The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written.Health professionals are encouraged to take them fully into account when exercising their clinical judgement.The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances
Loss of surface MHC I is an important mechanism by which cancer cells evade immune surveillance, and it can correlate with worse prognosis and resistance to immunotherapy. MHC I surface expression can be affected by genomic or transcriptional alterations to HLA-A/B/C, β2M, or the class I antigen processing machinery. In the case of transcriptional loss, we hypothesized that certain cancers might employ specific epigenetic programs to enforce downregulation of the MHC I pathway. Thus, we sought to identify novel MHC I regulators in MHC I-low cancers. In particular, we focused on Merkel cell carcinoma (MCC), a rare but aggressive neuroendocrine skin cancer that is caused by the Merkel cell polyomavirus in 80% of cases. Notably, MHC I downregulation is prevalent in MCC. We first generated and characterized a series of patient-derived MCC cell lines, in which MHC I surface expression was low but inducible with IFN-γ. We then conducted genome-scale CRISPR-KO and open reading frame (ORF) gain-of-function screens in one of our virus-positive MCC lines, using FACS to select for perturbations that upregulated surface MHC I. One of the top hits from these screens was PRC1.1, a non-canonical Polycomb repressive complex. Polycomb complexes are known to mediate gene silencing through chromatin modification and play an important role in development and cancer. These studies suggest a possible role for PRC1.1 in suppressing MHC I in MCC.
Abstract Objectives We sought to identify baseline demographics and procedural factors that might independently predict in‐hospital stroke following transcatheter aortic valve implantation (TAVI). Background Stroke is a recognized, albeit infrequent, complication of TAVI. Established predictors of procedure‐related in‐hospital stroke; however, remain poorly defined. Methods We conducted an observational cohort analysis of the multicenter UK TAVI registry. The primary outcome measure was the incidence of in‐hospital stroke. Results A total of 8,652 TAVI procedures were performed from 2007 to 2015. There were 205 in‐hospital strokes reported by participating centers equivalent to an overall stroke incidence of 2.4%. Univariate analysis showed that the implantation of balloon‐expandable valves caused significantly fewer strokes (balloon‐expandable 96/4,613 [2.08%] vs. self‐expandable 95/3,272 [2.90%]; p = .020). After multivariable analysis, prior cerebrovascular disease (CVD) (odds ratio [OR] 1.51, 95% confidence interval [CI 1.05–2.17]; p = .03), advanced age at time of operation (OR 1.02 [0.10–1.04]; p = .05), bailout coronary stenting (OR 5.94 [2.03–17.39]; p = .008), and earlier year of procedure (OR 0.93 [0.87–1.00]; p = .04) were associated with an increased in‐hospital stroke risk. There was a reduced stroke risk in those who had prior cardiac surgery (OR 0.62 [0.41–0.93]; p = .01) and a first‐generation balloon‐expandable valve implanted (OR 0.72 [0.53–0.97]; p = .03). In‐hospital stroke significantly increased 30‐day (OR 5.22 [3.49–7.81]; p < .001) and 1‐year mortality (OR 3.21 [2.15–4.78]; p < .001). Conclusions In‐hospital stroke after TAVI is associated with substantially increased early and late mortality. Factors independently associated with in‐hospital stroke were previous CVD, advanced age, no prior cardiac surgery, and deployment of a predominantly first‐generation self‐expandable transcatheter heart valve.
Objective—To investigate the effects of QRS duration on characteristics of the left ventricular pressure pulse derived from the time course of functional mitral regurgitation by continuous wave Doppler.Design—Retrospective and prospective study of 50 patients with dilated cardiomyopathy, by electrocardiography, echocardiography, and Doppler cardiography.Setting—Tertiary cardiac referral centre.Patients—50 patients (mean age (SD) 58 (16)) with dilated cardiomyopathy, all with functional mitral regurgitation.Results—The values of QRS duration ranged widely, from 70 to 190 ms with a mean value of 110 ms, and were unimodally distributed. The overall duration of mitral regurgitation correlated positively with QRS time (r=0·65) over the entire range of values. When the duration of mitral regurgitation was divided into contraction, aortic ejection, and relaxation times, increased QRS duration prolonged contraction (r=0·51) and relaxation (r=0·52) times. Aortic ejection time was affected by RR interval (r=0·74). Duration of QRS correlated negatively with peak rate of rise in left ventricular pressure (+dP/dt) (r=−0·48), and positively with the time intervals from Q to peak pressure (r=0·49) and to peak +dP/dt (r=0·72), and also with those from the start of mitral regurgitation to peak pressure (r=0·49) and to peak +dP/dt (r=0·76). Duration of QRS did not directly affect the peak rate of left ventricular pressure fall (−dP/dt), or the isovolumic relaxation period.Conclusions—Values of QRS duration are unimodally distributed in patients with dilated cardiomyopathy, without evidence of a discrete group of patients with left bundle branch block. Prolonged QRS duration reduces peak +dP/dt, prolongs overall duration of the pressure pulse, the time to peak +dP/dt, and relaxation time. Duration of QRS must therefore be taken into account in assessing standard measurements of myocardial function in patients with dilated cardiomyopathy.
VARMA, C., et al .: Comparison Between Biventricular Pacing and Single Site Pacing in Patients with Poor Ventricular Function: A Hemodynamic Study. Biventricular pacing has been suggested as offering greater hemodynamic benefit than single site pacing in patients with advanced heart failure and left bundle branch block. This was tested using acute multisite pacing. Eighteen such patients were atrial‐sensed, ventricular multisite paced in random order for 5 minutes. The best achieved measure of cardiac output (CO), pulmonary capillary wedge pressure (PCWP) and left ventricular (LV) + dP/dt max at RV, LV, and biventricular pacing sites compared. Baseline PCWP, CO, and LV + dP/dt max were 20 ± 10 mmHg 4.8 ± 1.3 L/min and 680 ± 173 mmHg/s respectively. In all 18 patients CO and in 17 of 18 patients LV + dP/dt max and PCWP improved with pacing. In the group as a whole, no significant hemodynamic difference between pacing sites was observed in PCWP (pacing site RV 19 ± 10 mmHg, LV 17 ± 10, biventricular 18 ± 11) or CO (RV 5.2 ± 1.5 L/min, LV 5.1 ± 1.5, biventricular 5.3 ± 1.7). Increased stroke volume/PCWP with LV (5.6 ± 3.7 mLs/mmHg) and biventricular pacing ( 5.4 ± 4.0 ) were not significantly greater compared to RV pacing ( 4.7 ± 3.0 , ANOVA P = 0.20). Increase in LV + dP/dt max with pacing at LV (814 ± 190 mmHg/s) and biventricular ( 839 ± 290 ) sites was not significantly greater than the increase with RV pacing (769 ± 203 mmHg/s, ANOVA P = 0.30). Pacing in patients with heart failure and conduction delay can produce a hemodynamic benefit. There is individual variation in the pacing site that leads to the greatest improvement. In the group as a whole, biventricular and LV pacing produced only modest improvements compared to RV pacing. (PACE 2003; 26[Pt. I]:551–558)
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