Richard A. Jonas

Forty-one years of surgical experience with congenital supravalvular aortic stenosis.

OBJECTIVEnSeveral techniques for symmetric reconstruction of the aortic root in congenital supravalvular aortic stenosis have been developed, but it remains unclear whether these prove superior to patch enlargement of the noncoronary sinus alone. We reviewed our experience with surgical treatment of supravalvular aortic stenosis and investigated the impact of the surgical technique on long-term results.nnnMETHODS AND RESULTSnSeventy-five patients underwent operations to treat congenital supravalvular aortic stenosis at our institution between 1957 and 1998. Surgical procedures included patch enlargement of the noncoronary sinus only (n = 34), inverted bifurcated patch plasty (n = 35), and 3-sinus reconstruction of the aortic root (n = 6). There were 7 early deaths. Among those who survived the operation, 100% were alive at 5 years, 96% were alive at 10 years, and 77% were alive at 20 years. According to time-related analysis diffuse stenosis of the ascending aorta proved a risk factor for both survival and reoperation (P <.01 for each). Patients with multiple-sinus reconstructions of the aortic root accounted for only 2 of the 14 reoperations and none of the late deaths (both P <.001). Residual gradients were lower after multiple-sinus reconstruction of the aortic root (median 10 mm Hg vs 20 mm Hg for patch enlargement of the noncoronary sinus only, P =. 008), as was the prevalence of moderate aortic regurgitation at follow-up (3% vs 22%, P =.05).nnnCONCLUSIONSnResults of operations for supravalvular aortic stenosis improved greatly after the introduction of more symmetric reconstructions of the aortic root. Multiple-sinus reconstructions (inverted bifurcated patch plasty and 3-sinus reconstruction) resulted in superior hemodynamics and were associated with reductions in both mortality rate and need for reoperation.

The importance of patient-specific preoperative factors: an analysis of the society of thoracic surgeons congenital heart surgery database.

BACKGROUNDnThe most common forms of risk adjustment for pediatric and congenital heart surgery used today are based mainly on the estimated risk of mortality of the primary procedure of the operation. The goals of this analysis were to assess the association of patient-specific preoperative factors with mortality and to determine which of these preoperative factors to include in future pediatric and congenital cardiac surgical risk models.nnnMETHODSnAll index cardiac operations in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) during 2010 through 2012 were eligible for inclusion. Patients weighing less than 2.5 kg undergoing patent ductus arteriosus closure were excluded. Centers with more than 10% missing data and patients with missing data for discharge mortality or other key variables were excluded. Rates of discharge mortality for patients with or without specific preoperative factors were assessed across age groups and were compared using Fishers exact test.nnnRESULTSnIn all, 25,476 operations were included (overall discharge mortality 3.7%, n=943). The prevalence of common preoperative factors and their associations with discharge mortality were determined. Associations of the following preoperative factors with discharge mortality were all highly significant (p<0.0001) for neonates, infants, and children: mechanical circulatory support, renal dysfunction, shock, and mechanical ventilation.nnnCONCLUSIONSnCurrent STS-CHSD risk adjustment is based on estimated risk of mortality of the primary procedure of the operation as well as age, weight, and prematurity. The inclusion of additional patient-specific preoperative factors in risk models for pediatric and congenital cardiac surgery could lead to increased precision in predicting risk of operative mortality and comparison of observed to expected outcomes.

Novel diazinone derivatives separate myofilament Ca2+ sensitization and phosphodiesterase III inhibitory effects in guinea pig myocardium.

The inotropic state of the myocardium can be enhanced via an increase in cell Ca2+ loading or in myofilament responsiveness to Ca2+. Although different pharmacological agents combine these properties, no presently available drug acts predominantly as a myofilament sensitizer in situ. We have investigated the effects and the mechanism of action of novel diazinone derivatives, EMD 54622, EMD 53998, and EMD 54650 (developed by E. Merck, Darmstadt), on guinea pig myocardial preparations. Force- and ATPase-pCa relations in skinned fibers show differing potencies of these agents on myofilament sensitization: EMD 54622 greater than EMD 53998 much greater than EMD 54650. This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650 greater than EMD 53998 greater than EMD 54622. In isolated hearts studied at constant coronary flow, each of the three diazinone derivatives had a positive inotropic effect. In enzymatically dissociated left ventricular myocytes loaded with the Ca2+ probe indo-1, the positive inotropic effect of EMD 54622 occurred with no change in the amplitude of the cytosolic [Ca2+] (Cai) transient. In contrast, both EMD 53998 and EMD 54650 enhanced Cai transient and twitch contraction amplitudes. Length-indo-1 fluorescence relations were analyzed to determine the effects of the three substances on myofilament responsiveness to Ca2+. EMD 54622 enhanced and EMD 54650 had no effect on myofilament responsiveness to Ca2+. Less uniform results were obtained with EMD 53998 (in two of five cells the myofilament responsiveness to Ca2+ was increased, whereas in three other cells it was unaltered). Our results indicate that structural changes in the diazinone molecule shift the mechanism of action for the positive inotropic effect of the diazinone derivatives in the intact cell from a predominant myofilament sensitization (EMD 54622) to an enhancement in cell Ca2+ loading and an augmentation in the Cai transient (EMD 54650).

Neurobehavioral Abnormalities in Newborns with Congenital Heart Disease Requiring Open-Heart Surgery

In a prospective study, we evaluated the perioperative application of the Neonatal Intensive Care Unit Network Neurobehavioral Scale in a cohort of newborns with congenital heart disease (CHD). Infants with CHD were found to have suboptimal neurobehavioral performance compared with healthy infants without CHD, with particular vulnerability in the Regulation and Stress subscales.

Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation.

In the past 2 decades, it has become evident that individuals born with congenital heart disease (CHD) are at risk of developing life-long neurological deficits. Multifactorial risk factors contributing to neurodevelopmental abnormalities associated with CHD have been identified; however, the underlying causes remain largely unknown, and efforts to address this issue have only recently begun. There has been a dramatic shift in focus from newly acquired brain injuries associated with corrective and palliative heart surgery to antenatal and preoperative factors governing altered brain maturation in CHD. In this review, we describe key time windows of development during which the immature brain is vulnerable to injury. Special emphasis is placed on the dynamic nature of cellular events and how CHD may adversely impact the cellular units and networks necessary for proper cognitive and motor function. In addition, we describe current gaps in knowledge and offer perspectives about what can be done to improve our understanding of neurological deficits in CHD. Ultimately, a multidisciplinary approach will be essential to prevent or improve adverse neurodevelopmental outcomes in individuals surviving CHD.

Aprotinin confers neuroprotection by reducing excitotoxic cell death

OBJECTIVEnAprotinin is used in cardiac surgery for its anti-inflammatory and hemostatic benefits. Recent reports describe the neuroprotective effects of other serine protease inhibitors via reduced excitotoxic cell death, a common pathway causing cytotoxic edema induced in various neuropathologic conditions. The purpose of this study was to investigate whether aprotinin directly protects against glutamatergic excitotoxicity in cell cultures.nnnMETHODSnMixed cortical cultures containing neuronal and glial cells were prepared from fetal mice at 13 to 15 days gestation and plated on a layer of confluent astrocytes from 1- to 3-day-old postnatal pups. Near-pure neuronal culture containing less than 5% astrocytes was obtained from the same gestational stage and plated in multiwell vessels previously coated with poly-D-lysine and laminin. Both cultures were used at 12 to 14 days in vitro. Slowly triggered excitotoxicity was induced at 37 degrees C by 24-hour exposure to 12.5 microM N-methyl-D-aspartate or 50 microM kainate. Neuronal death was quantified by measuring the release of lactate dehydrogenase from damaged cells into the bathing medium. Data were analyzed by analysis of variance with post hoc Bonferroni comparisons.nnnRESULTSnAprotinin at a clinically relevant concentration of 100 KIU/mL significantly reduced N-methyl-D-aspartate-induced neuronal death in both pure and mixed cultures (P < .001). Aprotinin also reduced neuronal death induced by kainate from 36% to 23% in mixed cortical culture (P = .008) and from 40% to 27% in near-pure culture (P = .015), indicating that the neuroprotective effects of aprotinin are mediated directly through neurons.nnnCONCLUSIONnAprotinin provides direct neuroprotection against glutamatergic excitotoxicity as demonstrated by reduced neuronal death in near-pure neuronal cell culture. Additional studies are needed to evaluate the potential of aprotinin to reduce neurologic injury in patients at high risk of cerebral injury, including those undergoing circulatory arrest.

Abnormal neurogenesis and cortical growth in congenital heart disease

Congenital heart disease depletes SVZ neural stem/progenitor cell pools critical for normal cortical growth. Getting to the heart of the matter in brain development Congenital heart disease (CHD), the most common birth defect in newborns, can be associated with developmental delays. Although reduced blood flow, genetic factors, and brain injury are thought to contribute, the cellular mechanisms underlying abnormal brain development due to CHD are unclear. Morton et al. used a piglet model of neonatal hypoxia to study the relationship between neural stem/progenitor cells and cortical development. Chronic hypoxia reduced the number of stem/progenitor cells within the subventricular zone in piglet brains, which limited the number of interneurons and cortical growth. These findings were also seen in brain tissue from human infants with CHD. Long-term neurological deficits due to immature cortical development are emerging as a major challenge in congenital heart disease (CHD). However, cellular mechanisms underlying dysregulation of perinatal corticogenesis in CHD remain elusive. The subventricular zone (SVZ) represents the largest postnatal niche of neural stem/progenitor cells (NSPCs). We show that the piglet SVZ resembles its human counterpart and displays robust postnatal neurogenesis. We present evidence that SVZ NSPCs migrate to the frontal cortex and differentiate into interneurons in a region-specific manner. Hypoxic exposure of the gyrencephalic piglet brain recapitulates CHD-induced impaired cortical development. Hypoxia reduces proliferation and neurogenesis in the SVZ, which is accompanied by reduced cortical growth. We demonstrate a similar reduction in neuroblasts within the SVZ of human infants born with CHD. Our findings demonstrate that SVZ NSPCs contribute to perinatal corticogenesis and suggest that restoration of SVZ NSPCs’ neurogenic potential is a candidate therapeutic target for improving cortical growth in CHD.

Personal Glimpses Into the Evolution of Truncus Arteriosus Repair

Truncus arteriosus (common arterial trunk) is an uncommon but complex congenital heart anomaly. Until the early 1970s, typically, patients died between the age of a few weeks to six months. Congestive heart failure owing to large pulmonary blood flow and truncal valve regurgitation was the major cause of death until innovative surgical techniques were discovered. In 1963, Herbert Sloan at the University of Michigan completed the first repair using a nonvalved conduit with long-term survival (not reported until 1974). At the Mayo Clinic, Rastelli and McGoon studied and completed the first repair with a valved homograft in 1967. In 1976, Ebert used the 12-mm Hancock valved conduit in infants under six months of age (University of California, San Francisco). In Boston (mid-1980s), Jonas and Castañeda used aortic homografts, which greatly reduced bleeding as a postoperative complication. In the early 1990s, Bove (University of Michigan) reported outstanding results with an approach based on primary repair within the first few days of life for patients with truncus arteriosus. Improved prognosis for patients with truncus arteriosus resulted from these corrective operations by analyzing the natural history of this condition while applying innovative ideas, improved technology, and perioperative care.

Prolonged White Matter Inflammation After Cardiopulmonary Bypass and Circulatory Arrest in a Juvenile Porcine Model

BACKGROUNDnWhite matter (WM) injury is common after neonatal cardiopulmonary bypass (CPB). We have demonstrated that the inflammatory response to CPB is an important mechanism of WM injury. Microglia are brain-specific immune cells that respond to inflammation and can exacerbate injury. We hypothesized that microglia activation contributes to WM injury caused by CPB.nnnMETHODSnJuvenile piglets were randomly assigned to 1 of 3 CPB-induced brain insults (1, no-CPB; 2, full-flow CPB; 3, CPB and circulatory arrest). Neurobehavioral tests were performed. Animals were sacrificed 3 days or 4 weeks postoperatively. Microglia and proliferating cells were immunohistologically identified. Seven analyzed WM regions were further categorized into 3 fiber connections (1, commissural; 2, projection; 3, association fibers).nnnRESULTSnMicroglia numbers significantly increased on day 3 after CPB and circulatory arrest, but not after full-flow CPB. Fiber categories did not affect these changes. On post-CPB week 4, proliferating cell number, blood leukocyte number, interleukin (IL)-6 levels, and neurologic scores had normalized. However, both full-flow CPB and CPB and circulatory arrest displayed significant increases in the microglia number compared with control. Thus brain-specific inflammation after CPB persists despite no changes in systemic biomarkers. Microglia number was significantly different among fiber categories, being highest in association and lowest in commissural connections. Thus there was a WM fiber-dependent microglia reaction to CPB.nnnCONCLUSIONSnThis study demonstrates prolonged microglia activation in WM after CPB. This brain-specific inflammatory response is systemically silent. It is connection fiber-dependent which may impact specific connectivity deficits observed after CPB. Controlling microglia activation after CPB is a potential therapeutic intervention to limit neurologic deficits after CPB.

Surgical Management of Absent Pulmonary Valve Syndrome.

The author’s approach to the management of tetralogy of Fallot with absent pulmonary valve is described, including the technique of homograft replacement of the central pulmonary arteries for the neonate who presents with profound respiratory compromise.