Mohamed Ly

Surgical management of congenital heart defects associated with heterotaxy syndrome

OBJECTIVE Heterotaxy syndrome (HS) is generally associated with complex congenital cardiac defects and has a high morbidity and mortality despite recent surgical progress. Only few reports deal with an overall surgical population. METHODS Between 1989 and 2008, 139 patients with HS entered a programme of surgical repair. Fifty-one patients were suitable for univentricular heart repair (UVR) and 88 for biventricular repair (BVR). Among those tracked for UVR, two were switched to BVR and 11 from BVR to UVR. Median age at first surgery was 4.4 months (range: 3 days to 43 years] of whom 34 were neonates. The mean number of surgical procedure per patient was 1.99. Primary BVR was performed in 37 patients. Re-operation was required in 22 patients, 15 after BVR and seven after UVR (p>0.05). RESULTS The overall mortality was 20.8%. It was 7.2% after the first surgery, 6.6% after the second and 11.5% after the third. The overall mortality in patients with univentricular physiology was 25.5% and 18.2% in the biventricular group (p<0.05). According to the surgical track, in the UVR group, mortality was 18% and 15.6% in the BVR group (p=NS). This rate was 40% in patients with long-lasting palliation (p<0.05 vs both other groups). Median follow-up was 127 months (range: 1 month to 19 years). The overall survival rate at 15 years was 70.6%. When considering ventricular anatomy, survival rates at 15 years were 69% for the univentricular group and 74.2% for the biventricular group (p>0.05). According to the type of surgical approach, at 15 years they were 85.1% for UVR and 77% for BVR (p=NS). For the palliation group, it was 15% only at 15 years (p<0.05 vs both other groups). Risk factors for overall mortality were neonatal surgery, long-standing palliation, total anomalous pulmonary vein return (TAPVR) and right ventricular outflow tract obstruction (RVOTO). At the last visit, all survivors were in the New York Heart Association (NYHA) class I to II and only two presented with supraventricular arrhythmias. CONCLUSIONS HS remains a difficult situation with high morbidity and mortality. An aggressive approach to repair TAPVR when present should be considered. Early decision to track the patient in either uni- or biventricular repair programme should avoid long-lasting deleterious palliation.

Right ventricular failure secondary to chronic overload in congenital heart diseases: benefits of cell therapy using human embryonic stem cell-derived cardiac progenitors.

OBJECTIVE Despite the increasing incidence of right ventricular (RV) failure in adult patients with congenital heart disease, current therapeutic options are still limited. By contrast to left-heart diseases, cell-based myocardial regeneration applied to the right ventricle is poorly studied, even though it may be a therapeutic solution. As human embryonic stem cell-derived cardiac progenitors seem to be good candidates owing to their proliferation capacity, our aim was to assess, in a large animal model of overloaded RV dysfunction, the feasibility and effects of such a cell therapy. METHODS Human MesP1(+)/SSEA-1(+) cardiogenic mesodermal cells were administered using multiple intramyocardial injections 4 months after a surgical procedure mimicking the repaired tetralogy of Fallot, and their effects were observed 3 months later on hemodynamic, rhythmic, and histologic parameters. RESULTS All pigs (sham n = 6, treated n = 6) survived without complication, and cell therapy was clinically well tolerated. Although functional, contractility, and energetics parameters evolved similarly in both groups, benefits regarding arrhythmic susceptibility were observed in the treated group, associated with a significant decrease of peri-myocyte fibrosis (5.71% ± 2.49% vs 12.12% ± 1.85%; P < .01) without interstitial fibrosis change (5.18% ± 0.81% vs 5.49% ± 1.01%). Such a decrease could be related to paracrine effects, as no human cells could be detected within the myocardium. CONCLUSIONS Cell therapy using intramyocardial injections of human MesP1(+)/SSEA-1(+) cardiogenic mesodermal cells seems to have benefits regarding overloaded RV tissue remodeling and arrhythmic susceptibility, but this mode of administration is not sufficient to obtain a significant improvement in RV function.

Long-term outcomes of the arterial switch operation for transposition of the great arteries and ventricular septal defect and/or aortic arch obstruction.

OBJECTIVES Long-term outcomes after the arterial switch operation (ASO) for complex transposition of the great arteries (TGA) should be clarified. METHODS A retrospective study was conducted in patients operated on between 1982 and 1998. Overall 220 postoperative survivors, 79.1% with a ventricular septal defect, 13.2% with multiple ventricular septal defects, and 29.1% with aortic arch obstruction, were followed for 17 years (0-28 years). RESULTS The conditional survival rate was 96.7% [95% confidence interval (CI): 94.4-99.1] at 25 years. Late sudden death occurred in 2 asymptomatic patients. The cumulative incidence rate of death or reinterventions was 3.8% (95% CI: 2.9-4.8) at 25 years, with age at ASO <10 days and aortic regurgitation at discharge identified as independent risk factors. The cumulative incidence rate of neoaortic regurgitation was 41.6% (95% CI: 20.5-62.8) at 25 years with an aorto-pulmonary diameter mismatch at the time of the ASO, age at ASO <10 days and aortic regurgitation at discharge identified as independent risk factors. At the last follow-up, 53 patients (24.1%) had neoaortic root dilatation with an aortic sinus z-score ≥3 and 6 of them had a Bentall operation at a median delay of 14.1 years since the ASO. The only independent factors for neoaortic root dilatation were male sex and an aorto-pulmonary diameter mismatch at the time of the ASO. CONCLUSIONS Despite a continual rate of reinterventions, long-term survival and cardiovascular outcome are excellent after ASO for complex TGA. Dilatation of the neoaortic root and neoaortic regurgitation may be observed with time and 2 late sudden deaths occurred, justifying a close follow-up in all patients.

Experimental Evidence of Bacterial Colonization of Human Coronary Microvasculature and Myocardial Tissue during Meningococcemia

ABSTRACT Meningococcal septic shock is associated with profound vasoplegia, early and severe myocardial dysfunction, and extended skin necrosis responsible for a specific clinical entity designated purpura fulminans (PF). PF represents 90% of fatal meningococcal infections. One characteristic of meningococcal PF is the myocardial dysfunction that occurs in the early phase of sepsis. Furthermore, hemodynamic studies have shown that the prognosis of meningococcal sepsis is directly related to the degree of impairment of cardiac contractility during the initial phase of the disease. To gain insight into a potential interaction of Neisseria meningitidis with the myocardial microvasculature, we modified a previously described humanized mouse model by grafting human myocardial tissue to SCID mice. We then infected the grafted mice with N. meningitides. Using the humanized SCID mouse model, we demonstrated that N. meningitidis targets the human myocardial tissue vasculature, leading to the formation of blood thrombi, infectious vasculitis, and vascular leakage. These results suggest a novel mechanism of myocardial injury in the course of severe N. meningitidis sepsis that is likely to participate in primary myocardial dysfunction.

Atrio-ventricular valve regurgitation in univentricular hearts: outcomes after repair

OBJECTIVES The aim was to describe the early and mid-term outcome after atrio-ventricular valve (AVV) repair in patients with univentricular hearts (UVHs) and to identify risk factors for AVV reoperation and death. METHODS This study is a retrospective review of patients undergoing valve repair for AVV regurgitation at any stage of univentricular palliation from 1998 to 2014. Patient- and procedure-related variables were analysed. RESULTS A total of 31 consecutive patients underwent 38 procedures for ≥ moderate AVV regurgitation at a median age of 3.6 years. Thirty-two percent of patients had a common AVV, 26% had two AVVs, 22% had a dominant tricuspid valve and 19% had a dominant mitral valve. All patients underwent valve repair as a first procedure without early mortality. At discharge, patients preserved their ventricular function (fractional shortening <30%: preoperative 16% vs postoperative 22.5%, NS). In 19% (n = 6) of patients, the procedure was considered as failed because of significant residual regurgitation. There were three late deaths [median delay: 1 year (range 0.7-13.6)] and three heart transplantations. Six patients underwent seven AVV reoperations [median delay: 2 years (range 0.2-7.6)]. Longer intensive care stay (P = 0.022), longer total postoperative hospital stay (P = 0.039), higher total number of surgeries (P = 0.039), lower body mass index (P = 0.042) and higher preoperative mean pulmonary pressure (P = 0.047) were univariate risk factors for death/transplantation. Failed first AVV repair (P = 0.01), higher total number of surgeries (P = 0.026), lower body mass index (P = 0.031), male gender (P = 0.031) and need for valve repair before bidirectional cavopulmonary connection (P = 0.036) were univariate risk factors for AVV reoperation. In multivariate analysis, no univariate risk factor reached statistical significance. Freedom from death/transplantation was 84% (CI 95%: 70%-98%) at 5 and 10 years. Survival free from AVV reoperation was 72% (CI 95%: 52%-92%) at 5 years and 62% at 10 years (CI 95%: 36%-88%). Mean follow-up of survivors was 4.7 years (SD ± 4.3; range 0.2-15.6). At last visit, 96% of survivors were in NYHA Class I-II. Ninety-two percent had a ≤ mild residual regurgitation. CONCLUSIONS In patients with a UVH and ≥ moderate AVV regurgitation, AVV repair is feasible without postoperative deterioration of their ventricular function. Nevertheless, these patients remain at increased risk for death/transplantation and AVV reoperation.

Heart transplantation in adults with congenital heart disease

With the advances in congenital cardiac surgery and postoperative care, an increasing number of children with complex congenital heart disease now reach adulthood. There are already more adults than children living with a congenital heart defect, including patients with complex congenital heart defects. Among these adults with congenital heart disease, a significant number will develop ventricular dysfunction over time. Heart failure accounts for 26-42% of deaths in adults with congenital heart defects. Heart transplantation, or heart-lung transplantation in Eisenmenger syndrome, then becomes the ultimate therapeutic possibility for these patients. This population is deemed to be at high risk of mortality after heart transplantation, although their long-term survival is similar to that of patients transplanted for other reasons. Indeed, heart transplantation in adults with congenital heart disease is often challenging, because of several potential problems: complex cardiac and vascular anatomy, multiple previous palliative and corrective surgeries, and effects on other organs (kidney, liver, lungs) of long-standing cardiac dysfunction or cyanosis, with frequent elevation of pulmonary vascular resistance. In this review, we focus on the specific problems relating to heart and heart-lung transplantation in this population, revisit the indications/contraindications, and update the long-term outcomes.

Standard and Strain Measurements by Echocardiography Detect Early Overloaded Right Ventricular Dysfunction: Validation against Hemodynamic and Myocyte Contractility Changes in a Large Animal Model

Background Early detection of right ventricular (RV) failure is required to improve the management of patients with congenital heart diseases. The aim of this study was to validate echocardiography for the early detection of overloaded RV dysfunction, compared with hemodynamic and myocyte contractility assessment. Methods Using a porcine model reproducing repaired tetralogy of Fallot, RV function was evaluated over 4 months using standard echocardiography and speckle‐tracking compared with hemodynamic parameters (conductance catheter). Sarcomere shortening and calcium transients were recorded in RV isolated myocytes. Contractile reserve (&Dgr;Emax) was assessed by &bgr;‐adrenergic stimulation in vivo (dobutamine 5 &mgr;g/kg) and ex vivo (isoproterenol 100 nM). Results Six operated animals were compared with four age‐ and sex‐matched controls. In the operated group, hemodynamic RV efficient ejection fraction was significantly decreased (29.7% [26.2%–34%] vs 42.9% [40.7%–48.6%], P < .01), and inotropic responses to dobutamine were attenuated (&Dgr;Emax was 51% vs 193%, P < .05). Echocardiographic measurements of fraction of area change, tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity (S′) and RV free wall longitudinal systolic strain and strain rate were significantly decreased. Strain rate, S′, and tricuspid annular plane systolic excursion were correlated with &Dgr;Emax (r = 0.75, r = 0.78, and r = 0.65, respectively, P < .05). These alterations were associated in RV isolated myocytes with the decrease of sarcomere shortening in response to isoproterenol and perturbations of calcium homeostasis assessed by the increase of spontaneous calcium waves. Conclusions In this porcine model, both standard and strain echocardiographic parameters detected early impairments of RV function and cardiac reserve, which were associated with cardiomyocyte excitation‐contraction coupling alterations. HighlightsTwo‐dimensional speckle‐tracking is a valid tool if compared to the conductance catheter to detect early RV systolic dysfunction.Despite load dependency, alterations of both echocardiographic standard and strain parameters are consistent with RV and myocyte contractile impairments.Subclinical alterations of RV systolic standard and strain parameters should be considered as the first sign of RV dysfunction and should require specific management in patients with right heart diseases.

0391: Atrio-ventricular valve regurgitation in univentricular hearts: outcomes after repair

Objective To describe the early and midterm outcome after atrio-ventricular valve (AVV) procedure in patients with univentricular hearts (UVH) and to identify risk factors for AVV reoperation and death. Methods Retrospective review of patients undergoing procedure for AVV regurgitation at any phase of univentricular palliation from 1998-2013. Patient and procedure related variables were analyzed. Results 28 consecutive patients underwent 34 procedures for moderate+ AVV regurgitation at a median age of 3.7 years. 29% of patients had a common, 25% had dominant left, 14% had dominant right AVV and 32% two AVV. All patients benefited from valve repair at first procedure without early mortality. At hospital discharge patients preserved their ventricular function (FS Conclusion Patients with UVH and moderate+ atrio-ventricular valve regurgitation can profit from AVV repair without deterioration of their ventricular function but remain at increased risk for death and AVV reoperation.

0089 : Echocardiography and right ventricular function: validation of functional criteria compared to in-vivo and ex-vivo contractility parameters

Background Right ventricular (RV) dysfunction is a major determinant of long-term survival in congenital heart diseases. Early echocardiographic detection of RV failure is mandatory, but recent parameters need to be validated. Aims Objectives were to: (1) validate standard and strain echocardiographic parameters for evaluation of RV systolic function, compared to hemodynamic parameters; (2) assess the accuracy of these parameters for early detection of RV failure. Methods Combined RV overload as observed in repaired tetralogy of Fallot was surgically reproduced in 2-month-old piglets (n=6). Age-matched piglets were used as controls (n=4). RV function was evaluated at baseline and 4 months of follow-up by standard and strain echocardiographic parameters, compared to hemodynamic (conductance catheter). Sarcomere shortening and calcium transients were recorded in RV isolated myocytes (IonOptix). Contractile reserve was assessed by in-vivo (dobutamine 5奯kg) and ex-vivo (isoprenaline 100nM) ?-adrenergic stimulation. Results 4 months after surgery, hemodynamic RV ejection fraction (FEVD) was significantly decreased (29.7% [26.2-34] vs 42.9% [40.7-48.6], p Conclusion In this model, both standard and strain echocardiographic parameters allowed the detection of early impairments of RV function and cardiac reserve, which are associated with cardiac excitation-contraction coupling alterations.

0090 : Human cardiac progenitor cell seeded-collagen patches for cell therapy applied to right ventricular dysfunction: preliminary results in a large animal model

Background Cell therapy using intramyocardial injections of cardiac progenitors issued from human embryonic stem cells showed benefits on overloaded right ventricular (RV) tissue remodelling and arrhythmic susceptibility but this delivery mode failed to improve RV function. Our aim was to evaluate in a porcine model of overloaded RV dysfunction a new delivery mode of such therapy. Methods A combined overloaded RV dysfunction was obtained in piglets using a surgical procedure mimicking repaired tetralogy of Fallot. After 4 months, cell therapy was surgically administrated using 2 types of human NKX2.5+ cardiac progenitor cell-seeded collagen patches applied on the epicardium: QGel® and pressured-patches. Myocardial function was measured 1 month after transplantation by conductance catheter technique and echocardiography (standard and strain). The fate of progenitors was studied using antibodies directed against Ki67, CD31, actinin and Islet1. Results All pigs survived without any complication. Pressured-patches allowed human progenitors to migrate across the complete myocardium while QGel® patches restricted the cell migration to only a third of the myocardium. In both cases, progenitors differentiated toward the cardiac lineage assessed by Islet1 and actinin expression and maintained their proliferation capacity. Concerning RV function, only pressured-patches (N=3) tended to improve the contractility (Emax slope). By contrast, this parameter decreased in QGel® patches animals (N=2). Moreover, in 2 pressured-patch animals, standard echocardiographic functional parameters (FAC, TAPSE, s’wave) were maintained while 2D strain and strain rate values increased. Conclusion Cell therapy using seeded-patches was more conservative for engrafted cells than intramyocardial injections but only pressured-patches seemed to give benefits on overloaded RV function and contractility. These first promising results need to be checked at longer term.