Heterogeneous Mutations Lead to Hypoplastic Left Heart Syndrome and can be Treated With Human Umbilical Cord Blood Mononuclear Cells

Ayeir Karnwie-Tuah, Jacob Fettig, Samuel MillerDepartment of Biology and Biochemistry

University of Northwestern--St. Paul, St. Paul, MN

Figure 3

Table 1

We suggest that further study should focus on intramyocardial injection of stem cells derived from mononuclear cells of the human umbilical cord. This treatment has been shown to be a safe and effective treatment of abnormal development of cardiac myocytes in the right ventricle on mammalian subjects (Oommen et al, 2015). Figure 3 shows this procedure maintains normal body weight, temperature, heart rate and QRS readings following the operation. Treatment should include gene therapy of the DNA topoisomerase II gene to reduce or eliminate the chance of tumor cells growing on the heart after treatment (Wyles et al, 2014).

This model works through altering the expression of several genes related to blood volume, myocyte development and heart function allowing them to work correctly. This treatment could return normal right ventricular function and a reversal of many of the genetic mutations that have arisen from the syndrome itself (Oomen et al, 2015).

Significance

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References

Hypoplastic Left heart syndrome is a congenital heart defect that causes the left side of the heart to be underdeveloped. The current cause of this condition is unknown and treatments include heart transplants or surgery. We hypothesize that this condition is due to many mutations in cardiac myocyte development and growth. Rationale for this would be its effect on the miRNA expression of the cell, specific genes which seem to be mutated and mutated beta-androgenic regulation of the right ventricle. We believe that the best way to combat HLHS is through an intramyocardial injection of mononuclear human umbilical cord stem cells. This stem cell treatment method has shown to be successful in the right ventricle of non-human test subjects by altering many of the genes related to myocyte development and heart function. Along with this, we suggest gene therapy on the DNA topoisomerase II gene to reduce the chances of tumors arising. This method has been shown to be effective and safe in numerous tests on murine rats and pigs.

Abstract

We hypothesize that heterogeneous mutations affecting cardiac myocyte development and growth lead to Hypoplastic Left Heart Syndrome (Jiang et. al., 2014). We also hypothesize that an intramyocardial injection of mononuclear stem cells derived from human umbilical cord blood will be a safe and effective alternative treatment.

Hypothesis

According to studies performed by Elliot et al. (2003) there are many genes that relate to heart function (Table 1). Alterations in one or more of these genes have been shown to cause a variety of different malfunction in myocyte development and differentiation which causes underdevelopment of the ventricles and atria of one or both sides of the heart (Oommen et al 2015). Selected gene expression and β-AR regulation and signaling in the systemic RV of children with HLHS differs from the normal, NF, pediatric RV and undergoes unique changes in the setting of failed surgical palliation. These genes have been shown to affect the androgenic signal pathways of the cell which in turn cause the heart to incorrectly respond to epinephrine and norepinephrine and have been shown to cause heart failure upon repeated activation of this pathway (Miyamoto, 2014).

Stem cell injections have been successful when tested with respect to the right ventricle of murine rats and pigs (Cantero, 2015). The reason for this success is it is capable of reversing many of the changes in the genome through the use of stem cells. This allows many of the affected pathways to return to normal function and structure (Oomen et al, 2015).

Rationale

Figure 1&2

Figure 1: Pictured on the left is a normal human heart with all corresponding blood vessels and on the right is a heart affected by HLHS. (Hardiman, 2011)

Hypoplastic Left Heart Syndrome (HLHS) is a rare congenital heart defect that results in underdevelopment of the left side of the heart (figure 1). This results in an inability of the infant to pump blood from the heart to the rest of the body efficiently.

The cause is currently unclear, however there is a correlation between families having more than one child affected by the disease, suggesting a genetic link (Oomman, 2015). See Table 1.

Current treatments for HLHS include surgical palliation to allow the right ventricle to provide systemic circulation, or heart transplant.

Unfortunately, these procedures are very high risk and offer the patient little chance of recovery (Figure 2, Jenkins et. al, 2000). Typical 1-, 5- and 10-year survival is 75%, 70% and 65%, respectively (Winlaw, 2012). Operative mortality of stage I palliation is between 10%-20%, ventricular failure at 16 years after surgical palliation is around 40%, and 20% of infants listed for a heart transplant die while waiting (Hardiman, 2013). These outcomes reveal a need to explore non-surgical treatments.

Background

Table 1: Combined results of array comparative genomic hybridization and sequencing analysis (Iascone et al 2011)

Figure 3: Data taken to show the safety over a period of 20 days for injecting Murine rats with .2, .4 and .8 million mononuclear stem cells derived from the blood of human umbilical cord blood. (A) Records body weight gain for post injection time. (B) Records body temperature post injection. (C) Records heart rate post injection. (D) Records the QRS readings of the control versus individuals having an injection of .8 million cells.(Oommen et al 2015)

Because the current treatment options for Hypoplastic Left Heart Syndrome are so high risk, non surgical options need to be explored. Using hUCB mononuclear cells to remodel the heart in vivo would be far less invasive than surgical palliation and requires far less wait time than a transplant. This alternative has been safely tested on animal models and therefore should be considered as options to replace the current dangerous surgical methods (Oommen et al, 2015). Additionally, hUCB cells are readily available and present a minimal ethical dilemma.

Innovation

Figure 2: Survival curves for transplantation and staged surgery. (Jenkins et. al, 2000)

Figure 1

Figure 2