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

Study Overview
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Brief Summary
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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: 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). 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. 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.

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

Conditions
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Idiopathic Dilated Cardiomyopathy

Intervention / Treatment
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* Drug: Carvedilol
* Drug: Metoprolol succinate
* Drug: Metoprolol succinate + doxazosin


Participation Criteria
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Eligibility Criteria
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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: Calcium channel blockers Theophylline Tricyclic antidepressants Monoamine oxidase inhibitors β-agonists β-adrenergic blocking agent (oral) Any investigational cardiovascular medication or involvement in another investigational trial 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Non-failing control<br>Patients with normal ejection fraction who underwent a single myocardial biopsy and received no β-blocker therapy | |
| Active Comparator: Metoprolol succinate<br>Idiopathic dilated cardiomyopathy patients randomized to metoprolol succinate titrated to a goal of 200 mg by mouth daily for 18 months | Drug: Metoprolol succinate<br> <br> * Other names: Toprol XL;|
| Active Comparator: Metoprolol succinate + doxazosin<br>Idiopathic dilated cardiomyopathy patients who were randomized to receive metoprolol succinate and doxazosin titrated to a goal of 200 mg and 8 mg by mouth daily for 18 months | Drug: Metoprolol succinate + doxazosin<br> <br> * Other names: Carduran;|
| Active Comparator: Carvedilol<br>Idiopathic dilated cardiomyopathy patients who were randomized to receive carvedilol titrated to a goal of 25 mg by mouth twice daily for 18 months | Drug: Carvedilol<br> <br> * Other names: Coreg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months | The primary clinical outcome will be LVEF response at 12 months defined as an improvement in LVEF of ≥ 8% at 12 months or if not available, ≥5% at 3 months in the absence of an adverse clinical outcome. Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in LVEF at 3 Months | A secondary outcome will be LVEF response at 3 months, defined as an improvement of ≥ 5% Data are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. | 3 months | 
| Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device. | Clinical status at 18 months will be assessed at time of study completion, specifically for the composite outcome of all-cause mortality, need for heart transplant, or need for ventricular assist device. Outcomes are not presented for non-failing controls, who only went baseline evaluation and did not undergo treatment, given that they did not have heart failure. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ejection fraction, beta-blocker, carvedilol, metoprolol, myocardial gene expression, human heart, ventricular remodeling, wall stress, adrenergic signaling, myosin heavy chain