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Completed

NCT Number: NCT01052428

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

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.

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Key information

Conditions

Mitral Regurgitation Cardiovascular Diseases Edema Heart Diseases Heart Valve Diseases Mitral Valve Insufficiency Pathological Conditions, Signs and Symptoms Signs and Symptoms Ventricular Dysfunction Ventricular Dysfunction, Left

Age range

19 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

University of Alabama at Birmingham

Birmingham, Alabama, 35294-2180, United States

About this study

In Western society, the most common causes of chronic mitral regurgitation (MR) are ischemic heart disease and myxomatous degeneration of the valve, resulting in prolapse, ruptured chordae or partial flail leaflet. Current indications for surgery are only for patients with severe MR and either notable symptoms or overt Left Ventricular (LV) dysfunction (ejection fraction < 60%, end-systolic diameter > 40 mm). Therefore, despite the availability of surgery, most patients with MR of moderate severity are not immediate candidates for surgery, warranting analysis of potential beneficial effects of medical treatment. Chronic therapy with vasodilators reduces LV wall stress and thereby delays the need for valve replacement in aortic regurgitation; however, no such data are currently available in patients with chronic MR using standard vasodilators or agents that block the renin angiotensin system (RAS).

In a clinically-relevant dog model of MR, the investigators have shown increased LV ACE and chymase expression, increased LV angiotensin II but, as opposed to pressure overload, there was an absence of fibrosis with net extracellular matrix (ECM) degradation and activation of matrix metalloproteinases (MMPs). However, blockade of the RAS does not improve (and may actually exacerbate) LV remodeling in MR. Interestingly, the investigators and others have shown that ß1-receptor blockade (ß1-RB) is more effective than RAS blockade in attenuating progressive LV remodeling and ECM degradation in MR. Moreover, increased sympathetic drive and inflammation has been identified in patients with chronic MR. ß1-RB reduced plasma markers of inflammation in patients with heart failure and resulted in substantial reverse LV remodeling in patients with heart failure. Taken together, activation of the adrenergic nervous system early in the course of volume overload contributes to increased production of reactive inflammatory species (RIS) and that one mechanism underlying the salutary effects of ß1-blockade may relate to attenuation of myocardial formation of RIS with subsequent beneficial effects on MMP activation and ECM and LV remodeling and function.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Patients who have Moderate MR documented by color flow doppler:

  • 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).

Exclusion criteria

  • 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.

Exclusion criteria

Related to MRI

  • Severe claustrophobia.
  • Presence of a pacemaker or non-removable hearing aid.
  • Presence of metal clips in the body.

Treatment and study plan

metoprolol succinate (Toprol XL)

Drug

Toprol XL 100 mg once a day for 2 years

Placebo

Drug

Placebo 100 mg once a day for 2 years

Primary outcomes

  1. Left Ventricular End Diastolic Volume Indexed to Body Surface Area

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

    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.

  2. Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume

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

    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.

  3. Left Ventricular End-Diastolic Radius to Wall Thickness

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

    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.

  4. Left Ventricular End Systolic Volume Indexed to Body Surface Area

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

    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. Left Ventricular Ejection Fraction

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

    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.

  6. Systolic Longitudinal Strain

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

    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.

  7. Peak Early Filling Rate: Rate of Change Over Time

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

    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.

Sponsors and collaborators

Lead sponsor

University of Alabama at Birmingham

Other

Collaborators

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

Registry information

Acronym: P1A1

Important dates

Study start
2004
Primary completion
2010
Study completion
2010
First posted
Jan 20, 2010
Registry last updated
Nov 22, 2012

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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