Phenotype-genotype spectrum of a cohort of congenital muscular dystrophies: a single-centre experience from India.

Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8 years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India.

Effects of membrane and flexural stiffnesses on aortic valve dynamics: identifying the mechanics of leaflet flutter in thinner biological tissues.

Valvular pathologies that induce deterioration in the aortic valve are a common cause of heart disease among aging populations. Although there are numerous available technologies to treat valvular conditions and replicate normal aortic function by replacing the diseased valve with a bioprosthetic implant, many of these devices face challenges in terms of long-term durability. One such phenomenon that may exacerbate valve deterioration and induce undesirable hemodynamic effects in the aorta is leaflet flutter, which is characterized by oscillatory motion in the biological tissues. While this behavior has been observed for thinner bioprosthetic valves, the specific underlying mechanics that lead to leaflet flutter have not previously been identified. This work proposes a computational approach to isolate the fundamental mechanics that induce leaflet flutter in thinner biological tissues during the cardiac cycle. The simulations in this work identify reduced flexural stiffness as the primary factor that contributes to increased leaflet flutter in thinner biological tissues, while decreased membrane stiffness and mass of the thinner tissues do not directly induce flutter in these valves. The results of this study provide an improved understanding of the mechanical tissue properties that contribute to flutter and offer significant insights into possible developments in the design of bioprosthetic tissues to account for and reduce the incidence of flutter.

Thinner biological tissues induce leaflet flutter in aortic heart valve replacements.

Valvular heart disease has recently become an increasing public health concern due to the high prevalence of valve degeneration in aging populations. For patients with severely impacted aortic valves that require replacement, catheter-based bioprosthetic valve deployment offers a minimally invasive treatment option that eliminates many of the risks associated with surgical valve replacement. Although recent percutaneous device advancements have incorporated thinner, more flexible biological tissues to streamline safer deployment through catheters, the impact of such tissues in the complex, mechanically demanding, and highly dynamic valvular system remains poorly understood. The present work utilized a validated computational fluid-structure interaction approach to isolate the behavior of thinner, more compliant aortic valve tissues in a physiologically realistic system. This computational study identified and quantified significant leaflet flutter induced by the use of thinner tissues that initiated blood flow disturbances and oscillatory leaflet strains. The aortic flow and valvular dynamics associated with these thinner valvular tissues have not been previously identified and provide essential information that can significantly advance fundamental knowledge about the cardiac system and support future medical device innovation. Considering the risks associated with such observed flutter phenomena, including blood damage and accelerated leaflet deterioration, this study demonstrates the potentially serious impact of introducing thinner, more flexible tissues into the cardiac system.

Immersogeometric fluid-structure interaction modeling and simulation of transcatheter aortic valve replacement.

The transcatheter aortic valve replacement (TAVR) has emerged as a minimally invasive alternative to surgical treatments of valvular heart disease. TAVR offers many advantages, however, the safe anchoring of the transcatheter heart valve (THV) in the patients anatomy is key to a successful procedure. In this paper, we develop and apply a novel immersogeometric fluid-structure interaction (FSI) framework for the modeling and simulation of the TAVR procedure to study the anchoring ability of the THV. To account for physiological realism, methods are proposed to model and couple the main components of the system, including the arterial wall, blood flow, valve leaflets, skirt, and frame. The THV is first crimped and deployed into an idealized ascending aorta. During the FSI simulation, the radial outward force and friction force between the aortic wall and the THV frame are examined over the entire cardiac cycle. The ratio between these two forces is computed and compared with the experimentally estimated coefficient of friction to study the likelihood of valve migration.