Matthew T. Lahti

6-month aortic valve implantation of an off-the-shelf tissue-engineered valve in sheep.

Diseased aortic valves often require replacement, with over 30% of the current aortic valve surgeries performed in patients who will outlive a bioprosthetic valve. While many promising tissue-engineered valves have been created in the lab using the cell-seeded polymeric scaffold paradigm, none have been successfully tested long-term in the aortic position of a pre-clinical model. The high pressure gradients and dynamic flow across the aortic valve leaflets require engineering a tissue that has the strength and compliance to withstand high mechanical demand without compromising normal hemodynamics. A long-term preclinical evaluation of an off-the-shelf tissue-engineered aortic valve in the sheep model is presented here. The valves were made from a tube of decellularized cell-produced matrix mounted on a frame. The engineered matrix is primarily composed of collagen, with strength and organization comparable to native valve leaflets. In vitro testing showed excellent hemodynamic performance with low regurgitation, low systolic pressure gradient, and large orifice area. The implanted valves showed large-scale leaflet motion and maintained effective orifice area throughout the duration of the 6-month implant, with no calcification. After 24 weeks implantation (over 17 million cycles), the valves showed no change in tensile mechanical properties. In addition, histology and DNA quantitation showed repopulation of the engineered matrix with interstitial-like cells and endothelialization. New extracellular matrix deposition, including elastin, further demonstrates positive tissue remodeling in addition to recellularization and valve function. Long-term implantation in the sheep model resulted in functionality, matrix remodeling, and recellularization, unprecedented results for a tissue-engineered aortic valve.

Dabigatran versus Warfarin after Mechanical Mitral Valve Replacement in the Swine Model

ABSTRACT Background: Mechanical heart valve replacement is an absolute indication for anticoagulation. We report our experience comparing dabigatran to warfarin as thromboembolic prophylaxis after mechanical mitral valve replacement in the swine model. Methods: Nineteen swine underwent mitral valve replacement with a regulatory approved, 27 mm mechanical valve. Two control groups consisted of three animals receiving no anticoagulation and five animals receiving warfarin (5 mg once a day [QD], adjusted to maintain international normalized ratio [INR] from 2.0 to 2.5). The experimental group consisted of 11 animals receiving dabigatran (20 mg/kg twice a day [BID]). The study period was 90 days. The primary outcome was animal mortality; secondary outcomes included presence of thrombus and bleeding complications. Results: The experimental group had four full-term survivors (40.0%); there were no full-term survivors in either control group. The average length of survival was 50.3 days in the experimental group compared with 18.7 and 15.6 days for the no anticoagulation and warfarin groups, respectively (p = .017). Valve thrombus was observed in all study groups. Hemorrhagic complications were present in 40% of the warfarin group and 27% of the dabigatran group. Conclusions: There was a significant mortality benefit to the use of dabigatran as thromboembolic prophylaxis when compared with warfarin in the setting of mechanical heart valve replacement in the swine model. There was also a decreased incidence of bleeding complications in the dabigatran group compared with the warfarin group. Valve thrombus was observed in all study groups. Any conclusions regarding the rate of thrombus formation are outside the scope of this study and merit further investigation.

Internal aortic annuloplasty: a novel technique.

ABSTRACT Background: The purpose of this study was to define an experimental model and a reproducible surgical technique for the preclinical assessment of safety and biocompatibility of a novel intra-annular internal aortic annulus repair device. Methods: Adult sheep were implanted with HAART Incs 19 mm aortic annulus repair device via a transverse aortotomy using standard anesthetic, surgical, and cardiopulmonary bypass techniques. Animals were closely monitored throughout the study period until the time of elective sacrifice at 30 or 60 days. Results: Six adult sheep, mean age 63.2 weeks, mean weight 68.8 kg, underwent aortic annuloplasty with a 19 mm annuloplasty frame. Five of the sheep remained stable until scheduled sacrifice. The primary outcome of this study was animal mortality. Early mortality was seen in only one animal (16.7%), due to a surgical complication. Mild-to-moderate aortic insufficiency was observed in all animals upon echocardiographic examination at the time of elective sacrifice. Conclusions: Of the six animals that underwent aortic annuloplasty, there was one early death due to surgical complication. The remaining five subjects were clinically stable at the time of elective sacrifice. Any conclusions regarding the cause of the observed aortic insufficiency are beyond the scope of this feasibility study but would need to be fully evaluated in the preclinical assessment of any internal aortic annuloplasty device. We have shown that we have developed a reproducible surgical technique in a physiologically appropriate model for the preclinical assessment of internal aortic annulus repair devices.

Corrigendum: Tissue engineering of acellular vascular grafts capable of somatic growth in young lambs

Nature Communications 7: Article number: 12951 (2016); Published 27 September 2016; Updated 17 January 2017 The authors inadvertently omitted Richard Bianco, who provided consultation for the experimental surgical services, from the author list. This has now been corrected in both the PDF and HTML versions of the Article.

Carpentier-Edwards aortic pericardial bioprosthetic valve as a valid control in preclinical in vivo ovine studies

To progress into clinical practice, a bioprosthetic heart valve must first pass through the preclinical evaluation phase. The International Standards Organization (ISO) recommends implantation of concurrent controls in any evaluation of a new or modified heart valve. A total of 8 adult sheep underwent aortic valve replacement, receiving either the CE Perimount Magna 3000 aortic pericardial bioprosthetic valve or the CE Perimount RSR aortic pericardial bioprosthetic valve, Model 2800. We performed serial blood sampling, echocardiography, angiography and necropsy after euthanasia. All 8 sheep survived until the end of their study term. Our 2-dimensional echocardiographic analysis showed a mean pressure gradient of 37.4±6.0mmHg at 14 days and 37.0±5.9mmHg at 90 days; mean cardiac output was 10.0±2.8l/min at 14 days and 9.6±1.6l/min at 90 days. Angiography before euthanasia showed a mean aortic transvalvular gradient of 32.3±15.3mmHg. At euthanasia, we saw no evidence of calcification in any of the valves. In our study, we found that both models of the CE bioprosthetic heart valve we tested proved to be valid controls, in the aortic position, in sheep-with no evidence of calcification. Most important, the valves we tested had a few model-related problems, allowing a clear determination of their suitability for introduction into a clinical trial. Investigators now have additional insight into the safety of these 2 models of valves and perhaps will be able to reduce the number of controls implanted.