Monoallelic loss-of-function BMP2 variants result in BMP2-related skeletal dysplasia spectrum.

PURPOSE: Bone morphogenic proteins (BMPs) regulate gene expression that is related to many critical developmental processes, including osteogenesis for which they are named. In addition, BMP2 is widely expressed in cells of mesenchymal origin, including bone, cartilage, skeletal and cardiac muscle, and adipose tissue. It also participates in neurodevelopment by inducing differentiation of neural stem cells. In humans, BMP2 variants result in a multiple congenital anomaly syndrome through a haploinsufficiency mechanism. We sought to expand the phenotypic spectrum and highlight phenotypes of patients harboring monoallelic missense variants in BMP2. METHODS: We used retrospective chart review to examine phenotypes from an international cohort of 18 individuals and compared these with published cases. Patient-derived missense variants were modeled in zebrafish to examine their effect on the ability of bmp2b to promote embryonic ventralization. RESULTS: The presented cases recapitulated existing descriptions of BMP2-related disorders, including craniofacial, cardiac, and skeletal anomalies and exhibit a wide phenotypic spectrum. We also identified patients with neural tube defects, structural brain anomalies, and endocrinopathies. Missense variants modeled in zebrafish resulted in loss of protein function. CONCLUSION: We use this expansion of reported phenotypes to suggest multidisciplinary medical monitoring and management of patients with BMP2-related skeletal dysplasia spectrum.

Haemodynamic parameters in postmenopausal women - beneficial effect of moderate continuous exercise training.

INTRODUCTION AND OBJECTIVE: Physical effort plays a positive role in reducing the risk of cardiovascular diseases. The aim of this study was to assess the cardiovascular status in postmenopausal women after several years of regular amateur training. MATERIAL AND METHODS: A total of 55 generally healthy females aged 50-70 years, of whom 38 were members of a senior exercise group and 17 comprised a control group, were enrolled in the study. Parameters of blood flow, vascular resistance, myocardial contractility and thoracic fluid content were measured in a 10-minute supine resting test by impedance cardiography. Thereafter, central blood pressure, augmentation index and pulse wave velocity were measured by applanation tonometry. RESULTS: Exercising women have a better outcome than the control group, when evaluated both with impedance cardiography and with applanation tonometry. They have a lower heart rate - HR (65.1 vs 71.5; p = 0.033), higher blood flow (stroke index - SI, 58.6 vs 50.3; p = 0.040), better myocardial contractility (acceleration index - ACI, 108.8 vs 88.1; p = 0.027), higher preload (thoracic fluid content index - TFCI, 20.5 vs 18.1; p = 0.002), lower afterload (systemic vascular resistance index - SVRI, 1972.9 vs 2110.5; p = 0.026), lower central systolic blood pressure - cBPsys (119.0 vs 129.5; p = 0.037), lower augmentation pressure - AP (10.3 vs 15.0; p = 0.044) and lower pulse wave velocity - PWV (7.4 vs 8.4; p = 0.001). CONCLUSIONS: Regular moderate continuous aerobic exercise training has a beneficial impact on the cardiovascular system in postmenopausal women.

Endothelial function is disturbed in a hypertensive diabetic animal model of HFpEF: Moderate continuous vs. high intensity interval training.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction, but the molecular mechanisms still remain unclear. Whether exercise training (ET) along with which optimal modality can improve endothelial function is controversial. The present study used a hypertensive, diabetic-driven HFpEF animal model (ZSF1 rats) to determine whether different training modalities (moderate-continuous (MCT) and high-intensity interval training (HIIT)) could reverse endothelial dysfunction and to understand the underlying molecular mechanisms. METHODS AND RESULTS: The development of HFpEF in ZSF1 obese animals was confirmed by echocardiography and hemodynamic measurements. Thereafter, animals were randomized into following groups: 1) sedentary, 2) 8 weeks of MCT, 3) 8 weeks of HIIT. ZSF1 lean animals served as control. In vitro measurement of endothelial function in aortic rings revealed significantly impaired endothelial-dependent and -independent vasodilation in HFpEF, which was reversed by MCT and HIIT. At the molecular level, the development of endothelial dysfunction was associated with a reduced expression / activation of endothelial nitric oxide synthase (eNOS), an increase in NADPH and activation of c-Jun N-terminal protein kinase (JNK), a reduced collagen I/III ratio and a reduced lining of the vessel wall by endothelial cells. ET primarily decreased NADPH oxidase expression, and JNK activation, elevated collagen I/III ratio while further improving aortic endothelial cell coverage. CONCLUSIONS: The present study provides evidence that endothelial dysfunction occurs in experimental HFpEF and that ET, independent of the studied training modality, reverses endothelial dysfunction and specific molecular alterations. ET may therefore provide an important therapeutic intervention for HFpEF patients.