PCI Complexes Research Articles

Coronary angiography following transcatheter aortic valve replacement: Insights from the SWEDEHEART registry.

Transcatheter aortic valve replacement (TAVR) is the most common treatment in patients with symptomatic severe aortic stenosis (AS). As concomitant coronary artery disease is common in AS patients, access to the coronary arteries following TAVR is of increasing importance. This study evaluated the incidence and risk factors for unplanned coronary angiography following TAVR and, using fluoroscopic time as a surrogate, analyzed the complexity of coronary artery cannulation. All patients who underwent TAVR in Sweden between 2008 and 2022 were identified using the SWEDEHEART registry. The cumulative incidence of coronary angiography after TAVR was analyzed with mortality as a competing risk. Angiography and PCI complexity were analyzed using fluoroscopic time and compared across different transcatheter heart valve designs. Out of 9806 patients, 566 subsequently required coronary angiography. The incidence was highest for three-vessel and/or left main disease. Younger age, the extent of prior coronary artery disease, and peripheral vascular disease were associated with an increased risk of coronary angiography. Fluoroscopy time was increased in TAVR patients compared to the control group with the longest fluoroscopy times observed in cases involving supra-annular and self-expanding valves. The incidence of coronary angiography following TAVR is still low. Younger patients and patients with concomitant coronary artery disease have a higher risk. Procedural time is longer in patients with a previous THV replacement. As TAVR is emerging as the first-line treatment in patients with longer life expectancy, facilitating coronary access is an important factor when considering which THV device to implant.

Efficacy and safety of P2Y12 inhibitor monotherapy after complex PCI: a collaborative systematic review and meta-analysis.

Complex percutaneous coronary intervention (C-PCI) is associated with an increased risk of ischaemic and bleeding complications. We aimed to assess the safety and efficacy of a 1-3-month dual antiplatelet therapy (DAPT) regimen followed by P2Y12 inhibitor monotherapy after C-PCI. We conducted a meta-analysis of randomized trials comparing a 1-3-month DAPT regimen followed by P2Y12 inhibitor monotherapy with standard (≥12 months) DAPT in patients undergoing C-PCI. C-PCI criteria and the co-primary bleeding and ischaemic outcomes were determined according to each trial. Secondary outcomes included major bleeding, all-cause death, myocardial infarction, and stent thrombosis. All outcomes were evaluated at 12 months after randomization. We used hazard ratios (HRs) and 95% confidence interval (CI) as a metric of choice for treatment effects with random-effects models. Among 8299 screened studies, five randomized trials fulfilled the eligibility criteria. In the pooled population of 34615 patients, 8818 (25.5%) underwent C-PCI. As compared with standard DAPT, a 1-3-month DAPT regimen followed by P2Y12 inhibitor monotherapy reduced the bleeding risk in C-PCI (HR:0.66, 95% CI:0.44-0.98) and non-C-PCI (HR:0.60, 95% CI:0.45-0.79) patients (P-interaction=0.735). Furthermore, the risk for the primary ischaemic endpoint was similar in patients randomized to either arm, with significant effect modification by PCI complexity showing an enhanced benefit of 1-3-month DAPT in patients undergoing C-PCI (C-PCI, HR:0.69, 95% CI:0.48-1.00; non-C-PCI, HR:1.04, 95% CI:0.84-1.30; P-interaction=0.028). As compared with a standard DAPT, a 1-3-month DAPT regimen followed by P2Y12 inhibitor monotherapy reduced bleeding complications after C-PCI without increasing the risk of ischaemic events.PROSPERO-registered (CRD42021259271).

Effect of aspirin discontinuation according to individualised patient bleeding and ischemic risks after PCI: a TWILIGHT trial sub-analysis

Abstract Background The TWILIGHT trial demonstrated a reduction in BARC 2, 3 or 5 (BARC-235) bleeding without an increase in ischemic events at 1-year in high-risk PCI patients randomized to placebo or aspirin (ASA) on a background of ticagrelor 3-months after PCI. However, the effect of ASA discontinuation according to baseline risk of bleeding and ischemic events remain unclear. Purpose To a) develop separate models to predict the risk of bleeding and ischemic events, and b) to assess treatment effect of ASA discontinuation across the risk strata. Methods Using the TWILIGHT patient database (N=7,119), two multivariable models, one for BARC-235 bleeding and one for CV death, nonfatal MI or nonfatal ischemic stroke (ischemic endpoint) were developed, and their predictive capacity was assessed. The effect of randomized treatment on bleeding and ischemic events across different patient risk-group categories as determined by the risk scores was investigated. Results At 1-year, 350 (5.4%) patients experienced a BARC-235 bleeding event and 258 (3.6%) experienced an ischemic event. Independent predictors of BARC-235 included haemoglobin levels at index PCI, proton-pump inhibitor non-use at discharge, age, liver disease and active smoking (c-statistic 0.64). Independent predictors of the ischemic outcome included a positive troponin ACS, prior CABG, diabetes, age, peripheral artery disease, prior PCI, a history of congestive heart failure, active smoking, the level of index PCI complexity, and prior MI (c-statistic 0.71). The risk of a BARC-235 almost doubled between patients in lower versus higher bleeding risk categories (4.3% versus 7.9%) and ischemic risk more than tripled between patients in lower versus higher ischemic risk categories (2.0% versus 7.0%) (see Figure 1). There was no evidence of a differential treatment effect for dual antiplatelet therapy versus ticagrelor monotherapy across the different risk categories of bleeding (interaction P=0.54) and ischemic risk (interaction P=0.95) (Table 1). Conclusion Individual patient bleeding and ischemic risks after PCI can both be readily characterised with good discrimination. The effect of ASA discontinuation in preventing bleeding in ticagrelor-treated patients was consistent regardless of baseline bleeding risk. There was no evidence for increased ischemic events with ASA discontinuation according to baseline ischemic risk. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): AstraZenecaIcahn School of Medicine at Mount Sinai

Prospective application of a risks-adjusted antithrombotic protocol in elderly patients treated with the last generation of everolimus-eluting stents. The SIERRA-75 (EPIC-05) registry

Abstract Background Elderly patients show a higher incidence of ischemic and bleeding events after PCI. Purpose We sought to investigate clinical outcomes in elderly patients revascularized with last generation everolimus-eluting stent (EES) treated with antithrombotic strategies guided by bleeding and ischemic risks. Methods Prospective multicenter registry including patients over 75 years revascularized with EES and subsequent antithrombotic therapy guided according to a protocol based on clinical presentation, PCI complexity and the PRECISE DAPT score. The primary safety endpoint was a composite of cardiac death, myocardial infarction and definitive/probable stent thrombosis and the primary efficacy endpoint was TLR. An historical matched group of patients treated with current drug eluting stents other than EES was used as control. Results Finally, 1,064 patients were included, 80.8±4.2 years, 36.6% women, 72% ACS and 53.6% complex PCI. Primary safety endpoint was met in 6.2% and primary efficacy endpoint in 1.5%. Bleeding BARC 2–5 was reported in 7.8% and definite or probable stent thrombosis in 1.3%. The multivariable adjusted model showed no significant association of the prescribed short/long therapies with any endpoint. No stent thrombosis were reported in the subgroup with shorter DAPT duration. As compared to control group, bleeding BARC 2–5 was significantly lower in SIERRA-75 group (7.4% vs 10.2%, p=0.04) as well as the composite of MACE and bleeding (14.3% vs 18.5%, p=0.02). Conclusions In elderly population the use of last generation EES along with a predefined risks-adjusted antithrombotic regimen seems to be associated with an improved prognosis in terms of ischemic and bleeding outcomes. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Abbott Laboratories

Guiding Catheters for Transradial Approach: New Designs and Summary of Experiences with VDL/VDR Catheters. A Novel Score for PCI Technical Complexity

In one multicenter and several single-center studies involving 202 cases, new shapes of transradial access PCI guide catheters were tested following a standardized original protocol. The evaluation included a newly designed score for PCI complexity. Three operators successfully performed the 40 cases of the multicenter study, scoring intermediate to difficult 66% of the cases. New shapes were tested for left and right coronary artery and saphenous vein graft PCIs, with right or left transradial access. The new shapes performed adequately, including in 5F sizing. PCI success and fluoroscopy time were related to the score of complexity.

The disordered PCI-binding human proteins CSNAP and DSS1 have diverged in structure and function.

Intrinsically disordered proteins (IDPs) regularly constitute components of larger protein assemblies contributing to architectural stability. Two small, highly acidic IDPs have been linked to the so‐called PCI complexes carrying PCI‐domain subunits, including the proteasome lid and the COP9 signalosome. These two IDPs, DSS1 and CSNAP, have been proposed to have similar structural propensities and functions, but they display differences in their interactions and interactome sizes. Here we characterized the structural properties of human DSS1 and CSNAP at the residue level using NMR spectroscopy and probed their propensities to bind ubiquitin. We find that distinct structural features present in DSS1 are completely absent in CSNAP, and vice versa, with lack of relevant ubiquitin binding to CSNAP, suggesting the two proteins to have diverged in both structure and function. Our work additionally highlights that different local features of seemingly similar IDPs, even subtle sequence variance, may endow them with different functional traits. Such traits may underlie their potential to engage in multiple interactions thereby impacting their interactome sizes.

Abstract 16507: Complex Percutaneous Coronary Intervention Features Worsen Prognosis in Diabetic Patients: Insights From a Large Single-center Registry

Introduction: Despite the increasing number of complex percutaneous coronary interventions (CPCI), data regarding outcomes following CPCI in patients with diabetes mellitus (DM) are scarce. Hypothesis: Compared to the general population, diabetic patients undergoing CPCI have worse prognosis. Methods: We analyzed data of patients who underwent PCI in a tertiary-care center between 2009 and 2017. Patients were divided into 2 groups (CPCI and non-CPCI) stratified by presence of DM. CPCI was defined as having ≥1 of the following: stent length >60 mm, ≥3 stents implanted, ≥3 lesions, ≥3 target vessels, bifurcation with ≥2 stents, or chronic total occlusion. The main outcome was major adverse cardiac events (MACE), a composite of death, myocardial infarction (MI) and target vessel revascularization (TVR) at 1 year. Results: Out of 20,412 patients included, 5,038 (24.7%) underwent CPCI. Patients with DM constituted 46.5% (n=9,494) of the overall cohort and 44.5% (n=2,240) of CPCI group. Among patients undergoing CPCI, diabetics were younger, more likely to be female, and had more cardiovascular risk factors (kidney disease, dyslipidemia, and hypertension) than non-diabetics. In addition, diabetic patients had more advanced coronary disease (multivessel disease, high syntax score, and longer lesion length). At 1 year, diabetic patients had higher risk of MACE than non-diabetic, regardless of PCI complexity ( Figure 1 ). Nonetheless, there was a significant interaction between CPCI and diabetes in terms of mortality at 1 year (p-interaction=0.009). In contrast, compared to non-diabetics, a higher risk of TVR ( adj HR 1.49, 95% CI [1.24 - 1.78], p <0.001) and bleeding ( adj HR 1.45, 95% CI [1.05 - 1.98], p=0.02) was observed in diabetics undergoing non-CPCI but not CPCI. Conclusion: Diabetic patients are at higher risk of MACE than the general population regardless of PCI complexity. Yet, 1-year mortality is substantially higher in diabetics undergoing CPCI than non-CPCI.

Low-dose prasugrel versus clopidogrel in elderly patients with high clinical and PCI complexity.

Low-dose prasugrel versus clopidogrel in elderly patients with high clinical and PCI complexity.

Accuracy of the PARIS score and PCI complexity to predict ischemic events in patients treated with very thin stents in unprotected left main or coronary bifurcations.

The PARIS risk score (PARIS-rs) and percutaneous coronary intervention complexity (PCI-c) predict clinical and procedural residual ischemic risk following PCI. Their accuracy in patients undergoing unprotected left main (ULM) or bifurcation PCI has not been assessed. The predictive performances of the PARIS-rs (categorized as low, intermediate, and high) and PCI-c (according to guideline-endorsed criteria) were evaluated in 3,002 patients undergoing ULM/bifurcation PCI with very thin strut stents. After 16 (12-22) months, increasing PARIS-rs (8.8% vs. 14.1% vs. 27.4%, p < .001) and PCI-c (15.2% vs. 11%, p = .025) were associated with higher rates of major adverse cardiac events ([MACE], a composite of death, myocardial infarction [MI], and target vessel revascularization), driven by MI/death for PARIS-rs and target lesion revascularization/stent thrombosis for PCI-c (area under the curves for MACE: PARIS-rs 0.60 vs. PCI-c 0.52, p-for-difference < .001). PCI-c accuracy for MACE was higher in low-clinical-risk patients; while PARIS-rs was more accurate in low-procedural-risk patients. ≥12-month dual antiplatelet therapy (DAPT) was associated with a lower MACE rate in high PARIS-rs patients, (adjusted-hazard ratio 0.42 [95% CI: 0.22-0.83], p = .012), with no benefit in low to intermediate PARIS-rs patients. No incremental benefit with longer DAPT was observed in complex PCI. In the setting of ULM/bifurcation PCI, the residual ischemic risk is better predicted by a clinical risk estimator than by PCI complexity, which rather appears to reflect stent/procedure-related events. Careful procedural risk estimation is warranted in patients at low clinical risk, where PCI complexity may substantially contribute to the overall residual ischemic risk.

Germline Maintenance Through the Multifaceted Activities of GLH/Vasa in Caenorhabditis elegans P Granules.

Vasa homologs are ATP-dependent DEAD-box helicases, multipotency factors, and critical components that specify and protect the germline. They regulate translation, amplify piwi-interacting RNAs (piRNAs), and act as RNA solvents; however, the limited availability of mutagenesis-derived alleles and their wide range of phenotypes have complicated their analysis. Now, with clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), these limitations can be mitigated to determine why protein domains have been lost or retained throughout evolution. Here, we define the functional motifs of GLH-1/Vasa in Caenorhabditis elegans using 28 endogenous, mutant alleles. We show that GLH-1's helicase activity is required to retain its association with P granules. GLH-1 remains in P granules when changes are made outside of the helicase and flanking domains, but fertility is still compromised. Removal of the glycine-rich repeats from GLH proteins progressively diminishes P-granule wetting-like interactions at the nuclear periphery. Mass spectrometry of GLH-1-associated proteins implies conservation of a transient piRNA-amplifying complex, and reveals a novel affinity between GLH-1 and three structurally conserved PCI (26S Proteasome Lid, COP9, and eIF3) complexes or "zomes," along with a reciprocal aversion for assembled ribosomes and the 26S proteasome. These results suggest that P granules compartmentalize the cytoplasm to exclude large protein assemblies, effectively shielding associated transcripts from translation and associated proteins from turnover. Within germ granules, Vasa homologs may act as solvents, ensuring mRNA accessibility by small RNA surveillance and amplification pathways, and facilitating mRNA export through germ granules to initiate translation.

P3180The effect of PCI complexity on the efficacy and safety of dabigatran dual therapy vs warfarin triple therapy in atrial fibrillation: a subgroup analysis from the RE-DUAL PCI trial

P3180The effect of PCI complexity on the efficacy and safety of dabigatran dual therapy vs warfarin triple therapy in atrial fibrillation: a subgroup analysis from the RE-DUAL PCI trial

Incremental value of preprocedural coronary computed tomographic angiography to classical coronary angiography for prediction of PCI complexity in left main stenosis

Introduction: The aim of our study was to assess the incremental value of Coronary Computed Tomography Angiography (CCTA) added to classical coronary angiography, for complex characterization of coronary lesions and prediction of procedural complexity in patients with significant left main (LM) stenoses. Material and Methods: Thirty-six patients with LM disease were enrolled in the study, and each subject underwent CCTA followed by coronary angiography and percutaneous revascularization. Results: Logistic regression analysis indicated a good correlation between the angiographic-calculated and the CCTA-derived Syntax scores for the whole group (r = 0.87, p 11.5 vs 25.2 +/-11.3, p = 0.01 for CCTA). In the same time, Ca scoring was significantly higher and plaque volumes were significantly larger in cases requiring complex revascularization procedures (299.5 +/-359.6 vs 917.3 +/-495.4, p = 0.04 for calcium score, 79.7 +/-28.5 vs 108.7 +/-25.3 mm3, p = 0.002 for plaque volumes). Multivariate analysis identified the following CCTA parameters as significant predictors of increased risk for complex intervention in LM lesions: plaque volume (OR 8.00, p = 0.008), Ca scoring (OR 6.37, p = 0.02) and CCTA Syntax score (OR 6.87, p = 0.01). Conclusions: CCTA derived parameters provide incremental information to classical coronary angiography for preoperative assessment of lesion severity in complex left main stenosis. CCTA derived Syntax score significantly correlates with the classical Coronary Angiography Syntax score and identifies the subgroup of patients who will be more exposed to procedural complications during the revascularization interventions.

047 Trends in access site choice and PCI outcomes: insights from the UK national PCI dataset

BackgroundThere has been a drive to change access site practice for PCI with the aim of reducing access site complications. This is increasingly important with the shift to more acute...

Dual function of Rpn5 in two PCI complexes, the 26S proteasome and COP9 signalosome.

Subunit composition and architectural structure of the 26S proteasome lid is strictly conserved between all eukaryotes. This eight-subunit complex bears high similarity to the eukaryotic translation initiation factor 3 and to the COP9 signalosome (CSN), which together define the proteasome CSN/COP9/initiation factor (PCI) troika. In some unicellular eukaryotes, the latter two complexes lack key subunits, encouraging questions about the conservation of their structural design. Here we demonstrate that, in Saccharomyces cerevisiae, Rpn5 plays dual roles by stabilizing proteasome and CSN structures independently. Proteasome and CSN complexes are easily dissected, with Rpn5 the only subunit in common. Together with Rpn5, we identified a total of six bona fide subunits at roughly stoichiometric ratios in isolated, affinity-purified CSN. Moreover, the copy of Rpn5 associated with the CSN is required for enzymatic hydrolysis of Rub1/Nedd8 conjugated to cullins. We propose that multitasking by a single subunit, Rpn5 in this case, allows it to function in different complexes simultaneously. These observations demonstrate that functional substitution of subunits by paralogues is feasible, implying that the canonical composition of the three PCI complexes in S.cerevisiae is more robust than hitherto appreciated.

PCI Complexes: Beyond the Proteasome, CSN, and eIF3 Troika

The bipartite PCI domain serves as the principal scaffold for proteasome lid, CSN, and eIF3, complexes that influence protein life span. PCI domains are also found in newly identified complexes directing nucleic acid regulation. The breadth of functions associated with the extended PCI family is a factor of shared subunits, among them a common factor Sem1/DSS1 that facilitates complex assembly.

The COP9 signalosome-like complex in S. cerevisiae and links to other PCI complexes

The COP9 signalosome (CSN), the lid subcomplex of the proteasome and translational intitation factor 3 (eIF3) share structural similarities and are often referred to as the PCI family of complexes. In multicellular eukaryotes, the CSN is highly conserved as an 8-subunit complex but in Saccharomyces cerevisiae the complex is rather divergent. We further characterize the composition and properties of the CSN in budding yeast and its interactions with these related complexes. Using the generalized profile method we identified CSN candidates, four with PCI domains: Csn9, Csn10, Pci8/Csn11, and Csn12, and one with an MPN domain, Csn5/Rri1. These proteins and an additional interactor, Csi1, were tested for pairwise interactions by yeast two-hybrid and were found to form a cluster surrounding Csn12. Csn5 and Csn12 cofractionate in a complexed form with an apparent molecular weight of roughly 250 kDa. However, Csn5 migrates as a monomer in Δ csn12 supporting the pivotal role of Csn12 in stabilizing the complex. Confocal fluorescence microscopy detects GFP-tagged Csn5 preferentially in the nucleus, whereas in absence of Csn12, Csn10, Pci8/Csn11, or Csi1, Csn5 is delocalized throughout the cell, indicating that multiple subunits are required for nuclear localization of Csn5. Two CSN subunits, Csn9 and Csi1, interact with the proteasome lid subunit Rpn5. Pci8/Csn11 has previously been shown to interact with eIF3. Together, these results point to a network of interactions between these three structurally similar, yet functionally diverse, complexes.

Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation

Activated protein C (APC) is inhibited by two major plasma inhibitors (PCIs). To find evidence for in vivo complexation of APC, immunoblotting studies were performed on plasmas of 85 patients with suspected disseminated intravascular coagulation (DIC). Samples from 62 of these patients contained 5% to 35% of protein C antigen in APC:inhibitor complexes, indicating that protein C activation and inhibition had occurred. In 24 normal plasmas, no detectable APC:PCI complexes were observed (less than 5%). Patients with higher levels of complexes had more abnormal coagulation test data for DIC. The major band of APC complexes detected by anti-protein C antibodies did not react with antibodies to the heparin-dependent protein C inhibitor (PCI- 1) previously described. Rather, APC was complexed with another recently described plasma protein C inhibitor, PCI-2. Immunoblotting studies for protein S, the cofactor for APC, revealed that the majority of the DIC patient plasmas contained a higher than normal proportion of protein S in cleaved form, suggesting that protein S may have been proteolytically inactivated. Protein S total antigen levels were also found to be low in DIC patients, excluding those with malignancy. These studies support the hypothesis that the protein C pathway is activated during DIC.

Activation and Complexation of Protein C and Cleavage and Decrease of Protein S in Plasma of Patients With Intravascular Coagulation

AbstractActivated protein C (APC) is inhibited by two major plasma inhibitors (PCIs). To find evidence for in vivo complexation of APC, immunoblotting studies were performed on plasmas of 85 patients with suspected disseminated intravascular coagulation (DIC). Samples from 62 of these patients contained 5% to 35% of protein C antigen in APC:inhibitor complexes, indicating that protein C activation and inhibition had occurred. In 24 normal plasmas, no detectable APC:PCI complexes were observed (<5%). Patients with higher levels of complexes had more abnormal coagulation test data for DIC. The major band of APC complexes detected by anti-protein C antibodies did not react with antibodies to the heparin-dependent protein C inhibitor (PCI-1) previously described. Rather, APC was complexed with another recently described plasma protein C inhibitor, PCI-2. Immunoblotting studies for protein S, the cofactor for APC, revealed that the majority of the DIC patient plasmas contained a higher than normal proportion of protein S in cleaved form, suggesting that protein S may have been proteolytically inactivated. Protein S total antigen levels were also found to be low in DIC patients, excluding those with malignancy. These studies support the hypothesis that the protein C pathway is activated during DIC.