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ORIGINAL RESEARCH
Ahead of print publication  

A Study on Fetal Intracardiac Echogenic Foci: Pondering Possible Etiology of Echogenicity with Histopathology Correlation


1 Division of Paediatric Cardiology, St. Gregorios Cardio-Vascular Centre, Fetal Cardiac Services, Parumala, Kerala, India
2 Department of Anatomy, Christian Medical College, Ludhiana, Punjab, India
3 Department of Pathology, Cardiovascular and Thoracic Division, Seth GS Medical College, Mumbai, Maharashtra, India
4 Department of Cardiology, Prime Heart Institute, Chandigarh, India

Date of Submission14-Oct-2020
Date of Acceptance14-Jan-2021
Date of Web Publication23-May-2021

Correspondence Address:
Saji Philip,
Division of Paediatric and Fetal Cardiology, St. Gregorios Cardio-Vascular Centre, Parumala, Pathanamthitta (DT) - 689 626, Kerala
India

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiae.jiae_70_20

  Abstract 

Objective: The objective of this study is to determine the frequency, location, and delineation of the echogenicity of intracardiac echogenic foci (ICEF) and to ponder the possible etiology of ICEF. Materials and Methods: Retrospective study of 2445 referred cases in second and third trimester for fetal cardiac ultrasound scan from 2010 to 2020, targeted for ruling out congenital heart disease were evaluated and analyzed in detail for ICEF. Further postnatal follow-up was done in 64 cases of ICEF till 7 years of age to see the natural course. Histopathology was performed from one case of fetal autopsy at 19 weeks of gestation for further correlation. Results: Among the fetal cardiac ultrasound cases, 323 (13.2%) showed ICEF (95% confidence interval 11.9–14.6). Majority of these ICEF (96%) were in the left ventricular cavity, and then both ventricles (3%) and remaining in right ventricle and all were located within the papillary muscles. On follow-up of 66 postnatal cases, ICEF had resolved in 97% by 5 years of age. Only two cases reported to have congenital heart disease. No chromosomal anomalies was associated in any case. Histopathology of fetal heart specimen in one case revealed myxomatous degeneration at the apices of the papillary muscle. Conclusion: Frequency of single ICEF is much higher in the left ventricle, and it is invariably located within the upper third of the anterior papillary muscle in such cases. As the gestational age advances, ICEF can resolve in utero, and further complete resolution is seen by 1–7 years of postnatal life. Variability in the echogenicity could be part of transformation of myxomatous tissues to fibrosis or microcalcification. In this study, ICEF have no particular association with congenital heart disease or chromosomal association.

Keywords: Coronary artery remodeling, intracardiogenic echogenic foci, left ventricular echogenic foci, multiple echogenic foci, right ventricular echogenic foci



How to cite this URL:
Philip S, Philip SE, Vaideeswar P, Singh U P. A Study on Fetal Intracardiac Echogenic Foci: Pondering Possible Etiology of Echogenicity with Histopathology Correlation. J Indian Acad Echocardiogr Cardiovasc Imaging [Epub ahead of print] [cited 2021 Oct 17]. Available from: https://www.jiaecho.org/preprintarticle.asp?id=316637


  Introduction Top


Intracardiac echogenic focus or foci (ICEF) are defined as any bright linear or spherical echogenic focus or spot within the ventricles detected by fetal cardiac ultrasound at any gestational age. This was first described by Schechter et al., in 1987.[1] ICEF are found more often in left ventricle (LV) and incidence may vary from 0.46%–20%, with or without any association with chromosomal abnormalities, particularly trisomy 21.[2],[3],[4],[5],[6] In some reports, the echogenic foci were considered to be a normal variant in the development of papillary muscles and chordae tendineae. ICEF is still one of the early soft ultrasonographic markers along with choroid plexus cysts, abdominal echogenicity, and pyelectasis extensively studied for chromosomal anomalies.[7],[8],[9] However, studies on etiology, and further postnatal follow-up with histopathology are seldom seen in the literature. Therefore, we performed a 10-year retrospective study on the incidence of ICEF referred for fetal cardiac ultrasound scan. Postnatal follow-up evaluation was done to know anatomical location and its natural course. We also tried to determine any association of ICEF with congenital heart disease or chromosomal anomalies. Autopsy with histopathological study could be performed in one case of ICEF for pondering possible etiology behind this bright focus, the so called “golf balls.”


  Materials and Methods Top


A 10-year retrospective study was conducted from the hospital fetal cardiac registry of 2445 fetal cases, from 2010 to 2020. All cases were referred in second and third trimesters of pregnancy, aged between 19 and 57 years, from the obstetrics department of nearby hospitals, clinics, and other scanning centers to rule out congenital heart disease. We searched for echogenic foci located within the ventricles which were included in the study whereas bright echogenicity occurring elsewhere was excluded. Resolving echogenic foci noticed by fetal cardiac scan was also included in our classification, and defined as when the brightness of echogenic foci became insignificant (echogenicity as tiny or linear or with less brightness and <1.4 mm in the width) when compared to the previous well-demarcated significant echogenic foci (≥1.5 mm). Furthermore, the same definition was applied in the postnatal echocardiographic follow-up. We did not do any intra- and inter-observer variability assessment since the detection of ICEF is already well demarcated in routine obstetric ultrasound scans. Echogenic foci can be single or multiple. As per the location identified, we have further classified it as right ventricular ICEF, left ventricular ICEF, and bilateral ICEF. Reports of antenatal double marker test and nuchal thickening with nasal bone scan were verified as initial screening to know any association of chromosomal anomalies. It was later further confirmed by postnatal clinical examination by neonatologist to rule out any association of aneuploidy with ICEF. No case warranted karyotype studies such as analysis of amniocentesis or chorionic villi sampling or free cell deoxyribonucleic acid (DNA) tests, since no additional soft-tissue markers were detected by the anomaly scan done at various centers by referral doctors. However, quadruple and fetal cell-free DNA test were advised in cases with congenital heart disease and in cases presenting without basic screening test.

The study was approved by the hospital ethics committee (approval no. IRB04/20th Jan/2020).

Two-dimensional echocardiogram

Two-dimensional (2D) echocardiographic examinations were performed utilizing either Mindray M7 or GE T9 ultrasound machine with 3.5-MHz curved linear array transducer. Fetal cardiac ultrasound examinations were specially performed by first author himself and further focused on ICEF with detailed cardiac structural evaluation by segmental approach particularly referred for bright intracardiac focus. Apical four-chamber view with zooming-in mode was preferably used to evaluate the locations and morphology of those bright foci. In cases with difficulty in seeing the bright focus due to technical or other reasons, other possible views were also was considered to locate the same. In general, detection of ICEF from only one view and less bright shadow, <1.4 mm in width was considered to be insignificant or resolving ICEF.

Autopsy and histopathological study

Autopsy was performed in one case with an aim of doing histopathology of the bright focus detected by cardiac ultrasound examination after taking consent from the parents at 19 weeks of gestation. This was a case of single left ventricular ICEF diagnosed at 18 weeks of gestation in a structurally normal heart with severe bilateral hydronephrosis and hydroureters. Fetus was terminated because of adverse renal outcome, explained by the pediatric surgeon. We could not do blood sampling for karyotyping since the specimen was sent with 10% formalin preservation. We examined kidneys and all other organs along with intracardiac examination, and the heart was also sent for histopathology. Sections of entire heart were made, and slides were stained with hematoxylin and eosin stain for the histopathology study of the ICEF. Embryological development of coronary artery to the papillary muscle was considered to understand the possible etiology further.

Postnatal follow up

Although ICEF is a benign condition, a postnatal follow-up was aimed at knowing how fast or how often the ICEF resolved as the age advanced. For this purpose, 126 cases of antenatally diagnosed ICEF were enrolled for postnatal follow-up, but 60 cases dropped out at the first visit at 3 months of age. Sixty-six completed the follow-up study by 2D echocardiogram which extended up to 7 years of age. Thus, all 126 cases were initially screened at 3 months, and then 66 were followed up at 5 months and till 7 years of age. Resolving or insignificant ICEF were arbitrarily defined as <1.4 mm width of the brightness measured by transthoracic 2D echocardiogram with less brightness of the focus from the previous scan.

Statistical analysis

Data were entered into Microsoft Excel and analyzed using SPSS (version 20) for Windows. Proportion of ICEF and its various patterns are presented as frequency, percentage, and 95% confidence interval. Appropriate statistical diagrams were also used.


  Results Top


Fetal cardiac ultrasound

In the retrospective study of 2445 fetal cardiac ultrasound scans, 323 (13.2%) showed ICEF (95% confidence interval 11.9–14.6) and 96% of these ICEF were seen in the LV, 1% in the right ventricle, and remaining in both ventricles [Figure 1] and [Figure 2] and [Table 1]. The LV-ICEF were seen as a single focus in 88% or as multiple foci in 11% or as resolving foci in 1% [Figure 1] [Figure 2] [Figure 3]. Single LV-ICEF was always [Figure 3]a seen at the apex or upper third of anterior papillary muscle, whereas multiple LV-ICEF (n = 35) were seen at the apices of both anterior (74%) and posterior (26%) papillary muscle or multiple foci at the anterior papillary muscles alone [Figure 1] and [Figure 2]. LV-ICEF was much easily detected than right ventricular ICEF in both cardiac and routine obstetric ultrasound scans. ICEF in the right ventricle was single and mainly located at the anterior papillary muscle of the tricuspid valve; multiple foci in right ventricle were never detected.
Figure 1: Data on intra cardiac echogenic foci (ICEF). (a) Pie chart shows that ICEF were detected in 13% (n=323) of the 2445 cases of fetal cardiac ultra sound scan, (b) Pie chart shows ventricular distribution of ICEF, (c) Bar chart shows different patterns of LV-ICEF. BL: bilateral, RVEF: right ventricular echogenic foci, LVEF: Left ventricular echogenic foci, MULTI: Multiple, RESO: Resolving

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Figure 2: (a-d) Trans-abdominal two-dimensional fetal cardiac ultrasound on different types of intracardiac echogenic foci located in the anterior papillary muscle (APM): (a) Shows left ventricular echogenic focus (LVEF), a bright spherical spot located within the APM of the left ventricle (LV) at 18-week gestational age (GA), (b) Bilateral EF, bright two foci in each ventricle within the APM of tricuspid valve (TV) and mitral valve (MV) at 22 -week GA, (c) Right ventricular echogenic focus (RVEF), a single bright spot in APM of TV, at 24-week GA, (d) A composite of drawing depicts RVEF at the apex of APM of TV, LV is near to the stomach (s) at the left side of spine (SP) and descending aorta (D/DSAO), (e-g) Trans-abdominal two-dimensional fetal cardiac ultrasound of apical four-chamber view showing single and multiple LVEF: (e) Single LVEF, (f and g) Multiple LVEF located at the apex of APM

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Figure 3: Fetal and post-natal two-dimensional echocardiogram showing resolution of single and multiple left ventricular echogenic foci (LVEF). (a) Fetal trans-abdomeninal apical four-chamber view showing single LVEF at the apex of anterior papillary muscle (APM) at 23-week gestation, (b) Same case on postnatal two-dimensional transthoracic apical four-chamber view at 7-months of infancy showed single LVEF, (c) Parasternal long-axis view shows resolving focus as lesser brightness at 12-months and leaving an insignificant faint focus, <1.4 mm at 18months of age. (d and f) Postnatal follow up of LVEF: (d) Parasternal long-axis view shows multiple LVEF at the apex of APM at 8-months of infancy, (e and f) Short-axis and apical four-chambers views showing resolving faint insignificant foci, <1.4 mm at 1 year of age. LA: Left atrium, PPM: Posterior papillary muscle, RV: Right ventricle

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Table 1: Detailed description of intracardiac echogenic foci studied in the fetal and postnatal life

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Postnatal follow up of echogenic foci

Transthoracic 2D echocardiogram [Figure 3]b [Figure 3]c [Figure 3]d [Figure 3]e [Figure 3]f follow-up in the postnatal period was performed in 66 cases. In 92.5% (n = 61) cases at 1-year, 0% at 3-year, 4.5% at 5-year (n = 3), and 3% (n = 2) at 7-year of age, ICEF had resolved to an insignificant tiny linear or spherical brightness (<1.4 mm) [Figure 3]c and [Figure 3]f and [Table 1]. In 3% (n = 2), the LV-ICEF persisted at 5-year age, but subsequently, decreased in size and echogenicity by 7-year age, consistent with a diagnosis of resolved ICEF. Thus, 97% of the IECF resolved by 5 years of age.

Marker tests with integrated nuchal thickening and nasal bone scan revealed low risk for trisomy 13, 18, and 21 in almost all cases. Further, postnatal clinical examination also revealed no evidence of trisomy or any other chromosomal associations or structural heart disease in association with ICEF, except in two cases, diagnosed with tetralogy of Fallot in one case and another with ventricular septal defect where echogenic focus was single, and cell-free DNA test was advised which was negative for aneuploidies.

Histopathology of echogenic foci

Autopsy was conducted in one fetus at 19 weeks of gestation and the heart was found to be structurally normal. There was no grossly visible thickening or fibrosis at the apices or the bellies of the anterior papillary muscle that would have corresponded with ICEF. However, histopathology of the sections taken from that area revealed myocardial cells, few endocardial cushion-like cells at the atrioventricular side of the interventricular septum and partly with persistence of myxoid tissue almost like the endocardial cushion tissue at the tips of the papillary muscle [Figure 4]a.
Figure 4: (a) Undulating bundles of fibro-myxoid tissue at the tip of the papillary muscle attached to the mitral valve (H and E, × 250). (b-e) A composite of drawing depicts the developmental events leading to mature coronary arteries and development of papillary muscle and chordae tendineae: (b) First, a coronary plexus (Red) covered in pericytes (Blue) migrates over the surface of the heart and into the myocardium. (c and d) The plexus vessels attach to the aorta to initiate blood flow, triggering arterial remodeling (red) that ultimately leads to mature arteries. (e) Schematic of the development of papillary muscle and chordae tendineae from the endocardial cushion. AO: Aorta, AVC: Atrioventricular canal, CA: Coronary artery, CT: Chordae tendineae, PA: Pulmonary artery, PM: Papillary muscle, SS: Septum secundum, SP: Septum primum[13,14]

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  Discussion Top


Intracardiac echogenic foci

Fetal ICEF is frequently observed in routine obstetric ultrasound, and even more commonly in scans targeted for fetal echocardiogram. ICEF is, as mentioned above, defined as any bright linear or spherical echogenic spots or foci within the ventricles detected by fetal 2D echocardiogram at any gestational age.[1] Incidence of ICEF from the published results may vary from as low as 0.36 if calculated from the total number of cases of routine obstetric ultrasound scans, to as high as 20% if calculated from the total number of targeted fetal cardiac ultrasound scans, and chances of counting repeated scan numbers could also be high. Thus, 13% of ICEF seen in our studies from fetal cardiac scans is within the acceptable range of published data.[1],[2],[3],[4],[5],[6],[7] Cardiac echogenic foci are considered as one of the markers seen in association with chromosomal defects in many publications. The presence of two or more markers such as mild renal pelvic dilation, choroid plexus cysts or echogenic foci may associate with aneuploidy but one particular marker alone in the first trimester is unlikely with trisomy.[8],[9] These soft ultrasonographic markers such as choroid plexus cysts, echogenic cardiac foci and pyelectasis have also been extensively investigated in the second trimester.[10],[11],[12],[13],[14] In fetuses, choroid plexus cysts were seen to be more common in the first than the second trimester, but pyelectasis and hyperechogenic foci in the heart had similar prevalence in the first and second trimesters.[12],[13],[14] One case report was published on a 16-week fetus, in whom detection of increased nuchal translucency thickness and bilateral ICEF led to the prenatal diagnosis of truncus arteriosus and cytogenetics confirmed CATCH 22.[15] From our retrospective data, antenatal double marker test, and integrated nuchal thickening were done and showed low risk of trisomy, and further postnatal clinical evaluation confirmed no association with aneuploidy.

Embryology of the papillary muscle and coronary artery development

Around the right and left atrioventricular canals, the primitive mesenchyme cells proliferate to form collars of endocardial cushions. The ventricular surface of proliferated mass is excavated to form the atrioventricular valves which are attached to the ventricular wall by the trabecular cords. Later, these cords are transformed into the chordae tendineae and papillary muscles[16] [Figure 4]e. A plexus of blind epicardial capillaries appears on the heart at 5th to 6th weeks of life. The epicardium is a vital source for angiogenic growth factors that stimulate coronary plexus development [Figure 4]b. Cell-tracing analysis suggests that coronary endothelium arises from three different progenitor populations: the sinus venosus endocardium, ventricular endocardium, and the proepicardium. Coronary cells represent more than 60% of the non-myocyte populations in the heart and are critical in providing blood flow as well as regulating myocardial metabolism.[17],[18],[19] This endothelial coronary plexus eventually anastomoses with the aortic root at the level of the sinotubular junction, and connecting right and left arterial coronary vessels and further remodeling takes place.[17],[19],[20],[21],[22] [Figure 4]c [Figure 4]d. Hence, a proper coronary vasculature development is essential for late-embryonic cardiac tissue homeostasis and efficiently supports the oxygenation of myocardial tissue. We strongly consider that myxomatous changes or fibro-calcification develops due to insufficient early development of epicardial coronary plexus and the poor remodeling of coronary arteries detected as ICEF of the apical segment of the papillary muscles. This process may further intensify by failure of the angiogenetic progenitors or any changes to the master regulators or extracellur matrix protein.[13]

Histopathology of intra cardiac echogenic foci

Very few publications provide histopathology correlation of ICEF. The cause and exact location of these foci have remained speculative by ultrasound scan. But the follow-up postnatal and infancy echocardiograms have shown the location to be at the upper third of the apex of the papillary muscles, and not at the chordae tendineae level. Doubtful cases were further evaluated postnatally and were proved as within the apex of the papillary muscle. Brown et al. studied three autopsy cases and noted that the only consistent histologic finding present in all three fetuses was mineralization within a papillary muscle and the chordae tendineae were normal.[23] Another pathologic correlation study on echogenic foci in six fetal heart specimen between 20 and 22-week gestation by Tennstedt et al. found that in all six cases, histologically, coarse intramyocardial calcifications surrounded by fibrotic tissue were seen within the papillary muscle.[24] In our histopathology study at 19-week gestation, ICEF was seen as endocardial cushion like or myxomatous tissue.[Figure 4]a This may change from myxomatous to fibrous structure or may show mineralization depending on remodelling of coronary arteries or as the gestational age enhances, and echogenicity will vary accordingly.

Regenerative potency of the myocardium in infancy

In our study, ICEF at the apex of papillary muscle showed complete restoration to non-echogenic areas or less brightness on follow-up 2D echocardiograms during the infancy or early childhood and this prompted us to study the regenerative potency of myocardium. Zeng B et al. performed a study in an animal model using 5-bromode-oxycytidine staining which is commonly used in the detection of proliferating cells in living tissues of the experimental models. This study showed positive cardiomyocytes, consistent with cardiomyocyte proliferation surrounding the area of infarction or injured areas.[25],[26] Such regenerative capacity of the surrounding myocardium will restore the damaged tissues.[27],[28] Accordingly, fetal inflammatory response and fetal myocardial proliferation in experimental models suggested faster remodelling in the fetal and infancy period than in the adult population where extracellular matrix, cell migration, gene expression, and progenitor cell function would matter.[29],[30]


  Conclusion Top


Among the different types of fetal ICEF, the frequency of single ICEF was much higher in the LV than multiple or right sided foci. All were confined only to the apex or upper third of the papillary muscle which could be due to insufficient early development of epicardial coronary plexus to the embryological remodelling stage of coronary arteries to the papillary muscle. Thus, transformation of the myxomatous tissues to fibrosis or microcalcification may give rise to varying echogenicity. As the age advances, ICEF can resolve completely in both intra uterine and post-natal life, possibly due to potent regenerative healing capacity in the early childhood. The presence of two or more soft tissue markers may have significance, but otherwise single ICEF alone is a benign in nature.

Recommendation

This study should stimulate other investigators to explore and endorse or authorize this possible hypothesis of ICEF. More fetal autopsy studies may be needed for endorsing the etiology of ICEF, especially in the area of fetal coronary artery development to papillary muscles.

Acknowledgement

Ms Nisha Kurian, Assistant Professor, Department of community Medicine, Pushpagiri Medical College, Thiruvalla.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Lehman CD, Nyberg DA, Winter TC 3rd, Kapur RP, Resta RG, Luthy DA. Trisomy 13 syndrome: Prenatal US findings in a review of 33 cases. Radiology 1995;194:217-22.  Back to cited text no. 7
    
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Economides DL, Whitlow BJ, Kadir R, Lazanakis M, Verdin SM. First trimester sonographic detection of chromosomal abnormalities in an unselected population. Br J Obstet Gynaecol 1998;105:58-62.  Back to cited text no. 8
    
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Sharma B, Chang A, Red-Horse K. Coronary artery development: Progenitor cells and differentiation pathways. Annu Rev Physiol 2017;79:1-9.  Back to cited text no. 13
    
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Machlitt A, Tennstedt C, Körner H, Bommer C, Chaoui R. Prenatal diagnosis of 22q11 microdeletion in an early second-trimester fetus with conotruncal anomaly presenting with increased nuchal translucency and bilateral intracardiac echogenic foci. Ultrasound Obstet Gynecol 2002;19:510-3.  Back to cited text no. 15
    
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