ORCID Profile
0000-0002-6879-5343
Current Organisation
Vanderbilt University Medical Center
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Publisher: Oxford University Press (OUP)
Date: 20-06-2018
DOI: 10.1093/CVR/CVY156
Abstract: Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia–reperfusion (I/R), a pathological condition associated with cardiomyocyte osmotic stress. TRPV4 protein expression increased in cardiomyocytes of Aged (24–27 months) mice compared with Young (3–6 months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1 μmol/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4−/−) mice. In Aged, pharmacological inhibition of TRPV4 (1 μmol/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I/R-induced cardiac damage. Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.JCIN.2018.03.019
Abstract: The aim of this study was to assess the implications of concomitant tricuspid regurgitation (TR) in patients undergoing valve-in-valve (VIV) transcatheter aortic valve replacement. Patients undergoing VIV transcatheter aortic valve replacement with concomitant TR may have worse outcomes, and optimal management remains undetermined. The multicenter PARTNER 2 (Placement of Aortic Transcatheter Valves) VIV trial enrolled patients with symptomatic degenerated surgical aortic bioprostheses who were at high risk for reoperation. Outcomes were assessed between patients with mild or no TR versus moderate or severe TR. A total of 237 patients underwent VIV procedures (mean age 78.7 ± 10.8 years, mean Society of Thoracic Surgeons score 9.1 ± 4.8%). In this cohort, 162 patients (68.4%) had mild or no TR, and 75 patients (31.6%) had moderate or severe TR. Although there was no difference in New York Heart Association functional class III or IV symptomatic status (89.3% vs. 91.4% p = 0.62) or moderate or severe right ventricular dysfunction (9.4% vs. 16.9% p = 0.11), patients with moderate or severe TR were more likely to be at high surgical risk, with a Society of Thoracic Surgeons score of >8 (62.7% vs 46.9% p = 0.02). There was no difference in a composite endpoint of death and rehospitalization between moderate or severe TR and mild or no TR, either at 30 days (10.7% vs. 9.9% p = 0.85) or at 1-year follow-up (24.1% vs. 23.2% p = 0.80). There was a significant reduction in overall moderate or severe TR from baseline at 30 days (31.1% vs. 21.1% p = 0.002), which was sustained at 1-year follow-up (38.0% vs. 22.8% p = 0.004). Despite higher predicted surgical risk, the presence of TR was not a predictor of long-term outcomes. Importantly, there was significant reduction in TR severity at both short- and long-term follow-up. In selected patients undergoing VIV transcatheter aortic valve replacement, it may be appropriate to conservatively manage concomitant TR.
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for Brian Lindman.