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).

Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model.

A recent trend has emerged that involves myocardial injection of biomaterials, containing cells or acellular, following myocardial infarction (MI) to influence the remodeling response through both biological and mechanical effects. Despite the number of different materials injected in these approaches, there has been little investigation into the importance of material properties on therapeutic outcomes. This work focuses on the investigation of injectable hyaluronic acid (MeHA) hydrogels that have tunable mechanics and gelation behavior. Specifically, two MeHA formulations that exhibit similar degradation and tissue distribution upon injection but have differential moduli (approximately 8 versus approximately 43 kPa) were injected into a clinically relevant ovine MI model to evaluate the associated salutary effect of intramyocardial hydrogel injection on the remodeling response based on hydrogel mechanics. Treatment with both hydrogels significantly increased the wall thickness in the apex and basilar infarct regions compared with the control infarct. However, only the higher-modulus (MeHA High) treatment group had a statistically smaller infarct area compared with the control infarct group. Moreover, reductions in normalized end-diastolic and end-systolic volumes were observed for the MeHA High group. This group also tended to have better functional outcomes (cardiac output and ejection fraction) than the low-modulus (MeHA Low) and control infarct groups. This study provides fundamental information that can be used in the rational design of therapeutic materials for treatment of MI.

In vivo chronic myocardial infarction characterization by spin locked cardiovascular magnetic resonance.

BACKGROUND: Late gadolinium enhanced (LGE) cardiovascular magnetic resonance (CMR) is frequently used to evaluate myocardial viability, estimate total infarct size and transmurality, but is not always straightforward is and contraindicated in patients with renal failure because of the risk of nephrogenic systemic fibrosis. T2- and T1-weighted CMR alone is however relatively insensitive to chronic myocardial infarction (MI) in the absence of a contrast agent. The objective of this manuscript is to explore T1ρ-weighted rotating frame CMR techniques for infarct characterization without contrast agents. We hypothesize that T1ρ CMR accurately measures infarct size in chronic MI on account of a large change in T1ρ relaxation time between scar and myocardium. METHODS: 7Yorkshire swine underwent CMR at 8 weeks post-surgical induction of apical or posterolateral myocardial infarction. Late gadolinium enhanced and T1ρ CMR were performed at high resolution to visualize MI. T1ρ-weighted imaging was performed with a B1 = 500 Hz spin lock pulse on a 3 T clinical MR scanner. Following sacrifice, the heart was excised and infarct size was calculated by optical planimetry. Infarct size was calculated for all three methods (LGE, T1ρ and planimetry) and statistical analysis was performed. T1ρ relaxation time maps were computed from multiple T1ρ-weighted images at varying spin lock duration. RESULTS: Mean infarct contrast-to-noise ratio (CNR) in LGE and T1ρ CMR was 2.8 ± 0.1 and 2.7 ± 0.1. The variation in signal intensity of tissues was found to be, in order of decreasing signal intensity, LV blood, fat and edema, infarct and healthy myocardium. Infarct size measured by T1ρ CMR (21.1% ± 1.4%) was not significantly different from LGE CMR (22.2% ± 1.5%) or planimetry (21.1% ± 2.7%; p < 0.05).T1ρ relaxation times were T1ρinfarct = 91.7 ms in the infarct and T1ρremote = 47.2 ms in the remote myocardium. CONCLUSIONS: T1ρ-weighted imaging using long spin locking pulses enables high discrimination between infarct and myocardium. T1ρ CMR may be useful to visualizing MI without the need for exogenous contrast agents for a wide range of clinical cardiac applications such as to distinguish edema and scar tissue and tissue characterization of myocarditis and ventricular fibrosis.

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.

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.

Influence of injectable hyaluronic acid hydrogel degradation behavior on infarction-induced ventricular remodeling.

Increased myocardial wall stress after myocardial infarction (MI) initiates the process of adverse left ventricular (LV) remodeling that is manifest as progressive LV dilatation, loss of global contractile function, and symptomatic heart failure, and recent work has shown that reduction in wall stress through injectable bulking agents attenuates these outcomes. In this study, hyaluronic acid (HA) was functionalized to exhibit controlled and tunable mechanics and degradation once cross-linked, in an attempt to assess the temporal dependency of mechanical stabilization in LV remodeling. Specifically, two hydrolytically degrading (low and high HeMA-HA, degrading in ~3 and 10 weeks, respectively) and two stable (low and high MeHA, little mass loss even after 8 weeks) hydrogels with similar initial mechanics (low: ~7 kPa; high: ~35-40 kPa) were evaluated in an ovine model of MI. Generally, the more stable hydrogels maintained myocardial wall thickness in the apical and basilar regions more efficiently (low MeHA: apical: 6.5 mm, basilar: 7 mm, high MeHA: apical: 7.0 mm basilar: 7.2 mm) than the hydrolytically degrading hydrogels (low HeMA-HA: apical: 3.5 mm, basilar: 6.0 mm, high HeMA-HA: apical: 4.1 mm, basilar: 6.1 mm); however, all hydrogel groups were improved compared to infarct controls (IC) (apical: 2.2 mm, basilar: 4.6 mm). Histological analysis at 8 weeks demonstrated that although both degradable hydrogels resulted in increased inflammation, all treatments resulted in increased vessel formation compared to IC. Further evaluation revealed that while high HeMA-HA and high MeHA maintained reduced LV volumes at 2 weeks, high MeHA was more effective at 8 weeks, implying that longer wall stabilization is needed for volume maintenance. All hydrogel groups resulted in better cardiac output (CO) values than IC.

Rotating frame spin lattice relaxation in a swine model of chronic, left ventricular myocardial infarction.

T1ρ relaxation times were quantified in a swine model of chronic, left ventricular myocardial infarction. It was found that there were low frequency relaxation mechanisms that suppress endogenous contrast at low spin-lock amplitudes and in T2-weighted images. A moderate amplitude spin-locking pulse could overcome these relaxation mechanisms. Relaxation dispersion data were measured over a range of RF field amplitudes, and a model was formulated to include dipole-dipole relaxation modulated by molecular rotation and an apparent exchange mechanism. These techniques may find some use in the clinic for the observation of chronic, left ventricular cardiac remodeling.

A Multidisciplinary Pathway for the Diagnosis and Treatment of Infectious Endocarditis.

Clinical pathways can be useful when disparate clinical-pathologic groups converge on a common diagnostic and therapeutic trajectory. The progressive increase in the incidence of endocarditis in the US has included higher-risk subjects whose candidacy for aggressive cardiac surgical intervention may be highly resource-intensive, prohibitively high risk, or delayed and possibly deferred by comorbidities. We sought to define the sequence, application, and resolution of multidisciplinary endocarditis team decision-making in 4 distinct clinical groups.

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.

Left Ventricular Assist Device Inflow Cannula Insertion Depth Influences Thrombosis Risk.

Left ventricular assist device (LVAD) use has continued to grow. Despite recent advances in technology, LVAD patients continue to suffer from devastating complications, including stroke and device thrombosis. Among several variables affecting thrombogenicity, we hypothesize that insertion depth of the inflow cannula into the left ventricle (LV) influences hemodynamics and thrombosis risk. Blood flow patterns were studied in a patient-derived computational model of the LV, mitral valve (MV), and LVAD inflow cannula using unsteady computational fluid dynamics (CFD). Hundreds of thousands of platelets were tracked individually, for two inflow cannula insertion depth configurations (12 mm-reduced and 27 mm-conventional) using platelet-level (Lagrangian) metrics to quantify thrombogenicity. Particularly in patients with small LV dimensions, the deeper inflow cannula insertion resulted in much higher platelet shear stress histories (SH), consistent with markedly abnormal intraventricular hemodynamics. A larger proportion of platelets in this deeper insertion configuration was found to linger in the domain for long residence times (RT) and also accumulated much higher SH. The reduced inflow depth configuration promoted LV washout and reduced platelet SH. The increase of both SH and RT in the LV demonstrates the impact of inflow cannula depth on platelet activation and increased stroke risk in these patients. Inflow cannula depth of insertion should be considered as an opportunity to optimize surgical planning of LVAD therapy.

Accuracy of Doppler blood pressure measurement in continuous-flow left ventricular assist device patients.

AIMS: Accurate blood pressure (BP) measurement in continuous-flow ventricular assist device (CF-VAD) patients is imperative to reduce stroke risk. This study assesses the accuracy of the Doppler opening pressure method compared with the gold standard arterial line method in CF-VAD patients. METHODS AND RESULTS: In a longitudinal cohort of HeartMate II and HVAD patients, arterial line BP and simultaneously measured Doppler opening pressure were obtained. Overall correlation, agreement between Doppler opening pressure and arterial line mean vs. systolic pressure, and the effect of arterial pulsatility on the accuracy of Doppler opening pressure were analysed. A total of 1933 pairs of Doppler opening pressure and arterial line pressure readings within 1 min of each other were identified in 154 patients (20% women, mean age 55 ± 15, 50% HeartMate II and 50% HVAD). Doppler opening pressure had good correlation with invasive mean arterial pressure (r = 0.742, P < 0.0001) and more closely approximated mean than systolic BP (mean error 2.4 vs. -8.4 mmHg). Arterial pulsatility did not have a clinically significant effect on the accuracy of the Doppler opening pressure method. CONCLUSIONS: Doppler opening pressure should be the standard non-invasive method of BP measurement in CF-VAD patients.

The future of cardiac transplantation.

The first human-to-human heart transplant was performed 50 years ago in 1967. Heart transplantation has now entered an era of tremendous growth and innovation. The future of heart transplantation is bright with the advent of newer immunosuppressive medications and strategies that may even result in tolerance. Much of this progress in heart transplant medicine is predicated on a better understanding of acute and chronic rejection pathways through basic science studies. The future will also include personalized medicine where genomics and molecular science will dictate customized treatment for optimal outcomes. The introduction of mechanical circulatory support (MCS) devices has changed the landscape for patients with severe heart failure to stabilize the most ill patient and make them better candidates for heart transplant. As ex vivo preservation takes hold, we may witness an expansion of the donor pool through the use of donation after cardiac death (DCD) donors. In addition, further geographical donor heart sharing through ex vivo preservation may further decrease waitlist mortality by enabling longer distance donor hearts to be allocated for the sickest waitlist patient. It is no doubt an exciting time to be involved in the field of heart transplantation. In this perspective, we will summarize the present state of heart transplantation and discuss various innovations that are being pursued.

Cystic teratoma of the pancreas: presentation, evaluation and management.

CONTEXT: Congenital cystic lesions of the pancreas are rare findings. Furthermore, a dermoid cyst of the pancreas is exceptionally uncommon. A review of the world literature shows 18 documented cases. The pre-operative evaluation of this lesion is rather questionable, with definitive diagnosis taking place intra-operatively. CASE REPORT: A 52-year-old male with a symptomatic, 3-cm cystic-type mass in the pancreas. CONCLUSIONS: From our case presentation and review of the world literature, we hope to establish an increased awareness in the diagnostic evaluation of these patients.

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.

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.

A technique for in vivo mapping of myocardial creatine kinase metabolism.

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine protons from creatine with protons in bulk water can be exploited to image creatine through chemical exchange saturation transfer (CrEST) in myocardial tissue. We show that CrEST provides about two orders of magnitude higher sensitivity compared to (1)H magnetic resonance spectroscopy. Results of CrEST studies from ex vivo myocardial tissue strongly correlate with results from (1)H and (31)P magnetic resonance spectroscopy and biochemical analysis. We demonstrate the feasibility of CrEST measurement in healthy and infarcted myocardium in animal models in vivo on a 3-T clinical scanner. As proof of principle, we show the conversion of phosphocreatine to creatine by spatiotemporal mapping of creatine changes in the exercised human calf muscle. We also discuss the potential utility of CrEST in studying myocardial disorders.