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Title and Author Functional Mitral Regurgitation – Current Therapies: What Determines the Future of the Ventricle?Eugene A. Grossi, MD Abstract Human data suggest that the LV remodeling pathways are related to myocardial mass lost & amount of scar replacement, which in turn leads to an associated increase in LV dimension, and triggering of remote cardiomyocyte apoptosis. Intrinsic in cardiac remodeling is the increase of cardiomyocyte length & decrease of end-diastolic wall thickness via a chronic volume overload. Strong laboratory evidence indicates that mechanical tension (stress/strain) is responsible for activating the apoptotic pathway. Remodeling is also effected by activation of neuroendocrine systems including activation of adrenergic cardiac nerves, activation of the renin-angiotensin-aldosterone system, and release of atrial natriuretic peptide. The question are– 1) which of the above mechanisms dominates the remodeling response in a particular patient, and 2) when is negative remodeling irreversible in the setting of FMR? In an ovine model, Gorman et al. randomized (1:1) 20 animals (8-weeks post-infarct with =2+ IMR) to either no treatment or undersized ring annuloplasty. At six months, the annuloplasty group had significantly less regurgitation (0.3+0.1 vs. 3.4+0.6); however, the LV volumes in the treatment group (ESV=82.1+15.6ml; EDV=110.4+22.1ml) were not significantly different from the control group (ESV=81.1+8.6ml; EDV=111.1+16.5ml). Levine et al, on the other hand, created a model with infarcts in 18 sheep: 12 had an LA-LV shunt and 6 had the shunt closed after 1 month (repair group). Reverse remodeling occurred in the repair group at 3 months, with EDV and ESV 135% and 128% of baseline versus 220% and 280% without repair. This shows that MR repair can reverse remodeling, reduce LV volumes, maintain contractility, activate intracellular signals promoting hypertrophy and opposing apoptosis, and reduce matrix proteolytic activity. These animal models do not produce definite answers to the question of remodeling and it is unknown where the divide between reversible/irreversible reshaping occurs. Clinical models also exist, but ongoing CTSN protocols for moderate and severe IMR fail to stratify study groups by left ventricular end-diastolic dimension. Dion et al demonstrated LV reverse remodeling is sustained over time for LVEDD=65mm, while Duran et al showed that continual LV dilation and remodeling often makes initial repairs ineffective. Lastly, the RESTOR-MV Trial used a ventricular shape change device to compare reduction annuloplasty to ventricular shape change for FMR. Reduction annuloplasty showed a discrepancy between degree of MR reduction and improved survival/ better symptom relief. In some patients an irreversible and overwhelming trigger for ongoing negative cardiac remodeling exists. In these patients the ventricle will continue to dilate despite correcting the MR. In order to resolve this issue, we seek to answer the following: 1) Where is the cutoff for a 'valve-only solution' in patients with FMR? 2) Is there a differential between the remodeling mechanism of ischemic and non-ischemic etiology? Why/why not? 3) How can we uncouple pathophysiologic responses to break the cycle of negative ventricular remodeling? 4) How can we determine the optimal timeframe post– MI to intervene, and what treatment is most appropriate? Key Research Gap Requiring NHLBI Leadership What are the driving mechanisms for ongoing cardiac remodeling (both positive and negative) when functional MR is treated? Which patients will benefit from repair or replacement alone and which patients will benefit from a ventricular repair? Key Citations 1: Outcomes of the RESTOR-MV Trial (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve). Grossi EA, Patel N, Woo YJ, Goldberg JD, Schwartz CF, Subramanian V, Feldman T, Bourge R, Baumgartner N, Genco C, Goldman S, Zenati M, Wolfe JA, Mishra YK, Trehan N, Mittal S, Shang S, Mortier TJ, Schweich CJ Jr; RESTOR-MV Study Group. J Am Coll Cardiol. 2010 Dec 7;56(24):1984-93.2: Elimination of ischemic mitral regurgitation does not alter long-term left ventricular remodeling in the ovine model. Matsuzaki K, Morita M, Hamamoto H, Noma M, Robb JD, Gillespie MJ, Gorman JH 3rd, Gorman RC. Ann Thorac Surg. 2010 Sep;90(3):788-94. 3: Early repair of moderate ischemic mitral regurgitation reverses left ventricular remodeling: a functional and molecular study. Beeri R, Yosefy C, Guerrero JL, Abedat S, Handschumacher MD, Stroud RE, Sullivan S, Chaput M, Gilon D, Vlahakes GJ, Spinale FG, Hajjar RJ, Levine RA. Circulation. 2007 Sep 11;116(11 Suppl):I288-93. |
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Copyright © 2012 American Association for Thoracic Surgery
All rights reserved. IMPORTANT REMINDER: The preceding information is intended only to provide
general guidance and not as a definitive basis for diagnosis or treatment in any particular case.
It is very important that you consult a doctor about any specific medical problem or question.
All rights reserved. IMPORTANT REMINDER: The preceding information is intended only to provide
general guidance and not as a definitive basis for diagnosis or treatment in any particular case.
It is very important that you consult a doctor about any specific medical problem or question.