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.

Anatomic Repair of Congenitally Corrected Transposition: Reappraisal of Eligibility Criteria.

Several criteria to identify suitable candidates for anatomic repair in congenitally corrected transposition (cc-TGA) have been proposed. The purpose of this study was to critically re-evaluate adequacy of these recommendations in our patient cohort. All cc-TGA patients undergoing anatomic repair between 2010 and 2019 were reviewed. Evaluated eligibility criteria for repair included age ≤ 15 years, LV mass index ≥ 45-50 g/m2, LV mass/volume ratio > 0.9-1.5 and systolic LV to right ventricle pressure ratio > 70-90% among others. Repair failure was defined as postoperative early mortality or LV dysfunction requiring mechanical circulatory support. Twenty-five patients were included (median [interquartile range] age at surgery 1.8 years [0.7;6.6]; median postoperative follow-up 3.2 years [0.7;6.3]). Median preoperative LV ejection fraction was 60% [56;64], indexed LV mass 48.5 g/m2 [43.7;58.1] and LV mass/volume ratio 1.5 [1.1;1.6], respectively. A total of 12 patients (48%) did not meet at least one of the previously recommended criteria, however, all but two patients (92%) experienced favorable early outcome. Of 7 patients (28%) with indexed LV mass < 45 g/m2, 6 were successfully operated. There were two early repair failures (8%) with LV dysfunction: one patient died and one required mechanical circulatory support but recovered well. Surgery was performed successfully in patients with LV mass and volume Z-scores as low as - 2 and - 2.5, respectively. Anatomic correction for cc-TGA can be performed with excellent early outcome and is feasible even in patients with LV mass below previously recommended cut-offs. The use of LV mass and volume Z-scores might help to refine eligibility criteria.

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.

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.

Modified extracardiac Fontan with a fenestrated pericardial patch.

Extracardiac Fontan is a preferred treatment strategy in many centers treating patients with single ventricle physiology, and many of these centers regularly include a fenestration between the extracardiac conduit and the common atrium. Spontaneous closure of the fenestration is a common complication of this technique and is independently associated with increased morbidity and mortality. Recently, we introduced a novel technique for fenestration of the extracardiac conduit wherein a pericardial patch is utilized at the fenestration point with excellent outcomes in the midterm fenestration patency rates, thus reducing the risk of acute post-Fontan complications.

Early and long-term outcomes comparing neonates, infants, and preadolescents requiring extracorporeal membrane oxygenation for heart failure.

BACKGROUND: Application of extracorporeal membrane oxygenation in pediatric patients with severe heart failure steadily increases. Differentiation of outcomes and survival of diverse pediatric groups is of interest for adequate therapy. METHODS: Between January 2008 and December 2016, a total of 39 pediatric patients needed veno-arterial extracorporeal membrane oxygenation support in our department. Patients were retrospectively divided into three groups: neonates (<30 days), infants (>30 days/<1 year), and toddlers/preadolescents (>1 year). Early outcomes as well as mid- and long-term survival up to 7-year follow-up were analyzed. RESULTS: Basic demographics significantly differed in terms of age, height, and weight among the groups in accordance with the intended group categorization (p < 0.05). Survival after 30 days of extracorporeal membrane oxygenation application was equally distributed among the groups, and 44% of all patients survived. In terms of survival to discharge, no significant differences were found among groups. In total, 28% of patients survived up to 7 years. Infants were significantly more likely to undergo elective surgery (p < 0.001) and were predominantly weaned off extracorporeal membrane oxygenation, whereas need for urgent surgery (p < 0.001) was significantly higher in neonate group in comparison to other groups. Multinominal logistic regression analysis revealed significantly higher odds for need for re-exposure in infant group in comparison to toddler/preadolescent group as well as for incidence of neurological impairment of toddler/preadolescent group in comparison to neonate group (odds ratio = 14.67, p = 0.009 and odds ratio = 34.67, p = 0.004, respectively). Kaplan-Meier survival estimation analysis revealed no significant differences in terms of mid- and long-term survival among the groups (Breslow p = 0.198 and log-rank p = 0.213, respectively). CONCLUSION: Veno-arterial extracorporeal membrane oxygenation is a lifesaving therapeutic chance for pediatric patients in the setting of either failure to wean from cardiopulmonary bypass or failed resuscitation from cardiac arrest. A fair part of patients could be saved by using this technology. Survival rate among the groups was similar.

Pediatric patients requiring extracorporeal membrane oxygenation in heart failure: 30-day outcomes; mid- and long-term survival. A single center experience.

Nowadays, an increasing number of neonatal and pediatric patients with severe heart failure benefits from extracorporeal membrane oxygenation (ECMO) support. A total of 39 pediatric patients needed venoarterial ECMO (vaECMO) support in our department between January 2008 and December 2016. Patients were retrospectively divided in two groups: 30-day survivor group (17 patients) and 30-day nonsurvivor group (22 patients). Outcome and factors predictive for 30-day mortality and mid- as well as long-term survival up to 7-year follow-up were analyzed by univariate analysis and Kaplan-Meier survival estimation. Basic demographics and preoperative characteristics did not differ between groups (P > 0.05). 67% of patients were successfully weaned off ECMO and 44% survived 30-day after ECMO application. After 7-year follow-up 28% of pediatric patients were alive. Thirty-day survivors were significantly more likely to undergo elective cardiac surgery (P = 0.001), whereas significantly more 30-day nonsurvivors underwent urgent surgery (P = 0.004). Odds of incidence of catecholamine refractory circulatory failure, failed myocardial recovery, and cerebral edema was significantly higher in 30-day nonsurvivor group (41.6-fold, 16-fold, and 2.5-fold, respectively). Kaplan-Meier survival estimation analysis revealed significant differences in terms of mid- and long-term survival among neonates, infants, toddlers, and preadolescents (Breslow P = 0.037 and Log-Rank P = 0.028, respectively). vaECMO provides an efficient therapy option for life-threatening heart disorders in neonates and pediatric patients being at high risk for myocardial failure leading to circulatory arrest. Urgency of surgery effected on higher mortality, but there was no difference in terms of mortality in 30-day survivor group in comparison to 30-day nonsurvivor group among neonates, infants, toddlers, and preadolescents.

Hyperbaric oxygen in patients with ischemic stroke following cardiac surgery: a retrospective observational trial.

BACKGROUND: Hyperbaric oxygenation (HBO2) involves breathing 100% oxygen under elevated ambient pressure in a hyperbaric chamber, thereby dissolving oxygen in the plasma. This results in an increase of arterial partial pressure of oxygen (pO2). Though well established in experimental studies, HBO2 treatment for ischemic stroke is still under discussion. METHODS: From 2002-2014 HBO2 (2.2 bar, 90 minutes one/day; average number per patient: 4.7) was applied in 49 consecutive patients (32 males, 17 females, mean age: 68.8 years, range 31.2 - 83.9) with acute neurological deficit following cardiac surgery (CABG 15; combined surgery 14; valve surgery 11; aneurysm repair 8; malformation 1). Patients' history including TIA or stroke and carotid artery pathology were documented. Both degree and type of neurological deficit was evaluated by a scoring system (0-4) before and after HBO2 treatment. RESULTS: Before HBO2 therapy, the average motor deficit score was 2.45 and the average speech disorder score was 0.55, as compared with an average motor deficit of 1.12 and an average speech disorder of 0.27 afterward (α=0.0001, α=0.009). The majority of patients had an overall improvement of 2 score-points after HBO2 therapy (n=23 patients). Probit analysis showed that for a 50% response/probability (LC50) of having an overall outcome of ≥2 scoring points, an estimate of 4.3 HBO2 therapy sessions is necessary. CONCLUSIONS: HBO22 therapy was associated with significant improvement in patients with acute neurological deficits due to ischemic stroke following cardiac surgery. Though this fact suggests gas embolism as the most likely cause of stroke in this collective, other underlying pathologies cannot be ruled out. Randomized studies are needed for further evaluation.

Socioeconomic Status and Access to Care for Pediatric and Adult Congenital Heart Disease in Universal Health Coverage Models.

Congenital heart disease (CHD) is the most common major congenital anomaly, affecting one in every 100 live births. Whereas over 90% of children born with CHD in low- and middle-income countries cannot access the care they need, early detection, advances in management, and financial risk protection have resulted in over 90% of children with CHD in high-income countries surviving into adulthood. Despite the presence of universal health coverage, barriers to accessing high-quality cardiovascular and non-cardiovascular care for CHD remain common. Lower socioeconomic status has been associated with differential access to cardiac care and poorer outcomes across multiple cardiovascular conditions and subspecialties. In this review article, we describe the relationship between socioeconomic status and access to CHD care in countries with universal health coverage models. We further evaluate notable challenges and opportunities to improve equitable, high-quality CHD care in these countries.

Tissue-engineered and autologous pericardium in congenital heart surgery: comparative histopathological study of human vascular explants.

OBJECTIVES: The goal of this histological study was to assess the biocompatibility of vascular patches used in the repair of congenital heart defects. METHODS: We examined tissue-engineered bovine (n = 7) and equine (n = 7) patches and autologous human pericardium (n = 7), all explanted due to functional issues or follow-up procedures. Techniques like Movat-Verhoeff, von Kossa and immunohistochemical staining were used to analyse tissue composition, detect calcifications and identify immune cells. A semi-quantitative scoring system was implemented to evaluate the biocompatibility aspects, thrombus formation, extent of pannus, inflammation of pannus, cellular response to patch material, patch degradation, calcification and neoadventitial inflammation. RESULTS: We observed distinct material degradation patterns among types of patches. Bovine patches showed collagen disintegration and exudate accumulation, whereas equine patches displayed edematous swelling and material dissolution. Biocompatibility scores were lower in terms of cellular response, degradation and overall score for human autologous pericardial patches compared to tissue-engineered types. The extent of pannus formation was not influenced by the type of patch. Bovine patches had notable calcifications causing tissue hardening, and foreign body giant cells were more frequently seen in equine patches. Plasma cells were frequently detected in the neointimal tissue of engineered patches. CONCLUSIONS: Our results confirm the superior biocompatibility of human autologous patches and highlight discernible variations in the changes of patch material and the cellular response to patch material between bovine and equine patches. Our approach implements the semi-quantitative scoring of various aspects of biocompatibility, facilitating a comparative quantitative analysis across all types of patches, despite their inherent differences.