Riccardo Pofi1, Elisa Giannetta1, Nicola Galea1, Marco Francone2, Federica Campolo1, Federica Barbagallo1, Daniele Gianfrilli1, Mary Anna Venneri1, Tiziana Filardi1, Cristiano Cristini3, Gabriele Antonini3, Roberto Badagliacca4, Giacomo Frati5, Andrea Lenzi1, Iacopo Carbone2, Andrea M Isidori6. 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; Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) NEUROMED, Pozzilli, Italy. 6. Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy. Electronic address: andrea.isidori@uniroma1.it.
Abstract
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 (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. 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).
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 (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. 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).
Authors: Katrīna D Neiburga; Baiba Vilne; Sabine Bauer; Dario Bongiovanni; Tilman Ziegler; Mark Lachmann; Simon Wengert; Johann S Hawe; Ulrich Güldener; Annie M Westerlund; Ling Li; Shichao Pang; Chuhua Yang; Kathrin Saar; Norbert Huebner; Lars Maegdefessel; Rüdiger Lange; Markus Krane; Heribert Schunkert; Moritz von Scheidt Journal: Biomolecules Date: 2021-11-12
Authors: Miriam Longo; Lorenzo Scappaticcio; Paolo Cirillo; Antonietta Maio; Raffaela Carotenuto; Maria Ida Maiorino; Giuseppe Bellastella; Katherine Esposito Journal: Biomolecules Date: 2022-02-08