REmodelling in Diabetic CardiOmapathy: Gender Response to PDE5i InhibiTOrs
Condition: Diabetic Cardiomyopathy; Diabetes Mellitus Type 2
MeSH terms: Cardiomyopathies; Diabetic Cardiomyopathies; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

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: 
      DCM is yet unclear and gender differences at baseline and a specific treatment have not been
      indicated. The study aims to characterize DCM, measuring molecular and neuroendocrine
      assessment to relate cardiac kinetic. The investigators will perform a randomized,
      placebo-controlled, double-blind study enrolling 120 diabetic patients with DCM, to evaluate
      gender responses to 5 months of PDE5Ai. The 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.

      In vitro studies have shown that phosphodiesterase 5 overexpression reduces cGMP levels and
      exacerbates remodeling. The investigators already studied the effects of 3-months 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.

      T2DM is also considered a state of persistent inflammation that likely plays a role in
      development cardiovascular disease. Some studies have suggested that inflammation may impair
      the tissue repair process in diabetes, which appears delayed, unsupervised, and associated
      with higher levels of circulating classical monocytes.

      The interaction between angiogenic cells and the endothelium is still critical for
      inflammatory cells to move and home in specific tissue sites in various pathological
      conditions. The Tie2 receptor is highly enriched in the endothelium and actively signals
      vascular quiescence. It is also expressed by in a unique subset of monocytes, Tie2-expressing
      monocytes (TEMs), which have been considered crucial for tissue remodeling and repair. Tie2
      is stimulated by angiopoietin-1 (Ang1), a protein secreted by peri-endothelial cells and
      platelets. In the context of inflammation, a paralog of Ang1 called Ang2 competitively
      inhibits Tie2, normal endothelialcell function depends in part on a tightly regulated balance
      between Ang1 and Ang2. There is evidence of angiopoietin deregulation T2DM.

      Several studies demonstrate that PDE5 inhibitors, have cardioprotective effects in different
      conditions, particularly in in diabetes. PDE5is reduce circulating inflammatory cytokines,
      protect against tissue damage, exert an anti-inflammatory response, preserve endothelial cell
      function and increase angiogenic mediators, including Ang1 in mouse models. The PDE5is also
      improves metabolism and these effects are extended to adipose tissue function.

      Another diabetic complication is Diabetic polyneuropathy (DPN). DPN is characterized by loss
      and degeneration of neurons, Schwann cells, and neuronal fibers resulting in slowing of nerve
      conduction velocities.

      cGMP is involved in the regulation of many neural functions, including neurotransmission,
      long term potentiation, gene expression, and even neurotoxicity and neurodegeneration.
      Hyperglycemia up-regulates PDE-5 in Schwann cells and reduces their proliferation and
      migration. Schwann cells play an important role in regenerating the peripheral nervous system
      by their capacity to proliferate, migrate, and secrete numerous factors that control nerve
      regeneration. Decreased proliferation of Schwann cells has also been demonstrated in both
      human and experimental models of diabetes. Therefore, reduction of cGMP levels by
      hyperglycemia suppresses Schwann cell proliferation and migration. Elevation of cGMP by
      blockage of PDE5 with sildenafil completely abolished and reverses the effect of
      hyperglycemia on Schwann cells in mice.

      These changes are accompanied by change in serum neurotropic factors that are witnesses of
      active remodeling and regeneration at the neuronal level. Many studies in diabetic mice
      demonstrated that cGMP induces Schwann cells to synthesize nerve growth factor (NGF),
      neurotropic 3 (NT3) and BDNF.

      One third of diabetes patients suffers from diabetic nephropathy (DN), a leading cause of
      end-stage renal disease. To date, effective treatment in halting or reversing the natural
      progression of DN remains uncertain. The pathophysiology is multifactorial and the molecular
      pathways involved are complex. Glomerular endothelial cell injury plays a major role in the
      development and progression of diabetic kidney disease, that is considered the result of
      converging hemodynamic and metabolic insults.

      In kidney PDE5 is expressed in the glomeruli, mesangial cells, cortical tubules, inner
      medullary collecting duct and plays a critical role in the regulation of excretory function.
      In diabetes, glomerular cGMP production is decreased, PDE5 activity is increased and changes
      in the cGMP-NO pathway leads to a rise in intra-glomerular pressure.

      PDE5 inhibitors may have an active role in the management of DN by reducing
      glomerulosclerosis and proteinuria and improving vascular inflammation and podocyte count in
      experimental diabetes models. These findings, together with the modulation of inflammatory
      and angiogenic mediators, and endothelial function in murine and human models, support the
      use of PDE5i to prevent complications of the diabetic kidney. Intriguingly, sildenafil, a
      potent PDE5i, was also associated with improved kidney function in patients with pulmonary
      arterial hypertension and in type-2 diabetes (T2DM) patients.

      We 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);

        -  neuroendocrine (e.g. natriuretic peptides), metabolic markers, chemokines , circulating
           and cellular angiogenesis mediators might identify those asymptomatic patients at
           greatest risk of developing the diabetic complications (cardiomyopathy, neuropathy,
           nephropathy);

        -  neuroendocrine (e.g. natriuretic peptides), metabolic markers, chemokines , circulating
           and cellular angiogenesis mediators able to predict response to treatment with PDE5i and
           the evolution of diabetic complications;

        -  chronic treatment with PDE5i could restore or shut down neurological diabetic damage;

        -  chronic treatment with PDE5i could restore or shut down renal diabetic damage.

      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).

      Quantification of a cluster of biomarkers predictive of disease progression: metabolic and
      neuroendocrine markers, pro-fibrotic and pro-inflammatory circulating chemokines.

      Evaluation of gender differences in the anti-remodeling effect of PDE5A inhibition in T2DM
      patients The investigators will perform a randomized, placebo-controlled, double-blind study
      enrolling 120 patients (females and males) with T2DM and diabetic cardiomyopathy. Patients
      will be randomized to treatment with PDE5Ai 20 mg / day or placebo for 5 consecutive months.

      The outcomes will be evaluated before and 1 and 5 months after therapy.

      Cardiovascular, endothelial and metabolic indices, and oxidative stress markers will be
      evaluated in all patients and related to CMR cardiac kinetic and metabolic parameters and
      fibrosis 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, recoil rate with contraction dynamics);

        -  changes in myocardial fibrosis replacement amount (global contrast-enhanced T1
           relaxation time, percentage of myocardial surface area, quantified by T1-mapping
           technique);

      Diagnostic procedures will include:

        -  physical examination with measurement of anthropometric parameters (weight, waist
           circumference, hip circumference) and vital signs (blood pressure, heart rate);

        -  blood sampling for assessing glucose and lipid metabolism, liver, renal, hematopoietic
           and coagulative function, thyroid and androgen hormones, inflammatory parameters
           (cytokines, monocyte subpopulations);

        -  quantification of peripheral blood mononuclear cells (PBMC) subpopulations by flow
           cytometry;

        -  Circulating and cellular angiogenesis mediators assessment (angiogenic factors;
           cytokines, receptors and other angiogenic factors) by qRT-PCR and ELISA;

        -  SF36, FSFI (in women), IEFF e IPSS (in men) questionnaires, Infectious Diseases
           Questionnaire;

        -  cardiac exam, electrocardiogram and standard 2-D echocardiography with Tissue Doppler
           Imaging for diastolic function assessment and speckle tracking for cardiac kinetics
           measurement;

        -  assessment of body composition by a whole-body DEXA scan;

        -  magnetic resonance imaging (MRI) with contrast-enhanced cardiac tagging for evaluating
           kinetic parameters (torsion) and T1-mapping for assessing cardiac fibrosis;

      Neurological examination to assess signs and symptoms related to polyneuropathy and autonomic
      neuropathy.

      Specifically:

        -  evaluation of different sensitivity (diapason for vibratory, cotton wool for touch and
           pinprick for to pain);

        -  presence / reduction / absence of deep tendon reflexes;

        -  any motor deficits.

      If any signs or symptoms consistent with diabetic neuropathy, to diagnosis confirm, these
      patients will undergo to a standard nerve conduction study for the large-caliber fibers (by
      registration of sensory potential stimulation from the sural, ulnar and radial nerve surface,
      and motors potential stimulation from peroneal and ulnar nerve). Those with large fiber
      neuropathy will be evaluate for small caliber fibers injuries with:

        -  evoked potentials laser;

        -  Quantitative Sensory Testing (QST);

        -  skin biopsy.

        -  renal doppler ultrasonography for the detection of possible renal complications through
           measurements of kidney volume and resistive index (RRI).
    

Intervention name(s): Tadalafil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 20 mg/die (1 capsule); Placebo 20 mg/die (1 capsule)
Other intervention name(s): Cialis 20 mg
Intervention MeSH terms: Tadalafil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diabetic Cardiomyopathy; Genders; Phosphodiesterase 5A inhibitors; endothelial dysfunction; inflammation; diabetic complications