Search

BACKGROUNDMineralocorticoid receptor (MR) activation induces fibrosis. Urinary proteomic profiling (UPP) detects thousands of sequenced peptides, mainly derived from collagen. No previous study applied UPP to generate insights in the antifibrotic actions of MR antagonism.METHODSBased on urine sample availability, subsets of the open HOMAGE trial (n=290; 23.8% women; median age: 73 years) and the double-blind PRIORITY trial (n=110; 21.8% women; 64 years) were analyzed as discovery and replication data sources. In the open HOMAGE trial, patients at risk of heart failure were randomized to usual therapy or usual therapy combined with spironolactone 25-50 mg/d. In the double-blind PRIORITY trial, type-2 diabetic patients with normal renal function were randomized to placebo or spironolactone 25 mg/d, both given on top of usual therapy. UPP relied on capillary electrophoresis coupled with mass spectrometry. In HOMAGE, the PICP/CITP ratio was calculated from serum PICP and serum CITP, which are markers of type-1 collagen synthesis and degradation, respectively. After rank-normalization of the biomarker distributions, between-group differences in the biomarker changes were analyzed by multivariable models. Correlations between the changes in urinary peptides and in serum CITP, derived from mature type-1 collagen, were compared between groups, using Fisher Z transform.RESULTSIn the HOMAGE and PRIORITY analytical subsets, patients had detectable signals of 1498 urinary peptides. Follow-up totaled 9 months in HOMAGE and was 30 months (median) in PRIORITY. All changes in urinary peptides that remained significantly different (PP≤0.0129). Correlations between changes from baseline to follow-up in urinary type-1 collagen fragments and CITP were positive often reaching significance if fragments increased during follow-up, but were nonsignificant if fragments decreased during follow-up. There were no between-group differences in these correlations.CONCLUSIONSMR antagonism predominantly reduces collagen-derived urinary peptides. Inhibition of collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Clinical PerspectiveWhat Is New?Few studies addressed the association between urinary and serum markers of fibrosis and how MR antagonism influences urinary peptides derived from collagen.MR antagonism reduces collagen-derived urinary peptides. Inhibition of type-1 collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Correlations between changes from baseline to follow-up in type-1 collagen and in CITP were positive if fragments increased during follow-up and nonsignificant if fragments decreased.What Are the Clinical Implications?Spironolactone inhibits fibrosis, supporting the use of MRAs in patients at risk of heart failure or chronic kidney disease.UPP profiling opens new research perspectives in documenting the antifibrotic properties of novel drug classes, such as nonsteroidal MR antagonists or sodium-glucose cotransporter-2 inhibitors.The development of novel medicines that would promote collagen degradation in addition to MRAs would strengthen the therapeutic armamentarium to modify fibrosis.GRAPHICAL ABSTRACT

Background Optimising blood pressure (BP) control is one of the most important modifiable risk factors in preventing subsequent stroke where the risk increases by one-third for every 10 mmHg rise in systolic BP. This study evaluated the feasibility and potential effectiveness of blood pressure self-monitoring with planned medication titration, to inform a definitive trial of the intervention, in patients with a previous stroke or transient ischaemic attack (TIA). Methods Patients with a history of stroke/TIA and sub-optimal BP control were invited to take part in a mixed methods feasibility study for a randomised controlled trial. Those meeting the inclusion criteria with systolic BP >130 mmHg were randomised to a self-monitoring intervention group or usual care group. The intervention involved self-monitoring BP twice a day for 3 days within a 7-day period, every month, following text message reminders. Treatment escalation, based on a pre-agreed plan by the general practitioner (GP) and patient, was initiated according to the results of these readings. Semi-structured interviews were carried out with patients and clinicians and analysed thematically. Results Of those identified, 47% (32/68) attended for assessment. Of those assessed, 15 were eligible for recruitment and were consented and randomised to the intervention or control group on a 2:1 basis. Of those randomised, 93% (14/15) completed the study and there were no adverse events. Systolic BP was lower in the intervention group at 3 months. Participants found the intervention acceptable and easy to use. GPs found it easy to incorporate into their practice activity without increasing workload. Conclusions TASMIN5S, an integrated blood pressure self-monitoring intervention in patients with a previous stroke/TIA, is feasible and safe to deliver in primary care. A pre-agreed three-step medication titration plan was easily implemented, increased patient involvement in their care, and had no adverse effects. This feasibility study provides important information to inform a definitive trial to determine the potential effectiveness of the intervention in patients post-stroke or TIA. Trial registration ISRCTN57946500. Registered on 12/08/2019.