Biomarker and imaging responses to spironolactone in subclinical diabetic cardiomyopathy.
BACKGROUND
Subclinical diabetic cardiomyopathy (DCM) is frequent in asymptomatic subjects with type 2 diabetes (T2DM). We sought the response of functional and fibrosis markers to therapy in a trial of aldosterone antagonism for treatment of DCM.


METHODS
Biochemical, anthropometric, and echocardiographic data were measured in 225 subjects with T2DM. Myocardial function was evaluated with standard echocardiography and myocardial deformation; ischaemia was excluded by exercise echocardiography. Calibrated integrated backscatter and post-contrast T1 mapping from cardiac magnetic resonance imaging were used to assess myocardial structure. Amino-terminal propeptides of pro-collagen type I (PINP) and III (PIIINP), the carboxy-terminal propeptide of pro-collagen type I (PICP) and transforming growth factor beta-1 were measured from peripheral blood or urine to assess myocardial collagen turnover.


RESULTS
Diastolic dysfunction was identified in 81 individuals, of whom 49 (25 male, age 60 ± 10 years) were randomized to spironolactone 25 mg/day or placebo therapy for 6 months. Groups were well-matched at baseline. Spironolactone therapy was associated with improvements in diastolic filling profile (Δpeak E wave velocity -4 ± 15 vs. 9 ± 10 ms, P = 0.001; ΔE/A ratio -0.1 ± 0.3 vs. 0.2 ± 0.2, P < 0.001) and cIB values (-21.2 ± 4.5 dB vs. -18.0 ± 5.2 dB, P = 0.026; ΔcIB -5.1 ± 6.8 vs. -1.3 ± 5.2, P = 0.030). ΔcIB was independently associated with spironolactone therapy (β = 0.320, P = 0.026) but not Δblood pressure. With intervention, pro-collagen biomarkers (ΔPINP P = 0.92, ΔPICP P = 0.25, ΔPIIINP P = 0.52, and ΔTGF-β1 P = 0.71) and T1 values (P = 0.54) remained similar between groups.


CONCLUSIONS
Spironolactone-induced changes in myocardial structure and diastolic properties in DCM are small, and are unassociated with changes in collagen biomarkers or T1 values.
School of Medicine, The University of Queensland, Brisbane, Australia.
Christine L
CL
Jellis
School of Medicine, The University of Queensland, Brisbane, Australia.
Julian W
JW
Sacre
Heart's 1st, Greenslopes Private Hospital, Brisbane, Australia.
Jeremy
J
Wright
School of Medicine, The University of Queensland, Brisbane, Australia.
Carly
C
Jenkins
School of Medicine, The University of Queensland, Brisbane, Australia.
Brian
B
Haluska
School of Medicine, The University of Queensland, Brisbane, Australia.
Leanne
L
Jeffriess
School of Medicine, The University of Queensland, Brisbane, Australia.
Jennifer
J
Martin
School of Medicine, The University of Queensland, Brisbane, Australia Menzies Research Institute of Tasmania, Hobart, Australia tom.marwick@utas.edu.au.
Thomas H
TH
Marwick
D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000188:drug therapy; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004452:Echocardiography / Q000379:methods; D005500:Follow-Up Studies; D006801:Humans; D016014:Linear Models; D019028:Magnetic Resonance Imaging, Cine / Q000379:methods; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010446:Peptide Fragments / Q000097:blood* / Q000187:drug effects; D011347:Procollagen / Q000097:blood* / Q000187:drug effects; D011446:Prospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D016037:Single-Blind Method; D013148:Spironolactone / Q000627:therapeutic use*; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
D015415:Biomarkers; D010446:Peptide Fragments; D011347:Procollagen; C047202:procollagen Type I N-terminal peptide; D013148:Spironolactone
Pro-collagen biomarkers; T1 mapping; backscatter; diabetic cardiomyopathy; diastolic dysfunction; myocardial fibrosis; spironolactone