SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope

Therapeutic options that directly enhance cardiomyocyte contractility in chronic heart failure (HF) therapy are currently limited and do not improve prognosis. In fact, most positive inotropic agents, such as β-adrenoreceptor agonists and PDE inhibitors, which have been assessed in HF patients, cause increased mortality as a result of arrhythmia and sudden cardiac death. Cardiac sarcoplasmic reticulum Ca²⁺-ATPase2a (SERCA2a) is a key protein involved in sequestration of Ca²⁺ into the sarcoplasmic reticulum (SR) during diastole. There is a reduction of SERCA2a protein level and function in HF, which has been successfully targeted via viral transfection of the SERCA2a gene into cardiac tissue in vivo. This has enhanced cardiac contractility and reduced mortality in several preclinical models of HF. Theoretical concerns have been raised regarding the possibility of arrhythmogenic adverse effects of SERCA2a gene therapy due to enhanced SR Ca²⁺ load and induction of SR Ca²⁺ leak as a result. Contrary to these concerns, SERCA2a gene therapy in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias. The potential mechanisms for this unexpected beneficial effect, as well as mechanisms of enhancement of cardiac contractile function, are reviewed in this article.     

Ease of use of two autoinjectors in patients with multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: results of the randomized,crossover REDEFINE study

Background: For interferon beta-1a subcutaneously three times weekly (IFN β-1a SC tiw), administration options include manually injected prefilled syringes; a preassembled, single-use autoinjector; and a reusable autoinjector. This study evaluated patient-perceived ease of use of two injection devices.

Research design and methods: REDEFINE, a Phase IV, multicenter crossover study, randomized patients with multiple sclerosis and ≥5 weeks’ IFN β-1a 44 μg SC tiw use to 4 weeks using a single-use autoinjector, then 4 weeks using a reusable autoinjector, or vice versa. The primary endpoint was the proportion rating each ‘easy’ or ‘very easy’, with/without regard to previous device experience.

Results: Of 97 randomized patients, 29 had most recent experience with manual injection; 23 with single-use autoinjector; and 45 with reusable autoinjector. 68.4% found using the single-use autoinjector very easy or easy, versus 77.9% for the reusable device (difference ?9.5%; p = 0.200). 40.0% versus 29.5% found the respective devices very easy (difference 10.5%; p = 0.203).

Conclusions: Most patients found both autoinjectors easy or very easy to use. Having two viable options may help accommodate patient preferences. Ease of administration and patient satisfaction relates to adherence; satisfied patients may more likely be adherent.

Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02019550).