Towards Allograft Longevity: Leveraging Omics Technologies to Improve Heart Transplant Outcomes.

PURPOSE OF REVIEW: Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival. RECENT FINDINGS: Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care. The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT.

Diaphragmatic plication among lung transplant patients: A single-center experience.

BACKGROUND: There is lack of data reporting outcomes among patients needing diaphragmatic plication (DP) during or after lung transplantation (LT). We sought to assess the association of DP with post-transplant spirometry among other outcomes. METHODS: We included all patients who underwent LT between 2012 and 2016 (n = 324, mean age 56.3±13.4 years; M:F 198:126). We compared early and late outcomes based on the need for DP. RESULTS: The frequency of diaphragmatic dysfunction (DD) on pre-transplant fluoroscopy was 52.2%. A total of 38 DP procedures were performed among 37 patients (11.4% of LT patients). DP was done for anatomic (sizing or spacing issues) or functional indications (symptomatic DD). While patients with DP had significantly lower spirometry throughout the 3-year follow-up period, their slope of decline, functional assessments at the first annual visit, the risk of CLAD, and mortality were similar to patients without DP. A sub-group analysis limited to patients with restrictive lung diseases as the transplant indication had similar findings. CONCLUSIONS: Pre-transplant DD is common among LT candidates although it did not predict the need for DP. DP may be performed for functional or anatomic indications especially for addressing the donor-recipient size mismatch. Despite the lack of favorable effect on post-transplant spirometry, patients undergoing DP have acceptable and comparable early and late outcomes.

Impact of cerebrovascular accidents on lung transplant survival.

BACKGROUND: Cerebrovascular accidents (CVA) are a source of postoperative morbidity. Existing data on CVA after lung transplantation (LT) are limited. We aimed to evaluate the impact of CVA on LT survival. METHODS: A retrospective analysis of LT recipients at the University of Texas Southwestern Medical Center was performed. Data was obtained from the institutional thoracic transplant database between January 2012 and December 2018, which consisted of 476 patients. Patients were stratified by the presence of a postoperative CVA. Univariate comparisons of baseline characteristics, operative variables, and postoperative outcomes between the cohorts were performed. Survival was analyzed by Kaplan-Meier method. Aalen's additive regression model was utilized to assess mortality hazard over time. RESULTS: The incidence of CVA was 4.2% (20/476). Lung allocation score was higher in the CVA cohort (46.2 [41.7, 57.3] vs. 41.5 [35.8, 52.2], p = 0.04). There were no significant differences in operative variables. CVA patients had longer initial intensive care unit (ICU) stays (316 h [251, 557] vs. 124 [85, 218], p < 0.001) and longer length of stay (22 days [17, 53] vs. 15 [11, 26], p = 0.007). CVA patients required more ICU readmissions (35% vs. 15%, p = 0.02) and had a lower rates of home discharge (35% vs. 71%, p < 0.001). Thirty-day mortality was higher in the CVA cohort (20% vs. 1.3%, p < 0.001). Overall survival was lower in the CVA cohort (log rank p = 0.044). CONCLUSIONS: Postoperative CVA following LT was associated with longer ICU stays, more ICU readmissions, longer length of stay, and fewer home discharges. Thirty day and long-term mortality were significantly higher in the CVA group.

Myocardial Substrate Oxidation and Tricarboxylic Acid Cycle Intermediates During Hypothermic Machine Perfusion.

BACKGROUND: The optimal substrate for hypothermic machine perfusion preservation of donor hearts is unknown. Fatty acids, acetate, and ketones are preferred substrates of the heart during normothermic perfusion, but cannot replete the tricarboxylic acid (TCA) cycle directly. Propionate, an anaplerotic substrate, can replenish TCA cycle intermediates and may affect cardiac metabolism. The purpose of this study was to determine myocardial substrate preferences during hypothermic machine perfusion and to assess if an anaplerotic substrate was required to maintain the TCA cycle intermediate pool in perfused hearts. METHODS: Groups of rat hearts were perfused with carbon-13 (13C)-labeled substrates (acetate, ß-hydroxybutyrate, octanoate, with and without propionate) at low and high concentrations. TCA cycle intermediate concentrations, substrate selection, and TCA cycle flux were determined by gas chromatography/mass spectroscopy and 13C magnetic resonance spectroscopy. RESULTS: Acetate and octanoate were preferentially oxidized, whereas ß-hydroxybutyrate was a minor substrate. TCA cycle intermediate concentrations except fumarate were higher in substrate-containing perfusion groups compared with either the no-substrate perfusion group or the no-ischemia control group. CONCLUSIONS: The presence of an exogenous, oxidizable substrate is required to support metabolism in the cold perfused heart. An anaplerotic substrate is not essential to maintain the TCA cycle intermediate pool and support oxidative metabolism under these conditions.

Cardiac transplantation in adults with congenital heart disease: A single center case series.

BACKGROUND: Adult congenital heart disease (CHD) transplant recipients historically experienced worse survival early after transplantation. We aim to review updated trends in adult CHD transplantation. METHODS: We performed a single center case series of adult cardiac transplants from January 2013 through July 2020. Outcomes of patients with CHD were compared to non-CHD. The primary outcome was overall survival. Secondary outcomes included a variety of post-operative complications. RESULTS: 18/262 (7%) transplants were CHD recipients. CHD patients were younger with median age 41 (32-47) versus 58 (48-65) (P < .001). Fontan circulation for single ventricle physiology was present in 4/18 (22%) of CHD recipients, while 16/18 (89%) had systemic right ventricles. CHD recipients had higher rates of previous cardiovascular operations (94% vs. 51%, P < .001). 9/18 (50%) of CHD patients required reconstructive procedures at the time of transplant. Operative and cardiopulmonary bypass times were longer for the CHD cohort (7.5 h [6.6-8.5] vs. 5.6 h [4.6-7] P < .001) and (197 min [158-240] vs. 130 [105-167] P < .001), respectively. There were no differences in operative complications or survival between CHD and non-CHD recipients. CONCLUSIONS: These data highlight the added technical challenges of performing adult CHD transplants. However, similar outcomes can be achieved as for non-CHD recipients. SUMMARY: Modern advances in palliation of congenital heart defects (CHD) has led to increased survival into adulthood. Many of these patients require heart transplantation as adults. There are limited data on adult CHD transplantation. Historically, these patients have had worse perioperative outcomes with improved long-term survival. We retrospectively analyzed 262 heart transplants at a single center, 18 of which were for adult CHD. Here, we report our series of 18 CHD recipients. We detail the palliative history of all CHD patients and highlight the added technical challenges for each of the 18 patients at transplant. In our analysis, CHD patients had more prior cardiovascular surgeries as well as longer transplant operative and bypass times. Despite this, there were no differences in perioperative and long-term outcomes. We have added patient and institution specific data for transplanting patients with adult CHD. We hope that our experience will add to the growing body of literature on adult CHD transplantation.

Epidemiology and risk factors for varicella zoster virus reactivation in heart transplant recipients.

Heart transplant (HT) recipients are at higher risk of varicella zoster virus (VZV) reactivation. Risk factors for VZV reactivation are currently not well defined, impeding the ability to design and implement strategies to minimize the burden of this illness in this population. Automated data extraction tools were used to retrieve data from the electronic health record (EHR) of all adult HT recipients at our center between 2010 and 2016. Information from the Organ Procurement and Transplantation Network Standard Analysis and Research Files was merged with the extracted data. Potential cases were manually reviewed and adjudicated using consensus definitions. Cumulative incidence and risk factors for VZV reactivation in HT recipients were assessed by the Kaplan-Meier method and Cox modeling, respectively. In 203 HT recipients, the cumulative incidence of VZV reactivation at 8-years post-transplantation was 26.4% (95% CI: 17.8-38.0). The median time to VZV reactivation was 2.1 years (IQR, 1.5-4.1). Half (14/28) of the cases experienced post-herpetic neuralgia (PHN). Post-transplant CMV infection (HR 9.05 [95% CI: 3.76-21.77) and post-transplant pulse-dose steroids (HR 3.19 [95% CI: 1.05-9.68]) were independently associated with a higher risk of VZV reactivation in multivariable modeling. Identification of risk factors will aid in the development of targeted preventive strategies.

Cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on health care and cardiac surgery. We report cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic. METHODS: A detailed survey was sent to recruit participating adult cardiac surgery centers in North America. Data regarding cardiac surgeons' perceptions and changes in practice were analyzed. RESULTS: Our study comprises 67 institutions with diverse geographic distribution across North America. Nurses were most likely to be redeployed (88%), followed by advanced care practitioners (69%), trainees (28%), and surgeons (25%). Examining surgeon concerns in regard to COVID-19, they were most worried with exposing their family to COVID-19 (81%), followed by contracting COVID-19 (68%), running out of personal protective equipment (PPE) (28%), and hospital resources (28%). In terms of PPE conservation strategies among users of N95 respirators, nearly half were recycling via decontamination with ultraviolet light (49%), followed by sterilization with heat (13%) and at home or with other modalities (13%). Reuse of N95 respirators for 1 day (22%), 1 week (21%) or 1 month (6%) was reported. There were differences in adoption of methods to conserve N95 respirators based on institutional pandemic phase and COVID-19 burden, with higher COVID-19 burden institutions more likely to resort to PPE conservation strategies. CONCLUSIONS: The present study demonstrates the impact of COVID-19 on North American cardiac surgeons. Our study should stimulate further discussions to identify optimal solutions to improve workforce preparedness for subsequent surges, as well as facilitate the navigation of future healthcare crises.

Acute Kidney Injury in Patients Undergoing Cardiopulmonary Bypass for Lung Transplantation.

BACKGROUND: Cardiopulmonary bypass (CPB) is often used to support patients undergoing lung transplantation who are intolerant of anatomic manipulation or single lung ventilation during the procedure. However, CPB may be associated with adverse outcomes. We evaluated the hypothesis that CPB is associated with increased acute kidney injury (AKI) and postoperative mortality after lung transplantation. MATERIALS AND METHODS: This was a retrospective review of our institutional lung transplant database at the University of Texas Southwestern Medical Center from 2012 to 2018. Patients were grouped based on their need for CPB. The primary outcome was AKI within 48 h of transplantation, which was defined as Kidney Disease Improving Global Outcomes stage 1 or greater. Secondary outcomes included all-cause mortality. RESULTS: A total of 426 patients underwent lung transplantation with 39.0% (n = 166) requiring CPB. There were no differences in demographics and comorbidities, including baseline renal function, between CPB and no CPB. CPB use was higher in recipients with interstitial lung diseases and primary pulmonary hypertension. Median lung allocation score was higher in those needing CPB (47 [interquartile range, 40-59] versus 39 [interquartile range, 35-47]). Patients requiring CPB were significantly more likely to experience AKI (61.44% versus 36.5.3%, P < 0.01) and postoperative hemodialysis (6.6% versus 0.4%, P < 0.01). On multivariable analysis, CPB was significantly associated with postoperative AKI (odds ratio, 1.66; 95% CI, 1.01-2.75; P = 0.04). Thirty-day mortality was higher in patients undergoing CPB (4.2% versus 0.8%, P = 0.03). CONCLUSIONS: CPB for lung transplantation is associated with a higher incidence of AKI, renal failure requiring hemodialysis, and 30-d mortality. CPB should be used selectively for lung transplantation.

Incidence and variables associated with 30-day mortality after lung transplantation.

BACKGROUND: With the introduction of the lung allocation score (LAS), sicker patients are prioritized for lung transplantation (LT). There is a lack of data regarding variables independently associated with 30-day mortality after LT. METHODS: We queried the UNOS database for adult patients undergoing LT between 1989 and 2014. Patients with dual organ or previous transplantation and those with missing survival data were excluded. Mortality during the first 30 days after LT was the primary outcome variable. RESULTS: The yearly trends indicate a statistically significant reduction in the 30-day mortality during the study period (P < 0.001, overall mortality: 5.5%) which has continued in the post-LAS era (P = 0. 014, overall mortality: 3.6%). Among patients with 30-day mortality, "primary non-function" (n = 118, 72.8%) was reported as the most common etiology. Transplant indication of vascular diseases, history of non-transplant cardiac or lung surgery, mean pulmonary pressures >35 mm Hg, disabled functional status, ECMO support, high LAS, ischemic time >6 hours, and blunt injury as the mechanism of donor death are independently associated with 30-day mortality. CONCLUSION: The incidence of early mortality after LT continues to decline in the post-LAS era. Apart from the mechanism of donor death and ischemic time, early mortality appears to be primarily driven by the recipient characteristics.

Evaluation of current strategies for surveillance and management of donor-specific antibodies: Single-center study.

BACKGROUND: Although the presence of donor-specific antibodies (DSA) is known to impact lung allograft, limited data exist regarding DSA management. METHODS: We did a retrospective study at our center evaluating DSA management in adult lung transplant recipients undergoing lung transplantation between January 1, 2010 and June 30, 2014. Study follow-up was completed through October 2017. All recipients were stratified into 2 groups based on the presence or absence of DSA. Those with DSA were evaluated for the impact of treatment of DSA. The primary outcomes were postlung transplant survival and freedom from bronchiolitis obliterans syndrome (BOS), subset of chronic lung allograft dysfunction (CLAD). Simon-Makuch method was used to estimate overall survival and BOS-free survival to account for DSA as time-dependent covariate. Survival differences between the groups were analyzed using time-dependent Cox proportional hazards model. RESULTS: Sixty-four percent of 194 total subjects developed post-lung transplant DSA. Overall survival was different with worse survival in the DSA positive group that never cleared DSA (P = .002). BOS-free survival was lower, but did not reach significance in this group. Response to treatment was poor, with only 12 of 47 (25.5%) who received treatment demonstrating clearance of DSA. CONCLUSIONS: Donor-specific antibodies prevalence is high after lung transplantation. Clearance of DSA correlated with improved outcomes. Current therapeutic strategies against DSA are relatively ineffective. Multicenter collaborative studies will be required to evaluate current treatment strategies and other innovative modalities.

Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation).

Letermovir was approved by the Food and Drug Administration (FDA) in November 2017 for use in adult cytomegalovirus (CMV)-seropositive allogeneic stem cell transplant (SCT) recipients for primary prophylaxis of CMV infection and disease. We report off-label use of letermovir for secondary prophylaxis of genotype-confirmed ganciclovir-resistant cytomegalovirus (CMV) syndrome (UL 97 mutation [C603W]) in a heart transplant recipient initially treated with intravenous cidofovir followed by foscarnet, both discontinued due to unacceptable toxicities.

Predictors of outcome among patients on extracorporeal membrane oxygenation as a bridge to lung transplantation.

BACKGROUND: There is a lack of data regarding clinical variables associated with successful bridge to lung transplantation (LT) using extracorporeal membrane oxygenation (ECMO) support. METHODS: We reviewed the institutional database for patients supported with veno-venous (VV) or veno-arterial ECMO as a bridge to LT (n=25; mean age: 50.6±14.2 years). We recorded clinical and laboratory variables, findings on echocardiogram and development of organ dysfunction along with hospital and one-year survival. Variables were compared between patients successfully bridged to LT versus those who were not. RESULTS: The most common diagnostic group was interstitial lung disease (18/25, 72%). VV-ECMO was used in the majority (84%). Fifteen patients (60%) were successfully bridged to LT, and the majority were alive at 1 year (14/15, 93.3%). The presence of right ventricular systolic dysfunction on pre-ECMO echocardiogram was associated with increased risk of unsuccessful bridging (OR, 95% CI: 2.67, 1.01-6.99, P=.041). While on ECMO, trough albumin levels <2.5 gm%, peak blood urea nitrogen levels >35 mg/dL and positive fluid balance were also associated with failure to bridge to LT. CONCLUSIONS: Among patients awaiting LT, the presence of RV systolic dysfunction before ECMO initiation along with worsening renal functions, low albumin levels, and volume overload is associated with poor outcomes.

In-hospital cardiopulmonary arrests in patients with left ventricular assist devices.

UNLABELLED: Background: Basic and advanced cardiac life support guidelines do not address resuscitation of patients with continuous-flow (CF) left ventricular assist devices (LVADs). As the population of LVAD patients increases, it becomes important to understand how to provide emergency care to such patients. METHODS AND RESULTS: We retrospectively reviewed a consecutive series of patients with an implanted CF-LVAD who had an in-hospital cardiopulmonary arrest at our medical center from January 2011 to October 2013. We compared them with a matched cohort of patients without LVADs who had an inhospital cardiopulmonary arrest during the same time period. Code documentation was used to determine arrest characteristics, perfusion assessment techniques, and time to cardiopulmonary resuscitation (CPR) initiation. There were 415 in-hospital arrests during the study period, and 4% (n 5 16) occurred in patients with CF-LVADs. Response teams used various approaches to assess arterial perfusion, including palpation or Doppler of the arterial pulse and measurement of blood pressure by Doppler or arterial line. Nine of the 16 patients required CPR, but only 5 (56%) received CPR in !2 minutes. In the control group (n 5 32) of patients without an LVAD, 22 received CPR, which was initiated within 2 minutes in all (100%) of the patients. CONCLUSIONS: Cardiopulmonary arrests in LVAD patients accounted for 4% of all arrests in our center. We identified important time delays in CPR initiation, highlighting the need to develop resuscitation guidelines for this patient population.

Holmium:YAG laser bronchoscopy ablation of benign and malignant airway obstructions: an 8-year experience.

Patients suffering from severe tracheobronchial obstruction are vulnerable to dyspnea, respiratory failure, obstructive pneumonia, and death. Treatment with a holmium:YAG laser, an alternative to the neodymium:YAG laser, may provide symptomatic relief. This is the largest case series to date describing the application of the holmium:YAG laser via bronchoscopy for benign and malignant obstructive disease. The data were retrospectively collected from 99 patients, with either benign or malignant tracheobronchial obstruction, who underwent 261 interventional bronchoscopy procedures in the operating room with laser ablation between January 2004 and November 2011. Categorical variables were analyzed with the chi-square and Fisher's exact tests as appropriate in contingency tables, whereas Student's t-test was performed for comparison of continuous variables. Patient follow-up was concluded on September 15, 2013. The holmium:YAG laser was used in 261 procedures performed on 99 patients with either benign or malignant disease. Symptomatic improvement was demonstrated in 90 % of all benign etiology cases and 77 % of all malignant etiology cases. Within the benign and malignant subgroups, improvement was dependent on anatomical location rather than etiology of the lesion. Complications occurred in 2.3 % of the procedures, with mortality in less than 1 % of procedures. Results confirm the usefulness and safety of the holmium:YAG laser in the treatment of patients with severe benign and malignant obstructive tracheobronchial obstructions. The holmium:YAG laser is an appealing alternative to the neodymium:YAG laser.

Ventricular assist device using a thoracotomy-based implant technique: Multi-Center Implantation of the HeartMate 3 in Subjects With Heart Failure Using Surgical Techniques Other Than Full Median Sternotomy (HM3 SWIFT).

OBJECTIVES: The HeartMate 3 (Abbott) left ventricular assist device provides substantial improvement in long-term morbidity and mortality in patients with advanced heart failure. The Implantation of the HeartMate 3 in Subjects With Heart Failure Using Surgical Techniques Other Than Full Median Sternotomy study compares thoracotomy-based implantation clinical outcomes with standard median sternotomy. METHODS: We conducted a prospective, multicenter, single-arm study in patients eligible for HeartMate 3 implantation with thoracotomy-based surgical technique (bilateral thoracotomy or partial upper sternotomy with left thoracotomy). The composite primary end point was survival free of disabling stroke (modified Rankin score >3), or reoperation to remove or replace a malfunctioning device, or conversion to median sternotomy at 6-months postimplant (elective transplants were treated as a success). The primary end point (noninferiority, -15% margin) was assessed with >90% power compared with a propensity score-matched cohort (ratio 1:2) derived from the Multi-Center Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 continued access protocol. RESULTS: The study enrolled 102 patients between December 2020 and July 2022 in the thoracotomy-based arm at 23 North American centers. Follow-up concluded in December 2022. In the Implantation of the HeartMate 3 in Subjects With Heart Failure Using Surgical Techniques Other Than Full Median Sternotomy study group, noninferiority criteria was met (absolute between-group difference, -1.2%; Farrington Manning lower 1-sided 95% CI, -9.3%; P < .0025) and event-free survival was not different (85.0% vs 86.2%; hazard ratio, 1.01; 95% CI, 0.58-2.10). Length of stay with thoracotomy-based implant was longer (median, 20 vs 17 days; P = .03). No differences were observed for blood product utilization, adverse events (including right heart failure), functional status, and quality of life between cohorts. CONCLUSIONS: Thoracotomy-based implantation of the HeartMate 3 left ventricular assist device is noninferior to implantation via standard full sternotomy. This study supports thoracotomy-based implantation as an additional standard for surgical implantation of the HeartMate 3 left ventricular assist device.

Tolerability of sirolimus: a decade of experience at a single cardiac transplant center.

Sirolimus is used in cardiac transplant recipients to prevent rejection, progression of cardiac allograft vasculopathy, and renal dysfunction. However, sirolimus has many potential side effects and its tolerability when used outside of clinical trials is not well established. We describe a decade of experience with sirolimus in cardiac transplant recipients at our institution. We retrospectively reviewed records of all adult cardiac transplant recipients living between September 1999 and February 2010 (n = 329) and identified 67 patients (20%) who received sirolimus. The indications for sirolimus were cardiac allograft vasculopathy (67%), renal dysfunction (25%), rejection (4%), and intolerability of tacrolimus (3%). One-third of patients discontinued sirolimus at a median (25th, 75th percentiles) of 0.9 (0.2, 1.6) yr of duration. Over 70% of subjects experienced an adverse event attributed to sirolimus. Adverse events were associated with higher average sirolimus levels (9.1 ng/mL vs. 7.1 ng/mL, p = 0.004). We conclude that sirolimus is frequently used in cardiac transplant recipients (20%) and commonly causes side effects, often necessitating discontinuation. Higher average sirolimus levels were associated with adverse events, suggesting that tolerability may improve if levels are maintained within the lower end of the current therapeutic range; however, the improvement in tolerability would need to be balanced with the potential for decreased efficacy.

Spatial distribution and network morphology of epicardial, endocardial, interstitial, and Purkinje cell-associated elastin fibers in porcine left ventricle.

Cardiac extracellular matrices (ECM) play crucial functional roles in cardiac biomechanics. Previous studies have mainly focused on collagen, the major structural ECM in heart wall. The role of elastin in cardiac mechanics, however, is poorly understood. In this study, we investigated the spatial distribution and microstructural morphologies of cardiac elastin in porcine left ventricles. We demonstrated that the epicardial elastin network had location- and depth-dependency, and the overall epicardial elastin fiber mapping showed certain correlation with the helical heart muscle fiber architecture. When compared to the epicardial layer, the endocardial layer was thicker and has a higher elastin-collagen ratio and a denser elastin fiber network; moreover, the endocardial elastin fibers were finer and more wavy than the epicardial elastin fibers, all suggesting various interface mechanics. The myocardial interstitial elastin fibers co-exist with the perimysial collagen to bind the cardiomyocyte bundles; some of the interstitial elastin fibers showed a locally aligned, hinge-like structure to connect the adjacent cardiomyocyte bundles. This collagen-elastin combination reflects an optimal design in which the collagen provides mechanical strength and elastin fibers facilitate recoiling during systole. Moreover, cardiac elastin fibers, along with collagen network, closely associated with the Purkinje cells, indicating that this ECM association could be essential in organizing cardiac Purkinje cells into "fibrous" and "branching" morphologies and serving as a protective feature when Purkinje fibers experience large deformations in vivo. In short, our observations provide a structural basis for future in-depth biomechanical investigations and biomimicking of this long-overlooked cardiac ECM component.

Maintenance of pig brain function under extracorporeal pulsatile circulatory control (EPCC).

Selective vascular access to the brain is desirable in metabolic tracer, pharmacological and other studies aimed to characterize neural properties in isolation from somatic influences from chest, abdomen or limbs. However, current methods for artificial control of cerebral circulation can abolish pulsatility-dependent vascular signaling or neural network phenomena such as the electrocorticogram even while preserving individual neuronal activity. Thus, we set out to mechanically render cerebral hemodynamics fully regulable to replicate or modify native pig brain perfusion. To this end, blood flow to the head was surgically separated from the systemic circulation and full extracorporeal pulsatile circulatory control (EPCC) was delivered via a modified aorta or brachiocephalic artery. This control relied on a computerized algorithm that maintained, for several hours, blood pressure, flow and pulsatility at near-native values individually measured before EPCC. Continuous electrocorticography and brain depth electrode recordings were used to evaluate brain activity relative to the standard offered by awake human electrocorticography. Under EPCC, this activity remained unaltered or minimally perturbed compared to the native circulation state, as did cerebral oxygenation, pressure, temperature and microscopic structure. Thus, our approach enables the study of neural activity and its circulatory manipulation in independence of most of the rest of the organism.

Glucose is an ineffective substrate for preservation of machine perfused donor hearts.

BACKGROUND: Machine perfusion with oxygenated preservation solution can support donor heart metabolism but the preservation solution should contain an oxidizable substrate to improve cellular energetics. We hypothesized that myocardial metabolism can be influenced by exogenous substrates in the preservation solution. METHODS: Eight groups of isolated rat hearts (n = 4/group) were perfused with University of Wisconsin Machine Perfusion Solution containing carbon 13 ((13)C) labeled glucose (2.5 mM, 5 mM, 10 mM, or 20 mM) or pyruvate (5 mM, 10 mM, 20 mM, or 40 mM). Hearts were perfused at 0.5 mL/min for 6 h at 8°C, and myocardial oxygen consumption (MVO(2)) was measured. At end-perfusion, magnetic resonance spectroscopy was performed on ventricular extracts to determine the contribution of exogenous, labeled substrate to glycolysis and oxidative metabolism by (13)C incorporation into metabolic intermediates. RESULTS: MVO(2) and perfusion conditions did not differ amongst groups. Exogenous glucose was metabolized by anaerobic glycolysis and contributed little to oxidative metabolism as measured by (13)C incorporation into metabolic intermediates. Pyruvate led to greater lactate enrichment via the lactate dehydrogenase reaction. Enrichment of tricarboxylic acid (TCA) cycle intermediates was also greater in all pyruvate groups compared with glucose-containing groups (P < 0.05). Anaplerosis was increased in all pyruvate groups (P < 0.05). CONCLUSIONS: The preservation solution substrate composition influences myocardial substrate metabolism during machine perfusion preservation of donor hearts. Exogenous glucose is a minor substrate in machine perfused myocardium, is primarily metabolized by glycolysis and does not contribute appreciably to oxidative metabolism. Pyruvate appears more effective in supporting myocardial metabolism. Further experiments examining the influences of substrate modifications on reperfusion function are warranted.