Effects of Ivabradine on Patients with Depressed Left Ventricular Function after Cardiac Resynchronization Therapy.

Background: The potential synergistic effect of ivabradine and cardiac resynchronization therapy (CRT) in heart failure (HF) patients has rarely been studied. We aimed to evaluate the clinical benefits of ivabradine in patients with left ventricular dysfunction following CRT implantation. Methods: Two hundred and thirty-one patients receiving CRT were consecutively enrolled between January 2014 and December 2018 from two HF centers. A total of 123 patients had left ventricular ejection fraction (LVEF) < 40% and resting sinus heart rate (HR) ≥ 75 bpm after six months of CRT implantation. Among these patients, 45 were treated with ivabradine (Group 1), and 78 did not receive ivabradine treatment (Group 2). Results: Baseline characteristics and prescription rates of HF medications other than ivabradine were similar between the two groups. In Group 1, the mean HR decreased from 82.2 ± 11.4 bpm to 76.3 ± 10.5 bpm (p = 0.012), and the mean LVEF increased from 29.9 ± 6.5% to 38.8 ± 12.4% (p < 0.001). Atrial pacing percentage, biventricular pacing percentage, and burden of atrial fibrillation (AF) were not significantly different between the two groups during the study period. The patients' daily physical activity increased significantly in Group 1 compared to Group 2 (Δ daily activity 0.4 ± 0.7 hours/day vs. -0.1 ± 7.2 hours/day, p < 0.001). Conclusions: Ivabradine could effectively reduce HR and improve physical activity. It was safe to use and did not increase AF burden or affect biventricular pacing percentage in CRT recipients.

Sacubitril/valsartan in heart failure with reduced ejection fraction patients: Real world experience on advanced chronic kidney disease, hypotension, and dose escalation.

BACKGROUND: Angiotensin receptor and neprilysin inhibition (ARNI) has been shown to reduce cardiovascular mortality by 20% as compared with enalapril in a randomized controlled trial. However, there is a paucity of real-world data on the effects of ARNI in heart failure patients with reduced ejection fraction (HFrEF), especially those with concurrent renal impairment or hypotension. METHODS: Between 2016 and 2017, we recruited 466 HFrEF patients treated with sacubitril/valsartan (Group A) and 466 patients managed with standard HF treatment without ARNI (Group B) in a HF referral center. Baseline characteristics and clinical outcomes were collected between both groups. RESULTS: Baseline characteristics were comparable between the two groups. During a follow-up period of 15 months, death from cardiovascular causes or first unplanned hospitalization for HF occurred in 100 patients in Group A (21.5%) and 144 in Group B (30.9%, hazard ratio 0.66; 95% CI 0.51-0.85; p=0.001). The incidences of deaths from any causes, cardiovascular death, sudden death, and HF re-hospitalization were all significantly lower in Group A than Group B patients. Among patients with different chronic kidney disease stages and normotensive patients, treatment with sacubitril/valsartan showed more favorable outcomes than treatment with standard HF care without ARNI. However, in patients with baseline systolic blood pressure lower than 100mmHg, there were no significant differences of outcomes in both groups. Among Group A patients, escalation of sacubitril/valsartan was associated with better outcomes. CONCLUSIONS: Our study demonstrated the effectiveness of sacubitril/valsartan on HFrEF patients in real world practice, including those with advanced renal impairment.

Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease.

Enterovirus A71 (EV-A71) has emerged as a major pathogen causing hand, foot, and mouth disease, as well as neurological disorders. The host immune response affects the outcomes of EV-A71 infection, leading to either resolution or disease progression. However, the mechanisms of how the mammalian innate immune system detects EV-A71 infection to elicit antiviral immunity remain elusive. Here, we report that the Toll-like receptor 3 (TLR3) is a key viral RNA sensor for sensing EV-A71 infection to trigger antiviral immunity. Expression of TLR3 in HEK293 cells enabled the cells to sense EV-A71 infection, leading to type I, IFN-mediated antiviral immunity. Viral double-stranded RNA derived from EV-A71 infection was a key ligand for TLR3 detection. Silencing of TLR3 in mouse and human primary immune cells impaired the activation of IFN-ß upon EV-A71 infection, thus reinforcing the importance of the TLR3 pathway in defending against EV-A71 infection. Our results further demonstrated that TLR3 was a target of EV-A71 infection. EV-A71 protease 2A was implicated in the downregulation of TLR3. Together, our results not only demonstrate the importance of the TLR3 pathway in response to EV-A71 infection, but also reveal the involvement of EV-A71 protease 2A in subverting TLR3-mediated antiviral defenses.

Deoxyribonuclease-inhibitory antibodies in systemic lupus erythematosus.

Deoxyribonucleases (DNases) are key enzymes for digesting DNA. Abnormalities in the function of these enzymes may contribute to the development of anti-DNA antibodies in systemic lupus erythematosus (SLE). In this study, we used bovine DNase 1-coated ELISA plates to screen anti-DNase antibodies in SLE patients. About 62% of the sera of SLE patients (63/101) were positive for anti-DNase antibodies compared to only 8% of normal controls (8/98). A positive correlation was also found between the concentrations of anti-DNase and anti-DNA antibodies in sera of SLE patients. Affinity-purified anti-DNase immunoglobulin G (IgG) from pooled sera of SLE patients bound to bovine DNase as well as DNA. A synthetic peptide, corresponding to the catalytic site of DNase, was able to completely inhibit the binding of anti-DNase IgG to DNase. In addition to bovine DNase, the anti-DNase IgG also bound to and inhibited the enzymatic activities of DNase present in streptococcal supernatants and human urine. Immunization of lupus-prone NZB/NZW mice with bovine DNase enhanced the production of anti-DNase and DNA antibodies, and accelerated the occurrence of proteinuria. Taken together, these results suggest that DNase-inhibitory antibodies which recognize a conserved epitope near the catalytic site of DNase may act in the pathogenesis of SLE.