Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.
Mechanical circulatory support technology is continually improving. However, adverse complications do occur with devastating consequences, for example, pump thrombosis that may develop in several parts of the pump system. The aim of this study was to design an experimental clot/thrombosis model to register and analyze acoustic signals from the left ventricular assist device (LVAD) HeartMate II (HMII) (Thoratec Corporation, Inc., Pleasanton, CA, USA) and detect changes in sound signals correlating to clots in the inflow, outflow, and pump housing. Using modern telecom techniques, it was possible to register and analyze the HMII pump-specific acoustic fingerprint in an experimental model of LVAD support using a mock loop. Increase in pump speed significantly (P < 0.005) changed the acoustic fingerprint at certain frequency (0–23 000 Hz) intervals (regions: R1–3 and peaks: P1,3–4). When the ball valves connected to the tubing were narrowed sequentially by ∼50% of the inner diameter (to mimic clot in the out- and inflow tubing), the frequency spectrum changed significantly (P < 0.005) in P1 and P2 and R1 when the outflow tubing was narrowed. This change was not seen to the same extent when the lumen of the ball valve connected to the inflow tube was narrowed by ∼50%. More significant (P < 0.005) acoustic changes were detected in P1 and P2 and R1 and R3, with the largest dB figs. in the lower frequency ranges in R1 and P2, when artificial clots and blood clots passed through the pump system. At higher frequencies, a significant change in dB figs. in R3 and P4 was detected when clots passed through the pump system. Acoustic monitoring of pump sounds may become a valuable tool in LVAD surveillance.
There is increasing evidence for successful management of end-stage heart failure with continuous-flow left ventricular assist device (CF-LVAD) technology. However, passive flow adjustment at fixed CF-LVAD speed is susceptible to flow balancing issues as well as adverse hemodynamic effects relating to the diminished arterial pulse pressure and flow. With current therapy, flow cannot be adjusted with changes in venous return, which can vary significantly with volume status. This limits the performance and safety of CF-LVAD. Active flow adjustment strategies have been proposed to improve the synchrony between the pump and the native cardiovascular system, mimicking the Frank-Starling mechanism of the heart. These flow adjustment strategies include modulation by CF-LVAD pump speed by synchrony and maintenance of constant flow or constant pressure head, or a combination of these variables. However, none of these adjustment strategies have evolved sufficiently to gain widespread attention. Herein we review the current challenges and future directions of CF-LVAD therapy and sensor technology focusing on the development of a physiologic, long-term active flow adjustment strategy for CF-LVADs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.