Diabetic Cardiomiopathy Progression is Triggered by miR122-5p and Involves Extracellular Matrix: A 5-Year Prospective Study |
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Authors: | Riccardo Pofi Elisa Giannetta Nicola Galea Marco Francone Federica Campolo Federica Barbagallo Daniele Gianfrilli Mary Anna Venneri Tiziana Filardi Cristiano Cristini Gabriele Antonini Roberto Badagliacca Giacomo Frati Andrea Lenzi Iacopo Carbone Andrea M. Isidori |
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Affiliation: | 1. Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy;2. Department of Radiological, Oncological and Pathological Sciences, “Sapienza” University of Rome, Rome, Italy;3. Department of Obstetrical and Gynaecological Sciences and Urological Sciences, “Sapienza” University of Rome, Rome, Italy;4. Department of Cardiovascular and Respiratory Diseases, “Sapienza” University of Rome, Rome, Italy;5. Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy;6. Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) NEUROMED, Pozzilli, Italy |
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Abstract: | ObjectivesThe purpose of this study was to follow the long-term progression of diabetic cardiomyopathy by combining cardiac magnetic resonance (CMR) and molecular analysis.BackgroundThe evolution of diabetic cardiomyopathy to heart failure affects patients’morbidity and mortality. CMR is the gold standard to assess cardiac remodeling, but there is a lack of markers linked to the mechanism of diabetic cardiomyopathy progression.MethodsFive-year longitudinal study on patients with type 2 diabetes mellitus (T2DM) enrolled in the CECSID (Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes) trial compared with nondiabetic age-matched controls. CMR with tagging together with metabolic and molecular assessments were performed at baseline and 5-year follow-up.ResultsA total of 79 men (age 64 ± 8 years) enrolled, comprising 59 men with T2DM compared with 20 nondiabetic age-matched controls. Longitudinal CMR with tagging showed an increase in ventricular mass (ΔLVMi = 13.47 ± 29.66 g/m2; p = 0.014) and a borderline increase in end-diastolic volume (ΔEDVi = 5.16 ± 14.71 ml/m2; p = 0.056) in men with T2DM. Cardiac strain worsened (Δσ = 1.52 ± 3.85%; p = 0.033) whereas torsion was unchanged (Δθ = 0.24 ± 4.04°; p = 0.737), revealing a loss of the adaptive equilibrium between strain and torsion. Contraction dynamics showed a decrease in the systolic time-to-peak (ΔTtP = ?35.18 ± 28.81 ms; p < 0.001) and diastolic early recoil-rate (ΔRR = ?20.01 ± 19.07 s-1; p < 0.001). The ejection fraction and metabolic parameters were unchanged. Circulating miR microarray revealed an up-regulation of miR122-5p. Network analysis predicted the matrix metalloproteinases (MMPs) MMP-16 and MMP-2 and their regulator (tissue inhibitors of metalloproteinases) as targets. In db/db mice we demonstrated that miR122-5p expression is associated with diabetic cardiomyopathy, that in the diabetic heart is overexpressed, and that, in vitro, it regulates MMP-2. Finally, we demonstrated that miR122-5p overexpression affects the extracellular matrix through MMP-2 modulation.ConclusionsWithin 5 years of diabetic cardiomyopathy onset, increasing cardiac hypertrophy is associated with progressive impairment in strain, depletion of the compensatory role of torsion, and changes in viscoelastic contraction dynamics. These changes are independent of glycemic control and paralleled by the up-regulation of specific microRNAs targeting the extracellular matrix. (Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes [CECSID]; NCT00692237) |
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Keywords: | cardiac hypertrophy cardiac magnetic resonance diabetes mellitus heart failure with preserved ejection fraction metalloproteinase CMR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" cardiac magnetic resonance ECM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" extracellular matrix EDVi" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" indexed end-diastolic volume EF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" ejection fraction HF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" heart failure HfpEF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" heart failure with preserved ejection fraction HfrEF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" heart failure with reduced ejection fraction LGE" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" late gadolinium enhancement LV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" left ventricle LVMi" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" indexed left ventricular mass miRNA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" microRNA MMP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" matrix metalloproteinase mRNA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0180" }," $$" :[{" #name" :" text" ," _" :" messenger RNA qPCR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" quantitative polymerase chain reaction RR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0200" }," $$" :[{" #name" :" text" ," _" :" recoil rate TtP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0220" }," $$" :[{" #name" :" text" ," _" :" time to peak T2DM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0230" }," $$" :[{" #name" :" text" ," _" :" type 2 diabetes mellitus |
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