Tadalafil Effects in Left Ventricle Diastolic Dysfunction in Resistant Hypertensive Patients

Study Overview
=================
Brief Summary
-----------------
Left ventricle diastolic dysfunction (LVDD) is associated with resistant hypertension. In addition, brain natriuretic peptide (BNP) levels are elevated when LVDD is present. It has been shown that phosphodiesterase-5 (PDE5) inhibition improves left ventricle diastolic function in hypertensive rats, despite any difference in blood pressure levels. Also, left ventricle diastolic function enhancement reduces BNP concentration in hypertensive patients. However, it is unknown if these effects exists in humans with resistant hypertension. Therefore, this study was developed to evaluate if the use of a PDE5 inhibitor (tadalafil) for 2 weeks improves LVDD and its effects in BNP levels in resistant hypertensive patients.

Detailed Description
-----------------
Resistant hypertensive patients have a high incidence of left ventricle diastolic dysfunction (LVDD). Lowering blood pressure levels improves diastolic function, however, there is no proved effective treatment specifically for this disease. Studies in hypertensive rats have shown presence of phosphodiesterase-5 in cardiac cells and an improvement in left ventricle diastolic function using a phosphodiesterase-5 (PDE5) inhibitor, the sildenafil. PDE5 has also been demonstrated in human heart cells with cardiac disease. In addition, LVDD is associated with high levels of brain natriuretic peptide (BNP), which reduces with diastolic function improvement. Therefore, it is reasonable to suppose that PDE-5 inhibitor use in humans with LVDD and resistant hypertension could improve diastolic function. Objective: Evaluate the chronic effect of a PDE-5 inhibitor on LVDD and BNP levels in resistant hypertensive patients. Casuistic and methods: 20 resistant hypertensive patients with LVDD types I and II will be evaluated with echocardiography study, ambulatory blood pressure monitoring (ABPM), office blood pressure measurements, endothelial function analysis using the brachial artery flow mediation dilation technique (FMD) and BNP plasma levels. Then, the subjects will receive oral placebo for 2 weeks. After this period, the same exams will be repeated. Two weeks later, the protocol will be performed again to the same 20 patients, using tadalafil (the longest half-life PDE-5 inhibitor) 20mg orally instead of the placebo. Hypothesis: investigators hypothesize that the use of tadalafil will improve left ventricle diastolic function with BNP reduced levels and this effect will be independent of blood pressure decrease or endothelial function improvement.

Official Title
-----------------
Phosphodiesterase-5 Inhibitor (Tadalafil) Two Weeks Administration Period Effects in Left Ventricle Diastolic Dysfunction and BNP Levels in Resistant Hypertensive Patients

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Other: sugar pill
* Drug: Tadalafil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: resistant hypertension (according to Resistant Hypertension - American Heart Association Statement - 2008); compliance with antihypertensive treatment; age >35 years; left ventricle diastolic dysfunction types I and II Exclusion Criteria: valvulopathy decompensated heart failure important cardiac arrhythmias nephropathy hepatopathy autoimmune disease tabagism decompensated diabetes uncontrolled dislipidemia

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: sugar pill<br>Intervention: sugar pill | Other: sugar pill<br>* Sugar pills: 20mg orally, once a day for 2 weeks<br>* Other names: No brand name.;|
| Active Comparator: tadalafil<br>Intervention: tadalafil | Drug: Tadalafil<br>* Tadalafil pills: 20mg orally, once a day for 2 weeks.<br>* Other names: Cialis, Lilly, USA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Left Ventricle Diastolic Dysfunction | Outcome measurement assessed by Echocardiogram before and after a 2-week tadalafil administration period. | Baseline and 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in endothelial function | Outcome measure assessed by flow-mediated dilation before and after a 2-week tadalafil administration period. | baseline and 2 weeks | 
| Change in blood pressure levels | Blood pressure measurements assessed before and after a 2-week tadalafil administration period. | Baseline and 2 weeks | 
| Change in B-type Natriuretic Peptide (BNP-32) levels | Plasma brain natriuretic peptide (BNP-32)assessed before and after a 2-week tadalafil administration period | Baseline and 2 weeks | 
| Change in cyclic guanosine monophosphate (cGMP) levels | Cyclic guanosine monophosphate (cGMP) levels assessed before and after a 2-week tadalafil administration period | Baseline and 2 weeks | 
| Change in nitrite levels | Nitrite levels assessed before and after a 2-week tadalafil administration period. | Baseline and 2 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tadalafil, Resistant Hypertension, Left Ventricle Diastolic Dysfunction, Brain natriuretic peptide