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

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

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 Overview

• Status: Completed
• Conditions: Idiopathic Dilated Cardiomyopathy
• Intervention / Treatment: Drug: Carvedilol; Drug: Metoprolol succinate; Drug: Metoprolol succinate + doxazosin

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80220
      • University of Colorado Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Myocardial Gene Expression at 3 Months	Changes in myocardial mRNA expression at 3 months compared to baseline using targeted quantitative polymerase chain reaction and genome wide microarray assays. Due to the large number of results genes interrogated (~ 20,000 genes), these results will instead be uploaded to the Gene Expression Omnibus.	3 months
Change in Myocardial Gene Expression at 12 Months	Changes in myocardial mRNA expression at 12 months compared to baseline using targeted quantitative polymerase chain reaction and Affymetrix genome-wide microarray assays. 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
Change in Myocardial microRNA Expression at 3 Months	Changes in myocardial microRNA expression at 3 months compared to baseline using an Affymetrix microRNA microarray assay. 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
Change in Myocardial microRNA Expression at 12 Months	Changes in myocardial microRNA expression at 12 months compared to baseline using an Affymetrix microRNA microarray assay. 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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); GlaxoSmithKline; AstraZeneca
• Investigators: Principal Investigator: Michael R Bristow, MD PhD, University of Colorado School of Medicine

Publications and helpful links

General Publications

• Sucharov CC, Kao DP, Port JD, Karimpour-Fard A, Quaife RA, Minobe W, Nunley K, Lowes BD, Gilbert EM, Bristow MR. Myocardial microRNAs associated with reverse remodeling in human heart failure. JCI Insight. 2017 Jan 26;2(2):e89169. doi: 10.1172/jci.insight.89169.
• Kao DP, Lowes BD, Gilbert EM, Minobe W, Epperson LE, Meyer LK, Ferguson DA, Volkman AK, Zolty R, Borg CD, Quaife RA, Bristow MR. Therapeutic Molecular Phenotype of beta-Blocker-Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy. Circ Cardiovasc Genet. 2015 Apr;8(2):270-83. doi: 10.1161/CIRCGENETICS.114.000767. Epub 2015 Jan 30.

Study record dates

Study Major Dates

• Study Start: September 1, 2000
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: February 22, 2013
• First Submitted That Met QC Criteria: February 22, 2013
• First Posted (Estimated): February 26, 2013

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: ejection fraction; carvedilol; human heart; beta-blocker; metoprolol; myocardial gene expression; ventricular remodeling; wall stress; adrenergic signaling; myosin heavy chain
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Metoprolol; Carvedilol; Doxazosin
• Other Study ID Numbers: 00-0242; 2R01HL048013 (U.S. NIH Grant/Contract)