Cardiovascular Biomarkers Associated With Cardiac Abnormalities in Patients With Turner Syndrome

Logan Symson₁ and Nella Delva₂

Affiliation

1.      Walnut Hills High School, 3250 Victory Pkwy, Cincinnati, OH 45207, logan.symson@gmail.com

2.      College of medicine, Florida State University 1115 W Call Street, FL 32304,

nella.delva@med.fsu.edu

Turner Syndrome is a genetic condition in females where one of the X chromosomes (sex chromosomes) is missing or partially missing, consequently resulting in a variety of medical and developmental problems. Among these difficulties are short stature, ovarian failure/infertility, and cardiovascular abnormalities. Current research has found significant correlations between both aortic dissection and arterial stiffness and certain molecular biomarkers in young patients with TS. This review article will discuss specific biomarkers associated with cardiac abnormalities in TS, as well as the possible clinical applications of this new information about biomarkers. The following methods open a path to allow early insight into cardiovascular malformations in TS patients using better and more improved techniques other than cardiac imaging. In this review article, various cardiovascular biomarkers including osteoprotegerin, B-type natriuretic peptides, and N-terminal natriuretic peptides, have been found associated with cardiac anomalies in Turner Syndrome (TS) in youths will be discussed.  These genes are important due to the current need for a more effective application of biomarkers for cardiac observation and diagnosis. Recent findings regarding vascular biomarkers and cardiac malformations will be discussed including their respective clinical applications for treatment and diagnosis.

Keywords: Turner Syndrome, biomarkers, cardiac abnormalities, osteoprotegerin, natriuretic peptides

Introduction

Turner Syndrome (TS) is a sex-linked chromosomal disorder, currently affecting about 1 in 2,500 (live) female births [1]. The condition is caused by partial or complete monosomy, which is when one chromosome is found in a cell that is meant to be diploid (containing two sets of chromosomes), of the X chromosome. This monosomy generally occurs due to spontaneous and/or random nondisjunction occurring either during mitosis or meiosis. TS  affects only females, due to males having just one X chromosome. Human embryo development requires at least one X chromosome to become viable, so male embryos with simply a Y chromosome cannot exist. Common effects of TS in 1 female affected by the syndrome are short stature, delayed/insufficient growth and development, ovarian and reproductive failure, and an increased risk of fatal cardiovascular complications [2].

Cardiac Abnormalities of Turner Syndrome

Studies have found many dangerous cardiac anomalies in patients with TS. Unfortunately, 95% of girls with TS that develop aortic dissection (AoD) also have bicuspid aortic valves (BAV), demonstrating that vascular changes can occur prior to the structural changes themselves [2]. Recent studies have also determined that there is a significant correlation between TS and various other aortic abnormalities and partial anomalous pulmonary venous return (PAPVR) [1]. Many of these cardiac malformations, such as the elongation of the transverse aortic arch and coarctation of the aorta (CoA), bicuspid aortic valve (BAV), and aortic sinus dilation could later provide an increased risk of aortic dissection, which is often deadly. Due to the commonality of cardiac anomalies in girls with TS, regular imaging is strongly advised in order to ensure early diagnosis of cardiac malformations leading to early treatment and access to more effective therapy for patients. Cardiac imaging becomes necessary to determine a TS patient’s cardiovascular health and early detection, both crucial in TS patients. For instance, Echocardiography is a type of cardiac imaging used to capture images of these potentially lethal cardiac structures, however, the quality and effectiveness of these images generally tend to decrease as patients get older. Another example is magnetic resonance imaging (MRI). However, the downside is that MRI methods are often very expensive, making them inaccessible to a large population of patients with TS [1]. For those reasons, researchers are looking into the use of vascular biomarkers and their relationships with the probability of cardiac malformations. Biomarker correlations could provide a much more accessible and easily performed cardiac assessment than many imaging processes.

Vascular Biomarkers Associated with Turner Syndrome

Three main biomarkers have been recently researched as potential candidates for cardiac assessing in TS patients: osteoprotegerin (OPG), B-type natriuretic peptides (BNP), and N-terminal natriuretic peptides (nt-BNP). All of these biomarkers are soluble vascular biomarkers (SVBs) and are currently being studied as possible cardiovascular assessment methods [2]. OPG is a glycoprotein, part of the tumor necrosis factor (TNF) receptor superfamily, and is employed in the body as a false receptor, thus blocking various biological interactions [3]. OPG has demonstrated an ability to foresee the fatality of coronary artery disease in adults, OPG levels are raised in various cardiac conditions, including general heart failure. In pediatric patients, OPG levels are elevated when the patients have three or more cardiovascular conditions [2]. BNP and nt-BNP are both neurohormones, and show correlation with certain cardiac abnormalities. BNP levels in adults are elevated in the presence of certain cardiovascular conditions, such as hypertension and coronary artery disease. Both BNP and nt-BNP levels have demonstrated a relationship with the seriousness of aortic stenosis (narrowed aortic valve), have predicted when a valve replacement is necessary due to aortic stenosis, and can predict the fatal risk of aortic stenosis [2].

Correlation Between the Biomarkers and Cardiovascular Implications in TS Patients

Research, demonstrated in Table 1, has proved that there are correlations between higher levels of nt-BNP and BNP and cardiovascular anomalies/risks in TS patients, in both pediatric and adult patients, as compared to control populations, which are composed of participants who do not have TS. Furthermore, TS patients tended to have lower levels of OPG than the control group did.

Citation	Biomarker Observed	Population	Main Findings
Gravholt study [4]	nt-BNP	TS patients (9) Control group (8) Mean age: 29.7 ± 5.6 years	nt-BNP levels were considerably higher in the TS group as compared to the control group.
Gutin study [5]	nt-BNP	TS patients (114) Control group (27) Aged 18-67 Mean age: 37.4 ± 12 years	There was a significant correlation between high levels of nt-BNP and descending aortic diameter (DAD) in TS patients. In addition, TS patients with DAD had much higher levels of nt-BNP than those without.
Uçar study [6]	BNP	TS patients (61) Control group (61) Aged 6.6-21.3 Mean age: 12.6 years	TS patients had much higher BNP levels than the control participants did, and higher levels of BNP were correlated with arterial stiffness.
Buzi study [7]	OPG	Control group (46) Aged 1-14 Mean age: 7.8 TS patients (10) Mean age: 10.8 (No TS patients were on estrogen replacement, but were on human GH therapy)	OPG levels begin high in infancy and decrease with age, and OPG levels in TS patients were lower than in the controls.
Trolle study [8]	OPG	Controls (68) TS patients (99) Age matched	OPG levels were much lower in the TS patients, and OPG levels held a significant relationship to a descending aortic diameter.

Table 1: various studies conducted to determine biomarker correlation with cardiovascular implications in TS patients as compared to a non-TS control group. All data obtained from source 2. 

Cardiac Biomarkers associated with Cardiac Abnormalities in TS patients

Previous studies have shown that there are correlations between OPG, nt-BNP, and BNP and various cardiovascular implications of Turner Syndrome. It has been found that OPG levels have a positive relationship (OPG levels are raised when there is underlying aortic dilation) with aortic dilation in adults with TS, demonstrating that OPG can possibly be used to detect aortic dilation in adult TS patients [7]. Both BNP and nt-BNP levels have been found to be raised in TS patients overall, but especially in those with nocturnal hypertension, when blood pressure increases during the sleep stages [4]. Along with nocturnal hypertension, BNP levels, observed in young TS patients, were raised in TS patients with arterial stiffness [6]. Therefore, it can be concluded that BNP levels can be assessed in both young and mature TS patients in order to expose signs of underlying cardiovascular disease.

Future Clinical Applications

As discussed, there are various biomarkers associated with TS cardiac abnormalities which represent a plethora of opportunities for clinical application. This is particularly important for providing a more accessible method of cardiac observation for TS patients and more effective inventions. While the average echocardiogram costs about $1000-$3000 without insurance [10], biomarker testing in similar scenarios costs about $477, therefore making it more accessible [11]. While there is still much to be discovered in the field of vascular biomarkers to have a strong understanding of TS and its respective clinical correlation to TS cardiac abnormalities, current studies are quite promising in addressing the matter of accessibility when using genetic markers as a potential diagnostic tool.

References

[1] Kim, Hee Kyung et al. “Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population.” AJR. American journal of roentgenology vol. 196,2 (2011): 454-60. doi:10.2214/AJR.10.4973

[2] Mavinkurve, Meenal, and Clodagh S O'Gorman. “Can Brain Natriuretic Peptides and Osteoprotegerin Serve As Biochemical Markers for the Detection of Aortic Pathology in Children and Adolescents with Turner Syndrome?.” Frontiers in endocrinology vol. 8 142. 4 Jul. 2017, doi:10.3389/fendo.2017.00142

[3]Buzi, F et al. “Serum osteoprotegerin and receptor activator of nuclear factors kB (RANKL) concentrations in normal children and in children with pubertal precocity, Turner's syndrome and rheumatoid arthritis.” Clinical endocrinology vol. 60,1 (2004): 87-91. doi:10.1111/j.1365-2265.2004.01951.x 

[4] Gravholt, Claus Højbjerg et al. "Nocturnal hypertension and impaired sympathovagal tone in Turner syndrome". J Hypertens. 2006, 24. 353-360.

[5] Gutin, Liat S et al. “N-terminal pro-brain natriuretic peptide levels and aortic diameters.” American heart journal vol. 164,3 (2012): 419-24. doi:10.1016/j.ahj.2012.06.021

[6]Uçar, Ahmet et al. “Increased arterial stiffness in young normotensive patients with Turner syndrome: associations with vascular biomarkers.” Clinical endocrinology vol. 82,5 (2015): 719-27. doi:10.1111/cen.12626

[7]Buzi, F et al. “Serum osteoprotegerin and receptor activator of nuclear factors kB (RANKL) concentrations in normal children and in children with pubertal precocity, Turner's syndrome and rheumatoid arthritis.” Clinical endocrinology vol. 60,1 (2004): 87-91. doi:10.1111/j.1365-2265.2004.01951.x

[8] Fradley, Michael G et al. “Reference limits for N-terminal-pro-B-type natriuretic peptide in healthy individuals (from the Framingham Heart Study).” The American journal of cardiology vol. 108,9 (2011): 1341-5. doi:10.1016/j.amjcard.2011.06.057

[9]James D. Wilkinson, Melissa Diamond, Tracie L. Miller, The promise of cardiovascular biomarkers in assessing children with cardiac disease and in predicting cardiovascular events in adults,Progress in Pediatric Cardiology,Volume 32, Issue 1, 2011, Pages 25-34, ISSN 1058-9813, https://doi.org/10.1016/j.ppedcard.2011.06.006 (https://www.sciencedirect.com/science/article/pii/S1058981311000397)

[10 Weatherspoon, Deborah, and Mary Sweeney. “Will Medicare Pay for an Echocardiogram?” Healthline, 7 August 2020, https://www.healthline.com/health/medicare/does-medicare-pay-for-echocardiogram. Accessed 21 May 2023.

[11]Hess, Lisa M et al. “Costs of biomarker testing among patients with metastatic lung or thyroid cancer in the USA: a real-world commercial claims database study.” Journal of medical economics vol. 26,1 (2023): 43-50. doi:10.1080/13696998.2022.2154479