Activated factor X stimulates atrial endothelial cells and tissues to promote remodelling responses through AT1R/NADPH oxidases/SGLT1/2.

AIMS: Atrial fibrillation (AF), the most common cardiac arrhythmia favouring ischemic stroke and heart failure involves left atrial remodelling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodelling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. METHODS AND RESULTS: AECs collected from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-ß-gal) activity. In AECs, FXa increased ROS formation, senescence (SA-ß-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-ß and collagen-1/3a) and pro-remodelling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which were prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodelling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. CONCLUSION: FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodelling and pro-fibrotic responses in AECs and human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodelling and the progression of atrial fibrillation substrate.

A review of therapeutic approaches for post-infarction left ventricular remodeling.

Left ventricular remodeling is an adaptive process initially developed in response to acute myocardial infarction (AMI), but it ends up with negative adverse outcomes such as infarcted wall thinning, ventricular dilation, and cardiac dysfunction. A prolonged excessive inflammatory reaction to cardiomyocytes death and necrosis plays the crucial role in the pathophysiological mechanisms. The pharmacological treatment includes nitroglycerine, ß-blockers, ACEi/ARBs, SGLT2i, mineralocorticoid receptor antagonists, and some miscellaneous aspects. Stem cells therapy, CD34+ cells transplantation and gene therapy constitute the promissing therapeutic approaches for post AMI cardiac remodeling, thereby enhancing angiogenesis, cardiomyocytes differenciation and left ventricular function on top of inhibiting apoptosis, inflammation, and collagen deposition. All these lead to reduce infarct size, scar formation and myocardial fibrosis.

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.

The Conundrum of Occult Cancer Screening in Venous Thromboembolism: Lessons from the REMOTEV Registry.

(1) Background and Objectives: Venous thromboembolism (VTE) is strongly associated with cancer, and may be the first event revealing occult neoplasia. Nonetheless, the reasonable extent of the etiological assessment after an unprovoked VTE event remains debated. The main objective of this study was to evaluate the incidence of occult neoplasia one year after an episode of VTE, in consecutively hospitalized patients for VTE from the REMOTEV registry. The secondary objectives were to assess the performance of the various tests used for occult cancer screening in a real-life setting and analyze the risk factors associated with the discovery of cancer and the 1-year prognosis. (2) Methods: REMOTEV is a prospective, non-interventional cohort study of patients with acute VTE. Patients included in the registry from 23 October 2013 to 28 July 2018 were analyzed after a follow-up of 12 months. Cancer detection was performed according to local practices and consisted of a limited strategy to which an abdominal ultrasound was added. In the presence of suggestive clinical manifestations, further examinations were performed on an individual basis. (3) Results: A total of 993 patients were included in the study. At 1 year, the incidence of newly diagnosed cancer was low (5.3%). Half of the detected cancers were metastatic at discovery (51%) and had a poor global prognosis (32% of mortality at 1 year). Admission pulmonary CT scans as well as (thoracic)-abdomino-pelvic CT scans (when performed) were responsible for the majority of detected cancers. Age over 65 years and the concomitant presence of an unusual site and lower-limb deep vein thrombosis were the only factors associated with occult neoplasia in this cohort. After 1-year FU, mortality was higher in cancer patients (HR 6.0 (CI 95% 3.5−10.3, p < 0.0001)), and cancer evolution was the leading cause of death in the cancer group. (4) Conclusions: In REMOTEV, VTE-revealed occult cancer prevalence was low, but similar to recent reports and associated with higher age, multiple thrombotic sites and worse prognosis.

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 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.

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.

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.