Background and Aim of the Study: Negative impact of prosthesis-patient mismatch (PPM) on long term survival after valve replacement has been reported. However, the effect of PPM after bioprosthetic mitral valve replacement (MVR) has not yet been well examined. The purpose of this study was to investigate the effect of PPM on late outcomes after bioprosthetic MVR for mitral regurgitation (MR). Methods: A total of 181 patients underwent bioprosthetic MVR between April 2008 and December 2016. After excluding patients with mitral stenosis and those with incomplete data, 128 patients were included in the study. Postoperative transthoracic echocardiography was performed for all patients and the effective orifice area (EOA) was calculated using the pressure half-time method. The effective orifice area index (EOAI) was calculated by the formula: EOA/body surface area (BSA). PPM was defined as a postoperative EOAI ≤ 1.2 cm2/m2. The characteristics and outcomes were compared between the groups. Results: There were 34 patients (26.6%) with PPM and 94 patients (73.4%) without PPM. Although proportion of males and BSA were higher in the PPM group, valve size distributions were similar between the two groups. There were no significant differences in the in-hospital mortality and morbidities. Multivariable analysis showed that PPM was an independent predictor of late mortality (hazard ratio [HR] 3.38; 95% confidence interval [CI] 1.69-6.75; p = .001) and death from heart failure (HR 31.03, 95% CI 4.49-214.40, p < .001). Conclusions: PPM after MVR for MR was associated with long-term mortality and death from heart failure.
OBJECTIVES: Monitoring cerebral autoregulation may help identify the lower limit of autoregulation in individual patients. Mean arterial blood pressure below lower limit of autoregulation appears to be a risk factor for postoperative acute kidney injury. Cerebral autoregulation can be monitored in real time using correlation approaches. However, the precise thresholds for different cerebral autoregulation indexes that identify the lower limit of autoregulation are unknown. We identified thresholds for intact autoregulation in patients during cardiopulmonary bypass surgery and examined the relevance of these thresholds to postoperative acute kidney injury. DESIGN: A single-center retrospective analysis. SETTING: Tertiary academic medical center. PATIENTS: Data from 59 patients was used to determine precise cerebral autoregulation thresholds for identification of the lower limit of autoregulation. These thresholds were validated in a larger cohort of 226 patients. METHODS AND MAIN RESULTS: Invasive mean arterial blood pressure, cerebral blood flow velocities, regional cortical oxygen saturation, and total hemoglobin were recorded simultaneously. Three cerebral autoregulation indices were calculated, including mean flow index, cerebral oximetry index, and hemoglobin volume index. Cerebral autoregulation curves for the three indices were plotted, and thresholds for each index were used to generate threshold- and index-specific lower limit of autoregulations. A reference lower limit of autoregulation could be identified in 59 patients by plotting cerebral blood flow velocity against mean arterial blood pressure to generate gold-standard Lassen curves. The lower limit of autoregulations defined at each threshold were compared with the gold-standard lower limit of autoregulation determined from Lassen curves. The results identified the following thresholds: mean flow index (0.45), cerebral oximetry index (0.35), and hemoglobin volume index (0.3). We then calculated the product of magnitude and duration of mean arterial blood pressure less than lower limit of autoregulation in a larger cohort of 226 patients. When using the lower limit of autoregulations identified by the optimal thresholds above, mean arterial blood pressure less than lower limit of autoregulation was greater in patients with acute kidney injury than in those without acute kidney injury. CONCLUSIONS: This study identified thresholds of intact and impaired cerebral autoregulation for three indices and showed that mean arterial blood pressure below lower limit of autoregulation is a risk factor for acute kidney injury after cardiac surgery.
We investigated the effect of postural changes on cerebral circulation by measuring carotid artery blood flow (CABF) in the supine position and during head-up tilt (HUT) test using a Doppler flow meter. Subjects included 10 patients with neurally mediated syncope, 10 patients with orthostatic intolerance, 8 with epilepsy, aged between 8 to 24 years (mean ± SD, 13.9 ± 4.1 years). The test caused pallor and dizziness in 16 patients (symptomatic), while no symptoms were recognized in the other 12 patients (asymptomatic). Significant reductions in the mean CABF (Fm), maximum CABF (Fs) and minimum CABF (Fd), components of the CABF waveform, were noticed during HUT compared to before HUT (supine), and these reductions in symptomatic patients were more severe than those in asymptomatic patients (Fm: - 2.8 ± 2.0 SD vs - 0.7 ± 1.4 SD; Fs: - 2.7 ± 1.5 SD vs - 0.9 ± 1.3 SD; Fd: - 4.5 ± 2.8 SD vs - 2.2 ± 2.1 SD). Reductions in Fm, Fs and Fd in the symptomatic patients during HUT lasted longer than those of the asymptomatic patients, being statistically significant for Fm and Fs (Fm: p < 0.01; Fs: p < 0.05). The criteria during HUT for distinguishing neurally mediated syncope (NMS) from others was Fs: < - 4 SD and Fd: < - 5 SD. Our data suggest that reduction of CABF should be carefully evaluated for the diagnosis of neurally mediated syncope in pediatric patients. Such a reduction might be an essential mechanism of syncopal attacks.
O-GlcNAcylation is a dynamic, reversible posttranslational modification (PTM) that regulates a multitude of biological processes. Fluctuations in O-GlcNAC of various calcium handling proteins impact their functionality in cardiomyocytes. Here, we show for the first time that TRPC6, a nonselective receptor-operated cation channel and mediator of hypertrophy and fibrosis, is constitutively O-GlcNAcylated in the ankyrin repeat domain (AR4), at Ser 14, Thr 70, and Thr 221 within the N-terminal cytoplasmic segment. Of these, only substitution of Thr 221 with alanine (T221A) results in a change of function, notably a hyperactive TRPC6 channel with 5X greater increase in consequent NFAT promoter activity, which is a marker of TRPC6 calcium signaling. Patch-clamp analysis of T221A mutant channels found a 75-80% increased conductance compared to WT. Myocardial injection of T221A in homozygous TRPC6 KO mice by AAV-9 mediated gene transfer results in systolic dysfunction, hypertrophy, and cardiac fibrosis, by loss of OGlcNAc modification at site T221. T221 is highly conserved across species and found in the AR4 domain, which forms the core structure of TRPC6 intracellular domain. Mutating the site in its closest homologs, TRPC3 and TRPC7, also activates channel activity. T221 O-GlcNAcylation also protects the nascent protein from premature proteasomal degradation. Molecular modeling from the crystal structure of human TRPC6 predicts that OGlcNACylation stabilizes electrostatic interactions with the 193-203 loop near AR4, and loop connecting AR4 to the linker helix 1 (LH1) at S199, E200, and E246. Mutating these sites to alanine also increases TRPC6-NFAT signaling similar to what was observed in the T221A mutant. In summary, this study highlights that O-GlcNAcylation of TRPC6 is an important PTM needed to stabilize channel function, and its decline results in gain-of-function related diseases.
