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

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.

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.

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

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 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 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 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 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. 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 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.

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.

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

Olson LJ, Subramanian R, Ackermann DM, Orszulak TA, Edwards WD. Surgical pathology of the mitral valve: a study of 712 cases spanning 21 years. Mayo Clin Proc. 1987 Jan;62(1):22-34. doi: 10.1016/s0025-6196(12)61522-5.

Otto CM. Timing of surgery in mitral regurgitation. Heart. 2003 Jan;89(1):100-5. doi: 10.1136/heart.89.1.100. No abstract available.

Wisenbaugh T, Essop R, Rothlisberger C, Sareli P. Effects of a single oral dose of captopril on left ventricular performance in severe mitral regurgitation. Am J Cardiol. 1992 Feb 1;69(4):348-53. doi: 10.1016/0002-9149(92)90232-n.

Rothlisberger C, Sareli P, Wisenbaugh T. Comparison of single dose nifedipine and captopril for chronic severe mitral regurgitation. Am J Cardiol. 1994 May 15;73(13):978-81. doi: 10.1016/0002-9149(94)90148-1. No abstract available.

Wisenbaugh T, Sinovich V, Dullabh A, Sareli P. Six month pilot study of captopril for mildly symptomatic, severe isolated mitral and isolated aortic regurgitation. J Heart Valve Dis. 1994 Mar;3(2):197-204.

Marcotte F, Honos GN, Walling AD, Beauvais D, Blais MJ, Daoust C, Lisbona A, McCans JL. Effect of angiotensin-converting enzyme inhibitor therapy in mitral regurgitation with normal left ventricular function. Can J Cardiol. 1997 May;13(5):479-85.

Host U, Kelbaek H, Hildebrandt P, Skagen K, Aldershvile J. Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 1997 Sep 1;80(5):655-8. doi: 10.1016/s0002-9149(97)00445-1.

Tischler MD, Rowan M, LeWinter MM. Effect of enalapril therapy on left ventricular mass and volumes in asymptomatic chronic, severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 1998 Jul 15;82(2):242-5. doi: 10.1016/s0002-9149(98)00325-7.

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. 2001 Mar 1;87(5):570-6. doi: 10.1016/s0002-9149(00)01433-8.

Gaasch WH, Aurigemma GP. Inhibition of the renin-angiotensin system and the left ventricular adaptation to mitral regurgitation. J Am Coll Cardiol. 2002 Apr 17;39(8):1380-3. doi: 10.1016/s0735-1097(02)01766-7. No abstract available.

Stewart JA Jr, Wei CC, Brower GL, Rynders PE, Hankes GH, Dillon AR, Lucchesi PA, 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. 2003 Mar;35(3):311-9. doi: 10.1016/s0022-2828(03)00013-0.

Perry GJ, Wei CC, Hankes GH, Dillon SR, Rynders P, Mukherjee R, Spinale FG, Dell'Italia LJ. Angiotensin II receptor blockade does not improve left ventricular function and remodeling in subacute mitral regurgitation in the dog. J Am Coll Cardiol. 2002 Apr 17;39(8):1374-9. doi: 10.1016/s0735-1097(02)01763-1.

Dell'italia LJ, Balcells E, Meng QC, Su X, Schultz D, Bishop SP, Machida N, Straeter-Knowlen IM, Hankes GH, Dillon R, Cartee RE, Oparil S. Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. Am J Physiol. 1997 Aug;273(2 Pt 2):H961-70. doi: 10.1152/ajpheart.1997.273.2.H961.

Nemoto S, Hamawaki M, De Freitas G, Carabello BA. Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation. J Am Coll Cardiol. 2002 Jul 3;40(1):149-54. doi: 10.1016/s0735-1097(02)01926-5.

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. 2003 Jul 15;108(2):225-30. doi: 10.1161/01.CIR.0000079226.48637.5A. Epub 2003 Jul 7.

Tsutsui H, Spinale FG, Nagatsu M, Schmid PG, Ishihara K, DeFreyte G, Cooper G 4th, Carabello BA. Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest. 1994 Jun;93(6):2639-48. doi: 10.1172/JCI117277.

Mehta RH, Supiano MA, Oral H, Grossman PM, Montgomery DS, Smith MJ, Starling MR. Compared with control subjects, the systemic sympathetic nervous system is activated in patients with mitral regurgitation. Am Heart J. 2003 Jun;145(6):1078-85. doi: 10.1016/S0002-8703(03)00111-X.

Mehta RH, Supiano MA, Oral H, Grossman PM, Petrusha JA, Montgomery DG, Briesmiester KA, Smith MJ, Starling MR. 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 Dec 1;86(11):1193-7. doi: 10.1016/s0002-9149(00)01201-7.

Oral H, Sivasubramanian N, Dyke DB, Mehta RH, Grossman PM, Briesmiester K, Fay WP, Pagani FD, Bolling SF, Mann DL, Starling MR. Myocardial proinflammatory cytokine expression and left ventricular remodeling in patients with chronic mitral regurgitation. Circulation. 2003 Feb 18;107(6):831-7. doi: 10.1161/01.cir.0000049745.38594.6d.

Kukin ML, Kalman J, Charney RH, Levy DK, Buchholz-Varley C, Ocampo ON, Eng C. 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. 1999 May 25;99(20):2645-51. doi: 10.1161/01.cir.99.20.2645.

Yue TL, Cheng HY, Lysko PG, McKenna PJ, Feuerstein R, Gu JL, Lysko KA, Davis LL, Feuerstein G. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther. 1992 Oct;263(1):92-8.

Flesch M, Maack C, Cremers B, Baumer AT, Sudkamp M, Bohm M. Effect of beta-blockers on free radical-induced cardiac contractile dysfunction. Circulation. 1999 Jul 27;100(4):346-53. doi: 10.1161/01.cir.100.4.346.

Chin BS, Langford NJ, Nuttall SL, Gibbs CR, Blann AD, Lip GY. Anti-oxidative properties of beta-blockers and angiotensin-converting enzyme inhibitors in congestive heart failure. Eur J Heart Fail. 2003 Mar;5(2):171-4. doi: 10.1016/s1388-9842(02)00251-9.

Bristow MR. Mechanistic and clinical rationales for using beta-blockers in heart failure. J Card Fail. 2000 Jun;6(2 Suppl 1):8-14.

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 May 28;105(21):2512-7. doi: 10.1161/01.cir.0000017264.66561.3d.

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 Apr 11;101(14):1729-35. doi: 10.1161/01.cir.101.14.1729.

Lopez B, Querejeta R, Varo N, Gonzalez A, Larman M, Martinez Ubago JL, Diez J. Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation. 2001 Jul 17;104(3):286-91. doi: 10.1161/01.cir.104.3.286.

Cracowski JL, Tremel F, Marpeau C, Baguet JP, Stanke-Labesque F, Mallion JM, Bessard G. Increased formation of F(2)-isoprostanes in patients with severe heart failure. Heart. 2000 Oct;84(4):439-40. doi: 10.1136/heart.84.4.439. No abstract available.

Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A. Elevated levels of 8-iso-prostaglandin F2alpha 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. 1998 Apr 28;97(16):1536-9. doi: 10.1161/01.cir.97.16.1536.

Nonaka-Sarukawa M, Yamamoto K, Aoki H, Takano H, Katsuki T, Ikeda U, Shimada K. Increased urinary 15-F2t-isoprostane concentrations in patients with non-ischaemic congestive heart failure: a marker of oxidative stress. Heart. 2003 Aug;89(8):871-4. doi: 10.1136/heart.89.8.871.

Mak S, Newton GE. The oxidative stress hypothesis of congestive heart failure: radical thoughts. Chest. 2001 Dec;120(6):2035-46. doi: 10.1378/chest.120.6.2035.

Rouleau JL, Pitt B, Dhalla NS, Dhalla KS, Swedberg K, Hansen MS, Stanton E, Lapointe N, Packer M; Canadian Prospective RandOmized FlosequInan Longevity Evaluation Investigators. Prognostic importance of the oxidized product of catecholamines, adrenolutin, in patients with severe heart failure. Am Heart J. 2003 May;145(5):926-32. doi: 10.1016/s0002-8703(02)94782-4.

Lopez Farre A, Casado S. Heart failure, redox alterations, and endothelial dysfunction. Hypertension. 2001 Dec 1;38(6):1400-5. doi: 10.1161/hy1201.099612.

Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail. 2002 May-Jun;8(3):132-40. doi: 10.1111/j.1527-5299.2002.00717.x.

Wachtell K, Palmieri V, Olsen MH, Gerdts E, Papademetriou V, Nieminen MS, Smith G, Dahlof B, Aurigemma GP, Devereux RB. Change in systolic left ventricular performance after 3 years of antihypertensive treatment: the Losartan Intervention for Endpoint (LIFE) Study. Circulation. 2002 Jul 9;106(2):227-32. doi: 10.1161/01.cir.0000021601.49664.2a.

Ahmed MI, Aban I, Lloyd SG, Gupta H, Howard G, Inusah S, Peri K, Robinson J, Smith P, McGiffin DC, Schiros CG, Denney T Jr, Dell'Italia LJ. A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation. J Am Coll Cardiol. 2012 Aug 28;60(9):833-8. doi: 10.1016/j.jacc.2012.04.029. Epub 2012 Jul 18.