Mechanically assisted bidirectional cavopulmonary shunt in neonates and infants: An acute human pilot study.

OBJECTIVE: Poor survival following surgical palliation for hypoplastic left heart syndrome (HLHS) raises the question of the need for a paradigm shift. This is the first human study to investigate the possibility of primary "in-series" palliation in neonates and infants with HLHS in an acute setting with the aid of 2 types of mechanical assist: superior vena cava (SVC)-to-pulmonary artery (PA) pump assist and SVC-to-right atrium (RA) oxygenation assist. METHODS: By rearranging the cannula sites and flow rates for modified ultrafiltration, 2 types of mechanically assisted bidirectional cavopulmonary shunt (BCPS) circulation were simulated for 20 minutes. Three neonates undergoing a stage I Norwood procedure were assigned to SVC-PA pump assist, and 3 infants undergoing stage II BCPS were assigned to SVC-RA oxygenation assist. Hemodynamic parameters, blood gas values, and arterial (SaO2) and regional cerebral tissue (rCTO2) saturations were analyzed. RESULTS: All 6 patients completed the study without hemodynamic compromise. In the SVC-PA pump assist group, a mean arterial pressure >40 mm Hg was maintained. SVC pressure was lower (P = .01) and cerebral perfusion pressure (CPP) was higher (P = .03) during the last 10 minutes of assist compared with Norwood physiology. SaO2 >80%, rCTO2 >60%, and mixed venous saturation ≥59% were maintained, comparable to values with Norwood physiology. In the SVC-RA oxygenation assist group, with full or 50% support, mean blood pressure >50 mm Hg, SVC pressure <15 mm Hg, mixed venous saturation >50%, and CPP >40 mm Hg were maintained, which were comparable to BCPS physiology. CONCLUSIONS: Two types of mechanical assist to support primary in-series palliation are feasible in the acute setting. Both modes of mechanical assist maintained oxygenation, as well as systemic and cerebral perfusion.

Is indexed preoperative superior vena cava blood flow a risk factor in patients undergoing bidirectional cavopulmonary shunt?

BACKGROUND: This study evaluated the effect of a new measurement-superior vena cava (SVC) flow-and anatomic factors on postoperative arterial oxygen saturation and clinical outcome in patients who underwent bidirectional cavopulmonary shunt (BCPS). METHODS: We reviewed 19 patients who underwent a BCPS between January 2009 and May 2011 who also had SVC blood flow measurements. Median age was 6 months (range, 2 to 29 months). Body weight was 7.0 ± 1.7 kg. Bilateral SVCs were present in 4. SVC flow was measured at the time of BCPS by a Transonic flow probe (Transonic Systems Inc, Ithaca, NY). SVC flow, preoperative hemodynamics, pulmonary artery size, and clinical outcome were analyzed to determine risk for morbidity and death. RESULTS: Mean absolute and indexed pre-BCPS SVC flow was 0.65 ± 0.23 L/min and 1.63 ± 0.55 L/min/m(2) or 91.1 ± 30.8 mL/kg/min, respectively. In all but 1 patient, the SVC flow was increased after BCPS from 1.63 ± 0.55 to 1.99 ± 0.57 L/min/m(2) (p = 0.005). There was a significant positive correlation between pre-BCPS and post-BCPS SVC flow (r = 0.627, p = 0.029). Pulmonary artery size correlated with post-BCPS SVC flow (r = 0.560, p = 0.016). Two patients with preoperative SVC flow of below 1.0 L/min/m(2) died or required BCPS takedown. SVC size did not correlate with BCPS flow (r = 0.231, p = 0.356). Univariate analysis indicated pre-BCPS pulmonary artery pressure was a risk factor for low arterial oxygen saturation (≤ 75%) immediately after BCPS (p = 0.042) and at discharge (p = 0.030). CONCLUSIONS: A new indicator-low SVC flow, may be a marker for BCPS failure or death, suggesting that the SVC flow vs size is more important in predicting successful BCPS.

Primary in-series palliation of hypoplastic left heart syndrome with mechanical lung assist in neonatal pigs.

Less than optimal outcomes for hypoplastic left heart syndrome may be related to unstable in-parallel circulation. Mechanical lung assist by (1) superior vena cava to right atrium pump with oxygenation (oxygenator assist), or (2) superior vena cava to pulmonary artery pump (pump assist) may permit successful neonatal in-series palliation. Nineteen 15-day-old piglets underwent single ventricle and bidirectional cavopulmonary shunt (BCPC) creation without mechanical lung assist (n = 8), with pump assist (n = 5), or with oxygenator assist (n = 6). Baseline hemodynamic measurements were not different between groups. Median survival for the cavopulmonary shunt alone, pump assist, and oxygenator assist groups was 28, 180, and 180 minutes, respectively (p = 0.0006). No differences in arterial oxygen concentration or bicarbonate levels were detected. Arterial carbon dioxide (p < or = 0.007) was higher in the cavopulmonary shunt alone versus lung assist groups. Cavopulmonary shunt alone animals had decreased mean arterial pressure (p < 0.02) and cerebral perfusion pressure (p = 0.029) and elevated left atrial pressure compared with lung assist groups (p < 0.05). This data demonstrates creation of a novel translational neonatal BCPC model in which mechanical lung assist augments survival. Early BCPC death was related to poor ventricular function and an inability to ventilate, issues that were improved with both types of lung assist.

Mechanical cavopulmonary assist maintains pulmonary and cerebral blood flow in a piglet model of a bidirectional cavopulmonary shunt with high pulmonary vascular resistance.

OBJECTIVES: We tested mechanical cavopulmonary blood flow assist by incorporating a novel miniature centrifugal pump into a 1(1/2)-ventricle type cavopulmonary connection in neonatal pigs. METHODS: Nine 3-week-old piglets (mean body weight, 10.2 kg) were used: mechanical cavopulmonary assist (n = 6) and controls (n = 3). A bidirectional cavopulmonary connection between the superior vena cava and the main pulmonary artery was created. The superior vena cava and pulmonary artery were also connected by cannulas with an interposed centrifugal pump. The cavoarterial mechanical cavopulmonary assist was performed at pump speeds of 1500, 2000, 2500, and 3000 rpm. Retrograde superior vena caval flow was limited by a band on the superior vena cava. A bidirectional cavopulmonary connection was created in the control animals, which then had a pure 1(1/2)-ventricle repair physiology without mechanical support. Hemodynamics, blood gas, and cerebral blood flow measured by ultrasound were analyzed. Catheter-based dilatation of the surgically created superior vena cava obstruction was tested. RESULTS: Incremental increases in pump speed augmented bidirectional cavopulmonary shunt blood flow (P =.03) and diminished superior vena caval pressure (P =.03), thereby improving cerebral perfusion pressure. Pump flow of 3000 rpm was equivalent to baseline superior vena caval flow (before caval flow, 392 +/- 48 mL/min vs MCPA, 371 +/- 120 mL/min; mean +/- SD; P = not significant). The mechanical cavopulmonary assist group had higher Doppler velocities of the middle cerebral artery and higher transcerebral oxygen difference(P < .05) than controls. Balloon dilatation of the superior vena cava band was successful. CONCLUSIONS: Mechanical cavopulmonary assist maintained bidirectional cavopulmonary shunt flow, thereby sustaining primary bilateral cavopulmonary shunt physiology in a neonatal pig model of high pulmonary vascular resistance. The mechanical cavopulmonary assist maintained cerebral blood flow and metabolism with an adequate transcerebral pressure gradient.

Smooth muscle protein 22alpha-mediated patchy deletion of Bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling.

Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22alpha;TRE-Cre/LoxP;R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O2) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.

A novel mechanical lung assist system sustains primary bidirectional cavopulmonary shunt circulation in pigs.

Primary creation of a bidirectional cavopulmonary shunt (BCPS), which provides a stable in-series circulation, might improve survival in patients with hypoplastic left heart syndrome. However, pulmonary vascular immaturity and high pulmonary vascular resistance must be overcome to achieve a successful primary neonatal BCPS. This study tested the hypothesis that a novel mechanical lung assist (MLA) system would permit a primary BCPS in juvenile pigs. A BCPS (1(1/2) ventricle repair physiology) was created in nine 4-5-week-old pigs (mean weight 17.9 kg), followed by MLA with a miniature centrifugal pump and a hand-made double-lumen cannula for 2 hours. Systemic and cerebral hemodynamic and metabolic data were evaluated. A mean BCPS flow of 331 +/- 56 ml/min was obtained with a mean pump speed of 3899 +/- 306 rpm at 30 minutes after MLA initiation. Adequate oxygenation, ventilation, and hemodynamics were maintained. Transcranial Doppler ultrasound demonstrated consistent pre- and postoperative peak systolic and diastolic velocities of the middle cerebral artery, indicating sustained cerebral perfusion pressure. This study demonstrated that the MLA is able to sustain a high-resistance BCPS and provides a strategy or rationale for developing a primary neonatal cavopulmonary connection in appropriately selected neonates with congenital heart disease.

ROCK controls matrix synthesis in vascular smooth muscle cells: coupling vasoconstriction to vascular remodeling.

Tenascin-C (TN-C) is an extracellular matrix (ECM) protein expressed within remodeling systemic and pulmonary arteries (PAs), where it supports vascular smooth muscle cell (SMC) proliferation. Previously, we showed that A10 SMCs cultivated on native type I collagen possess a spindle-shaped morphology and do not express TN-C, whereas those on denatured collagen possess a well-defined F-actin stress fiber network, a spread morphology, and they do express TN-C. To determine whether changes in cytoskeletal architecture control TN-C, SMCs on denatured collagen were treated with cytochalasin D, which decreased SMC spreading and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling effectors required for TN-C transcription. Next, to determine whether cell shape, dictated by the F-actin cytoskeleton, regulates TN-C, different geometries of SMCs (ranging from spread to round) were engineered on denatured collagen: as SMCs progressively rounded, ERK1/2 activity and TN-C transcription declined. Because RhoA and Rho kinase (ROCK) regulate cell morphology by controlling cytoskeletal architecture, we reasoned that these factors might also regulate TN-C. Indeed, SMCs on denatured collagen possessed higher levels of RhoA activity than those on native collagen, and blocking RhoA or ROCK activities attenuated SMC spreading, ERK1/2 activity, and TN-C expression in SMCs on denatured collagen. Thus, ROCK controls the configuration of the F-actin cytoskeleton and SMC shape in a manner that is permissive for ERK1/2-dependent production of TN-C. Finally, we showed that inhibition of ROCK activity suppresses SMC TN-C expression and disease progression in hypertensive rat PAs. Thus, in addition to its role in regulating vasoconstriction, ROCK also controls matrix production.

Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension.

Transgenic mice overexpressing the calcium binding protein, S100A4/Mts1, occasionally develop severe pulmonary vascular obstructive disease. To understand what underlies this propensity, we compared the pulmonary vascular hemodynamic and structural features of S100A4/Mts1 with control C57Bl/6 mice at baseline, following a 2-week exposure to chronic hypoxia, and after 1 and 3 months "recovery" in room air. S100A4/Mts1 mice had greater right ventricular systolic pressure and right ventricular hypertrophy at baseline, which increased further with chronic hypoxia and was sustained after 3 months "recovery" in room air. These findings correlated with a heightened response to acute hypoxia and failure to vasodilate with nitric oxide or oxygen. S100A4/Mts1 mice, when compared with C57Bl/6 mice, also had impaired cardiac function judged by reduced ventricular elastance and decreased cardiac output. Despite higher right ventricular systolic pressures with chronic hypoxia, S100A4/Mts1 mice did not develop more severe PVD, but in contrast to C57Bl/6 mice, these features did not regress on return to room air. Microarray analysis of lung tissue identified a number of genes differentially upregulated in S100A4/Mts1 versus control mice. One of these, fibulin-5, is a matrix component necessary for normal elastin fiber assembly. Fibulin-5 was localized to pulmonary arteries and associated with thickened elastic laminae. This feature could underlie attenuation of pulmonary vascular changes in response to elevated pressure, as well as impaired reversibility.

Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension.

BACKGROUND: We previously reported that administration of elastase inhibitors reverses fatal pulmonary arterial hypertension (PAH) in rats by inducing smooth muscle cell (SMC) apoptosis. We showed in pulmonary artery (PA) organ culture that the mechanism by which elastase inhibitors induce SMC apoptosis involves repression of matrix metalloproteinase (MMP) activity and subsequent signaling through alphavbeta3-integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH. METHODS AND RESULTS: In this study, we first showed in PA organ culture that MMP inhibition or alphavbeta3-integrin blockade with agents in clinical and preclinical use (SC-080 and cilengitide, respectively) mediates SMC apoptosis and regression of medial hypertrophy. We also documented similar results with an EGFR tyrosine kinase inhibitor. We then induced PAH in rats by injection of monocrotaline and, at day 21, began a 2-week treatment with SC-080, cilengitide, or the EGFR inhibitor PKI166. No vehicle- or cilengitide-treated animal survived beyond 2 weeks. Administration of SC-080 resulted in 44% survival at 2 weeks, and PKI166 therapy resulted in 78% and 54% survival in daily or 3-times-weekly treated animals, respectively. Four weeks after cessation of PKI166, we documented survivals of 50% and 23% in the 2 treatment groups, associated with reductions in pulmonary pressure, right ventricular hypertrophy, and abnormally muscularized distal arteries. CONCLUSIONS: We propose that selective blockade of EGFR signaling may be a novel strategy to reverse progressive, fatal PAH.

Outcomes of mitral valve replacement in children: a competing-risks analysis.

OBJECTIVE: We sought to define patient characteristics, outcomes, and associated factors after mitral valve replacement in children. METHODS: We included 104 children undergoing at least one mitral valve replacement between 1980 and 2003 and reviewed clinical records. Competing-risks methodology was used to determine time-related prevalence and associated risk factors after initial mitral valve replacement for death and repeat replacement. RESULTS: The underlying mitral valve disease was congenital in 83%, rheumatic in 13%, Marfan syndrome in 3%, and isolated endocarditis in 1%, with 64% having primarily regurgitation, 16% having stenosis, 20% having both, and 32% having undergone previous valvotomy, valvuloplasty, or repair. There were 137 valve replacements, with 26 patients having more than one. Valve prosthesis type was St Jude Medical in 37%, Bjork-Shiley in 25%, Carbomedics in 20%, Ionescu-Shiley in 10%, and other types in 8%. Both early and late complications were common. Median age at the initial replacement was 5.9 years (range, birth to 19 years). Competing-risks analysis predicted 19% to have died at 15 years after initial replacement, with risk factors including noncongenital valve morphology, lower weight, and longer duration of cardiopulmonary bypass. A repeat replacement was predicted for 71%, with risk factors including the presence of multiple left-heart obstructive lesions and Ionescu-Shiley valve prosthesis. CONCLUSIONS: Mitral valve replacement might be necessary in children with extremely dysplastic valves and severe hemodynamic impairment or after failed repair. However, with the appropriate selection of the prosthetic valve and reduction of cardiopulmonary bypass time, surgeons might decrease mortality and increase prosthesis longevity.

Low molecular weight heparin and unfractionated heparin are both effective at accelerating pulmonary vascular maturation in neonatal rabbits.

BACKGROUND: Creation of a bi-directional cavopulmonary shunt after the Norwood procedure for hypoplastic left heart syndrome is delayed to allow pulmonary vascular resistance to fall with maturation of the pulmonary vascular bed. We hypothesized that unfractionated heparin (UFH) and low molecular weight heparin (LMWH), which promote angiogenesis and inhibit smooth muscle cell growth, could accelerate this process. METHODS AND RESULTS: Fifty-six newborn rabbits were randomly selected to receive UFH 225U/kg (n=12), LMWH 1 mg/kg (n=14), LMWH 10 mg/kg (n=16), or saline (n=14) by subcutaneous injection every 12 hours for 14 days. Treatment with heparin reduced mean pulmonary artery (PA) pressure by 12% to 16% relative to controls [9.0+/-0.2 (UFH), 9.4+/-0.1 (LMWH 1 mg/kg), 9.2+/-0.2 (LMWH 10 mg/kg) versus 10.7+/-0.2 mm Hg (saline), P=0.0001]. Lower PA pressures were associated with reduced alveolar:arterial ratio consistent with enhanced pulmonary angiogenesis in heparin treated animals [8+/-1 (UFH), 13+/-2 (LMWH 1 mg/kg), 12+/-2 (LMWH 10 mg/kg) versus 23+/-5 (saline), P<0.03]. Reduced PA medial wall thickness and muscularization, two additional features of pulmonary vascular maturation, were also more evident in heparin treated animals. Mean PA pressures in 14-day-old rabbits treated with heparin were lower than those measured in control rabbits less than 7 weeks of age suggesting that heparin shortens the pulmonary vascular maturation process by over 60%. CONCLUSIONS: These results indicate that both UFH and LMWH are effective at accelerating pulmonary vascular maturation in newborn rabbits. This raises the possibility that administration of heparin to children after the Norwood procedure might allow for earlier conversion to a bi-directional cavopulmonary shunt.

Extending the usable size range of homografts in the pulmonary circulation: outcome of bicuspid homografts.

BACKGROUND: Small-sized homografts are often not available, making the use of surgically reduced cryopreserved homograft conduits appealing. METHODS: From January 1993 to January 2000, 21 large homografts were size-reduced by excising one leaflet and were implanted in the pulmonary circulation. Valve function was compared with 21 children-matched for weight, homograft size, and year of operation-who received a standard homograft. RESULTS: Implanted homograft size and patient weight were equivalent in both the bicuspid and standard groups. Median (range) in-hospital peak instantaneous echocardiographic gradient across the valve was 0 mm Hg (0 to 19) in the bicuspid group versus 0 mm Hg (0 to 17) in the standard group (p = 0.65). Median (range) in-hospital pulmonary insufficiency (scale of 0 to 4) was 2 (0 to 3) in the bicuspid group versus 1.5 (0 to 3) in the standard group (n = 10, p = 0.34). At a follow-up of 54+/-29 months there was no significant difference in conduit reinterventions between the groups. CONCLUSIONS: Surgical creation of a bicuspid valve in the pulmonary circulation results in a functionally equivalent conduit compared with standard homograft as measured by early and midterm valve function.