Sarcolemmal Ca2+ entry has been shown to be the predominant mechanism responsible for Ca2+ transient in fetal immature cardiomyocytes, while sarcoplasmic reticulum (SR) Ca2+ release is responsible for 90% of Ca2+ transient in adult mouse cardiomyocytes. However, most of the studies have been conducted either on primary cultures or on isolated myocytes, in which the SR function has been possibly underestimated. To investigate developmental changes of SR function in immature hearts under physiological condition, we analyzed Ca2+ transients in beating whole hearts, stimulated electrically at 0.5 Hz after loading with Fluo-3, in fetal and neonatal mice. Thapsigargin (SR Ca2+ ATPase inhibitor) prolonged the time to 50% relaxation of Ca2+ transients significantly even at early embryonic stages. After ryanodine (RyR inhibitor) application, the amplitude of the Ca2+ transients was reduced by 72.8 ± 4.2%, while after nifedipine (L-type Ca2+ channel inhibitor), nickel (T-type Ca2+ channel inhibitor), and SEA0400 (reverse mode Na+-Ca2+ exchanger inhibitor) application, the amplitude was reduced by only 34.4 ± 4.2%, 26.5 ± 4.2%, and 16.7 ± 6.6%, respectively. In addition, the amplitude of caffeine induced Ca2+ transient developmentally increased from embryonic to neonatal stages. These results suggest that SR becomes functional in Ca2+ homeostasis even on early embryonic hearts.
Congenital heart diseases are the most common type of human birth defects, resulting in a significant mortality worldwide. Cardiac outflow tract abnormalities often show severe illness, thus, it is important to understand their clinical manifestation in association with abnormal morphogenesis. Recent advances in molecular embryology have revealed that the heart arises from multiple distinct embryonic origins. Two different sources of cardiac progenitor cell lineages, termed as the second heart field and cardiac neural crest cells, are known to interact with each other and both contribute to the development of the cardiac outflow tract. Understandings of regulatory mechanisms of these cardiac progenitor cells have important implications for the interpretation of the outflow tract development and provide new insights into the morphogenesis of congenital outflow tract abnormalities. Numerous cardiac transcription factors regulate these progenitor cells during the heart development. Elucidation of the functional network of these transcription factors and characterization of transcriptional cascades for interaction between different progenitor lineages has provided a molecular framework and is essential for understanding the pathology of congenital cardiac outflow tract abnormalities associated with abnormal formation of three-dimensional structure. This review outlines the recent discoveries of development of the normal heart and the genetic basis of congenital cardiac outflow tract abnormalities.
A 9-month-old female infant underwent complete repair for double outlet right ventricle (Fallot type). She made a good recovery until 6 days after repair when she developed a high fever. Blood cultures indicated a methicillin-resistant Staphylococcus aureus (MRSA) infection. Although the fever subsided with the use of antibiotics, an echocardiogram disclosed vegetation on the surface of the ventricular septal defect (VSD) patch on postoperative day (POD) 15. She was diagnosed as postoperative infective endocarditis. As recurrent VSD shunt was not detected, antibiotic therapy was continued. On POD 20, acute right heart failure and acute hepatic failure rapidly developed, and an echocardiogram disclosed the left ventricular-right atrial shunt. As the reoperation under the hypocoagulable state carries considerable risk of bleeding, continuous hemodiafiltration (CHDF) and slow plasma exchange was induced, and the reoperation was undertaken after the recovery of coagulability. The VSD patch and the outflow patch was replaced by new ePTFE patches, and the tricuspid valvuloplasty was undertaken. She had a relapse of infection after the reoperation, but she recovered from circulatory instability and was discharged from the hospital 75 days after the reoperation. We report this case with particular emphasis on the rapid progress of acute hepatic failure in postoperative left ventricular-right atrial shunt due to postoperative infective endocarditis.
We successfully treated two low birth weight infants with congenital complete atrioventricular block due to autoimmune reaction evoked by trans-placental maternal antibodies. Case 1: A female delivered by emergent Cesarean section at 32 weeks and 2 days of gestational age due to pericardial fluid collection revealed by fetal echocardiolography. The infant weighed 1,628 g, and her heart rate was 60 bpm. Case 2: A male boy, one of DD twins whose sibling was healthy. He was born at 34 weeks and 3 days of gestational age, weighed 1,902 g, and his heart rate was 42 bpm. Both patients immediately underwent emergent temporary epicardial pacing lead implantation. On extracorporeal temporary pacing, they gained approximately 1 kg weight. At 49 and 59 days of age, respectively, they underwent permanent epicardial pacemaker implantation on an elective basis and have been doing well. In this retrospective study, we concluded that our pacemaker implantation protocol could be justified in terms of efficacy and safety for treatment of this critical disease.
We performed serum cytokines measurement, immunological tests by flow cytometry (FCM) and histopathological examination for a postoperative Fontan patient complicated with PLE following antecedent infection. A 6-years-old boy with asplenia had a atrioventricular septal defect with hypoplastic left ventricle and underwent a Fontan operation. The patient developed refractory PLE 2 years after surgery. The mean albumin level remained 2.0-2.5 g/dl. FCM analysis of the patient demonstrated lymphopenia and a marked decrease in the number of CD4 T lymphocytes, resulting in a low CD4/CD8 ratio (0.14). Histopathological studies showed chronic inflammatory enteritis. The patient was treated with prednisolone and cyclosporine, and his edema was relieved as serum albumin rose to approximately 3.0 g/dl. His immune status also gradually improved. Immunological tests using FCM and a histopathological examination were essential in the decision on the treatment strategy and for monitoring of the treatment response among PLE patients after the Fontan operation, which was supposed to be associated with immune dysfunction.
Protein-losing enteropathy (PLE) is a serious complication of congenital heart disease (CHD) and is associated with pronounced mortality. Medical management of PLE has only been partially successful. This patient improved temporarily using heparin therapy after a Rastelli operation for complete atrioventricular septal defect, double outlet right ventricle, and pulmonary atresia. However, the patient suffered a recurrence of PLE after three months of being weaned off heparin. The patient was switched to steroid therapy, then a combination of heparin and a small amount of steroid therapy, and finally only heparin therapy. Unfortunately, the patient died due to respiratory failure. The treatment of PLE with heparin therapy requires frequent subcutaneous injections, which are unpleasant for the patient. Although heparin therapy was temporarily effective, it did not lead to complete remission.