Apoptotic cell suicide initiated by ligation of CD95 (Fas/APO-1) occurs through recruitment, oligomerization and autocataly-

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Caspase-3 is synthesized as a dormant proenzyme and is maintained in an inactive conformation by an Asp-Asp-Asp ''safetycatch'' regulatory tripeptide contained within a flexible loop near the large-subunit͞small-subunit junction. Removal of this ''safety catch'' results in substantially enhanced autocatalytic maturation as well as increased vulnerability to proteolytic activation by upstream proteases in the apoptotic pathway such as caspase-9 and granzyme B. The safety catch functions through multiple ionic interactions that are disrupted by acidification, which occurs in the cytosol of cells during the early stages of apoptosis. We propose that the caspase-3 safety catch is a key regulatory checkpoint in the apoptotic cascade that regulates terminal events in the caspase cascade by modulating the triggering of caspase-3 activation.

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BackgroundHeart failure (HF) is a major cardiovascular disease with increasing prevalence. Thiamine deficiency occurs in 33% of patients with HF. However, the effectiveness of thiamine supplementation in HF is not known.MethodsIn a placebo-controlled randomized two-period crossover feasibility trial, patients age ≥ 60 years with HF and reduced ejection fraction (HFrEF, EF ≤ 45%) will be randomized to thiamine 500 mg oral capsule once daily or placebo for 3 months, then crossed over to the other intervention after a 6-week washout period. The primary outcome is recruitment rate. Secondary outcomes include feasibility and clinical measures. Feasibility outcomes include refusal rate, retention rate, and compliance rate. Secondary clinical outcomes include left ventricular ejection fraction, peak global longitudinal strain measured by echocardiography, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ) quality of life score, and clinical outcomes (all-cause mortality, HF hospitalizations, and HF emergency room visits).DiscussionThiamine is potentially a safe and low-cost treatment for older patients with HFrEF. Results from this study will inform the feasibility of a large clinical trial with clinical endpoints. The findings will be published in a peer review journal and presented at a relevant conference. This study has received full approval from the Hamilton Integrated Research Ethics Board (18-4537) and Health Canada (210603). This trial is funded by the Hamilton Health Sciences New Investigator Grant (15-387) and the McMaster/St. Peter’s Hospital Chair of Aging.Trial registrationNCT03228030 (ClinicalTrials.gov), registered July 24, 2017.

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