Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome.

Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l-knocked down murine cardiomyocytes and hearts of Ppp1r13l-deficient mice. The hypersensitivity to lipopolysaccharide was NF-κB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients' fibroblasts. RNA sequencing of Ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomal-recessive cardio-cutaneous syndrome in humans and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors.

Transcatheter closure of right-to-left interatrial shunts to resolve hypoxemia.

BACKGROUND: Right-to-left interatrial shunts through an atrial septal defect or patent foramen ovale may result from congenital and acquired conditions. Right-to-left shunts may occur with normal pulmonary artery pressure and resistance as in right ventricular outflow tract obstruction leading to hypertrophy and reduced diastolic function, in right ventricle ischemia, myocarditis or cardiomyopathy and in orthodeoxia-platypnea syndrome. METHODS: We have tested the tolerance of trans-catheter closure of right-to-left interatrial shunts in 5 selected patients in whom the morphology and hemodynamics implied that it would be well-tolerated and improve functional capacity. Right-to-left shunt was demonstrated in 5 profoundly cyanotic patients by trans-thoracic and trans-esophageal echocardiography with intravenous injection of agitated saline. The patients were catheterized for hemo-dynamic study and tested for tolerance of transient balloon occlusion of the defects. RESULTS: Diastolic right ventricular dysfunction with elevated end-diastolic pressure was the primary cause of right-to-left shunt. Most shunts occur via atrial septal defects. Patients' ability to tolerate temporary balloon occlusion of the defects predicted a favorable outcome following permanent device occlusion. Cyanosis resolved in all patients following closure of the defects without congestive right heart failure. A marked improvement in functional capacity was observed in 4 patients. One died of preinterventional hypoxic brain damage. CONCLUSION: Transcatheter closure of right-to-left shunts is well-tolerated and a rewarding approach. It should be applied in selected patients following careful morphologic and hemodynamic evaluation. Tolerance of temporary occlusion of the defect is predictive of a favorable procedural outcome.

The familial form of atrial septal defect.

BACKGROUND: The secundum atrial septal defect accounts for 10% of congenital heart disease. Familial occurrence is rare and may present as an isolated lesion or with conduction and skeletal abnormalities. Predisposing genes were described. OBJECTIVES: To evaluate familial defect's prevalence and associated anomalies and assess the yield of screening. METHODS: Family history, physical, electrocardiographic and echocardiographic evaluation of 286 ASD patients and families regarding heart disease, conduction and skeletal anomalies were performed. RESULTS: Eleven new families with familial defects were identified yielding 28 patients. The rate of transmission was 40-100%, suggestive of autosomal dominant inheritance. Parents were healthy in four families with multiple offspring with ASDs. Two families had ASDs with atrioventricular conduction abnormalities in five of six subjects, not requiring pacing. One subject had skeletal malformation. Ten patients had surgery, 12 had transcatheter ASD closure and six await treatment. CONCLUSIONS: In view of the high prevalence of familial occurrence of secundum ASD (10% of all ASD patients), we recommend screening all first degree relatives of ASD patients for cardiac, conduction and skeletal anomalies. Although a routine genetic investigation is not yet available, genetic patterns of inheritance may be compatible with autosomal dominant inheritance. Healthy parents of affected offspring may suggest a variable gene penetrance or past spontaneous ASD closure. Conduction anomalies may be present or may develop throughout life, and thus should be periodically screened for.

Anomalous origin of the main stem of the left coronary artery from the pulmonary trunk presenting with left ventricular hypertrophy.

Patients with anomalous origin of the left coronary artery from the pulmonary trunk may present with paroxysmal angina on exertion, congestive heart failure, dyspnoea, syncope or sudden death. The association of such anomalous origin of the left coronary artery from the pulmonary trunk with a hypertrophic left ventricle is extremely rare. In our cohort of patients with anomalous origin of the left coronary artery from the pulmonary trunk, two presented with a hypertrophic left ventricle. We discuss these cases, accompanied by a review of the English literature describing different morphological anomalies of the coronary arteries associated with left ventricular hypertrophy. Whether the hypertrophy is a result of the evolvement of the collateral coronary system, or due to an additional pathological gene for hypertrophic obstructive cardiomyopathy, remains an enigma. The hypertrophy may have served as a compensatory mechanism accounting for the atypical clinical presentation. We further discuss the possible factors associating the occurrence of anomalous origin of the left coronary artery from the pulmonary trunk and myohypertrophy, supported by the documentation of the regression of hypertrophy following surgical correction of the anomalous arterial origin as seen in our patients.