Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease) (P1A1)

This study has been completed.
Sponsor:
Collaborators:
AstraZeneca
Information provided by (Responsible Party):
Dr. Louis J. Dell'Italia, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT01052428
First received: January 15, 2010
Last updated: November 16, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Mitral Regurgitation
Drug: metoprolol succinate (Toprol XL)
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • Left Ventricular End Diastolic Volume Indexed to Body Surface Area [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • 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) ] [ Designated as safety issue: Yes ]
    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.

  • Left Ventricular End-Diastolic Radius to Wall Thickness [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Left Ventricular End Systolic Volume Indexed to Body Surface Area [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Left Ventricular Ejection Fraction [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Systolic Longitudinal Strain [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Peak Early Filling Rate: Rate of Change Over Time [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 38
Study Start Date: August 2004
Study Completion Date: July 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Toprol XL
beta 1 receptor blockade; generic name metoprolol succinate
Drug: metoprolol succinate (Toprol XL)
Toprol XL 100 mg once a day for 2 years
Placebo Comparator: Placebo
Pill that looks like Toprol XL but does not have the active ingredients
Drug: Placebo
Placebo 100 mg once a day for 2 years

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   19 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:Patients who have Moderate MR documented by color flow doppler:

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

Exclusion Criteria:

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

Exclusion Criteria Related to MRI

  1. Severe claustrophobia.
  2. Presence of a pacemaker or non-removable hearing aid.
  3. Presence of metal clips in the body.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01052428

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294-2180
Sponsors and Collaborators
University of Alabama at Birmingham
AstraZeneca
Investigators
Principal Investigator: Louis . J. Dell'Italia, M.D University of Alabama at Birmingham
  More Information

Publications:
1. Dell'Italia LJ. Mitral Regurgitation. In Hurst The Heart. Eds. O'Rourke, Sclhant, Alexader, Fuster. 11th Edition, Chapter 57 pp 1169-1695, 2004.
3. Otto Otto C. Timing of surgery in mitral regurgitation. Heart 89:100-105, 2003
5. Rothisberger C, Sareli P, Wisenbaugh T: Comparison of single dose nifedipine and captopril for chronic severe mitral regurgitation. Am J Cardiol 73:978-981, 1994.
6. Wisenbaugh T, Sinovich V, Dullbh A, Sareli P: Six month pilot study of captopril for mildly symptomatic, severe isolated mitral and isolated aortic regurgitation. J Heart Valve Dis 3:197-204, 1994.
7. Marcotte F, Honos G, Walling A, et al: Effect of angiotensin converting enzyme inhibitor therapy in mitral regurgitation with normal left ventricular function. Can J Cardiol 13:479-485, 1997.
8. Host U, Kelbaek H, Hildebrandt P, Skagen K, Aldershvile J: Effect of Ramipril on mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 80:655-658, 1997.
9. Tischler M, Rowan M, LeWinter M: Effect of Enalapril on left ventricular mass and volumes in asymptomatic chronic, severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 82:242-245, 1998.
10. Dujardin KS, Enriquez-Sarano M, Bailey KR, Seward JB, Tajik AJ: Effect of losartan on degree of mitral regurgitation quantified by echocardiography. Am J Cardiol 87:570-576, 2001.
12. Stewart JA, Wei C-C, Brower GL, Rynders PE, Hankes GH, Dillon AR, Lucchesi P, Janicki JS, Dell'Italia LJ. Cardiac Mast Cell and Chymase Mediated Matrix Metalloproteinase Activity and Left Ventricular Remodeling in Mitral Regurgitation in the Dog. J Mol Cell Cardiol 35:311-319, 2003.
13. Perry, GJ, Wei CC, Su X, Bishop SP, Hankes GH, Dillon GH, Mukherjee R, Spinale FG Dell'Italia LJ. Afterload reduction and blockade of the tissue renin angiotensin system does not improve left ventricular and cardiomyocyte remodeling in chronic mitral regurgitation. J Am Coll Cardiol 39:1374-1379, 2002.
14. Dell'Italia LJ, Balcells E, Meng QC, Su X, Schultz D, Bishop SP, Machida, N, Straeter-Knowlen I, Hankes, GH, Dillon R, Cartee RE, Oparil S. Volume overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in the dog Am J Physiol (Heart Circ Physiol 42) 273:H961-H970, 1997.
16. Tallaj J, Wei CC, Hankes GH, Holland M, Rynders P, Dillon AR, Ardell JL, Armour JA, Lucchesi PA, Dell'Italia LJ. Beta1-adrenergic receptor blockade attenuates angiotensin II-mediated catecholamine release into the cardiac interstitium in mitral regurgitation. Circulation 108:225-230, 2003.
17. Tsutsui H, Spinale FG, Nagatsu M, Schmid PG, Ishihara K, DeFreyte G, Cooper IV G, Carabello BA: Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest 93:2639-2648, 1994.
18. Mehta RH, Supiano MA, Oral H et al. Compared with control subjects, the systemic sympathetic nervous system is activated in patients with mitral regurgitation. Am Heart J 2003;145:1078-85.
19. Mehta RH, Supiano MA, Oral H et al. Relation of systemic sympathetic nervous system activation to echocardiographic left ventricular size and performance and its implications in patients with mitral regurgitation. Am J Cardiol 2000;(86):1193-7.
21. Kukin ML, Kalman J, Charney RH, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 99:2645-2651, 1999.
22. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and ß adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 263: 92-98, 1992.
23. Flesch M, Maack C, Cremers B, et al. Effect of ß-blockers on free radical-induced cardiac contractile dysfunction. Circulation 100:346-353, 1999.
24. Chin BSP, Langford NJ, Nuttall SL, Gibbs CR, Blann AD, Lip GYH. Anti-oxidant properties of beta-blockers and angiotensin-converting enzyme inhibitors in congestive heart failure. Eur J Heart Failure 5:171-174, 2003.
25. Bristow MR. Mechanistic and clinical rationales for using beta-blockers in heart failure. J Cardiac Failure 6(2 Suppl 1):8-14, 2000.
26. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation. 2002;105:2512-247.
27. Querejeta R, Varo N, Lopez B, Larman M, Artinano E, Etayo JC, Martinez Ubago JL, Gutierrez-Stampa M, Emparanza JI, Gil MJ, Monreal I, Mindan JP, Diez J. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation. 2000;101:1729-35.
29. Cracowski JL, Tremel F, Marpeau C, et al. Increased formation of F2-isoprostanes in patients with severe heart failure. Heart 84:439-440, 2000.
30. Mallat Z, Philip I, Lebret M, et al. Elevated levels of 8-iso-prostaglandin F2 in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 97:1536-1539, 1998.
33. Rouleau JL, Pitt B, Dhalla NS, Dhalla KS, Swedberg K, Hansen MS, Stanton E, Lapointe N, Packer M. for the Canadian Prospective RandOmized Flosequlanan Longevity Evaluation (PROFILE) Investigators. Prognostic importance of the oxidized product of catecholamines, adrenolutin, in patients with heart failure. Am Heart J 145:926-932, 2003.
36. Wachtell K, Palmieri V, Olsen MH et al. Change in Systolic Left Ventricular Performance After 3 Years of Antihypertensive Treatment: The Losartan Intervention for Endpoint (LIFE) Study. Circulation 106:227-232, 2002.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dr. Louis J. Dell'Italia, Professor, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT01052428     History of Changes
Other Study ID Numbers: F040601008
Study First Received: January 15, 2010
Results First Received: July 29, 2011
Last Updated: November 16, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Alabama at Birmingham:
Chronic MR
Volume Overload
Beta-1 receptor blocker
LV remodelling, LV dimensions
LV systolic function
LV diastolic dysfunction
Cardiac MRI

Additional relevant MeSH terms:
Mitral Valve Insufficiency
Water Intoxication
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Water-Electrolyte Imbalance
Metabolic Diseases
Poisoning
Substance-Related Disorders
Metoprolol
Metoprolol succinate
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 26, 2014