PMID- 33221242
OWN - NLM
STAT- MEDLINE
DCOM- 20211008
LR  - 20211008
IS  - 1876-7591 (Electronic)
IS  - 1876-7591 (Linking)
VI  - 14
IP  - 6
DP  - 2021 Jun
TI  - Diabetic Cardiomiopathy Progression is Triggered by miR122-5p and Involves 
      Extracellular Matrix: A 5-Year Prospective Study.
PG  - 1130-1142
LID - S1936-878X(20)30916-5 [pii]
LID - 10.1016/j.jcmg.2020.10.009 [doi]
AB  - OBJECTIVES: The purpose of this study was to follow the long-term progression of 
      diabetic cardiomyopathy by combining cardiac magnetic resonance (CMR) and 
      molecular analysis. BACKGROUND: The 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. METHODS: Five-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. RESULTS: A 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 (DeltaLVMi = 13.47 +/- 29.66 
      g/m(2); p = 0.014) and a borderline increase in end-diastolic volume 
      (DeltaEDVi = 5.16 +/- 14.71 ml/m(2); p = 0.056) in men with T2DM. Cardiac strain 
      worsened (Deltasigma = 1.52 +/- 3.85%; p = 0.033) whereas torsion was unchanged (Deltatheta = 0.24 
      +/- 4.04 degrees ; 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 
      (DeltaTtP = -35.18 +/- 28.81 ms; p < 0.001) and diastolic early recoil-rate 
      (DeltaRR = -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. 
      CONCLUSIONS: Within 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).
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Pofi, Riccardo
AU  - Pofi R
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Giannetta, Elisa
AU  - Giannetta E
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Galea, Nicola
AU  - Galea N
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Francone, Marco
AU  - Francone M
AD  - Department of Radiological, Oncological and Pathological Sciences, "Sapienza" 
      University of Rome, Rome, Italy.
FAU - Campolo, Federica
AU  - Campolo F
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Barbagallo, Federica
AU  - Barbagallo F
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Gianfrilli, Daniele
AU  - Gianfrilli D
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Venneri, Mary Anna
AU  - Venneri MA
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Filardi, Tiziana
AU  - Filardi T
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Cristini, Cristiano
AU  - Cristini C
AD  - Department of Obstetrical and Gynaecological Sciences and Urological Sciences, 
      "Sapienza" University of Rome, Rome, Italy.
FAU - Antonini, Gabriele
AU  - Antonini G
AD  - Department of Obstetrical and Gynaecological Sciences and Urological Sciences, 
      "Sapienza" University of Rome, Rome, Italy.
FAU - Badagliacca, Roberto
AU  - Badagliacca R
AD  - Department of Cardiovascular and Respiratory Diseases, "Sapienza" University of 
      Rome, Rome, Italy.
FAU - Frati, Giacomo
AU  - Frati G
AD  - Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University 
      of Rome, Latina, Italy; Istituti di Ricovero e Cura a Carattere Scientifico 
      (IRCCS) NEUROMED, Pozzilli, Italy.
FAU - Lenzi, Andrea
AU  - Lenzi A
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
FAU - Carbone, Iacopo
AU  - Carbone I
AD  - Department of Radiological, Oncological and Pathological Sciences, "Sapienza" 
      University of Rome, Rome, Italy.
FAU - Isidori, Andrea M
AU  - Isidori AM
AD  - Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy. 
      Electronic address: andrea.isidori@uniroma1.it.
LA  - eng
SI  - ClinicalTrials.gov/NCT00692237
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201118
PL  - United States
TA  - JACC Cardiovasc Imaging
JT  - JACC. Cardiovascular imaging
JID - 101467978
RN  - 0 (MIRN122 microRNA, human)
RN  - 0 (MicroRNAs)
SB  - IM
CIN - JACC Cardiovasc Imaging. 2021 Jun;14(6):1143-1145. PMID: 33744152
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/complications/genetics
MH  - Extracellular Matrix
MH  - Humans
MH  - Longitudinal Studies
MH  - Mice
MH  - *MicroRNAs
MH  - Predictive Value of Tests
MH  - Prospective Studies
OTO - NOTNLM
OT  - cardiac hypertrophy
OT  - cardiac magnetic resonance
OT  - diabetes mellitus
OT  - heart failure with preserved ejection fraction
OT  - metalloproteinase
COIS- Funding Support And Author Disclosures The work was funded by the Italian 
      Ministry of University and Research MIUR - PRIN 2015ZTT5KB. Dr. Isidori has 
      received consultation fees, unconditional grants, and hospitality to conferences 
      from IBSA, Takeda, and IPSEN. Dr. Filardi received hospitality to conferences 
      from Sanofi and Merck. All other authors have reported that they have no 
      relationships relevant to the contents of this paper to disclose.
EDAT- 2020/11/23 06:00
MHDA- 2021/10/09 06:00
CRDT- 2020/11/22 20:33
PHST- 2020/08/10 00:00 [received]
PHST- 2020/10/14 00:00 [revised]
PHST- 2020/10/15 00:00 [accepted]
PHST- 2020/11/23 06:00 [pubmed]
PHST- 2021/10/09 06:00 [medline]
PHST- 2020/11/22 20:33 [entrez]
AID - S1936-878X(20)30916-5 [pii]
AID - 10.1016/j.jcmg.2020.10.009 [doi]
PST - ppublish
SO  - JACC Cardiovasc Imaging. 2021 Jun;14(6):1130-1142. doi: 
      10.1016/j.jcmg.2020.10.009. Epub 2020 Nov 18.