Postoperative Troponin Levels in Children Undergoing Open Heart Surgery With and Without Coronary Intervention.

We aimed to characterize the ranges, temporal trends, influencing factors, and prognostic significance of postoperative troponin levels after congenital heart surgery. This single-center retrospective study included patients from 2006 to 2021 who had ≥ 1 postoperative troponin-T measurement collected within 96 h of congenital heart surgery (CHS). Patients were grouped as Anomalous Aortic Origin of the Coronary Artery-"AAOCA repair," or congenital heart surgery with "Other Coronary Interventions" other than AAOCA repair, or "No Coronary Intervention." In each group, information on concomitant surgery requiring one or more of the following-atriotomy, ventriculotomy, right ventricular muscle bundle resection, and/or septal myectomy-was collected. Clinical correlates of troponin values were analyzed in three postoperative windows: < 8, 8-24, and 24-48 h. The highest median [range] troponin levels (ng/mL) for the samples were 0.34 [0.06, 1.32] at < 8 h for "AAOCA repair," 1.35 [0.14, 12.0] at < 8 h for those undergoing CHS with "Other Coronary Interventions," and 0.87 [0.06, 25.1] at 8-24 h for those undergoing CHS with "No Coronary Interventions." Atriotomy was associated with higher median troponin levels in the AAOCA group at < 8 h (0.40 [0.31, 0.77] vs. 0.29 [0.17, 0.54], P = 0.043) and in the Other Coronary Intervention group at 8-24 h (1.67 [1.04, 2.63] vs. 0.40 [0.19, 1.32], P = 0.002). Patients experiencing major postoperative complications (vs. those who did not) had higher troponin levels in the AAOCA group as early as 8-24 h (0.36 [0.24, 0.57] vs. 0.21 [0.14, 0.33], P = 0.03). Similar findings were noted in the Coronary Intervention (2.20 [1.34, 3.90] vs. 1.11 [0.51, 2.90], P = 0.028) and No Coronary Intervention (2.2 [1.49, 15.1] vs. 0.74 [0.40, 2.34], P = 0.027) groups but earlier at < 8 h. In the AAOCA group, 2/18 (11%) troponin outliers experienced cardiac arrest in comparison to 0/80 (0%) non-outliers (P = 0.032). In the Other Coronary Intervention group, troponin outliers had longer median times to ICU discharge (10 vs. 4 days) and hospital discharge (21 vs. 10 days) (both P < 0.001). Postoperative troponin levels depend on a multitude of factors and may have prognostic value in patients undergoing congenital heart surgery with coronary interventions.

Contemporary Socioeconomic and Childhood Opportunity Disparities in Congenital Heart Surgery.

BACKGROUND: While singular measures of socioeconomic status have been associated with outcomes after surgery for congenital heart disease, the multifaceted pathways through which a child's environment impacts similar outcomes remain incompletely characterized. We sought to evaluate the association between childhood opportunity level and adverse outcomes after congenital heart surgery. METHODS: Data from patients undergoing congenital cardiac surgery from January 2011 to January 2020 at a quaternary referral center were retrospectively reviewed. Outcomes of interest included predischarge (early) mortality or transplant, postoperative hospital length-of-stay, inpatient cost of hospitalization, postdischarge (late) mortality or transplant, and late unplanned reintervention. The primary predictor was a US census tract-based, nationally-normed composite metric of contemporary child neighborhood opportunity comprising 29 indicators across 3 domains (education, health and environment, and socioeconomic), categorized as very low, low, moderate, high, and very high. Associations between childhood opportunity level and outcomes were evaluated using logistic regression (early mortality), generalized linear (length-of-stay and cost), Cox proportional hazards (late mortality), or competing risk (late reintervention) models, adjusting for baseline patient-related factors, case complexity, and residual lesion severity. RESULTS: Of 6133 patients meeting entry criteria, the median age was 2.0 years (interquartile range, 3.6 months-8.3 years). There were 124 (2.0%) early deaths or transplants, the median postoperative length-of-stay was 7 days (interquartile range, 5-13 days), and the median inpatient cost was $76 000 (interquartile range, $50 000-130 000). No significant association between childhood opportunity level and early mortality or transplant was observed (P=0.21). On multivariable analysis, children with very low and low opportunity had significantly longer length-of-stay and incurred higher costs compared with those with very high opportunity (all P<0.05). Of 6009 transplant-free survivors of hospital discharge, there were 175 (2.9%) late deaths or transplants, and 1008 (16.8%) reinterventions at up to 10.5 years of follow-up. Patients with very low opportunity had a significantly greater adjusted risk of late death or transplant (hazard ratio, 1.7 [95% CI, 1.1-2.6]; P=0.030) and reintervention (subdistribution hazard ratio, 1.9 [95% CI, 1.5-2.3]; P<0.001), versus those with very high opportunity. CONCLUSIONS: Childhood opportunity level is independently associated with adverse outcomes after congenital heart surgery. Children from resource-limited settings thus constitute an especially high-risk cohort that warrants closer surveillance and tailored interventions.

Direct Cardiac Compression Devices to Augment Heart Biomechanics and Function.

The treatment of end-stage heart failure has evolved substantially with advances in medical treatment, cardiac transplantation, and mechanical circulatory support (MCS) devices such as left ventricular assist devices and total artificial hearts. However, current MCS devices are inherently blood contacting and can lead to potential complications including pump thrombosis, hemorrhage, stroke, and hemolysis. Attempts to address these issues and avoid blood contact led to the concept of compressing the failing heart from the epicardial surface and the design of direct cardiac compression (DCC) devices. We review the fundamental concepts related to DCC, present the foundational devices and recent devices in the research and commercialization stages, and discuss the milestones required for clinical translation and adoption of this technology.

Impact of Residual Lesion Severity on Neurodevelopmental Outcomes Following Congenital Heart Surgery in Infancy and Childhood.

Children with congenital heart disease are at increased risk of neurodevelopmental delay throughout their lifespan. This risk is exacerbated following congenital heart surgery (CHS) in infancy. However, there are few modifiable risk factors for postoperative neurodevelopmental delay. In this study, we assessed the Residual Lesion Score (RLS), a quality assessment metric that evaluates residual lesion severity following CHS, as a predictor of neurodevelopmental delay. This was a single-center, retrospective review of patients who underwent CHS from 01/2011 to 03/2021 and post-discharge neurodevelopmental evaluation from 12 to 42 months of age using the Bayley Scales of Infant Development, 3rd Edition (BSID-III). RLS was assigned per published criteria: RLS 1, no residua; RLS 2, minor residua; and RLS 3, major residua or pre-discharge reintervention. Associations between RLS and BSID-III scores, as well as trends in neurodevelopmental outcomes over time, were evaluated. Of 517 patients with median age at neurodevelopmental testing of 20.0 (IQR 18.0-22.7) months, 304 (58.8%), 146 (28.2%), and 67 (13.0%) were RLS 1, 2, and 3, respectively. RLS 3 patients had significantly lower scaled scores in the cognitive, receptive, and expressive communication, and fine and gross motor domains, compared with RLS 1 patients. Multivariable models accounted for 21.5%-31.5% of the variation in the scaled scores, with RLS explaining 1.4-7.3% of the variation. In a subgroup analysis, RLS 3 patients demonstrated relatively fewer gains in cognitive, expressive communication, and gross motor scores over time (all p < 0.05). In conclusion, RLS 3 patients are at increased risk for neurodevelopmental delay, warranting closer follow-up and greater developmental support for cognitive, language, and motor skills soon after surgery.

Mechanical strain triggers endothelial-to-mesenchymal transition of the endocardium in the immature heart.

BACKGROUND: Endothelial-to-mesenchymal-transition (EndMT) plays a major role in cardiac fibrosis, including endocardial fibroelastosis but the stimuli are still unknown. We developed an endothelial cell (EC) culture and a whole heart model to test whether mechanical strain triggers TGF-ß-mediated EndMT. METHODS: Isolated ECs were exposed to 10% uniaxial static stretch for 8 h (stretch) and TGF-ß-mediated EndMT was determined using the TGF-ß-inhibitor SB431542 (stretch + TGF-ß-inhibitor), BMP-7 (stretch + BMP-7) or losartan (stretch + losartan), and isolated mature and immature rats were exposed to stretch through a weight on the apex of the left ventricle. Immunohistochemical staining for double-staining with endothelial markers (VE-cadherin, PECAM1) and mesenchymal markers (αSMA) or transcription factors (SLUG/SNAIL) positive nuclei was indicative of EndMT. RESULTS: Stretch-induced EndMT in ECs expressed as double-stained ECs/total ECs (cells: 46 ± 13%; heart: 15.9 ± 2%) compared to controls (cells: 7 ± 2%; heart: 3.1 ± 0.1; p < 0.05), but only immature hearts showed endocardial EndMT. Inhibition of TGF-ß decreased the number of double-stained cells significantly, comparable to controls (cells/heart: control: 7 ± 2%/3.1 ± 0.1%, stretch: 46 ± 13%/15 ± 2%, stretch + BMP-7: 7 ± 2%/2.9 ± 0.1%, stretch + TGF-ß-inhibitor (heart only): 5.2 ± 1.3%, stretch + losartan (heart only): 0.89 ± 0.1%; p < 0.001 versus stretch). CONCLUSIONS: Endocardial EndMT is an age-dependent consequence of increased strain triggered by TGF- ß activation. Local inhibition through either rebalancing TGF-ß/BMP or with losartan was effective to block EndMT. IMPACT: Mechanical strain imposed on the immature LV induces endocardial fibroelastosis (EFE) formation through TGF-ß-mediated activation of endothelial-to-mesenchymal transition (EndMT) in endocardial endothelial cells but has no effect in mature hearts. Local inhibition through either rebalancing the TGF-ß/BMP pathway or with losartan blocks EndMT. Inhibition of endocardial EndMT with clinically applicable treatments may lead to a better outcome for congenital heart defects associated with EFE.

Endothelial-to-Mesenchymal Transition as Underlying Mechanism for the Formation of Double-Chambered Right Ventricle.

Double-chambered right ventricle (DCRV) is a progressive division of the right ventricular outflow tract (RVOT) often associated with a subaortic ventricular defect (VSD). The septation is caused by a mixture of hypertrophied muscle bundles and fibrous tissue, whereof the latter is of unclear pathogenesis. Our group has previously reported that flow disturbances lead to formation of fibroelastic tissue through a process called endothelial-to-mesenchymal transition (EndMT) but it is unclear whether the same mechanism exists in the RV. Tissue from patients undergoing repair of DCRV was examined to identify the histomorphological substrate of this tissue. Demographic and pre-/post-operative echocardiographic data were collected from nine patients undergoing surgery for DCRV. RVOTO tissue samples were histologically analyzed for myocardial hypertrophy, fibrosis, elastin content, and active EndMT (immunohistochemical double-staining for endothelial and mesenchymal markers and transcription factors Slug/Snail) and compared to four healthy controls. Indication for surgery were symptoms and progressive RVOT gradients. A highly turbulent flow jet through the RVOTO and VSD was observed in all patients with a preoperative median RVOT peak gradient of 77 mmHg (IQR 55.0-91.5), improved to 6 mmHg (IQR 4.5-17) postoperatively. Histological analysis revealed muscle and thick infiltratively growing fibroelastic tissue. EndMT was confirmed as underlying patho-mechanism of this fibroelastic tissue but the degree of myocardial hypertrophy was not different compared to controls (P = 0.08). This study shows for the first time that an invasive fibroelastic remodeling processes of the endocardium into the underlying myocardium through activation of EndMT contributes to the septation of the RVOT.

Digital solution for follow-up in congenital cardiac surgery.

BACKGROUND: In this era of public scrutiny, there is an ongoing need for innovative methods for patient follow-up. OBJECTIVES: As part of a quality initiative, we developed an automated post-operative follow-up system for patients following discharge after cardiac surgery at Boston Children's Hospital. METHODS: Discharge Communication (DisCo) is a web-based system developed at Boston Children's Hospital. An automated text and e-mail with a link to a health status survey are sent at 30 days and 1 year post-discharge in English/Spanish. If there is no response, surveys are completed via phone calls to the patient/patient's physician or chart review. Responses are stored in the DisCo database and the patient's medical record. Patients who underwent cardiac surgery and survived to hospital discharge from October, 2016 received the surveys. RESULTS: Overall, 3345 30-day and 2563 1-year surveys were sent between October, 2016 and June, 2020. Of 3345 30-day surveys, there were 3191 responses (95%). Of 2563 1-year surveys, there were 1807 responses (71%). Most patients/families responded directly to the link at 30 days (65% for paediatrics/75% for adults) and at 1 year (72% for paediatrics/78% for adults). Multi-variable logistic regression revealed that higher complexity of cardiac lesion, presence of major non-cardiac anomalies and presence of major residua were associated with readmission and catheter/surgical reinterventions. Non-cardiac anomalies were associated with increased need for services for learning, development or behaviour. CONCLUSIONS: DisCo provides a successful web-based health status assessment of patients following congenital cardiac surgery. It helps to identify high-risk patients who need closer follow-up.

Human endothelial colony-forming cells provide trophic support for pluripotent stem cell-derived cardiomyocytes via distinctively high expression of neuregulin-1.

The search for a source of endothelial cells (ECs) with translational therapeutic potential remains crucial in regenerative medicine. Human blood-derived endothelial colony-forming cells (ECFCs) represent a promising source of autologous ECs due to their robust capacity to form vascular networks in vivo and their easy accessibility from peripheral blood. However, whether ECFCs have distinct characteristics with translational value compared to other ECs remains unclear. Here, we show that vascular networks generated with human ECFCs exhibited robust paracrine support for human pluripotent stem cell-derived cardiomyocytes (iCMs), significantly improving protection against drug-induced cardiac injury and enhancing engraftment at ectopic (subcutaneous) and orthotopic (cardiac) sites. In contrast, iCM support was notably absent in grafts with vessels lined by mature-ECs. This differential trophic ability was due to a unique high constitutive expression of the cardioprotective growth factor neuregulin-1 (NRG1). ECFCs, but not mature-ECs, were capable of actively releasing NRG1, which, in turn, reduced apoptosis and increased the proliferation of iCMs via the PI3K/Akt signaling pathway. Transcriptional silencing of NRG1 abrogated these cardioprotective effects. Our study suggests that ECFCs are uniquely suited to support human iCMs, making these progenitor cells ideal for cardiovascular regenerative medicine.

Bilateral Erector Spinae Blocks Decrease Perioperative Opioid Use After Pediatric Cardiac Surgery.

OBJECTIVE: The present study examined the feasibility and efficacy of continuous bilateral erector spinae blocks for post-sternotomy pain in pediatric cardiac surgery. DESIGN: Prospective cohort study; patients were retrospectively matched 1:2 to control patients. Conditional logistic regression was used to compare dichotomous outcomes, and generalized linear models were used for continuous measures, both accounting for clusters. SETTING: Quaternary children's hospital, university setting. PARTICIPANTS: The study comprised 10 children ages five-to-17 years undergoing elective cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: Ultrasound-guided bilateral erector spinae blocks at the conclusion of the cardiac surgical procedure, with postoperative infusion of ropivacaine until chest tube removal. Postoperative management otherwise followed standardized guidelines. MEASUREMENTS AND MAIN RESULTS: Patient characteristics were similar in the two groups. The median time to completion of the bilateral blocks was 16.0 minutes (interquartile range [IQR] 14.8-19.3), and no major adverse events were identified. Pain scores were low in both groups. Postoperative opioid use at 48 hours, rendered as oral morphine equivalents, was significantly reduced in the patients receiving the blocks. Cluster-adjusted squared-root-transformed means ± standard error were 0.89 ± 0.06 mg/kg for patients receiving the blocks versus 1.05 ± 0.06 mg/kg for control patients (p = 0.04; raw medians 0.81 [IQR 0.41-1.04] v 1.10 [IQR 0.78-1.35] mg/kg, respectively). There were no differences in recovery metrics, length of stay, or complications. CONCLUSIONS: Bilateral erector spinae blocks were associated with a reduction in opioid use in the first 48 hours after pediatric cardiac surgery compared with a matched cohort from the enhanced recovery program. Larger studies are needed to determine whether this can result in an improvement in recovery and patient satisfaction.

Mitochondrial transplantation by intra-arterial injection for acute kidney injury.

Acute kidney injury is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury were investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon catheters. Following 60 min of ischemia, the balloon catheters were deflated and animals received either autologous mitochondria suspended in vehicle or vehicle alone, delivered as a single bolus to the renal arteries. The injected mitochondria were rapidly taken up by the kidney and were distributed throughout the tubular epithelium of the cortex and medulla. There were no safety-related issues detected with mitochondrial transplantation. Following 24 h of reperfusion, estimated glomerular filtration rate and urine output were significantly increased while serum creatinine and blood urea nitrogen were significantly decreased in swine that received mitochondria compared with those that received vehicle. Gross anatomy, histopathological analysis, acute tubular necrosis scoring, and transmission electron microscopy showed that the renal cortex of the vehicle-treated group had extensive coagulative necrosis of primarily proximal tubules, while the mitochondrial transplanted kidney showed only patchy mild acute tubular injury. Renal cortex IL-6 expression was significantly increased in vehicle-treated kidneys compared with the kidneys that received mitochondrial transplantation. These results demonstrate that mitochondrial transplantation by intra-arterial injection provides renal protection from ischemia-reperfusion injury, significantly enhancing renal function and reducing renal damage.

Mitochondrial transplantation enhances murine lung viability and recovery after ischemia-reperfusion injury.

The most common cause of acute lung injury is ischemia-reperfusion injury (IRI), during which mitochondrial damage occurs. We have previously demonstrated that mitochondrial transplantation is an efficacious therapy to replace or augment mitochondria damaged by IRI, allowing for enhanced muscle viability and function in cardiac tissue. Here, we investigate the efficacy of mitochondrial transplantation in a murine lung IRI model using male C57BL/6J mice. Transient ischemia was induced by applying a microvascular clamp on the left hilum for 2 h. Upon reperfusion mice received either vehicle or vehicle-containing mitochondria either by vascular delivery (Mito V) through the pulmonary artery or by aerosol delivery (Mito Neb) via the trachea (nebulization). Sham control mice underwent thoracotomy without hilar clamping and were ventilated for 2 h before returning to the cage. After 24 h recovery, lung mechanics were assessed and lungs were collected for analysis. Our results demonstrated that at 24 h of reperfusion, dynamic compliance and inspiratory capacity were significantly increased and resistance, tissue damping, elastance, and peak inspiratory pressure (Mito V only) were significantly decreased (P < 0.05) in Mito groups as compared with their respective vehicle groups. Neutrophil infiltration, interstitial edema, and apoptosis were significantly decreased (P < 0.05) in Mito groups as compared with vehicles. No significant differences in cytokines and chemokines between groups were shown. All lung mechanics results in Mito groups except peak inspiratory pressure in Mito Neb showed no significant differences (P > 0.05) as compared with Sham. These results conclude that mitochondrial transplantation by vascular delivery or nebulization improves lung mechanics and decreases lung tissue injury.

Mitochondrial transplantation ameliorates acute limb ischemia.

OBJECTIVE: Acute limb ischemia (ALI), the most challenging form of ischemia-reperfusion injury (IRI) in skeletal muscle tissue, leads to decreased skeletal muscle viability and limb function. Mitochondrial injury has been shown to play a key role in skeletal muscle IRI. In previous studies, we have demonstrated that mitochondrial transplantation (MT) is an efficacious therapeutic strategy to replace or to augment mitochondria damaged by IRI, allowing enhanced muscle viability and function in cardiac tissue. In this study, we investigated the efficacy of MT in a murine ALI model. METHODS: C57BL/6J mice (male, 10-12 weeks) were used in a model of ALI. Ischemia was induced by applying a tourniquet on the left hindlimb. After 2 hours of ischemia, the tourniquet was released, and reperfusion of the hindlimb was re-established; either vehicle alone (n = 15) or vehicle containing mitochondria (n = 33) was injected directly into all the muscles of the hindlimb. Mitochondria were delivered at concentrations of 1 × 106 to 1 × 109 per gram wet weight to each muscle, and the animals were allowed to recover. Sham mice received no ischemia or injections but were anesthetized for 2 hours and allowed to recover. After 24 hours of recovery, limb function was assessed by DigiGait (Mouse Specifics Inc, Boston, Mass), and animals were euthanized; the gastrocnemius, soleus, and vastus medialis muscles were collected for analysis. RESULTS: After 24 hours of hindlimb reperfusion, infarct size (percentage of total mass) and apoptosis were significantly decreased (P < .001, each) in the gastrocnemius, soleus, and vastus medialis muscles in MT mice compared with vehicle mice for all mitochondrial concentrations (1 × 106 to 1 × 109 per gram wet weight). DigiGait analysis at 24 hours of reperfusion showed that percentage shared stance time was significantly increased (P < .001) and stance factor was significantly decreased (P = .001) in vehicle compared with MT and sham mice. No significant differences in percentage shared stance time (P = .160) or stance factor (P = .545) were observed between MT and sham mice. CONCLUSIONS: MT ameliorates skeletal muscle injury and enhances hindlimb function in the murine model of ALI.

A Multi-Mode System for Myocardial Functional and Physiological Assessment during Ex Situ Heart Perfusion.

Ex situ heart perfusion (ESHP) has proven to be an important and valuable step toward better preservation of donor hearts for heart transplantation. Currently, few ESHP systems allow for a convenient functional and physiological evaluation of the heart. We sought to establish a simple system that provides functional and physiological assessment of the heart during ESHP. The ESHP circuit consists of an oxygenator, a heart-lung machine, a heater-cooler unit, an anesthesia gas blender, and a collection funnel. Female Yorkshire pig hearts (n = 10) had del Nido cardioplegia (4°C) administered, excised, and attached to the perfusion system. Hearts were perfused retrogradely into the aortic root for 2 hours before converting the system to an isovolumic mode or a working mode for further 2 hours. Blood samples were analyzed to measure metabolic parameters. During the isovolumic mode (n = 5), a balloon inserted in the left ventricular (LV) cavity was inflated so that an end-diastolic pressure of 6-8 mmHg was reached. During the working mode (n = 5), perfusion in the aortic root was redirected into left atrium (LA) using a compliance chamber which maintained an LA pressure of 6-8 mmHg. Another compliance chamber was used to provide an afterload of 40-50 mmHg. Hemodynamic and metabolic conditions remained stable and consistent for a period of 4 hours of ESHP in both isovolumic mode (LV developed pressure: 101.0 ± 3.5 vs. 99.7 ± 6.8 mmHg, p = .979, at 2 and 4 hours, respectively) and working mode (LV developed pressure: 91.0 ± 2.6 vs. 90.7 ± 2.5 mmHg, p = .942, at 2 and 4 hours, respectively). The present study proposed a novel ESHP system that enables comprehensive functional and metabolic assessment of large mammalian hearts. This system allowed for stable myocardial function for up to 4 hours of perfusion, which would offer great potential for the development of translational therapeutic protocols to improve dysfunctional donated hearts.

Impact of surgical pulmonary valve replacement on ventricular strain and synchrony in patients with repaired tetralogy of Fallot: a cardiovascular magnetic resonance feature tracking study.

BACKGROUND: In patients with repaired tetralogy of Fallot (TOF), a better understanding of the impact of surgical pulmonary valve replacement (PVR) on ventricular mechanics may lead to improved indications and outcomes. Therefore, we used cardiovascular magnetic resonance (CMR) feature tracking analysis to quantify ventricular strain and synchrony in repaired TOF patients before and after PVR. METHODS: Thirty-six repaired TOF patients (median age 22.4 years) prospectively underwent CMR a mean of 4.5 ± 3.8 months before PVR surgery and 7.3 ± 2.1 months after PVR surgery. Feature tracking analysis on cine steady-state free precession images was used to measure right ventricular (RV) and left ventricular (LV) circumferential strain from short-axis views at basal, mid-ventricular, and apical levels; and longitudinal strain from 4-chamber views. Intraventricular synchrony was quantified using the maximum difference in time-to-peak strain, the standard deviation of the time-to-peak, and cross correlation delay (CCD) metrics; interventricular synchrony was assessed using the CCD metric. RESULTS: Following PVR, RV end-diastolic volume, end-systolic volume, and ejection fraction declined, and LV end-diastolic volume and end-systolic volume both increased with no significant change in the LV ejection fraction. LV global basal and apical circumferential strains, and basal synchrony improved. RV global circumferential and longitudinal strains were unchanged, and there was a varied impact on synchrony across the locations. Interventricular synchrony worsened at the midventricular level but was unchanged at the base and apex, and on 4-chamber views. CONCLUSIONS: Surgical PVR in repaired TOF patients led to improved LV global strain and no change in RV global strain. LV and RV synchrony parameters improved or were unchanged, and interventricular synchrony worsened at the midventricular level.

Management of Systemic Right Ventricular Failure in Patients With Congenitally Corrected Transposition of the Great Arteries.

In recent decades, significant progress has been made in the diagnosis and management of congenitally corrected transposition of the great arteries (ccTGA). Nevertheless, gradual dysfunction and failure of the right ventricle (RV) in the systemic circulation remain the main contributors to mortality and disability for patients with ccTGA, especially after adolescence. Anatomic repair of ccTGA effectively resolves the problem of failure of the systemic RV and has good early and midterm results. However, this strategy is applicable primarily in infants and children up to their teens and has associated risks and limitations, and new challenges can arise in the late postoperative period. Patients with ccTGA manifesting progressive systemic RV dysfunction beyond adolescence represent the major challenge. Several palliative options such as cardiac resynchronization therapy, tricuspid valve repair or replacement, pulmonary artery banding, and implantation of an assist device into the systemic RV can be used to improve functional status and to delay the progression of ventricular dysfunction in patients who are not suitable for anatomic correction of ccTGA. For adult patients with severe systemic RV failure, heart transplantation currently remains the only long-term lifesaving procedure, although donor organ availability remains one of the most limiting factors in this type of therapy. This review focuses on current surgical and medical strategies and interventional options for the prevention and management of systemic RV failure in adults and children with ccTGA.

Endocardial fibroelastosis is caused by aberrant endothelial to mesenchymal transition.

RATIONALE: Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infant patients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce, and specific therapeutic targets are not yet known. OBJECTIVE: Here, we aimed to investigate the cellular origins of EFE tissue and to gain insights into the underlying molecular mechanisms to ultimately develop novel therapeutic strategies. METHODS AND RESULTS: By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial to mesenchymal transition. We further demonstrate that such aberrant endothelial to mesenchymal transition involving endocardial endothelial cells is caused by dysregulated transforming growth factor beta/bone morphogenetic proteins signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of bone morphogenetic proteins 5 and 7. Finally, we provide evidence that supplementation of exogenous recombinant bone morphogenetic proteins 7 effectively ameliorates endothelial to mesenchymal transition and experimental EFE in rats. CONCLUSIONS: In summary, our data point to aberrant endothelial to mesenchymal transition as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to bone morphogenetic proteins 7 as an effective treatment for EFE and its restriction of heart growth.

Mitochondrial Transplantation in Myocardial Ischemia and Reperfusion Injury.

Ischemic heart disease remains the leading cause of death worldwide. Mitochondria are the power plant of the cardiomyocyte, generating more than 95% of the cardiac ATP. Complex cellular responses to myocardial ischemia converge on mitochondrial malfunction which persists and increases after reperfusion, determining the extent of cellular viability and post-ischemic functional recovery. In a quest to ameliorate various points in pathways from mitochondrial damage to myocardial necrosis, exhaustive pharmacologic and genetic tools have targeted various mediators of ischemia and reperfusion injury and procedural techniques without applicable success. The new concept of replacing damaged mitochondria with healthy mitochondria at the onset of reperfusion by auto-transplantation is emerging not only as potential therapy of myocardial rescue, but as gateway to a deeper understanding of mitochondrial metabolism and function. In this chapter, we explore the mechanisms of mitochondrial dysfunction during ischemia and reperfusion, current developments in the methodology of mitochondrial transplantation, mechanisms of cardioprotection and their clinical implications.

Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model.

BACKGROUND/PURPOSE: Rodent adult-to-adult heterotopic heart transplantation is a well-established animal model, and the detailed surgical technique with several modifications has been previously described. In immature donor organ transplantation, however, the surgical technique needs to be revised given the smaller size and fragility of the donor graft. Here, we report our surgical technique for heterotopic abdominal (AHTx) and femoral (FHTx) neonatal rat heart transplantation based on an experience of over 300 cases. METHODS: Heterotopic heart transplantation was conducted in syngeneic Lewis rats. Neonatal rats (postnatal day 2-4) served as donors. AHTx was performed by utilizing the conventional adult-to-adult transplant method with specific modifications for optimal aortotomy and venous anastomosis. In the FHTx, the donor heart was vascularized by connecting the donor's aorta and pulmonary artery to the recipient's right femoral artery and vein, respectively, in an end-to-end manner. A specifically fashioned butterfly-shaped rubber sheet was used to align the target vessels properly. The transplanted graft was visually assessed for its viability and was accepted as a technical success when the viability met specific criteria. Successfully transplanted grafts were subject to further postoperative evaluation. Forty cases (AHTx and FHTx; n = 20 each) were compared regarding perioperative parameters and outcomes. RESULTS: Both models were technically feasible (success rate: AHTx 75% vs. FHTx 70%) by refining the conventional heterotopic transplant technique. Injury to the fragile donor aorta and congestion of the graft due to suboptimal venous connection were predominant causes of failure, leading to refractory bleeding and poor graft viability. Although the FHTx required significantly longer operation time and graft ischemic time, the in situ graft viabilities were comparable. The FHTx provided better postoperative monitoring as it enabled daily graft palpation and better echocardiographic visualization. CONCLUSIONS: We describe detailed surgical techniques for AHTx and FHTx while addressing neonatal donor-specific issues. Following our recommendations potentially reduces the learning curve to achieve reliable and reproducible results with these challenging animal models.