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.

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.

Heparin dosing in patients with Impella-supported cardiogenic shock.

BACKGROUND: Impella™ is increasingly used in cardiogenic shock. However, thromboembolic and bleeding events are frequent during percutaneous mechanical circulatory support (pMCS). OBJECTIVE: Therefore, we aimed to explore the optimal anticoagulation regime for pMCS to prevent thromboembolism and bleedings. METHODS: This hypothesis-generating multi-center cohort study investigated 170 patients with left-Impella™ support. We (A) compared bleeding/thrombotic events in two centers with therapeutic range (TR-aPTT) activated partial thromboplastin time (60-80s) and (B) compared events of these centers with one center with intermediate range aPTT (40-60s). RESULTS: After matching, there were no differences in patients' characteristics. In centers aiming at TR-aPTT, major bleeding was numerically lower with aPTT <60s within 48 h of left-Impella™ support, versus patients that achieved the aimed aPTT of ≥60s [aPTT ≥60s: 22 (37.3%) vs. aPTT<60s 14 (23.7%); Hazard ratio [HR], 0.62 (95%) CI, 0.28-1.38; p = 0.234]. Major cardiovascular and cerebrovascular adverse events (MACCE) did not differ between groups. In comparison of centers, TR-aPTT strategy showed higher major bleeding rates [TR: 8 (47.1%) vs. intermediate range: 1 (5.9%); HR, 0.06 (95%) CI, 0.01-0.45; p = 0.006]. MACCE were lower in the intermediate range aPTT group as well [TR 12 (70.6%) vs. intermediate range 5 (29.4%) HR, 0.32 (95%) CI, 0.11-0.92; p = 0.034]. CONCLUSION: This pilot analysis showed that lowering UFH-targets in left-Impella™ supported CS patients seems to be a safe and promising strategy for reducing major bleedings without increasing MACCE. This needs to be validated in larger, randomized clinical trials.

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.

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.

Left ventricular-aortic angle is associated with platelet reactivity in patients with aortic stenosis.

The impact of aortic stenosis on platelet reactivity is unclear. Previous studies reported contradicting results. The reason for this is unknown. It is known that flow alterations enhance platelet reactivity. A steep left ventricular-aortic angle (LV-AO-angle) is associated with turbulent flow in the aorta ascendens. Therefore, in this study, we hypothesized that LV-AO-angle is associated with platelet reactivity in patients with severe aortic stenosis. We included 289 patients with severe aortic stenosis and performed cardiac computertomography to assess the LV-AO-angle. Platelet function was evaluated by light transmission aggregometry. Platelet reactivity was higher in patients with a steep LV-AO-angle (ADP: <160°: 66.99% ±â€Š20.72% vs. ≥160°: 60.66% ±â€Š19.85%, P  = 0.009; collagen: <160°: 78.67% ±â€Š13.19% vs. ≥160°: 73.85% ±â€Š14.44%, P  = 0.003). Using Spearman correlation, ADP and collagen-induced aggregation was associated with LV-AO-angle (ADP: r  = -0.19, P  = 0.0009, R2  = 0.022; collagen: r  = -0.21, P  = 0.0004, R2  = 0.027). Apart from platelet reactivity, body weight, history of myocardial infarction and other factors were associated with steep LV-AO-angle. However, multivariate cox-regression (including body weight, comorbidities, history of MI and cardiac surgery, kidney function and laboratory parameters) revealed that LV-AO angle was a robust predictor of ADP and collagen-induced platelet aggregation. Steep LV-AO-angle is associated with enhanced platelet reactivity in patients with aortic stenosis. This could be the reason of contradicting results regarding platelet function in patients with aortic stenosis in previous studies. In addition, enhanced platelet reactivity in steep LV-AO-angle aortic stenosis patients might be a promising target in pathogenesis of aortic stenosis.

Staphylococcus aureus increases platelet reactivity in patients with infective endocarditis.

Thromboembolism is frequent in infective endocarditis (IE). However, the optimal antithrombotic regimen in IE is unknown. Staphylococcus aureus (SA) is the leading cause of IE. First studies emphasize increased platelet reactivity by SA. In this pilot study, we hypothesized that platelet reactivity is increased in patients with SA- IE, which could be abrogated by antiplatelet medication. We conducted a prospective, observatory, single-center cohort study in 114 patients with IE, with four cohorts: (1) SA coagulase positive IE without aspirin (ASA) medication, (2) coagulase negative IE without ASA, (3) SA coagulase positive IE with ASA, (4) coagulase negative IE with ASA. Platelet function was measured by Multiplate electrode aggregometry, blood clotting by ROTEM thromboelastometry. Bleeding events were assessed according to TIMI classification. In ASA-naïve patients, aggregation with ADP was increased with coag. pos. IE (coagulase negative: 39.47 ± 4.13 AUC vs. coagulase positive: 59.46 ± 8.19 AUC, p = 0.0219). This was abrogated with ASA medication (coagulase negative: 42.4 ± 4.67 AUC vs. coagulase positive: 45.11 ± 6.063 AUC p = 0.7824). Aspirin did not increase bleeding in SA positive patients. However, in SA negative patients with aspirin, red blood cell transfusions were enhanced. SA coagulase positive IE is associated with increased platelet reactivity. This could be abrogated by aspirin without increased bleeding risk. The results of this pilot study suggest that ASA might be beneficial in SA coagulase positive IE. This needs to be confirmed in clinical trials.

Excess Mortality in Aspirin and Dipyrone (Metamizole) Co-Medicated in Patients With Cardiovascular Disease: A Nationwide Study.

Background Pain is a major issue in our aging society. Dipyrone (metamizole) is one of the most frequently used analgesics. Additionally, it has been shown to impair pharmacodynamic response to aspirin as measured by platelet function tests. However, it is not known how this laboratory effect translates to clinical outcome. Methods and Results We conducted a nationwide analysis of a health insurance database in Germany comprising 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. Inverse probability of treatment weighting analysis was conducted to investigate the rate of mortality, myocardial infarction, and stroke/transient ischemic attack between patients on aspirin-dipyrone co-medication compared with aspirin-alone medication. Permanent aspirin-alone medication was given to 26,200 patients, and 5946 patients received aspirin-dipyrone co-medication. In the inverse probability of treatment weighted sample, excess mortality in aspirin-dipyrone co-medicated patients was observed (15.6% in aspirin-only group versus 24.4% in the co-medicated group, hazard ratio [HR], 1.66 [95% CI, 1.56-1.76], P<0.0001). Myocardial infarction and stroke/transient ischemic attack were increased as well (myocardial infarction: 1370 [5.2%] versus 355 [5.9%] in aspirin-only and co-medicated groups, respectively; HR, 1.18 [95% CI, 1.05-1.32]; P=0.0066, relative risk [RR], 1.14; number needed to harm, 140. Stroke/transient ischemic attack, 1901 [7.3%] versus 506 [8.5%] in aspirin-only and co-medicated groups, respectively; HR, 1.22 [95% CI, 1.11-1.35]; P<0.0001, RR, 1.17, number needed to harm, 82). Conclusions In this observational, nationwide analysis, aspirin and dipyrone co-medication was associated with excess mortality. This was in part driven by ischemic events (myocardial infarction and stroke), which occurred more frequently in co-medicated patients as well. Hence, dipyrone should be used with caution in aspirin-treated patients for secondary prevention.

Platelet reactivity is higher in e-cigarette vaping as compared to traditional smoking.

INTRODUCTION: Vaping emerges as alternative to standard tobacco smoking. However, there is evidence for critical cardiovascular, gastrointestinal and respiratory side effects. Nevertheless, long-term vaping effects on thrombocyte reactivity have not been investigated. Therefore, we investigated the influence of vaping on thrombocyte reactivity in comparison to standard smoking and non-smoking. METHODS: Platelet function was measured by Multiplate Impedance Aggregometry as area under the curve (AUC). Smoking habits and characteristics were assessed by questionnaire. Results were analyzed using inverse probability of treatment weighting (IPTW) and conventional t-tests to test for robustness. RESULTS: After IPTW adjustment, participants in all groups were balanced by age, gender, body height and weight. Collagen-induced aggregation was higher in vapers compared to non-smokers (non-smokers 52.55 ± 23.97 vs. vapers 66.63 ± 18.96 AUC, p = 0.002) and to smokers (vapers vs. smokers 49.50 ± 26.05 AUC, p < 0.0001). ADP-induced aggregation in vapers was higher compared to non-smokers (non-smokers 33.16 ± 16.61 vs. vapers 45.27 ± 18.67 AUC, p = 0.001) and was numerically increased compared to smokers (vapers vs. smokers 40.09 ± 19.80 AUC, p = 0.08). These findings remained robust in t-test analysis. CONCLUSION: This study provides first evidence that vaping leads to enhanced platelet reactivity compared to standard smoking and non-smoking. This suggests health effects of vaping might be more severe than previously assumed. Whether this effect translates to clinical outcome with a higher incidence of major cardiovascular events, should be evaluated in large-scaled clinical studies.

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.

Predictors of calcification distribution in severe tricuspid aortic valve stenosis.

We investigated aortic valve calcification (AVC) distribution and predictors for leaflet calcification patterns in patients with severe tricuspid aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR). Patients undergoing routine multi-sliced computed tomography (MSCT) for procedural planning were enrolled. MSCT data were transferred to a dedicated workstation for evaluation (3mensio Structural Heart™, Pie Medical Imaging BV, Maastricht, The Netherlands) and analyzed. Participants were separated into asymmetrical (AC) and symmetrical (SC) leaflet calcification and potential predictors for calcification distribution were identified with univariate and multivariate regression analysis. 567 Participants with severe tricuspid AS were divided into asymmetrical (AC, n = 443; 78.1%) and symmetrical (SC, n = 124; 21.9%) AVC. In AC, the non-coronary cusp was the most calcified cusp (n = 238; 57.7%). SC is more common in females (AC/SC: 49.2% vs. 67.7%; p < 0.0001). AVC was more severe in patients with AC, who also have larger aortic root dimensions. Multivariate analysis depicted, inter alia, left ventricular outflow tract (LVOT) calcification < 25 Agatston units (OR 1.81 [1.09-3.00], p = 0.021), a mean pressure gradient < 36 mmHg (OR 1.77 [1.03-3.05], p = 0.039), and an annulo-apical angle > 67° (OR 1.68 [1.00-2.80], p = 0.049) as predictors for SC, although with only moderate predictive value. Data from this retrospective analysis indicate that SC occurs more frequently in females. The cumulative leaflet calcification burden is higher in patients with AC, who also present with larger aortic root dimensions. The predictive value for prominent calcification of different aortic valve cusps in AC patients was only low to moderate.Trial registration number: NCT01805739.

Risk prediction of bleeding and MACCE by PRECISE-DAPT score post-PCI.

BACKGROUND: Guidelines recommend the PRECISE-DAPT (PD) score to adapt duration of dual antiplatelet therapy due to bleeding risk. However, there is first evidence that PD predicts mortality and ischemic events as well. METHODS: We investigated PD Score in 994 patients after percutaneous coronary intervention (PCI). PD was correlated with clinically frequently used scores. Major adverse cardiac and cerebrovascular events (MACCE) and Thrombolysis in Myocardial Infarction (TIMI) bleeding were assessed during one-year follow-up. RESULTS: 524 patients had PD < 25 and 470 patients PD ≥ 25 (47%). Rate of major and minor bleeding was higher in the PD ≥ 25 group (major bleeding: Hazard ratio [HR] 2.9, 95% confidence interval [Cl] 1.01-8.16, p = 0.049; minor bleeding: HR 3.94, 95% Cl 1.36-9.19, p = 0.0096). Rate of MACCE, death and myocardial infarction were higher as well (MACCE: HR 2.0, 95% Cl 1.52-2.71, p < 0.0001; death: HR 3.9, 95% Cl 2.12-5.68, p < 0.0001; MI: HR 2.1, 95% Cl 1.26-3.43, p = 0.0041). Rate of stroke/transient ischemic attack did not differ between groups. Discriminative potency to predict major and minor bleeding, MACCE, death and MI were high with nearly equal cut-off values calculated by Youden's index (YI) (major bleeding: Area under the curve [AUC] 0.66; p = 0.026; YI 32; minor bleeding: AUC 0.72; p = 0.001; YI 28; MACCE: AUC 0.62; p < 0.0001; YI 24). CONCLUSION: In our cohort, PD score predicted bleeding moderately in post-PCI patients. In this study, ischemic events were predicted as well. Adaption of antiplatelet therapy duration by PD score is accurate. Nevertheless, it should be well-balanced with patient-related risk for ischemic events.

Impact of Transcatheter Aortic Valve Implantation on Thrombin Generation and Platelet Function.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an evolving treatment of severe aortic valve stenosis. However, thromboembolic events such as stroke are common, predominantly early after TAVI. Optimal periprocedural antithrombotic regime is unknown. Especially, as antithrombotic medication enhances bleeding risk, thrombin generation and platelet function are crucial in the pathogenesis of ischemic events. However, the impact of the TAVI procedure on thrombin formation and platelet reactivity is not known by now. METHODS: We evaluated thrombin levels using thrombin-antithrombin (TAT) complexes and prothrombin fragments (PTFs) using enzyme-linked immunosorbent assay. Furthermore, platelet reactivity was measured via light transmission aggregometry before and 2 hours after TAVI in 198 patients. RESULTS: TAT complexes and PTF F1 + 2 substantially increased during TAVI. Postprocedurally, TAT complexes and PTF were significantly higher after TAVI compared with percutaneous coronary intervention due to acute myocardial infarction, while preprocedural TAT complexes and PTF F1 + 2 did not differ. In contrast, platelet reactivity was not altered early after TAVI. Only adenosine diphosphate-induced aggregation was reduced, reflecting preprocedural loading with clopidogrel. CONCLUSION: In this pilot study, we were able to demonstrate that thrombin generation is significantly increased early after TAVI, while platelet function is not affected. Increased thrombin concentrations may contribute to the high risk of postprocedural thromboembolic events. This leads to the hypothesis that extended peri-interventional anticoagulation early after TAVI may be an approach to reduce thromboembolic events.

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.

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.

Lipid lowering therapy in cardiovascular disease: From myth to molecular reality.

Lipid-lowering therapy is one major cornerstone of medical treatment of cardiovascular disease in order to modulate atherosclerosis. Statins, ezetimibe and novel PCSK9-inhibitors are already recommended in current guidelines and were shown to improve lipid profiles and have positive effects on the rate of ischemic events and cardiovascular mortality. Recent studies suggest that the concept of "The lower the better" might be valid at least regarding low density lipoproteins. In addition, lowering lipoprotein (a) still displays a major challenge in lipid therapy. Furthermore, also lowering triglycerides seems to improve cardiovascular outcome. Regarding triglycerides, icosapent ethyl, a polyunsaturated fatty acid recently attracted attention showing cardiovascular risk reduction due to triglyceride lowering. Therefore, new therapeutic strategies and drug classes are eagerly awaited. Targeting LDL, bempedoic acid and the siRNA inclisiran provide promising results. Moreover, regarding TG a monoclonal antibody called evinacumab and an antisense-oligonucleotide against ANGPTL3 showed effective TG-lowering. At least, using antisense-oligonucleotides against ApoC-III and Lp(a) resulted in promising outcomes. In this review, current and future options for lipid management are presented depending on different drug classes.

Enhanced Platelet Reactivity under Aspirin Medication and Major Adverse Cardiac and Cerebrovascular Events in Patients with Coronary Artery Disease.

Aspirin is indispensable in secondary prevention of ischemic events in patients with coronary artery disease (CAD). However, insufficient platelet inhibition despite aspirin medication is frequent. This is referred to as high on-treatment platelet reactivity (HTPR). Nevertheless, if this is associated with clinical outcome instead of only laboratory phenomenon remains unclear so far. In this study, we test whether patients with ischemic events have higher platelet reactivity despite aspirin medication than patients without ischemic events. In this prospective study of 72 CAD patients, we determined pharmacodynamic response to aspirin by arachidonic acid induced aggregation via light-transmission aggregometry and expressed as maximum of aggregation (MoA). During a mean follow-up duration of 3.2 years, major adverse cardiac and cerebrovascular events (MACCE), mortality, non-ST-elevation myocardial infarction (NSTEMI), and stroke were assessed as endpoints via yearly telephone interviews with the treating physician of the patients. Patients who suffered from MACCE, death, and NSTEMI had a significantly higher MoA than those without (MACCE: 5.4 vs. 16.4%, p < 0.05; death: 5.6 vs. 16.8%, p < 0.05; NSTEMI: 1.8 vs. 21%, p < 0.001). MoA did not differ with regard to the occurrence of stroke (10.1 vs. 14.9%, p = 0.59). Patients with MACCE, death, and NSTEMI show enhanced platelet reactivity despite aspirin medication as compared to patients without ischemic events. Hence, insufficient response to aspirin medication should be regarded as risk factor for ischemic events in CAD patients. Further trials are needed to assess options to overcome HTPR to aspirin.

Aspirin antiplatelet effects are associated with body weight.

BACKGROUND: Aspirin is indispensable in secondary prevention of ischemic events. Recently, it was reported that clinical aspirin effects are hampered in patients above 70 kg body weight. It is well known that a plethora of reasons beside obesity is associated with increased platelet reactivity and insufficient aspirin effects (HTPR). However, data regarding an association between pharmacodynamic response to aspirin and body weight are missing. METHODS: In this pilot study, we included 59 patients from University Hospital Duesseldorf. Impedance aggregometry was used to assess pharmacodynamic response to aspirin. RESULTS: AA-induced platelet reactivity was significantly higher in patients above 70 kg (<70 kg: 28.27 ± 26.33 vs. >70 kg: 45.93 ± 27.1, p = .035) and correlated well with the bodyweight of patients in this study (r = 0.33, R2 = 0.09, p = .016). According to this, insufficient pharmacodynamic response (HTPR) to aspirin was significantly more frequent in patients over 70 kg (<70 kg: 25% vs. >70 kg: 43%, p = .035). CONCLUSION: Insufficient pharmacodynamic response to aspirin is associated with body weight. This finding may play a role in the impaired clinical efficacy of aspirin in patients >70 kg. An optimal aspirin regime in these patients needs to be evaluated in large scale trials.