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

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.

Conditions

• Idiopathic Dilated Cardiomyopathy

Interventions

DRUG

Carvedilol

DRUG

Metoprolol succinate

DRUG

Metoprolol succinate + doxazosin

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

  collaborator NIH

• GlaxoSmithKline

  collaborator INDUSTRY

• AstraZeneca

  collaborator INDUSTRY

• University of Colorado, Denver

  lead OTHER

Principal Investigators

• Michael R Bristow, MD PhD · University of Colorado School of Medicine

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2000-09-30

Primary Completion

2009-03-31

Completion

2009-03-31

Countries

• United States

Study Locations