Avraham Lorber

Cardiomyocytes generated from CPVTD307H patients are arrhythmogenic in response to β-adrenergic stimulation.

Sudden cardiac death caused by ventricular arrhythmias is a disastrous event, especially when it occurs in young individuals. Among the five major arrhythmogenic disorders occurring in the absence of a structural heart disease is catecholaminergic polymorphic ventricular tachycardia (CPVT), which is a highly lethal form of inherited arrhythmias. Our study focuses on the autosomal recessive form of the disease caused by the missense mutation D307H in the cardiac calsequestrin gene, CASQ2. Because CASQ2 is a key player in excitation contraction coupling, the derangements in intracellular Ca2+ handling may cause delayed afterdepolarizations (DADs), which constitute the mechanism underlying CPVT. To investigate catecholamine‐induced arrhythmias in the CASQ2 mutated cells, we generated for the first time CPVT‐derived induced pluripotent stem cells (iPSCs) by reprogramming fibroblasts from skin biopsies of two patients, and demonstrated that the iPSCs carry the CASQ2 mutation. Next, iPSCs were differentiated to cardiomyocytes (iPSCs‐CMs), which expressed the mutant CASQ2 protein. The major findings were that the β‐adrenergic agonist isoproterenol caused in CPVT iPSCs‐CMs (but not in the control cardiomyocytes) DADs, oscillatory arrhythmic prepotentials, after‐contractions and diastolic [Ca2+]i rise. Electron microscopy analysis revealed that compared with control iPSCs‐CMs, CPVT iPSCs‐CMs displayed a more immature phenotype with less organized myofibrils, enlarged sarcoplasmic reticulum cisternae and reduced number of caveolae. In summary, our results demonstrate that the patient‐specific mutated cardiomyocytes can be used to study the electrophysiological mechanisms underlying CPVT.

Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.

Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5–13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.

The renin‐angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D–resistance rickets (HVDRR)

Vitamin D deficiency has been linked to hypertension and an increased prevalence of cardiovascular risk factors and disease. Studies in vitamin D receptor knockout (VDR KO) mice revealed an overstimulated renin‐angiotensin system (RAS) and consequent high blood pressure and cardiac hypertrophy. VDR KO mice correspond phenotypically and metabolically to humans with hereditary 1,25‐dihydroxyvitamin D–resistant rickets (HVDRR). There are no data on the cardiovascular system in human HVDRR. To better understand the effects of vitamin D on the human cardiovascular system, the RAS, blood pressure levels, and cardiac structures were examined in HVDRR patients. Seventeen patients (9 males, 8 females, aged 6 to 36 years) with hereditary HVDRR were enrolled. The control group included age‐ and gender‐matched healthy subjects. Serum calcium, phosphorous, creatinine, 25‐hydroxyvitamin D [25(OH)D],1,25‐dihydroxyvitamin D3 [1,25(OH)2D3], parathyroid hormone (PTH), plasma rennin activity (PRA), aldosterone, angiotensin II (AT‐II), and angiotensin‐converting enzyme (ACE) levels were determined. Ambulatory 24‐hour blood pressure measurements and echocardiographic examinations were performed. Serum calcium, phosphorus, and alkaline phosphatase values were normal. Serum 1,25(OH)2D3 and PTH but not PRA and ACE levels were elevated in the HVDRR patients. AT‐II levels were higher than normal in the HVDRR patients but not significantly different from those of the controls. Aldosterone levels were normal in all HVDRR patients. No HVDRR patient had hypertension or echocardiographic pathology. These findings reveal that 6‐ to 36‐year‐old humans with HVDRR have normal renin and ACE activity, mild but nonsignificant elevation of AT‐II, normal aldosterone levels, and no hypertension or gross heart abnormalities.

Cardiac Manifestations in Thiamine-Responsive Megaloblastic Anemia Syndrome

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. Other features of this syndrome gradually develop. We describe three TRMA patients with heart rhythm abnormalities and structural cardiac anomalies. Eight other reported TRMA patients also had cardiac anomalies. Recently, the TRMA gene, SLC19A2, was identified, encoding a functional thiamine transporter. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine in common cardiac abnormalities.

Sonographic Diagnosis of Fetal Vascular Rings in Early Pregnancy

The use of transvaginal ultrasound enabled the detection of a fetal vascular ring as early as 14 to 16 weeks gestation. Six fetuses with this anomaly were found in a study group of 5,896 pregnancies.

Brain abscess in children – epidemiology, predisposing factors and management in the modern medicine era

Aims:u2002 Brain abscess is rare in children. Predisposing factors are found in almost 85% of cases. Overall, 25% of brain abscesses develop in children, mostly in the 4–7u2003years age group. Our study aimed to characterize children with brain abscesses treated in our hospital, identify risk factors, pathogens and short‐term outcome.

Paracetamol effectiveness, safety and blood level monitoring during patent ductus arteriosus closure: a case series

Abstract Paracetamol was reported to be effective for patent ductus arteriosus (PDA) closure. We present a case series of PDA closure by paracetamol in seven premature infants. During the treatment, paracetamol blood levels did not exceed the recommended levels for analgesia and hyperthermia in six tested infants. None of the patients demonstrated significant disturbances of liver function.

Patient safety and outcomes from live case demonstrations of interventional cardiology procedures

OBJECTIVESnThe goal of this study was to examine the safety and results of interventional procedures performed during the broadcast of live case demonstrations.nnnBACKGROUNDnProfessional meetings using live case demonstrations to present cutting-edge technology are considered a valuable educational resource. There is an ongoing discussion on whether patients who are treated during live case demonstrations are exposed to a higher risk.nnnMETHODSnBetween 1998 and 2010, 101 patients were treated during live transmissions from a single center in 15 invasive-cardiology conferences. Technical success was defined as the ability to effectively perform the planned procedure without any major complication. The primary endpoint of the study was the composite occurrence of death, myocardial infarction, or stroke.nnnRESULTSnThe interventional procedures included coronary (n=66), carotid (n=15), peripheral (n=1), valvular (n=2), congenital heart disease (n=12), and complex electrophysiological mapping and ablation interventions (n=7). In 4 cases, the intended procedure was not done. The procedure was technically successful in 95%. In 5 cases, the procedure was unsuccessful because of the inability to cross a chronic total occlusion. There were no deaths during the hospital stay, and the composite primary endpoint occurred in 2 patients: a minor stroke following an atrial fibrillation ablation and a rise in serum troponin levels after percutaneous coronary intervention. These results were no different from those of 66 matched controls who underwent procedures performed by the same operators but not as live case demonstrations (relative risk: 0.32; 95% confidence interval: 0.02 to 3.62, p=0.62).nnnCONCLUSIONSnIn this consecutive series of interventional cardiology procedures that were performed by expert operators during live demonstration courses, the procedural and 30-day clinical outcomes were similar to those found in daily practice and to those that have been reported in the contemporary published data. These results suggest that broadcasting live case demonstrations in selected patients from selected centers may be safe.

Oral propranolol versus placebo for retinopathy of prematurity: a pilot, randomised, double-blind prospective study

Retinopathy of prematurity (ROP) can progress to neovascularisation (NV) and retinal detachment. Laser photocoagulation1 or intravitreal bevacizumab (Avastin)2 are the current interventions for severe ROP. Vascular endothelial growth factor (VEGF) plays a key role in ROP pathogenesis, being downregulated and upregulated in vaso-obliterative and vaso-proliferative phases of ROP, respectively. ROP and infantile haemangiomas share the same VEGF-mediated pathogenesis. Propranolol downregulates VEGF expression, and thus, mitigates progression of infantile haemangiomas3 and NV in oxygen-induced retinopathy in animals.4 We examined the safety and feasibility of propranolol for ROP.nnTwenty premature infants with ROP, born between 1 May 2010 and 31 July 2012 at 24–28 weeks’ gestation and birth weight <1500 g, were randomised either to oral propranolol (propranolol+sucrose 5%; n=10) or placebo (sucrose 5%; n=10) (figure 1). Inclusion criterion: evidence for ROP with any of the following: (a) stage 1 (zone I); (b) stage 2 or …

Comparative Changes of Pulmonary Artery Pressure Values and Tricuspid Valve Regurgitation Following Transcatheter Atrial Septal Defect Closure in Adults and the Elderly

OBJECTIVESnOpinions vary widely regarding the effectiveness of transcatheter atrial septal defect (ASD) closure in adults, especially in elderly patients. The purpose of this study was to evaluate and compare the hemodynamic changes after transcatheter ASD closure in two groups of patients, one aged 40-59 years (group 1) and one 60 years of age and older (group 2).nnnMETHODSnRetrospective analysis of patient files.nnnRESULTSnForty-six patients were evaluated (23 in each group). Older patients had a higher prevalence of cardiovascular risk factors and established coronary artery disease. There was no statistically significant difference between the two groups in Qp/Qs values, ASD diameter and occluder size. The elderly patients had significantly higher baseline systolic pulmonary artery pressure (PAp) levels -53 +/- 16.2 vs. 39 +/- 7.7 mm Hg, P = 0.003. One year following the procedure, the mean reduction in PAp values was 11.3% in group 1 and 19% in group 2 (P = 0.099). While significant baseline tricuspid regurgitation (TR) was more frequent in the elderly patients, no significant TR was observed in either group 1 year following the procedure.nnnCONCLUSIONnTranscatheter ASD closure resulted in significant hemodynamic improvement in all patients, but was even more beneficial in the elderly patient cohort.