Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Although cigarette smoking is the most important risk factor, not all smokers develop the disease. Previous studies have suggested a role for fat soluble vitamins D and A in the pathogenesis of COPD. To the best of our knowledge vitamin K has never been studied as a potential causative factor. In the lungs of COPD patients there is an imbalance between proteases degrading connective tissue components like elastin, and antiproteases protecting against this degenerative process. Desmosine only occurs in elastin and therefore its plasma levels reflect the rate of elastin degradation. Elastin has high affinity for calcium and during aging the calcium concentration in elastin rises. Elastin degradation and calcification are inter-related since degraded elastin is more susceptible to calcification and vice versa. Matrix Gla protein (MGP) is a vitamin K dependent protein and the strongest natural inhibitor of elastin calcification. We hypothesized that COPD patients have lower vitamin K status than smokers without COPD and that plasma desmosine levels are inversely associated with vitamin K status. A total of 186 subjects were included in this study, of whom 111 were COPD patients, 41 were (ex-)smokers without COPD and 34 were never-smokers. Dp-ucMGP (inactive MGP) is formed during vitamin K insufficiency, and its plasma levels were used as a surrogate marker for vitamin K status. Plasma dp-ucMGP was quantified using an ELISA technique based on conformation-specific antibodies. Plasma desmosine levels were measured with LC-MS/MS using deuterium labelled desmosine as internal standard. Significantly lower vitamin K status was found in COPD patients compared to (ex-)smoking controls (p=0.001). No significant difference in vitamin K status was found between (ex-)smokers without COPD and never-smokers. COPD patients had lower vitamin K status than never-smokers, although the difference was not statistically significant (p=0.08). Vitamin K status was inversely associated with plasma desmosine levels in both COPD patients and controls (p<0.001). We demonstrated poor vitamin K status in COPD patients and an inverse association between vitamin K status and the rate of elastin degradation. Our study is the first to suggest a potential role for vitamin K in the pathogenesis of COPD. An interventional trial is needed to clarify whether vitamin K supplementation has a positive effect on disease progression in COPD. Abstract ATS 2016 San Francisco
The RAPID trial is the single largest randomized placebo-controlled trial of alpha1-antitrypsin augmentation therapy completed to date. Ma et al. measured plasma desmosine levels in participants of this study and they presented the results of this very interesting study at the American Thoracic Society meeting 2015. In patients receiving alpha1-antitrypsin supplementation, plasma desmosine levels decreased significantly at 3 months and were further reduced at 1 year and 2 years compared to baseline desmosine levels. An increase in plasma desmosine levels was observed in the placebo group at 3 months and 1 year and 2 years compared to baseline levels. A significant treatment difference between groups (active arm versus placebo arm) was observed at every time point. Furthermore, plasma desmosine levels were inversely correlated with CT scan lung density decline. Ma et al. demonstrated with this study that plasma desmosine has great potential for use as a surrogate-endpoint in clinical trials to assess the effects of interventions on emphysema progression especially in alpha1-antitrypsin supplementation trials.