Injectable Microsphere Gel Progressively Improves Global Ventricular Function, Regional Contractile Strain, and Mitral Regurgitation After Myocardial Infarction

Abstract

Background There is continued need for therapies which reverse or abate the remodeling process following myocardial infarction (MI). In this study, we evaluate the longitudinal effects of calcium hydroxyapatite microsphere gel on regional strain, global ventricular function, and mitral regurgitation (MR) in a porcine MI model. Methods Twenty five Yorkshire swine were enrolled. Five were dedicated weight-matched controls. Twenty underwent posterolateral infarction by direct ligation of the circumflex artery and its branches. Infarcted animals were randomly divided into four groups: one week treatment, one week control, four week treatment, and four week control. Following infarction, animals received either twenty 150μl calcium hydroxyapatite gel or saline injections within the infarct. At their respective timepoints, echocardiograms, cardiac MRI, and tissue were collected for evaluation of MR, regional and global left ventricular function, wall thickness, and collagen content. Results Global and regional LV function were depressed in all infarcted subjects at one week compared to healthy controls. By four weeks post-infarction, global function had significantly improved in the calcium hydroxyapatite group compared to infarcted controls (EF 48.5±1.9% vs. 38.0±1.7%, p<0.01). Similarly, regional borderzone radial contractile strain (16.3±1.5% vs. 11.2±1.5%, p=0.04), MR grade (0.4±0.2 vs. 1.2±0.2, p=0.04), and infarct thickness (7.8±0.5mm vs. 4.5±0.2mm, p<0.01) were improved at this timepoint in the treatment group compared to infarct controls. Conclusions Calcium hydroxyapatite injection following MI progressively improves global LV function, borderzone function, and mitral regurgitation. Using novel biomaterials to augment infarct material properties is viable alternative in the current management of heart failure.

Invited Commentary

“…Using a clinically relevant large animal model of a pig with MI and threedimensional (3D) echocardiography, the Gorman Group and collaborators have recently reported that epicardial injection of Radiesse after MI increases infarct stiffness, reduces infarct expansion, and stabilizes the LV chamber size [4,5]. By using the novel high-resolution 3D magnetic resonance imaging (MRI) imaging technique, 4D velocityencoded MRI flow analysis, and the same animal model, this well-designed and interesting study extended their previous findings by showing that epicardial injection of Radiesse significantly improves global LV function, borderzone function, and mitral regurgitation after MI [6]. This translational research strongly suggests that Radiesse could be a promising new therapy for treating MI.…”

MRI evaluation of injectable hyaluronic acid-based hydrogel therapy to limit ventricular remodeling after myocardial infarction

“…Animals were first sedated with intramuscular ketamine injections (25–30 mg/kg), intubated, and mechanically ventilated. General anesthesia was maintained on mixed isoflurane (1.5–3.0%) and oxygen, which was delivered by volume-controlled ventilation (tidal volume 10–15 mg/kg) [28]. A posterolateral infarction was induced by ligation of the left circumflex artery (LCX) and select obtuse marginal (OM) branches.…”

“…Following infarct induction, thin MRI compatible, platinum wire markers were sutured to the epicardium to outline the infarct area. These markers were tracked for quantitative assessment of infarct expansion over time (Figure 2A) [28]. …”

“…Animals were sacrificed at 12 weeks and histological evaluation of Masson’s Trichrome and H&E staining was performed. Morphometric analysis was performed to assess infarct and remote myocardial wall thickness using calipers [28]. …”

“…LV volume imaging was performed using prospectively-gated 3D steady-state free precession (SSFP) cine MRI with the following imaging parameters: field of view = 300 × 244 mm 2 , matrix size = 192 × 156, repetition time = 3.11 ms, echo time = 1.53 ms, bandwidth = 1184 Hz/pixel, slice thickness = 4 mm, averages = 2 [28]. Assessment of infarct location and wall thickness occurred fifteen minutes following intravenous injection of 0.1 mmol/kg gadobenatedimeglumine (MultiHance; Bracco Diagnostics, Princeton, NJ) using a 3D LGE spoiled gradient echo sequence with the following parameters: field of view = 350 × 350 mm 2 , matrix size = 256 × 256, repetition time = 591.28 ms, echo time = 2.96 ms, inversion time = 200–300 ms, flip angle = 25°, averages = 2 [28].…”