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

Idiopathic Dilated Cardiomyopathy Clinical Trial

— BORG  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01798992
• Other study ID #: 00-0242
• Secondary ID: 2R01HL048013
• Status: Completed
• Phase: Phase 4
• Start date: September 2000
• Est. completion date: March 2009

Study information

• Verified date: November 2023
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: March 2009
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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. ß-agonists

6. ß-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 ß-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

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Idiopathic Dilated Cardiomyopathy

Intervention

Drug:
• Carvedilol

• Metoprolol succinate

• Metoprolol succinate + doxazosin

Locations

Country	Name	City	State
United States	University of Colorado Hospital	Denver	Colorado
United States	University of Utah Medical Center	Salt Lake City	Utah

Sponsors (4)

Lead Sponsor	Collaborator
University of Colorado, Denver	AstraZeneca, GlaxoSmithKline, National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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