Implantation of contemporary transcatheter aortic valves in small aortic annuli: the international multicentre TAVI-SMALL 2 registry.

BACKGROUND: Treatment of aortic stenosis in patients with small annuli is challenging and can result in prosthesis-patient mismatch (PPM). AIMS: We aimed to compare the forward flow haemodynamics and clinical outcomes of contemporary transcatheter valves in patients with small annuli. METHODS: The TAVI-SMALL 2 international retrospective registry included 1,378 patients with severe aortic stenosis and small annuli (annular perimeter <72 mm or area <400 mm2) treated with transfemoral self-expanding (SEV; n=1,092) and balloon-expandable valves (BEV; n=286) in 16 high-volume centres between 2011 and 2020. Analyses comparing SEV versus BEV and supra-annular (SAV; n=920) versus intra-annular valves (IAV; n=458) included inverse probability of treatment weighting (IPTW). The primary endpoints were the predischarge mean aortic gradient and incidence of severe PPM. The secondary endpoint was the incidence of more than mild paravalvular leak (PVL). RESULTS: The predischarge mean aortic gradient was lower after SAV versus IAV (7.8±3.9 vs 12.0±5.1; p<0.001) and SEV versus BEV implantation (8.0±4.1 vs 13.6±4.7; p<0.001). Severe PPM was more common with IAV and BEV when compared to SAV and SEV implantation, respectively, (8.8% vs 3.6%; p=0.007 and 8.7% vs 4.6%; p=0.041). At multivariable logistic regression weighted by IPTW, SAV protected from severe PPM regardless of its definition. More than mild PVL occurred more often with SEV versus BEV (11.6% vs 2.6%; p<0.001). CONCLUSIONS: In small aortic annuli, implantation of SAV and SEV was associated with a more favourable forward haemodynamic profile than after IAV and BEV implantation, respectively. More than mild PVL was more common after SEV than BEV implantation.

Individual Patient Data Meta-analysis of Drug-eluting Versus Bare-metal Stents for Percutaneous Coronary Intervention in Chronic Versus Acute Coronary Syndromes.

New-generation drug-eluting stents (DES) strongly reduce restenosis and repeat revascularization compared with bare-metal stents (BMS) for percutaneous coronary intervention. There is residual uncertainty as to whether other prognostically relevant outcomes are affected by DES versus BMS concerning initial presentation (chronic coronary syndrome [CCS] vs acute coronary syndrome [ACS]). We performed an individual patient data meta-analysis of randomized trials comparing new-generation DES versus BMS (CRD42017060520). The primary outcome was the composite of cardiac death or myocardial infarction (MI). Outcomes were examined at maximum follow-up and with a 1-year landmark. Risk estimates are expressed as hazard ratio (HR) with 95% confidence interval (CI). A total of 22,319 patients were included across 14 trials; 7,691 patients (34.5%) with CCS and 14,628 patients (65.5%) with ACS. We found evidence that new-generation DES versus BMS consistently reduced the risk of cardiac death or MI in both patients with CCS (HR 0.83, 95% CI 0.70 to 0.98, p <0.001) and ACS (HR 0.83, 95% CI 0.75 to 0.92, p <0.001) (p-interaction = 0.931). This benefit was mainly driven by a similar reduction in the risk of MI (p-interaction = 0.898) for both subsets (HRCCS 0.80, 95% CI 0.65 to 0.97; HRACS 0.79, 95% CI 0.70 to 0.89). In CCS and ACS, we found a time-dependent treatment effect, with the benefit from DES accumulating during 1-year follow-up, without offsetting effects after that. In conclusion, patients with CCS were slightly underrepresented in comparative clinical trials. Still, they benefited similarly to patients with ACS from new-generation DES instead of BMS with a sustained reduction of cardiac death or MI because of lower event rates within 1 year.

Procedural outcomes of the 34 mm EvolutR Transcatheter valve in a real-world population insights from the HORSE multicenter collaborative registry.

OBJECTIVES: The aim of this study was to evaluate outcomes of real-world patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) with the 34 mm Evolut R (Medtronic, Minneapolis, Minnesota). BACKGROUND: Larger aortic annulus has been associated with increased incidence of paravalvular leaks (PVLs) after TAVR. However, little is known, so far, about the performance of the 34 mm Evolut R in this setting. METHODS: From the multicenter, international, retrospective Horizontal Aorta in Transcatheter Self-expanding Valves (HORSE) registry, including patients who underwent TAVR for native severe AS, we selected patients treated with the 34 mm Evolut R evaluating procedural characteristics and VARC-2 defined device success. We also compared 34 mm Evolut R with other Evolut R sizes. RESULTS: Among the 4434 patients included in the registry, 572 (13%) received the 34 mm Evolut R valve. Mean age was 80.8 ± 6.5 years and the median STS PROM score was 4 [interquartile range 2-6]. Device success was achieved in 87.4% with 7.7% of PVLs; moreover, the rate of permanent pacemaker implantation (PPMI) was 22.4%. Patients who underwent 34 mm Evolut R implantation experienced more in-hospital permanent pacemaker implantation (22.4% vs. 15%; p < 0.001). At multivariate analysis, 34 mm Evolut R did not affect device success (OR: 0.81 [0.60-1.09]; p = 0.151). Device success was consistent with other THVs sizes (87.4% vs. 89.6%; p = 0.157). CONCLUSIONS: THV replacement in patients requiring 34 mm Evolut R has an acceptable performance. Compared to other Medtronic sizes it demonstrated to be comparable in terms of device success, despite an increased rate of pacemaker implantation.

Acceptance and safety of femoral versus radial access for percutaneous coronary intervention (PCI): results from a large monitor-controlled German registry (QuIK).

BACKGROUND: In 2015 and 2018, European Society of Cardiology guidelines for percutaneous coronary intervention (PCI) favoring radial access over femoral access were published. These recommendations were based on randomized trials suggesting that patients treated radially experienced reduced bleeding complications and all-cause mortality. We aimed to assess acceptance and results of radial access in a real-world scenario by analyzing all PCI cases in the Quality Assurance in Invasive Cardiology (QuIK) registry. METHODS: The QuIK registry prospectively collects data on all diagnostic and interventional coronary procedures from 148 private practice cardiology centers in Germany. Major adverse cardiac and cerebrovascular events (MACE) were defined as myocardial infarction, stroke, or death during hospitalization. RESULTS: From 2012 to 2018, 189,917 patients underwent PCI via either access method. The rate of radial approach steadily increased from 13 to 49%. The groups did not differ significantly with respect to age or extent of coronary disease. Femoral approach was significantly more common in patients with ST elevation myocardial infarction and cardiogenic shock. Overall, there were significant differences in MACE (radial 0.12%; femoral 0.24%; p < 0.0009) and access site complications (radial 0.2%; femoral 0.8% (p < 0.0009). CONCLUSION: Our data reveals an increase in use of radial access in recent years in Germany. The radial approach emerged as favorable regarding MACE in non-myocardial infarction patients, as well as favorable regarding access site complication regardless of indication for percutaneous intervention.

Drug-Eluting or Bare-Metal Stents for Left Anterior Descending or Left Main Coronary Artery Revascularization.

Background New-generation drug-eluting stents (DES) reduce target-vessel revascularization compared with bare-metal stents (BMS), and recent data suggest that DES have the potential to decrease the risk of myocardial infarction and cardiovascular mortality. We evaluated the treatment effect of DES versus BMS according to the target artery (left anterior descending [LAD] and/or left main [LM] versus other territories [no-LAD/LM]). Methods and Results The Coronary Stent Trialist (CST) Collaboration gathered individual patient data of randomized trials of DES versus BMS for the treatment of coronary artery disease. The primary outcome was the composite of cardiac death or myocardial infarction. Hazard ratios (HRs) with 95% CIs were derived from a 1-stage individual patient data meta-analysis. We included 26 024 patients across 19 trials: 13 650 (52.4%) in the LAD/LM and 12 373 (47.6%) in the no-LAD/LM group. At 6-year follow-up, there was strong evidence that the treatment effect of DES versus BMS depended on the target vessel (P-interaction=0.024). Compared with BMS, DES reduced the risk of cardiac death or myocardial infarction to a greater extent in the LAD/LM (HR, 0.76; 95% CI, 0.68-0.85) than in the no-LAD/LM territories (HR, 0.93; 95% CI, 0.83-1.05). This benefit was driven by a lower risk of cardiac death (HR, 0.83; 95% CI, 0.70-0.98) and myocardial infarction (HR, 0.74; 95% CI, 0.65-0.85) in patients with LAD/LM disease randomized to DES. An interaction (P=0.004) was also found for all-cause mortality with patients with LAD/LM disease deriving benefit from DES (HR, 0.86; 95% CI, 0.76-0.97). Conclusions As compared with BMS, new-generation DES were associated with sustained reduction in the composite of cardiac death or myocardial infarction if used for the treatment of LAD or left main coronary stenoses. Registration URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42017060520.

Drug-Eluting or Bare-Metal Stents for Left Anterior Descending or Left Main Coronary Artery Revascularization

BACKGROUND: New-generation drug-eluting stents (DES) reduce target-vessel revascularization compared with bare-metal stents (BMS), and recent data suggest that DES have the potential to decrease the risk of myocardial infarction and cardiovascular mortality. We evaluated the treatment effect of DES versus BMS according to the target artery (left anterior descending [LAD] and/or left main [LM] versus other territories [no-LAD/LM]). METHODS AND RESULTS: The Coronary Stent Trialist (CST) Collaboration gathered individual patient data of randomized trials of DES versus BMS for the treatment of coronary artery disease. The primary outcome was the composite of cardiac death or myocardial infarction. Hazard ratios (HRs) with 95% CIs were derived from a 1-stage individual patient data meta-analysis. We included 26 024 patients across 19 trials: 13 650 (52.4%) in the LAD/LM and 12 373 (47.6%) in the no-LAD/LM group. At 6-year follow-up, there was strong evidence that the treatment effect of DES versus BMS depended on the target vessel (P interaction=0.024). Compared with BMS, DES reduced the risk of cardiac death or myocardial infarction to a greater extent in the LAD/LM (HR, 0.76; 95% CI, 0.68­0.85) than in the no-LAD/LM territories (HR, 0.93; 95% CI, 0.83­1.05). This benefit was driven by a lower risk of cardiac death (HR, 0.83; 95% CI, 0.70­0.98) and myocardial infarction (HR, 0.74; 95% CI, 0.65­0.85) in patients with LAD/LM disease randomized to DES. An interaction (P=0.004) was also found for all-cause mortality with patients with LAD/LM disease deriving benefit from DES (HR, 0.86; 95% CI, 0.76­0.97). CONCLUSIONS: As compared with BMS, new-generation DES were associated with sustained reduction in the composite of cardiac death or myocardial infarction if used for the treatment of LAD or left main coronary stenoses.

Horizontal Aorta in Transcatheter Self-Expanding Valves: Insights From the HORSE International Multicentre Registry.

[Figure: see text].

Aortic angle distribution and predictors of horizontal aorta in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Horizontal aorta (HA) is an anatomical feature that can pose significant technical challenges for the successful positioning of the bioprosthetic valve during transcatheter aortic valve replacement (TAVR). Physiological range of aortic angle (AA) is unknown; hence there is no cutoff AA for classifying HA. Moreover, patient characteristics predicting HA are under-investigated. METHODS: This was a retrospective analysis of prospective collected data from 16 heart valve centers in Europe. The study utilized a common dataset with a priori agreed-upon definitions and variables. Eligible patients underwent TAVR between 2014 and 2020 and had multidetector computed tomographic imaging data available for determining the AA. The analysis described the distribution of AA and potential predictors of HA. Inter-center variability was also explored. RESULTS: For 4022 patients analyzed, the mean AA ± standard deviation was 49.4° ± 9.4° (median 49°, inter-quartile range [IQR] 12°, range 18-90°). There was no significant difference in mean AA between men and women (49.4° ± 9.1° vs. 49.6° ± 9.3°, respectively; p = 0.53); therefore, 49.4° was accepted as the cutoff value for HA in subsequent analyses. Covariates significantly associated with HA included age (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.04, p < 0.001), body mass index (OR: 1.06, 95% CI: 1.05-1.08, p < 0.01), previous cardiac surgery (OR: 0.58, 95% CI: 0.45-0.75, p < 0.001), and porcelain aorta (OR: 0.66, 95% CI: 0.52-0.85, p = 0.001). Some inter-center variability was observed. CONCLUSIONS: We defined 49.4° as the mean AA, and also associated predictors of HA in a large case series of patients with severe aortic stenosis candidates for TAVR.

A case report of sinoatrial arrest caused by temporal lobe epilepsy in subclinical glioblastoma.

BACKGROUND: Atrial fibrillation with symptomatic bradycardia, higher grade atrioventricular block, and sinus node disease are all common indications for permanent pacemaker implantation. The most frequent causes of sinus node disease treated with pacemaker implantation involve degenerative structural changes of the sinus node; less often, extrinsic causes (such as damage due to myocardial infarction or heightened parasympathetic nervous system activity) lead to pacemaker implantation. CASE PRESENTATION: A 50-year-old patient with syncope and documented sinoatrial arrest was referred. Neurologic exams (including CT and EEG) revealed no pathologies, so a pacemaker was implanted. Postoperatively, syncope occurred again due to a focal seizure during which sinus rhythm transitioned to atrial pacing by the device. Further neurologic testing revealed focal epilepsy. Six months later, stage IV glioblastoma was diagnosed and the patient was treated surgically. CONCLUSION: Intracerebral tumors should be considered in the differential diagnosis for patients with unexplained sinoatrial block, as well as in patients with repeat syncope after pacemaker implantation. Cranial MRI could aid the diagnostic workup of such cases.

Transcatheter Self-Expandable Valve Implantation for Aortic Stenosis in Small Aortic Annuli: The TAVI-SMALL Registry.

OBJECTIVES: The aim of this study was to evaluate and compare the outcomes of transcatheter self-expandable prostheses in patients with small annuli. BACKGROUND: Transcatheter aortic heart valves appear to have better performance than surgical valves in terms of prosthesis-patient mismatch, especially in patients with aortic stenosis with small aortic annuli. METHODS: TAVI-SMALL (International Multicenter Registry to Evaluate the Performance of Self-Expandable Valves in Small Aortic Annuli) is a retrospective registry of patients with severe aortic stenosis and small annuli (annular perimeter <72 mm or area <400 mm2 on computed tomography) treated with transcatheter self-expandable valves (n = 859; Evolut R, n = 397; Evolut PRO, n = 84; ACURATE, n = 201; Portico, n = 177). Primary endpoints were post-procedural mean aortic gradient, indexed effective orifice area, and rate of severe prosthesis-patient mismatch. RESULTS: Pre-discharge gradients were consistently low in every group, with a slight benefit with the Evolut R (8.1 mm Hg; 95% confidence interval [CI]: 7.7 to 8.5 mm Hg) and Evolut PRO (6.9 mm Hg; 95% CI: 6.3 to 7.6 mm Hg) compared with the ACURATE (9.6 mm Hg; 95% CI: 8.9 to 10.2 mm Hg) and Portico (8.9 mm Hg; 95% CI: 8.2 to 9.6 mm Hg) groups (p < 0.001). Mean indexed effective orifice area was 1.04 cm2/m2 (95% CI: 1.01 to 1.08 cm2/m2) with a trend toward lower values with the Portico. No significant differences were reported in terms of severe prosthesis-patient mismatch (overall rate 9.4%; p = 0.134), permanent pacemaker implantation (15.6%), and periprocedural and 1-year adverse events. Pre-discharge more than mild paravalvular leaks were significantly more common with the Portico (19.2%) and less common with the Evolut PRO (3.6%) compared with the Evolut R (11.8%) and ACURATE (9%) groups. CONCLUSIONS: Transcatheter self-expandable valves showed optimal clinical and echocardiographic results in patients with small aortic annuli, although supra-annular functioning transcatheter heart valves seemed to slightly outperform intra-annular functioning ones. The role of transcatheter aortic valve replacement with self-expandable valves for the treatment of aortic stenosis in patients with small annuli needs to be confirmed in larger trials.

Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials

Background New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear.Methods We did an individual patient data meta-analysis of randomized clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520.Findings We obtained individual data for 26 616 patients in 20 randomized trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78­0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71­0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78­1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88­1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50­0·80, p<0·001) and target-vessel revascularization (0·55, 0·50­0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year. Interpretation The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year. (AU)

Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials.

BACKGROUND: New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear. METHODS: We did an individual patient data meta-analysis of randomised clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520. FINDINGS: We obtained individual data for 26 616 patients in 20 randomised trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78-0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71-0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78-1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88-1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50-0·80, p<0·001) and target-vessel revascularisation (0·55, 0·50-0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year. INTERPRETATION: The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year. FUNDING: Bern University Hospital.

Differences in Vascular Response between Balloon Overstretch and Stent Overexpansion in Nonatherosclerotic Porcine Coronary Arteries.

Which preclinical models are best suited for restenosis research remains uncertain. Here we compared the restenotic responses after balloon or stent overstretch injury in a porcine coronary artery. A total of 30 coronary lesions in 5 pigs were treated by balloon overdilatation or oversized stent implantation at various balloon-to-artery (B:A) ratios. Four weeks later, the lesions were examined in vivo by using coronary angiography, intravascular ultrasound, and optical coherence tomography (OCT). At follow-up, the lumen area stenosis and plaque burden at the minimal lumen area site were greater in stented sites than in balloon injury site (lumen area stenosis, 21.7 ± 8.9% compared with 32.8 ± 12.1%; plaque burden, 30.1% ± 10.1% compared with 44.7% ± 10.1%, respectively). The remodeling index was significantly smaller for the balloon-injury group than the stent group (0.86 ± 0.11 compared with 1.00 ±0.04). Only the stent group that was dilated at a high B:A ratio resulted in increased plaque burden. In the balloon-injury sites, high B:A ratios were significantly associated with greater negative remodeling. Tissue morphology assessment by OCT revealed that the predominant pattern in balloon injury sites was homogeneous, whereas that in stented sites was a layered to heterogeneous pattern. Neointimal proliferation was significantly greater after oversized stenting than after balloon overstretch injury. Together these findings suggest that stent overexpansion of porcine coronary arteries might be appropriate for researching restenosis than is the balloon overstretch injury model.

RIP1-Dependent Programmed Necrosis is Negatively Regulated by Caspases During Hepatic Ischemia-Reperfusion.

Programmed necrosis (necroptosis), a newly discovered form of cell death, is mediated by receptor-interacting protein 1 (RIP1) and plays a pivotal role after myocardial, renal, and cerebral ischemia-reperfusion (I/R). The relevance of necroptosis in the postischemic liver remains, however, unclear. The aim of this study was to analyze the role of programed necrosis during hepatic I/R. C57BL6 mice were subjected to warm hepatic I/R (90 min/240 min). The animals were pretreated with either the RIP1 inhibitor necrostatin-1 (Nec-1, 3.5 µg kg) or vehicle (Nec-1inactive, 3.5 µg kg) administered systemically before ischemia. Sham-operated animals served as controls (n = 6 each group). The inflammatory response was evaluated by intravital microscopy. The hepatic transaminases alanine aminotransferase/aspartate aminotransferase in plasma as well as the activity of caspase-3 in tissue were determined as markers of hepatocellular injury. Leukocyte recruitment to the liver, sinusoidal perfusion failure, as well as the transaminase activities were strongly increased on I/R as compared with the sham-operated mice. Inhibition of the RIP1-dependent pathway with Nec-1, however, did not attenuate I/R-induced leukocyte migration, perfusion failure, and hepatocellular injury. Western blot analysis showed a baseline RIP1 expression in livers from sham-operated mice, whereas RIP1 expression was not detectable in both Nec-1-treated and vehicle-treated I/R group. Caspase-3 activity was significantly elevated after I/R in both postischemic groups. Our in vivo data show that RIP1-mediated necroptosis is not present in the postischemic liver and that I/R-induced caspase activation is associated with loss of RIP1 expression. Because caspases are able to cleave RIP1, we hypothesize that I/R-triggered caspase activation negatively regulates necroptosis and, thereby, determines apoptosis as a preferred route of cell death after hepatic I/R.

Modulating CD4+ T cell migration in the postischemic liver: hepatic stellate cells as new therapeutic target?

BACKGROUND: CD4+ T cells play a critical role during hepatic ischemia-reperfusion (I/R) injury although the mechanisms of their migration in the postischemic liver remain unclear. We answered the questions of whether hepatic stellate cells (HSCs) interact with CD4+ T cells during I/R of the liver and whether modulation of HSC activity affects T cell-dependent I/R injury. METHODS: In mice, migration of CD4+ T cells was analyzed in vivo using conventional intravital microscopy and two-photon microscopy. CD4+ T cell-HSC interactions were visualized after infusion of fluorescence-labeled CD4+ T cells into Cx3CR1 mice (mice exhibiting GFP-labeled HSCs) after I/R. Because the activation of HSC is controlled by endocannabinoid receptors, CB-1 and CB-2, the mice received treatment before I/R with the CB-2 agonist JWH-133 to reach HSC depletion or the CB-1 agonist arachidonylcyclopropylamide to activate HSCs. Sinusoidal perfusion and liver transaminases were used as markers of I/R injury. RESULTS: Hepatic I/R induced CD4+ T cell recruitment in sinusoids. More than 25% of adherent CD4+ T cells were colocalized with HSCs during reperfusion, suggesting a direct cell-cell interaction. The HSC deactivation with JWH-133 significantly attenuated the CD4+ T cell recruitment in the postischemic liver and reduced I/R injury as compared to the vehicle-treated group. The HSC hyperactivation by CB-1, however, did not affect T-cell migration and even increased perfusion failure. CONCLUSION: Our in vivo data suggest that CD4+ T cells interact with HSCs on their migration into the hepatic parenchyma, and a depletion or deactivation of HSCs protects the liver from T cell-dependent I/R injury.

Targeting platelet migration in the postischemic liver by blocking protease-activated receptor 4.

BACKGROUND: Platelets play a critical role during hepatic ischemia/reperfusion (I/R). Antiplatelet strategies during liver transplantation are, however, limited because of bleeding complications. Thrombin is activated during reperfusion and regulates platelet and endothelial cell function via protease-activated receptor 4 (PAR-4). Interventions at the level of PAR-4, the main platelet receptor for thrombin, are assumed to attenuate the proinflammatory effects of thrombin without affecting blood coagulation. The aim of our study was to analyze the impact of PAR-4 blockade on platelet recruitment and microvascular injury during hepatic I/R. METHODS: C57BL/6 mice undergoing hepatic I/R (90 min/60 min and 240 min) were treated either with a selective PAR-4 antagonist TcY-NH2 or vehicle. Sham-operated animals served as controls. Recruitment of freshly isolated and fluorescence-labeled platelets and CD4 T cells was analyzed using intravital video fluorescence microscopy. Parameters of tissue injury, regeneration, and blood coagulation were assessed in tissue/blood samples. RESULTS: Results show that treatment with TcY-NH2 attenuated I/R-induced platelet and CD4 T-cell recruitment, improved sinusoidal perfusion failure, and reduced apoptotic and necrotic injury. The protective effect of PAR-4 blockade did not suppress hemostasis or liver regeneration. CONCLUSION: Our in vivo data suggest PAR-4 as a potential target for future therapeutic strategies against platelet-mediated liver injury on transplantation.