Christopher A. Caldarone

Hypoplastic Left Heart Syndrome : Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients.

Factors Associated With Mortality and Reoperation in 377 Children With Total Anomalous Pulmonary Venous Connection

Background— We sought to determine era-specific changes in the incidence of mortality and reoperation in children with total anomalous pulmonary venous connection. Methods and Results— We reviewed the records of 377 children presenting from 1946 to 2005 with total anomalous pulmonary venous connection. Multivariable parametric regression models determined the incidence and risk factors for death and reoperation after repair. Pulmonary venous connection was supracardiac in 44%, infracardiac in 26%, cardiac in 21%, and mixed in 9%. Pulmonary venous obstruction was present in 48% at presentation, most frequently with infracardiac connection type (P<0.001). In total, 327 patients were repaired (median age, 1.7 months). Overall survival from repair was 65±6% at 14 years, with a current survival of 97%. Significant (P<0.01) incremental risk factors for postrepair death were cardiac connection type, earlier operation year, younger age at repair, use of epinephrine postoperatively, and postoperative pulmonary venous obstruction. More recent operation year was associated with younger age at repair (P<0.001), decreased use of deep hypothermic circulatory arrest (P<0.001), and use of specific drugs postoperatively (P<0.001). Risk-adjusted estimated 1-year survival for a patient repaired at birth with unfavorable morphology in 2005 is 37% (95% CI, 8 to 80) compared with 96% (95% CI, 91 to 99) for a patient with favorable morphology repaired at 1 year of age. Freedom from reoperation was 82±6% at 11 years after repair, with increased risk associated with mixed connection type (P=0.04) and postoperative pulmonary venous obstruction (P<0.001). Conclusions— Mortality after total anomalous pulmonary venous connection repair has decreased but remains highest in young patients and in those with cardiac connection type or pulmonary venous obstruction. Unfavorable anatomic characteristics remain important determinants of postrepair survival despite improved perioperative care.

Long-Term Survival After Mitral Valve Replacement in Children Aged <5 Years A Multi-Institutional Study

Background—Short- and long-term outcomes after prosthetic mitral valve replacement (MVR) in children aged <5 years are ill-defined and generally perceived as poor. The experience of the Pediatric Cardiac Care Consortium (45 centers, 1982 to 1999) was reviewed. Methods and Results—MVR was performed 176 times on 139 patients. Median follow-up was 6.2 years (range 0 to 20 years, 96% complete). Age at initial MVR was 1.9±1.4 years. Complications after initial MVR included heart block requiring pacemaker (16%), endocarditis (6%), thrombosis (3%), and stroke (2%). Patient survival was as follows: 1 year, 79%; 5 years, 75%; and 10 years, 74%. The majority of deaths occurred early after initial MVR, with little late attrition despite repeat MVR and chronic anticoagulation. Among survivors, the 5-year freedom from reoperation was 81%. Age-adjusted multivariable predictors of death include the presence of complete atrioventricular canal (hazard ratio 4.76, 95% CI 1.59 to 14.30), Shone’s syndrome (hazard ratio 3.68, 95% CI 1.14 to 11.89), and increased ratio of prosthetic valve size to patient weight (relative risk 1.77 per mm/kg increment, 95% CI 1.06 to 2.97). Age- and diagnosis-adjusted prosthetic size/weight ratios predicted a 1-year survival of 91% for size/weight ratio 2, 79% for size/weight ratio 3, 61% for size/weight ratio 4, and 37% for size/weight ratio 5. Conclusions—Early mortality after MVR can be predicted on the basis of diagnosis and the size/weight ratio. Late mortality is low. These data can assist in choosing between MVR and alternative palliative strategies.

A sutureless technique for the relief of pulmonary vein stenosis with the use of in situ pericardium.

Pulmonary vein (PV) stenosis develops as a progressive and usually lethal complication after surgical repair of total anomalous PV connection. Conventional surgical repair for the management of recurrent PV stenosis has been generally unsuccessful because of proliferative neointimal hyperplasia resulting in recurrent PV obstruction. The factors that result in recurrent stenosis after the usual types of patch venoplasty are unknown. We speculated that direct suturing of PVs and patch material may be the substrate for turbulent blood flow triggering intimal hyperplasia and eventual narrowing of the vein. On the basis of these considerations, we developed a sutureless technique for repairing PV stenosis with in situ pericardium. We present here its early but promising results. Patients PATIENT 1. Patient 1 was born in January 1995 with infradiaphragmatic total anomalous PV connection and severe obstruction of the descending vertical vein. On day 1, the infradiaphragmatic anomalous vein was ligated and the confluence was anastomosed to the left atrium under conditions of hypothermic circulatory arrest. At 6 months, the child had conspicuous tachypnea. Echocardiography revealed obstructed left PVs with a mean gradient of 7 mm Hg (peak 16 mm Hg) and suprasystemic right ventricular pressure. Angiocardiography demonstrated variable obstruction of all four PVs, with a mean pulmonary artery pressure of 38 mm Hg (systolic 92 mm Hg). At reoperation, obstruction of all PVs was confirmed. Under conditions of circulatory arrest, a pedicled flap of free right atrial wall–superior vena cava junction based at the inferior vena cava was used to patch the right-sided veins and carried behind the aorta to patch the left upper PV. The left lower vein was repaired with a flap created from the left atrial appendage. After that operation, the child had repeated admissions with respiratory tract infections, complicated at 1 year by hemoptysis. Echocardiography revealed recurrence of obstruction. At the second reoperation, atretic left-sided veins and severe stenosis of right-sided veins were noted. The PVs were opened, and an in situ pericardial sutureless patch was used for reconstruction. Echocardiography a year later showed patent veins, with mean gradients of 4 mm Hg on the right side and 5 mm Hg on the left. The estimated mean pulmonary artery pressure was 10 mm Hg. Perfusion lung scan showed 67% perfusion on the right side and 33% on the left. The child currently has no symptoms. PATIENT 2. Patient 2, a female infant, was born on January 1995 with total anomalous PV connection to coronary sinus with echocardiographic evidence of partial obstruction. At 2 weeks, she underwent repair consisting of unroofing of the coronary sinus, as described by Van Praagh and Harken. On completion of the procedure, the patient could not be weaned from cardiopulmonary bypass. At this time the right ventricular pressure was suprasystemic. The child was placed on extracorporeal membrane oxygenator and subsequently weaned after 3 days, with delayed sternal closure in 10 days as a result of persistent hemodynamic instability. Echocardiographic findings before discharge revealed unobstructed PV confluence–left atrium connection. However, echocardiography 4 months later revealed an obstructed right upper PV with a mean right ventricular pressure of 25 mm Hg. Perfusion scan showed 87% perfusion to the left lung and 13% to the right. Eleven months after the operation, echocardiography and cardiac catheterization revealed pulmonary hypertension, with a mean pulmonary artery pressure of 34 mm Hg and anatomically right PV stenosis. At reoperation, the presence of severe bilateral PV stenosis extending from left atrium a variable distance into the intraparenchymal PVs was confirmed. An in situ pericardial baffle was used for repair, as described here. Cardiac catheterization 6 months later revealed normal venous drainage on the left side and mild obstruction on the right side. The mean pulmonary artery pressure was 16 mm Hg. Perfusion lung scan showed 42% to left lung and 58% to right. The child has no symptoms at 15 months of postoperative follow-up. Technique. Standard cardiopulmonary bypass technique is used. The incision is made into the left atrium and extended into both upper and lower PV ostia separately (Fig. 1, A). This incision can be carried into the secondary, and if necessary, the tertiary branches of both the upper and lower lobe veins to a level at which the intima appears grossly normal. The pericardium overlying the entrance of the PVs is used to create an enlarged communication between the opened PVs and the left atrium. The neoatrium is created by suturing the pericardium to the epicardium of the left atrium, completely circumscribing the opening in the left atrium and PVs so that the PV effluent is contained by pericardium. The reconstruction is From the Division of Cardiovascular Surgery, Department of Surgery, Hospital of Sick Children, and University of Toronto Faculty of Medicine, Toronto, Ontario, Canada.

Risk, Clinical Features, and Outcomes of Thrombosis Associated With Pediatric Cardiac Surgery

Background— Thrombosis, usually considered a serious but rare complication of pediatric cardiac surgery, has not been a major clinical and/or research focus in the past. Methods and Results— We noted 444 thrombi (66% occlusive, 60% symptomatic) in 171 of 1542 surgeries (11%). Factors associated with increased odds of thrombosis were age <31 days (odds ratio [OR], 2.0; P=0.002), baseline oxygen saturation <85% (OR, 2.0; P=0.001), previous thrombosis (OR, 2.6; P=0.001), heart transplantation (OR, 4.1; P<0.001), use of deep hypothermic circulatory arrest (OR, 1.9 P=0.01), longer cumulative time with central lines (OR, 1.2 per 5-day equivalent; P<0.001), and postoperative use of extracorporeal support (OR, 5.2; P<0.001). Serious complications of thrombosis occurred with 64 of 444 thrombi (14%) in 47 of 171 patients (28%), and were associated with thrombus location (intrathoracic, 45%; extrathoracic arterial, 19%; extrathoracic venous, 8%; P<0.001), symptomatic thrombi (OR, 8.0; P=0.02), and partially/fully occluding thrombi (OR, 14.3; P=0.001); indwelling access line in vessel (versus no access line) was associated with lower risk of serious complications (OR, 0.4; P=0.05). Thrombosis was associated with longer intensive care unit (+10.0 days; P<0.001) and hospital stay (+15.2 days; P<0.001); higher odds of cardiac arrest (OR, 4.9; P<0.001), catheter reintervention (OR, 3.3; P=0.002), and reoperation (OR, 2.5; P=0.003); and increased mortality (OR, 5.1; P<0.001). Long-term outcome assessment was possible for 316 thrombi in 129 patients. Of those, 197 (62%) had resolved at the last follow-up. Factors associated with increased odds of thrombus resolution were location (intrathoracic, 75%; extrathoracic arterial, 89%; extrathoracic venous, 60%; P<0.001), nonocclusive thrombi (OR, 2.2; P=0.01), older age at surgery (OR, 1.2 per year; P=0.04), higher white blood cell count (OR, 1.1/109 cells per 1 mL; P=0.002), and lower fibrinogen (OR, 1.4/g/L; P=0.02) after surgery. Conclusions— Thrombosis affects a high proportion of children undergoing cardiac surgery and is associated with suboptimal outcomes. Increased awareness and effective prevention and detection strategies are needed.

Outcomes and Associated Risk Factors for Aortic Valve Replacement in 160 Children A Competing-Risks Analysis

Background— We sought to define patient characteristics, outcomes, and associated risk factors after aortic valve replacement (AVR) in children. Methods and Results— Clinical records from children undergoing AVR from 1974 to 2004 at our institution were reviewed. Competing-risks methodology determined the time-related prevalence of 3 mutually exclusive end states: death, repeated replacement, and survival without subsequent AVR and their associated risk factors. Longitudinal echocardiographic data were analyzed by mixed linear-regression models. Children (n=160) underwent 198 AVRs, with 33 having >1. Competing-risks analysis predicted that 10 years from the initial AVR, 19% had died without subsequent AVR, 34% underwent a second AVR, and 47% remained alive without replacement. Risk factors for death without a second AVR included lower weight (P<0.001) and younger age at AVR (P=0.04), performance of aortic arch reconstruction together with AVR (P=0.03), and nonautograft use (P=0.03). Risk factors for a second AVR included earlier operation year (P=0.04) and implantation of a bioprosthetic or homograft valve (P=0.004). Analysis of serial echocardiographic measurements showed that pulmonary autograft use was associated with slower progression of peak aortic gradient (P=0.002), smaller left ventricular dimension (P=0.04), and decreased prevalence of aortic regurgitation (P=0.04). Conclusions— Mortality and repeated valve replacement are common after initial AVR in children, especially in younger patients and those with bioprosthetic or homograft valves. Pulmonary autograft use is associated with decreased mortality, slower gradient progression, and smaller left ventricular dimension.

Clinical Features, Management, and Outcome of Children With Fetal and Postnatal Diagnoses of Isomerism Syndromes

Background— Isomerism is associated with a complex spectrum of anomalies. There is paucity of data on prenatally detected cases. Methods and Results— Between January 1990 and February 2004, 83 of 166 cases (50%) had a prenatal diagnosis of left isomerism (LAI; 52 of 97) or right isomerism (RAI; 31 of 69) at our institution. The spectrum of anomalies, management, and outcomes was compared for fetal and postnatal diagnoses of LAI and RAI. RAI more often than LAI was associated with AV septal defect (90% versus 56%; P<0.0001), pulmonary outflow obstruction (91% versus 37%; P<0.0001), total anomalous pulmonary venous drainage (73% versus 13%; P<0.0001), and abnormal VA connections (68% versus 33%; P<0.0001), whereas inferior vena cava interruption (3% versus 93%; P<0.0001), complete AV block (0% versus 13%; P=0.004), aortic obstruction (6% versus 33%; P<0.0001), and extracardiac defects (5% versus 25%; P=0.006) were less common. The spectrum of lesions was comparable for fetal and postnatal cases, except for AV block (fetal, 25%; postnatal, 0%; P=0.0002) and AV septal defect (fetal, 67%; postnatal, 42%; P=0.023) in LAI. Fetal demise was due mainly to pregnancy termination (LAI, 42%; RAI, 45%). Survival of actively managed children with LAI was significantly better than for those with RAI (P<0.0001) but did not differ with regard to fetal versus postnatal diagnosis. Most LAI cases required no intervention or underwent successful biventricular cardiac surgery (65%), unlike RAI cases (13%; P<0.0001). Conclusions— Prenatal diagnosis did not affect overall survival despite facilitated care. The prognosis of RAI was worse compared with LAI because of more complex associated cardiac defects and the inability to perform successful surgical procedures.

New Developments in the Treatment of Hypoplastic Left Heart Syndrome

In the current decade, the prognosis of newborns with hypoplastic left heart syndrome, previously considered a uniformly fatal condition, has dramatically improved through refinement of rapidly evolving treatment strategies. These strategies include various modifications of staged surgical reconstruction, orthotopic heart transplantation, and hybrid palliation using ductal stenting and bilateral pulmonary artery banding. The variety of treatment approaches are based on different surgical philosophies, and each approach has its unique advantages and disadvantages. Nonetheless, multiple experienced centers have reported improved outcomes in each one of those modalities. The purpose of this review is to outline recent developments in the array of currently available management strategies for neonates with hypoplastic left heart syndrome. Because the vast majority of deaths in this patient population occur within the first months of life, the focus of the review will be evaluation of the impact of these management strategies on survival in the neonatal and infant periods.

Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction

AIMS Pathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-β1 (TGF-β1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-β1 by inducing a conformational change in the latent complex. The mesenchymal integrins αvβ5 and αvβ3 are expressed in the heart, but their role in the activation of TGF-β1 remains elusive. Here, we test whether targeting αvβ5 and αvβ3 integrins reduces latent TGF-β1 activation by cardiac fibroblasts with the goal to prevent the formation of α-smooth muscle actin (α-SMA)-expressing cardiac myofibroblasts and their contribution to fibrosis. METHODS AND RESULTS Using a porcine model of induced right ventricular fibrosis and pro-fibrotic culture conditions, we show that integrins αvβ5 and αvβ3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-β1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-β1 activation by cardiac fibroblast contraction and loss of α-SMA expression, which is restored by adding active TGF-β1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-β1 activation and induction of α-SMA expression. CONCLUSIONS Integrins αvβ5 and αvβ3 both control myofibroblast differentiation by activating latent TGF-β1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-β1 activation by cardiac myofibroblasts and progression of fibrosis in the heart.

Hybrid Versus Norwood Strategies for Single-Ventricle Palliation

Background— Hybrid and Norwood strategies differ substantially in terms of stage II palliative procedures. We sought to compare these strategies with an emphasis on survival and reintervention after stage II and subsequent Fontan completion. Methods and Results— Of 110 neonates with functionally single-ventricle physiology who underwent stage I palliation between 2004 and 2010, 75 (69%) infants (Norwood, n=43; hybrid, n=32) who subsequently underwent stage II palliation were studied. Survival and reintervention rates after stage II palliation, anatomic and physiologic variables at pre-Fontan assessment, and Fontan outcomes were compared between the groups. Predictors for reintervention were analyzed. Freedom from death/transplant after stage II palliation was equivalent between the groups (Norwood, 80.4% versus hybrid, 85.6% at 3 years, P=0.66). Hybrid patients had a higher pulmonary artery (PA) reintervention rate (P=0.003) and lower Nakata index at pre-Fontan evaluation (P=0.015). Aortic arch and atrioventricular valve reinterventions were not different between the groups. Ventricular end-diastolic pressure, mean PA pressure, and ventricular function were equivalent at pre-Fontan assessment. There were no deaths after Fontan completion in either group (Norwood, n=25, hybrid, n=14). Conclusions— Survival after stage II palliation and subsequent Fontan completion is equivalent between the groups. The hybrid group had a higher PA reintervention rate and smaller PA size. Both strategies achieved adequate physiology for Fontan completion. Evolution of the hybrid strategy requires refinement to provide optimal PA growth.