Integrated multi-omic characterization of congenital heart disease.

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer2. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.

[Effect of milkvetch injection on immune function of children with tetralogy of Fallot after radical operation].

OBJECTIVE: To evaluate the effect of milkvetch injection (MI) on immune function of children with tetralogy of Fallot (TOF) after radical operation. METHODS: Forty-children with TOF were divided into two groups, the 20 in the control group treated with conventional treatment alone and the 20 in the treated group treated with conventional treatment plus 15 ml of MI every 12 hrs for 14 days. Changes of immunoglobulin, complements, lymphocyte phenotypes and cytokines were observed. RESULTS: In the treated group, the abnormally increased levels of IgG, IgM, C3, C4, CD8+ and CD19+ began to lower at lst-2nd week after treatment, and basically restored to the levels of normal at 3rd-4th week; while the decreased levels of IgA, CD3+, CD4+, CD4+/CD8+ ratio, CD3+/HLA-DR+ and CD3+/CD16+ -CD56+ raised gradually from the 1st week and restored to normal range at 2nd-3rd week. The IL-6 and tumor necrosis factor-alpha (TNF-alpha) levels in the plasma and supernatant, produced in vitro by peripheral blood mononuclear cells (PBMC) decreased gradually at 1st week and restored to the normal level at 3rd-4th weeks. The different value before and after treatment of the above-mentioned indexes in the treated group were superior to those in the control group (P<0.05 or P<0.01). CONCLUSION: MI could significantly improve the immune function of children with TOF after radical operation.

Facial and immunological anomalies associated with tetralogy of Fallot.

Dysmorphic facial features were present in 9 of 31 children with tetralogy of Fallot anatomy (29%). These anomalies included hypertelorism, low-set ears, small mouth, short philtrum, and micrognathia. Ten children had pulmonary atresia, 13 (42%) had a right aortic arch, and 13 had extracardiac congenital anomalies. There were 16 children in the series (52%) who had hospital admissions for important or recurrent infections, and 18 who had immune deficiency: low levels of T lymphocytes were found in 9, low levels of complement in 8, and low immunoglobulins in 3. Embryologically, the cardiac outflow tracts, the aortic arch, the face, and the thymus develop at the same time, and all receive migrating cells from the neural crest. Teratogenic factors possibly produce this constellation of anomalies, which is in the spectrum of the Di George syndrome (third and fourth pharyngeal pouch syndrome). It is of importance for the management of such children, that their immune deficiency be recognized and treated appropriately.

The immunocompetence of children with congenital heart disease.

We studied the immunocompetence of 18 children with conotruncal malformations (13 with tetralogy of Fallot, 5 with truncus arteriosus) and 22 children with cardiac shunt lesions. There were reduced total T cell percentages and T helper cells in the conotruncal group but no T cell abnormality in the shunt group. Also, 7 of the 18 cases in the conotruncal group had facial dysmorphism reminiscent of the Di George syndrome. These results suggest that patients with conotruncal malformations fall into the wide spectrum of the Di George syndrome. There was some humoral deficiency in both groups with reduced levels of immunoglobulins IgG and IgA and low levels of complement C3 and C4. The clinical records showed a high frequency of infections. Hospital admissions for these episodes had occurred in 61% of the conotruncal group and 32% of the shunt group. Thus, there is an increased susceptibility to infection in children with congenital heart disease, and the predilection to infection has an immunological basis.