sirolimus and Heart-Defects--Congenital

Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification.. To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations.. We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study.. Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined.. A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Topics: Acitretin; Administration, Cutaneous; Administration, Oral; Adolescent; Child; Child, Preschool; Costello Syndrome; Diagnosis, Differential; Ectodermal Dysplasia; Facies; Failure to Thrive; Female; France; Genetic Association Studies; Heart Defects, Congenital; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mutation; Noonan Syndrome; Prospective Studies; Proto-Oncogene Proteins B-raf; Sirolimus; Treatment Outcome; Young Adult

Both pre-gestational and gestational diabetes have an adverse impact on heart development, but little is known about the influence on the early stage of heart tube formation. Using early gastrulating chick embryos, we investigated the influence of high glucose on the process of heart tube formation, specifically during the primary heart field phase. We demonstrated that high-glucose exposure resulted in 3 types of heart tube malformation: 1) ventricular hypertrophy, 2) ventricular hypertrophy with dextrocardia and 3) ventricular hypertrophy and dextrocardia with the fusion anomaly of a bilateral primary heart tube. Next, we found that these malformation phenotypes of heart tubes might mainly originate from the migratory anomaly of gastrulating precardiac mesoderm cells rather than cell proliferation in the developmental process of bilateral primary heart field primordia. The treatment of rapamycin (RAPA), an autophagy inducer, led to a similar heart tube malformation phenotype as high glucose. Additionally, high-glucose exposure promoted the expression of the key autophagy protein LC3B in early chick tissue. Atg7 is strongly expressed in the fusion site of bilateral primary heart tubes. All of these data imply that autophagy could be involved in the process of high-glucose-induced malformation of the heart tube.

Topics: Animals; Autophagy; Cell Movement; Chick Embryo; Gastrula; Gastrulation; Gene Expression Regulation, Developmental; Glucose; Heart; Heart Defects, Congenital; Mesoderm; Organogenesis; Phenotype; Sirolimus; Stem Cells

Rhabdomyoma (RHM) is a benign cardiac tumour usually associated with tuberous sclerosis complex (TSC). Most RHMs are asymptomatic and regress spontaneously during the first years of life. Haemodynamically significant RHMs are classically treated with surgical excision. We present a case of a premature infant, born to a mother having TSC, with a prenatal diagnosis of pulmonary valve atresia and a large ventricular septal defect. Multiple cardiac RHMs were also present, including a large tumour affecting the right ventricular filling. Owing to the prematurity and low birth weight, the infant was inoperable. In this report, we describe our approach to pharmacologically reduce the RHM size using oral everolimus in preparation for a two-ventricle surgical repair of the structural cardiac defect. We also specifically describe the dose of everolimus that was used in this case to achieve therapeutic serum levels, which was seven times lower than the conventional dose applicable for older infants.

Topics: Administration, Oral; Antineoplastic Agents; Diagnosis, Differential; Everolimus; Heart Defects, Congenital; Heart Neoplasms; Heart Ventricles; Humans; Infant, Premature; Pulmonary Artery; Pulmonary Atresia; Rhabdomyoma; Sirolimus; Tuberous Sclerosis; Ultrasonography, Prenatal

Constitutive activation of mammalian target of rapamycin complex 1 (mTORC1), a key kinase complex that regulates cell size and growth, is observed with inactivating mutations of either of the tuberous sclerosis complex (TSC) genes, Tsc1 and Tsc2. Tsc1 and Tsc2 are highly expressed in cardiovascular tissue but their functional role there is unknown. We generated a tissue-specific knock-out of Tsc1, using a conditional allele of Tsc1 and a cre recombinase allele regulated by the smooth muscle protein-22 (SM22) promoter (Tsc1c/cSM22cre+/-) to constitutively activate mTOR in cardiovascular tissue. Significant gene recombination (∼80%) occurred in the heart by embryonic day (E) 15, and reduction in Tsc1 expression with increased levels of phosphorylated S6 kinase (S6K) and S6 was observed, consistent with constitutive activation of mTORC1. Cardiac hypertrophy was evident by E15 with post-natal progression to heart weights of 142 ± 24 mg in Tsc1c/cSM22cre+/- mice versus 65 ± 14 mg in controls (P < 0.01). Median survival of Tsc1c/cSM22cre+/- mice was 24 days, with none surviving beyond 6 weeks. Pathologic and echocardiographic analysis revealed severe biventricular hypertrophy without evidence of fibrosis or myocyte disarray, and significant reduction in the left ventricular end-diastolic diameter (P < 0.001) and fractional index (P < 0.001). Inhibition of mTORC1 by rapamycin resulted in prolonged survival of Tsc1c/cSM22cre+/- mice, with regression of ventricular hypertrophy. These data support a critical role for the Tsc1/Tsc2-mTORC1-S6K axis in the normal development of cardiovascular tissue and also suggest possible therapeutic potential of rapamycin in cardiac disorders where pathologic mTORC1 activation occurs.

Topics: Animals; Antibiotics, Antineoplastic; Cardiomegaly; Heart; Heart Defects, Congenital; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Microfilament Proteins; Multiprotein Complexes; Muscle Proteins; Myocytes, Cardiac; Organ Size; Proteins; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Maintaining arterial duct patency by stent implantation may be advantageous in congenital heart disease management algorithms. Rapamycin, an immunosuppressant drug that demonstrates antiproliferative properties and inhibits smooth muscle cell migration, may deter the intimal hyperplasia that occurs during spontaneous closure and after-stent implantation of the arterial duct.. Twenty-eight Yorkshire piglets (7 to 11 days old; weight, 2.2 to 4.9 kg) underwent stent implantation of the arterial duct (rapamycin-eluting (n=14) or bare metal (n=14) stents, 3.5-mm diameter) and were euthanized at 2, 4, and 6 weeks. Dissected arterial ducts were analyzed for lumen diameter, smooth muscle cell, and extracellular matrix components. Isolated arterial duct-derived smooth muscle cells were cultured in the presence or absence of rapamycin. Cellular proliferation rates were assessed by Ki-67 detection and [(3)H]-thymidine incorporation. No significant neointimal proliferation was present in either stent type at 2 weeks. At 4 weeks, the median luminal diameters of the bare metal stents were 87% (P=0.009), 54% (P=0.004), and 77% (P=0.004) that of the drug-eluting stents at the middle and aortic and pulmonary artery ends, respectively. At 6 weeks, the median luminal diameters of the bare metal stents were 0% (P=0.18), 5% (P=0.25), and 61% (P=0.13) that of the drug-eluting stents at the same respective levels. Complete histological occlusion was found in at least 1 level of the lumen in 9 pigs: 1 (17%) in the BMS group at 4 weeks, 5 (83%) in the BMS group at 6 weeks, and 3 (50%) in the DES group at 6 weeks. In vitro studies demonstrated 50%-lower proliferation rates in rapamycin-treated cultures of duct-derived smooth muscle cell cultures (P<0.001).. Rapamycin has antiproliferative actions on the arterial duct. Drug-eluting stents may be a more efficient tool than current palliative options for maintaining patency in critically duct-dependent states, but there may be a finite time-related benefit.

Topics: Animals; Animals, Newborn; Cell Division; Cells, Cultured; Drug-Eluting Stents; Ductus Arteriosus; Elastin; Heart Defects, Congenital; Hyperplasia; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Sirolimus; Sus scrofa; Tunica Intima; Ultrasonography

A few cases of isolated pulmonary artery have been successfully palliated by stenting the arterial duct using coronary stents. However, progressive luminal narrowing within the stent due to neointimal proliferation and peal formation is a considerable problem. We report the successful interventional palliation in a 7-week-old infant with isolated left pulmonary artery using sirolimus-eluting stents. In this unusual case, the isolated pulmonary artery was supplied by a duct-like remnant of a persistent fifth aortic arch, whereby the distal part of this vessel showed severe constriction. Implantation of two sirolimus-eluting coronary stents re-established good perfusion of the left pulmonary artery. Seven months after the procedure, echocardiography revealed that perfusion of the stented vessel and the left pulmonary artery was still very good. Stents eluting antimitotic agents also help to preserve the patency of small vessels in infants, and may be useful for ductal stenting.

Topics: Angioplasty, Balloon, Coronary; Aorta, Thoracic; Cardiac Catheterization; Cardiovascular Agents; Coronary Angiography; Ductus Arteriosus; Echocardiography; Female; Heart Defects, Congenital; Humans; Infant; Palliative Care; Prosthesis Design; Pulmonary Artery; Pulmonary Circulation; Sirolimus; Stents; Treatment Outcome; Vascular Patency

Myocardial bridging is the most common congenital coronary abnormality, and is frequently found on post-mortem cardiac examination. Although often asymptomatic, clinical presentation can vary from unstable angina to sudden cardiac death. Only isolated cases of using drug eluting stents (DES) for bridging segments have been described. Our objective was to retrospectively analyze a series of patients undergoing percutaneous coronary intervention (PCI) with DES for symptomatic myocardial bridging and follow post-procedure outcomes. Results revealed favorable peri-procedural angiographic and short-term clinical results with DES implantation. Although initial data regarding DES implantation for symptomatic myocardial bridging are promising, long-term follow up, particularly related to in-stent restenosis will be important.

Topics: Angioplasty, Balloon, Coronary; Cohort Studies; Coronary Angiography; Coronary Stenosis; Coronary Vessel Anomalies; Drug Delivery Systems; Female; Heart Defects, Congenital; Humans; Male; Myocardial Infarction; Paclitaxel; Prognosis; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sirolimus; Stents; Survival Analysis; Time Factors; Treatment Outcome; Vascular Patency