Patient case: 63-year-old female with aortic aneurysm; genetic feature: ACTA2

Clinical trial: REmodelling in Diabetic CardiOmapathy: Gender Response to PDE5i InhibiTOrs

Summary: Pathophysiology of diabetic cardiomyopathy (DCM) is yet unclear and gender differences at baseline and a specific treatment have not been indicated. The investigators already demonstrated the positive impact of phosphodiesterase type 5A (PDE5A) inhibition in men. The investigators' study aims to characterize DCM, measuring molecular and neuroendocrine assessment to relate to intramyocardial metabolism and cardiac kinetic. The investigators will perform a randomized, placebo-controlled, double-blind study enrolling 164 diabetic patients (females and males) with DCM, to evaluate gender responses to 6 months of PDE5A inhibitors (PDE5Ai). The investigators' study will describe gender differences in DCM features. The proposed research will test whether PDE5Ai could become a new target for antiremodeling drugs and to discover a molecular pathways affected by this class of drugs and a network of circulating markers for the early diagnosis, monitoring and prediction of response to treatment of DCM.

Detailed description: Pathophysiology of diabetic cardiomyopathy (DCM) is yet unclear and gender differences at baseline and a specific treatment have not been indicated. The investigators demonstrated the positive impact of phosphodiesterase type 5A (PDE5A) inhibition in men. The investigators' study aims to characterize DCM, measuring molecular and neuroendocrine assessment to relate to intramyocardial metabolism and cardiac kinetic. The investigators will perform a randomized, placebo-controlled, double-blind study enrolling 164 diabetic patients (females and males) with DCM, to evaluate gender responses to 6 months of PDE5A inhibitors (PDE5Ai). The investigators' study will describe gender differences in DCM features. The proposed research will test whether PDE5Ai could become a new target for antiremodeling drugs and to discover a molecular pathways affected by this class of drugs and a network of circulating markers for the early diagnosis, monitoring and treatment of DCM.
  The investigators will allow identifying a cluster of cardiovascular, metabolic and oxidative stress markers and miRNAs, whose variations together correlate with the DCM evolution and the prediction of risk and response to treatment.
  The investigators will evaluate if PDE5Ai could become a new target for antiremodeling drugs; if the mechanism of action is direct on cardiac tissue, independently of other secondary effects and gender related difference.
  Type 2 diabetes mellitus is associated with cardiac remodeling that may occur independently of ischemic heart disease, hypertension, or macrovascular complications.
  In vitro studies have shown that phosphodiesterase 5 overexpression reduces cGMP levels and exacerbates remodeling. The investigators already studied the effects of 3-month daily Inhibition of cGMP hydrolysis through a phosphodiesterase 5A inhibitor (PDE5i) on cardiac remodeling in a cohort of asymptomatic, middle-aged men with type 2 diabetes mellitus (T2DM). CMR imaging revealed that diabetic cardiomyopathy in these patients produced an uncoupling in left ventricular contraction between longitudinal strain, which is reduced, and cardiac axial rotation, which is increased. Characterized DCM at early asymptomatic stages in men, we identified two circulating markers, TGF-beta and MCP-1 increased and significantly related to cardiac kinetic parameters. Then, the investigators found that long-term PDE5i restored coupling by reducing torsion and improving strain. It also reduced the ratio of left ventricular mass to end-diastolic volume that is increased in the presence of concentric hypertrophy. Circulating markers TGF-beta and MCP-1, significantly decreased after PDE5i vs. Placebo.These data suggest that phosphodiesterase 5 inhibition could work as an antiremodeling drug by acting directly on cardiac tissue, independently of other secondary vascular, endothelial, or metabolic effects.
  However, these data need to be validated on a wide sample, for a longer duration of treatment, and including women, because of their high vulnerability to diabetic damage with preferential evolution in chronic heart failure, compared to males that frequently have ischemic complications.
  Recently, animal and human studies have described gene expression profiles associated with pathological hypertrophy. In particular, some microRNAs (miRNAs) altered expression in the cardiomyocyte (small RNA molecules involved in transcriptional regulation) [miR-208/1/133], were related to the onset of hypertrophy. Is unknown whether these or other miRNAs are able to predict the development of DCM and/or the effectiveness of treatment with PDE5i in T2DM.
  The investigators hypothesize that:
  -  there are gender differences in left ventricular myocardial remodeling of T2DM patients detectable with tagged-CMR in terms of myocardial strain and ventricular torsion
  -  gender-related features determine different cardiac response to PDE5i treatment detected by changes in ventricular contractility (strain and torsion on tagged-CMR) and metabolism (PCr-to-ATP ratio on 31P-CMR spectroscopy)
  -  neuroendocrine (e.g. natriuretic peptides) and metabolic markers and chemokines (e.g. MCP-1, TGF-ß) might identify those asymptomatic patients at greatest risk of developing the LV remodeling
  -  there are neuroendocrine (e.g. natriuretic peptides) , metabolic markers and chemokines (e.g. MCP-1,TGF-ß) able to predict response to treatment with PDE5i and the evolution of disease
  -  miRNA expression [miR-208a, 499, 1, 133, 126, 29, 233.222] will predict the development and evolution of cardiac remodeling and the effectiveness of treatment with PDE5i in T2DM patients
  The aims of the study are:
  Characterization of gender differences in DCM remodeling through a cluster of biomarkers indicative of the stage of the disease and CMR quantification of kinetic parameters (myocardial strain, ventricular torsion), fibrosis amount (T1-mapping technique) and metabolism (PCr-to- ATP ratio, measured by 31P-Spectroscopy) Quantification of a cluster of biomarkers predictive of disease progression: metabolic and neuroendocrine markers, pro-fibrotic and pro-inflammatory circulating chemokines and miRNAs Evaluation of gender differences in the anti-remodeling effect of PDE5A inhibition in T2DM patients Quantification of a cluster of biomarkers predictive of anti-remodeling response to PDE5Ai chronic administration The investigators will perform a randomized, placebo-controlled, double-blind study enrolling 164 patients (females and males) with T2DM and diabetic cardiomyopathy. Patients will be randomized to treatment with PDE5Ai 5 mg / day or placebo for 6 consecutive months.
  The outcomes will be evaluated before and 1,3 and 6 months after therapy.
  Cardiovascular (NT-ProBNP, TGFb, MCP1), endothelial (ET1, VEGF, P Selectin, ICAM1) and metabolic indices, and oxidative stress markers (iNOS, COX2, ROS, RANTES) will be evaluated in all patients and related to CMR cardiac kinetic and metabolic parameters and fibrosis in order to identify:
  -  gender differences in cardiac remodeling at baseline (overall patients included in the study) and in its evolution (Placebo group);
  -  effectiveness of PDE5i administration (PDE5i group) and potential gender differences in response to treatment.
  To identify circulating miRNAs the investigators performed specific quantitative Real-Time PCR analysis to target expression of different mature circulating miRNAs before and after one, three and six months of PDE5i treatment. In particular the investigators will analyze a panel of selected miRNAs, including heart-associated (miR-1, -133a, -208b, and -499), fibrosis-associated (miR-21 and miR-29b), leukocyte-associated (miR-146, -155, and -223), hyperglycemia-associate (miR-29, -222), vascular-associate (miR-126) miRNA. Then, we will analyze putative gender differences in miRNAs expression and the investigators will correlate miRNAs' expression pattern to cardiovascular and metabolic features.
  CMR assessment will perform in order to identify:
  -  gender differences in kinetic parameters of left ventricle (end-diastolic volume, end-systolic volume, stroke volume, wall motion score index, myocardial strain, torsion angle);
  -  changes in myocardial fibrosis replacement amount (global contrast-enhanced T1 relaxation time, percentage of myocardial surface area, quantified by T1-mapping technique);
  -  changes in myocardial metabolism (PCr-to-TP ratio, measured by 31P-Spectroscopy).
  All patients presenting unknown ischemic cardiomyopathy on CMR performed at baseline will be excluded from the study.
  Evaluation of potential toxicity will be monitored throughout the course of treatment.

Eligibility: Inclusion Criteria:
  -  age 35-75 years;
  -  Diagnosis of Type 2 Diabetes from at least 3 years;
  -  HbA1c < 10%;
  -  normal blood pressure or controlled hypertension;
  -  BMI < 40;
  Exclusion Criteria:
  -  congenital or valvular cardiomyopathy;
  -  ischemic heart disease;
  -  endocrine diseases: male hypogonadism, hyperthyroidism, adrenal diseases, pituitary diseases
  -  proliferative retinopathy or autonomic neuropathy;
  -  contraindications to sildenafil use or CMR imaging;

Relevance to patient case: not relevant