Survival with cardiac-resynchronization therapy in mild heart failure.

BACKGROUND: The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that early intervention with cardiac-resynchronization therapy with a defibrillator (CRT-D) in patients with an electrocardiographic pattern showing left bundle-branch block was associated with a significant reduction in heart-failure events over a median follow-up of 2.4 years, as compared with defibrillator therapy alone. METHODS: We evaluated the effect of CRT-D on long-term survival in the MADIT-CRT population. Post-trial follow-up over a median period of 5.6 years was assessed among all 1691 surviving patients (phase 1) and subsequently among 854 patients who were enrolled in post-trial registries (phase 2). All reported analyses were performed on an intention-to-treat basis. RESULTS: At 7 years of follow-up after initial enrollment, the cumulative rate of death from any cause among patients with left bundle-branch block was 18% among patients randomly assigned to CRT-D, as compared with 29% among those randomly assigned to defibrillator therapy alone (adjusted hazard ratio in the CRT-D group, 0.59; 95% confidence interval [CI], 0.43 to 0.80; P<0.001). The long-term survival benefit of CRT-D in patients with left bundle-branch block did not differ significantly according to sex, cause of cardiomyopathy, or QRS duration. In contrast, CRT-D was not associated with any clinical benefit and possibly with harm in patients without left bundle-branch block (adjusted hazard ratio for death from any cause, 1.57; 95% CI, 1.03 to 2.39; P=0.04; P<0.001 for interaction of treatment with QRS morphologic findings). CONCLUSIONS: Our findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit. (Funded by Boston Scientific; ClinicalTrials.gov numbers, NCT00180271, NCT01294449, and NCT02060110.).

Killing of schistosomes by elastase and hydrogen peroxide: implications for leukocyte-mediated schistosome killing.

Activated leukocytes participate in immunity to infection by the parasitic blood fluke Schistosoma mansoni. They attach to the surface of schistosomes and secrete schistosomicidal substances. Cationic proteins, hydrolytic enzymes, and oxidants, produced by the leukocytes, have been implicated in the damage to the schistosomes. To examine the possible involvement of elastase in the killing of schistosomes by leukocytes, young and adult stages of S. mansoni were treated in vitro with pancreatic elastase (PE) and neutrophil elastase (NE). Schistosomula, lung-stage schistosomula (LSS), and adult worms (AW) have been found to be sensitive to both PE and NE. Male AW were more sensitive to PE than female AW. The enzymatic activity of elastase is essential for its toxic effect because heat-inactivation and specific elastase inhibitors prevented elastase-mediated schistosome killing. Thus, alpha1-antitrypsin and the chloromethyl ketone (CMK)-derived tetrapeptides Ala-Ala-Pro-Val-CMK and Ala-Ala-Pro-Ala-CMK but not Ala-Ala-Pro-Phe-CMK and Ala-Ala-Pro-Leu-CMK blocked PE caseinolytic and schistosomulicidal activities. As shown previously, schistosomes are also efficiently killed by hydrogen peroxide. LSS appear to be more resistant than AW and early-stage schistosomula to the lytic effects of hydrogen peroxide. Cotreatment experiments with both elastase and hydrogen peroxide indicated that they exert an additive toxic effect and that hydrogen peroxide sensitizes schistosomula to the toxic effect of elastase but not vice versa. These results demonstrate, for the first time, that elastases may be toxic molecules used by neutrophils, eosinophils, and macrophages to kill various developmental stages of S. mansoni.