COVID-19 promotes endothelial dysfunction and thrombogenicity: role of proinflammatory cytokines/SGLT2 prooxidant pathway.

BACKGROUND: COVID-19 is associated with an increased risk of cardiovascular complications. Although cytokines have a predominant role in endothelium damage, the precise molecular mechanisms are far from being elucidated. OBJECTIVES: The present study hypothesized that inflammation in patients with COVID-19 contributes to endothelial dysfunction through redox-sensitive SGLT2 overexpression and investigated the protective effect of SGLT2 inhibition by empagliflozin. METHODS: Human plasma samples were collected from patients with acute, subacute, and long COVID-19 (n = 100), patients with non-COVID-19 and cardiovascular risk factors (n = 50), and healthy volunteers (n = 25). Porcine coronary artery endothelial cells (ECs) were incubated with plasma (10%). Protein expression levels were determined using Western blot analyses and immunofluorescence staining, mRNA expression by quantitative reverse transcription-polymerase chain reaction, and the level of oxidative stress by dihydroethidium staining. Platelet adhesion, aggregation, and thrombin generation were determined. RESULTS: Increased plasma levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were observed in patients with COVID-19. Exposure of ECs to COVID-19 plasma with high cytokines levels induced redox-sensitive upregulation of SGLT2 expression via proinflammatory cytokines IL-1ß, IL-6, and tumor necrosis factor-α which, in turn, fueled endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, von Willebrand factor secretion, and thrombin generation. The stimulatory effect of COVID-19 plasma was blunted by neutralizing antibodies against proinflammatory cytokines and empagliflozin. CONCLUSION: In patients with COVID-19, proinflammatory cytokines induced a redox-sensitive upregulation of SGLT2 expression in ECs, which in turn promoted endothelial injury, senescence, platelet adhesion, aggregation, and thrombin generation. SGLT2 inhibition with empagliflozin appeared as an attractive strategy to restore vascular homeostasis in COVID-19.

Drifting discrete Jovian radio bursts reveal acceleration processes related to Ganymede and the main aurora.

Radio detection at high time-frequency resolutions is a powerful means of remotely studying electron acceleration processes. Radio bursts have characteristics (polarization, drift, periodicity) making them easier to detect than slowly variable emissions. They are not uncommon in solar system planetary magnetospheres, the powerful Jovian "short bursts (S-bursts)" induced by the Io-Jupiter interaction being especially well-documented. Here we present a detection method of drifting radio bursts in terabytes of high resolution time-frequency data, applied to one month of ground-based Jupiter observations. Beyond the expected Io-Jupiter S-bursts, we find decameter S-bursts related to the Ganymede-Jupiter interaction and the main Jovian aurora, revealing ubiquitous Alfvénic electron acceleration in Jupiter's high-latitude regions. Our observations show accelerated electron energies are distributed in two populations, kilo-electron-Volts and hundreds of electron-Volts. This detection technique may help characterizing inaccessible astrophysical sources such as exoplanets.

Outcomes of patients with active cancer undergoing transcatheter aortic valve replacement.

BACKGROUND: Cardiovascular disease and cancer are the two leading causes of mortality worldwide, and their association presents a therapeutic challenge. Current data regarding the prognosis of active cancer in patients undergoing transcatheter aortic valve replacement are conflicting. AIM: To determine the impact and prognosis of active cancer in transcatheter aortic valve replacement. METHODS: All consecutive patients with severe aortic stenosis treated by transcatheter aortic valve replacement between February 2010 and May 2019 were enrolled in a prospective study. The cohort was divided according to the presence or absence of active cancer at baseline. The primary endpoint was all-cause mortality 1 year after the procedure. RESULTS: A total of 1,125 patients were enrolled: 1,037 (92.2%) without and 88 (7.8%) with active cancer. The most frequent cancers were haematological (36.4%), breast (14.8%) and prostate (14.8%), with 79.5% of patients receiving curative treatment and 17.0% receiving palliative treatment. The 1-year mortality rate was higher in patients with active cancer (27.3% vs. 13.9%; P<0.01), mainly driven by non-cardiovascular causes. An increased cardiovascular mortality rate at 2 years was seen in patients with active cancer (27.5% vs. 15.0%; P=0.03) compared with a similar rate at 1-year follow-up. Active cancer was a strong predictor of 1-year all-cause mortality (hazard ratio 2.46, 95% confidence interval 1.19-4.68; P=0.02). Major/life-threatening bleeding events at 1 year were more frequent in patients with active cancer (P=0.02). CONCLUSIONS: Among patients who undergo transcatheter aortic valve replacement, 1-year all-cause mortality is higher in those with active cancer. We also observed a trend towards increased long-term bleeding events in case of active cancer.

Combination of Primary Hemostatic Disorders and Atrial Fibrillation Increases Bleeding Events Following Transcatheter Aortic Valve Replacement.

Background Patients with atrial fibrillation (AF) are likely to have a poor prognosis including bleedings following transcatheter aortic valve replacement (TAVR). Closure time of adenosine diphosphate (CT-ADP) is a primary hemostasis point-of-care test and is a predictor of bleeding events following TAVR. We aimed to evaluate the impact of ongoing primary hemostatic disorders on bleeding events in TAVR patients with AF. Methods We enrolled 878 patients from our prospective registry. The primary endpoint was VARC-2 major/life-threatening bleeding complications (MLBCs) at 1 year after TAVR and secondary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 1 year, defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization. Ongoing primary hemostatic disorder was defined by a postprocedural CT-ADP >180 seconds. Results Patients with AF had a higher incidence of MLBCs (20 vs. 12%, p = 0.002), MACCE (29 vs. 20%, p = 0.002), and all-cause mortality (15 vs. 8%, p = 0.002) within 1 year compared to non-AF patients. When the cohort was split into four subgroups according to AF and CT-ADP >180 seconds, patients with AF and CT-ADP >180 seconds had the highest risk of MLBCs and MACCE. Multivariate Cox regression analysis confirmed that the patients with AF and CT-ADP >180 seconds had 3.9-fold higher risk of MLBCs, whereas those patients were no longer associated with MACCE after the adjustment. Conclusion In TAVR patients, AF with postprocedural CT-ADP >180 seconds was strongly associated with MLBCs following TAVR. Our study suggests that persistent primary hemostatic disorders contribute to a higher risk of bleeding events particularly in AF patients.

Baseline mean platelet volume is a strong predictor of major and life-threatening bleedings after transcatheter aortic valve replacement.

BACKGROUND: Bleeding following transcatheter aortic valve replacement (TAVR) has important prognostic implications. This study sought to evaluate the impact of baseline mean platelet volume (MPV) on bleeding events after TAVR. METHODS AND RESULTS: Patients undergoing TAVR between February 2010 and May 2019 were included. Low MPV (L-MPV) was defined as MPV ≤10 fL and high MPV (H-MPV) as MPV >10 fL. The primary endpoint was the occurrence of major/life-threatening bleeding complications (MLBCs) at one-year follow-up. Among 1,111 patients, 398 (35.8%) had L-MPV and 713 (64.2%) had H-MPV. The rate of MLBCs at 1 year was higher in L-MPV patients compared with H-MPV patients (22.9% vs. 17.7% respectively, p = 0.034). L-MPV was associated with vascular access-site complications (36.2% vs. 28.9%, p = 0.012), early (<30 days) major bleeding (15.6% vs. 9.4%, p<0.01) and red blood cell transfusion >2 units (23.9% vs. 17.5%, p = 0.01). No impact of baseline MPV on overall death, cardiovascular death and ischemic events (myocardial infarction and stroke) was evidenced. Multivariate analysis using Fine and Gray model identified preprocedural hemoglobin (sHR 0.84, 95%CI [0.75-0.93], p = 0.001), preprocedural L-MPV (sHR 1.64, 95%CI [1.16-2.32], p = 0.005) and closure time adenosine diphosphate post-TAVR (sHR 2.71, 95%CI [1.87-3.95], p<0.001) as predictors of MLBCs. CONCLUSIONS: Preprocedural MPV was identified as an independent predictor of MLBCs one year after TAVR, regardless of the extent of platelet inhibition and primary hemostasis disorders.

Impact of Primary Hemostasis Disorders on Late Major Bleeding Events among Anticoagulated Atrial Fibrillation Patients Treated by TAVR.

BACKGROUND: Bleeding events are among the striking complications following transcatheter aortic valve replacement (TAVR), and bleeding prediction models are crucially warranted. Several studies have highlighted that primary hemostasis disorders secondary to persistent loss of high-molecular-weight (HMW) multimers of the von Willebrand factor (vWF) and assessed by adenosine diphosphate closure time (CT-ADP) may be a strong predictor of late major/life-threatening bleeding complications (MLBCs). Pre-existing atrial fibrillation (AF) is a frequent comorbidity in TAVR patients and potentially associated with increased bleeding events after the procedure. OBJECTIVES: This study evaluated the impact of ongoing primary hemostasis disorders, as assessed by post-procedural CT-ADP > 180 s, on clinical events after TAVR among anticoagulated AF patients. METHODS: An ongoing primary hemostasis disorder was defined by post-procedure CT-ADP > 180 s. Bleeding complications were assessed according to the Valve Academic Research Consortium-2 (VARC-2) criteria. The primary endpoint was the occurrence of late MLBCs at one-year follow-up. The secondary endpoint was a composite of mortality, stroke, myocardial infarction, and rehospitalization for heart failure. RESULTS: In total, 384 TAVR patients were included in the analysis. Of these patients, 57 patients (14.8%) had a prolongated CT-ADP > 180 s. Increased MLBCs were observed in patients with CT-ADP > 180 s (35.1% versus 1.2%; p < 0.0001). Conversely, the occurrence of the composite endpoint did not differ between the groups. Multivariate analysis identified CT-ADP > 180 s (HR 28.93; 95% CI 9.74-85.95; p < 0.0001), bleeding history, paradoxical aortic stenosis (AS), and major vascular complications following TAVR as independent predictors of late MLBCs. CONCLUSION: Among patients with anticoagulated AF, a post-procedural CT-ADP > 180 s was identified as a strong independent predictor of late MLBCs. These findings suggest that persistent primary hemostasis disorders contribute to a higher risk of late bleeding events and should be considered for a tailored, risk-adjusted antithrombotic therapy after TAVR.

Impact of residual inflammation on myocardial recovery and cardiovascular outcome in Takotsubo patients.

AIMS: Recent insights have emphasized the importance of myocardial and systemic inflammation in Takotsubo syndrome (TTS). In a large registry of unselected patients, we sought to evaluate whether residual high inflammatory response (RHIR) could impact cardiovascular outcome after TTS. METHODS AND RESULTS: Patients with TTS were retrospectively included between 2008 and 2018 in three general hospitals. Three hundred eighty-five patients with TTS were split into three subgroups, according to tertiles of C-reactive protein (CRP) levels at discharge (CRP <5.2 mg/L, CRP range 5.2 to 19 mg/L, and CRP >19 mg/L). The primary endpoint was the impact of RHIR, defined as CRP >19 mg/L at discharge, on cardiac death or hospitalization for heart failure. Follow up was obtained in 382 patients (99%) after a median of 747 days. RHIR patients were more likely to have a history of cancer or a physical trigger. Left ventricular ejection fraction (LVEF) at admission and at discharge were comparable between groups. By contrast, RHIR was associated with lower LVEF at follow up (61.7% vs. 60.7% vs. 57.9%; P = 0.004) and increased cardiac late mortality (0% vs. 0% vs. 10%; P = 0.001). By multivariate Cox regression analysis, RHIR was an independent predictor of cardiac death or hospitalization for heart failure (hazard ratio: 1.87; 95% confidence interval: 1.08 to 3.25; P = 0.025). CONCLUSIONS: Residual high inflammatory response was associated with impaired LVEF at follow up and was evidenced as an independent factor of cardiovascular events. All together, these findings underline RHIR patients as a high-risk subgroup, to target in future clinical trials with specific therapies to attenuate RHIR.

Risk and Severity of COVID-19 and ABO Blood Group in Transcatheter Aortic Valve Patients.

While cardiovascular disease has been associated with an increased risk of coronavirus disease 2019 (COVID-19), no studies have described its clinical course in patients with aortic stenosis who had undergone transcatheter aortic valve replacement (TAVR). Numerous observational studies have reported an association between the A blood group and an increased susceptibility to SARS-CoV-2 infection. Our objective was to investigate the frequency and clinical course of COVID-19 in a large sample of patients who had undergone TAVR and to determine the associations of the ABO blood group with disease occurrence and outcomes. Patients who had undergone TAVR between 2010 and 2019 were included in this study and followed-up through the recent COVID-19 outbreak. The occurrence and severity (hospitalization and/or death) of COVID-19 and their associations with the ABO blood group served as the main outcome measures. Of the 1125 patients who had undergone TAVR, 403 (36%) died before 1 January 2020, and 20 (1.8%) were lost to follow-up. The study sample therefore consisted of 702 patients. Of them, we identified 22 cases (3.1%) with COVID-19. Fourteen patients (63.6%) were hospitalized or died of disease. Multivariable analysis identified the A blood group (vs. others) as the only independent predictor of COVID-19 in patients who had undergone TAVR (odds ratio (OR) = 6.32; 95% confidence interval (CI) = 2.11-18.92; p = 0.001). The A blood group (vs. others; OR = 8.27; 95% CI = 1.83-37.43, p = 0.006) and a history of cancer (OR = 4.99; 95% CI = 1.64-15.27, p = 0.005) were significantly and independently associated with disease severity (hospitalization and/or death). We conclude that patients who have undergone TAVR frequently have a number of cardiovascular comorbidities that may work to increase the risk of COVID-19. The subgroup with the A blood group was especially prone to developing the disease and showed unfavorable outcomes.

Paradoxical Increase of Stroke in Patients with Defect of High Molecular Weight Multimers of the von Willebrand Factors following Transcatheter Aortic Valve Replacement.

BACKGROUND: Stroke is a major cause of disability after transcatheter aortic valve replacement (TAVR) and stroke prediction models and data are crucially needed. Following TAVR, high molecular weight (HMW) multimers defect of von Willebrand factor (VWF) as assessed by closure time of adenosine diphosphate (CT-ADP) value > 180 seconds is an independent predictor of bleeding events. This study sought to identify predictors of ischemic neurological events in patients who underwent TAVR and the specific impact of HMW multimers defect of VWF. METHODS: Patients were prospectively enrolled between November 2012 and May 2018 at our institution. The CT-ADP, a point-of-care measure of hemostasis, was assessed the day before and 24 hours after the procedures. The rate of ischemic stroke and transient ischemic attack (TIA) was recorded up to 30 days after the procedures. RESULTS: Of 565 TAVR patients, ischemic stroke/TIA was observed in 21 (3.7%) patients within 30 days. Ischemic stroke/TIA was associated with major/life-threatening bleeding complications (MLBCs) (9 [43%] vs. 88 [16%], p = 0.002) and postprocedure CT-ADP > 180 seconds (10 [48%] vs. 116 [21%], p = 0.01). By multivariate analysis, MLBCs (odds ratio [OR]: 3.58; 95% confidence interval [CI]: 1.45-8.84; p = 0.006) and postprocedure CT-ADP > 180 seconds (OR: 3.38; 95% CI: 1.38-8.25; p = 0.008) were evidenced as independent predictors of ischemic stroke/TIA. CONCLUSION: MLBCs and CT-ADP > 180 seconds were identified as predictors for ischemic stroke or TIA. The present study suggests that the defects of HMW multimers of the VWFs may contribute not only to bleeding events but also to thrombotic events.

Impact of Antithrombotic Regimen and Platelet Inhibition Extent on Leaflet Thrombosis Detected by Cardiac MDCT after Transcatheter Aortic Valve Replacement.

The impact of antithrombotic regimen and platelet inhibition extent on subclinical leaflet thrombosis (SLT) detected by cardiac multidetector computed tomography (MDCT) after transcatheter aortic valve replacement (TAVR) is not well established. Hypoattenuation affecting motion (HAM) has been proposed as a surrogate marker of SLT, and is characterized by hypoattenuated leaflet thickening (HALT) and concomitant reduction in leaflet motion (RELM). We sought to investigate (i) the prevalence of HAM and HALT after TAVR detected by MDCT, (ii) the predictors of SLT, (iii) the impact of oral anticoagulant (OAC) and platelet inhibition extent assessed by platelet reactivity index vasodilator stimulated phosphoprotein (PRI-VASP) and closure time adenosine diphosphate (CT-ADP) on SLT. Of 187 consecutive patients who underwent TAVR from 1 August 2017 to 31 March 2018, 90 of them had cardiac CT at relevant follow-up. Clinical, biological, echocardiographic, procedural characteristics and treatments were collected before, at discharge, and 1 year after TAVR. P2Y12 platelet inhibition extent and primary haemostasis disorders were investigated using platelet PRI-VASP and CT-ADP point-of-care assays. Eighty-five post-TAVR CTs out of 90 were ranked for clarity and assessed with sufficient diagnostic quality. HAM was evidenced in 13 patients (15.3%) and HALT in 30 patients (35%). Procedural characteristics, including aortic valve calcium score, annulus size, or procedural heparin regimens, were equivalent between groups. Likewise, no impact of P2Y12 inhibition (PRI-VASP) nor primary haemostasis disorders (CT-ADP) on SLT could be evidenced. No impact of SLT on valve deterioration evaluated by transthoracic echocardiography (TTE) and clinical events could be established at 12 months follow-up. By multivariate analysis, lack of oral anticoagulant therapy at discharge (HR 12.130 CI 95% (1.394-150.582); p = 0.028) and higher haemoglobin levels were evidenced as the sole independent predictors of SLT. In four patients with HAM, MDCT follow-up was obtained after initiation of OAC therapy and showed a complete regression of HAM. SLT was evidenced in a sizeable proportion of patients treated by TAVR and was mainly determined by the lack of oral anticoagulant therapy. Conversely, no impact of platelet inhibition extent on SLT could be evidenced.

Antiplatelet Therapy in ACS Patients: Comparing Appropriate P2Y12 Inhibition by Clopidogrel to the Use of New P2Y12 Inhibitors.

AIM: In percutaneous coronary intervention (PCI)-treated acute coronary syndrome (ACS) patients on clopidogrel therapy, high on-treatment platelet adenosine diphosphate (ADP) reactivity was observed in numerous studies, with significant increases in non-fatal myocardial infarction, definite/probable stent thrombosis, or cardiovascular mortality. Compared to clopidogrel, prasugrel and ticagrelor provide more potent platelet inhibition. Whether new P2Y12 inhibitors reduce thrombotic events in a similar manner compared to the rate observed with appropriate P2Y12 inhibition by clopidogrel must still be determined. This study sought to compare long-term outcomes between clopidogrel responders (platelet reactivity index [PRI] vasodilator-stimulated phosphoprotein [VASP] ＜61%) and patients under prasugrel or ticagrelor therapy following PCI-treated ACS. METHODS: 730 ACS patients undergoing urgent PCI were prospectively enrolled into two groups: clopidogrel responders (n=448) and those under ticagrelor or prasugrel therapy (n=282). The primary endpoint was a composite of cardiovascular death, myocardial infarction, stent thrombosis, and stroke; the secondary endpoint comprised major hemorrhagic events. RESULTS: The median follow-up was 260±186 days. Clopidogrel patients were older and more likely to present non-ST segment elevation myocardial infarction, cardiovascular risk factors, atrial fibrillation, or prior vascular disease. After propensity score matching, the primary endpoint was met in 7.1% of the clopidogrel group and 4.1% of the prasugrel/ticagrelor group (p=0.43). Minor bleeding events were significantly reduced in the clopidogrel group (1.1% vs. 3%; p=0.03). In a multivariate analysis, the antiplatelet treatment strategy was not an independent primary endpoint predictor. CONCLUSION: In PCI-treated ACS patients, clopidogrel therapy and PRI VASP ＜61% were not associated with increased risks of thrombotic events compared to prasugrel or ticagrelor therapy.

Impact of Malignancies in the Early and Late Time Course of Takotsubo Cardiomyopathy.

BACKGROUND: Although the relationship between malignancies and catecholamine-induced myocardial stunning remains largely speculative, it has been suggested that the presence of cancer may lower the threshold for stress stimuli and/or may aggravate cardiac adrenoreceptor sensitivity. We sought to investigate whether associations exist between a previous or current diagnosis of malignancy, diagnostic parameters during hospitalization and death in takotsubo. METHODS AND RESULTS: The 154 takotsubo patients were retrospectively identified between May 2008 and December 2014. Previous history of malignancy was identified in 44 patients (28.5%). Cardiac arrest was present at admission in 13 patients (8.4%). Intra-aortic balloon pump was inserted in 16 patients (10.4%). In patients with malignancy, higher B-type natriuretic peptide (BNP), leukocyte and C-reactive protein (CRP) peaks could be observed during the hospital phase. Initial impairment of left ventricular ejection fraction was negatively related to BNP, leukocyte, and CRP peaks. At a median follow-up of 364 days, all-cause death occurred in 41 patients (26.6%) and cardiac death in 12 patients (7.7%). Multivariate Cox regression analysis identified malignancy (hazard ratio 4.77 (1.02-22.17), leukocyte peak and age as independent predictors of cardiac death. Malignancy (2.62 (1.26-5.44), leukocyte peak (1.05 (1.01-1.08) and initial cardiac arrest (6.68 (2.47-18.01) were identified as independent predictors of overall mortality. CONCLUSIONS: In the present takotsubo patients, the prevalence of malignancy was high and may have affected cardiovascular outcomes through the activation of inflammatory and neurohormonal mechanisms. (Circ J 2016; 80: 2192-2198).

The extent of P2Y12 inhibition by clopidogrel in diabetes mellitus patients with acute coronary syndrome is not related to glycaemic control: roles of white blood cell count and body weight.

It was the study objective to determine whether glycaemic control affects the extent of platelet inhibition by thienopyridines as assessed by vasodilator-stimulated phosphoprotein flow cytometry (VASP-FCT) in patients with diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI) during acute coronary syndrome (ACS). Although the proportion of high on-treatment residual platelet reactivity is higher in DM, the contributions of glycaemic control and other factors associated with DM, such as excess body weight and inflammation, to this impaired platelet inhibition by thienopyridines have not yet been fully characterised. In this study, the extent of P2Y12 ADP receptor pathway inhibition was evaluated by the VASP-FCT. Platelet activation was expressed as the platelet reactivity index (PRI). Low response to clopidogrel (LR) was defined as a PRI of >61%. Four hundred forty-five consecutive ACS patients (DM = 160, NDM = 285) were enrolled. The proportion of LR was higher in DM patients (50 vs. 37.5%). In DM, PRI was not correlated with glycosylated haemoglobin (HbA1c) or glycaemia. In a univariate analysis, LR was associated with age, male sex, overweight, and white blood cell count (WBC). In a multivariate analysis, WBC >10,000 and body weight >80 kg were the sole independent predictors of LR to clopidogrel (hazard ratio (HR) 3.02 [1.36-6.68], p=0.006 and HR 2.47 [1.14-5.35], p = 0.021, respectively). Conversely, in non-DM patients, ST-elevation myocardial infarction was the sole independent predictor of LR. In conclusion, in ACS DM patients undergoing PCI, the extent of P2Y12 inhibition by clopidogrel is not related to glycaemic control but is related to body weight and inflammatory status as assessed by the WBC.