Clinical trial NCT01798992: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Idiopathic Dilated Cardiomyopathy
Keywords: ejection fraction
beta-blocker
carvedilol
metoprolol
myocardial gene expression
human heart
ventricular remodeling
wall stress
adrenergic signaling
myosin heavy chain
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: GlaxoSmithKline
name: AstraZeneca
First posted: 2013-02-26
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: Improvement in Left Ventricular Ejection Fraction (LVEF) at 12 Months
timeFrame: 12 months
Secondary outcomes:
measure: Improvement in LVEF at 3 Months
timeFrame: 3 months
measure: Composite of All-cause Mortality, Need for Heart Transplant or Need for Ventricular Assist Device.
timeFrame: 18 months
Other outcomes:
measure: Change in Myocardial Gene Expression at 3 Months
timeFrame: 3 months
measure: Change in Myocardial Gene Expression at 12 Months
timeFrame: 12 months
measure: Change in Myocardial microRNA Expression at 3 Months
timeFrame: 3 months
measure: Change in Myocardial microRNA Expression at 12 Months
timeFrame: 12 months
Locations:
city: Denver
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Salt Lake City
country: United States
facility: University of Utah Medical Center
state: Utah
Study officials:
affiliation: University of Colorado School of Medicine
name: Michael R Bristow, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.