Jonas Wuopio1, Jørgen Hilden2, Carl Bring3, Jens Kastrup4, Ahmad Sajadieh5, Gorm Boje Jensen6, Erik Kjøller7, Hans Jørn Kolmos8, Anders Larsson9, Janus Christian Jakobsen10, Per Winkel11, Christian Gluud11, Axel C Carlsson12, Johan Ärnlöv13. 1. Department of Medicine, Mora County Hospital, Mora, Sweden. Electronic address: jonas.wuopio@ltdalarna.se. 2. Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark. 3. Department of Medicine, Lindesberg County Hospital, Lindesberg, Sweden. 4. Department of Cardiology, Rigshospitalet University of Copenhagen, Denmark. 5. Department of Cardiology, Bispebjerg & Frederiksberg Hospital University of Copenhagen, Denmark. 6. Department of Cardiology, Hvidovre Hospital University of Copenhagen, Denmark. 7. Department of Cardiology S, Herlev Hospital University of Copenhagen, Copenhagen, Denmark. 8. Department of Clinical Microbiology, Odense University Hospital, Denmark. 9. Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 10. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Cardiology, Holbæk Hospital, Denmark. 11. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 12. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden; Division for Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. 13. Division for Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden.
Abstract
BACKGROUND AND AIMS: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease. METHODS: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycingroup as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomesn = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs. RESULTS: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events. CONCLUSIONS: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.
RCT Entities:
BACKGROUND AND AIMS: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease. METHODS: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs. RESULTS:Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events. CONCLUSIONS:Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.
Authors: Per Winkel; Janus Christian Jakobsen; Jørgen Hilden; Gorm Boje Jensen; Erik Kjøller; Ahmad Sajadieh; Jens Kastrup; Hans Jørn Kolmos; Kasper Karmark Iversen; Mette Bjerre; Anders Larsson; Johan Ärnlöv; Christian Gluud Journal: BMJ Open Date: 2020-08-20 Impact factor: 2.692