74,6#
Morphology leaflet Bivelar valve 15,2
Hypoplasia of leaflet 10,2

*
p< 0,01vs The frequency of normal results and stenosis
#
p<0,01vs Frequency bivelar valve and hypoplasia leaflet
 19

Table 3.Comparison of findings of the mitral valve.

Finding Frequancy (%)

Normal finding 45,8
Morphology of the valve Stenosis 28,8
Atresia 25,4
Normal finding 89,8*
Morphology leaflet
Hypoplasia of leaflet 10,2

*
p< 0,01vs Frequency hypoplasia leaflet
 20

Table 4. Findings on pulmonary veins

Finding Frequency (%)

Normal finding 89,8
Hypoplasia of the pulmonary veins 6,8
Anomalous compound 3,4
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Figure legends

Figure 1. Comparison of the frequency of changes in the aorta and aortic arch.
*
p< 0,01vs frequency hypoplasia ascending aorta, coarctation of the aorta and aortic arch
interruption.

Figure 2. Comparison findings on the left ventricle.

*
p< 0,01vs frequency rudimentary left ventricle.

Figure 3. Comparison of the incidence of atrial septal defect (ASD), ventricular septal defect
(VSD), dustus persistent arteriosus (PDA) i foramen ovale apertuma (FOA).
*
p< 0,05 vs the incidence of atrial septal defect, ventricular septal defect and patent foramen
ovale apertum.

Figure 4. Comparison of the frequency of existence of one, two and three communications
*
p< 0,01 vs incidence of two and three communication.

Figure 5. Comparison of findings of the right ventricle

*
p< 0,01 vs frequency of isolated dilatation and isolated right ventricular hypertrophy.

Figure 6. Comparison of the frequency of causes of death.

*
p< 0,01 vs incidence of renal failure, sepsis, and pulmonary causes as the cause of death.

Figure 7. The frequency of identified histopathological findings on heart.

*
p< 0,01 vs the expected frequency of fibroelastosis.

Figure 8. The frequency of identified histopathological findings in the lungs.

Figure 9. The frequency of identified histopathological analysis of the blood vessels of the
lungs.
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