Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial

The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest.This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin.Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards.After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]:1.26 to 1.56; p 0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p 0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [pThe presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391)

Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts

Aims: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. Methods and Results: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. Conclusion: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia

Novel Cardiac-Specific Biomarkers and the Cardiovascular Continuum

The concept of the cardiovascular continuum, introduced during the early 1990s, created a holistic view of the chain of events connecting cardiovascular-related risk factors with the progressive development of pathological-related tissue remodelling and ultimately, heart failure and death. Understanding of the tissue-specific changes, and new technologies developed over the last 25–30 years, enabled tissue remodelling events to be monitored in vivo and cardiovascular disease to be diagnosed more reliably than before. The tangible product of this evolution was the introduction of a number of biochemical markers such as troponin I and T, which are now commonly used in clinics to measure myocardial damage. However, biomarkers that can detect specific earlier stages of the cardiovascular continuum have yet to be generated and utilised. The majority of the existing markers are useful only in the end stages of the disease where few successful intervention options exist. Since a large number of patients experience a transient underlying developing pathology long before the signs or symptoms of cardiovascular disease become apparent, the requirement for new markers that can describe the early tissue-specific, matrix remodelling process which ultimately leads to disease is evident. This review highlights the importance of relating cardiac biochemical markers with specific time points along the cardiovascular continuum, especially during the early transient phase of pathology progression where none of the existing markers aid diagnosis

Effects of gender and race on prognosis after myocardial infarction: Adverse prognosis for women, particularly black women

Controversy has arisen concerning whether gender influences the prognosis after myocardial infarction. Although some studies have shown there to be no difference between the sexes, most have indicated a worse prognosis for women, attributing this to differences in baseline characteristics. It has been further suggested that black women have a particularly poor prognosis after infarction. To determine the contribution of gender and race to the course of infarction, 816 patients with confirmed myocardial infarction who were enrolled in the Multi-center Investigation of the Limitation of Infarct Size (MILIS) were analyzed. Of those patients, 226 were women and 590 were men, 142 were black and 674 were white.The cumulative mortality rate at 48 months was 36% for women versus 21% for men (p < 0.001, mean follow-up 32 months). The cumulative mortality rate by race was 34% for blacks versus 24% for whites (p < 0.005). Both women and blacks exhibited more baseline characteristics predictive of mortality than did their male or white counterparts. It was possible to account for the greater mortality rate of blacks by identifiable baseline variables; however, even after adjustment, the mortality rate for women remained significantly higher (p < 0.002). The poorer prognosis for women was influenced by a particularly high mortality rate among black women (48%); the mortality rate for white women was 32%, for black men 23% and for white men 21%. The mortality for black women was significantly greater than that of the other subgroups. Thus, findings in the MILIS population indicate that the prognosis after myocardial infarction is worse for women, particularly black women

Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 4 trial

AbstractObjectives. The aim of our study was to determine a superior tbrombolytic regimen from three: anistreplase (APSAC), frontloaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy.Background. Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolyticantithrombotic regimens could improve the outcome achieved with standard regimens.Methods. To address this issue, 382 patients with acute myocardial infection were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point “unsatisfactory outcome” was a composite clinical end point assessed through hospital discharge.Results. Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]).Conclusions. Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome

c-kitpos GATA-4 High Rat Cardiac Stem Cells Foster Adult Cardiomyocyte Survival through IGF-1 Paracrine Signalling

Resident c-kit positive (c-kitpos) cardiac stem cells (CSCs) could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs) were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway

Three-dimension structure of ventricular myocardial fibers after myocardial infarction

<p>Abstract</p> <p>Background</p> <p>To explore the pathological changes of three-dimension structure of ventricular myocardial fibers after anterior myocardial infarction in dog heart.</p> <p>Methods</p> <p>Fourteen acute anterior myocardial infarction models were made from healthy dogs (mean weight 17.6 ± 2.5 kg). Six out of 14 dogs with old myocardial infarction were sacrificed, and their hearts were harvested after they survived the acute anterior myocardial infarction for 3 months. Each heart was dissected into ventricular myocardial band (VMB), morphological characters in infarction region were observed, and infarct size percents in descending segment and ascending segment were calculated.</p> <p>Results</p> <p>Six dog hearts were successfully dissected into VMB. Uncorresponding damages in myocardial fibers of descending segment and ascending segment were found in apical circle in anterior wall infarction. Infarct size percent in the ascending segment was significantly larger than that in the descending segment (23.36 ± 3.15 (SD) vs 30.69 ± 2.40%, P = 0.0033); the long axis of infarction area was perpendicular to the orientation of myocardial fibers in ascending segment; however, the long axis of the infarction area was parallel with the orientation of myocardial fibers in descending segment.</p> <p>Conclusions</p> <p>We found that damages were different in both morphology and size in ascending segment and descending segment in heart with myocardial infarction. This may provide an important insight for us to understand the mechanism of heart failure following coronary artery diseases.</p

Predictors, type, and impact of bleeding on the net clinical benefit of long-term ticagrelor in stable patients with prior myocardial infarction

BACKGROUND: Ticagrelor reduces ischemic risk but increases bleeding in patients with prior myocardial infarction. Identification of patients at lower bleeding risk is important in selecting patients who are likely to derive more favorable outcomes versus risk from this strategy. METHODS AND RESULTS: PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin—Thrombolysis in Myocardial Infarction 54) randomized 21 162 patients with prior myocardial infarction in a 1:1:1 fashion to ticagrelor 60 mg or 90 mg twice daily or placebo, with ticagrelor 60 mg approved for long-term use. TIMI major or minor bleeding was the primary end point for this analysis. Causes of bleeding were categorized by site and etiology, and independent predictors were identified. At 3 years, ticagrelor 60 mg increased the rate of TIMI major or minor bleeding by 2.0% versus placebo (1.4% placebo versus 3.4% ticagrelor). The bleeding excess was driven primarily by spontaneous gastrointestinal bleeds. A history of spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding but not of ischemic risk. Patients with at least 1 risk predictor had 3-fold higher rates of bleeding with ticagre-lor 60 mg versus those who had neither (absolute risk increase, 4.4% versus 1.5%; P=0.01). Patients with neither predictor had a more favorable benefit profile with ticagrelor 60 mg versus placebo including lower mortality (hazard ratio, 0.79; 95% CI, 0.65–0.96; P interaction = 0.03). CONCLUSIONS: In patients with prior myocardial infarction, bleeding with ticagrelor 60 mg twice daily is predominantly spontaneous gastrointestinal. A history of spontaneous bleeding requiring hospitalization or the presence of anemia identifies patients at higher risk of bleeding, and the absence of either identifies patients likely to have a more favorable net benefit with ticagrelor