Endocardial Fibroelastosis Is Caused by Aberrant Endothelial to Mesenchymal Transition

RATIONALE: Endocardial fibroelastosis (EFE) is a unique form of fibrosis which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through establishment of staged biventricular repair surgery in HLHS infant patients, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce and specific therapeutic targets are not yet known. OBJECTIVE: Here we aimed to investigate the cellular origins of EFE tissue and to gain insights into underlying molecular mechanisms to ultimately develop novel therapeutic strategies. METHODS AND RESULTS: By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial mesenchymal transition (EndMT). We further demonstrate that such aberrant EndMT involving endocardial endothelial cells is caused by dysregulated TGFβ/BMP signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of BMP5 and BMP7. Finally, we provide evidence that supplementation of exogenous recombinant BMP7 effectively ameliorates EndMT and experimental EFE in rats. CONCLUSIONS: In summary our data point to aberrant EndMT as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to BMP7 as an effective treatment for EFE and its restriction of heart growth

Relationships between fetal body weight of Wistar rats at term and the extent of skeletal ossification

We investigated the relationship between fetal body weight at term (pregnancy day 21) and the extent of ossification of sternum, metacarpus, metatarsus, phalanges (proximal, medial and distal) of fore- and hindlimbs and cervical and coccygeal vertebrae in Wistar rats. The relationships between fetal body weight and sex, intrauterine position, uterine horn, horn size, and litter size were determined using historical control data (7594 fetuses; 769 litters) of untreated rats. Relationships between body weight and degree of ossification were examined in a subset of 1484 historical control fetuses (154 litters) which were subsequently cleared and stained with alizarin red S. Fetal weight was independent of horn size, uterine horn side (left or right) or intrauterine position. Males were heavier than females and fetal weight decreased with increasing litter size. Evaluation of the skeleton showed that ossification of sternum, metacarpus and metatarsus was extensively complete and independent of fetal weight on pregnancy day 21. In contrast, the extent of ossification of fore- and hindlimb phalanges and of cervical and sacrococcygeal vertebrae was dependent on fetal body weight. The strongest correlation between body weight and degree of ossification was found for hindlimb, medial and proximal phalanges. Our data therefore suggest that, in full-term rat fetuses (day 21), reduced ossification of sternum, metacarpus and metatarsus results from a localized impairment of bone calcification (i.e., a malformation or variation) rather than from general growth retardation and that ossification of hindlimb (medial and proximal) phalanges is a good indicator of treatment-induced fetal growth retardation

Seasonal variation in incidence of acute myocardial infarction in a sub-Arctic population: the Tromsø Study 1974-2004

Background: A seasonal pattern with higher winter morbidity and mortality has been reported for acute myocardial infarction (MI). The magnitude of the difference between peak and nadir season has been associated with latitude, but results are inconsistent. Studies of seasonal variation of MI in population-based cohorts, based on adjudicated MI cases, are few. We investigated the monthly and seasonal variation in first-ever nonfatal and fatal MI in the population of Tromsø in northern Norway, a region with a harsh climate and extreme seasonal variation in daylight exposure. Design: Prospective population-based cohort study. Methods: A total of 37 392 participants from the Tromsø Study enrolled between 1974 and 2001 were followed throughout 2004. Each incident case of MI was validated by the review of medical records and death certificates. MI incidence rates for months and seasons were analyzed for seasonal patterns with Poisson regression and the Cosinor procedure. All analyses were stratified by sex, age and smoking status. Results: A total of 1893 first-ever MIs were registered, of which 592 were fatal. There was an 11 % (95% confidence interval: 1.00–1.23, P = 0.04) increased risk of incident MI during winter (November-January) compared with nonwinter seasons, with no statistically significant interaction with sex, age, smoking or calendar year. Other seasonal modelling gave similar but not statistically significant results. Conclusion: We found a small increase in risk of incident MI during the darkest winter months. Populations living in sub-Arctic areas may be adapted to face climate exposure during winter through behavioural protection