Background Injectable, acellular biomaterials hold promise to limit left ventricular (LV) remodeling and heart failure precipitated by infarction through bulking and/or stiffening the infarct region. A material with tunable properties (e.g., mechanics, degradation) that can be delivered percutaneously has not yet been demonstrated. Catheter deliverable soft hydrogels with in vivo stiffening to enhance therapeutic efficacy achieve these requirements. Methods and Results We developed a hyaluronic acid hydrogel that utilizes a tandem crosslinking approach, where the first crosslinking (guest-host, GH) enabled injection and localized retention of a soft (<1kPa) hydrogel. A second crosslinking reaction (dual-crosslinking, DC) stiffened the hydrogel (41.4±4.3kPa) after injection. Posterolateral infarcts were investigated in an ovine model (n≥6 per group), with injection of saline (MI control), GH, or DC. Computational (day 1), histological (1 day, 8 wk), morphological and functional (0, 2, 8 wk) outcomes were evaluated. Finite element modeling projected myofiber stress reduction (>50%, P<0.001) with DC but not GH injection. Remodeling, assessed by infarct thickness and LV volume, was mitigated by hydrogel treatment. Ejection fraction was improved, relative to MI at 8 weeks, with DC (37% improvement, P=0.014) and GH (15% improvement, P=0.058) treatments. Percutaneous delivery via endocardial injection was investigated with fluoroscopic and echocardiographic guidance, with delivery visualized by MRI. Conclusions A percutaneous delivered hydrogel system was developed, and hydrogels with increased stiffness were most effective in ameliorating LV remodeling and preserving function. Ultimately, engineered systems such as these have the potential to provide effective clinical options to limit remodeling in patients after infarction.

A quantitative analysis of adventitial inflammation of the coronary artery with intimal lesions is described in 12 patients who suffered coronary death and had had unstable angina (crescendo angina) at rest (group 1). After autopsy in these patients we examined epon-embedded cross sections by light and electron microscopy, paying particular attention to the adventitia, and compared these results with those in six patients who had had angina but died of noncardiac causes (group 2) and those in 22 patients who did not have angina (group 3). Of the 132 segments from group 1 patients, 39 (30%) were narrowed 76% to 100% by atherosclerotic plaque (group 2, 27%; group 3, 1%), and 23 (17%) had occlusive thrombi. Of the 264 sections (two from each segment) from group 1 that were examined, 98 (37%) (group 2, 15%; group 3, 9%) revealed clustered infiltration of inflammatory cells in the adventitia, half of which were associated with vascular nerve involvement. These findings in the adventitia may be related to the vasospastic component of unstable angina. Circulation 71, No. 4, 709-716, 1985. THE SIGNIFICANCE of coronary artery spasm in patients with ischemic heart disease has been emphasized recently, as diagnostic techniques and methodology have improved.' Previously reported morphologic results obtained at autopsy in patients with coronary artery disease have been mainly concerned with the effects of the intimal lesions, such as the degree of luminal narrowing,4 thrombus,5 and rupture of atheroma.6 The once-emphasized inflammatory lesions in the adventitia of atherosclerotic coronary arteries7 have recently been largely ignored. However, they may have a significant role in causing coronary artery spasm because the coronary adventitia is richly innervated with autonomic fibers. In this report 12 patients with unstable angina culminating in sudden death or acute myocardial infarction were studied at autopsy as a representative sample of vasospastic angina in the waxing phase. The coronary artery of each was examined, with particular attention to the adventitia, with light and electron

Background Annuloplasty ring dehiscence is a well described mechanism of mitral valve repair failure. Defining the mechanisms underlying dehiscence may facilitate its prevention. Methods Factors governing suture dehiscence were examined using an ovine model. Following undersized ring annuloplasty in live animals (N=5), Cyclic Force (FC) acting on sutures during cardiac contraction were measured using custom transducers. FC was measured at 10 suture positions, throughout cardiac cycles with peak left ventricular pressure (LVPmax) of 100, 125, and 150mmHg. Suture pullout testing was conducted on explanted mitral annuli (N=12) to determine suture holding strength at each position. Finally, relative collagen density differences at suture sites around the annulus were assessed by two-photon excitation fluoroscopy. Results Anterior FC exceeded posterior at each LVPmax (e.g. 2.8±1.3 vs. 1.8±1.2N at LVPmax=125mmHg, p<0.01). Anterior holding strength exceeded posterior (6.4±3.6 vs. 3.9±1.6N, p<0.0001). Based on FC at LVPmax=150mmHg, margin of safety before suture pullout was vastly higher between the trigones (exclusive) versus elsewhere (4.8±0.9 versus 1.9±0.5N, p<0.001). Margin of safety exhibited strong correlation to collagen density (R2=0.947). Conclusions Despite lower cyclic loading on posterior sutures, the weaker posterior mitral annular tissue creates higher risk of dehiscence, apparently due to reduced collagen content. Sutures placed atop the trigones are less secure than predicted, due to a combination of reduced collagen and higher overall rigidity in this region. These findings highlight the inter-trigonal tissue as the superior anchor, and have implications on the design and implantation techniques for next-generation mitral prostheses.

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