Multi-omic and multispecies analysis of right ventricular dysfunction.

BACKGROUND: Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. METHODS: Transcriptomics and proteomics analyses defined the pathways associated with cardiac magnetic resonance imaging (MRI)-derived values of RV hypertrophy, dilation, and dysfunction in control and pulmonary artery banded (PAB) pigs. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare molecular responses across species. RESULTS: PAB pigs displayed significant right ventricle/ventricular (RV) hypertrophy, dilation, and dysfunction as quantified by cardiac magnetic resonance imaging. Transcriptomic and proteomic analyses identified pathways associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the 3 species. FAO and ETC proteins and transcripts were mostly downregulated in rats but were predominately upregulated in PAB pigs, which more closely matched the human response. All species exhibited similar dysregulation of the dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy pathways. CONCLUSIONS: The porcine metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and pigs may more accurately recapitulate metabolic aspects of human RVF.

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure.

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified multiple pathways that were associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the three species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs, which more closely matched the human data. Thus, the pig PAB metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and that pigs more accurately recapitulate the metabolic aspects of human RVF.

New Model for the Assessment of Transcatheter Aortic Valve Replacement Devices in Sheep.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an effective therapy in treating high-risk patients suffering from aortic stenosis. Animal models used to evaluate safety and efficacy of TAVR devices prior to clinical use lack a stenotic aortic annulus, a critical impediment to long-term TAVR device evaluation. We sought to create a reproducible model of aortic stenosis using a modified aortic annuloplasty (MAA) procedure in sheep, followed by deployment and long-term evaluation of TAVR devices using this model. METHODS: Twelve sheep underwent the MAA procedure and were recovered. Transthoracic echocardiography (TTE) was used to monitor changes in the aortic annulus in the postoperative period. At 60 days post-MAA, Test group animals were anesthetized for TAVR insertion and Control animals underwent a necropsy. Test animals were recovered following TAVR insertion and observed for a postoperative period of 140 days. RESULTS: Twelve sheep survived the annuloplasty procedure and the 60-day recovery period. Gross examination of seven Control group animals revealed the implanted annuloplasty ring segments formed hard protrusions into the aortic annulus. Five sheep in the Test group underwent successful deployment of Abbott's experimental TAVR device without evidence of migration. Examination at 140 days post-TAVR insertion showed all devices tightly anchored within the modified aortic annulus. CONCLUSIONS: The MAA procedure creates stenotic segments in the aortic annulus with adequate rigidity for anchorage and long-term evaluation of TAVR devices. This represents the first model that successfully mimics human aortic stenosis and provides a clinically relevant TAVR deployment platform for long-term evaluation in sheep.

Establishing Background Pathologic Changes of Valve Replacement Surgery in Sheep.

PURPOSE: Sheep are the standard preclinical model for assessing safety of novel replacement heart valves, yet the anatomic and pathologic effects of invasive surgery, including those involving cardiopulmonary bypass (CPB), are unknown. Thus, we aimed to determine the gross, hematologic and biochemical effects of sham mitral and aortic replacement valve procedures in sheep to establish a useful control for evaluation of novel replacement valves. METHODS: Six control sheep were examined without any surgical intervention. Six sham mitral valve replacements (MVR) and six sham aortic valve replacements (AVR) were performed on 12 sheep. Complete blood counts and serum biochemistry were performed throughout the study. Sheep were sacrificed with a necropsy performed at 90 days. RESULTS: Renal infarcts (RIs) were the most frequently observed lesion, averaging 4.7 in control sheep, 2.5 with MVR and 5.8 with AVR. The number of infarcts strongly correlated with total estimated area of infarcted kidney (r = .84, p < .01). Additional cardiac interventions were significantly correlated with increased numbers of RIs (r = .85, p < .01). There was no correlation between number of RIs and time on CPB, or between AVR and MVR procedures. CONCLUSION: The sheep model for AVR and MVR requires invasive surgery and CPB, which are associated with background anatomic and pathologic changes, especially in cases with additional surgical cardiac interventions. These findings serve as a critical control for future evaluation and development of novel replacement valves in order to distinguish device-related safety issues from expected outcomes of the surgical procedure and normal background changes in sheep.

Pediatric tri-tube valved conduits made from fibroblast-produced extracellular matrix evaluated over 52 weeks in growing lambs.

There is a need for replacement heart valves that can grow with children. We fabricated tubes of fibroblast-derived collagenous matrix that have been shown to regenerate and grow as a pulmonary artery replacement in lambs and implemented a design for a valved conduit consisting of three tubes sewn together. Seven lambs were implanted with tri-tube valved conduits in sequential cohorts and compared to bioprosthetic conduits. Valves implanted into the pulmonary artery of two lambs of the first cohort of four animals functioned with mild regurgitation and systolic pressure drops <10 mmHg up to 52 weeks after implantation, during which the valve diameter increased from 19 mm to a physiologically normal ~25 mm. In a second cohort, the valve design was modified to include an additional tube, creating a sleeve around the tri-tube valve to counteract faster root growth relative to the leaflets. Two valves exhibited trivial-to-mild regurgitation at 52 weeks with similar diameter increases to ~25 mm and systolic pressure drops of <5 mmHg, whereas the third valve showed similar findings until moderate regurgitation was observed at 52 weeks, correlating to hyperincrease in the valve diameter. In all explanted valves, the leaflets contained interstitial cells and an endothelium progressing from the base of the leaflets and remained thin and pliable with sparse, punctate microcalcifications. The tri-tube valves demonstrated reduced calcification and improved hemodynamic function compared to clinically used pediatric bioprosthetic valves tested in the same model. This tri-tube valved conduit has potential for long-term valve growth in children.

Anisotropic Polytetrafluoroethylene Cardiovascular Conduits Spontaneously Expand in a Growing Lamb Model.

BACKGROUND: Insertion of conduits from the right ventricle (RV) to the pulmonary artery (PA) is a commonly used technique for repair of congenital heart defects. The vast majority of infants and children will require reoperation and/or re-intervention to replace the conduit. Some children may require multiple reoperations, with the risk of death and morbidity increasing significantly with each subsequent operation. We evaluated the feasibility and performance of a relatively novel anisotropic conduit for cardiovascular repair in the growing lamb model. MATERIALS AND METHODS: Lambs were allocated into a control (n = 3) or test (n = 4, anisotropic) conduit group. Control conventional polytetrafluoroethylene (PTFE) conduits or test anisotropic expanded PTFE (ePTFE) based test conduits measuring 10-11 mm in diameter were sewn as interpositional grafts in the main pulmonary artery (MPA) and followed up to 6 months. Clinical and echocardiographic evaluations were performed monthly with hemodynamic and angiographic assessment at 3 and 6 months. RESULTS: Control conduits did not expand, all 3 animals developed one or more adverse events including tachypnea, ascites, inappetence, lethargy, and mortality due to severe right heart failure and significantly higher peak trans-conduit gradients (48.5 ± 5.1 p = 0.02). The test conduits spontaneously expanded up to 14.8 ± 0.8 mm in diameter, no adverse events were observed in any animals and trans-conduit gradients were significantly lower (27.0 ± 8.3, p = 0.02). CONCLUSIONS: Anisotropic ePTFE conduits can be safely implanted in growing lambs with stable hemodynamics. This spontaneously expanding anisotropic conduit may represent a novel approach to congenital heart repairs that would avoid the need for reoperation or multiple operations.

Feasibility Study of Catheter-Based Interventions for Anisotropic Expanded Polytetrafluoroethylene Cardiovascular Conduits in a Growing Lamb Model.

BACKGROUND: Cardiovascular repair in children often requires implant of conduits which do not have growth potential and will require reoperation. In the current study we sought to determine the feasibility of catheter-based interventions of anisotropic conduits inserted as interposition grafts in the main pulmonary artery (MPA) of growing lambs. METHODS: Lambs underwent interpositional implant of either an anisotropic expanded polytetrafluoroethylene (ePTFE) (Test) conduit or conventional PTFE (Control) conduit. In the postoperative period, lambs were anesthetized and underwent catheter-based interventions consisting of hemodynamic and angiographic data collection, balloon dilation and/or stenting of the conduit at 3, 6 or 9 month postoperative time point. RESULTS: At 3 months, control lambs showed significant increases in right ventricular pressures and trans-conduit gradients in comparison to test lambs. Test conduit diameters were significantly larger compared to controls due to spontaneous radial expansion of the anisotropic conduit. Balloon dilation of test conduits at 3 and 6 months showed a reduction in RV pressure and statistically significant improvement in the RV outflow tract gradient as well as significant increase in graft diameter, compared to both control and pre-dilation conditions. Furthermore, the test conduit diameter increased significantly compared to the pre-balloon and control conditions at each time point. Necropsy of test conduits showed no evidence of tears, perforations, or clot and smooth interiors with well-healed anastomoses. CONCLUSIONS: Anisotropic conduits implanted as interposition grafts in the MPA show spontaneous expansion, and can safely and effectively undergo catheter-based interventions, with significant increases in graft diameter occurring after balloon dilation.

Porcine Model of the Arterial Switch Operation: Implications for Unique Strategies in the Management of Hypoplastic Left Ventricles.

There are no reports on the performance of the arterial switch operation (ASO) in a normal heart with normally related great vessels. The objective of this study was to determine whether the ASO could be performed in a healthy animal model. Cardiopulmonary bypass (CPB) and coronary translocation techniques were used to perform ASO in neonatal piglets or a staged ASO with prior main pulmonary artery (PA) banding. Primary ASO was performed in four neonatal piglets. Coronary translocation was effective with angiograms confirming patency. Piglets could not be weaned from CPB due to right ventricle (RV) dysfunction. To improve RV function for the ASO, nine piglets had PA banding. All survived the procedure. Post-banding RV pressure increased from a mean of 20.3 ± 2.2 mmHg to 36.5 ± 7.3 mmHg (p = 0.007). At 58 ± 1 days post-banding, piglets underwent cardiac MRIs revealing RV hypertrophy, and RV pressure overload with mildly reduced RV function. Catheterization confirmed RV systolic pressures of 84.0 ± 6.7 mmHg with LV systolic pressure 83.3 ± 6.7 mmHg (p = 0.43). The remaining five PA banded piglets underwent ASO at 51 ± 0 days post-banding. Three of five were weaned from bypass with patent coronary arteries and adequate RV function. We were able to successfully perform an arterial switch with documented patent coronary arteries on standard anatomy great vessels in a healthy animal model. To our knowledge this is the first time this procedure has been successfully performed. The model may have implications for studying the failing systemic RV, and may support a novel approach for management of borderline, pulsatile left ventricles.

Implantation of a Tissue-Engineered Tubular Heart Valve in Growing Lambs.

Current pediatric heart valve replacement options are suboptimal because they are incapable of somatic growth. Thus, children typically have multiple surgeries to replace outgrown valves. In this study, we present the in vivo function and growth potential of our tissue-engineered pediatric tubular valve. The valves were fabricated by sewing two decellularized engineered tissue tubes together in a prescribed pattern using degradable sutures and subsequently implanted into the main pulmonary artery of growing lambs. Valve function was monitored using periodic ultrasounds after implantation throughout the duration of the study. The valves functioned well up to 8 weeks, 4 weeks beyond the suture strength half-life, after which their insufficiency index worsened. Histology from the explanted valves revealed extensive host cell invasion within the engineered root and commencing from the leaflet surfaces. These cells expressed multiple phenotypes, including endothelial, and deposited elastin and collagen IV. Although the tubes fused together along the degradable suture line as designed, the leaflets shortened compared to their original height. This shortening is hypothesized to result from inadequate fusion at the commissures prior to suture degradation. With appropriate commissure reinforcement, this novel heart valve may provide the somatic growth potential desired for a pediatric valve replacement.

The Hancock® Valved Conduit for Right Ventricular Outflow Tract Reconstruction in Sheep for Assessing New Devices.

BACKGROUND AND AIM OF THE STUDY: Xenograft conduits have been used successfully to repair congenital heart defects, but are prone to failure over time. Hence, in order to improve patient outcomes, better xenografts are being developed. When evaluating a conduit's performance and safety it must first be compared against a clinically available control in a large animal model. The study aim was to evaluate a clinically available xenograft conduit used in right ventricular outflow tract (RVOT) reconstruction in a sheep model. METHODS: RVOT reconstruction was performed in 13 adult and juvenile sheep, using the Medtronic Hancock® Bioprosthetic Valved Conduit (Hancock conduit). The method had previously been used on patients, and a newly modified variant termed 'RVOT Extraction' was employed to facilitate the surgical procedure. Animals were monitored over predetermined terms of 70 to 140 days. Serial transthoracic echocardiography, intracardiac pressure measurements and angiography were performed. On study completion the animals were euthanized and necropsies performed. RESULTS: Two animals died prior to their designated study term due to severe valvular stenosis and distal conduit narrowing, respectively. Thus, 11 animals survived the study term, with few or no complications. Generally, maximal and mean transvalvular pressure gradients across the implanted conduits were increased throughout the postoperative course. Among 11 full-term animals, seven conduits were patent with mild or no pseudointimal proliferation and with flexible leaflets maintaining the hemodynamic integrity of the valve. CONCLUSIONS: RVOT reconstruction using the Hancock conduit was shown to be successful in sheep, with durable and efficient performances. With its extensive clinical use in patients, and ability for long-term use in sheep (as described in the present study) it can be concluded that the Hancock conduit is an excellent control device for the evaluation of new xenografts in future preclinical studies.

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

Treatment of congenital heart defects in children requiring right ventricular outflow tract reconstruction typically involves multiple open-heart surgeries because all existing graft materials have no growth potential. Here we present an 'off-the-shelf' vascular graft grown from donor fibroblasts in a fibrin gel to address this critical unmet need. In a proof-of-concept study, the decellularized grafts are implanted as a pulmonary artery replacement in three young lambs and evaluated to adulthood. Longitudinal ultrasounds document dimensional growth of the grafts. The lambs show normal growth, increasing body weight by 366% and graft diameter and volume by 56% and 216%, respectively. Explanted grafts display physiological strength and stiffness, complete lumen endothelialization and extensive population by mature smooth muscle cells. The grafts also show substantial elastin deposition and a 465% increase in collagen content, without signs of calcification, aneurysm or stenosis. Collectively, our data support somatic growth of this completely biological graft.

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.

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.

Blood outgrowth endothelial cells alter remodeling of completely biological engineered grafts implanted into the sheep femoral artery.

Hemocompatibility of tissue-engineered vascular grafts remains a major hurdle to clinical utility for small-diameter grafts. Here we assessed the feasibility of using autologous blood outgrowth endothelial cells to create an endothelium via lumenal seeding on completely biological, decellularized engineered allografts prior to implantation in the sheep femoral artery. The 4-mm-diameter, 2- to 3-cm-long grafts were fabricated from fibrin gel remodeled into an aligned tissue tube in vitro by ovine dermal fibroblasts prior to decellularization. Decellularized grafts pre-seeded with blood outgrowth endothelial cells (n = 3) retained unprecedented (>95 %) monolayer coverage 1 h post-implantation and had greater endothelial coverage, smaller wall thickness, and more basement membrane after 9-week implantation, including a final week without anti-coagulation therapy, compared with contralateral non-seeded controls. These results support the use of autologous blood outgrowth endothelial cells as a viable source of endothelial cells for creating an endothelium with biological function on decellularized engineered allografts made from fibroblast-remodeled fibrin.

Dabigatran versus warfarin after mechanical mitral valve replacement in the swine model.

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.

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 Inc's 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.

Transmural atrial fibrosis after epicardial and endocardial argon-powered CryoMaze ablation.

BACKGROUND: The CryoMaze procedure is usually limited to endocardial ablation under cardio-pulmonary bypass. Epicardial ablation is considered inferior as endocardial islets of atrial tissue could theoretically remain viable, protected from cryoinjury by epicardial fat and endocardial circulating warm blood. Novel argon-powered cryoprobes with lower ablation temperatures have recently become available. It is unclear if these instruments can reliably induce transmural atrial fibrosis by epicardial cryoablation on the beating heart. METHODS: Ten sheep were divided into two equal groups. CryoMaze ablations were applied using an argon-powered cryoprobe with an ablation temperature of -185°C. In the control group, standardized ablations (n = 50) were applied endocardially under cardiopulmonary bypass. In the experimental group, corresponding ablations (n = 50) were applied epicardially on the beating heart. Postoperatively the animals were monitored for 30 days. At necropsy, the lesions were explanted and analyzed histologically for evidence of transmural fibrosis. RESULTS: Two animals in the control group and one animal in the experimental group died prematurely. Autopsy of the remaining animals showed that all lesions (n = 70) had retained their structural integrity. In the control group, histology demonstrated transmural fibrosis in 94% (28/30) of the endocardially applied lesions. In the experimental group, histology demonstrated transmural fibrosis in 95% (38/40) of the epicardially applied lesions. Statistical analysis revealed no significant difference between the two groups (p = 0.96). CONCLUSION: Argon-powered epicardial cryoablation on the beating heart is as efficient in inducing transmural fibrosis as the traditional technique of endocardial ablation under cardio-pulmonary bypass.

In-vivo experience with the Triflo trileaflet mechanical heart valve.

BACKGROUND AND AIM OF THE STUDY: The in-vivo performance of the Triflo trileaflet mechanical valve was evaluated in an ovine model. The aim of long-term follow up was to gather site-specific performance data demonstrating device safety, as required for regulatory approval of this new valve design, prior to its use in clinical trials. METHODS: The Triflo trileaflet valve was implanted in 26 sheep using 29-mm mitral (n=8; animal body weight 63.3 +/- 10.3 kg, age 112.0 +/- 30.7 weeks) or 21-mm aortic mechanical valves (n=19; body weight 73.0 +/- 4.36 kg, age 112.6 +/- 23.6 weeks) using standard techniques. Animals were allocated to 150- or 365-day survival cohorts. The 150-day cohort was further subdivided into mitral valve (n=6) and aortic valve (n=11) implants. The 365-day cohort was organized into aortic (n=7) and mitral (n=2) implants. Angiography, echocardiography, and pathology were performed to assess valve performance. RESULTS: Angiographically monitored pressure measurements for the trileaflet mitral valve at 150 and 365 days were within established ranges in terms of mean aortic pressure, systolic and diastolic aortic pressure, and left ventricular end-diastolic pressure. In animals receiving a mitral valve the transvalvular gradient was 3.5 +/- 0.71 mmHg at 365 days, and 0.2 +/- 0.4 mmHg at 150 days. The Triflo mitral valve had only mild (physiologic) regurgitation. Cardiac output was within normal limits in animals receiving the Triflo valve in the aortic position. Laboratory values reflected no ongoing infection or destruction of blood cells as a result of device implantation. No significant abnormality was noted at necropsy in any animal, except for evidence of thromboembolic events in the kidneys (4-20%). Pathological evaluation was reflected by mild to moderate fibrous tissue formation at the inflow orifice (n=15), and minimal growth was observed in the outflow tract of one valve. This was consistent with that seen in sheep implanted with a standard St. Jude Medical bileaflet valve. CONCLUSION: The study results showed the Triflo valve to perform to safety levels comparable with those of the standard St. Jude Medical bileaflet design, when implanted in the aortic and mitral positions. Additional analysis of historic control data suggested that the trileaflet valve design may offer a reduction in outflow tract obstruction by allowing for a greater effective orifice area index when compared to an equal-sized-orifice bileaflet valve. Notably, the Triflo valve was associated with a statistically significant reduction in myocardial hypertrophy, further reducing the potential for patient-prosthesis mismatch. Overall, the Triflo valve appeared to more closely emulate the hemodynamic properties of the native tissue valve than the traditional bileaflet design. Hence, the trileaflet design may offer the function of a tissue valve while retaining the durability of the mechanical valve.