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"Levine, Robert A"
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Genetics of syndromic and non-syndromic mitral valve prolapse
Mitral valve prolapse (MVP) is a common condition that affects 2%–3% of the general population. MVP is thought to include syndromic forms such as Marfan syndrome and non-syndromic MVP, which is the most frequent form. Myxomatous degeneration and fibroelastic deficiency (FED) are regarded as two different forms of non-syndromic MVP. While FED is still considered a degenerative disease associated with ageing, frequent familial clustering has been demonstrated for myxomatous MVP. Familial and genetic studies led to the recognition of reduced penetrance and large phenotypic variability, and to the identification of prodromal or atypical forms as a part of the complex spectrum of the disease. Whereas autosomal dominant mode is the common inheritance pattern, an X linked form of non-syndromic MVP was recognised initially, related to Filamin-A gene, encoding for a cytoskeleton protein involved in mechanotransduction. This identification allowed a comprehensive description of a new subtype of MVP with a unique association of leaflet prolapse and paradoxical restricted motion in diastole. In autosomal dominant forms, three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32. Although deciphering the underlying genetic defects is still a work in progress, DCHS1 mutations have been identified (11p15.4) in typical myxomatous disease, highlighting new molecular pathways and pathophysiological mechanisms leading to the development of MVP. Finally, a large international genome-wide association study demonstrated the implication of frequent variants in MVP development and opened new directions for future research. Hence, this review focuses on phenotypic, genetic and pathophysiological aspects of MVP.
Journal Article
Ethnographic Studies of Childhood: A Historical Overview
In this article, I briefly survey the ethnographic research literature on childhood in the 20th century, beginning with the social and intellectual contexts for discussions of childhood at the turn of the 20th century. The observations of Bronislaw Malinowski and Margaret Mead in the 1920s were followed by later ethnographers, also describing childhood, some of whom criticized developmental theories; still others were influenced initially by Freudian and other psychoanalytic theories and later by the suggestions of Edward Sapir for research on the child's acquisition of culture. The Six Cultures Study led by John Whiting at midcentury was followed by diverse trends of the period after 1960-including field studies of infancy, the social and cultural ecology of children's activities, and language socialization. Ethnographic evidence on hunting and gathering and agricultural peoples was interpreted in evolutionary as well as cultural and psychological terms. The relationship between ethnography and developmental psychology remained problematic.
Journal Article
Brainstem Auditory Evoked Potentials Suggest a Role for the Ventral Cochlear Nucleus in Tinnitus
Numerous studies have demonstrated elevated spontaneous and sound-evoked brainstem activity in animal models of tinnitus, but data on brainstem function in people with this common clinical condition are sparse. Here, auditory nerve and brainstem function in response to sound was assessed via auditory brainstem responses (ABR) in humans with tinnitus and without. Tinnitus subjects showed reduced wave I amplitude (indicating reduced auditory nerve activity) but enhanced wave V (reflecting elevated input to the inferior colliculi) compared with non-tinnitus subjects matched in age, sex, and pure-tone threshold. The transformation from reduced peripheral activity to central hyperactivity in the tinnitus group was especially apparent in the V/I and III/I amplitude ratios. Compared with a third cohort of younger, non-tinnitus subjects, both tinnitus, and matched, non-tinnitus groups showed elevated thresholds above 4 kHz and reduced wave I amplitude, indicating that the differences between tinnitus and matched non-tinnitus subjects occurred against a backdrop of shared peripheral dysfunction that, while not tinnitus specific, cannot be discounted as a factor in tinnitus development. Animal lesion and human neuroanatomical data combine to indicate that waves III and V in humans reflect activity in a pathway originating in the ventral cochlear nucleus (VCN) and with spherical bushy cells (SBC) in particular. We conclude that the elevated III/I and V/I amplitude ratios in tinnitus subjects reflect disproportionately high activity in the SBC pathway for a given amount of peripheral input. The results imply a role for the VCN in tinnitus and suggest the SBC pathway as a target for tinnitus treatment.
Journal Article
Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis
Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by combining single cell sequencing and in vivo approaches, a population of human pre-valvular endocardial cells (HPVCs) can be derived from pluripotent stem cells. HPVCs express gene patterns conforming to the E9.0 mouse atrio-ventricular canal (AVC) endocardium signature. HPVCs treated with BMP2, cultured on mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, undergo endothelial-to-mesenchymal transition and express markers of valve interstitial cells of different valvular layers, demonstrating cell specificity. Extending this model to patient-specific induced pluripotent stem cells recapitulates features of mitral valve prolapse and identified dysregulation of the SHH pathway. Concurrently increased ECM secretion can be rescued by SHH inhibition, thus providing a putative therapeutic target. In summary, we report a human cell model of valvulogenesis that faithfully recapitulates valve disease in a dish.
There are few human models that can recapitulate valve development in vitro. Here, the authors derive human pre-valvular endocardial cells (HPVCs) from iPSCs and show they can recapitulate early valvulogenesis, and patient derived HPVCs have features of mitral valve prolapse and identified SHH dysregulation.
Journal Article
Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve
Endothelial-mesenchymal transformation (EMT) is a critical event for the embryonic morphogenesis of cardiac valves. Inducers of EMT during valvulogenesis include VEGF, TGF-β1, and wnt/β-catenin (where wnt refers to the wingless-type mammary tumor virus integration site family of proteins), that are regulated in a spatiotemporal manner. EMT has also been observed in diseased, strain-overloaded valve leaflets, suggesting a regulatory role for mechanical strain. Although the preponderance of studies have focused on the role of soluble mitogens, we asked if the valve tissue microenvironment contributed to EMT. To recapitulate these microenvironments in a controlled, in vitro environment, we engineered 2D valve endothelium from sheep valve endothelial cells, using microcontact printing to mimic the regions of isotropy and anisotropy of the leaflet, and applied cyclic mechanical strain in an attempt to induce EMT. We measured EMT in response to both low (10%) and high strain (20%), where low-strain EMT occurred via increased TGF-β1 signaling and high strain via increased wnt/β-catenin signaling, suggesting dual strain-dependent routes to distinguish EMT in healthy versus diseased valve tissue. The effect was also directionally dependent, where cyclic strain applied orthogonal to axis of the engineered valve endothelium alignment resulted in severe disruption of cell microarchitecture and greater EMT. Once transformed, these tissues exhibited increased contractility in the presence of endothelin-1 and larger basal mechanical tone in a unique assay developed to measure the contractile tone of the engineered valve tissues. This finding is important, because it implies that the functional properties of the valve are sensitive to EMT. Our results suggest that cyclic mechanical strain regulates EMT in a strain magnitude and directionally dependent manner.
Journal Article
Mechanical effects of MitraClip on leaflet stress and myocardial strain in functional mitral regurgitation – A finite element modeling study
MitraClip is the sole percutaneous device approved for functional mitral regurgitation (MR; FMR) but MR recurs in over one third of patients. As device-induced mechanical effects are a potential cause for MR recurrence, we tested the hypothesis that MitraClip increases leaflet stress and procedure-related strain in sub-valvular left ventricular (LV) myocardium in FMR associated with coronary disease (FMR-CAD).
Simulations were performed using finite element models of the LV + mitral valve based on MRI of 5 sheep with FMR-CAD. Models were modified to have a 20% increase in LV volume (↑LV_VOLUME) and MitraClip was simulated with contracting beam elements (virtual sutures) placed between nodes in the center edge of the anterior (AL) and posterior (PL) mitral leaflets. Effects of MitraClip on leaflet stress in the peri-MitraClip region of AL and PL, septo-lateral annular diameter (SLAD), and procedure-related radial strain (Err) in the sub-valvular myocardium were calculated.
MitraClip increased peri-MitraClip leaflet stress at end-diastole (ED) by 22.3±7.1 kPa (p<0.0001) in AL and 14.8±1.2 kPa (p<0.0001) in PL. MitraClip decreased SLAD by 6.1±2.2 mm (p<0.0001) and increased Err in the sub-valvular lateral LV myocardium at ED by 0.09±0.04 (p<0.0001)). Furthermore, MitraClip in ↑LV_VOLUME was associated with persistent effects at ED but also at end-systole where peri-MitraClip leaflet stress was increased in AL by 31.9±14.4 kPa (p = 0.0268) and in PL by 22.5±23.7 kPa (p = 0.0101).
MitraClip for FMR-CAD increases mitral leaflet stress and radial strain in LV sub-valvular myocardium. Mechanical effects of MitraClip are augmented by LV enlargement.
Journal Article
Malignant Mitral Valve Prolapse: Risk and Prevention of Sudden Cardiac Death
Purpose of Review
The purpose of this review is to explore the prevalence and risk factors for a malignant phenotype in mitral valve prolapse (MVP) characterized by life-threatening ventricular arrhythmias and sudden cardiac arrest and death (SCD), including mechanistic and pathophysiologic findings and mechanism-based potential therapies.
Recent Findings
A malignant phenotype in MVP characterized by life-threatening arrhythmias has long been recognized, although MVP is often benign. Efforts to identify this malignant phenotype have revealed potential risk factors for SCD that include elongated, myxomatous leaflets, ECG changes, and complex ventricular ectopy. More recently, malignant MVP has been associated with myocardial fibrosis in the papillary muscles and inferobasal left ventricular wall. This localization suggests a central role of prolapse-induced mechanical forces on the myocardium in creating an arrhythmogenic substrate and triggering life-threatening arrhythmias. This mechanism for fibrosis is also consistent with imaging evidence of prolapse-induced mechanical changes in the papillary muscles and inferobasal left ventricular wall. Currently, no therapy to prevent SCD in malignant MVP has been established and limited clinical data are available. Mechanistic information and prospective study have the potential to identify patients at risk of SCD and preventive strategies.
Summary
Malignant MVP relates to unique properties and mechanical abnormalities in the mitral valve apparatus and adjacent myocardium. Increased understanding of disease mechanisms and determinants of arrhythmias is needed to establish effective therapies.
Journal Article
Prevalence of Rheumatic Heart Disease in First-degree Relatives of Index-cases: A Systematic Review and Meta-Analysis
Background: Rheumatic heart disease (RHD) is the leading cause of cardiac death in children, with over 300,000 annual fatalities. Immunological, genetic, and environmental factors contribute to an increased risk of RHD. It remains unclear whether first-degree relatives have a higher RHD prevalence than the regional average. Methods: We performed a systematic review and meta-analysis of echocardiographic screening studies reporting the prevalence of RHD in family members of individuals with RHD or acute rheumatic fever. PubMed, Embase, Cochrane, and Lilacs databases were searched. Finding Forrester RHD was classified as per the 2012 World Heart Federation criteria. Random-effects models assessed definite RHD prevalence in study groups. Results: Four of the 1160 studies were included, with 776 first-degree relatives screened. Two studies were from Africa, one from South America, and one from Oceania. In the first-degree relatives of index cases, the prevalence of RHD was 7% (95% confidence interval [CI] 3.7-13). The control group, individuals screened with no known RHD cases in their family, had a lower prevalence than first-degree relatives (risk ratio [RR] 0.44, 95% CI 0.26-0.75). There was no difference in the prevalence of RHD among siblings and parents of cases. Conclusion: RHD prevalence in first-degree relatives of index cases was more significant than the There is an overall prevalence of non-relatives from the respective region, which suggests that genetic predisposition may play a role. In future studies of RHD, the systematic screening of first-degree relatives should be considered with a better control group—socioeconomic, region, age, and sex-matched.
Journal Article