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Motoya Hayase, M.D.
Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation
Background
Congestive heart failure (CHF) is associated with high rates of repeat hospitalization and poor outcomes. Mitral regurgitation (MR) has become increasingly understood to be independently associated with significantly poorer prognosis. Current treatment options for patients with heart failure compounded with MR include surgical annuloplasty, medical management, and bi-ventricular pacing. Though in selected cohorts each approach has been demonstrated to relieve symptoms and improve outcomes, each current therapeutic option has significant known limitations. Surgical annuloplasty is highly effective in reducing MR, but in the target patient population is associated with high procedure morbidity and mortality. Medical management generally does not address the underlying MR. Bi-ventricular pacing is indicated in only a subgroup of MR patients and often does not result in reduction of MR.
Objectives
Our objective was to develop a safe, percutaneous means of directly treating MR of ischemic or cardiomypathic origins in a heart failure patient. We sought to demonstrate high potential procedure safety and efficacy in relevant animal models, and also the means to adjust or remove the treatment effect in response to the varying natural course of this disease state. We also sought to characterize the geometric remodeling requirements of a successful implant using both animal models and geometric analysis of successful surgical annuloplasties.
Methods
The Percutaneous Transvenous Mitral Annuloplasty method was developed primarily in various relevant ovine models of ischemic mitral regurgitation and chronic heart failure. The PTMA method is based upon the placement of a novel multi-lumen delivery catheter in the coronary sinus and great cardiac vein. Nitinol treatment devices are then introduced individually or in combination into the multi-lumen delivery catheter to reduce the anterior-posterior dimension of the mitral annulus. The method is intended to allow for precise geometric manipulation of the mitral annulus while treatment effect is observed via echo. Multiple cohorts of animals were prepared using established methods of inducing mitral regurgitation including surgical infarction, percutaneous infarction, and rapid ventricular pacing. The ovine model has previously been demonstrated as an excellent analog for human CHF. Each model has both advantages and limitations, though the primary disadvantages are high costs, highly variable results and time-consuming preparations. In the various ovine models we evaluated the ability of the PTMA method to reduce IMR acutely as verified by real-time 3D echocardiography (Philips 7500). The geometric characteristics of a successful PTMA procedure were also evaluated. Based upon the established characteristics of a successful PTMA correction, a permanent implant method and procedure was developed and verified via chronic implantation in healthy and infracted subject animals. Sustained implant geometric correction was evaluated verified by serial echocardiography, fluoroscopy (OEC 9800), and multi-detector computed tomography imaging. Chronic implant results were evaluated by timed sacrifice and histopathology. Also, on a limited and temporary basis, initial human evaluation of the PTMA method has been conducted in patients scheduled for surgical annuloplasty.
Results
The PTMA method has been demonstrated to be acutely effective in representative ovine models of chronic MR, both ischemic and rapid paced origins. In a series of 5 ovine models successful IMR reduction as assessed by the jet area method (5.1 ± 2.3 to 1.2 ± 0.8 cm2). Annular reduction was observed throughout the cardiac cycle (24 ± 2.0 to 20 ± 2.0 systole, 31 ± 2.0 to 25 ± 2.0 diastole). All reductions were achieved with a stable implant. Permanent implants were demonstrated to generate a sustained reduction of anterior-posterior dimension for up to 6 months of chronic implantation. (22 ± 2.1 to 15 ± 2.5 n=10 subjects). In multiple subjects the late adjustment or removal of treatment effect has been demonstrated without adverse sequels. Histopathology of explanted hearts has shown stable, favorable endothelialization of the device into the venous anatomy. Initial human acute case experience in a limited series of cases has demonstrated the feasibility of accessing and manipulating the mitral valve annulus with the PTMA device and approach.
Conclusions
The PTMA method has been shown promising potential as a safe and versatile method for the percutaneous treatment of ischemic mitral regurgitation. Initial human feasibility studies continue and initiation of first-in-man permanent implants are planned.
