Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction.

BACKGROUND: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system. RESULTS: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress. CONCLUSIONS: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05603520 and NCT01805739.

Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease.

BACKGROUND: Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease. METHODS: AVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS. RESULTS: Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3ß-Wnt-ß-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. CONCLUSIONS: Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.

Impact of gender in patients with device-related thrombosis after left atrial appendage closure - A sub-analysis from the multicenter EUROC-DRT-registry.

BACKGROUND: Device-related thrombosis (DRT) is a common finding after left atrial appendage closure (LAAC) and is associated with worse outcomes. As women are underrepresented in clinical studies, further understanding of sex differences in DRT patients is warranted. METHODS AND RESULTS: This sub-analysis from the EUROC-DRT-registry compromises 176 patients with diagnosis of DRT after LAAC. Women, who accounted for 34.7% (61/176) of patients, were older (78.0 ± 6.7 vs. 74.9 ± 9.1 years, p = .06) with lower rates of comorbidities. While DRT was detected significantly later in women (173 ± 267 vs. 127 ± 192 days, p = .01), anticoagulation therapy was escalated similarly, mainly with initiation of novel oral anticoagulant (NOAC), vitamin K antagonist (VKA) or heparin. DRT resolution was achieved in 67.5% (27/40) of women and in 75.0% (54/72) of men (p = .40). In the remaining cases, an intensification/switch of anticoagulation was conducted in 50.% (9/18) of men and in 41.7% (5/12) of women. Final resolution was achieved in 72.5% (29/40) cases in women, and in 81.9% (59/72) cases in men (p = .24). Women were followed-up for a similar time as men (779 ± 520 vs. 908 ± 687 days, p = .51). Kaplan-Meier analysis revealed no difference in mortality rates in women (Hazard Ratio [HR]: 1.73, 95%-Confidence interval [95%-CI]: .68-4.37, p = .25) and no differences in stroke (HR: .83, 95%-CI: .30-2.32, p = .72) within 2 years after LAAC. CONCLUSION: Evaluation of risk factors and outcome revealed no differences between men and women, with DRT in women being diagnosed significantly later. Women should be monitored closely to assess for DRT formation/resolution. Treatment strategies appear to be equally effective.

Importance of pseudoaneurysms after TAVI - a retrospective analysis of 2063 patients.

Background: Bifemoral arterial access is common in patients undergoing transcatheter aortic valve implantation (TAVI), with a primary treatment access (TAVI access) and a secondary non-TAVI access. Pseudoaneurysm (PSA) is an important complication of femoral arterial puncture. Major vascular complications after TAVI are well described, but little is known about PSA. Patients and methods: A total of 2063 patients underwent transfemoral TAVI between January 2014 and January 2020. Vascular ultrasound of the common femoral artery was assessed before and after TAVI. We compared patient characteristics, periprocedural risk scores, procedural characteristics, and access site bleeding events according to Valve Academic Research Consortium 3 (VARC-3) criteria, length of stay (LOS), and all-cause mortality at one year between patients with (46) and without (2017) PSA. Results: The incidence of PSA after TAVI was 2.2% (46/2063). All PSA were successfully treated with ultrasound-guided manual compression (UGMC) or thrombin injection (UGTI) without complications. Patients with PSA had lower platelet counts (210×1000/µl vs. 234×1000/µl; p<0.05), more heart failure symptoms on admission (91% vs. 25%; p<0.05), were more often treated with (N)OACs for atrial fibrillation (AF; 54% vs. 38%; p <0.05), and were less often treated with aspirin (35% vs. 51%; p<0.03). Multivariate analysis identified secondary access site (odds ratio [OR] 8.11; p<0.001) and (N)OAC therapy (OR 1.31; p = 0.037) as risk factors for PSA development. PSA is associated with VARC-3 type 1-3 access site bleeding and longer LOS (15.2 ± 11.3 d vs. 11.6 ± 8.9 d; p<0.01), but this did not affect one year mortality (17% vs. 14%; p = 0.53). Conclusions: Pseudoaneurysms are an important complication after TAVI and are associated with access site bleeding and prolonged hospital stay. (N)OAC therapy and secondary access are important risk factors. Pseudoaneurysms can be safely and effectively treated with thrombin injection and do not affect one-year mortality.

TAVR: nemesis of NOACs?

Data on non-vitamin K antagonist oral anticoagulants (NOACs) in transcatheter aortic valve replacement (TAVR) patients are controversial. In patients without atrial fibrillation (AF), rivaroxaban showed enhanced ischemia and bleeding as compared to standard of care. ENVISAGE showed enhanced bleeding in AF patients as compared to vitamin K antagonist (VKA). Only apixaban was non-inferior but failed superiority regarding bleeding in AF patients after TAVR. One could hypothesize that this might be due to pharmacokinetics of NOACs. Therefore, we compared outcome in rivaroxaban/edoxaban (once-daily) and apixaban (twice-daily) treated patients. 568 patients with indication for permanent oral anticoagulation due to AF undergoing TAVR were analyzed via inverse probability of treatment weighting. Valve academic research consortium complications during 30-day follow-up were assessed. Bleeding complications were similar in once-daily and twice-daily NOACs (major: 22 (7.5%) vs. 14 (5.3%), p = 0.285; minor: 66 (22.4%) vs. 46 (17.4%), p = 0.133). Complications did not change when splitting the cohort in the different agents apixaban, rivaroxaban and edoxaban. These findings remained robust after multivariate analysis. In summary, twice-daily and once-daily NOACs did not differ regarding bleeding complications in a hypothesis generating real-world cohort of TAVR patients with AF.

Optimal Antithrombotic Regimen in Left Atrial Appendage Occlusion: The Gordian Knot?

Percutaneous left atrial appendage occlusion (LAAO) is an option to reduce the risk of stroke in patients with atrial fibrillation and high bleeding risk. However, device-related thrombosis (DRT) post LAAO is feared as complication. Simard et al. found a very high incidence of DRT compared to other trials. However, antithrombotic regimen and used devices have not been compared between studies. We compared DRT formation, antithrombotic regimen and used device in the recent DRT study, the Amplatzer IDE trial, and the Düsseldorf (DUS) LAAO registry. Occluder thrombosis occurred in 25.3% in the DRT study, 3.8% in the Amulet IDE trial, and 3.3% in the DUS LAAO registry (p < 0.0001). Oral anticoagulation-based regimen was more frequent in the DRT study compared to the DUS LAAO registry, whereas dual antiplatelet regimen was more frequent in the DUS LAAO registry (p < 0.0001). Amplatzer amulet was more frequently used in the DUS LAAO registry as compared to the DRT study (p < 0.0001). DRT is a feared complication after LAAO and seems to be dependent on antiplatelet treatment and underlying device. A clinical study controlling for device and antithrombotic regimen is needed to smash this Gordian knot.

High On-Treatment Platelet Reactivity: Aspirin versus Clopidogrel.

BACKGROUND: Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6-12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA. METHODS: In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed. RESULTS: 755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy. CONCLUSION: Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI.

A simplified cardiac damage staging predicts the outcome of patients undergoing TAVR-A multicenter analysis.

BACKGROUND: A significant number of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) suffer from extra-aortic cardiac damage. Few studies have investigated strategies to quantify cardiac damage and stratify patients accordingly in different risk groups. The aim of this retrospective multicenter study was to provide a user-friendly simplified staging system based on the proposed classification system of Généreux et al. as a tool to evaluate the prognosis of patients undergoing TAVR more easily. Moreover, we analyzed changes in cardiac damage after TAVR. METHODS: We assessed cardiac damage in patients, who underwent TAVR at the Heart Center Bonn or Düsseldorf, using pre- and postprocedural transthoracic echocardiography. Patients were assigned to the staging system proposed by Généreux et al. according to the severity of their baseline cardiac damage. Based on the established system, we created a simplified staging system to facilitate improved applicability. Finally, we compared clinical outcomes between the groups and evaluated changes in cardiac damage after TAVR. RESULTS: A total of 933 TAVR patients were included in the study. We found a significant association between cardiac damage and 1-year all-cause mortality (stage 0: 0% vs. stage 1: 3% vs. stage 2: 6.6%; p < 0.009). In multivariate analysis, cardiac damage was an independent predictor of 1-year all-cause mortality (hazard ratio: 2.0, 95% confidence interval: 1.1-3.8; p = 0.03). CONCLUSIONS: In patients undergoing TAVR, cardiac damage is associated with enhanced mortality. A simplified staging system can help identify patients at high risk for an adverse outcome.

Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.

RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Early restenosis of a direct flow transcatheter aortic valve prosthesis.

Due to limited case numbers, severe Direct flow™ transcatheter device restenosis is, until now, a rare event with unknown long-term incidence, but challenging several treatment strategies. This case report gives an overview of possible interventional treatment considerations in this context that might occur more often in the future due to expected valve deterioration processes in the next years.

Computed tomography derived predictors of permanent pacemaker implantation after transcatheter aortic valve replacement: A meta-analysis.

OBJECTIVES: This meta-analysis sought to assess predictors of permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) with focus on preprocedural multi-slice computed tomography (MSCT) derived data. BACKGROUND: Transcatheter aortic valve replacement (TAVR) has expanded to a well-established treatment for severe symptomatic aortic stenosis at high and intermediate surgical risk. PPI after TAVR remains one of the most frequent procedure-related complications and appears to be influenced by several factors. METHODS: The authors conducted a literature search in PubMed/MEDLINE and EMBASE databases to identify studies that investigated preprocedural MSCT data and the rate of PPI following TAVR with new-generation devices. RESULTS: Ten observational studies (n = 2707) met inclusion criteria for the final analysis. PPI was performed in 387 patients (14.3%) after TAVR. Patients requiring PPI had a larger annulus perimeter (MD: 1.66 mm; p < .001) and a shorter membranous septum length (MD: -1.1 mm; p < .05). Concerning calcification distribution, patients with requirement for new pacemaker implantation showed increased calcification of the left coronary cusp (MD: 47.6 mm3 ; p < .001), and the total left ventricular outflow tract (MD: 24.42 mm3 ; p < .01). Lower implantation depth (MD: 0.95 mm; p < .05) and oversizing (MD: 1.52%; p < .05) were procedural predictors of PPI following TAVR. CONCLUSIONS: Besides the well-known impact of electrocardiographic and procedure-related factors on conduction disturbances, MSCT derived distribution of the aortic valve and left ventricular outflow tract calcification, as well as membranous septum length, are associated with an increased risk of PPI following TAVR.

Contemporary use of balloon aortic valvuloplasty and evaluation of its success in different hemodynamic entities of severe aortic valve stenosis.

OBJECTIVES: To evaluate outcome assessment of percutaneous balloon aortic valvuloplasty (BAV) in different flow and gradient patterns of severe aortic stenosis (AS). BACKGROUND: The mean pressure gradient reduction after BAV is an often-used surrogate parameter to evaluate procedural success. The definition of a successful BAV has not been evaluated in different subgroups of severe AS, which were introduced in the latest guidelines on the management of patients with valvular heart disease. METHODS: In this observational study, consecutive patients from July 2009 to March 2018 undergoing BAV were divided into normal-flow high-gradient (NFHG), low-flow low-gradient (LFLG), and paradoxical low-flow low-gradient (pLFLG) AS. Baseline characteristics, hemodynamic, and clinical information were collected and compared. RESULTS: One-hundred-fifty-six patients were grouped into NFHG (n = 68, 43.5%), LFLG (n = 68, 43.5%), and pLFLG (n = 20, 12.8%) AS. Mean age of the study population was 81 years. Cardiogenic shock or refractory heart failure (46.8%) was the most common underlying reasons for BAV. Spearman correlation revealed that the mean pressure gradient reduction, determined by echocardiography, had a moderate correlation with the increase in the aortic valve area (AVA) in patients with NFHG AS (ρ: 0.529, p < .001) but showed no association in patients with LFLG (ρ: 0.017, p = .289) and pLFLG (ρ: 0.030, p = .889) AS. BAV as bridge to surgical or transcatheter aortic valve replacement was possible in 44.2% of patients, with no difference between groups (p = .070). CONCLUSION: The mean pressure gradient reduction might be an adequate surrogate parameter for BAV success in patients with NFHG AS but is not suitable for patients with other hemodynamic entities.

Cardiac magnetic resonance T2 mapping and feature tracking in athlete's heart and HCM.

OBJECTIVES: Distinguishing hypertrophic cardiomyopathy (HCM) from left ventricular hypertrophy (LVH) due to systematic training (athlete's heart, AH) from morphologic assessment remains challenging. The purpose of this study was to examine the role of T2 mapping and deformation imaging obtained by cardiovascular magnetic resonance (CMR) to discriminate AH from HCM with (HOCM) or without outflow tract obstruction (HNCM). METHODS: Thirty-three patients with HOCM, 9 with HNCM, 13 strength-trained athletes as well as individual age- and gender-matched controls received CMR. For T2 mapping, GRASE-derived multi-echo images were obtained and analyzed using dedicated software. Besides T2 mapping analyses, left ventricular (LV) dimensional and functional parameters were obtained including LV mass per body surface area (LVMi), interventricular septum thickness (IVS), and global longitudinal strain (GLS). RESULTS: While LVMi was not significantly different, IVS was thickened in HOCM patients compared to athlete's. Absolute values of GLS were significantly increased in patients with HOCM/HNCM compared to AH. Median T2 values were elevated compared to controls except in athlete's heart. ROC analysis revealed T2 values (AUC 0.78) and GLS (AUC 0.91) as good parameters to discriminate AH from overall HNCM/HOCM. CONCLUSION: Discrimination of pathologic from non-pathologic LVH has implications for risk assessment of competitive sports in athletes. Multiparametric CMR with parametric T2 mapping and deformation imaging may add information to distinguish AH from LVH due to HCM. KEY POINTS: • Structural analyses using T2 mapping cardiovascular magnetic resonance imaging (CMR) may help to further distinguish myocardial diseases. • To differentiate pathologic from non-pathologic left ventricular hypertrophy, CMR including T2 mapping was obtained in patients with hypertrophic obstructive/non-obstructive cardiomyopathy (HOCM/HNCM) as well as in strength-trained athletes. • Elevated median T2 values in HOCM/HNCM compared with athlete's may add information to distinguish athlete's heart from pathologic left ventricular hypertrophy.

Predictors of functional mitral regurgitation recurrence after percutaneous mitral valve repair.

We aimed to identify predictors of mitral regurgitation recurrence (MR) after percutaneous mitral valve repair (PMVR) in patients with functional mitral regurgitation (FMR). Patients with FMR were enrolled who underwent PMVR using the MitraClip® device. Procedural success was defined as reduction of MR of at least one grade to MR grade ≤ 2 + assessed at discharge. Recurrence of MR was defined as MR grade 3 + or worse at one year after initially successful PMVR. A total of 306 patients with FMR underwent PMVR procedure. In 279 out of 306 patients (91.2%), PMVR was successfully performed with MR grade ≤ 2 + at discharge. In 11.4% of these patients, MR recurrence of initial successful PMVR after 1 year was observed. Recurrence of MR was associated with a higher rate of heart failure rehospitalization during the 12 months follow-up (52.0% vs. 30.3%; p = 0.029), and less improvement in New York Heart Association (NYHA) functional class [68% vs. 19% of the patients presenting with NYHA functional class III or IV one year after PMVR when compared to patients without recurrence (p = 0.001)]. Patients with MR recurrence were characterized by a higher left ventricular sphericity index {0.69 [Interquartile range (IQR) 0.64, 0.74] vs. 0.65 (IQR 0.58, 0.70), p = 0.003}, a larger left atrium volume [118 (IQR 96, 143) ml vs. 102 (IQR 84, 123) ml, p = 0.019], a larger tenting height 10 (IQR 9, 13) mm vs. 8 (IQR 7, 11) mm (p = 0.047), and a larger mitral valve annulus [41 (IQR 38, 43) mm vs. 39 (IQR 36, 40) mm, p = 0.015] when compared to patients with durable optimal long-term results. In a multivariate regression model, the left ventricular sphericity index [Odds Ratio (OR) 1.120, 95% Confidence Interval (CI) 1.039-1.413, p = 0.003)], tenting height (OR 1.207, 95% CI 1.031-1.413, p = 0.019), and left atrium enlargement (OR 1.018, 95% CI 1.000-1.038, p = 0.047) were predictors for MR recurrence after 1 year. In patients with FMR, baseline parameters of advanced heart failure such as spherical ventricle, tenting height and a large left atrium might indicate risk of recurrent MR one year after PMVR.

Aortic valve calcification is subject to aortic stenosis severity and the underlying flow pattern.

Sex- and flow-related aortic valve calcification (AVC) studies are still limited in number, and data on the exact calcium quantity and distribution are scarce. Therefore, we aimed to (1) re-define the best threshold of AVC load to distinguish severe from moderate aortic stenosis (AS) in common AS entities and to (2) evaluate differences in the aortic annulus and left ventricular outflow tract (LVOT) calcium load. Nine hundred and thirty-eight patients with contrast-enhanced cardiac MSCT and moderate-to-severe aortic stenosis (AS) were retrospectively enrolled. Patients with severe AS ≤ 1.0 cm2 (n = 841) were further separated into three AS entities: high gradient (HGAS, n = 370, 44.0%), paradoxical low gradient (pLGAS, n = 333, 39.6%), and classical low gradient (LGAS, n = 138, 16.4%). AVC, leaflet, and LVOT calcification were quantified. Aortic valve calcification scores were highest in severe HGAS, and lower in severe pLGAS and classical LGAS. In all severity and AS entities, the non-coronary cusp (NCC) was the most calcified one. LVOT calcification was consistently comparable between gender and AS entities. Accuracy of logistic regression was the highest in HGAS (male vs. female: AVC > 2156 Agatston units (AU), c-index 0.76; vs. AVC > 1292 AU, c-index 0.85; or AVC density > 406 AU/cm2, c-index 0.82; vs. > 259 AU/cm2, c-index 0.86; each p < 0.0001*) to diagnose severe AS. AVC could only be used in men to differentiate between severe LGAS and moderate AS. Data from this retrospective analysis indicate that the NCC is subject to pre-dominant degeneration throughout gender, AS severity, and several AS entities. AVC was consistently comparable in severe pLGAS and classical LGAS, but only AVC in severe LGAS could sufficiently distinguish from moderate AS in men. LVOT calcification failed to be a reliable indicator of accelerating AS.

Aspirin I.V. Loading during Elective Percutaneous Coronary Intervention.

Additional loading dose of acetylsalicylic acid (ASA) during percutaneous coronary interventions (PCIs) despite permanent oral ASA medication is frequently applicated. The impact on platelet reactivity and clinical events is not known. In this pilot study, we aimed to analyze high on-treatment platelet reactivity (HTPR) to aspirin in patients undergoing elective PCI. Platelet reactivity was measured using light-transmission aggregometry in 100 patients on permanent low-dose ASA medication undergoing elective PCI. Platelet reactivity measured by arachidonic acid-induced maximum of aggregation (MoA) in patients with versus without additional peri-procedural ASA loading (500 mg i.v.) was compared. HTPR was defined as MoA >20% for ASA. Major adverse cerebro- and cardiovascular events (MACCEs) and bleeding events were evaluated during hospital course. HTPR rate was similar in both groups (HTPR to ASA: loading vs. control 6% vs. 16%, odds ratio [OR] = 0.33, 95% confidence interval [CI] 0.08-1.35, p = 0.12). In-hospital MACCEs were not different between groups (MACCE: loading vs. control: 0 vs. 0 patient, OR = 1.32, 95% CI 0.03-67.95, p = 0.89). Thrombolysis in myocardial infarction minimal bleedings were numerically higher in patients without ASA loading dose. In this pharmacodynamic pilot study, additional ASA loading did not reduce HTPR to ASA. Furthermore, ASA loading did not increase in-hospital MACCE and bleeding complications.

MTX Treatment Does Not Improve Outcome in Mice with AMI.

BACKGROUND: Targeting inflammation in patients with coronary artery disease and/or acute myocardial infarction (AMI) is a matter of debate. Methotrexate (MTX) is one of the most widely used immunosuppressants. Cardiovascular Inflammation Reduction Trial (CIRT) recently failed to demonstrate reduced cardiovascular events in MTX-treated patients. However, it is not known if long-term MTX treatment improves cardiac outcome in AMI. Therefore, in this study, we investigated the postischemic phase in MTX-treated mice undergoing AMI. METHODS: Wild-type mice received MTX medication intraperitoneally for 2 weeks. Afterward, AMI was induced by transient left anterior ascending artery ligation. Postischemic cardiac damage after 24 h was assessed. RESULTS: MTX treatment did not affect infarct size as compared to control (IS/AAR: Con 76.20% ± 12.37%/AAR vs. MTX 73.51 ± 11.72%/AAR, p = 0.64). Moreover, systolic function and structural parameters did not differ between groups (24hejection fraction: Con 36.49 ± 3.23% vs. MTX 32.77 ± 2.29%, p = 0.41; 24hLVID; d: Con 3.57 ± 0.17 mm vs. MTX 3.19 ± 0.13 mm, p = 0.14). Platelets were increased by MTX (Con 1,442 ± 69.20 × 103/mm3 vs. MTX 1,920 ± 68.68 × 103/mm3, p < 0.0001). White blood cell and RBC as well as rate of monocytes, granulocytes, lymphocytes, and serum amyloid P levels were equal. CONCLUSION: MTX medication did not improve postischemic cardiac damage in a murine model of AMI. Future trials are needed to identify and investigate other anti-inflammatory targets to improve cardiovascular outcome.

Novel insights on outcome in horizontal aorta with self-expandable new-generation transcatheter aortic valve replacement devices.

BACKGROUND: The impact of a horizontal aorta (HA) on adverse events (AE) following in transcatheter aortic valve replacement (TAVR) is dealt controversially. Using new-generation self-expandable devices, we aimed to reevaluate an appropriate threshold of the aortic root angulation (ARA) in terms of HA and its impact on outcome. METHODS: The 466 consecutive patients, who underwent transfemoral TAVR with self-expandable new-generation devices, were analyzed. Patients were classified into cases with HA (ARA ≥ 51°; n = 225; 48%) and without HA (ARA <51°; n = 241; 52%). Primary endpoints were device success and 30-day mortality. Secondary endpoints were specific AE according to VARC-2 definitions. RESULTS: Contrast use (107.6 ± 50.1 vs. 94.1 ± 46.1 ml; p = .033) and radiation dose (3,176 [1,928-5,596] vs. 2,651 [1,643-4,394] Gyxcm2 ; p = .016) were higher in HA. Primary device success was comparable (97.1 vs. 97.8%; p = .773). A 30-day mortality (3.3 vs. 0.4%; p = .038, plogrank = 0.025), stroke (7.1 vs. 2.7%; p = .033), and major vascular complications (MVASC) (6.6 vs. 2.7%; p = .050) were more frequent in HA. Pronounced calcification of the noncoronary cusp and left ventricular outflow tract, the condition of HA, as well as repositioning maneuvers were independent predictors for overall specific AE. CONCLUSION: An HA above 51° is associated with an increased rate of stroke, MVASC, and 30-day mortality. Valve size and asymmetric calcification affect the incidence of repositioning maneuvers and subsequent VARC-2 AE, indicating that an HA-together with specific anatomic features-remains a crucial factor for TAVR-related outcome with self-expandable new-generation devices.

Patients with severe aortic stenosis and coexisting pulmonary hypertension treated by transapical transcatheter aortic valve replacement-Is there a need for increased attention?

OBJECTIVES: Aim of this study is to elucidate the impact of pulmonary hypertension on patients treated with a transapical aortic valve replacement. BACKGROUND: In patients with aortic stenosis (AS) the coexistence of pulmonary hypertension (PH) is associated with increased peri-operative risk for surgical aortic valve replacement. For transcatheter aortic valve replacement (TAVR), it is unknown whether transapical TAVR (TA-TAVR) is associated with increased peri-interventional risk in PH patients. METHODS: We performed a single center analysis in 189 patients with severe AS with (AS + PH) or without PH (AS - PH) undergoing TA-TAVR. PH was defined by mean pulmonary artery pressure ≥25 mmHg assessed by right heart catheterization (exclusion of 64 patients due to missing results). As the primary endpoint a combination of 30-day mortality or cardiopulmonary resuscitation (CPR) was analyzed. RESULTS: Seventy three patients (58.4%) had PH. Increased peri-interventional risk in AS + PH patients was reflected by an increased rate of the primary endpoint in comparison to AS - PH patients (24.7 vs. 3.8%; p = .002). A higher proportion of acute kidney injury (34.2 vs. 15.7%; p = .025) was found in AS + PH patients while AS - PH patients showed a higher rate of bleeding in comparison AS + PH patients (18.5 vs. 6.8% p = .050). CONCLUSION: Patients with AS + PH treated by TA-TAVR are at increased peri-interventional risk for severe complications in comparison to AS - PH patients. Therefore, the identification of preventive therapeutic strategies is needed. CLASSIFICATIONS: TAVR, transapical, pulmonary hypertension, aortic stenosis.

Impact of Combined "CHADS-BLED" Score to Predict Short-Term Outcomes in Transfemoral and Transapical Aortic Valve Replacement.

BACKGROUND: High CHA2DS2-VASC and HAS-BLED scores are linked to increased mortality in structural and nonstructural cardiovascular interventions irrespective of the presence of atrial fibrillation (AF) or oral anticoagulation. We aimed to use the aforementioned scores to quantify the risk of 30-day mortality, major vascular and bleeding events (MVASC/BARC), and cerebrovascular insults (CVI) in patients undergoing different access routes in transcatheter aortic valve replacement (TAVR). METHODS: Out of 1329 patients, 980 transfemoral (TF) TAVR (73.7%) and 349 transapical (TA) TAVR (26.3%) were included. CHA2DS2-VASC, HAS-BLED, and combined "CHADS-BLED" scores were calculated and compared to the predictive value of the established EuroSCORE and STS score. RESULTS: In all-comers TF TAVR patients, the applied risk models showed only poor association with 30-day mortality while, in patients with concomitant AF, a strong association was observed using the combined CHADS-BLED score (c-index: 0.83; 95% CI: 0.76-0.91; p < 0.0001). Concerning 30-day mortality, only the STS score for TF TAVR (c-index: 0.68; 95% CI: 0.59-0.76; p = 0.001) and EuroSCORE for TA TAVR (c-index: 0.66; 95% CI: 0.56-0.76; p = 0.005) could show some predictive value. High CHADS-BLED was associated with enhanced CVI (3.0% vs. 7.2%;p=0.0039 ∗ ) and more frequent MVASC/BARC (3.2% vs. 6.3%; p = 0.0362) in the all-comers TAVR cohort. All risk models failed in the prediction of CVI and MVASC/BARC for TA TAVR patients. CONCLUSION: The combined CHADS-BLED score was a strong predictor for 30-day mortality in TF TAVR patients with AF. A high CHADS-BLED score showed a good predictive value for major vascular and bleeding events as well as CVI in TF TAVR patients. This study is registered at clinical trials (NCT01805739).