Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)

NCT01052428 | Completed Phase 2 Results DMC

• 1 other identifier: F040601008
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that beta-1 receptor blockade (ß1-RB) attenuates extracellular matrix (ECM) degradation and progressive adverse Left Ventricular (LV) remodeling and failure in the volume overload of mitral regurgitation (MR). Patients without coronary artery disease and moderate MR, as assessed by color/flow Doppler echocardiography, will be randomized to ß1-RB vs. placebo to address the following aims: \*Aim 1: Establish whether ß1-RB attenuates adverse LV remodeling compared to placebo in patients with non-surgical, chronic MR. Using 3-dimensional magnetic resonance imaging (MRI) and tissue tagging, LV function and geometry will be assessed at baseline and every 6 months for up to 2 years. Aim 2: Determine whether indices of inflammation correlate with degree of LV remodeling and whether ß1-RB decrease indices of inflammation and collagen turnover. At the time of MRI, blood samples for collagen breakdown products, matrix metalloproteinase (MMP) activity, and markers of excess production of reactive inflammatory species (RIS) will be obtained and related to changes in LV remodeling defined by serial 3-dimensional MRI and tissue tagging.

Conditions

Mitral Regurgitation

Keywords

Chronic MR; Volume Overload; Beta-1 receptor blocker; LV remodelling, LV dimensions; LV systolic function; LV diastolic dysfunction; Cardiac MRI

Outcome Measures

Primary Outcomes (7)

• Left Ventricular End Diastolic Volume Indexed to Body Surface Area

  Left Ventricular End Diastolic Volume Indexed to Body Surface Area: As an indicator of heart size, the blood volume of the heart is related to the body size. The end diastolic volume is the blood volume of the heart at the end of filling, just before contraction. The relation of heart blood volume to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium.

  5 visits per Participant over 2 years (about every 6 months)

• Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume

  Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume As an indicator of heart muscle mass and heart blood volume, the mass indexed to end diastolic volume determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a three-dimensional analysis. The values that are too high or too low indicate a diseased myocardium.

  5 visits per Participant over 2 years (about every 6 months)

• Left Ventricular End-Diastolic Radius to Wall Thickness

  Left Ventricular End-Diastolic Radius to Wall Thickness As an indicator of heart muscle mass and heart volume chamber diameter, the end-diastolic radius indexed to end diastolic wall thickness determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a two-dimensional analysis. The values that are too high or too low indicate a diseased myocardium.

  5 visits per Participant over 2 years (about every 6 months)

• Left Ventricular End Systolic Volume Indexed to Body Surface Area

  Left Ventricular End Systolic Volume Indexed to Body Surface Area As an indicator of heart size, the blood volume of the heart is related to the body size. The end systolic volume is the blood volume of the heart at the end of contraction and is an index of the pump function of the heart. This relation to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium.

  5 visits per Participant over 2 years (about every 6 months)

• Left Ventricular Ejection Fraction

  Left Ventricular Ejection Fraction Is a calculation of heart pump function determined from the volume after complete filling minus the volume after complete contraction divided by the volume after complete filling. A value of 55% or greater is normal.

  5 visits per Participant over 2 years (about every 6 months)

• Systolic Longitudinal Strain

  Systolic Longitudinal Strain. By identifying two points on the heart, the strain is the difference between the distance between these two points at the end of filling of the heart and the end of contraction divided by the length at the end of filling. Thus, the measure is like the ejection fraction, however the strain is more localized to a specified segment in the heart muscle. The higher values indicate a healthy heart.

  5 visits per Participant over 2 years (about every 6 months)

• Peak Early Filling Rate: Rate of Change Over Time

  Peak Early Filling Rate The peak early filling rate of change is calculated from the slope of the volume during the early filling of the heart with respect to time. The higher values indicate a very healthy heart muscle and lower values are indicative of a very stiff muscle.

  5 visits per Participant over 2 years (about every 6 months)

Study Arms (2)

Toprol XL

ACTIVE COMPARATOR

beta 1 receptor blockade; generic name metoprolol succinate

Drug: metoprolol succinate (Toprol XL)

Placebo

PLACEBO COMPARATOR

Pill that looks like Toprol XL but does not have the active ingredients

Drug: Placebo

Interventions

metoprolol succinate (Toprol XL) DRUG

Toprol XL 100 mg once a day for 2 years

Toprol XL

Placebo DRUG

Placebo 100 mg once a day for 2 years

Placebo

Eligibility Criteria

• Age: 19 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• LV ejection fraction \> 55%; LV end-systolic dimension \< 4.0 cm.
• Quantifiable by Doppler-Echo equal or more than moderate in severity.
• Organic disease of the mitral valve demonstrated by echocardiography (not normal valve as in functional or ischemic MR).
• Isolated MR (no valve disease other than mild tricuspid or pulmonic regurgitation by Doppler-Echocardiography that is often associated with mitral valve prolapse).
• Asymptomatic (or mildly symptomatic but not considered as candidates for immediate surgery by their attending physician).

You may not qualify if:

• Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion.
• Previous myocardial infarction or percutaneous coronary intervention.
• Hypertrophic cardiomyopathy, congenital or pericardial disease.
• Aortic valve disease (\> trace aortic regurgitation or mean gradient \> 10 mmHg).
• Mitral stenosis (mean gradient \>5 mmHg, valve area \< 1.5 cm2).
• Intolerance or contraindication to Beta1-AR blockade.
• Renal failure with creatinine \> 2.5 mg/dl.
• Hypertension requiring medical treatment or renal artery stenosis.
• Severe comorbidity: liver disease, malignancy, collagen vascular, steroid requirement.
• Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential).
• Uncontrolled (rate \> 120/min) or recent (\<4 weeks) atrial fibrillation.
• Routine, regular use of anti-inflammatory medications.
• Severe claustrophobia.
• Presence of a pacemaker or non-removable hearing aid.
• Presence of metal clips in the body.

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• AstraZeneca: collaborator

Study Sites (1)

University of Alabama at Birmingham

Birmingham, Alabama, 35294-2180, United States

Location

Related Publications (37)

• 1. Dell'Italia LJ. Mitral Regurgitation. In Hurst The Heart. Eds. O'Rourke, Sclhant, Alexader, Fuster. 11th Edition, Chapter 57 pp 1169-1695, 2004.

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  PMID: 22818065 DERIVED

MeSH Terms

Conditions

Mitral Valve Insufficiency; Edema; Ventricular Dysfunction, Left

Interventions

Metoprolol

Condition Hierarchy (Ancestors)

Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Ventricular Dysfunction

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Results Point of Contact

• Title: Louis J. Dell'Italia, M.D.
• Organization: University of Alabama at Birmingham

loudell@uab.edu

205-934-0850

Study Officials

• Louis . J. Dell'Italia, M.D

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 15, 2010
• First Posted: January 20, 2010
• Study Start: August 1, 2004
• Primary Completion: July 1, 2010
• Study Completion: July 1, 2010
• Last Updated: November 22, 2012
• Results First Posted: April 16, 2012

Record last verified: 2012-11

Locations

US (1)