Investigation of cardiac remodeling and cardiac function on fetuses conceived via artificial reproductive technologies: a review

Introduction

It is a well-established fact that the use of artificial reproductive technologies (ART), including intra-uterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI), has met an enormous worldwide expansion, as infertility rates are raising globally. According to WHO (World Health Organization), infertility affects one out of six couples [1]. Infertility rates globally have been calculated to be 17.5 % in 2023, while previous studies estimated that infertility affected 8–12 % of the whole earth’s population [2]. WHO also stated that affordable and high-quality fertility care has to be provided in couples desire childbearing [1]. As a result, more than nine million babies have been born through ART, as the safety, popularity and accessibility of these technologies are following a skyward trend [3].

There is no doubt that ART have helped millions of infertile couples to create their family. Although the use of ART is considered safe for both the mother and her child, there are some concerns regarding prenatal, perinatal, postnatal and also long-term risks for the children or adults conceived via ART. Preterm birth, low birth weight and congenital malformations are some of the perinatal risks that have been associated with ART [4]. Recent data from the worldwide literature provided evidence that ART fetuses present also cardiac remodeling and sub-clinical dysfunction in utero, resulting in alterations in vasculature which persist postnatally and until adolescence. Therefore, ART individuals might be in an increased risk for cardiovascular disease (CVD) in adulthood [5].

This review presents an overview of the expanding knowledge about the main patterns leading to cardiac remodeling in ART fetuses, the data from the current literature occupied with this hot topic are summarized and finally, some of the strategies that have the potential to prevent CVD in postnatal life are also suggested.

Pathophysiology of cardiac remodeling of ART fetuses

Heart has an essential role in embryonic and fetal life and our knowledge about its contribution in fetal life is now starting to expand. Heart is the first organ which develops and its role is crucial for blood, nutrients and oxygen supply to the developing fetus. Heart is also a kinetic organ which has the potential to alter its structure, size and form, according to a sub-optimal environment or disease, in order to maintain an efficient function, ensuring an optimal supply to the fetal organs [6].

Therefore, intrauterine environment during fetal life plays the most significant role for the optimal cardiac structure and function [6]. Factors which have to be ideal in order to have an excellent cardiac function are; myocyte contractility, fiber orientation, tissue elasticity, pressure and volume load, electrical activation and myocardial perfusion. Additionally, as fetal cardiac remodeling happens during early development, cardiac shape and micro-structure are still prone to changes [6].

Another interesting fact is that fetal cardiac remodeling is more evident in the right heart, reflecting its dominance during fetal life, as the right heart has the responsibility to supply the fetal organs and the placenta with blood, nutrients and oxygen. Also, a higher sensibility of the right fetal heart to loading conditions is another factor that causes the right heart to be more prone to cardiac remodeling. Most of the changes that the fetal heart undergoes in order to maintain an optimal function, are leading to sub-clinical cardiac dysfunction. Nevertheless, under persistent circumstances, cardiac remodeling might result to clinical cardiac failure, which in utero is presented as fetal hydrops [6].

What current literature has proven so far

Studying fetal heart is a challenging task. Conventional ECG (electrocardiogram) and CT (computerized tomography) have no role in intrauterine life. Regarding MRI, it is also difficult to provide conclusive results due to the small size of fetal heart and the increased fetal heart rate. Consequently, for the assessment of cardiac remodeling in utero, fetal echocardiography presents the most attractive characteristics; it has high reproducibility and it is highly feasible for measuring cardiac dimensions, structure and shape [6].

Nevertheless, fetal cardiac function is even a more demanding and complex procedure. Myocardial shortening, longitudinal, radial and circumferential contraction have to be evaluated for cardiac function. A recently introduced technique which really succors cardiac function evaluation is speckle-tracking echocardiography (STE). With this technique, myocardial mechanism is directly analyzed by tracking tissue pixels in the myocardium throughout the cardiac cycle [4]. Another parameter which is frequently evaluated for fetal cardiac remodeling and mainly ventricular diastolic and systolic function in utero is the Myocardial Performance Index (MPI). MPI is measured with Doppler assessment and it is the result of the lowing equation: MPI=(IVCT + IVRT)/ET (IVCT, isovolumetric contraction time: ET, ejection time) [14]. An overview of the studies that have been occupied with cardiac remodeling on ART fetuses is presented in Table 1.

One of the pioneers investigating cardiac remodeling in ART fetuses is Valenzuela- Alcaraz and her associates [8]. These authors, on their very first study occupied with this subject, published in 2013, investigated cardiac remodeling in ART fetuses. They evaluated cardiac shape and function in 100 ART and 100 spontaneously conceived fetuses. Their data proved that ART fetuses have dilated atria, increased myocardial wall thickness and lower ventricular sphericity indexes. Regarding cardiac function, ART fetuses presented statistically significantly decreased right longitudinal function and impaired isovolumic relaxation time (decrease in tricuspid E′ and E deceleration time). Additionally, left ejection fraction and ring displacement was also statistically significant decreased in ART fetuses compared to the controls. Expectantly, these changes were more prominent in the right side of the heart [8].

Boutet et al., gave an insight whether infertility per se or IVF procedure is the main cause of fetal cardiac remodeling [15]. They evaluated cardiac remodeling in 96 IVF fetuses, 97 spontaneously conceived fetuses whose parents were assumed as infertile (trying to conceived for more than 12 months) and 96 spontaneously conceived fetuses from fertile parents. IVF fetuses presented a similar cardiac phenotype presented by Valenzuela- Alcaraz et al. [8]; dilated atria, more globular right ventricles and thicker myocardial walls. Cardio-thoracic ration was also increased in IVF fetuses compared to controls. Cardiac function was also sub-optimal in IVF fetuses, as fetal heart rate was elevated, tricuspid ring displacement was reduced, accompanied by an increased left myocardial performance index (MPI). The authors concluded that infertility per se is not responsible for cardiac remodeling in utero [15].

A recent trial from Bi et al. [16], also endorsed the findings above. The authors investigated cardiac remodeling in 88 ART and 85 SC fetuses. ART fetuses had larger atria and more globular ventricles, following the same pattern as in the previous studies. In this trial, cardiac function of ART fetuses was extensively evaluated through the STE technology. Expectantly, ART fetuses presented sub-clinical cardiac dysfunction with reduced global longitudinal strain of the left ventricle indicating sub-optimal left systolic function. Tricuspid ring displacement was also lower in ART fetuses.

Persistence of cardiac remodeling in postnatal life

Evidence based on follow-up studies on IVF individuals during adult life, agree that cardiovascular remodeling and sub-clinical dysfunction is evident in this population. As cardiac remodeling takes place in a critical stage of development, some of the alteration on cardiac shape, structure and function have the potential to persist postnatally, making ART adults more prone to CVD in adulthood [6]. Increased arterial blood pressure, increased intima-media thickness, abnormal myocardial and vascular endothelial function due to altered lipid metabolism are also found in IVF adults [8], 13], [21], [22], [23]. Studies among late children and adolescents conceived by ART showed also dysfunctional changes in systemic and pulmonary circulation and premature sub-clinical atherosclerosis [24].

Ceelen et al., in 2008, were the first who provided evidence proving that ART children have elevated blood pressure [25]. Meister et al. [26], also investigated blood pressure in 54 apparently healthy and without any risk factor for CVD adolescences and young adults, born via ART. 46 matched controls were also included to the study. The authors concluded that ART group showed premature vascular aging and higher blood pressure compared to the controls [26]. This finding was also proved in an important meta-analysis run by Guo et al. in 2017 investigating the blood pressure of 2,112 children conceived by ART. The authors came to the conclusion that there was a small, though statistically significant increase on blood pressure measurements in ART children compared to their counterparts [27].

Valenzuela-Alcaraz and her group, also followed up the ART fetuses within their first month of life and also at 6 months. Their results concerning infants and neonates were also very interesting. The authors noted that at the first follow-up visit (1 month old), ART neonates presented significantly higher diastolic blood pressure compared to spontaneously conceived fetuses. Systolic blood pressure did not show any statistically significant difference. Moreover, aortic and carotid intima-media thickness (IMT) were increased in ART neonates. During the second follow-up visit, within the sixth month of life, blood pressure and aortic IMT remained statistically significantly elevated in ART infants compared to controls. Additionally, ART infants had increased right atrial size, lower right sphericity index and thicker right ventricular wall. Cardiac output was preserved in ART infants. However, ART infants showed a significantly decreased shortening fraction and increased heart rate. Regarding cardiac function, ART fetuses also showed signs of both systolic and diastolic dysfunction as measured by significant decreases in ring displacement, E deceleration time and tissue Doppler velocities. Finally, isovolumic relaxation time was significantly elevated when compared to controls. Interestingly, even postnatally, cardiac remodeling was more pronounced in the right heart [8].

On the other hand, Mizrak et al., provided data from their study, held in 2022, which disagree with the studies above. The authors investigated arterial stiffness and blood pressure in 100 ART children and compared them with 50 NC (naturally conceived) children, using magnetic resonance imaging (MRI). All children in both groups were 8–9 years old. Their results are quite interesting; there was not any significant difference between ART and NC children in terms of blood pressure, left ventricular ejection fraction, cardiac output and aorta distensibility [28]. One other study which is in line with Mizrak’s et al. trial, is this of Bi et al. [16]. In this study, 88 ART infants and 86 matched controls were followed up within the first two months of their life and they found only a slightly thinner relative wall thickness of the right ventricle and a higher tricuspid E/A ratio on ART infants. Importantly, these differences were not evident during the second follow-up, at 6 months. The authors assumed these findings as clinically insignificant [16].

Preventing measures to improve cardiovascular health in ART children and adults

Although there is definitive data from the literature proving clearly that ART provoke cardiovascular reprogramming, causing an advanced risk for CVD later in life, the role of other risk factors appearing later in life and their collaboration with the altered subclinical cardiovascular dysfunction resulting to CVD in adulthood is yet to be understood. The “second hit hypothesis” is well-established in biology of human oncology, indicating that a genetic or subclinical predisposition demands a second attack in order to be expressed into clinical disease. Concerning ART and CVD, the subclinical cardiovascular dysfunction requires environmental factors to result to clinical CVD. This “second hit” could be anything able to add an extra work to the subclinical affected myocardium, such as hypertension, dyslipidemia or arrhythmias [14].

Therefore, it is equitable to consider that in some degree, the subclinical dysfunction of the cardiovascular system of individuals conceived via ART could be reversed, ameliorate or undergone further contravention depending on life-style habits adopted in later life. Nevertheless, it is important to mention that alteration in everyday habits have the prospective to prevent CVD if they are adopted very early in life, giving the “window of opportunity”, where crucial interventions must be done in order to improve cardiovascular health [14].

Early identification of the children, adolescences and young adults in risk for CVD, and following preventing measures have major impact on their holistic health. Importantly, as the number of children born via ART is emerging, early interventions in this population carries also great benefits for public health [5]. Some measures that have the potential to decrease the cardiovascular risk in ART adults is breastfeeding, and maintaining a healthy diet with caution to conserve a healthy weight is crucial. More specifically, consumption of a diet rich in polyunsaturated fats, the use of omega-3 fatty acids, eicosapentaenoic and α-linolenic acids provide significant benefits in vascular and hemodynamic health of children and adolescences. Additionally, avoidance of smoking and frequent physical exercise are equally significant for CVD prevention [14].

Conclusions

There is no doubt that ART is a great medical achievement and has helped millions of couples to create their family. Nevertheless, ART is redefining biology and society and from a clinical point of view it is important to understand the potential impact and long-term health of the infants conceived via ART. In this review, the most recent data regarding cardiac remodeling and sub-clinical cardiac dysfunction in ART fetuses and infants have been presented. As ART adults are in greater risk for developing CVD, the identification of these fetuses which are at high risk for impaired cardiovascular health is vital, in order to offer them preventing measurements aiming to optimize their overall health.