How a “heart becomes a heart”: elucidating the genetic foundations of congenital heart disease
Scientists identify a finely tuned mechanism by which fetal heart muscle develops into a healthy, fully formed beating heart, providing an insight into the genetic causes of congenital heart disease.
Benoit Bruneau and researchers from The University of California (CA, USA) have identified two genes, Ezh2 and Six1, which play an important role in embryonic heart development, but appear to have different but interacting roles in utero and provide an indication of how the genetic basis of embryonic heart formation can have profound health consequences in later life. The new research highlights the importance of the effects of epigenetics in heart development, as the incorrect activation of genes in fetal development can lead to congenital heart disease (CHD), which will ultimately have consequences well into adulthood.
Bruneau explained that, “Approximately 1.3 million children and adults in the USA live with CHD, requiring daily medications, surgeries and, for some, heart transplants. An understanding of the epigenetic regulation of heart development could someday bring us closer to improving the lives of these individuals.”
Researchers removed the Ezh2 gene from the embryos of mice and monitored their heart development. Despite normal development in utero, heart problems began to develop after birth. This was linked to the inability of the removed Ezh2 gene to “shut down” the activity of Six1, which led to overgrowth of the heart muscle, a symptom associated with heart failure later in life. These results indicated the importance of studying the long-term effects of developmental epigenetics in CHD.
Six1 has previously been shown to play an important role in vertebrate development, while Ezh2 is involved with shutting off genes during transcription. Without the regulatory behavior of Ezh2, Six1 does not shut down during heart development, which may lead to problems such as overgrowth of tissue. Repression of cardiac cell development by Ezh2 appears to be necessary for postnatal cardiac homeostasis. Dilated cardiomyopathy is a type of CHD that has previously been linked to mutations in the gene Eya4, which is also regulated by Ezh2. An understanding of how Ezh2 regulates genes would catalyze further research into CHD treatments. Explaining further to Future Cardiology, Bruneau commented, “This finding is particularly exciting, as it clearly shows that events very early in development have an impact on postnatal physiology. We are currently expanding our scope to decipher the entire epigenetic blueprint of heart development, in order to better understand this important regulatory mechanism.”
The group comments that Six1 is one of many Ezh2-regulated genes that play a vital role in heart development. The next stage is determine exactly how Ezh2 regulates other genes, in order to begin to develop a complete genomic blueprint of how a “heart becomes a heart”.
Source: Delgado-Olguín P, Huang Y, Li X et al. Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat. Genet. doi:10.1038/ng.1068 (2012) (Epub ahead of print).
New plans for critical congenital heart disease screening in newborns
The US Secretary of Health and Human Services recently endorsed pulse oximetry tests, recommending the screening of newborns for critical congenital heart disease (CHD). The test measures oxygenation of hemoglobin in an easy, noninvasive manner and the results can indicate symptoms of critical CHD, which has led the American Academy of Pediatrics to publish a new policy statement describing strategies for carrying out the procedure, which addresses critical issues such as necessary equipment, personnel and training, and also provides specific recommendations for the assessment of saturation by using pulse oximetry, as well as appropriate management of a positive screening result.
According to the American Academy of Pediatrics, clinicians rely on prenatal ultrasound and physical examination of newborns to identify critical CHD and unfortunately, these approaches “fail to identify a significant number of cases of critical CHD, which may lead to late diagnosis with significant morbidity, permanent injury of vital organs and in some cases, death,” write members of the Section on Cardiology and Cardiac Surgery Executive Committee in the new report.
Plans have addressed each stage of the screening routine from training and equipment to management of screening results. The American Academy of Pediatrics is working with government agencies, clinicians and supporters to promote the screening plan and manage critical CHD checks in newborns.
Future plans for the screening policy will include working alongside state health departments to ensure that all stages of the procedure are up to standard. A main strategy is to ensure that newborns with positive critical CHD results are provided with enough resources for further testing, including pediatric cardiac evaluation.
Source: Mahle WT, Martin GR, Beekman RH et al. Endorsement of Health and Human Services recommendation for pulse oximetry screening for critical congenital heart disease. Section on Cardiology and Cardiac Surgery Executive Committee. Pediatrics 129(1), 190–192 (2012).
Determining the optimal relationship between oxygen saturation and hemoglobin concentrations in adults with cyanotic congenital heart disease
Research by Craig Broberg and his team at Oregon Health and Sciences University (OR, USA) has demonstrated a strong linear correlation between optimal hemoglobin levels and oxygen saturation in adults with cyanotic congenital heart disease (CHD). This correlation may be a useful tool for defining anemia in patients with cyanotic CHD and assessing physiologic compensation with different oxygen levels.
The researchers used a cross-sectional study to analyze blood test and exercise results from patients with different hemoglobin levels. Patients with evidence of inadequate erythropoiesis, such as iron and vitamin B12 deficiencies were excluded from optimal data sets. Out of 65 participants with cyanotic CHD, only 21 met the criteria for optimal hemoglobin levels. This rigorous exclusion resulted in a more linear relationship between oxygen saturation and hemoglobin concentration than previous studies and when compared with data from all 65 patients data combined. These results may translate to a way of predicting ideal hemoglobin levels for any given oxygen saturation in cyanotic CHD patients, particularly those with balanced erythropoiesis.
In a commentary for the International Society for Adult Cogenital Heart Disease, Anitra Romfh (Children‘s Hospital Boston, MA, USA) explained that this study provides a significant contribution to the care of cyanotic adult congenital patients and provides clinicians with a tool in order to assess the adequacy of physiologic compensation given an oxygen saturation.
Romfh explains further that, “This is particularly useful for patients in a balanced state of erythropoiesis. Not surprisingly, patients with an oxygen saturation of less than 75% had nonoptimal hemoglobin values. Previous studies have shown these patients to have elevated erythropoietin titers, suggesting the presence of a threshold saturation level below which many patients cannot mount an adequate erythrocytic response.”
In addition, Romfh believes that “Through its stringent exclusion criteria, the study also alerts the clinician to previously established factors that alter the expected relationship between hemoglobin and oxygen saturation. Knowledge of these criteria aids in identifying factors that may be limiting erythrocytic compensation.”
Although these results do not allow clinicians to predict levels in patients outside of optimal groupings, it does alert them to factors that affect this oxygen-to-hemoglobin relationship, such as erythropoiesis. Future research could use this information to examine ways to get patients with nonoptimal levels into a healthier range.
Sources: Broberg CS, Jayaweera AR, Diller GP et al. Seeking optimal relation between oxygen saturation and hemoglobin concentration in adults with cyanosis from congenital heart disease. Am. J. Cardiol. 107(4), 595–599 (2011); International Society for Adult Congenital Heart Disease: www.isachd.org/featuredarticle.php
– All stories written by Alicia Wooding