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Michael Silberbach

Publications and source records attributed to Michael Silberbach.

15 recordsLinked to original sources
PubMed2006

Natriuretic peptides and nitric oxide stimulate cGMP synthesis in different cellular compartments.

Cyclic nucleotide-gated (CNG) channels are a family of ion channels activated by the binding of cyclic nucleotides. Endogenous channels have been used to measure cyclic nucleotide signals in photoreceptor outer segments and olfactory cilia for decades. Here we have investigated the subcellular localization of cGMP signals by monitoring CNG channel activity in response to agonists that activate either particulate or soluble guanylyl cyclase. CNG channels were heterologously expressed in either human embryonic kidney (HEK)-293 cells that stably overexpress a particulate guanylyl cyclase (HEK-NPRA cells), or cultured vascular smooth muscle cells (VSMCs). Atrial natriuretic peptide (ANP) was used to activate the particulate guanylyl cyclase and the nitric oxide donor S-nitroso-n-acetylpenicillamine (SNAP) was used to activate the soluble guanylyl cyclase. CNG channel activity was monitored by measuring Ca2+ or Mn2+ influx through the channels using the fluorescent dye, fura-2. We found that in HEK-NPRA cells, ANP-induced increases in cGMP levels activated CNG channels in a dose-dependent manner (0.05-10 nM), whereas SNAP (0.01-100 microM) induced increases in cGMP levels triggered little or no activation of CNG channels (P < 0.01). After pretreatment with 100 microM 3-isobutyl-1-methylxanthine (IBMX), a nonspecific phosphodiesterase inhibitor, ANP-induced Mn2+ influx through CNG channels was significantly enhanced, while SNAP-induced Mn2+ influx remained small. In contrast, we found that in the presence of IBMX, both 1 nM ANP and 100 microM SNAP triggered similar increases in total cGMP levels. We next sought to determine if cGMP signals are compartmentalized in VSMCs, which endogenously express particulate and soluble guanylyl cyclase. We found that 10 nM ANP induced activation of CNG channels more readily than 100 muM SNAP; whereas 100 microM SNAP triggered higher levels of total cellular cGMP accumulation. These results suggest that cGMP signals are spatially segregated within cells, and that the functional compartmentalization of cGMP signals may underlie the unique actions of ANP and nitric oxide.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Association of pulmonary artery agenesis and hypoplasia of the lung.

Pulmonary artery agenesis and hypoplasia of the homolateral lung occasionally occurs as an isolated lesion, but more often has associated congenital cardiac anomalies. We present a case where pulmonary artery agenesis was the sole lesion in an asymptomatic child. Pulmonary artery agenesis should be suspected in asymptomatic patients if a plain chest X-ray shows asymmetric lung fields, lung hypoplasia, or hyperinflation of the contralateral lung. Echocardiography is the best tool to establish the diagnosis. In our opinion, invasive procedures, such as cardiac catheterization, may be postponed if there is no echocardiographic evidence of pulmonary hypertension.

Abnormalities, Multiple↗
PubMed2005

Extracorporeal life support in neonates, infants, and children after repair of congenital heart disease: modern era results in a single institution.

BACKGROUND: Extracorporeal life support has assumed a very effective role in the support of patients with refractory heart failure after repair of congenital heart disease, with hospital survival between 37% and 42%. We reviewed our results of different applications of extracorporeal life support in the last 2 years. METHODS: Between January 2001 and October 2003, 671 patients underwent surgery for congenital heart disease at our institution. We retrospectively reviewed the hospital and clinic charts of the patients who required extracorporeal life support postoperatively, and studied the factors associated with survival. RESULTS: Thirty-six patients (5.36%) received extracorporeal life support after surgery, between 1 day and 8 years of age (age < 30 days, n = 34). We divided the patients into four groups. Group 1 consisted of 13 patients who were electively placed on ventricular support without an oxygenator (univentricular assist device) after repair of single-ventricle disease. Group 2 consisted of 16 patients who required extracorporeal membrane oxygenation after surgery for failed hemodynamics. Group 3 consisted of 2 patients who required left ventricle support (left ventricular assist device) after surgery for two-ventricle disease but who did not require biventricular (extracorporeal membrane oxygenation) support. Group 4 consisted of 5 patients who required conversion from ventricular assist device to extracorporeal membrane oxygenation. Overall, 28 patients were weaned successfully (78%), and 24 survived to discharge (67%). Hospital survival in groups 1, 2, 3, and 4 was 100%, 50%, 100%, and 20%, respectively. Univariate factors associated with survival were age, weight, ventricular assist device type, duration, single-ventricle disease, reexploration, number of complications, and specific complications such as sepsis, renal failure, and pulmonary failure. CONCLUSIONS: Extracorporeal life support utilization was expanded to include different applications with different outcomes. The extracorporeal life support registry should be altered to reflect those changes.

Assisted Circulation↗
PubMed2005

The influence of valve physiology on outcome following aortic valvotomy for congenital bicuspid valve in children: 30-year results from a single institution.

OBJECTIVE: Aortic valvotomy is widely used for the treatment of congenital aortic stenosis in children. We sought to evaluate whether the predominant post-valvotomy physiology, aortic insufficiency (AI) or aortic stenosis (AS) independently affected patient outcome. METHODS: From 1972-2002, 57 children with congenital aortic stenosis underwent valvotomy. We divided age-matched patients with residual lesions based on their predominant pathology into three groups: Group I (n=14), patients with moderate AI; Group II (n=14), patients with moderate AS, and Group III (n=14), patients with combined AI and AS. Fifteen patients with severe AI or mild residual lesions following valvotomy were excluded from analysis. RESULTS: mean freedom from aortic valve replacement (AVR) was 11.2+/-1.7 years in Group I and 21.5+/-3.9 years in Group II, P=0.05. AVR was required in 11 patients (79%) in Group I vs. only 5 (36%) in Group II, P=0.05. Group III was intermediate, with 9 (64%) requiring AVR. At the time of AVR, patients with aortic stenosis had significantly higher fractional shortening % than those with insufficiency or combined lesions, (Group 1: 38.2+/-7.9 vs. Group II: 46.3+/-5.5 vs. Group III: 39.2+/-3.7, P=0.007). Patients in Group II also had less severely dilated ventricles (mm) than those in the other groups, (Group 1: 50.2+/-12.5 vs. Group II: 39.5+/-8.3 vs. Group III: 49.0+/-8.1, P=0.030). CONCLUSIONS: patients with predominant AI following valvotomy are more likely to need AVR sooner than those with residual stenosis without AI. Therefore, cautious use of repeat valvotomy using maneuvers to avoid AI (small balloons), may prolong freedom from aortic valve replacement in those patients with significant residual AS.

Aortic Valve↗
PubMed2005

Oversizing pulmonary homograft conduits does not significantly decrease allograft failure in children.

OBJECTIVE: Placement of oversized pulmonary ventricle-pulmonary artery conduits is routinely performed to decrease conduit failure in children. However, this practice has recently been challenged as somatic outgrowth may not be the main determinant of allograft failure in children. Our objective was to determine whether placement of oversized homografts for extracardiac pulmonary ventricle (PV) outflow tract reconstruction improves longevity in young children. METHODS: We reviewed 102 consecutive PV-PA conduits inserted in 70 patients less than 18 years between 1984 and 2003. Conduits placed in an anatomic position (n=23) as part of a Ross operation, were excluded. Conduits were initially stratified into two age groups: Group 1, those placed in patients 10 years. Normalization of conduit size to patient's body surface area at the time of insertion (z-value) was then performed to divide the conduits into oversized (O/S) and non-oversized (NO/S) groups. Determinants of conduit failure and allograft longevity were then compared between groups. RESULTS: Seventy-nine extracardiac conduits were placed, and 57 of these were in patients under 10 years of age. The majority had a diagnosis of tetralogy of Fallot (n=38), truncus arteriosus (n=19), pulmonary atresia with ventricular septal defect (n=12), or D-TGA with pulmonary stenosis and ventricular septal defect (n=7). Thirty-seven conduits were oversized (O/S) based on z-value, and 42 were non-oversized (NO/S), and the mean age at initial homograft placement was 7.0+/-7.5 years. Overall, oversizing conferred no significant advantage with respect to actuarial freedom from homograft replacement at 1, 5, or 10 years (96, 79, and 21%, O/S vs 93, 60, and 24%, NO/S), P=0.44. Oversizing was more frequent in Group 1 than Group 2 (53 vs 32%), and conduit failure was also more frequent with 49% requiring reoperation during the study period vs 38% in Group 2. In the subset of patients <or=10 years, both homograft explantation rate (50% O/S vs 48% NO/S) and median interval to conduit failure were similar between the O/S and NO/S patients (7.1 vs 4.8 years), P=0.340. Risk factors for conduit failure identified in multivariable regression analysis included the presence of pulmonary artery branch stenosis, lack of previous definitive repair, a diagnosis of pulmonary atresia, the need for percutaneous intervention. CONCLUSIONS: There is no significant benefit to placement of an oversized PV-PA homograft in this series of patients from a single institution. Even in young patients with rapid somatic growth, normalizing extracardiac allografts to BSA provides excellent conduit longevity and outcomes.

Adolescent↗
PubMed2004

Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.

Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.

Acetylcholinesterase↗
PubMed2004

Routine mechanical ventricular assist following the Norwood procedure--improved neurologic outcome and excellent hospital survival.

BACKGROUND: Although excellent survival following the Norwood procedure for palliation of hypoplastic left heart syndrome (HLHS) is being achieved by some, most centers, especially the ones with small surgical volume and limited experience, continue to struggle with initial results. Survivors often showed evidence of significant neurologic injury. The early postoperative care is labor-intensive as attempts are made to balance the systemic and pulmonary circulation for these infants. We report our experience with routine use of mechanical circulatory assist to support the increased cardiac output requirements present following Norwood procedure. METHODS: Eighteen consecutive infants undergoing Norwood operation for HLHS (Oregon Health & Science University [OHSU] 13; University of Louisville [UL] 5) were placed on a ventricular assist device (VAD) immediately following modified ultrafiltration in the operating room using the cardiopulmonary bypass (CPB) cannulas that were in the right atrium and the neoaorta. VAD flows were maintained at approximately 200 mL x kg(-1) x min(-1) and the patients were transported to the intensive care unit (ICU). Patients operated at OHSU also received neurodevelopmental testing before their Glenn procedure, approximately 4 to 6 months following their Norwood operation. RESULTS: All patients were stable on VAD support and no attempt was made to balance the systemic and pulmonary circulation. The ventilator was manipulated to achieve systemic Pa0(2) between 30 and 45 mm Hg and PaC0(2) between 35 and 45 mm Hg. Evidence of hypoperfusion (increasing lactates) was managed by increasing the VAD flow. Lactates normalized [< 2 mmol/L]) by 1.8 +/- 1.1 days following surgery. Average time of VAD support was 3.1 +/- 1.0 (range, 2 to 5 days) and average time until chest closure was 3.4 +/- 1.5 (range, 2 to 8 days). There were two cases of postoperative bleeding (11.1%) requiring reexploration and one case of mediastinitis (5.5%) in a patient who has now gone on to successful Glenn. Sixteen of the eighteen patients survived (hospital survival mean 89% with a 95% confidence interval of 63.9% to 98.1%; 12/13 OHSU [92.3%]; 4/5 UL [80%]). Neurodevelopmental testing using the Mullen Scales of Early Learning and the Vineland Adaptive Behavior Scale were normal for all infants tested. CONCLUSIONS: Routine postoperative use of VAD can support the increased cardiac output demands of infants following Norwood operation and results in a stable postoperative convalescence that does not require aggressive ventilator or inotrope manipulation. Although not a panacea, this strategy can simplify postoperative management, lead to excellent hospital survival, and possibly augment cerebral oxygen delivery, resulting in improved neurologic outcomes for this challenging group of patients.

Cardiac Surgical Procedures↗
PubMed2003

Atrial natriuretic peptide induces natriuretic peptide receptor-cGMP-dependent protein kinase interaction.

Circulating natriuretic peptides such as atrial natriuretic peptide (ANP) counterbalance the effects of hypertension and inhibit cardiac hypertrophy by activating cGMP-dependent protein kinase (PKG). Natriuretic peptide binding to type I receptors (NPRA and NPRB) activates their intrinsic guanylyl cyclase activity, resulting in a rapid increase in cytosolic cGMP that subsequently activates PKG. Phosphorylation of the receptor by an unknown serine/threonine kinase is required before ligand binding can activate the cyclase. While searching for downstream PKG partners using a yeast two-hybrid screen of a human heart cDNA library, we unexpectedly found an upstream association with NPRA. PKG is a serine/threonine kinase capable of phosphorylating NPRA in vitro; however, regulation of NPRA by PKG has not been previously reported. Here we show that PKG is recruited to the plasma membrane following ANP treatment, an effect that can be blocked by pharmacological inhibition of PKG activation. Furthermore, PKG participates in a ligand-dependent gain-of-function loop that significantly increases the intrinsic cyclase activity of the receptor. PKG translocation is ANP-dependent but not nitric oxide-dependent. Our results suggest that anchoring of PKG to NPRA is a key event after ligand binding that determines distal effects. As such, the NPRA-PKG association may represent a novel mechanism for compartmentation of cGMP-mediated signaling and regulation of receptor sensitivity.

Animals↗