Purkinje fibers of the avian heart express a myogenic transcription factor program distinct from cardiac and skeletal muscle.

A rhythmic heart beat is coordinated by conduction of pacemaking impulses through the cardiac conduction system. Cells of the conduction system, including Purkinje fibers, terminally differentiate from a subset of cardiac muscle cells that respond to signals from endocardial and coronary arterial cells. A vessel-associated paracrine factor, endothelin, can induce embryonic heart muscle cells to differentiate into Purkinje fibers both in vivo and in vitro. During this phenotypic conversion, the conduction cells down-regulate genes characteristic of cardiac muscle and up-regulate subsets of genes typical of both skeletal muscle and neuronal cells. In the present study, we examined the expression of myogenic transcription factors associated with the switch of the gene expression program during terminal differentiation of heart muscle cells into Purkinje fibers. In situ hybridization analyses and immunohistochemistry of embryonic and adult hearts revealed that Purkinje fibers up-regulate skeletal and atrial muscle myosin heavy chains, connexin-42, and neurofilament protein. Concurrently, a cardiac muscle-specific myofibrillar protein, myosin-binding protein-C (cMyBP-C), is down-regulated. During this change in transcription, however, Purkinje fibers continue to express cardiac muscle transcription factors, such as Nkx2.5, GATA4, and MEF2C. Importantly, significantly higher levels of Nkx2.5 and GATA4 mRNAs were detected in Purkinje fibers as compared to ordinary heart muscle cells. No detectable difference was observed in MEF2C expression. In culture, endothelin-induced Purkinje fibers from embryonic cardiac muscle cells dramatically down-regulated cMyBP-C transcription, whereas expression of Nkx2.5 and GATA4 persisted. In addition, myoD, a skeletal muscle transcription factor, was up-regulated in endothelin-induced Purkinje cells, while Myf5 and MRF4 transcripts were undetectable in these cells. These results show that during and after conversion from heart muscle cells, Purkinje fibers express a unique myogenic transcription factor program. The mechanism underlying down-regulation of cardiac muscle genes and up-regulation of skeletal muscle genes during conduction cell differentiation may be independent from the transcriptional control seen in ordinary cardiac and skeletal muscle cells.

Fetal diagnosis of atrioventricular septal defect with dextrocardia in trisomy 18.

On prenatal ultrasound atrioventricular septal defect is often diagnosed in infants with Down syndrome based on an abnormal four-chamber view of the heart. A unique case of atrioventricular septal defect with dextroposition of the heart in an infant with trisomy 18 is presented.

A cross between truncus arteriosus communis and aortopulmonary septal defect: a hitherto undescribed entity.

Case history and necropsy findings of a 5-month-old infant with a unique heart defect with features of truncus arteriosus communis and aortopulmonary defect in combination with severe tricuspid stenosis are presented. There is a wide spectrum of remarkable heart defects between truncus arteriosus communis and aortopulmonary septal defect.

Increased insulin-like growth factor-1 protein in human left ventricular hypertrophy.

Animal models of cardiac hypertrophy demonstrated increased expression of insulin-like-growth factor-1 (IGF-1) in the heart. To study protein expression of insulin-like-growth factor 1 in left ventricular hypertrophy (LVH) in humans 11 hearts of autopsy cases with LVH were compared to 11 controls using immunohistochemical staining with anti-human IGF-1. LVH was defined as thickening of the left ventricular wall which ranged from 1.6 to 2.5 cm with hearts weights from 400 to 900 g. Immunohistochemical staining for IGF-1 was increased in the presence of LVH. In cases of LVH 37.9 +/- 3.5% of the cross-sectional myocardial area stained positively for IGF-1 compared to 6.8 +/- 2.9% in controls (P < 0.001). The findings support the hypothesis that IGF-1 has a role in the pathogenesis of LVH in humans. The increase of IGF-1 protein with LVH suggests reactivation of the cardiac IGF-1 genes in the hypertrophied adult cardiomyocyte.

Increased forskolin stimulation of lymphocyte-adenylate cyclase in normotensive subjects predisposed to essential hypertension.

Since a significant heritability has been shown for forskolin stimulation of lymphocyte adenylate cyclase activity in twins, we evaluated lymphocyte forskolin-stimulated adenylate cyclase activity with respect to a familial predisposition towards essential hypertension. Lymphocyte adenylate cyclase activity was measured in broken cell preparations of 32 male normotensive volunteers with (n = 15) and without (n = 17) a positive family history of hypertension. The maximal forskolin stimulation of adenylate cyclase activity was significantly higher in the positive compared with the negative group (maximal stimulation of activity 53.5 +/- 3.4 versus 41.2 +/- 1.9 pmol cyclic AMP (cAMP)/mg protein per min; P less than 0.01). Dose-response curves showed a significantly greater stimulation of adenylate cyclase activity in the positive group at forskolin concentrations of 10(-7) to 2 x 10(-4) mol/l. The median effective dose (ED50) and adenylate cyclase activity in the absence of forskolin were similar in both groups. We conclude that lymphocyte forskolin-stimulated adenylate cyclase activity may depend in part on hereditary factors associated with a familial predisposition to essential hypertension.