One-year follow-up results from AUGMENT-HF: a multicentre randomized controlled clinical trial of the efficacy of left ventricular augmentation with Algisyl in the treatment of heart failure.

AIMS: AUGMENT-HF was an international, multicentre, prospective, open-label, randomized, controlled evaluation testing the hypothesis that Algisyl (injectable calcium alginate hydrogel) is superior to standard medical therapy (SMT) for improving functional capacity and clinical outcomes in patients with advanced heart failure (HF). We previously reported results following 6 months of follow-up. This report presents the results from 1 year of extended follow up for this clinical trial. METHODS AND RESULTS: We enrolled 78 patients with advanced HF, randomized (1:1), to Algisyl with SMT or SMT alone as previously reported. Patient inclusion criteria were LVEF ≤35%, peak VO2 of 9.0-14.5 mL/min/kg and LV end-diastolic diameter (LVEDD) index 30-40 mm/m(2) (LVEDD/body surface area). Patients must have been on stable, evidence-based therapy for HF. A total of 58 patients, mean age 62.3 ± 9.6 years, with ischaemic (57.7%) or non-ischaemic (42.3%) HF completed 12 months of follow-up. Treatment with Algisyl was associated with improved peak VO2 at 12 months; treatment effect vs. control of +2.10 mL/kg/min (95% confidence interval 0.96-3.24, P < 0.001). Statistically significant improvements were observed for VO2 at anaerobic threshold, 6-min walk test distance, and NYHA functional class (all P < 0.001). Through 12 months of follow-up there were 4 (10.5%) deaths in the control group and 9 (22.5%) deaths in the Algisyl group. CONCLUSIONS: Algisyl in addition to SMT was more effective than SMT alone for providing sustained 1-year benefits in exercise capacity, symptoms, and clinical status for patients with advanced HF. These data support larger clinical evaluations of this novel therapy.

The feasibility and safety of Algisyl-LVR™ as a method of left ventricular augmentation in patients with dilated cardiomyopathy: initial first in man clinical results.

BACKGROUND: A tissue engineering approach to augment the left ventricular wall has been suggested as a means to treat patients with advanced heart failure. This study evaluated the safety and feasibility of Algisyl-LVR™ as a method of left ventricular augmentation in patients with dilated cardiomyopathy undergoing open-heart surgery. METHODS AND RESULTS: Eleven male patients (aged 44 to 74years) with advanced heart failure (NYHA class 3 or 4), a left ventricular ejection fraction (LVEF) of <40% and requiring conventional heart surgery received Algisyl-LVR delivered into the LV myocardial free wall. Serial echocardiography, assessment of NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ) and 24-hour Holter monitoring were obtained at baseline, days 3 and 8 (for echocardiography and Holter monitoring), and at 3, 6, 12, 18 and 24months. A total of 9 (81.8%) patients completed 24months of follow-up. Two patients withdrew consent after day 8 and at the 3month visit. Operative mortality was 0% (n=10 with 30day follow-up). There were no adverse events attributed to Algisyl-LVR. Mean LVEF improved from 27.1 (±7.3) % at screening to a mean LVEF of 34.8 (±18.6) % 24months post-discharge. Improvements of NYHA class were corroborated with improvements in KCCQ summary scores. Holter monitor data showed a significant decrease in the episodes of nonsustained ventricular tachycardia following administration of Algisyl-LVR. CONCLUSIONS: Administration of Algisyl-LVR to patients with advanced HF at the time of cardiac surgery is feasible and safe; warranting continued development of Algisyl-LVR as a potential therapy in patients with advanced HF.

A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial).

AIMS: AUGMENT-HF was an international, multi-centre, prospective, randomized, controlled trial to evaluate the benefits and safety of a novel method of left ventricular (LV) modification with alginate-hydrogel. METHODS: Alginate-hydrogel is an inert permanent implant that is directly injected into LV heart muscle and serves as a prosthetic scaffold to modify the shape and size of the dilated LV. Patients with advanced chronic heart failure (HF) were randomized (1 : 1) to alginate-hydrogel (n = 40) in combination with standard medical therapy or standard medical therapy alone (Control, n = 38). The primary endpoint of AUGMENT-HF was the change in peak VO2 from baseline to 6 months. Secondary endpoints included changes in 6-min walk test (6MWT) distance and New York Heart Association (NYHA) functional class, as well as assessments of procedural safety. RESULTS: Enrolled patients were 63 ± 10 years old, 74% in NYHA functional class III, had a LV ejection fraction of 26 ± 5% and a mean peak VO2 of 12.2 ± 1.8 mL/kg/min. Thirty-five patients were successfully treated with alginate-hydrogel injections through a limited left thoracotomy approach without device-related complications; the 30-day surgical mortality was 8.6% (3 deaths). Alginate-hydrogel treatment was associated with improved peak VO2 at 6 months-treatment effect vs. CONTROL: +1.24 mL/kg/min (95% confidence interval 0.26-2.23, P = 0.014). Also 6MWT distance and NYHA functional class improved in alginate-hydrogel-treated patients vs. Control (both P < 0.001). CONCLUSION: Alginate-hydrogel in addition to standard medical therapy for patients with advanced chronic HF was more effective than standard medical therapy alone for improving exercise capacity and symptoms. The results of AUGMENT-HF provide proof of concept for a pivotal trial. TRIAL REGISTRATION NUMBER: NCT01311791.

Bioinjection treatment: effects of post-injection residual stress on left ventricular wall stress.

Injection of biomaterials into diseased myocardium has been associated with decreased myofiber stress, restored left ventricular (LV) geometry and improved LV function. However, its exact mechanism(s) of action remained unclear. In this work, we present the first patient-specific computational model of biomaterial injection that accounts for the possibility of residual strain and stress introduced by this treatment. We show that the presence of residual stress can create more heterogeneous regional myofiber stress and strain fields. Our simulation results show that the treatment generates low stress and stretch areas between injection sites, and high stress and stretch areas between the injections and both the endocardium and epicardium. Globally, these local changes are translated into an increase in average myofiber stress and its standard deviation (from 6.9 ± 4.6 to 11.2 ± 48.8 kPa and 30 ± 15 to 35.1 ± 50.9 kPa at end-diastole and end-systole, respectively). We also show that the myofiber stress field is sensitive to the void-to-size ratio. For a constant void size, the myofiber stress field became less heterogeneous with decreasing injection volume. These results suggest that the residual stress and strain possibly generated by biomaterial injection treatment can have large effects on the regional myocardial stress and strain fields, which may be important in the remodeling process.

Algisyl-LVR™ with coronary artery bypass grafting reduces left ventricular wall stress and improves function in the failing human heart.

BACKGROUND: Left ventricular (LV) wall stress reduction is a cornerstone in treating heart failure. Large animal models and computer simulations indicate that adding non-contractile material to the damaged LV wall can potentially reduce myofiber stress. We sought to quantify the effects of a novel implantable hydrogel (Algisyl-LVR™) treatment in combination with coronary artery bypass grafting (i.e. Algisyl-LVR™+CABG) on both LV function and wall stress in heart failure patients. METHODS AND RESULTS: Magnetic resonance images obtained before treatment (n=3), and at 3 months (n=3) and 6 months (n=2) afterwards were used to reconstruct the LV geometry. Cardiac function was quantified using end-diastolic volume (EDV), end-systolic volume (ESV), regional wall thickness, sphericity index and regional myofiber stress computed using validated mathematical modeling. The LV became more ellipsoidal after treatment, and both EDV and ESV decreased substantially 3 months after treatment in all patients; EDV decreased from 264 ± 91 ml to 146 ± 86 ml and ESV decreased from 184 ± 85 ml to 86 ± 76 ml. Ejection fraction increased from 32 ± 8% to 47 ± 18% during that period. Volumetric-averaged wall thickness increased in all patients, from 1.06 ± 0.21 cm (baseline) to 1.3 ± 0.26 cm (3 months). These changes were accompanied by about a 35% decrease in myofiber stress at end-of-diastole and at end-of-systole. Post-treatment myofiber stress became more uniform in the LV. CONCLUSIONS: These results support the novel concept that Algisyl-LVR™+CABG treatment leads to decreased myofiber stress, restored LV geometry and improved function.

Polymer-based restoration of left ventricular mechanics.

Heart failure continues to be a major health care concern with relatively few options for severely advanced heart failure patients. The hallmark of heart failure is the progressive dilatation of the left ventricle, thinning of the left ventricular wall leading to increased wall stress and increased myocardial oxygen consumption. Applying Laplace's law to the failing dilated ventricle, left ventricular augmentation utilizes a tissue engineering strategy to increase wall thickness and reduce chamber diameter, resulting in a decrease in wall stress and improved left ventricular function. A review of the rationale for an in situ tissue engineering approach for this treatment of heart failure and early clinical results of the Algisyl-LVR™ program are presented.