Dextrocardia

Cardiac Axis in Early Gestation and Congenital Heart Disease

Congenital heart defects represent the most common structural anomalies observed in the fetal population, and they are often associated with significant morbidity and mortality.

The fetal cardiac axis, which indicates the orientation of the heart in relation to the chest wall, is formed by the angle between the anteroposterior axis of the chest and the interventricular septum of the heart. Studies conducted during the first trimester have demonstrated promising outcomes with respect to the applicability of cardiac axis measurement in fetuses with congenital heart defects as well as fetuses with extracardiac and chromosomal anomalies, which may result in improved health outcomes and reduced healthcare costs.

The main aim of this review article was to highlight the cardiac axis as a reliable and powerful marker for the detection of congenital heart defects during early gestation, including defects that would otherwise remain undetectable through the conventional four-chamber view.

Primary Ciliary Dyskinesia - An Update on the Genetics of Underlying Pathological Mechanisms

One of the rapidly growing groups of diseases known as ciliopathies is primary ciliary dyskinesia (PCD), a rare hereditary illness of the motile cilia. Different clinical symptoms of primary ciliary dyskinesia include infertility, left-right lateralization abnormalities, and chronic upper and lower respiratory tract disorders. Our knowledge of the genetics underlying primary ciliary dyskinesia has significantly increased in recent years. Involved in the formation, shape, and operation of motile cilia are axonemal, cytoplasmic, and regulatory proteins that are encoded by a rising number of disease-associated genes and pathogenic mutations. We now have a better grasp of the clinical signs and symptoms of motile ciliopathies because of advances in our understanding of cilia genetics and the function of the proteins expressed. These developments have altered how we approach primary ciliary dyskinesia diagnostic testing. The clinical characteristics of primary ciliary dyskinesia, the evolution of diagnostics, and the discovery of previously unknown genotype-phenotype connections in primary ciliary dyskinesia will all be covered in this review paper.

Notch Signalling Pathways and Their Importance in the Treatment of Cancers

Background: The Notch pathway is an evolutionarily conserved, intercellular signalling system which is present in all multicellular organisms and mammals. The Notch pathway plays an important role in the embryonic development as it controls cell proliferation, cell differentiation and binary cell fate decisions.

Objective: In the present review, we highlight the Notch signalling pathway components i.e. Notch receptors, ligands, effector, and their regulators. We also discuss the tumor biology of the Notch pathway involved in various cancers.

Results: Interestingly, the Notch signalling pathway is dysregulated in many cancers. Notch may serve as oncogene or tumor suppressor and plays an important role in cancers of the liver, pancreas, endometrium of uterus, ovary, prostate, bladder and colon. The activation of Notch pathway plays a vital role in the progression of some cancer. In addition, Notch pathway activation was also shown to drive chemoresistance in cancer, as well. Chemotherapeutically, combined NOTCH1 inhibitor synergistically attenuated chemotherapy-enriched cancer stem cell population both in vitro and in vivo. This may prove to be beneficial in the treatment of cancer.

Conclusion: The Notch inhibitors possess anti-proliferative effects on cancer, thereby serving as a new treatment for cancer.

Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.

Left-Right Asymmetry in Embryonic Development and Breast Cancer: Common Molecular Determinants?

At the first glance the vertebrate body appears to be symmetric, however, left and right sides are different. This is tightly controlled during embryonic development, and may as well affect the spatial occurrence of diseases. In the embryo, determination of the left and right sides takes place before and during gastrulation. Its failure results in heterotaxia, a diverse group of congenital laterality disorders characterized by left-right displacement of organs. In recent years, our knowledge about the molecular control of left-right asymmetry during embryonic development has grown considerably. However, almost nothing is known about the etiology of cancer laterality. Mammary carcinoma is 5 - 10% more likely to arise in the left breast. The left side of the body is also 10% more prone to melanoma development. Whereas the right predominance of lung, ovarian and testicular cancer might be explained by the greater organ mass on that side, possible reasons for left predominance of mammary carcinoma and melanoma are highly speculative. Sleeping behavior, handedness, nursing behavior and asymmetric sun exposure were named. A possible interrelation between the molecular control of left-right asymmetry and cancer has not yet been discussed in detail. Here we present an overview of molecules involved in both processes, focusing on laterality of breast cancer. Several secreted and membrane-bound growth factors such as Nodal, Lefty, FGF, HB-EGF and HGF as well as transcription factors (e.g. Pitx2, FoxA2) may be candidates with such overlapping functions. Studies on cancer laterality in transgenic mice are needed to make progress in this neglected research field.

Heart Transplantation in Biventricular Congenital Heart Disease: Indications, Techniques, and Outcomes

Heart transplantation is an accepted therapeutic modality for end-stage congenital heart disease for both biventricular and univentricular anomalies. Many transplant centers have pushed the limits of transplantation to include patients with high pulmonary vascular resistance, high panel reactive antibodies, positive cross-matches, and ABOincompatibility. Excellent results have been possible, particularly with the development of improved diagnostic and therapeutic algorithms to prevent and treat rejection, infection, and post-transplant lymphoproliferative disease. Late graft failure and chronic rejection remain vexing problems. The vast majority of patients with biventricular congenital heart disease have undergone prior cardiac surgical procedures. Indications for transplantation in this subgroup are primarily progressive refractory heart failure following prior cardiac surgical reconstructive procedures. Contraindications to transplantation mimic those for other forms of end-stage heart disease. A determination of pulmonary vascular resistance is important in listing patients with biventricular congenital heart disease for heart transplantation. Modifications in the implant technique are necessary and vary depending on underlying recipient anatomy. Risk factors for perioperative outcomes in patients with biventricular congenital heart disease include the need for reoperation, the degree of anatomic reconstruction necessary during the implant procedure, and the degree of antibody sensitization, in addition to a number of other recipient and donor factors. Postoperative outcomes and survival are very good but remain inferior to those with cardiomyopathy in most series. In conclusion, patients with end-stage biventricular congenital heart disease represent a complex group of patients for heart transplantation, and require careful evaluation and management to ensure optimal outcomes.