.Ischemic mitral regurgitation (IMR), or """"""""functional"""""""" MR as a consequence of coronary heart disease, continues to defy surgical attempts to repair the mitral valve in a predictable fashion because we still do not understand the mechanisms responsible for IMR. Postoperative survival is only about 55 percent after 5 years, and debate continues as to whether repair is preferable to replacement. While ring annuloplastyworks in most patients with annular dilation and normal leaflet motion, such an approach can be unreliable in those who have """"""""complex"""""""" MR jets and/or apical leaflet tethering, which results in restricted systolic leaflet motion. Our ignorance of the mechanisms responsible for IMR has been reduced by work in experimental models of acute IMR, but the real clinical problem and surgical challenge is patients with chronic I1 IR. Chronic animal experiments are rare due to high cost and the inescapable animal attrition that these preparations entail. Clinical progress, however, will continue to be tentative and empirical until controlled studies of chronic IMR are performed which tell us how and why these morphologically normal valves leak. We propose to apply our myocardial marker technology (which can measure submillimeter instantaneous changes in leaflet, annular, papillary muscle, and left ventricular 3-D geometry and dynamic motion throughout the cardiac cycle on a beat-to-beat basis) to determine the mechanisms responsible for chronic IMR in an ovine myocardial infarction model and to define how the therapeutic effects of ring annuloplasty differ from those of a novel trans-annular suture reparative technique (Septal-Lateral Annular Cinching, or """"""""SLAC""""""""), which we have shown can eliminate acute IMR. To address these issues, we set forth the following Specific Aims: #1) To elucidate the basic pathophysiology o chronic ischemic mitral regurgitation, with particular emphasis on the 3-D geometry of the mitral leaflets in relation t about one another and to the other components of the mitral valvular-ventricular complex. This work will define for the frst time the causal basis of chronic IMR as a function of the evolving interrelationships between leaflet, annular, and ventricular pathologic abnormalities. #2) To investigate in a randomized, controlled fashion a new surgical treatment, """"""""SLAC,"""""""" for chronic IMR and to determine the mechanistic basis for the beneficial effects conferred by either the conventional surgical approach (undersized ring annuloplasty) or this new SLAC technique based on differences in LV remodeling, interactions between leaflet, annular, and ventricular 3-D dynamics, and valvular competency. Comparison of the effects of ring annuloplasty and SLAC on LV geometry as well as leaflet and annular 3-D motion and dynamics will reveal why patients might benefit from one approach versus the other, beyond simply eliminating the MR. These experiments promise to add fundamental knowledge which will lead to more intelligent design of new, more effective, and more predictable surgical approaches for patients with CAD and chronic ischemic mitral regurgitation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067025-03
Application #
6638739
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Buxton, Denis B
Project Start
2001-06-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$371,068
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Thourani, Vinod H; Kodali, Susheel; Makkar, Raj R et al. (2016) Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet 387:2218-25
Biviano, Angelo B; Nazif, Tamim; Dizon, Jose et al. (2016) Atrial Fibrillation Is Associated With Increased Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement: Insights From the Placement of Aortic Transcatheter Valve (PARTNER) Trial. Circ Cardiovasc Interv 9:e002766
Kapadia, Samir; Agarwal, Shikhar; Miller, D Craig et al. (2016) Insights Into Timing, Risk Factors, and Outcomes of Stroke and Transient Ischemic Attack After Transcatheter Aortic Valve Replacement in the PARTNER Trial (Placement of Aortic Transcatheter Valves). Circ Cardiovasc Interv 9:
Lindman, Brian R; Maniar, Hersh S; Jaber, Wael A et al. (2015) Effect of tricuspid regurgitation and the right heart on survival after transcatheter aortic valve replacement: insights from the Placement of Aortic Transcatheter Valves II inoperable cohort. Circ Cardiovasc Interv 8:
Stephens, Elizabeth H; Fahrenholtz, Monica M; Connell, Patrick S et al. (2015) Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction. Cardiovasc Eng Technol 6:151-9
Kapadia, Samir; Stewart, William J; Anderson, William N et al. (2015) Outcomes of inoperable symptomatic aortic stenosis patients not undergoing aortic valve replacement: insight into the impact of balloon aortic valvuloplasty from the PARTNER trial (Placement of AoRtic TraNscathetER Valve trial). JACC Cardiovasc Interv 8:324-333
Stephens, Elizabeth H; Connell, Patrick S; Fahrenholtz, Monica M et al. (2015) Heterogeneity of Mitral Leaflet Matrix Composition and Turnover Correlates with Regional Leaflet Strain. Cardiovasc Eng Technol 6:141-50
Lindman, Brian R; Stewart, William J; Pibarot, Philippe et al. (2014) Early regression of severe left ventricular hypertrophy after transcatheter aortic valve replacement is associated with decreased hospitalizations. JACC Cardiovasc Interv 7:662-73
Pibarot, Philippe; Weissman, Neil J; Stewart, William J et al. (2014) Incidence and sequelae of prosthesis-patient mismatch in transcatheter versus surgical valve replacement in high-risk patients with severe aortic stenosis: a PARTNER trial cohort--a analysis. J Am Coll Cardiol 64:1323-34
Kvitting, John-Peder Escobar; Kari, Fabian A; Fischbein, Michael P et al. (2013) David valve-sparing aortic root replacement: equivalent mid-term outcome for different valve types with or without connective tissue disorder. J Thorac Cardiovasc Surg 145:117-26, 127.e1-5; discussion 12

Showing the most recent 10 out of 107 publications