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.

Brief Title

REmodelling in Diabetic CardiOmapathy: Gender Response to PDE5i InhibiTOrs

Official Title

Phase IV Study on New Insights in Remodeling of Diabetic Cardiomyopathy: Gender Difference in Intramyocardial, Molecular and Neuroendocrine Assessment in Response to Chronic Inhibition of Cyclic GMP Phosphodiesterase 5A

Brief Summary

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

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.

Inclusion Criteria:

  -  age 45-80 years;

  -  Diagnosis of Type 2 Diabetes from at least 3 years;

  -  HbA1c < 10%;

  -  normal blood pressure or controlled hypertension;

  -  BMI < 40;

  -  SIV ≥ 11 mm men, ≥ 10 women and/or diastolic dysfunction (PW-doppler and TDI)

Exclusion Criteria:

  -  current use of PDE5 inhibitors;

  -  congenital or valvular cardiomyopathy;

  -  ischemic heart disease;

  -  proliferative retinopathy;

  -  contraindications to tadalafil use (hypersensitivity to tadalafil, nitrates use,
     severe cardiovascular disorders such as unstable angina or severe heart failure,
     severe hepatic impairment, blood pressure <90/50 mmHg, recent history of stroke or
     myocardial infarction and known hereditary degenerative retinal disorders such as
     retinitis pigmentosa);

  -  contraindications to CMR imaging with mdc (patients with implant such as cardiac
     pacemakers, insulin pumps, neurostimulators and cochlear implants, or metallic
     fragments, clips or devices, or severe renal failure with GFR < 30mL/min/1.73 m2);

  -  cronic or acute atrial fibrillation.