Effect of Beta-blockers on Structural Remodeling and Gene Expression in the Failing Human Heart

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Brief Title

Effect of Beta-blockers on Structural Remodeling and Gene Expression in the Failing Human Heart

Official Title

Beta-blocker Effect on Structural Remodeling and Gene Expression in the Failing Human Heart

Brief Summary

      The primary goal of the study is to measure in the intact human heart, the alterations in
      gene expression over time that are associated with reverse remodeling in response to
      β-blockade. The second goal is to investigate the signaling mechanisms which in turn are
      responsible for these changes in gene expression, and the third goal is to determine the
      relationship between intrinsic systolic dysfunction and remodeling of the left ventricle.
      This will be accomplished by measuring ventricular size, function, and gene expression in
      myocardial tissue samples obtained by percutaneous biopsy prior to initiation of β-blockade
      and at 3 and 12 months after start of therapy. The specific Aims and Hypotheses to be tested
      are:

        1. Aim: Determine the changes in gene expression associated with changes in intrinsic
           systolic function and with functional decompensation in the intact, failing human heart.

           a. Hypothesis: Changes in the expression of select genes precede or accompany changes in
           left ventricular systolic function in humans with idiopathic dilated cardiomyopathy
           (IDC).

        2. Aim: Identify signaling mechanisms responsible for alterations in expression of key
           genes involved in mediation of ventricular hypertrophy or contractile dysfunction.

           a. Hypothesis: Myocardial-failure-associated regulation of select messenger ribonucleic
           acids and proteins are related to left ventricular wall stress and neurohormonal
           signaling.

        3. Aim: In the relationship between contractile dysfunction and dilatation/remodeling,
           determine the relationship between contractile dysfunction and structural remodeling.

           b. Hypothesis: the contractile dysfunction is primary and structural remodeling
           secondary.
    


Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months

Secondary Outcome

 Improvement in LVEF at 3 Months

Condition

Idiopathic Dilated Cardiomyopathy

Intervention

Carvedilol

Study Arms / Comparison Groups

 Non-failing control
Description:  Patients with normal ejection fraction who underwent a single myocardial biopsy and received no β-blocker therapy

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

56

Start Date

September 2000

Completion Date

March 2009

Primary Completion Date

March 2009

Eligibility Criteria

        Inclusion Criteria:

          -  Idiopathic dilated cardiomyopathy with New York Heart Association Class II-IV symptoms

          -  No evidence of coronary artery disease by angiography within 2 years of randomization

          -  If female, patient is (a) surgically sterile or (b) practices an accepted method of
             birth control and has negative serum pregnancy test

          -  Patient has been on other conventional cardiac heart failure(CHF) therapy at least 3
             weeks prior to baseline assessments (includes angiotensin converting enzyme
             inhibitors, digoxin, diuretics, and/or vasodilators)

          -  Patient has left ventricular ejection fraction < 40% by radionuclide ventriculography
             within 60 days of randomization

          -  Patient must demonstrate mental and physical ability and willingness to follow all
             study-specific instructions

          -  Patient must voluntarily sign Institutional Review Board (IRB)-approved informed
             consent form prior to any study-specific procedure

        Exclusion Criteria:

          -  Patient has heart failure due to or associated with uncorrected primary valvular
             disease, uncorrected thyroid disease, obstructive/hypertrophic cardiomyopathy,
             pericardial disease, amyloidosis, active myocarditis, or malfunctioning artificial
             heart valve.

          -  Patient is actively on heart transplant list or anticipated to be within 6 months of
             randomization

          -  Patient is receiving any of the following medicines:

               1. Calcium channel blockers

               2. Theophylline

               3. Tricyclic antidepressants

               4. Monoamine oxidase inhibitors

               5. β-agonists

               6. β-adrenergic blocking agent (oral)

               7. Any investigational cardiovascular medication or involvement in another
                  investigational trial

               8. Flecainide, encainide, propafenone, sotalol, disopyramide, or amiodarone

          -  Patient has a contraindication to β-blockade (eg asthma)

          -  Patient has another life-threatening disease with life expectancy < 2 years due to
             other illness

          -  Patient has active hepatic, renal, hematologic, gastrointestinal, immunologic,
             endocrine, metabolic, or central nervous system disease which may adversely affect the
             safety and efficacy of the study drug or life span of the patient

          -  Unstable decompensated heart failure (evidence of hypoperfusion, acute pulmonary
             edema, or hypotension with SBP < 80 mm Hg)

          -  Patient is actively abusing ethanol or illicit drugs within 3 months of randomization

          -  Patient has an automatic implantable cardiac defibrillator that has fired within 3
             months of randomization

          -  Patient has an asymptomatic waking, resting heart rate < 50 bpm or symptomatic
             bradycardia < 60 bpm.

          -  Patient has uncontrolled insulin-dependent diabetes mellitus with a history of
             frequent hypoglycemia episodes

          -  Patient has a high degree atrioventricular block (Mobitz Type II or complete heart
             block)

          -  Patient is unable to tolerate magnetic resonance imaging procedures

          -  Patient has demonstrated non-compliance with previous medical regimens
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Michael R Bristow, MD PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01798992

Organization ID

00-0242

Secondary IDs

2R01HL048013

Responsible Party

Sponsor

Study Sponsor

University of Colorado, Denver

Collaborators

 National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Michael R Bristow, MD PhD, Principal Investigator, University of Colorado School of Medicine


Verification Date

July 2018