Gianluca Lucchese

Two decades of experience with the Ross operation in neonates, infants and children from the Italian Paediatric Ross Registry

Objective Children undergoing Ross operation were expected to have longer autograft, but shorter homograft durability compared with adults. In order to define the outcome in the second decade after Ross operation in children, a nationwide review of 23 years of experience was undertaken. Methods 305 children underwent Ross operation in 11 paediatric units between 1990 and 2012. Age at surgery was 9.4±5.7 years, indication aortic stenosis in 103 patients, regurgitation in 109 and mixed lesion in 93. 116 (38%) patients had prior procedures. Root replacement was performed in 201 patients, inclusion cylinder in 14, subcoronary grafting in 17 and Ross–Konno in 73. Results There were 10 (3.3%) hospital and 12 late deaths (median follow-up 8.7 years). Survival was 93±2% and 89±3% and freedom from any reoperation was 76±3% and 67±6% at 10 and 15 years. 34 children had autograft 37 reoperations (25 replacement, 12 repair): three required transplantation after reoperation. Freedom from autograft reoperation was 86±3% and 75±6% at 10 and 15 years. 32 children had right heart redo procedures, and only 25 (78%) conduit replacements (15-year freedom from replacement, 89±4%). Prior operation (p=0.031), subcoronary implant (p=0.025) and concomitant surgical procedure (p=0.004) were risk factors for left heart reoperation, while infant age (p=0.015) was for right heart. The majority (87%) of late survivors were in NYHA class I, 68% free from medication and six women had pregnancies. Conclusions Despite low hospital risk and satisfactory late survival, paediatric Ross operation bears substantial valve-related morbidity in the first two decades. Contrary to expectation, autograft reoperation is more common than homograft.

Reparative surgery of the pulmonary autograft: experience with Ross reoperations

OBJECTIVE Autograft valve and root pathology is the leading cause of Ross procedure failure. To define risk and outcome of autograft valve/root repair at reoperation, a 17-year experience was analysed. METHODS One hundred and thirty-two consecutive late survivors underwent cross-sectional clinical and echocardiographic examination on average 10.8 ± 14.7 years (range 0.4-17) after Ross procedure. Study endpoints were hospital and late morbidity, freedom from autograft reoperation, freedom from root/valve replacement and functional outcome after valve/root repair. RESULTS Twenty-seven (20%) patients underwent 33 cardiac reoperations, the first on average 7.7 ± 4.5 years (range 0.08-16.2) after Ross operation. Nineteen had undergone root replacement, 5 inclusion cylinder and 3 subcoronary grafting. Indication was root pathology in 17 (63%) patients and isolated valve in 10. Surgery consisted in valve repair/sparing in 17 patients and valve/root replacement in 10, with no hospital mortality. Freedom from any autograft valve/root reoperation was 74 ± 5% at 15 years. No patient with valve/root replacement required second reoperation. Instead, 6/17 (35%) patients having autograft valve repair/sparing and followed for 4.2 ± 2.9 years (range 0.3-10.8) required re-repair/AVR, while 11 present mild AI or less. Freedom from autograft valve/root replacement was 83 ± 5% at 15 years. At multivariate analysis, predictors of reoperation were age at Ross (P = 0.002) and use of root technique (P = 0.049). Failure of autograft valve repair/sparing was associated with isolated valve pathology (P = 0.014) and earlier reoperation (P = 0.002). Pre-repair autograft insufficiency was significant at univariate analysis only (P = 0.01). CONCLUSIONS Autograft reoperation carries negligible hospital risk. Pulmonary valve sparing or repair is feasible in half of patients with Ross failure. Concomitant root remodelling and absence of preoperative severe valve dysfunction predict successful and durable repair.

Diagnosis of infection in paediatric veno-arterial cardiac extracorporeal membrane oxygenation: role of procalcitonin and C-reactive protein

OBJECTIVES Plasma concentration of procalcitonin (PCT) and its value in the diagnosis of infection in paediatric patients treated with extracorporeal membrane oxygenation (ECMO) are undefined. This study aimed to define the levels of PCT and C-reactive protein (CRP) in paediatric cardiac ECMO patients and to determine their role in predicting infection, severity of organ dysfunction and clinical outcome. METHODS PCT and CRP plasma concentrations were measured daily in 20 consecutive infants and young children treated with veno-arterial ECMO. Each patient was examined daily for signs of infection and multiple organ dysfunction syndrome (MODS). A total of 139 patient days were classified for infection and MODS. RESULTS The median PCT and CRP plasma concentrations were not increased during infection: 2.4 vs 8.8 ng/ml and 223.8 vs 240.6 mg/l, in patients with vs without infection, respectively. PCT, but not CRP, was significantly elevated during MODS (10.9 vs 1.85 ng/ml) (P = 0.001). The area under the receiver operating characteristic (ROC) curve was 0.984 for PCT (95% confidence interval [CI], 0.962-1.000) compared with 0.347 for CRP (95% CI, 0.211-0.484) (P = 0.001). Only PCT differed significantly in patients weaned from ECMO who survived (2.6 ng/ml) vs patients not weaned from ECMO (10.5 ng/ml) (P = 0.001). The area under the ROC curve was 0.871 (95% CI, 0.786-0.956) compared with 0.261 for CRP (95% CI, 0.145-0.377) (P = 0.001). CONCLUSIONS Neither PCT nor CRP are reliable markers of infection in paediatric cardiac ECMO patients. However, high levels of PCT are associated with MODS. PCT may be used as a prognostic indicator of clinical outcome in this high-risk population.

Hyperglycemia and angiotensin II cooperate to enhance collagen I deposition by cardiac fibroblasts through a ROS-STAT3-dependent mechanism

Cardiac fibroblasts significantly contribute to diabetes-induced structural and functional changes in the myocardium. The objective of the present study was to determine the effects of high glucose (alone or supplemented with angiotensin II) in the activation of the JAK2/STAT3 pathway and its involvement in collagen I production by cardiac fibroblasts. We observed that the diabetic environment 1) enhanced tyrosine phosphorylation of JAK2 and STAT3; 2) induced nuclear localization of tyrosine phosphorylated STAT3 through a reactive oxygen species-mediated mechanism, with angiotensin II stimulation further enhancing STAT3 nuclear accumulation; and 3) stimulated collagen I production. The effects were inhibited by depletion of reactive oxygen species or silencing of STAT3 in high glucose alone or supplemented with exogenous angiotensin II. Combined, our data demonstrate that increased collagen I deposition in the setting of high glucose occurred through a reactive oxygen species- and STAT3-dependent mechanism. Our results reveal a novel role for STAT3 as a key signaling molecule of collagen I production in cardiac fibroblasts exposed to a diabetic environment.

Repair of Congenitally Dysplastic Aortic Valve by Bicuspidization: Midterm Results

BACKGROUND Repair of congenital aortic valve (CAV) lesions may be achieved by creation of either tricuspid or bicuspid valve morphology. To define feasibility and outcome of CAV repair by bicuspidization a 10-year experience was reviewed. METHODS Between January 2002 and December 2011, 147 consecutive patients underwent operation for CAV insufficiency; 58 had valve or root repair (group 1) and 89 had valve or root replacement (group 2). Patients having repair were younger (42.9 vs 51.3 years, p=0.001), with lesser prevalence of severe insufficiency (72% vs 90%, p=0.002). In patients having repair, morphology of CAV was bicuspid in 51, monocuspid in 4, and quadricuspid in 3, whereas in the replacement group it was bicuspid in 87 and quadricuspid in 2 (p=0.04). Surgery consisted of an isolated aortic valve procedure in 20 versus 45 patients, associated with aortic root or ascending aortic repair in 38 versus 44 patients, in group 1 versus 2 (p=0.04). RESULTS There were no hospital and 3 late deaths during a mean follow-up of 3.8±2.5 years (range 0.2 to 10.0). Eight-year survival (89%±10% vs 97%±2% [p=0.7]), freedom from valve-related events (84%±10% vs 89%±4% [p=0.8]), and freedom from aortic valve reoperation (95%±3% vs 93%±3% [p=0.6]) were comparable. Risk factors for reoperation at univariate analysis were isolated valve surgery (p=0.001), Ross operation (p=0.001), and endocarditis (p=0.002). Follow-up echocardiography of repair patients showed mild or less aortic insufficiency in 51 (88%) and mild or less stenosis in 57 (98%). CONCLUSIONS Valve repair by preservation or creation of bicuspid morphology is feasible in almost half of all comers with CAV insufficiency, with satisfactory and stable midterm functional outcome. Rates of valve-related adverse events and reoperation are similar to those of patients having replacement.

Long-Term Follow-Up Study of Temporary Tricuspid Valve Detachment as Approach to VSD Repair without Consequent Tricuspid Dysfunction

Temporary tricuspid valve detachment improves the operative view of certain congenital ventricular septal defects (VSDs), but its long-term effects on tricuspid valve function are still debated. From 2002 through 2012, we performed a prospective study of 68 children (mean age, 1.28 ± 1.01 yr) who underwent transatrial closure of VSDs following temporary tricuspid valve detachment. Sixty patients had conoventricular and 8 had mid-muscular VSDs. All were in sinus rhythm. Seventeen patients had systemic pulmonary artery pressures. Preoperative echocardiograms showed trivial-to-mild tricuspid regurgitation in 62 patients and tricuspid dysplasia with severe regurgitation in 6 patients. Patients were clinically and echocardiographically monitored at 30 postoperative days, 3 months, 6 months, every 6 months thereafter for the first 2 years, and then once a year. No in-hospital or late death was observed at the median follow-up evaluation of 5.9 years. Mean intensive care unit and hospital stays were 1.6 ± 1.1 and 7.3 ± 2.7 days, respectively. Residual small VSDs occurred in 3 patients, and temporary atrioventricular block in one. After VSD repair, 62 patients (91%) had trivial or mild tricuspid regurgitation, and 6 moderate. Five of these last had severe tricuspid regurgitation preoperatively and had undergone additional tricuspid valve repair during the procedure. The grade of residual tricuspid regurgitation remained stable postoperatively, and no tricuspid stenosis was documented. All patients were in New York Heart Association class I at follow-up. Temporary tricuspid valve detachment is a simple and useful method for a complete visualization of certain VSDs without incurring substantial tricuspid dysfunction.

Pediatric veno-arterial extracorporeal membrane oxygenation in fulminant hemophagocytic lymphohistiocytosis.

To the Editor, Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease, which may be difficult to timely diagnose because the clinical presentation mimics other conditions like severe sepsis, hepatic failure, meningitis, and malignancies (1). Extracorporeal life support/extracorporeal membrane oxygenation (ECLS/ECMO) in the pediatric population for short-term bridge to recovery and decision or for long-term bridge to transplantation has become standard of care. The need to perform differential diagnosis of potentially recoverable conditions (myocarditis, sepsis, other) is imperative during fatal evolution of an unknown disease. However, the use of ECLS/ECMO as bridge to diagnosis is not well established (unclear risk/benefit, unclear cost-effectiveness). A 4-year-old male presenting with circulatory collapse and lethargy, in the absence of a reliable working diagnosis and with the possibility of a fulminant myocarditis episode with secondary central nervous system involvement, was transferred to our Pediatric Cardiac-Surgery Unit for emergent ECLS. Via left femoral artery and left internal jugular vein cannulation, veno-arterial ECMO was started using a pediatric magnetic levitation pump (Levitronix LLC, Waltham, MA, USA), a polymethylpentene-coated oxygenator (EOS ECMO, Sorin-Group, Mirandola, Italy), and biocompatible circuits (A.g.i.l.e. Eurosets, Medolla, Italy). In line with the hypothesis of viral myocarditis or encephalitis, steroid pulse therapy with dexamethasone was administered. After 24 h of ECMO support and wash out of sedative drugs, neurological evaluation was compatible with nonreactive mydriasis. Considering the need for electroencephalogram (EEG) examination and the risk of electrical interference with the ECMO device, echocardiographic assessment was repeated to establish feasibility of weaning from mechanical life support. Given the evidence of slight improvement in biventricular function, gradual weaning from ECMO was completed (Fig. 1A). At first, hemodynamic parameters were stable, cardiac rhythm was 70/bpm, stable lactate, with marked polyuria. EEG tracing was isoelectric and compatible with brain death. After a few hours, multiple organ failure had progressed, and the patient died on the same day due to III-grade AV heart block followed by asystole on second day of hospital stay. Autopsy was performed to define the diagnosis. Histopathologic analysis of specimens taken during autopsy of bone marrow and lymph nodes determined the diagnosis of HLH. Bone marrow showed infiltrating histiocytes with abundant cytoplasm and oval or lobulated nuclei with prominent nucleoli. Most of the histiocytes showed phagocytosis of red blood cell (Fig. 1B). Widespread infiltration of histiocytes and marked hypocellularity of other cellular elements were even shown in the lymph nodes and bone marrow. HLH incidence is reported to be 1.2 cases-permillion persons per year with a male to female ratio 1:1. Virus-associated HLH (VAHS), first described by Risdall et al. (2), is related to herpes viruses, cytomegalovirus, human parvovirus B19, human herpes virus type 6, adenovirus, rubella virus, HIV, and influenza virus. A prognostically unfavorable form of VAHS is associated with Epstein–Barr virus (EBV), called EBV-HLH, which develops mostly in children and young adults and shows fulminant and fatal manifestations. Although the VAHS occurs most commonly in children and adolescents living in Asian counties, for unclear reasons, it has also been reported to occur sporadically in Western countries (3). It is uniformly fatal without treatment and mortality remains significant for patients treated in accordance with the HLH-94 protocol (2.5-year survival rates, range 10–85%). Intensive supportive care is crucial during the acute phase of illness to prevent the numerous lifethreatening complications that may develop, but is not always a sufficient condition to prevent fatal evolution. In this setting, ECMO support offers a chance to stabilize circulatory and respiratory function thereby allowing for recovery of ventricular function. HLH is a systemic disease and, without suitable therapy, there is no possibility to modify the prognosis. Unfortunately, HLH is difficult to diagnose, because it mimics other fatal disease processes (myocarditis, meningoencephalitis, sepsis), which doi:10.1111/aor.12115 bs_bs_banner

Comparison Between D901 Lilliput 1 and Kids D100 Neonatal Oxygenators: Toward Bypass Circuit Miniaturization

Progress in biomaterial technology and improvements in surgical and perfusion strategy ameliorated morbidity and mortality in pediatric cardiac surgery. In this study, we describe our clinical experience comparing performance of two neonatal oxygenators. From January 2002 to March 2011, 159 infants with less than 5 kg body weight underwent heart surgery. Ninety-four patients received a D901 Lilliput 1 oxygenator with standard bypass circuit (group A), while 65 received a D100 Kids with miniaturized bypass circuit (group B). Miniaturization consisted in shortened arterial, venous, cardioplegia, and pump-master lines. Priming composition consisted in Ringers acetate solution with addition of albumin and blood, with target hematocrit of 24% or greater. In group B cardiopulmonary bypass (CPB) was vacuum-assisted and started with an empty venous line. Modified ultrafiltration and Cell-Saver blood infusion was routinely applied in both groups. Average ± standard deviation (SD) age at repair was 37 ± 38 days in group A and 59 ± 60 days in group B (P = 0.005). Average ± SD weight, height, and body surface area were 3.5 ± 0.7 kg, 52 ± 4 cm, and 0.22 ± 0.03 m(2) , respectively, in group A, and 3.7 ± 1 kg, 53 ± 5 cm, and 0.23 ± 0.02 m(2) , respectively, in group B (P = not significant [NS]). Male sex was predominant (55 vs. 58%, P = NS). Priming volume was 524 ± 67 mL (group A) and 337 ± 53 mL (group B) (P = 0.001). There were no statistical differences in hemoglobin at the start, during, and at the end of CPB, but group A required higher blood volume added to the prime (111 ± 33 vs. 93 ± 31 mL, P = 0.001). In group B, two surgical procedures were completed in total hemodilution. In group B, CPB time and aortic cross-clamp time were shorter than in group A (106 ± 52 vs. 142 ± 78 min and 44 ± 31 vs. 64 ± 31 min, respectively, P = 0.001). There were 16 hospital deaths in group A and 4 in group B (P = 0.04). Durations of mechanical ventilation and intensive care unit stay were 5.3 ± 3.2 vs. 4.1 ± 3.2 days (P = 0.02) and 6.5 ± 4.9 vs. 5.1 ± 3 days (P = 0.03), respectively. There were significant differences in inotropic score (1083 ± 1175 vs. 682 ± 938, P = 0.04) and blood postoperative transfusion (153 ± 226 vs. 90 ± 61 mL, P = 0.04). Twenty-seven patients in group A and 10 in group B presented with major adverse postoperative complications (P = 0.04). Use of neonatal oxygenators with low priming volume, associated with a miniaturized bypass circuit, seems to be a favorable strategy to decrease postoperative morbidity after cardiac surgery in neonates and infants.

Impaired angiotensin II-extracellular signal-regulated kinase signaling in failing human ventricular myocytes.

Angiotensin II was reported to induce insulin-like growth factor-I and endothelin-1 gene expression and peptide release by ventricular cardiomyocytes. However, the progression from cardiac hypertrophy to failure in humans is characterized by a reduced myocyte expression of insulin-like growth factor-I and endothelin-1, notwithstanding the enhanced cardiac generation of angiotensin II. In the present study we investigated the functional status of the signaling pathways responsible for angiotensin II-induced endothelin-1 and insulin-like growth factor-I formation in human ventricular myocytes isolated from patients with dilated (n = 19) or ischemic (n = 14) cardiomyopathy and nonfailing donor hearts (n = 6). In human nonfailing ventricular myocytes, angiotensin II (100 nmol/l) induced insulin-like growth factor-I and endothelin-1 gene expression, and peptide release was mediated by extracellular signal-regulated kinase activation and inhibited by extracellular signal-regulated kinase antagonism (PD98059, 30 μmol/l), endothelin-1 formation being partially reduced also by c-Jun N-terminal kinase inhibition (SP600125, 10 μmol/l); insulin-like growth factor-I and endothelin-1 formations were unaffected by the inhibition of p38 mitogen-activated protein kinase (SB203580, 10 μmol/l) and Janus tyrosine kinase 2 (AG490, 10 μmol/l). In failing myocytes, angiotensin II failed to induce insulin-like growth factor-I and endothelin-1 formation; angiotensin II-induced extracellular signal-regulated kinase activation was significantly impaired (−88% vs. controls) although c-Jun NH2-terminal kinase activation was preserved. The impaired extracellular signal-regulated kinase phosphorylation in failing myocytes was associated with increased myocyte levels of mitogen-activated protein kinase phosphatases. Therefore, the altered growth factor production in failing myocytes is associated with a significant derangement in intracellular signaling.

Minimal-access median sternotomy for aortic valve replacement

A variety of minimally-invasive approaches for aortic valve replacement (AVR) have been developed and are increasingly being utilized. The different approaches described, such as partial upper sternotomy, right parasternal thoracotomy or transverse sternotomy have the aim to decrease invasiveness and reduce surgical trauma. Whereas port access surgery with remote cannulation has the attendant risks inherent with peripheral cardiopulmonary bypass and limitations in terms of myocardial protection and adequate cardiac dearing, partial sternotomies or thoracotomies may be associated with suboptimal chest wall reconstruction. Here described is a technique of minimal-access aortic valve replacement, which entails limited skin incision and full median sternotomy. Advantages of the present approach include a superior cosmetic result, when compared to standard sternotomy incision, and the safety of the midline access, which may be immediately converted into standard approach, in case of need, and is associated with stable chest wall reconstruction. Selective indications and outcome of minimal-access AVR are discussed.