FGF21 modulates hippocampal cold-shock proteins and CA2-subregion proteins in neonatal mice with hypoxia-ischemia.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a neuroprotectant with cognitive enhancing effects but with poorly characterized mechanism(s) of action, particularly in females. Prior studies suggest that FGF21 may regulate cold-shock proteins (CSPs) and CA2-marker proteins in the hippocampus but empirical evidence is lacking. METHODS: We assessed in normothermic postnatal day (PND) 10 female mice, if hypoxic-ischemic (HI) brain injury (25 min 8% O2/92% N2) altered endogenous levels of FGF21 in serum or in the hippocampus, or its receptor ß-klotho. We also tested if systemic administration of FGF21 (1.5 mg/kg) modulated hippocampal CSPs or CA2 proteins. Finally, we measured if FGF21 therapy altered markers of acute hippocampal injury. RESULTS: HI increased endogenous serum FGF21 (24 h), hippocampal tissue FGF21 (4d), and decreased hippocampal ß-klotho levels (4d). Exogenous FGF21 therapy modulated hippocampal CSP levels, and dynamically altered hippocampal CA2 marker expression (24 h and 4d). Finally, FGF21 ameliorated neuronal damage markers at 24 h but did not affect GFAP (astrogliosis) or Iba1 (microgliosis) levels at 4d. CONCLUSIONS: FGF21 therapy modulates CSP and CA2 protein levels in the injured hippocampus. These proteins serve different biological functions, but our findings suggest that FGF21 administration modulates them in a homeostatic manner after HI. IMPACT: Hypoxic-ischemic (HI) injury in female post-natal day (PND) 10 mice decreases hippocampal RNA binding motif 3 (RBM3) levels in the normothermic newborn brain. HI injury in normothermic newborn female mice alters serum and hippocampal fibroblast growth factor 21 (FGF21) levels 24 h post-injury. HI injury in normothermic newborn female mice alters hippocampal levels of N-terminal EF-hand calcium binding protein 2 (NECAB2) in a time-dependent manner. Exogenous FGF21 therapy ameliorates the HI-mediated loss of hippocampal cold-induced RNA-binding protein (CIRBP). Exogenous FGF21 therapy modulates hippocampal levels of CA2-marker proteins after HI.

QRS Duration After Pulmonary Valve Replacement in Adults with Repaired Tetralogy of Fallot: Association with Ventricular Arrhythmia and Correlation with Right Ventricular Size.

The aim of this study is to analyze the relationship between QRS duration after pulmonary valve replacement (PVR) and ventricular arrhythmias (VA) in patients with repaired tetralogy of Fallot (ToF). ToF patients may face complications such as heart failure and VA after primary repair, often mitigated by PVR. Prior studies have shown a decrease in QRS duration and right ventricular (RV) size following PVR. It remains unclear whether a lack of QRS duration reduction identifies patients at risk of VA. We retrospectively identified adult patients with repaired ToF who underwent surgical or transcatheter PVR. EKG data (pre-PVR, 30 days to 1-year post-PVR, and closest to CMR) was collected. The primary endpoint was sustained ventricular tachycardia (VT), ICD shock for sustained VT, or inducible VT on EP study. 85 patients were included (median follow-up 3.6 years; median age 34 years; 51% females). The primary outcome was noted in 8 patients. Mean QRS duration decreased by 5 ms following PVR (p = 0.0001). Increased age at PVR, QRS ≥ 180 ms post-PVR, no reduction in QRS after PVR, and a history of VT were associated with higher risk of the primary endpoint. The change in QRS was linearly correlated with the change in RVEDVi (R = 0.66). Adults with repaired ToF experience a reduction in QRS duration post-PVR that correlates with the change of the RV size. Patients with QRS ≥ 180 ms post-PVR, no reduction in QRS, increased age at repair, and a history of VT are at risk for recurrent VT and warrant closer monitoring/ICD consideration.

Impact of Home Monitoring Program and Early Gastrostomy Tube on Interstage Outcomes following Stage 1 Norwood Palliation.

Nutritional management and home monitoring programs (HMPs) may be beneficial for improving interstage morbidity and mortality following stage I Norwood palliation (S1P) for hypoplastic left heart syndrome (HLHS). We recognized an increasing trend towards early feeding gastrostomy tube (GT) placement prior to discharge in our institution, and we aimed to investigate the effect of HMPs and GTs on interstage mortality and growth parameters. Single-institutional review at a tertiary referral center between 2008 and 2018. Individual patient charts were reviewed in the electronic medical record. Those listed for transplant or hybrid procedures were excluded. Baseline demographics, operative details, and interstage outcomes were analyzed in GT and non-GT patients (nGT). Our HMP was instituted in 2009, and patients were analyzed by era: I (early, 2008-2012), II (intermediate, 2013-2016), and III (recent, 2017-2018). 79 patients were included in the study: 29 nGTs and 50 GTs. GTs had higher number of preoperative risk factors more S1P complications, longer ventilation times, longer lengths of stay, and shorter times to readmission. There were no differences in interstage mortality or overall mortality between groups. There was one readmission for a GT-related issue with no periprocedural complications in the group. Weight gain doubled after GT placement in the interstage period while waiting periods for placement decreased across Eras. HMPs and early GTs, especially for patients with high-risk features, provide a dependable mode of nutritional support to optimize somatic growth following S1P.

Factors associated with the need for inotropic support following pulmonary artery banding surgery for CHD.

OBJECTIVE: We aimed to identify factors independently associated with the need for inotropic support for low cardiac output or haemodynamic instability after pulmonary artery banding surgery for CHD. METHODS: We performed a retrospective chart review of all neonates and infants who underwent pulmonary banding between January 2016 and June 2019 at our institution. Bivariate and multivariable analyses were performed to identify factors independently associated with the use of post-operative inotropic support, defined as the initiation of inotropic infusion(s) for depressed myocardial function, hypotension, or compromised perfusion within 24 hours of pulmonary artery banding. RESULTS: We reviewed 61 patients. Median age at surgery was 10 days (25%,75%:7,30). Cardiac anatomy was biventricular in 38 patients (62%), hypoplastic right ventricle in 14 patients (23%), and hypoplastic left ventricle in 9 patients (15%). Inotropic support was implemented in 30 patients (49%). Baseline characteristics of patients who received inotropic support, including ventricular anatomy and pre-operative ventricular function, were not statistically different from the rest of the cohort. Patients who received inotropic support, however, were exposed to larger cumulative doses of ketamine intraoperatively - median 4.0 mg/kg (25%,75%:2.8,5.9) versus 1.8 mg/kg (25%,75%:0.9,4.5), p < 0.001. In a multivariable model, cumulative ketamine dose greater than 2.5mg/kg was associated with post-operative inotropic support (odds ratio 5.5; 95% confidence interval: 1.7,17.8), independent of total surgery time. CONCLUSIONS: Inotropic support was administered in approximately half of patients who underwent pulmonary artery banding and more commonly occurred in patients who received higher cumulative doses of ketamine intraoperatively, independent of the duration of surgery.

Liposomal bupivacaine reduces opioid requirements following Ravitch repair for pectus excavatum.

Background and Aims: The management of post-operative pain after surgical repair of pectus excavatum with the Ravitch procedure is challenging. Although previous studies have compared various methods of pain control in these patients, few have compared different local anesthetics. This retrospective analysis compares the use of bupivacaine to its longer-acting form, liposomal bupivacaine, in patients who had undergone pectus excavatum repair with the Ravitch method. Material and Methods: Eleven patients who received local infiltration with liposomal bupivacaine were matched to 11 patients who received local infiltration utilizing bupivacaine with epinephrine. The primary outcome was total morphine milligram equivalents per kilogram body weight (MME/kg) over the complete length of hospital stay. Secondary outcomes included total cumulative diazepam, acetaminophen, ondansetron, and NSAID dose per kilogram body weight (mg/kg) over the course of the hospital stay, chest tube drainage (ml/kg body weight), number of post-operative hours until the first bowel movement, Haller Index, patient request for magnesium hydroxide, average pain scores from post-operative day 1 to post-operative day 5, and length of hospital stay. Continuous variables were reported as medians with inter-quartile ranges, and categorical values were reported as percentages and frequencies. Results: The total MME/kg [1.7 (1.2-2.4) vs 2.9 (2.0-3.9), P = 0.007] and hydromorphone (mg/kg) [0.1 (0.0-0.2) vs 0.3 (0.1-0.4), P = 0.006] use in the liposomal bupivacaine group versus bupivacaine with epinephrine was significantly reduced over total length of hospital stay. Similarly, there was a reduction in diazepam use in the liposomal bupivacaine group versus the bupivacaine group [0.4 (0.1-0.8) vs 0.6 (0.4-0.7), P = 0.249], but this did not reach statistical significance. The total dose of ondansetron (mg/kg) was not statistically different when comparing the liposomal bupivacaine group to the bupivacaine group [0.3 (0.0-0.5) vs 0.3 (0.2-0.6), P = 0.332]. Interestingly, the total dose of acetaminophen (mg/kg) was statistically increased in the liposomal bupivacaine group compared to the bupivacaine with epinephrine group [172 (138-183) vs 74 (55-111), P = 0.007]. Additionally, the total chest tube drainage (ml/kg) was significantly reduced in the liposomal bupivacaine group [9.3 (7.5-10.6) vs 12.8 (11.3-18.5), P = 0.027]. Finally, the percentage of patients without requests for magnesium hydroxide to promote laxation was significantly higher in the liposomal bupivacaine group than in the bupivacaine group (63.6% vs 18.2%, P = 0.027). Conclusion: The use of liposomal bupivacaine for local infiltration in patients who undergo the Ravitch procedure for pectus repair offers advantages over plain bupivacaine, including reduced opioid consumption and opioid-related side effects. However, more data are needed to understand the significance of these findings.

Hypoxia-ischemia-mediated effects on neurodevelopmentally regulated cold-shock proteins in neonatal mice under strict temperature control.

BACKGROUND: Neonates have high levels of cold-shock proteins (CSPs) in the normothermic brain for a limited period following birth. Hypoxic-ischemic (HI) insults in term infants produce neonatal encephalopathy (NE), and it remains unclear whether HI-induced pathology alters baseline CSP expression in the normothermic brain. METHODS: Here we established a version of the Rice-Vannucci model in PND 10 mice that incorporates rigorous temperature control. RESULTS: Common carotid artery (CCA)-ligation plus 25 min hypoxia (8% O2) in pups with targeted normothermia resulted in classic histopathological changes including increased hippocampal degeneration, astrogliosis, microgliosis, white matter changes, and cell signaling perturbations. Serial assessment of cortical, thalamic, and hippocampal RNA-binding motif 3 (RBM3), cold-inducible RNA binding protein (CIRBP), and reticulon-3 (RTN3) revealed a rapid age-dependent decrease in levels in sham and injured pups. CSPs were minimally affected by HI and the age point of lowest expression (PND 18) coincided with the timing at which heat-generating mechanisms mature in mice. CONCLUSIONS: The findings suggest the need to determine whether optimized therapeutic hypothermia (depth and duration) can prevent the age-related decline in neuroprotective CSPs like RBM3 in the brain, and improve outcomes during critical phases of secondary injury and recovery after NE. IMPACT: The rapid decrease in endogenous neuroprotective cold-shock proteins (CSPs) in the normothermic cortex, thalamus, and hippocampus from postnatal day (PND) 11-18, coincides with the timing of thermogenesis maturation in neonatal mice. Hypoxia-ischemia (HI) has a minor impact on the normal age-dependent decline in brain CSP levels in neonates maintained normothermic post-injury. HI robustly disrupts the expected correlation in RNA-binding motif 3 (RBM3) and reticulon-3 (RTN3). The potent neuroprotectant RBM3 is not increased 1-4 days after HI in a mouse model of neonatal encephalopathy (NE) in the term newborn and in which rigorous temperature control prevents the manifestation of endogenous post-insult hypothermia.

Bartonella endocarditis and diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition.

BACKGROUND: Bartonella endocarditis is often a diagnostic challenge due to its variable clinical manifestations, especially when it is first presented with involvement of organs other than skin and lymph nodes, such as the kidney. CASE PRESENTATION: This was a 13-year-old girl presenting with fever, chest and abdominal pain, acute kidney injury, nephrotic-range proteinuria and low complement levels. Her kidney biopsy showed diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition shown by immunofluorescence, which was initially considered consistent with systemic lupus erythematous-associated glomerulonephritis (lupus nephritis). After extensive workup, Bartonella endocarditis was diagnosed. Antibiotic treatment and valvular replacement surgery were undertaken with subsequent return of kidney function to normal range. CONCLUSION: This case demonstrates the importance of considering the full clinical picture when interpreting clinical, laboratory and biopsy findings, because the treatment strategy for infective endocarditis versus lupus nephritis is drastically different.

Perioperative and long-term outcomes of Ross versus mechanical aortic valve replacement.

BACKGROUND: The ideal aortic valve replacement strategy in young- and middle-aged adults remains up for debate. Clinical practice guidelines recommend mechanical prostheses for most patients less than 50 years of age undergoing aortic valve replacement. However, risks of major hemorrhage and thromboembolism associated with long-term anticoagulation may make the pulmonary autograft technique, or Ross procedure, a preferred approach in select patients. METHODS: Data were retrospectively collected for patients 18-50 years of age who underwent either the Ross procedure or mechanical aortic valve replacement (mAVR) between January 2000 and December 2016 at a single institution. Propensity score matching was performed and yielded 32 well-matched pairs from a total of 216 eligible patients. RESULTS: Demographic and preoperative characteristics were similar between the two groups. Median follow-up was 7.3 and 6.9 years for Ross and mAVR, respectively. There were no early mortalities in either group and no statistically significant differences were observed with respect to perioperative outcomes or complications. Major hemorrhage and stroke events were significantly more frequent in the mAVR population (p < .01). Overall survival (p = .93), freedom from reintervention and valve dysfunction free survival (p = .91) were equivalent. CONCLUSIONS: In this mid-term propensity score-matched analysis, the Ross procedure offers similar perioperative outcomes, freedom from reintervention or valve dysfunction as well as overall survival compared to traditional mAVR but without the morbidity associated with long-term anticoagulation. At specialized centers with sufficient expertize, the Ross procedure should be strongly considered in select patients requiring aortic valve replacement.

Surgical Gastrostomy in Pediatric Patients Undergoing Cardiac Surgery.

BACKGROUND: Practices of performing gastrostomy tubes vary across institutions for patients undergoing cardiac surgery. We aim to elucidate the outcomes of gastrostomy and the duration of feeding assistance in these patients. MATERIALS AND METHODS: Patients undergoing cardiac surgery (CS) at our institution from 2013 to 2017 were retrospectively reviewed using the Society of Thoracic Surgery database. A cohort of non-CS patients undergoing gastrostomy tube (g-tube) placement from 2013 to 2015 was used as control. Technical complications and postoperative feeding intolerance were analyzed. Duration of need for g-tube was also analyzed in patients undergoing CS. RESULTS: The CS group had 144 patients, and the non-CS group had 677 patients. CS patients had a higher incidence of feeding intolerance (18.8% versus 5.6%, P < 0.001) and took longer to attain full feeds (median of 2 versus 1 d, P < 0.001), and this was confirmed on propensity matched analysis. In addition, technical g-tube complications were similar in the two groups. No mortality in CS was attributed to the g-tube. 58% of patients undergoing CS were able to wean from g-tube feeding by 6-12 mo after g-tube placement. CONCLUSIONS: G-tube placement in patients undergoing CS by any technique is safe without increased complications. A significant portion of these patients was able to wean off supplemental enteral feeding assistance by a year after g-tube placement.

Bovine jugular vein conduit versus pulmonary homograft in the Ross operation.

OBJECTIVES: The Ross procedure involves using the native pulmonary valve for aortic valve replacement then replacing the pulmonary valve with an allograft or xenograft. We aimed to compare our age-matched experience with the bovine jugular vein conduit and the pulmonary homograft for pulmonary valve replacement during the Ross procedure in children. METHODS: Between 1998 and 2016, 15 patients <18 years of age underwent a Ross procedure using the bovine jugular vein conduit (Ross-Bovine Jugular Vein Conduit) at our institution. These patients were age-matched with 15 patients who had the Ross operation with a standard pulmonary homograft for right ventricular outflow tract reconstruction (Ross-Pulmonary Homograft). Paper and electronic medical records were retrospectively reviewed. RESULTS: The median age of the Ross-Bovine Jugular Vein Conduit and Ross-Pulmonary Homograft patients were 4.8 years (interquartile range 1.1-6.6) and 3.3 years (interquartile 1.2-7.6), respectively (p = 0.6). The median follow-up time for the Ross-Bovine Jugular Vein Conduit and Ross-Pulmonary Homograft groups were 1.7 years (interquartile range 0.5-4.9) and 6.8 years (interquartile range 1.9-13.4), respectively (p = 0.03). Overall, 5-year survival, freedom from redo aortic valve replacement, and freedom from pulmonary valve replacement were similar between groups. CONCLUSION: The bovine jugular vein conduit and pulmonary homograft have favourable mid-term durability when used for right ventricular outflow tract reconstruction for the Ross operation. The bovine jugular vein conduit may be a suitable replacement for appropriately sized patients undergoing a Ross aortic valve replacement, though longer follow-up is needed.

Short- and intermediate-term results of balloon aortic valvuloplasty and surgical aortic valvotomy in neonates.

BACKGROUND: Balloon aortic valvuloplasty and open surgical valvotomy are procedures to treat neonatal aortic stenosis, and there is controversy as to which method has superior outcomes. METHODS: We reviewed the records of patients at our institution since 2000 who had a balloon aortic valvuloplasty or surgical valvotomy via an open commissurotomy prior to 2 months of age. RESULTS: Forty patients had balloon aortic valvuloplasty and 15 patients had surgical valvotomy via an open commissurotomy. There was no difference in post-procedure mean gradient by transthoracic echocardiogram, which were 25.8 mmHg for balloon aortic valvuloplasty and 26.2 mmHg for surgical valvotomy, p = 0.87. Post-procedure, 15% of balloon aortic valvuloplasty patients had moderate aortic insufficiency and 2.5% of patients had severe aortic insufficiency, while no surgical valvotomy patients had moderate or severe aortic insufficiency. The average number of post-procedure hospital days was 14.2 for balloon aortic valvuloplasty and 19.8 for surgical valvotomy (p = 0.52). Freedom from re-intervention was 69% for balloon aortic valvuloplasty and 67% for surgical valvotomy at 1 year, and 43% for balloon aortic valvuloplasty and 67% for surgical valvotomy at 5 years (p = 0.60). CONCLUSIONS: Balloon aortic valvuloplasty and surgical valvotomy provide similar short-term reduction in valve gradient. Balloon aortic valvuloplasty has a slightly shorter but not statistically significant hospital stay. Freedom from re-intervention is similar at 1 year. At 5 years, it is slightly higher in surgical valvotomy, though not statistically different. Balloon aortic valvuloplasty had a higher incidence of significant aortic insufficiency. Long-term comparisons cannot be made given the lack of long-term follow-up with surgical valvotomy.

Early conversion of classic Fontan conversion may decrease term morbidity: single centre outcomes.

BACKGROUND: The initial classic Fontan utilising a direct right atrial appendage to pulmonary artery anastomosis led to numerous complications. Adults with such complications may benefit from conversion to a total cavo-pulmonary connection, the current standard palliation for children with univentricular hearts. METHODS: A single institution, retrospective chart review was conducted for all Fontan conversion procedures performed from July, 1999 through January, 2017. Variables analysed included age, sex, reason for Fontan conversion, age at Fontan conversion, and early mortality or heart transplant within 1 year after Fontan conversion. RESULTS: A total of 41 Fontan conversion patients were identified. Average age at Fontan conversion was 24.5 ± 9.2 years. Dominant left ventricular physiology was present in 37/41 (90.2%) patients. Right-sided heart failure occurred in 39/41 (95.1%) patients and right atrial dilation was present in 33/41 (80.5%) patients. The most common causes for Fontan conversion included atrial arrhythmia in 37/41 (90.2%), NYHA class II HF or greater in 31/41 (75.6%), ventricular dysfunction in 23/41 (56.1%), and cirrhosis or fibrosis in 7/41 (17.1%) patients. Median post-surgical follow-up was 6.2 ± 4.9 years. Survival rates at 30 days, 1 year, and greater than 1-year post-Fontan conversion were 95.1, 92.7, and 87.8%, respectively. Two patients underwent heart transplant: the first within 1 year of Fontan conversion for heart failure and the second at 5.3 years for liver failure. CONCLUSIONS: Fontan conversion should be considered early when atrial arrhythmias become common rather than waiting for severe heart failure to ensue, and Fontan conversion can be accomplished with an acceptable risk profile.

Congenital pulmonary lymphangiectasia and early mortality after stage 1 reconstruction procedures.

OBJECTIVES: Pulmonary lymphangiectasia associated with hypoplastic left heart syndrome with an intact or restrictive atrial septum may result from increased left atrial pressure, and is associated with worse outcomes following staged reconstruction due to lung dysfunction and significant hypoxaemia. Our objective was to characterise the incidence of pulmonary lymphangiectasia in cases of early mortality following stage 1 reconstructions. METHODS: An institutional cardiac surgical database was retrospectively searched for patients who died within 30 days following a stage 1 reconstruction between 1 January, 1984 and 31 December, 2013. During that period, 1669 stage 1 procedures were performed. Autopsy lung specimens were reviewed by a paediatric pathologist. Patients who died of suspected technical issues were excluded. RESULTS: A total of 54 patients were included, and of these seven cases (8.5%) of pulmonary lymphangiectasia were identified. The mean estimated gestational age was 38.2±2.4 weeks, and the mean birth weight was 3.0±0.6 kg. The median interval between surgery and death was 1 day (with a range from 0 to 18 days). The atrial septum was intact in one patient (14.3%), restrictive in three patients (42.9%), and unrestrictive in three patients (42.9%). CONCLUSIONS: Pulmonary lymphangiectasia may develop in hypoplastic left heart syndrome with or without a restrictive atrial septum. As standard prenatal diagnostic evaluations and treatment methods for pulmonary lymphangiectasia are limited, this may be an important contributor to early and late mortality following stage 1 reconstruction for hypoplastic left heart syndrome.

Beyond Ussing's chambers: contemporary thoughts on integration of transepithelial transport.

In the mid-20th century, Hans Ussing developed a chamber that allowed for the simultaneous measurement of current and labeled probe flux across epithelia. Using frog skin as a model, Ussing used his results to propose mechanisms of transcellular Na(+) and K(+) transport across apical (exterior/luminal) and basolateral (interior) membranes that is essentially unchanged today. Others took advantage of Ussing's chambers to study mucosal tissues, including bladder and intestines. It quickly became clear that, in some tissues, passive paracellular flux, i.e., across the tight junction, was an important component of overall transepithelial transport. Subsequent work demonstrated that activation of the apical Na(+)-glucose cotransporter SGLT1 regulated paracellular permeability such that intestinal paracellular transport could coordinate with and amplify transcellular transport. Intermediates in this process include activation of p38 MAPK, the apical Na(+)/H(+) exchanger NHE3, and myosin light chain kinase (MLCK). Investigators then focused on these processes in disease. They found that TNF induces barrier dysfunction via MLCK activation and downstream caveolin-1-dependent endocytosis of the tight junction protein occludin. TNF also inhibited NHE3, and both barrier loss and PKCα-dependent NHE3 inhibition were required for TNF-induced acute diarrhea, emphasizing the interplay between transcellular and paracellular transport. Finally, studies using immune-mediated inflammatory bowel disease models showed that mice lacking epithelial MLCK were initially protected, but became ill as epithelial damage progressed and provided a tight junction-independent means of barrier loss. None of these advances would have been possible without the insights provided by Ussing and others using Ussing's ingenious, and still useful, chambers.