Prenatal diagnosis of hypertrophic cardiomyopathy and myocardial hypertrophy – literature review

Aetiology of hypertrophic cardiomyopathy

Cardiomyopathies are rare conditions seen in paediatric population. The most common type is hypertrophic cardiomyopathy (HCM), which accounts for 25-40% of cases [1]. However, its prenatal diagnosis can be challenging, with an incidence rate of 6.2 per 100,000 people [2]. It is a histological and functional abnormality that results in abnormal structure of the heart.
Normally, the sarcomere is built of actin, myosin, titin, and Z-discs. The length of the sarcomere is consistent, which results in efficient contraction and relaxation of the heart muscle [3]. However, in case of HCM the sarcomere consists of mutated sarcomere, resulting in overbuild of the muscle and consequently hypercontractility with poor relaxation [4]. In an experiment done on Mybpc3-targeted knock-out HCM mouse model, Garcia-Canadilla et al. [5] proved that even before ventricular hypertrophy development myoarchitectural disarray can be detectable.
There are several conditions that can be linked to the development of the HCM in the fetus, the primary cause being a genetic disorder of the autosomal dominant inherited genes MYH7 [6] and MYBPC3, which are associated with the sarcomere. It is estimated that up to 80% of HCM with childhood onset has a genetic component [4, 7].
Because familial association is present in about 30-40% of cases [8], the family history is a crucial part of the examination, with special attention to sudden cardiac deaths in the family [9]. However, HCM can have many secondary causes: maternal diabetes, genetic conditions, metabolic disorders, such as Pompe disease, Noonan syndrome, or Beckwith-Wiedemann syndrome, twin-to-twin transfusion syndrome (TTTS) in the case of monochorionic twins, and congenital infections (Figure 1) [10-12].

Prenatal diagnosis of HCM

The diagnosis of HCM is usually made during prenatal life via fetal echocardiography, sometimes by fetal MRI [13, 14]. It is usually done during the second or third trimester examination, and normal cardiac anatomy seen in the second trimester does not exclude a diagnosis of HCM in the third trimester of pregnancy [15, 16]. It can be observed as the following:

• excessive growth of the left ventricle; it can reach also the right ventricle, or it can be presented with a generalized hypertrophy (Figure 2 A and B ),
• reduction in the volume of the chambers of the heart,
• decreased contractility of the ventricles with impaired diastolic function (Figure 3),
• asymmetrical growth of the intraventricular septum,
• fetal bradycardia, tachycardia, or other arrhythmias (Table 1) [17].

However, if we suspect hypertrophic cardiomyopathy, we should also consider other conditions that can present in a similar way or which can be associated with an HCM-like image. Similar symptoms can be seen in dilated cardiomyopathy, congenital heart defects, arrhythmias, and genetic disorders [18, 19].
Fetal echocardiography is especially important because HCM can lead to heart failure. During the gestation, in addition to the thickening of the walls, left ventricular outflow tract (LVOT) or right ventricular outflow tract (RVOT) obstruction [20] can occur, resulting in fetal hydrops and heart failure. Hence, the probability of a stillbirth is higher, and the delivery should take place in a tertiary centre in the presence of a neonatologist and a paediatric cardiologist.
To further assess fetal heart, different techniques should be used, such as tissue Doppler imaging (TDI) [21] and speckle tracking [22-24]. Their main positive being the early detection of cardiac abnormalities and dysfunction.
Additionally, HCM in rare cases can be related to congenital heart defects (CHD). In our centre there was a case of a fetus with prenatally diagnosed dextro-transposition of the great arteries (d-TGA), which also manifested with HCM.

Differential diagnosis of HCM and maternal diabetes

Diabetes is a common illness that concerns about 3-10% of pregnant women [25]. It is mostly related to increased insulin resistance, and it can be classified as diabetes de novo, or as pregestational or gestational diabetes type 1 or 2. Nowadays it is almost always detected, and the glucose levels can be controlled during the pregnancy by implementing a diabetic diet or by insulin injections, resulting in a decreased number of complications. Moreover, there are certain risk factors that increase the probability of developing diabetes during the pregnancy, mainly increased BMI, familial history of diabetes, maternal age over 30 years at conception, polycystic ovary syndrome, previous pregnancy resulting in macrosomic newborn (> 4000 g), etc. Additionally, pregestational diabetes itself can lead to adverse neonatal outcomes, such as low 5-min Apgar score, neonatal hyperbilirubinemia, neonatal hypoglycaemia, neonatal intensive care unit (NICU) admission, shoulder dystocia, birth trauma, or even stillbirth [26].
Moreover, maternal diabetes can elicit fetal macrosomia [27]. Those fetuses are prone to not only having myocardial hypertrophy, usually seen as increased thickness of the septum, but they are also more likely to develop other, often multiple, functional abnormalities seen in the third trimester of pregnancy [28], one of them being ductal constriction, which can impact neonates’ condition as respiratory problems in the adaptation period or as neonatal hyperbilirubinaemia, which requires phototherapy treatment [29]. Maternal diabetes can affect the fetus twofold, by changing fetal-placental circulation and by affecting the fetal heart. There are many factors that decide upon the severity of changes, mainly the type of DM and level of glucose and HbA1c in early pregnancy and the degree and duration of hyperglycaemia and hyperketonaemia [30]. Gestational diabetes is directly linked with fetal macrosomia, which is a result of fetal hyperinsulinaemia. Additionally, the mass of the heart increases, because of increased cell number and increased deposition of fat and glycogen synthesis in myocardial cells, resulting in thickening of the ventricular wall. Secondary to that, myocardial hypertrophy can lead to compromised fetal ventricular compliance and diastolic function [31-34]. Zielinsky et al. [35] also described lower shortening fracture of left atrium (LASF) in diabetic pregnancies with inverse linear correlation between interventricular septum thickness (IVST) measurement and LASF, suggesting that LASF could be an additional parameter used in assessing diastolic function, which was proven to be impaired in diabetic pregnancies, regardless of myocardial hypertrophy. Other studies also concluded that diabetic pregnancies are prone to experiencing diastolic dysfunction in fetal heart, even without the myocardial hypertrophy [36]. Another functional parameter that changes in maternal diabetes is tricuspid E/A index with lower values in diabetic pregnancies [37, 38]. Nevertheless, in most cases the myocardial hypertrophy in fetuses of diabetic mothers is a mild condition, limited to increased septal and/or wall thickness, which occurs in 40% of fetuses of diabetic mothers and is more common in PGDM than in GDM. Most commonly, it has a reversible nature, as the maternal hyperglycaemia resolves itself after birth, the need for the insulin production no longer exists, and the myocardial hypertrophy resolves after about 6 months [39].
However, in some cases it can have adverse consequence because hypertrophic septum can lead to transient subaortic stenosis, ergo to congestive heart failure (CHF) [40]. In diabetes, the septum is usually asymmetric, and it is diagnosed in the third trimester, correlating with fetal hyperinsulinaemia, which is a result of maternal hyperglycaemia [41].

Further management

If we suspect HCM, we should always be cautious. Monitoring of the fetus is advised, with regular fetal ultrasound and fetal echocardiography to establish fetal well-being. Additionally, we can look for the aetiology of the HCM with genetic testing of amniotic fluid to determine whether the cardiomyopathy is linked to disorders such as d-TGA, fetal anaemia [42], genetic aberrations (e.g. trisomy 13), or metabolic disorders, including Noonan and Beckwith-Wiedemann syndrome. Furthermore, we should assess the mother’s health to exclude maternal causes: pregestational, gestational diabetes, or autoimmune disorders.
The delivery should be planned in a tertiary centre with a neonatologist and paediatric cardiologist present. Paediatric echocardiography should be done in the newborn, and function of the heart should be assessed. After birth, in the case of hypertrophy caused by maternal diabetes, it can resolve on its own with no further complications and implications for the postnatal life, usually in about 6-24 months [40]. Nevertheless, in the case of familial HCM and other genetic disorders, it should be strictly monitored by a paediatric cardiologist to prevent development of heart failure.
The differentiation of diabetes-induces hypertrophy and structural hypertrophic cardiomyopathy is important in fetal diagnosis because further management differs between them. Prenatal diagnosis of HCM can have a positive impact on a child’s life in the future, as nowadays targeted treatment, e.g. Mawakamten, is available, but so far only after 12 years of age [43]. This policy is, however, related to our subject. Prenatal diagnosis of myocardial hypertrophy unrelated to maternal diabetes may speed the postnatal diagnosis and treatment, and probably in the future will lead to earlier care and better outcome.

Conclusions

Fetal echocardiography is a gold standard in the detection of the hypertrophic cardiomyopathy. Certain anomalies can be observed during the examination that can lead to the diagnosis, such as increased IVST measurement or impaired systolic and/or diastolic function. Maternal diabetes is an important risk factor of myocardial hypertrophy development. Fetal MRI can also be a supporting tool in diagnosing the HCM prenatally. Early detection and early treatment in the future may change the natural course of this cardiac anomaly.

Disclosures

Ethical considerations: none.
This research received no external funding.
The authors declare no conflict of interest.

References