Percutaneous transluminal angioplasty of femoropopliteal veins for treatment of post-thrombotic syndrome.

Background: Controversy persists concerning the endovascular treatment of the post-thrombotic syndrome (PTS), particularly if femoropopliteal veins are involved. Methods: We screened consecutive patients with PTS who underwent percutaneous transluminal angioplasty (PTA) of femoropopliteal veins using posterior tibial or popliteal vein access who had at least 3-month follow-up. Our assessment included the evaluation of primary and secondary patency of the treated segments by Doppler ultrasound (DUS) and clinical outcomes measured by the change in Villalta score as well as ulcer healing. Results: Among 29 patients, 8 (27.7%) were women and the mean (SD) age was 53.3 (13.6) years. Posterior tibial vein and popliteal access were used in 26 (89.7%) and 3 patients (10.3%), respectively. 13 (44.8%) patients had prior (n = 11, 37.9%) or concomitant (n = 9, 31.0%) endovascular treatment of the iliac or common femoral veins. At a median follow-up of 395 days (Q1: 205-Q3: 756 days), primary patency of femoropopliteal veins was 79.3% (95% CI 64.6-94.1%) and secondary patency was 82.8% (95% CI, 69.0-96.5%). The percentage of patients with moderate or severe PTS according to the Villalta score decreased from baseline to last follow-up from 34.5% to 18.5% and from 31% to 14.8%, respectively (p<0.003). Overall, the mean (SD) Villalta score decreased from 11.5 (1.7) to 8.0 (1.7) (p<0.0001). Postprocedural complete ulcer healing occurred in 4 out of 5 (80%) patients. Two (6.9%) patients developed new ulcers. No major bleeding, pulmonary embolism, stroke, or death occurred. Conclusion: PTA of femoropopliteal veins via posterior tibial or popliteal vein access appears to improve the severity of PTS with acceptable patency rates.

Clinical outcomes of a balloon-expandable stent for symptomatic obstructions of the subclavian or innominate arteries.

Background: Upper-extremity peripheral arterial disease (PAD) may present with a broad spectrum of signs and symptoms. If an endovascular treatment is planned, percutaneous angioplasty and stent placement may lead to a better patency compared to percutaneous angioplasty alone. We assessed the characteristics and clinical course of patients with upper-extremity PAD who received angioplasty and a balloon-expandable stent. Patients and methods: We analyzed data from consecutive patients treated with angioplasty and placement of a balloon-expandable BeSmooth Peripheral Stent System® (Bentley, Germany) at the Angiology Department (University Hospital Zurich) between 2018 and 2022. The primary outcome was re-intervention at the target lesion within 6 months from index angioplasty and during available follow-up. The study was approved by the local ethical commission. Results: A total of 27 patients were treated. The median age was 70 (Q1-Q3: 60-74) years and 59% were men. The subclavian artery (74%) represented the most frequently treated target lesion, followed by the innominate artery (26%). The mean improvement in blood pressure in the treated arm was 21 (95%CI 7 to 35) mmHg at 24 hours and 29 (95%CI 15 to 43) mmHg at 6 months. At 6 months, 2 (8%) patients required a target lesion re-intervention. During the remaining follow-up period up to 24 months, one of these two patients required additional intervention and a total of 3 (11%) patients died due to sepsis, cancer, and unknown causes, respectively. Conclusions: Percutaneous catheter-based treatment with a balloon-expandable stent for symptomatic upper extremity PAD appeared to be effective and safe.

Post procedural risk assessment in patients undergoing trans aortic valve implantation according to the age, creatinine, and ejection fraction-7 score: Advantages of age, creatinine, and ejection fraction-7 in stratification of post-procedural outcome.

BACKGROUND: Post-procedural risk stratification based on renal function after trans aortic valve implantation (TAVI) was assessed by means of a modified age, creatinine, and ejection fraction (ACEF) score using the lowest glomerular filtration rate (GFR), obtained within 1 week after valve implantation. We refer to the score as ACEF-7 score. METHODS: The Zurich- and Cardiocentro Ticino TAVI-Cohorts comprised of 424, and 137 patients, who were not on hemodialysis and had already survived the first post-procedural week. Zurich patients were stratified into tertiles of ACEF-7 score (ACEF-7Low ≤ 2.45 (n = 138), ACEF-7Mid 2.46-4.38 (n = 142), and ACEF-7High ≥ 4.39 (n = 144) and compared for survival using KM curves. Euroscore II, Society of Thoracic Surgeons (STS), and ACEF were also calculated at baseline in all patients and assessed for prognostic significance in predicting the primary outcome of 1-year all-cause mortality using univariate and multivariate Cox regression models. Results were then confirmed in the Cardiocentro cohort. RESULTS: Six months (18.1% vs. 6.3% vs. 2.9% P < 0.001) and 1-year all-cause mortality (24.3% vs. 12.7% % vs. 5.8%, P < 0.001), as well as the composite of death or rehospitalization (35% vs. 20% vs. 11% P < 0.001) occurred significantly more frequently in the ACEF-7High compared to the other groups. Both Euroscore II and STS score were not predictors of mortality in our cohort. In a multivariate Cox regression model corrected for gender, Acute Kidney Injury, and baseline ACEF score, the ACEF-7 score was an independent predictor of 1-year all-cause mortality as a per point increment HR 1.512 [95% CI 1.227-1.862, P < 0.001] and as ACEF-7High (≥4.39); HR 5.541 [1.694-18.120]). In addition, the ACEF-7 tertiles showed a significant (P = 0.02) net reclassification improvement of 16% when compared to baseline tertiles of ACEF score, when assessing 1-year all-cause mortality. CONCLUSION: Post-procedural risk stratification using the simple ACEF-7 score significantly better predicted long-term outcome than commonly used risk-scores. Practical implications could include contrast sparing and renal protection in high-risk patients, emphasizing the importance of preventative measures.

Ticagrelor, but not clopidogrel active metabolite, displays antithrombotic properties in the left atrial endocardium.

AIMS: Oral anticoagulation is considered standard therapy for stroke prevention in atrial fibrillation (AF). Endocardial activation triggers expression of pro-thrombotic mediators including tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), and contributes to thrombus formation in the left atrial appendage (LAA) of AF patients. Recently, pleiotropic effects of specific P2Y12 receptor antagonists were demonstrated; however, whether these drugs possess antithrombotic effects on LAA endocardial cells currently remains unknown. METHODS AND RESULTS: LAA were obtained from 14 patients with known AF undergoing elective cardiac surgery including LAA removal at the University Hospital Zurich. LAA endocardial cells were isolated and pre-incubated with ticagrelor (10-7, 10-6, 10-5M) or clopidogrel active metabolite (CAM) (1.5 × 10-8, 1.5 × 10-7, 1.5 × 10-6 M) before stimulation with tumour necrosis factor-alpha (TNF-α) (10 ng/mL). Finally, TF and PAI-1 expression and activity were analysed. Ticagrelor, unlike CAM, concentration dependently decreased TNF-α-induced TF expression and TF activity in LAA endocardial cells. Further, ticagrelor, but not CAM reduced PAI-1 expression and enzyme activity in TNF-α-stimulated LAA endocardial cells. In contrast, TF pathway inhibitor (TFPI) remained unaffected by both dugs. CONCLUSION: Ticagrelor, but not CAM, reduces expression and activity of TF and PAI-1 in LAA endocardial cells isolated from patients with AF, indicating possible local antithrombotic effects. Such pleiotropic properties of ticagrelor may contribute to a reduction in thromboembolic complications in patients with AF.

Intracardiac versus transesophageal echocardiography for left atrial appendage occlusion with watchman.

BACKGROUND: Left atrial appendage occlusion (LAAO) is mostly performed by transesophageal echocardiography (TEE) guidance. Intracardiac echocardiography (ICE) may be an alternative imaging modality for LAAO that precludes the need for general anesthesia or sedation. METHODS AND RESULTS: All consecutive single center, single operator LAAO candidates were analyzed. Baseline clinical and procedural characteristics and in-hospital outcomes were compared between patients in whom a Watchman was implanted with ICE vs. TEE guidance. In 76 consecutive patients the Watchman device was deployed under ICE in 32 patients (42%) and under TEE guidance in 44 patients (58%). Baseline characteristics were comparable between groups, except that patients in the TEE group were older (81 [75-85] years vs. 75 [68-80] years, P = 0.007). Total injected contrast media as well as fluoroscopy time were comparable between groups (90 ml [54-140] vs. 85 ml [80-110], P = 0.86 and 7.9 min [6.4-15.5] vs. 9.8 min [7.0-13.2], P = 0.51, for TEE vs. ICE, respectively). However, time from femoral venous puncture to transseptal puncture and to closure was longer in the ICE group (14 min [7.3-20] vs. 6 min [3.3-11], P = 0.007 and 48 min [40-60] vs. 34.5 min [27-44], P = 0.003, respectively). In the TEE group one patient suffered esophageal erosion with bleeding, which was managed conservatively and one non-LAAO related in-hospital mortality occurred in an 88-year-old patient. Device implantation success rate was 100% in both groups. No device embolization, no significant peri-device leak, no tamponade, no stroke, and no access site bleeding occurred in any patient. Total hospital stay for stand-alone LAAO was comparable between groups (2 days [2-2] vs. 2 days [2-3.3], P = 0.17, in ICE vs. TEE, respectively). CONCLUSIONS: ICE guidance for LAAO with the Watchman device is feasible and comparable to TEE and may become the preferred imaging modality for LAAO. © 2016 Wiley Periodicals, Inc.

PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design.

BACKGROUND: Impaired re-endothelialization and stent thrombosis are a safety concern associated with drug-eluting stents (DES). PI3K/p110α controls cellular wound healing pathways, thereby representing an emerging drug target to modulate vascular homoeostasis after injury. METHODS AND RESULTS: PI3K/p110α was inhibited by treatment with the small molecule inhibitor PIK75 or a specific siRNA. Arterial thrombosis, neointima formation, and re-endothelialization were studied in a murine carotid artery injury model. Proliferation and migration of human vascular smooth muscle cell (VSMC) and endothelial cell (EC) were assessed by cell number and Boyden chamber, respectively. Endothelial senescence was evaluated by the ß-galactosidase assay, endothelial dysfunction by organ chambers for isometric tension. Arterial thrombus formation was delayed in mice treated with PIK75 when compared with controls. PIK75 impaired arterial expression and activity of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); in contrast, plasma clotting and platelet aggregation did not differ. In VSMC and EC, PIK75 inhibited expression and activity of TF and PAI-1. These effects occurred at the transcriptional level via the RhoA signalling cascade and the transcription factor NFkB. Furthermore, inhibition of PI3K/p110α with PIK75 or a specific siRNA selectively impaired proliferation and migration of VSMC while sparing EC completely. Treatment with PIK75 did not induce endothelial senescence nor inhibit endothelium-dependent relaxations. In line with this observation, treatment with PIK75 selectively inhibited neointima formation without affecting re-endothelialization following vascular injury. CONCLUSION: Following vascular injury, PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization. Hence, PI3K/p110α represents an attractive new target in DES design.

Carbamylated low-density lipoprotein induces endothelial dysfunction.

AIMS: Cardiovascular events remain the leading cause of death in Western world. Atherosclerosis is the most common underlying complication driven by low-density lipoproteins (LDL) disturbing vascular integrity. Carbamylation of lysine residues, occurring primarily in the presence of chronic kidney disease (CKD), may affect functional properties of lipoproteins; however, its effect on endothelial function is unknown. METHODS AND RESULTS: Low-density lipoprotein from healthy donors was isolated and carbamylated. Vascular reactivity after treatment with native LDL (nLDL) or carbamylated LDL (cLDL) was examined in organ chambers for isometric tension recording using aortic rings of wild-type or lectin-like-oxidized LDL receptor-1 (LOX-1) transgenic mice. Reactive oxygen species (ROS) and nitric oxide (NO) production were determined using electron spin resonance spectroscopy. The effect of LDL-carbamyl-lysine levels on cardiovascular outcomes was determined in patients with CKD during a median follow-up of 4.7 years. Carbamylated LDL impaired endothelium-dependent relaxation to acetylcholine or calcium-ionophore A23187, but not endothelium-independent relaxation to sodium nitroprusside. In contrast, nLDL had no effect. Carbamylated LDL enhanced aortic ROS production by activating NADPH-oxidase. Carbamylated LDL stimulated endothelial NO synthase (eNOS) uncoupling at least partially by promoting S-glutathionylation of eNOS. Carbamylated LDL-induced endothelial dysfunction was enhanced in LOX-1 transgenic mice. In patients with CKD, LDL-carbamyl-lysine levels were significant predictors for cardiovascular events and all-cause mortality. CONCLUSIONS: Carbamylation of LDL induces endothelial dysfunction via LOX-1 activation and increased ROS production leading to eNOS uncoupling. This indicates a novel mechanism in the pathogenesis of atherosclerotic disease which may be pathogenic and prognostic in patients with CKD and high plasma levels of cLDL.

Caffeic acid phenethyl ester inhibits endothelial tissue factor expression.

Caffeic acid phenethyl ester (CAPE) is a component of honeybee hives with various beneficial properties. Tissue factor (TF), the key trigger of thrombosis, is expressed in human endothelial cells. This study was designed to investigate whether CAPE modulates TF expression in human aortic endothelial cells (HAECs). Western blots and real-time polymerase chain reactions were performed. CAPE (10(-7)-10(-5) M) inhibited tumor necrosis factor (TNF)-α induced endothelial TF protein expression by 2.1-fold at 10(-5) M (p<0.0001). Similarly, TF surface activity was reduced (p<0.02). In contrast, TF mRNA expression, TF promoter activity, and mitogen-activated protein (MAP) kinase activation remained unaltered. In conclusion, CAPE inhibits TF protein expression and activity at the posttranscriptional level thereby exhibiting anti-thrombotic potential.

Percutaneous large-bore aspiration embolectomy with veno-arterial extracorporal membrane oxygenation support or standby in patients with high-risk pulmonary embolism and contraindications to thrombolysis: a preliminary single centre experience.

AIMS: Large-bore catheter aspiration embolectomy reduces thrombus burden and right ventricle strain and improves haemodynamics after pulmonary embolism (PE). Sparse data are available for patients with high-risk PE and contraindications to thrombolysis or thrombolysis failure, particularly if veno-arterial extracorporal membrane oxygenation (VA-ECMO) is required. METHODS AND RESULTS: All patients with acute high-risk PE and contraindications to thrombolysis undergoing FlowTriever® percutaneous embolectomy and VA-ECMO circulatory support (or standby) at the University Hospital Zurich between April 2021 and August 2022 were retrospectively analysed. The primary outcome was the combination of recurrent PE, heart failure hospitalization, and all-cause death at 30 days. The analysis included 15 patients: mean age was 63.1 years and 14 (93%) were men. Overall, four (27%) patients presented with cardiac arrest, eight (53%) with ongoing obstructive shock, and three (20%) with persistent arterial hypotension. Veno-arterial extracorporal membrane oxygenation was implanted prior to aspiration embolectomy in eight (53%) patients. Three of seven patients without initial VA-ECMO support experienced periprocedural cardiac arrest, of whom two received ECMO support before completion of embolectomy. Veno-arterial extracorporal membrane oxygenation weaning was successful in all patients after a mean of 5.4 days. There was one periprocedural death in a patient who did not receive VA-ECMO support following a periprocedural cardiac arrest. The primary outcome at 30 days occurred in five (33.3%; 95% confidence interval 13.0-61.3%) patients. CONCLUSION: This study provides preliminary evidence for the feasibility of percutaneous large-bore aspiration embolectomy in combination with VA-ECMO support (or standby) in patients with high-risk PE and contraindications to thrombolysis.

Antibody-mediated PCSK9 neutralization worsens outcome after bare-metal stent implantation in mice.

AIMS: Despite advances in pharmacotherapy and device innovation, in-stent restenosis (ISR) and stent thrombosis (ST) remain serious complications following percutaneous coronary intervention (PCI) procedure with stent implantation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme involved in plasma cholesterol homeostasis and recently emerged as a therapeutic target for hypercholesterolemia. Antibody-based PCSK9 inhibition is increasingly used in different subsets of patients, including those undergoing PCI. However, whether PCSK9 inhibition affects outcome after stent implantation remains unknown. METHODS AND RESULTS: 12 to 14 weeks old C57Bl/6 mice underwent carotid artery bare-metal stent implantation. Compared to sham intervention, stent implantation was associated with increased expression of several inflammatory mediators, including PCSK9. The increase in PCSK9 protein expression was confirmed in the stented vascular tissue, but not in plasma. To inhibit PCSK9, alirocumab was administered weekly to mice before stent implantation. After 6 weeks, histological examination revealed increased intimal hyperplasia in the stented segment of alirocumab-treated animals compared to controls. In vitro, alirocumab promoted migration and inhibited the onset of senescence in primary human vascular smooth muscle cells (VSMC). Conversely, it blunted the migration and increased the senescence of endothelial cells (EC). CONCLUSION: Antibody-based PCSK9 inhibition promotes in-stent intimal hyperplasia and blunts vascular healing by increasing VSMC migration, while reducing that of EC. This effect is likely mediated, at least in part, by a differential effect on VSMC and EC senescence. The herein-reported data warrant additional investigations concerning the use of PCSK9 inhibitors in patients undergoing PCI with stent implantation.

Clinical outcomes of ultrasound-assisted coagulation monitoring-adjusted catheter-directed thrombolysis for acute pulmonary embolism.

BACKGROUND: Ultrasound-assisted catheter-directed thrombolysis (USAT) may reverse right ventricular dysfunction due to acute pulmonary embolism (PE) with a favorable safety profile. METHODS: We studied intermediate-high- and high-risk acute PE patients who underwent USAT at the University Hospital Zurich, 2018-2022. The USAT regimen included alteplase 10 mg per catheter over 15 h, therapeutic-dosed heparin, and dosage adaptations based on routinely monitored coagulation parameters, notably anti-factor Xa activity and fibrinogen. We focused on the mean pulmonary arterial pressure (mPAP) and the National Early Warning Score (NEWS) before and after USAT, and reported the incidence of hemodynamic decompensation, PE recurrence, major bleeding, and death over 30 days. RESULTS: We included 161 patients: 96 (59.6 %) were men and the mean age was 67.8 (SD 14.6) years. Mean PAP decreased from a mean of 35.6 (SD 9.8) to 25.6 (SD 8.2) mmHg, whereas the NEWS decreased from a median of 5 (Q1-Q3 4-6) to 3 (Q1-Q3 2-4) points. No cases of hemodynamic decompensation occurred. One (0.6 %) patient had an episode of recurrent PE. Two (1.2 %) major bleeding events occurred, including one (0.6 %) intracranial, fatal hemorrhage in a patient with high-risk PE, severe heparin overdosing, and a recent head trauma (with negative CT scan of the brain performed at baseline). No other deaths occurred. CONCLUSIONS: USAT resulted in a rapid improvement of hemodynamic parameters among patients with intermediate-high risk acute PE and selected ones with high-risk acute PE, without any recorded deaths related to PE itself. A strategy including USAT, therapeutic-dosed heparin, and routinely monitored coagulation parameters may partly explain the overall very low rate of major bleeding.

Dietary α-linolenic acid inhibits arterial thrombus formation, tissue factor expression, and platelet activation.

OBJECTIVE: Plant-derived α-linolenic acid (ALA) may constitute an attractive cardioprotective alternative to fish-derived n-3 fatty acids. However, the effect of dietary ALA on arterial thrombus formation remains unknown. METHODS AND RESULTS: Male C57Bl/6 mice were fed a high-ALA or low-ALA diet for 2 weeks. Arterial thrombus formation was delayed in mice fed a high-ALA diet compared with those on a low-ALA diet (n=7; P<0.005). Dietary ALA impaired platelet aggregation to collagen and thrombin (n=5; P<0.005) and decreased p38 mitogen-activated protein kinase activation in platelets. Dietary ALA impaired arterial tissue factor (TF) expression, TF activity, and nuclear factor-κB activity (n=7; P<0.05); plasma clotting times and plasma thrombin generation did not differ (n=5; P=not significant). In cultured human vascular smooth muscle and endothelial cells, ALA inhibited TF expression and activity (n=4; P<0.01). Inhibition of TF expression occurred at the transcriptional level via the mitogen-activated protein kinase p38 in smooth muscle cells and p38, extracellular signal-regulated kinases 1 and 2, and c-Jun N-terminal kinases 1 and 2 in endothelial cells. CONCLUSIONS: ALA impairs arterial thrombus formation, TF expression, and platelet activation and thereby represents an attractive nutritional intervention with direct dual antithrombotic effects.

[Update on Pulmonary Embolism: Guideline-Based Diagnosis and Therapy of an Exemplary Case]. / Update zum Thema Lungenembolie: leitliniengerechte Diagnostik und Therapie anhand eines Fallbeispiels.

Update on Pulmonary Embolism: Guideline-Based Diagnosis and Therapy of an Exemplary Case Abstract. In the evaluation of acute pulmonary embolism, a swift and focused diagnostic process is crucial and has an impact on prognosis. An initial clinical assessment is done in haemodynamically stable patients, followed by determination of D-dimer or immediate imaging by computer tomography if the clinical (pre-test) probability is high. After confirming the diagnosis of pulmonary embolism, the most appropriate anticoagulant regiment should be selected and patients should be candidate for a structured follow-up plan. The initial anticoagulant therapy regime is determined by a number of factors, including haemodynamic stability (or potential need for reperfusion treatments), demographic characteristics and comorbidities. While anticoagulation is usually recommended for the first 3-6 months, re-evaluation of therapy after acute therapy is mandatory. In addition, the possibility of chronic thrombo-embolic pulmonary hypertension (CTEPH) or a post-PE syndrome should be considered if symptoms persist after 3-6 months.

Major adverse limb events in patients with femoro-popliteal and below-the-knee peripheral arterial disease treated with either sirolimus-coated balloon or standard uncoated balloon angioplasty: a structured protocol summary of the "SirPAD" randomized controlled trial.

BACKGROUND: Peripheral arterial disease is a progressive atherosclerotic disease with symptoms ranging from an intermittent claudication to acute critical limb ischemia and amputations. Drug-coated balloons and stents were developed to prevent neo-intimal proliferation and restenosis after percutaneous transluminal angioplasty. Randomized controlled trials showed that drug-coated, notably paclitaxel-coated, devices reduce restenosis, late lumen loss, and the need for target lesion re-vascularization compared with uncoated ones. However, the size of these trials was too small to prove superiority for "hard" clinical outcomes. Moreover, available studies were characterized by too restrictive eligibility criteria. Finally, it remains unclear whether paclitaxel-coated balloons may impair long-term survival. Alternative drug-coated balloons, the so-called limus-based analogs, have been approved for clinical use in patients with peripheral arterial disease. By encapsulating sirolimus in phospholipid drug nanocarriers, they optimize adhesion properties of sirolimus and provide better bioavailability. METHODS: In this investigator-initiated all-comer open-label phase III randomized controlled trial, we will evaluate whether sirolimus-coated balloon angioplasty is non-inferior and eventually superior, according to a predefined hierarchical analysis, to uncoated balloon angioplasty in adults with infra-inguinal peripheral arterial disease requiring endovascular angioplasty. Key exclusion criteria are pregnancy or breastfeeding, known intolerance or allergy to sirolimus, and participation in a clinical trial during the previous 3 months. The primary efficacy outcome is the composite of two clinically relevant non-subjective "hard" outcomes: unplanned major amputation of the target limb and endovascular or surgical target lesion re-vascularization for critical limb ischemia occurring within 1 year of randomization. The primary safety outcome includes death from all causes. DISCUSSION: By focusing on clinically relevant outcomes, this study will provide useful information on the efficacy and safety of sirolimus-coated balloon catheters for infra-inguinal peripheral arterial disease in a representative ("all-comer") population of unselected patients. As regulatory agencies had raised safety concerns in patients exposed to paclitaxel-coated devices (versus uncoated ones), collect mortality data up to 5 years after randomization will be collected. TRIAL REGISTRATION: ClinicalTrials.gov NCT04238546.

Aging induces endothelial dysfunction while sparing arterial thrombosis.

OBJECTIVE: To assess the effects of aging on arterial thrombus formation by comparing 2-year-old with 11-week-old C57Bl6 mice. METHODS AND RESULTS: Aging is a major risk factor for cardiovascular disease. In humans, assessing the direct effects of aging on vascular homeostasis is difficult because it occurs in the presence of other risk factors. Arterial thrombosis is the critical event in cardiovascular diseases; however, it is not known whether aging per se promotes its occurrence. Mice represent an interesting system to address this issue because they age without spontaneously developing other risk factors. Organ chamber experiments confirmed the advanced level of aging of old mice. As previously shown, old mice exhibited endothelial dysfunction; however, arterial thrombosis induced by photochemical injury was unchanged. Arterial tissue factor expression and activity; expressions of tissue factor pathway inhibitor, thrombomodulin, and plasminogen activator inhibitor 1; prothrombin time; partial thromboplastin time; thrombin-antithrombin complex; and platelet activation were comparable in both groups. CONCLUSIONS: Although these results cannot be directly extrapolated to humans, this study contributes novel important information on the direct effect of aging on arterial thrombosis and underscores the importance of controlling modifiable risk factors in aged individuals.

[The Role of Percutaneous Coronary Revascularization in Chronic Coronary Syndromes]. / Perkutane koronare Revaskularisation beim chronischen Koronarsyndrom: wann sinnvoll, wann nicht?

The Role of Percutaneous Coronary Revascularization in Chronic Coronary Syndromes Abstract. Coronary heart disease represents the leading cause of morbidity and mortality worldwide. Optimal management of these patients is therefore crucial and includes lifestyle changes, optimal medical therapy, and coronary revascularization. This review summarizes diagnostic and therapeutic strategies of patients with chronic coronary syndromes, focusing on the 2019 European Society of Cardiology (ESC) guidelines for the diagnosis and management of chronic coronary syndromes. In particular, the role of invasive assessment and coronary revascularization in chronic coronary syndromes is discussed.

Postprocedural Troponin Elevation and Mortality After Transcatheter Aortic Valve Implantation.

Background This study sought to investigate the role of postprocedural troponin elevations in mortality prediction after transcatheter aortic valve implantation and to define the threshold at which clinically relevant postprocedure myocardial injury determines mortality. Methods and Results A total of 1333 consecutive patients with transcatheter aortic valve implantation with available postprocedural high-sensitivity cardiac troponin T measurements were included in the analysis. The threshold at which postprocedure myocardial injury determines long-term mortality was identified using restricted cubic spline analysis. A >18.3-fold increase of troponin above the upper reference limit was identified as threshold for relevant postprocedure myocardial injury. Associations remained significant in a landmark analysis between 30 days and 2 years (hazard ratio [HR], 1.61, [95% CI, 1.13-2.28]; P=0.01), after adjusting for known confounders (adjusted HR, 1.90 [95% CI, 1.40-2.57]; P<0001), and in subgroups of patients with coronary artery disease (adjusted HR, 2.17 [95% CI, 1.44-3.29]; P<0.001), renal dysfunction (adjusted HR, 1.88 [95% CI, 1.35-2.62]; P<0.001), and intermediate/high surgical risk (adjusted HR, 2.70 [95% CI, 1.40-5.22]; P=0.003). Conclusions This study determined a troponin threshold for the identification of patients at increased mortality risk after transcatheter aortic valve implantation. The proposed definition of postprocedure myocardial injury advances risk stratification in patients with transcatheter aortic valve implantation and may assist in postprocedural patient management.

Laminin receptor activation inhibits endothelial tissue factor expression.

Tissue factor (TF) is an important trigger of arterial thrombosis. The green tea catechin epigallocatechin-3-gallate (EGCG) is a ligand of the 67-kDa laminin receptor (67LR) and exhibits cardioprotective effects. This study investigates whether 67LR regulates TF expression in human endothelial cells. Immunofluorescence demonstrated that human aortic endothelial cells expressed 67LR. Cells grown on laminin expressed 35% less TF in response to TNF-alpha (TNF-alpha) than those grown on fibronectin (n=6; p<0.001). EGCG (1-30 microM) inhibited TNF-alpha and histamine induced endothelial TF expression and activity in a concentration dependent manner resulting in 87% reduction of TF expression (n=5; p<0.001); in contrast, expression of tissue factor pathway inhibitor was not affected (n=4; p=NS). In vivo administration of EGCG (30 mg/kg/day) inhibited TF activity in carotid arteries of C57BL6 mice. Real-time PCR and promoter studies revealed that EGCG decreased TF expression at the transcriptional level and impaired activation of the mitogen activated protein (MAP) kinase JNK 1/2, but not ERK or p38. Similarly, the JNK 1/2 inhibitor SP600125 (1 microM) impaired TF promoter activity (n=4; p<0.001) and protein expression (n=4; p<0.001). 67LR blocking antibodies blunted the inhibitory effect of EGCG on both TF protein expression and JNK activation. In contrast, vascular cell adhesion molecule 1 (VCAM-1) was not affected by laminin nor EGCG, and its expression was not regulated by JNK. EGCG did not affect TNF-alpha stimulated NFkB activation. Laminin receptor activation inhibits endothelial TF expression by impairing JNK phosphorylation. Thus, 67LR may be a potential target for the development of novel anti-thrombotic therapies.

Multimodality imaging derived energy loss index and outcome after transcatheter aortic valve replacement.

AIMS: To assess whether the combination of transthoracic echocardiography (TTE) and multidetector computed tomography (MDCT) data affects the grading of aortic stenosis (AS) severity under consideration of the energy loss index (ELI) in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: Multimodality imaging was performed in 197 patients with symptomatic severe AS undergoing TAVR at the University Hospital Zurich, Switzerland. Fusion aortic valve area index (fusion AVAi) assessed by integrating MDCT derived planimetric left ventricular outflow tract area into the continuity equation was significantly larger as compared to conventional AVAi (0.41 ± 0.1 vs. 0.51 ± 0.1 cm2/m2; P < 0.01). A total of 62 patients (31.4%) were reclassified from severe to moderate AS with fusion AVAi being >0.6 cm2/m2. ELI was obtained for conventional AVAi and fusion AVAi based on sinotubular junction area determined by TTE (ELILTL 0.47 ± 0.1 cm2/m2; fusion ELILTL 0.60 ± 0.1 cm2/m2) and MDCT (ELIMDCT 0.48 ± 0.1 cm2/m2; fusion ELIMDCT 0.61 ± 0.05 cm2/m2). When ELI was calculated with fusion AVAi the effective orifice area was >0.6 cm2/m2 in 85 patients (43.1%). Survival rate 3 years after TAVR was higher in patients reclassified to moderate AS according to multimodality imaging derived ELI (78.8% vs. 67%; P = 0.01). CONCLUSION: Multimodality imaging derived ELI reclassifies AS severity in 43% undergoing TAVR and predicts mid-term outcome.

Diagnostic performance of angiography-based quantitative flow ratio for the identification of myocardial ischemia as assessed by 13N-ammonia myocardial perfusion imaging positron emission tomography.

BACKGROUND: Quantitative flow ratio (QFR) is a novel, adenosine-free method for functional lesion interrogation based on 3-dimensional quantitative coronary angiography and computational algorithms. We sought to investigate the diagnostic performance of QFR versus myocardial perfusion imaging positron emission tomography (MPI-PET), which yields the highest accuracy for detection of myocardial ischemia. METHODS: Diagnostic performance of QFR versus MPI-PET was assessed in consecutive patients undergoing both clinically indicated coronary angiography and 13N-ammonia MPI-PET within a six-month period. RESULTS: Out of 176 patients (439 coronary arteries), 19.3% were women. Percent area stenosis was 45 [32-58] %. Myocardial ischemia on 13N-ammonia MPI-PET was detected in 106 (24.1%) vessel territories and hemodynamic significance defined as contrast-flow vessel QFR ≤ 0.80 was observed in 83 (18.9%) vessels. Diagnostic accuracy, sensitivity, and specificity of contrast-flow vessel QFR for the prediction of myocardial ischemia on 13N-ammonia MPI-PET were 92.5 (95% CI 89.6-94.7) %, 73.6 (95% CI 64.1-81.7) %, and 98.5 (95% CI 96.5-99.5) %, respectively. The AUCs for contrast-flow vessel QFR, percent diameter stenosis, and percent area stenosis were 0.85 (95% CI 0.81-0.88, p < 0.001), 0.76 (95% CI 0.71-0.79, p < 0.001) and 0.75 (95% CI 0.70-0.79, p < 0.001), respectively. CONCLUSIONS: QFR, a novel diagnostic tool for functional coronary lesion assessment, provides good diagnostic agreement with MPI-PET and superior diagnostic accuracy for the detection of myocardial ischemia as compared to anatomic indices. Future studies will have to determine the non-inferiority of QFR to fractional flow reserve with respect to clinical outcomes.