No abstract

SummaryBackground Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebocontrolled randomised trials to show its efficacy.

In this review, the authors reflect upon the role of coronary physiology in the modern management of coronary artery disease. They critically appraise the scientific background of the instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR), from early experimental studies to validation studies against indexes of ischemia, to clinical trials assessing outcome. At this important juncture for the field, the authors make predictions for the future of physiological stenosis assessment, outlining developments for both iFR and FFR in new clinical domains beyond the confines of stable angina. With a focus on the evolving future of iFR and FFR, the authors describe how physiological assessment with iFR may advance its application from simply justifying to guiding revascularization.

Purpose: The expression of the ETS-related gene (ERG) is low or undetectable in benign prostate epithelial cells. High prevalence of ERG overexpression in prostate cancer cells due to TMPRSS2-ERG fusions suggest for causal roles of ERG protein in the neoplastic process. TMPRSS2-ERG fusion junctions have been extensively studied in prostate cancer. However, virtually nothing is known about the nature of full-length transcripts and encoded proteins. This study focuses on qualitative and quantitative features of full-lengthTMPRSS2-ERG transcripts in prostate cancer. Experimental Design: Full-lengthTMPRSS2-ERG transcripts were cloned and sequenced from a cDNA library generated from pooled RNA of six TMPRSS2-ERG fusion^positive prostate tumors. The encoded ERG proteins were analyzed in HEK293 cells. Copy numbers of TMPRSS2-ERG splice variants were determined by quantitative reverse transcription-PCR in laser capture microdissected prostate cancer cells. Results: Two types of TMPRSS2-ERG cDNAs were identified: type I, which encodes full-length prototypical ERG protein (ERG1, ERG2, ERG3), and type II, encoding truncated ERG proteins lacking the ETS domain (ERG8 and a new variant,TEPC). In microdissected prostate tumor cells from 122 patients, relative abundance of these variants was in the following order: ERG8 > TEPC > ERG 3 > ERG1/2 with combined overexpression rate of 62.3% in prostate cancer. Increased ratio of type I over type II splice forms showed a trend of correlation with less favorable pathology and outcome.Conclusions: Qualitative and quantitative features of specific ERG splice variants defined here promise to enhance the utility of ERG as a biomarker and therapeutic target in prostate cancer.Molecular genetic evaluations of prostate cancer are defining mutational and expression alterations of critical oncogenes involved in disease onset and/or progression (reviewed in refs. 1 -3). Discovery of prevalent chromosomal rearrangements/ translocations leading to the activation of ETS transcription factors (predominantly ERG) through the androgen receptorregulated TMPRSS2 gene promoter underscore the critical roles of ERG-encoded protein in prostate cancer (4 -7). Because ERG represents the majority of TMPRSS2-ETS factor alterations described thus far (6, 7), we have focused on the expression and regulation of TMPRSS2-ERG in prostate cancer. Oncogenic functions of ETS factors, including ERG, have also been implicated in diverse cancers (8).Structure and function of ERG-encoded proteins remain to be defined in prostate cancer. ERG consists of 17 exons spanning about 300 kb and generates at least nine alternate splice forms, seven of them coding for protein products of varying sizes (9). These ERG splice variants have been primarily described in nonprostate tissues. Despite the large body of data on the TMPRSS2-ERG fusion junctions in prostate cancer (reviewed in refs. 6, 7), virtually nothing is known about the full-length TMPRSS2-ERG transcripts in prostate cancer, including the existence and relative a...

The diagnostic accuracy of FFR-CT varies markedly across the spectrum of disease. This analysis allows clinicians to interpret the diagnostic accuracy of individual FFR-CT results. In combination with patient-specific factors, clinicians can use FFR-CT to judge when the cost and risk of an invasive angiogram may safely be avoided.

ObjectivesThe study sought to determine the coronary flow characteristics of angiographically intermediate stenoses classified as discordant by fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR).BackgroundDiscordance between FFR and iFR occurs in up to 20% of cases. No comparisons have been reported between the coronary flow characteristics of FFR/iFR discordant and angiographically unobstructed vessels.MethodsBaseline and hyperemic coronary flow velocity and coronary flow reserve (CFR) were compared across 5 vessel groups: FFR+/iFR+ (108 vessels, n = 91), FFR–/iFR+ (28 vessels, n = 24), FFR+/iFR– (22 vessels, n = 22), FFR–/iFR– (208 vessels, n = 154), and an unobstructed vessel group (201 vessels, n = 153), in a post hoc analysis of the largest combined pressure and Doppler flow velocity registry (IDEAL [Iberian-Dutch-English] collaborators study).ResultsFFR disagreed with iFR in 14% (50 of 366). Baseline flow velocity was similar across all 5 vessel groups, including the unobstructed vessel group (p = 0.34 for variance). In FFR+/iFR– discordants, hyperemic flow velocity and CFR were similar to both FFR–/iFR– and unobstructed groups; 37.6 (interquartile range [IQR]: 26.1 to 50.4) cm/s vs. 40.0 [IQR: 29.7 to 52.3] cm/s and 42.2 [IQR: 33.8 to 53.2] cm/s and CFR 2.36 [IQR: 1.93 to 2.81] vs. 2.41 [IQR: 1.84 to 2.94] and 2.50 [IQR: 2.11 to 3.17], respectively (p > 0.05 for all). In FFR–/iFR+ discordants, hyperemic flow velocity, and CFR were similar to the FFR+/iFR+ group; 28.2 (IQR: 20.5 to 39.7) cm/s versus 23.5 (IQR: 16.4 to 34.9) cm/s and CFR 1.44 (IQR: 1.29 to 1.85) versus 1.39 (IQR: 1.06 to 1.88), respectively (p > 0.05 for all).ConclusionsFFR/iFR disagreement was explained by differences in hyperemic coronary flow velocity. Furthermore, coronary stenoses classified as FFR+/iFR– demonstrated similar coronary flow characteristics to angiographically unobstructed vessels.

Aims  The optimal method of revascularization for patients with left main coronary artery disease (LMCAD) is controversial. Coronary artery bypass graft surgery (CABG) has traditionally been considered the gold standard therapy, and recent randomized trials comparing CABG with percutaneous coronary intervention (PCI) with drug-eluting stents (DES) have reported conflicting outcomes. We, therefore, performed a systematic review and updated meta-analysis comparing CABG to PCI with DES for the treatment of LMCAD. Methods and results  We systematically identified all randomized trials comparing PCI with DES vs. CABG in patients with LMCAD. The primary efficacy endpoint was all-cause mortality. Secondary endpoints included cardiac death, myocardial infarction (MI), stroke, and unplanned revascularization. All analyses were by intention-to-treat. There were five eligible trials in which 4612 patients were randomized. The weighted mean follow-up duration was 67.1 months. There were no significant differences between PCI and CABG for the risk of all-cause mortality [relative risk (RR) 1.03, 95% confidence interval (CI) 0.81–1.32; P = 0.779] or cardiac death (RR 1.03, 95% CI 0.79–1.34; P = 0.817). There were also no significant differences in the risk of stroke (RR 0.74, 95% CI 0.35–1.50; P = 0.400) or MI (RR 1.22, 95% CI 0.96–1.56; P = 0.110). Percutaneous coronary intervention was associated with an increased risk of unplanned revascularization (RR 1.73, 95% CI 1.49–2.02; P < 0.001). Conclusion  The totality of randomized clinical trial evidence demonstrated similar long-term mortality after PCI with DES compared with CABG in patients with LMCAD. Nor were there significant differences in cardiac death, stroke, or MI between PCI and CABG. Unplanned revascularization procedures were less common after CABG compared with PCI. These findings may inform clinical decision-making between cardiologists, surgeons, and patients with LMCAD.

Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year.