Increasing Utilization of Extended Criteria Donor Hearts for Transplantation: The OCS Heart EXPAND Trial.

BACKGROUND: Extended criteria donor (ECD) hearts available with donation after brain death (DBD) are underutilized for transplantation due to limitations of cold storage. OBJECTIVES: This study evaluated use of an extracorporeal perfusion system on donor heart utilization and post-transplant outcomes in ECD DBD hearts. METHODS: In this prospective, single-arm, multicenter study, adult heart transplant recipients received ECD hearts using an extracorporeal perfusion system if hearts met study criteria. The primary outcome was a composite of 30-day survival and absence of severe primary graft dysfunction (PGD). Secondary outcomes were donor heart utilization rate, 30-day survival, and incidence of severe PGD. The safety outcome was the mean number of heart graft-related serious adverse events within 30 days. Additional outcomes included survival through 2 years benchmarked to concurrent nonrandomized control subjects. RESULTS: A total of 173 ECD DBD hearts were perfused; 150 (87%) were successfully transplanted; 23 (13%) did not meet study transplantation criteria. At 30 days, 92% of patients had survived and had no severe PGD. The 30-day survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of heart graft-related serious adverse events within 30 days was 0.17 (95% CI: 0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months, respectively, and was comparable with concurrent nonrandomized control subjects. CONCLUSIONS: Use of an extracorporeal perfusion system resulted in successfully transplanting 87% of donor hearts with excellent patient survival to 2 years post-transplant and low rates of severe PGD. The ability to safely use ECD DBD hearts could substantially increase the number of heart transplants and expand access to patients in need. (International EXPAND Heart Pivotal Trial [EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol; NCT03835754).

Correlates of 90-Day Mortality Among People Who Do and Do Not Inject Drugs With Infective Endocarditis in Seattle, Washington.

Background: Infective endocarditis (IE) remains highly morbid, but few studies have evaluated factors associated with IE mortality. We examined correlates of 90-day mortality among people who inject drugs (PWID) and people who do not inject drugs (non-PWID). Methods: We queried the electronic medical record for cases of IE among adults ≥18 years of age at 2 academic medical centers in Seattle, Washington, from 1 January 2014 to 31 July 2019. Cases were reviewed to confirm a diagnosis of IE and drug use status. Deaths were confirmed through the Washington State death index. Descriptive statistics were used to characterize IE in PWID and non-PWID. Kaplan-Meier log-rank tests and Cox proportional hazard models were used to assess correlates of 90-day mortality. Results: We identified 507 patients with IE, 213 (42%) of whom were PWID. Sixteen percent of patients died within 90 days of admission, including 14% of PWID and 17% of non-PWID (P = .50). In a multivariable Cox proportional hazard model, injection drug use was associated with a higher mortality within the first 14 days of admission (adjusted hazard ratio [aHR], 2.33 [95% confidence interval {CI}, 1.16-4.65], P = .02); however, there was no association between injection drug use and mortality between 15 and 90 days of admission (aHR, 0.63 [95% CI, .31-1.30], P = .21). Conclusions: Overall 90-day mortality did not differ between PWID and non-PWID with IE, although PWID experienced a higher risk of death within 14 days of admission. These findings suggest that early IE diagnosis and treatment among PWID is critical to improving outcomes.

Comparison of Neurologic Event Rates Among HeartMate II, HeartMate 3, and HVAD.

Strokes remain a leading cause of morbidity and mortality in patients with ventricular assist devices (VADs). Varying study populations, event definitions, and reporting methods make direct comparison of neurologic event risk across clinical trials and registries challenging. We aim to highlight important differences among major VAD studies and standardize rates of neurologic events to facilitate a comprehensive and objective comparison. We systematically identified and analyzed key clinical trials and registries evaluating the HeartMate II (HMII), HeartMate 3 (HM3), and HVAD devices. Reported neurologic events were nonexclusively categorized into ischemic stroke, hemorrhagic stroke, disabling stroke, fatal stroke, and other neurologic events per the studies' definitions. Event rates were standardized to events per patient-year (EPPY) and freedom from event formats. Seven key clinical trials and registries were included in our analysis. There is significant variation and overlap in neurologic event rates for the three VAD platforms across clinical trials (all neurologic events [EPPY]: HM3 0.17-0.21; HMII 0.19-0.26; HVAD 0.16-0.28). None performs consistently better for all types of neurologic events. Furthermore, stroke rates among VAD trials correlated with baseline stroke risk factors including ischemic etiology, history of atrial fibrillation, and history of prior stroke.

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

Injectable biomaterials are an attractive therapy to attenuate left ventricular (LV) remodeling after myocardial infarction (MI). Although studies have shown that injectable hydrogels improve cardiac structure and function in vivo, temporal changes in infarct material properties after treatment have not been assessed. Emerging imaging and modeling techniques now allow for serial, non-invasive estimation of infarct material properties. Specifically, cine magnetic resonance imaging (MRI) assesses global LV structure and function, late-gadolinium enhancement (LGE) MRI enables visualization of infarcted tissue to quantify infarct expansion, and spatial modulation of magnetization (SPAMM) tagging provides passive wall motion assessment as a measure of tissue strain, which can all be used to evaluate infarct properties when combined with finite element (FE) models. In this work, we investigated the temporal effects of degradable hyaluronic acid (HA) hydrogels on global LV remodeling, infarct thinning and expansion, and infarct stiffness in a porcine infarct model for 12 weeks post-MI using MRI and FE modeling. Hydrogel treatment led to decreased LV volumes, improved ejection fraction, and increased wall thickness when compared to controls. FE model simulations demonstrated that hydrogel therapy increased infarct stiffness for 12 weeks post-MI. Thus, evaluation of myocardial tissue properties through MRI and FE modeling provides insight into the influence of injectable hydrogel therapies on myocardial structure and function post-MI.

Regional myocardial three-dimensional principal strains during postinfarction remodeling.

BACKGROUND: The purpose of this study was to quantify myocardial three-dimensional (3D) principal strains as the left ventricle (LV) remodels after myocardial infarction (MI). Serial quantification of myocardial strains is important for understanding the mechanical response of the LV to MI. Principal strains convert the 3D LV wall-based strain matrix with three normal and three shear elements, to a matrix with three nonzero normal elements, thereby eliminating the shear elements, which are difficult to physically interpret. METHODS: The study was designed to measure principal strains of the remote, border zone, and infarct regions in a porcine model of post-MI LV remodeling. Magnetic resonance imaging was used to measure function and strain at baseline, 1 week, and 4 weeks after infarct. Principal strain was measured using 3D acquisition and the optical flow method for displacement tracking. RESULTS: Principal strains were altered as the LV remodeled. Maximum principal strain magnitude decreased in all regions, including the noninfarcted remote, while maximum principal strain angles rotated away from the radial direction in the border zone and infarct. Minimum principal strain magnitude followed a similar pattern; however, strain angles were altered in all regions. Evolution of principal strains correlated with adverse LV remodeling. CONCLUSIONS: Using a state-of-the-art imaging and optical flow method technique, 3D principal strains can be measured serially after MI in pigs. Results are consistent with progressive infarct stretching as well as with decreased contractile function in the border zone and remote myocardial regions.

Sutureless mitral valve replacement: initial steps toward a percutaneous procedure.

PURPOSE: Transcatheter mitral valve replacement would represent a major advance in heart valve therapy. Such a device requires a specialized anchoring and sealing technology. This study was designed to test the feasibility of a novel mitral valve replacement device (the sutureless mitral valve [SMV]) designed to anchor and seal in the mitral position without need for sutures. DESCRIPTION: The SMV is a self-expanding device consisting of a custom-designed nitinol framework and a pericardial leaflet valve mechanism. EVALUATION: Ten sheep underwent successful surgical SMV device implantation. All animals underwent cardiac catheterization 6 hours postoperatively. Hemodynamic, angiographic, echocardiographic and necroscopic data were recorded. The mean aortic cross-clamp time was 9.5 ± 3.1 minutes. Echocardiography and angiography revealed excellent left ventricular systolic function, no significant perivalvular leak, no mitral valve stenosis, no left ventricular outflow tract obstruction, and no aortic valve insufficiency. Necropsy demonstrated that the SMV devices were anchored securely. CONCLUSIONS: This study demonstrates the feasibility and short-term success of sutureless mitral valve replacement using a novel SMV device.

Directed epicardial assistance in ischemic cardiomyopathy: flow and function using cardiac magnetic resonance imaging.

BACKGROUND: Heart failure after myocardial infarction (MI) is a result of increased myocardial workload, adverse left ventricular (LV) geometric remodeling, and less efficient LV fluid movement. In this study we utilize cardiac magnetic resonance imaging to evaluate ventricular function and flow after placement of a novel directed epicardial assist device. METHODS: Five swine underwent posterolateral MI and were allowed to remodel for 12 weeks. An inflatable bladder was positioned centrally within the infarct and secured with mesh. The device was connected to an external gas exchange pump, which inflated and deflated in synchrony with the cardiac cycle. Animals then underwent cardiac magnetic resonance imaging during active epicardial assistance and with no assistance. RESULTS: Active epicardial assistance of the infarct showed immediate improvement in LV function and intraventricular flow. Ejection fraction significantly improved from 26.0% ± 4.9% to 37.3% ± 4.5% (p < 0.01). End-systolic volume (85.5 ± 12.7 mL versus 70.1 ± 11.9 mL, p < 0.01) and stroke volume (28.5 ± 4.4 mL versus 39.9 ± 3.1 mL, p = 0.03) were also improved with assistance. End-diastolic volume and regurgitant fraction did not change with treatment. Regional LV flow improved both qualitatively and quantitatively during assistance. Unassisted infarct regional flow showed highly discoordinate blood movement with very slow egress from the posterolateral wall. Large areas of stagnant flow were also identified. With assistance, posterolateral wall blood velocities improved significantly during both systole (26.4% ± 3.2% versus 12.6% ± 1.2% maximum velocity; p < 0.001) and diastole (54.3% ± 9.3% versus 24.2% ± 2.5% maximum velocity; p < 0.01). CONCLUSIONS: Directed epicardial assistance can improve LV function and flow in ischemic cardiomyopathy. This novel device may provide a valuable alternative to currently available heart failure therapies.

In vitro mitral valve simulator mimics systolic valvular function of chronic ischemic mitral regurgitation ovine model.

BACKGROUND: This study was undertaken to evaluate an in vitro mitral valve (MV) simulator's ability to mimic the systolic leaflet coaptation, regurgitation, and leaflet mechanics of a healthy ovine model and an ovine model with chronic ischemic mitral regurgitation (IMR). METHODS: Mitral valve size and geometry of both healthy ovine animals and those with chronic IMR were used to recreate systolic MV function in vitro. A2-P2 coaptation length, coaptation depth, tenting area, anterior leaflet strain, and MR were compared between the animal groups and valves simulated in the bench-top model. RESULTS: For the control conditions, no differences were observed between the healthy animals and simulator in coaptation length (p = 0.681), coaptation depth (p = 0.559), tenting area (p = 0.199), and anterior leaflet strain in the radial (p = 0.230) and circumferential (p = 0.364) directions. For the chronic IMR conditions, no differences were observed between the models in coaptation length (p = 0.596), coaptation depth (p = 0.621), tenting area (p = 0.879), and anterior leaflet strain in the radial (p = 0.151) and circumferential (p = 0.586) directions. MR was similar between IMR models, with an asymmetrical jet originating from the tethered A3-P3 leaflets. CONCLUSIONS: This study is the first to demonstrate the effectiveness of an in vitro simulator to emulate the systolic valvular function and mechanics of a healthy ovine model and one with chronic IMR. The in vitro IMR model provides the capability to recreate intermediary and exacerbated levels of annular and subvalvular distortion for which IMR repairs can be simulated. This system provides a realistic and controllable test platform for the development and evaluation of current and future IMR repairs.

Contractile mitral annular forces are reduced with ischemic mitral regurgitation.

OBJECTIVE: Forces acting on mitral annular devices in the setting of ischemic mitral regurgitation are currently unknown. The aim of this study was to quantify the cyclic forces that result from mitral annular contraction in a chronic ischemic mitral regurgitation ovine model and compare them with forces measured previously in healthy animals. METHODS: A novel force transducer was implanted in the mitral annulus of 6 ovine subjects 8 weeks after an inferior left ventricle infarction that produced progressive, severe chronic ischemic mitral regurgitation. Septal-lateral and transverse forces were measured continuously for cardiac cycles reaching a peak left ventricular pressure of 90, 125, 150, 175, and 200 mm Hg. Cyclic forces and their rate of change during isovolumetric contraction were quantified and compared with those measured in healthy animals. RESULTS: Animals with chronic ischemic mitral regurgitation exhibited a mean mitral regurgitation grade of 2.3 ± 0.5. Ischemic mitral regurgitation was observed to decrease significantly septal-lateral forces at each level of left ventricular pressure (P < .01). Transverse forces were consistently lower in the ischemic mitral regurgitation group despite not reaching statistical significance. The rate of change of these forces during isovolumetric contraction was found to increase significantly with peak left ventricular pressure (P < .005), but did not differ significantly between animal groups. CONCLUSIONS: Mitral annular forces were measured for the first time in a chronic ischemic mitral regurgitation animal model. Our findings demonstrated an inferior left ventricular infarct to decrease significantly cyclic septal-lateral forces while modestly lowering those in the transverse. The measurement of these forces and their variation with left ventricular pressure contributes significantly to the development of mitral annular ischemic mitral regurgitation devices.

Optimized local infarct restraint improves left ventricular function and limits remodeling.

BACKGROUND: Preventing expansion and dyskinetic movement of a myocardial infarction (MI) can limit left ventricular (LV) remodeling. Using a device designed to produce variable alteration of infarct stiffness and geometry, we sought to understand how these parameters affect LV function and remodeling early after MI. METHODS: Ten pigs had posterolateral infarctions. An unexpanded device was placed in 5 animals at the time of infarction and 5 animals served as untreated controls. One week after MI animals underwent magnetic resonance imaging to assess LV size and regional function. In the treatment group, after initial imaging, the device was expanded with 2, 4, 6, 8, and 10 mL of saline. The optimal degree of inflation was defined as that which maximized stroke volume (SV). The device was left optimally inflated in the treatment animals for 3 additional weeks. RESULTS: One week after MI, device inflation to 6 mL or greater significantly (p < 0.05) decreased end-systolic volume (0 mL, 59.9 mL ± 3.8; 6 mL, 54.0 mL ± 3.1; 8 mL, 50.5 mL ± 4.8; and 10 mL, 46.1 mL ± 2.2) and increased ejection fraction (EF) (0 mL, 0.346 ± 0.016; 6 mL, 0.0397 ± 0.009; 8 mL, 0.431 ± 0.027; and 10 mL, 0.441 ± 0.009). Systolic volume significantly (p < 0.05) improved for the 6 mL and 8 mL volumes (0 mL, 31.2 mL ± 2.6; 6 mL, 35.7 mL ± 2.0; and 8 mL, 37.5 mL ± 1.9) but trended downward for 10 mL (36.6 mL ± 2.8). At 4 weeks after MI, end-diastolic volume and end-systolic volume were unchanged from 1-week values in the treatment group while the control group continued to dilate. Systolic volume (38.2 ± 4.4 mL vs 34.0.1 ± 4.8 mL, p = 0.08) and EF (0.360 ± 0.026 vs 0.276 ± 0.014, p = 0.04) were also better in the treatment animals. CONCLUSIONS: Optimized isolated infarct restraint can limit adverse LV remodeling after MI. The tested device affords the potential for a patient-specific therapy to preserve cardiac function after MI.

Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide.

BACKGROUND: Manifestations of reperfusion injury include myocyte death leading to infarction, contractile dysfunction, and vascular injury characterized by the "no-reflow" phenomenon. Mitochondria-produced reactive oxygen species are believed to be centrally involved in each of these aspects of reperfusion injury, although currently no therapies reduce reperfusion injury by targeting mitochondria specifically. METHODS AND RESULTS: We investigated the cardioprotective effects of a mitochondria-targeted peptide, Bendavia (Stealth Peptides), across a spectrum of experimental cardiac ischemia/reperfusion models. Postischemic administration of Bendavia reduced infarct size in an in vivo sheep model by 15% (P=0.02) and in an ex vivo guinea pig model by 38% to 42% (P<0.05). In an in vivo rabbit model, the extent of coronary no-reflow was assessed with Thioflavin S staining and was significantly smaller in the Bendavia group for any given ischemic risk area than in the control group (P=0.0085). Myocardial uptake of Bendavia was ≈25% per minute, and uptake remained consistent throughout reperfusion. Postischemic recovery of cardiac hemodynamics was not influenced by Bendavia in any of the models studied. Isolated myocytes exposed to hypoxia/reoxygenation showed improved survival when treated with Bendavia. This protection appeared to be mediated by lowered reactive oxygen species-mediated cell death during reoxygenation, associated with sustainment of mitochondrial membrane potential in Bendavia-treated myocytes. CONCLUSIONS: Postischemic administration of Bendavia protected against reperfusion injury in several distinct models of injury. These data suggest that Bendavia is a mitochondria-targeted therapy that reduces reperfusion injury by maintaining mitochondrial energetics and suppressing cellular reactive oxygen species levels. (J Am Heart Assoc. 2012;1:e001644 doi: 10.1161/JAHA.112.001644.).

Posterior leaflet augmentation in ischemic mitral regurgitation increases leaflet coaptation and mobility.

BACKGROUND: Restoring leaflet coaptation is the primary objective in repair of ischemic mitral regurgitation (IMR). The common practice of placing an undersized annuloplasty ring partially achieves this goal by correcting annular dilation; however, annular reduction has been demonstrated to exacerbate posterior leaflet tethering. Using a sheep model of IMR, we tested the hypothesis that posterior leaflet augmentation (PLA) combined with standard annuloplasty sizing increases leaflet coaptation more effectively than undersized annuloplasty alone. METHODS: Eight weeks after posterobasal myocardial infarction, 15 sheep with 2+ or greater IMR underwent annuloplasty with either a 24-mm annuloplasty ring (24-mm group, n = 5), 30-mm ring (30-mm group, n = 5), or 30-mm ring with concomitant augmentation of the posterior leaflet (PLA group, n = 5). Using three-dimensional echocardiography, postrepair coaptation zone and posterior leaflet mobility were assessed. RESULTS: Leaflet coaptation length after repair was greater in the PLA group (4.1 ± 0.3 mm) and the 24-mm group (3.8 ± 0.5 mm) as compared with the 30-mm group (2.7 ± 0.6 mm, p < 0.01). Leaflet coaptation area was significantly greater in the PLA group (121.5 ± 6.6 mm(2)) as compared with the 30-mm group (77.5 ± 17.0 mm(2)) or the 24-mm group (92.5 ± 17.9 mm(2), p < 0.01). Posterior leaflet mobility was significantly greater in the PLA group as compared with the 30-mm group or the 24-mm group. CONCLUSIONS: Posterior leaflet augmentation combined with standard-sized annuloplasty enhances leaflet coaptation more effectively than either standard-sized annuloplasty or undersized annuloplasty alone. Increased leaflet coaptation after PLA provides redundancy to IMR repair, and may decrease incidence of both recurrent IMR and mitral stenosis.

An ovine model of pulmonary insufficiency and right ventricular outflow tract dilatation.

BACKGROUND AND AIM OF THE STUDY: The treatment of pulmonary insufficiency (PI) following reconstructive surgery of the right ventricular outflow tract (RVOT) in repair of the tetralogy of Fallot remains a significant challenge. The study aim was to establish an ovine model of dilated RVOT and PI, and to quantify the degree of PI and right ventricular remodeling over an eight-week period, using magnetic resonance imaging (MRI). METHODS: Five sheep underwent baseline MRI scanning and catheterization. The weight-indexed right and left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and pulmonary regurgitant fraction (RF) were measured at baseline. The animals then underwent pulmonary valvectomy and transannular patch repair of the RVOT. Repeat MRI and hemodynamic measurements were obtained after an eight-week period. RESULTS: The indexed RVEDV increased from 49 +/- 4.0 ml/m2 at baseline to 80 +/- 10.3 ml/m2 at eight weeks after valvectomy (p = 0.01), while the indexed RVESV increased from 13 +/- 3.4 ml/m2 to 33 +/- 8.8 ml/m2 (p = 0.01). The indexed RVSV increased from 36 +/- 3.7 ml/m2 to 47 +/- 1.7 ml/m2 (p = 0.01). The RVEF at baseline was 74 +/- 6%, and this decreased to 59 +/- 5% at follow up (p = 0.02). The RF at baseline was 0 +/- 0% and was increased to 37 +/- 3% at eight weeks after valvectomy (p < 0.001). The left ventricular (LV) function was also diminished: LVEF at baseline was 67 +/- 2%, versus 49 +/- 10% at follow up (p = 0.01). Both, the RV and LV end-diastolic pressures were significantly elevated at follow up. CONCLUSION: All five animals developed pulmonary regurgitation sufficient to cause significant RV dilatation and diminished RV and LV functions. This model may be used to investigate novel therapeutic approaches in the treatment of this difficult clinical problem.