Robert Gorman - US grants

DESCRIPTION (provided by applicant): Congestive heart failure (CHF) contributes to the death of 250,000 Americans yearly. 70% of heart failure cases are now due to coronary artery disease (CAD) and post myocardial infarction (MI) ventricular remodeling. Current operations that restore the failing left ventricle (LV) to a more normal size and shape have been generally ineffective in improving survival in end stage CHF patients. In the initial funding period of this project, using well characterized ovine models of post infarction ventricular remodeling, we demonstrated that early infarct expansion (IE) or stretching is a powerful stimulus for adverse remodeling. In corollary, IE is a potential target for preventive surgical intervention. Ischemic mitral regurgitation (EMR) could not be demonstrated to exacerbate remodeling during early (8 weeks) remodeling. In this competitive renewal the efficacy of early ventricular restraint as a technique to prevent adverse remodeling and CHF will be assessed using clinically relevant experimental scenarios that employ long post MI follow up periods (8 months). The importance of IMR to long-term remodeling will also be studied. The efficacy and durability of flat and saddle-shaped annuloplasty devices used alone or in combination with ventricular wrapping in preventing remodeling associated with early IMR will be also be evaluated. The effect of ventricular wrapping on LV systolic and diastolic function will be measured serially over an 8 month period to confirm that stabilizing ventricular geometry correlates with preserved LV function and does not impair diastolic performance. The goal of the project is, therefore, to establish and optimize the major technical parameters for operations designed to prevent adverse remodeling by the early amelioration of infarct expansion and/or IMR. The acceptance and successful clinical implementation of early surgical intervention to prevent post infarction remodeling will be enhanced by an imaging modality that identifies patients early after MI that are at high risk for long-term adverse remodeling and CHF. We intend to develop real time contrast enhanced 3D echocardiography as such an imaging technique. The strength of this proposal and likelihood of success are greatly enhanced by industrial collaborative relationships that we have developed with Phillips Medical Systems (3D echocardiographic assessment of ventricular and mitral valve remodeling), Acorn Cardiovascular, Inc. (supply and design of cardiac restraint devices) and St. Jude Medical, Inc. (supply and design of saddle shaped annuloplasty devices).

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Congestive heart failure (CHF) has reached epidemic proportions in the United States. The significant majority of these cases are the result of postinfarction LV remodeling. It is now established that early infarct expansion initiates an inexorable myopathic process in normally perfused myocardium that leads to a CHF. Infarct stiffening can prevent adverse remodeling and reperfusion therapy is currently the best available means to accomplish this. However, reperfusion therapy often fails to influence remodeling especially after long ischemic intervals. Much has been learned about pathophysiology and pathology of myocardial ischemia/reperfusion (I/R) but a comprehensive understanding of this very complex phenomenon has been illusive. It is not the central focus of this proposal to explore the mechanism of myocardial reperfusion injury (although the apoptosis studies will provide new information on how this unique form of cell death contributes to I/R injury) but rather to exploit what is already known to improve the results of reperfusion therapy for acute myocardial infarction. Our hypothesis is that even very limited myocardial salvage (too small to improve contractile function) within the area at risk can alter infarct material properties enough to prevent early infarct expansion, stabilize postinfarction ventricular geometry and prevent the development of CHF. A well-established sheep model of postinfarction ventricular remodeling and progressive CHF will be used. The effect of unmodified and modified reperfusion after varying ischemic intervals on infarct expansion and the outcome of remodeling will be assessed using the imaging techniques of sonomicrometry array localization and quantitative echocardiography. Myocytes are lost at the time of reperfusion due to necrosis, apoptosis and/or microvascular no reflow. Adenosine, abciximab and minocycline have been selected to modify the infarct reperfusate because they have been demonstrated in clinical and/or experimental studies and confirmed in the sheep model to limit infarct size within in the area at risk by affecting one or more of the mechanisms of cell loss that occur during myocardial ischemia/reperfusion. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Ischemic mitral regurgitation (IMR) affects 1.6 to 2.8 million Americans and increases mortality even when mild. There is a strong graded relationship between the severity of IMR and reduced survival. Valve incompetence in IMR occurs due to a variable combination of leaflet tethering and annular dilation. Mitral valve (MV) repair with undersized annuloplasty rings has become the preferred treatment; however, while annuloplasty effectively addresses annular dilatation, it does not improve and may exacerbate leaflet tethering. MV repair is associated with a 30% recurrence rate of significant IMR (e2+) within 6 months after surgery. This high recurrence rate significantly limits the efficacy of MV repair for IMR. It is likely that a standardized and reliably efficacious surgical therapeutic approach to IMR will not be achievable until the confounding phenomena of recurrent mitral regurgitation can be better understood and subsequently neutralized. A patient-specific approach to treatment, guided by preoperative imaging-based risk stratification for recurrent IMR, is apt to be the best means for achieving this important goal. It is the intent of the proposed project to develop such a tool for risk stratification. The central hypothesis of this proposal is that the degree of pre-repair mitral leaflet tethering determines the degree of recurrent mitral regurgitation after ring annuloplasty for IMR. We further hypothesize that leaflet tethering can be effectively quantified preoperatively by echocardiography and that three-dimensional echocardiography (3DE) is superior to standard two-dimensional echocardiography (2DE) for predicting the degree of recurrent IMR. The proposed study seeks to develop echocardiographic techniques to predict, preoperatively, the degree of recurrent IMR that can be expected for an individual patient within the first year after surgery. The anticipated results of the proposed study will allow surgeons to determine which IMR patients are best treated with standard MV repair (i.e. ring annuloplasty) and which are better served by valve replacement. Such an approach will limit recurrent IMR and simultaneously maximize the number of patients who realize the benefits of MV repair. Both results will improve clinical outcomes. We propose to enroll 378 patients at three high-volume cardiac surgical centers over a 5 year period. Intraoperative 2DE and 3DE parameters will be correlated with the degree of recurrent IMR at 6 and 12 months after surgery.

? DESCRIPTION (provided by applicant): Over 1 million Americans suffer a myocardial infarction (MI) each year and many experience post-MI left ventricular (LV) remodeling, which is manifest as progressive changes in LV structure and function. Post-MI LV remodeling is responsible for nearly 70% of all heart failure (HF) cases. HF severely disables 5 million Americans and kills more than 250,000 each year. The proposed project is based on a highly significant translational research approach that seeks to develop a clinically applicable, minimally invasive treatment strategy focused on the newly formed MI intended to interrupt LV remodeling and prevent the development of symptomatic HF. Infarct expansion (stretching) results from progressive changes in MI material properties and has been identified as the biomechanical phenomena that initiates and sustains adverse LV remodeling. The proposed project will build on and advance our previously completed work, which demonstrated that preventing infarct expansion by surgically placed restraint devices significantly reduces LV remodeling. The overarching goal of this project is to establish that targeted delivery of novel biomaterials that have been engineered to induce a phenotypic shift in responding macrophages from the M1 (proteolytic) phenotype to the M2 (reparative) phenotype, will promote extracellular matrix (ECM) stability, favorably alter infarct material properties, limit infarct expansion and improve LV remodeling. In Specific Aim 1 we will test the hypothesis that targeted delivery of monocyte chemoattractant protein-1 (MCP-1) into the infarct region by a hyaluronic acid (HA) hydrogel carrier shifts responding macrophage polarization in favor of the M2 phenotype, which promotes ECM stability, favorably alters infarct material properties, limits infarct expansion and improves LV remodeling. In Specific Aim 2 we will test the hypothesis that the targeted delivery to the infarct region of PLGA microspheres and MCP-1 in a HA-hydrogel carrier will synergistically potentiate both macrophage polarization in favor of the M2 phenotype and ECM stability further reducing infarct expansion and limiting LV remodeling when compared to PLGA microspheres or MCP-1 delivery alone. The significance of the proposed project is further enhanced by the use of a clinically relevant large animal MI model and the application in Specific Aim 3 of minimally invasive catheter-based epicardial approaches for biomaterial delivery guided by state-of-the-art electroanatomic infarct mapping. Both of which heighten the potential for rapid clinical translation of the proposed work.

Ischemic mitral regurgitation (IMR) is a consequence of adverse left ventricular (LV) remodeling after myocardial infarction (MI). As a result of a lack of conclusive data regarding the best surgical approach (valve repair vs. replacement) the Cardiothoracic Surgical Trials Network (CTSN) conducted two multicenter, randomized trials to evaluate the relative benefits of these two surgical approaches to IMR. Unfortunately, the CTSN IMR trials did not establish the optimal surgical approach. Results of the CTSN Severe IMR trial demonstrated no difference in LV reverse remodeling between repair and replacement groups. However, subgroup analysis highlighted the negative implications of recurrent IMR. IMR recurred much more frequently in the repair group, resulting in more heart-failure related adverse events. Importantly, repair patients with recurrent IMR had no reduction in LV volume, while repair patients without recurrence experienced LV volume reduction that was superior to patients having valve replacement. These results strongly suggest that a patient- specific approach to surgical treatment guided by preoperative imaging-based risk stratification that is predictive of recurrent IMR would be useful for optimizing surgical results. During the initial funding period of this project, our group at the University of Pennsylvania (Penn) demonstrated that measures of mitral leaflet tethering derived from pre-operative 3D echocardiography (3DE) and a custom valve modeling algorithm accurately predicted the recurrence of IMR after valve repair. The goal of this competitive renewal is to provide conclusive evidence that pre- operative risk-based repair/replacement stratification using 3DE significantly reduces recurrent IMR and, more importantly, improves LV remodeling, long-term clinical outcomes and survival for patients with IMR. We propose to use two existing data sets to achieve our intended goal expeditiously and at limited expense: (1) as part of the initially funded project we have recruited 85 patients with IMR that have had pre-repair 3DE and have been followed prospectively to assess for recurrence of IMR. We propose to continue this recruitment at Penn to enlarge our cohort to 120 patients to allow further development and validation of an optimal predictive algorithm for recurrent IMR after MV repair; (2) the CTSN IMR trials data base which includes 551 IMR patients randomized to either MV repair (n=276), MV replacement (n=125) or CABG alone (n=150); 180 of the CTSN cohort have had pre-operative 3DE. All CTSN patients also have extensive echocardiographic and long-term clinical follow-up, which is ongoing. In Aim 1 we will establish the optimal 3DE-based predictive algorithm for recurrent IMR from candidate algorithms developed from continued recruitment of IMR repair patients at Penn. In Aim 2 we will assess the benefit of using the ideal predictive algorithm from Aim 1 on the incidence of recurrent IMR and long-term clinical outcomes in the CTSN IMR Trials data base. Finally, in Aim 3 we will develop a technique for automatic 3D segmentation and geometric modeling of the mitral valve and LV to allow for real-time risk-based repair/replacement stratification in the operating room for patients having surgery for IMR.

Summary: The bicuspid aortic valve (BAV) is the most common cardiac congenital anomaly and affects ~1.4% of the population, with an approximate 2:1 male predominance. Due to the widespread availability and routine use of screening echocardiography, the identification of asymptomatic young patients with BAV has become increasingly common. It has been estimated that 30%-50% of BAV patients will require surgical intervention at some point in their life (1). Surgery is most commonly required for calcific aortic valve disease (CAVD) that results in symptomatic aortic stenosis (AS); less commonly required for aortic insufficiency (AI), ascending aortic aneurysm, and dissection. In aortic valve replacement (AVR) patients under 50 years old having AS, virtually all of them have BAV. In fact, until the age of 70 BAV patients outnumber those with tricuspid aortic valve (TAV) having AVR for AS. Between 71-80 years of age BAV and TAV occur in approximately equal numbers in symptomatic AS patients, and not until over the age of 80 do TAV patients predominate (2). While multiple factors are likely involved in the prevalence of AS in BAV patients and its relation to aortic dissection, the presence of a BAV is consistently an exceptionally strong risk factor for premature AS. Yet, in spite of this strong clinical association it is not currently possible to assess which patients with BAV are at highest risk for developing AS, preventing a rational basis for BAV patient risk stratification. We thus hypothesize that sensitive, clinically derivable functional indices can be obtained from patient-specific dynamic BAV anatomy that, when combined with population-based leaflet properties, will yield clinically relevant patient-specific strategies for identifying BAV patients at high risk for developing symptomatic AS in the future. Narrative: The bicuspid aortic valve (BAV) is the most common cardiac congenital anomaly. Due to the widespread availability and routine use of screening echocardiography, development of clinical methods for the identification of asymptomatic young patients with BAV is now realistic. We thus plan to develop sensitive, clinically derivable functional indices that will yield clinically relevant patient- specific strategies for identifying BAV patients at high risk.

Contact PD/PI: GORMAN, JOSEPH Ischemic Mitral Regurgitation (IMR) is a major clinical problem. Our group has demonstrated that IMR is a heterogeneous disease with two general subpopulations.(1) In one group, IMR results from moderate annular dilatation and profound leaflet tethering. We have shown these patients are best treated by valve replacement.(1, 2) In the second subpopulation, IMR is the result of severe annular dilatation (i.e. minimal leaflet tethering). Here, ring annuloplasty has been shown to be an effective treatment, provided the ring remains anchored to the annulus. The Achilles heel of these repairs is the higher suture forces required to downsize these large annuli, which predisposes to dehiscence. Ring dehiscence is estimated to underlie 13- 42% of reoperations for procedure-related repair failures.(3-5) Dehiscence occurs when the suture holding strength of the local tissue is exceeded by the force on the suture. We have developed novel transducers to measure ring suture force and quantified the effects of ring type, sizing, suture position, annular histology, and holding strength on dehiscence likelihood.(6-9) These studies have mechanistically demonstrated that ring flexibility significantly reduces suture forces, specifically in the weakest region of annular tissue. These results suggest that the incorporation of segmental ring flexibility to the already known functional benefits of saddle shape will produce IMR-specific rings that restore valve geometry while reducing dehiscence likelihood even in the setting of suboptimal suture placement. To this end, the following specific aims have been designed to prove the hypothesis: In the setting of IMR, new hybrid rigid-flexible annuloplasty rings are capable of both restoring normal valve geometry and reducing ring suture forces to a magnitude that overcomes the effect of suboptimal suture placement that otherwise would lead to an increased likelihood for dehiscence.

Ischemic mitral regurgitation (IMR) occurs when a mitral valve (MV) is rendered incompetent by left ventricular (LV) remodeling induced by a myocardial infarction (MI). IMR is present in over 50% of patients with reduced LV function undergoing coronary artery bypass grafting (CABG) and affects at least 300,000 Americans. The magnitude of the problem is significant and is expected to grow substantially during the next 20 years as the population ages. MV repair with undersized ring annuloplasty is currently the preferred treatment for IMR. However, 1/3 of all patients treated this way develop significant recurrent IMR within 12 months. Using our real time 3D echocardiography (rt-3DE) image software we have demonstrated that IMR in humans is heterogeneous. In some patients the cause of IMR is annular dilatation and flattening. While in others leaflet tethering is the major pathology. In recent work we have demonstrated that it is in the latter group that undersized ring annuloplasty does not provide durable IMR repair. There is now agreement that adjunctive procedures are required to treat IMR caused by leaflet tethering. But there is no consensus regarding the best procedure. Despite significant interest in developing these procedures the reported data are from small, single center retrospective studies. Multi-center registries and randomized trials would be necessary to prove which procedure is superior. Given the number of proposed procedures and the complexity and duration of such studies it is highly unlikely that IMR procedure optimization could be effectively carried out this way. It is thus becoming clear that novel computational approaches directed towards optimized annuloplasty ring design and leaflet augmentation procedures can substantially reduce wasted time by minimizing trial-and-error approaches. We thus hypothesize that our state-of-the-art MV computational models, which can directly utilize rt-3DE imaging data coupled to novel effective MV leaflet and chordae tendonae (MVCT) structures, can be used in conjunction with clinically applicable large animal models to develop quantitatively optimize devices and procedures to treat IMR secondary to leaflet tethering. To prove this hypothesis the following specific aims will be achieved by leveraging our group's expertise in: 1) the pathogenesis of IMR, 2) IMR animal models, 3) rt-3DE MV imaging, 4) annuloplasty ring design, 4) MV cell-tissue coupled models, and 5) micro- and macro-anatomically accurate MV finite element models.