Impact of the coronavirus disease 2019 pandemic on drug overdoses in the United States and the effect on cardiac transplant volume and survival.

BACKGROUND: Drug overdose (DO) deaths rose to unprecedented levels during the coronavirus disease 2019 (COVID-19) pandemic. This study examines the impact of COVID-19 on the availability of cardiac allografts from DO donors and the implications of DO donor use on recipient survival. METHODS: Heart transplants reported to the United Network for Organ Sharing from January 2017 to November 2019 ("pre-COVID") and from March 2020 to June 2021 ("COVID pandemic") were analyzed with respect to DO donor status. Outcomes were analyzed using Kaplan-Meier survival and Cox regression to identify predictors of survival. Characteristics of discarded cardiac allografts were also compared by DO donor status. RESULTS: During the COVID-19 pandemic, 27.2% of cardiac allografts were from DO donors vs 20.5% pre-COVID, a 32.7% increase (p < 0.001). During the pandemic, DO donors were younger (84.7% vs 76.3% <40 years, p < 0.001), had higher cigarette use (16.1% vs 10.8%, p < 0.001), higher cocaine use (47.4% vs 19.7%, p < 0.001), and higher incidence of hepatitis C antibodies (26.8% vs 6.1%, p < 0.001) and RNA positivity (16.2% vs 4.2%, p < 0.001). While DO donors were less likely to require inotropic support (30.8% vs 35.4%, p = 0.008), they were more likely to have received cardiopulmonary resuscitation (95.3% vs 43.2%, p < 0.001). Recipient survival was equivalent using Kaplan-Meier analysis (log-rank, p = 0.33) and survival probability at 36 months was 85.6% (n at risk = 398) for DO donors vs 83.5% (n at risk = 1,633) for all other donors. Cox regression demonstrated that DO donor status did not predict mortality (hazard ratio 1.05; 95% confidence interval 0.90-1.23, p = 0.53). CONCLUSIONS: During the COVID-19 pandemic, there was a 32.7% increase in heart transplants utilizing DO donor hearts, and DO became the most common mechanism of death for donors. The use of DO donor hearts did not have an impact on short-term recipient survival.

Computational design of custom therapeutic cells to correct failing human cardiomyocytes.

Background: Myocardial delivery of non-excitable cells-namely human mesenchymal stem cells (hMSCs) and c-kit+ cardiac interstitial cells (hCICs)-remains a promising approach for treating the failing heart. Recent empirical studies attempt to improve such therapies by genetically engineering cells to express specific ion channels, or by creating hybrid cells with combined channel expression. This study uses a computational modeling approach to test the hypothesis that custom hypothetical cells can be rationally designed to restore a healthy phenotype when coupled to human heart failure (HF) cardiomyocytes. Methods: Candidate custom cells were simulated with a combination of ion channels from non-excitable cells and healthy human cardiomyocytes (hCMs). Using a genetic algorithm-based optimization approach, candidate cells were accepted if a root mean square error (RMSE) of less than 50% relative to healthy hCM was achieved for both action potential and calcium transient waveforms for the cell-treated HF cardiomyocyte, normalized to the untreated HF cardiomyocyte. Results: Custom cells expressing only non-excitable ion channels were inadequate to restore a healthy cardiac phenotype when coupled to either fibrotic or non-fibrotic HF cardiomyocytes. In contrast, custom cells also expressing cardiac ion channels led to acceptable restoration of a healthy cardiomyocyte phenotype when coupled to fibrotic, but not non-fibrotic, HF cardiomyocytes. Incorporating the cardiomyocyte inward rectifier K+ channel was critical to accomplishing this phenotypic rescue while also improving single-cell action potential metrics associated with arrhythmias, namely resting membrane potential and action potential duration. The computational approach also provided insight into the rescue mechanisms, whereby heterocellular coupling enhanced cardiomyocyte L-type calcium current and promoted calcium-induced calcium release. Finally, as a therapeutically translatable strategy, we simulated delivery of hMSCs and hCICs genetically engineered to express the cardiomyocyte inward rectifier K+ channel, which decreased action potential and calcium transient RMSEs by at least 24% relative to control hMSCs and hCICs, with more favorable single-cell arrhythmia metrics. Conclusion: Computational modeling facilitates exploration of customizable engineered cell therapies. Optimized cells expressing cardiac ion channels restored healthy action potential and calcium handling phenotypes in fibrotic HF cardiomyocytes and improved single-cell arrhythmia metrics, warranting further experimental validation studies of the proposed custom therapeutic cells.

In silico Cell Therapy Model Restores Failing Human Myocyte Electrophysiology and Calcium Cycling in Fibrotic Myocardium.

Myocardial delivery of human c-kit+ cardiac interstitial cells (hCICs) and human mesenchymal stem cells (hMSCs), an emerging approach for treating the failing heart, has been limited by an incomplete understanding of the effects on host myocardium. This computational study aims to model hCIC and hMSC effects on electrophysiology and calcium cycling of healthy and diseased human cardiomyocytes (hCM), and reveals a possible cardiotherapeutic benefit independent of putative regeneration processes. First, we developed an original hCIC mathematical model with an electrical profile comprised of distinct experimentally identified ion currents. Next, we verified the model by confirming it is representative of published experiments on hCIC whole-cell electrophysiology and on hCIC co-cultures with rodent cardiomyocytes. We then used our model to compare electrophysiological effects of hCICs to other non-excitable cells, as well as clinically relevant hCIC-hMSC combination therapies and fused hCIC-hMSC CardioChimeras. Simulation of direct coupling of hCICs to healthy or failing hCMs through gap junctions led to greater increases in calcium cycling with lesser reductions in action potential duration (APD) compared with hMSCs. Combined coupling of hCICs and hMSCs to healthy or diseased hCMs led to intermediate effects on electrophysiology and calcium cycling compared to individually coupled hCICs or hMSCs. Fused hCIC-hMSC CardioChimeras decreased healthy and diseased hCM APD and calcium transient amplitude compared to individual or combined cell treatments. Finally, to provide a theoretical basis for optimizing cell-based therapies, we randomized populations of 2,500 models incorporating variable hMSC and hCIC interventions and simulated their effects on restoring diseased cardiomyocyte electrophysiology and calcium handling. The permutation simulation predicted the ability to correct abnormal properties of heart failure hCMs in fibrotic, but not non-fibrotic, myocardium. This permutation experiment also predicted paracrine signaling to be a necessary and sufficient mechanism for this correction, counteracting the fibrotic effects while also restoring arrhythmia-related metrics such as upstroke velocity and resting membrane potential. Altogether, our in silico findings suggest anti-fibrotic effects of paracrine signaling are critical to abrogating pathological cardiomyocyte electrophysiology and calcium cycling in fibrotic heart failure, and support further investigation of delivering an optimized cellular secretome as a potential strategy for improving heart failure therapy.

Attempt at off-label balloon valvuloplasty post-dilation for intuity sutureless valve.

Alternatives to traditional aortic valve replacement now form part of the valve surgeon's armamentarium. Sutureless valves offer decreased bypass and crossclamp times, excellent maneuverability, and promising outcomes. We present a case of a sutureless aortic valve replacement for a late failed David procedure, complicated by postoperative development of severe paravalvular regurgitation. We attempted off-label balloon post-dilation to improve expansion of the valve, however paravalvular regurgitation persisted. The patient underwent subsequent aortic valve replacement using a mechanical valve and experienced no further paravalvular leak.

Single and Double Lung Transplantation Have Equivalent Survival for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Several studies have described improved survival with double lung transplant (DLT) compared with single lung transplant (SLT) in pulmonary fibrosis. To avoid the innate selection bias of including patients exclusively listed for SLT or DLT, this study analyzed those deemed appropriate for either procedure at time of listing. METHODS: All consecutive adult lung transplants for idiopathic pulmonary fibrosis provided by the Scientific Registry of Transplant Recipients were retrospectively reviewed (2007-2017). Isolated lobar transplants (n = 11) or patients listed only for SLT (n = 1834) or DLT (n = 2372) were excluded. Group stratification was based on the ultimate procedure (SLT vs DLT). Group propensity matching was performed based on 24 recipient and donor characteristics. Recipient demographics, donor demographics, and outcomes were compared between groups. RESULTS: During the study period 45% (974/2179) and 55% (1205/2179) of patients ultimately received SLT and DLT, respectively. After propensity matching 466 matched patients remained in each group. SLT patients were less likely to require prolonged (>48 hours) ventilator support than DLT patients. There was also a trend toward reduced rates of posttransplant renal failure and hospital length of stay in SLT recipients. Whether analyzed by time of listing or time of transplant, survival was similar between groups. CONCLUSIONS: In recipients concurrently listed for SLT and DLT overall survival was similar regardless of the eventual procedure. These data suggest that the previously purported survival advantage for DLT may purely represent selection bias and should not preclude the use of SLT in appropriately selected idiopathic pulmonary fibrosis patients.

Mechanical Blood-Immersed Bearings in Continuous-Flow Rotary Blood Pumps.

Mechanical blood-immersed bearings have been used in many continuous-flow rotary blood pumps to reduce friction between relatively moving parts, but their use has been associated with a significant incidence of pump thrombosis. As newer cardiac assist devices with more advanced bearings become available, the rate of pump thrombosis will likely decrease. Nevertheless, it is important to understand the design limitations of mechanical bearings as pumps utilizing them are still in use as chronic support devices and especially in the acute setting for temporary support devices. A properly designed journal bearing should support the spinning rotor with no surface-to-surface contact between the bearing and journal surfaces. The journal continuously undergoes orbital motion within the bearing, which can be "stable" or "unstable." Unstable orbital motion causes the journal to move progressively off-center until it collides with the bearing, and even minor variations in manufacturing can create off-design operation and dynamic instability of the journal. Since blood is the lubricant in most clinically-used rotary blood pumps, lubricant viscosity can vary abruptly in response to changes in hematocrit or plasma protein concentration. Additionally, shear stress from the high-speed rotor can cause hemolysis and plasma protein denaturation. We reviewed theoretical design and operating principles of mechanical bearings and discuss why the phenomenon of mechanical bearing thrombosis may be an inherent design issue dependent on variables that are beyond the control of clinicians.

Impact of the Opioid Epidemic on Lung Transplantation: Donor, Recipient, and Discard Characteristics.

BACKGROUND: The national opioid epidemic may have expanded the donor pool for lung transplant, but concerns remain regarding infectious risks and allograft function. This study compared donor and recipient characteristics, outcomes, and reasons for organ discard between overdose death donors (ODDs) and all other mechanism-of-death donors. METHODS: Data on adult lung transplants from 2000 to 2017 were provided by the Scientific Registry of Transplant Recipients. Pulmonary allografts used in multiple organ transplants were excluded. Donor and recipient demographics, outcomes, and organ discard were analyzed with regards to ODDs since 2010. Discard analysis was limited to donors who had at least 1 organ transplanted but their pulmonary allografts discarded. RESULTS: From 2010 to 2017, 7.3% of lung transplants (962/13,196) were from ODDs, over a 3-fold increase from the 2.1% (164/7969) in 2000 to 2007. ODDs were younger but more likely to have a history of smoking and hepatitis C or an abnormal bronchoscopy finding. Overall survival was similar between ODD and non-ODD groups. ODDs of discarded pulmonary allografts were younger and more likely to be hepatitis C positive but were less likely to have a history of smoking than their non-ODD counterparts. CONCLUSIONS: Rates of ODD use in lung transplant have increased in accordance with the opioid epidemic, but there remains a significant pool of ODD pulmonary allografts with favorable characteristics that are discarded. With no significant difference in survival between ODD and non-ODD recipients, further expansion of this donor pool may be appropriate, and pulmonary allografts should not be discarded based solely on ODD status.

Early airway dehiscence: Risk factors and outcomes with the rising incidence of extracorporeal membrane oxygenation as a bridge to lung transplantation.

BACKGROUND: Anastomotic complications occur in 7% to 18% of lung transplant recipients, among which airway dehiscence (AD) is particularly catastrophic. Using multi-institutional registry data, this study compared preoperative recipient/donor risk factors and outcomes in patients with and without AD and analyzed the effect of extracorporeal membrane oxygenation (ECMO) on the incidence of AD. METHODS: Data on adult lung transplants from 2007 to 2017 were provided by the Scientific Registry of Transplant Recipients. Patients receiving isolated lobar transplantation and patients with unknown AD status were excluded. Multivariable logistic regression identified independent risk factors for AD. Kaplan-Meier curves and log-rank tests describe mortality and graft survival. RESULTS: Of 18 122 lung transplants, 275 (1.5%) experienced AD. While the incidence of ECMO steadily increased from 0.7% to 5.9% over the study period, the incidence of AD remained relatively constant. Multivariable analysis revealed recipient male gender and prolonged ( > 48 hours) posttransplant mechanical ventilation as independent predictive factors for AD, while advanced donor age and single left lung transplant were protective factors. Recipient chronic steroid use, recipient diabetes, donor diabetes, and donor smoking history were not predictive of AD. Mortality and graft failure were significantly worse in the AD group. CONCLUSIONS: Despite increased ECMO utilization, the incidence of AD has remained stable. Multiple independent risk factors for AD were identified and poor postoperative outcomes confirmed. However, many known impediments to wound healing such as recipient chronic steroid use, recipient and donor diabetes, and donor smoking were not identified as risk factors for AD, reinforcing the critical role of technical performance.

Impact of the Opioid Epidemic on Heart Transplantation: Donor Characteristics and Organ Discard.

BACKGROUND: The national opioid epidemic has expanded the donor pool for heart transplantation, but concerns remain regarding infectious risk and allograft function. This study compared donor and recipient characteristics, outcomes, and reasons for organ discard between overdose-death donors (ODDs) and donors with all other mechanism of death. METHODS: Data on adult cardiac transplants from 2010 to 2017 were provided by the Scientific Registry of Transplant Recipients. Cardiac allografts used in multiple organ transplantations were excluded. Recipient and donor characteristics and organ discard were analyzed with regard to ODDs. Kaplan-Meier curves and log-rank tests described mortality survival. RESULTS: A total of 1,710 of 15,904 (10.8%) cardiac transplantations were from ODDs, approximately a 10-fold increase from 2000 (1.2%). ODDs were more frequently older than 40 years of age (87.2% vs 70.1%; p < 0.001), had higher rates of substance abuse, were more likely hepatitis C positive (1.3% vs 0.2%; p < 0.001), and less frequently required inotropic support at the time of procurement (38.4% vs 44.8%; p < 0.001). Overall survival was not different between the groups (p = 0.066). Discarded ODD allografts were more likely to be hepatitis C positive (30.8% vs 5.3%; p < 0.001) and to be identified as conveying increased risk by the Public Health Services (63.3% vs 13.2%; p < 0.001), but they were less likely to be discarded because of a diseased organ state (28.2% vs 36.1%; p < 0.001). CONCLUSIONS: Rates of ODDs have increased corresponding with the worsening opioid epidemic. Even though ODDs have higher rates of hepatitis C, cardiac allograft quality indices are favorable, and recipient outcomes are similar when compared with non-ODDs, a finding indicating that greater use of this donor pool may be appropriate.