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