Cardiac magnetic resonance imaging derived quantification of myocardial ischemia and scar improves risk stratification and patient management in stable coronary artery disease

Background: Quantification of myocardial ischemia and necrosis might ameliorate prognostic models and lead to improved patient management. However, no standardized consensus on how to assess and quantify these parameters has been established. The aim of this study was to quantify these variables by cardiac magnetic resonance imaging (CMR) and to establish possible incremental implications in cardiovascular risk prediction. Methods: This study is a retrospective analysis of patients with known or suspected coronary artery disease (CAD) referred for adenosine perfusion CMR was performed. Myocardial ischemia and necrosis were assessed and quantified using an algorithm based on standard first-pass perfusion imaging and late gadolinium enhancement (LGE). The combined primary endpoint was defined as cardiac death, non-fatal myocardial infarction, and stroke. Results: 845 consecutive patients were enrolled into the study. During the median follow-up of 3.64 [1.03; 10.46] years, 61 primary endpoints occurred. Patients with primary endpoint showed larger extent of ischemia (10.7 ± 12.25% vs. 3.73 ± 8.29%, p < 0.0001) and LGE (21.09 ± 15.11% vs. 17.73 ± 10.72%, p < 0.0001). A risk prediction model containing the extent of ischemia and LGE proved to be superior in comparison to all other models (χ² increase: from 39.678 to 56.676, integrated discrimination index: 0.3851, p = 0.0033, net reclassification index: 0.11516, p = 0.0071). The ben­eficial effect of revascularization tended to be higher in patients with greater extents of ischemia, though statistical significance was not reached. Conclusions: Quantification of myocardial ischemia and LGE was shown to significantly improve existing risk prediction models and might thus lead to an improvement in patient management

Myocardial strain characteristics and outcomes after transcatheter aortic valve replacement

   Background: Objective of this study was to make an assessment of standard functional and defor­mation parameters (strain) in patients after transcatheter aortic valve replacement (TAVR) by cardiac magnetic resonance imaging (CMR) and the evaluation of their prognostic impact. Methods: Patients undergoing TAVR received CMR on a 1.5 T whole-body scanner at 3 months after the procedure. Deformation parameters (strain, strain rate, velocity, displacement) were assessed in lon­gitudinal, circumferential and radial orientation using a feature tracking approach. Primary outcome measure was defined according to Valve Academic Research Consortium-2 (VARC-2) criteria. Results: Eighty-three patients formed the study population. Deformation parameters were significantly reduced in all three orientations for strain (longitudinal: –12.1 ± 5.4% vs. –15.9 ± 1.96%, p < 0.0001; radial: 34.4 ± 15.3% vs. 47.2 ± 11.4%, p < 0.0001; circumferential: –16.8 ± 4.3% vs. –21.1 ± 2.5%, p < 0.0001) and strain rate (longitudinal: –0.79 ± 0.33%/s vs. –0.91 ± 0.23%/s, p = 0.043; radial: 2.5 ± 1.2%/s vs. 2.9 ± 0.9%, p = 0.067; circumferential: –1.1 ± 0.6%/s vs. –1.3 ± 0.3%/s, p = 0.006) in comparison to a healthy control population. Median follow-up was 614 days. During this period, 13 endpoints occurred (cumulative event rate of 10.7%). Patients with event by trend exhibited poorer strain and strain rate in longitudinal and radial orientation without reaching statistical significance (longitudinal strain: –11.2 ± 5.4% vs. –12.3 ± 5.4%, p = 0.52; longitudinal strain rate: –0.73 ± ± 0.23%/s vs. 0.80 ± 0.35%/s, p = 0.53; radial strain: 29.5 ± 19.6% vs. 35.2 ± 14.5%, p = 0.24; radial strain rate: 2.2 ± 1.6%/s vs. 2.6 ± 1.2%/s, p = 0.31). Conclusions: Assessment of left ventricular deformation parameters by CMR revealed functional abnormalities in comparison to healthy controls. Prognostic significance remains to be further investi­gated.

Drug-coated balloon: an effective alternative to stent strategy in small-vessel coronary artery disease—a meta-analysis

BackgroundSmall-vessel coronary artery disease (CAD) is frequently observed in coronary angiography and linked to a higher risk of lesion failure and restenosis. Currently, treatment of small vessels is not standardized while having drug-eluting stents (DES) or drug-coated balloons (DCBs) as possible strategies. We aimed to conduct a meta-analytic approach to assess the effectiveness of treatment strategies and outcomes for small-vessel CAD.MethodsComprehensive literature search was conducted using PubMed, Embase, MEDLINE, and Cochrane Library databases to identify studies reporting treatment strategies of small-vessel CAD with a reference diameter of ≤3.0 mm. Target lesion revascularization (TLR), target lesion thrombosis, all-cause death, myocardial infarction (MI), and major adverse cardiac events (MACE) were defined as clinical outcomes. Outcomes from single-arm and randomized studies based on measures by means of their corresponding 95% confidence intervals (CI) were compared using a meta-analytic approach. Statistical significance was assumed if CIs did not overlap.ResultsThirty-seven eligible studies with a total of 31,835 patients with small-vessel CAD were included in the present analysis. Among those, 28,147 patients were treated with DES (24 studies) and 3,299 patients with DCB (18 studies). Common baseline characteristics were equally distributed in the different studies. TLR rate was 4% in both treatment strategies [0.04; 95% CI 0.03–0.05 (DES) vs. 0.03–0.07 (DCB)]. MI occurred in 3% of patients receiving DES and in 2% treated with DCB [0.03 (0.02–0.04) vs. 0.02 (0.01–0.03)]. All-cause mortality was 3% in the DES group [0.03 (0.02–0.05)] compared with 1% in the DCB group [0.01 (0.00–0.03)]. Approximately 9% of patients with DES developed MACE vs. 4% of patients with DCB [0.09 (0.07–0.10) vs. 0.04 (0.02–0.08)]. Meta-regression analysis did not show a significant impact of reference vessel diameter on outcomes.ConclusionThis large meta-analytic approach demonstrates similar clinical and angiographic results between treatment strategies with DES and DCB in small-vessel CAD. Therefore, DES may be waived in small coronary arteries when PCI is performed with DCB

Cusp-overlap view reduces conduction disturbances and permanent pacemaker implantation after transcatheter aortic valve replacement even with balloon-expandable and mechanically-expandable heart valves

BackgroundConduction disturbances demanding permanent pacemaker implantation (PPI) remain a common complication after transcatheter aortic valve replacement (TAVR). Optimization of the implantation depth (ID) by introducing the cusp-overlap projection (COP) technique led to a reduced rate of PPI when self-expanding valves were used.ObjectivesThe aim of the present study was to determine if using the novel COP view is applicable for all types of TAVR prosthesis and results in a higher ID and reduced incidence of new conduction disturbances and PPI.MethodsIn this prospective case-control study 586 consecutive patients undergoing TAVR with either balloon-expandable Edwards SAPIEN S3 (n = 280; 47.8%), or mechanically expandable Boston LOTUS Edge heart valve prostheses (n = 306; 52.2%) were included. ID as well as rates of periprocedural PPI and left bundle branch block (LBBB) were compared between the conventional three-cusp coplanar (TCC) projection and the COP view for implantation.ResultsOf 586 patients, 282 (48.1%) underwent TAVR using COP, whereas in 304 patients (51.9%) the TCC view was applied. Using COP a significantly higher ID was achieved in Edwards SAPIEN S3 TAVR procedures (ID mean difference −1.0 mm, 95%−CI −1.9 to −0.1 mm; P = 0.029), whereas the final platform position did not differ significantly between both techniques when a Boston LOTUS Edge valve was used (ID mean difference −0.1 mm, 95%-CI −1.1 to +0.9 mm; P = 0.890). In Edwards SAPIEN S3 valves, higher ID was associated with a numerically lower post-procedural PPI incidence (4.9% vs. 7.3%; P = 0.464). Moreover, ID was significantly deeper in patients requiring PPI post TAVR compared to those without PPI [8.7 mm (6.8–10.6 mm) vs. 6.5 mm (6.1–7.0 mm); P = 0.005]. In Boston LOTUS Edge devices, COP view significantly decreased the incidence of LBBB post procedure (28.1% vs. 47.9%; P < 0.001), while PPI rates were similar in both groups (21.6% vs. 25.7%; P = 0.396).ConclusionThe present study demonstrates the safety, efficacy and reproducibility of the cusp-overlap view even in balloon-expandable and mechanically-expandable TAVR procedures. Application of COP leads to significantly less LBBB in repositionable Boston LOTUS Edge valves and a numerically lower PPI rate in Edwards SAPIEN S3 valves post TAVR compared to the standard TCC projection. The results should encourage to apply the COP view more widely in clinical practice

A New CYP2E1 Inhibitor, 12-Imidazolyl-1-dodecanol, Represents a Potential Treatment for Hepatocellular Carcinoma

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD. © 2021 Torsten Diesinger et al

Die Rolle der Cytochrom P450-Isoform 2E1 und deren Inhibierung durch 12-Imidazolyldodecanol im Cisplatin-induzierten Nierenversagen

Das akute, Medikamenten-induzierte Nierenversagen stellt aufgrund seiner Häufigkeit und seiner Bedeutung hinsichtlich Mortalität und Morbidität eine Herausforderung für die klinische Medizin dar. Es häufen sich Anhaltspunkte, die auf eine Rolle der Cytochrom P450-abhängigen Monooxygenasen in seiner Entstehung hinweisen. Insbesondere beim Nierenschaden, der als Folge einer Therapie mit Cisplatin auftritt, wurde eine Interaktion zwischen dem Chemotherapeutikum und der CYP-Isoform 2E1 postuliert. Zur Klärung dieser Frage sollte auf zellulärer Ebene die Interaktion von Cisplatin beziehungsweise 12-ID-ol mit der Cytochrom-Isoform 2E1 nachgewiesen werden. Weiterhin sollten die Auswirkungen einer Cisplatin-Exposition auf Nierenzellen bezüglich Viabilität, Zelltod, Apoptose, ROS-Belastung und mitochondrialer Integrität beleuchtet werden. Schließlich sollten die so gewonnenen Ergebnisse auf ein lebendiges Modell übertragen werden. So konnte gezeigt werden, dass Cisplatin zu einer gesteigerten ROS-Belastung mit anschließendem Verlust der mitochondrialen Integrität in den Nierenzellen führt, was in einer Abnahme der Viabilität der betroffenen Zellen mündet. Dabei konnte nachgewiesen werden, dass in Abhängigkeit der eingesetzten Cisplatin-Konzentration Zelltodmechanismen ausgelöst werden, die entweder zur Apoptose oder zur Nekrose führen. Weiterhin konnten Anhaltspunkte gefunden werden, die eine Interaktion von Cisplatin mit dem Cytochrom 2E1 nahelegen. Schließlich konnte ein Tierversuchsmodell etabliert werden, in dem die nierenschädigende Wirkung einer Cisplatin-Applikation nachvollzogen werden konnte. Im nächsten Schritt konnte gezeigt werden, dass sich die negativen Effekte von Cisplatin durch eine gleichzeitige Behandlung mit 12-ID-ol deutlich abschwächen ließen. Damit konnten Argumente erarbeitet werden, die für das therapeutische Potential einer spezifischen Hemmung fremdstoffmetabolisierender Enzyme im Rahmen der Medikamenten-induzierten Nephrotoxizität sprechen