Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4ß7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.

Cost Savings Analysis of Early Extubation Following Congenital Heart Surgery.

The clinical benefit of early extubation following congenital heart surgery has been demonstrated; however, its effect on resource utilization has not been rigorously evaluated. We sought to determine the cost savings of implementing an early extubation pathway for children undergoing surgery for congenital heart disease. We performed a cost savings analysis after implementation of an early extubation strategy among children undergoing congenital heart surgery at British Columbia Children's Hospital (BCCH) over a 2.5-year period. All patients undergoing one of the eight Society of Thoracic Surgeons (STS) benchmark operations, ASD repair, or bidirectional cavopulmonary anastomosis were included in the analysis (n = 370). We compared our data to aggregate STS multi-institutional data from a contemporary cohort. We estimated daily costs for ICU care, ward care, medications, imaging, additional procedures, and allied health care using an administrative database. Direct costs, indirect costs, and cost savings were estimated. Simulation methods, Monte Carlo, and bootstrapping were used to calculate the 95% credible intervals for all estimates. The mean cost savings per procedure was $12,976 and the total estimated cost savings over the study period at BCCH was $4.8 million with direct costs accounting for 91% of cost savings. Sensitivity analysis demonstrated a mean cost savings range of $11,934-$14,059 per procedure. Early extubation is associated with substantial cost savings due to reduced hospital resource utilization. Implementation of an early extubation strategy following congenital heart surgery may contribute to improved resource utilization.

Temporal trends in incidence and long-term case fatality of stroke among children from 1994 to 2007.

OBJECTIVE: To examine the trends in incidence and long-term case fatality of childhood stroke in New Jersey using a statewide administrative database for the years 1994-2007. METHODS: We assessed demographic and clinical information for children with stroke using the Myocardial Infarction Data Acquisition System (MIDAS) database. We ascertained deaths by matching MIDAS records to New Jersey Death Registration Files at 30 days, 1 year, and 5 years from the index stroke. RESULTS: During the 14-year study period, 715 children were hospitalized for a first time with stroke. Age-adjusted incidence of stroke demonstrated a significant quadratic trend in which the rates decreased from 1994 to a nadir at 1999-2001 and increased thereafter (overall p for trend = 0.06 with quadratic term p = 0.02). Better treatment of sickle cell disease with transfusion therapy after year 1998 (p = 0.007) and improved diagnostic accuracy of MRI (p = 0.009) may partially explain these trends. Thirty-day, 1-year, and 5-year case fatality rates were 12.3%, 15.7%, and 17.5%, respectively. At all time periods, adjusted survival from hemorrhagic stroke was significantly lower than that from ischemic stroke (p = 0.0005). CONCLUSIONS: After an initial decrease, the incidence of pediatric stroke is rising. Children with hemorrhagic stroke had a 2 times higher risk of death than those with ischemic stroke. Whereas approximately 70% of all deaths occurred within the first month of hospitalization, an additional 5.2% of the initial study cohort died over the next 5 years.

Genetic variation in cholinergic muscarinic-2 receptor gene modulates M2 receptor binding in vivo and accounts for reduced binding in bipolar disorder.

Genetic variation in the cholinergic muscarinic-2 (M(2)) receptor gene (CHRM2) has been associated with the risk for developing depression. We previously reported that M(2)-receptor distribution volume (V(T)) was reduced in depressed subjects with bipolar disorder (BD) relative to depressed subjects with major depressive disorder (MDD) and healthy controls (HCs). In this study, we investigated the effects of six single-nucleotide polymorphisms (SNPs) for CHRM2 on M(2)-receptor binding to test the hypotheses that genetic variation in CHRM2 influences M(2)-receptor binding and that a CHRM2 polymorphism underlies the deficits in M(2)-receptor V(T) observed in BD. The M(2)-receptor V(T) was measured using positron emission tomography and [(18)F]FP-TZTP in unmedicated, depressed subjects with BD (n=16) or MDD (n=24) and HCs (n=25), and the effect of genotype on V(T) was assessed. In the controls, one SNP (with identifier rs324650, in which the ancestral allele adenine (A) is replaced with one or two copies of thymine (T), showed a significant allelic effect on V(T) in the pregenual and subgenual anterior cingulate cortices in the direction AA

Lung transplantation in infants and toddlers from 1990 to 2004 at St. Louis Children's Hospital.

In a retrospective, single-center cohort study, outcomes of infants and toddlers undergoing lung transplant at St. Louis Children's Hospital between 1990 and 2004 were compared to older children. Patients with cystic fibrosis (exclusively older children) and those who underwent heart-lung, liver-lung, single lung or a second transplantation were excluded from comparisons. One hundred nine lung transplants were compared. Thirty-six were in infants <1 year old, 26 in toddlers 1-3 years old and 47 in children >3 years old. Graft survival was similar for infants and toddlers (p = 0.35 and p = 0.3, respectively) compared to children over 3 years old at 1 and 3 years after transplant. Significantly more infants (p < 0.0001 and p = 0.003) and toddlers (p = 0.002 and p = 0.03) were free from acute rejection and bronchiolitis obliterans compared to older patients. While most infants and toddlers had only minimal lung function impairment, and achieved normal to mildly delayed developmental scores, somatic growth remained depressed 5 years after transplant. Lung transplantation in infants and young children carries similar survival rates to older children and adults. Further insights into the unique immunologic aspects of this group of patients may elucidate strategies to prevent acute and chronic rejection in all age groups.

Effectiveness of statins in Medicare-eligible patients and patients < 65 years using clinical practice data.

OBJECTIVE: This study compared effectiveness of rosuvastatin (RSV) with other statins on lowering LDL-C and LDL-C goal attainment among Medicare-eligible patients (age >or= 65 years) and patients with age < 65 years treated in usual clinical practice to provide evidence of real-world effectiveness of statins. METHODS: Retrospective cohort study was conducted in patients, newly prescribed statin therapy during August 2003 to May 2005. Patient inclusion criteria: no prior prescription for dyslipidaemic medication in the preceding 12 months, continuously enrolled for >or= 15 months and >or= 90-day supply of statin. Effectiveness of RSV in reducing LDL-C and attaining LDL-C goal when compared with other statins was evaluated using multivariate regression, adjusting for baseline LDL-C, age, gender, smoking, hypertension, coronary heart disease (CHD), systolic blood pressure and therapy duration. RESULTS: Adjusted per cent LDL-C reduction was significantly greater (p < 0.05) with RSV (24.3% for >or= 65 and 28.5% for < 65) compared with ATV (17.5%, 21.3%), SMV (14.8%, 18.4%), PRV (11.3%, 15.8%), FLV (10.7%, 20.6%) and LOV (13.3%, 14.4%). Among patients in both age groups at high or moderate CHD risk, a greater proportion of RSV patients attained LDL-C goal (76.0% for age group >or= 65 years and 78.4% for age group < 65 years) vs. 50.5-73.0% for >or= 65 and 51.3-71.5% for < 65 years of age on other statins (p < 0.0001). CONCLUSIONS: Rosuvastatin is more effective in lowering LDL-C in Medicare-eligible patients and patients < 65 years of age when compared with other statins in usual clinical practice. Moreover, RSV patients had higher LDL-C goal attainment rates when compared with other statins in high- and moderate-risk patients. The study results have implications for clinicians in selecting the optimal statin to meet individual patient care needs.

Comparative effectiveness of rosuvastatin versus other statin therapies in patients at increased risk of failure to achieve low-density lipoprotein goals.

OBJECTIVES: Statins are increasingly used in the treatment of hypercholesterolemia. Research has shown difficulty in attaining LDL-C goals in routine clinical practice, especially in patients at high risk for coronary events. This study identified risk factors associated with failure to attain LDL-C goals in routine clinical practice and examined the effectiveness of rosuvastatin compared to other statins in patients presenting with these risk factors. METHODS: This retrospective observational study used administrative claims data on patients receiving statins. After stratifying patients into baseline National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) risk categories, logistic regression allowed identification of factors predicting failure to attain LDL-C goal. Separate analyses compared failure rates between rosuvastatin and other statins in patients at an increased risk of goal attainment failure. RESULTS: Of the 4661 patients identified, 50% and 14% had baseline NCEP ATP III high and moderate risk status, respectively. Risk factors associated with goal attainment failure were percentage change required to achieve goal > or = 30%, NCEP high risk status, percentage change required 15-29%, and NCEP moderate risk status. Patients at an increased risk of failure exhibited significantly higher failure rates in all other statin groups compared to rosuvastatin. CONCLUSIONS: This study demonstrates that patients requiring > or = 15% change in LDL-C or NCEP high or moderate risk patients are at a higher risk of goal attainment failure. Rosuvastatin is more effective compared to other statins in patients with these risk factors and given variations in clinical profiles of branded and generic statins, these results may aid in identifying patients most likely to benefit from rosuvastatin compared to other statin therapies. Validating the results of this study in other patient populations would help increase the generalizability of study findings.

Variability among Alternaria solani isolates associated with early blight of tomato.

Variability among isolates of Alternaria solani, the causal agent of early blight of tomato, from Northern and Southern parts of India was determined based on conidial morphology, pathogenicity tests and random amplified polymorphic DNA (RAPD) techniques. The isolates varied with respect to size of conidia and number of septa. The average size of conidia varied from 150-224.9 microm x 12.4-17.2 microm. The number of horizontal (4-14), vertical (0-3) and beak (0-8) septa also varied among the isolates. The test isolates differed in the virulence pattern on ten tomato genotypes under screen house conditions. Based on disease severity, test isolates were categorized into three main groups. Isolates RAS (Rohtak) and HAS-I (Hisar) were more virulent than all other isolates. None of the genotypes were completely resistant to all the test isolates. The analysis of RAPD profiles showed that there was a high level of genetic variability among the isolates of A. solani. The cluster analysis based on similarity coefficients separated the ten A. solani isolates into two major clusters. There was no evidence for geographical clustering of isolates with high levels of genetic similarity, suggesting that isolates are widely spread across India.

Aortopulmonary size discrepancy is not a contraindication to the pediatric Ross operation.

BACKGROUND: Modification of the aortic annulus or the ascending aorta, or both, may be required in pediatric patients undergoing the Ross operation. The fate of these autografts remains uncertain. METHODS: Retrospective review of 15 patients undergoing Ross operation without aortic annular modification (group 1), 11 patients requiring annular reduction (group 2, n = 11), and 8 patients requiring annular enlargement (group 3, n = 8). Autograft function and dimensions were evaluated by echocardiography. RESULTS: Autograft insufficiency was less than or equal to mild in 33 patients and moderate in 1 patient. The annulus body surface area ratio increased in group 1 from 19.7 +/- 5 to 20.3 +/- 5 mm/M2 (p = 0.8). The average annular reduction in group 2 was 5 +/- 1.5 mm, and 10 of 11 patients required reduction of the ascending aorta (mean 11 +/- 5 mm). The annulus body surface area ratio increased from 18.6 +/- 7 to 20.5 +/- 9 mm/M2 (p = 0.2). The mean augmentation in annulus diameter in group 3 was 6 +/- 4 mm; the annulus body surface area ratio decreased from 23.7 +/- 14 to 20.3 +/- 8 mm/M2 (p = 0.5). CONCLUSIONS: We continue to offer the Ross operation to pediatric patients even when aortic annular or ascending aortic size discrepancies mandate surgical modifications.

Recurrence and malignancy rates in a benign colorectal neoplasm patient cohort: results of a 5-year analysis in a managed care environment.

OBJECTIVE: To estimate the apparent recurrence rates of benign neoplasms and the development of malignant colorectal neoplasms over a 5-yr period in a high risk managed care population. METHODS: Using the CPT and ICD-9 CM codes, a cohort of subjects with benign neoplasms were identified with a colonoscopy in 1992 from a longitudinal claims database (MarketScan). Three groups of subjects (benign neoplasms with polypectomy, benign neoplasms without polypectomy, and no neoplasms) were evaluated. Five-year recurrence rates of benign or new malignant colorectal neoplasms were determined for the baseline benign neoplasms with polypectomy and no neoplasm groups. For the benign neoplasm without polypectomy, only rates for malignancy were evaluated. RESULTS: Of 16,293 subjects at baseline, 39.50% were diagnosed with benign and 5.50% with malignant neoplasms. The 5-yr cumulative incidence of benign neoplasms in subjects without an index neoplasm (n = 8,967) was 7.92% compared to the recurrence of 40.93% in subjects with a benign neoplasm and polypectomy (n = 4,046) at baseline (p < 0.001). The 5-yr cumulative incidence rates of malignant colorectal neoplasms in the no neoplasm (n = 8,967) and benign neoplasm groups (n = 6,438) were 1.81% and 2.55%, respectively (p < 0.005). A lower 5-yr malignancy rate was observed in benign neoplasm group with polypectomy (2.17%) compared to the benign neoplasm group without polypectomy (3.18%) (p < 0.05). CONCLUSION: The high recurrence rate of benign colorectal neoplasms and a higher incidence of colorectal cancer in subjects at high risk (history of benign colorectal neoplasm) highlight a healthcare opportunity for surveillance and/or interventions to reduce the morbidity associated with colorectal neoplasms.

Psychometric evaluation of the 12-item short-form health survey (SF-12) in osteoarthritis and rheumatoid arthritis clinical trials.

BACKGROUND: The psychometric properties of the 12-Item Short-Form Health Survey (SF-12), a subset of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), have been tested in the general population and certain disease states. OBJECTIVE: The purpose of this study was to evaluate the psychometric properties of the SF-12 as a generic measure of health-related quality of life (HRQoL) in osteoarthritis (OA) and rheumatoid arthritis (RA) patient populations in clinical trials. METHODS: Data were aggregated from 5 clinical trials evaluating the efficacy of non-steroidal anti-inflammatory drugs in OA (n = 651) and RA (n = 693) patients. Patient assessments in these trials were made using the SF-36 and commonly used clinical measures of OA and RA at baseline and after up to 6 weeks of treatment. For the items of the SF-36 contained in the SF-12, the item missing rate, computability of scores, floor and ceiling effects, factor structure, and item-component correlations were evaluated. Clinical variables and correlations of physical component summary (PCS-12) and mental component summary (MCS-12) scores of the SF-12 with the corresponding SF-36 component summary scores (PCS-36 and MCS-36) were also examined. Analyses were conducted separately for OA and RA patients. RESULTS: A low individual SF-12 item missing rate (0.29% to 2.30%) and a high percentage score computability (90.9%-94.3%) were observed at baseline. No floor or ceiling effects at baseline were observed. The scree plot confirmed the 2-factor structure of the SF-12 items. Items belonging to the physical component correlated more strongly with the PCS-12 than with the MCS-12; similarly, items belonging to the mental component correlated more strongly with the MCS-12 than with the PCS-12. The correlations between the PCS-12 and PCS-36 and between the MCS-12 and MCS-36 ranged from 0.92 to 0.96 (P < 0.001) at baseline and at week 2, 4, or 6. Significant correlations ranging from -0.09 to -0.58 (P < 0.05) were observed between the SF-12 scores and clinical variables. CONCLUSION: The SF-12 appears to be a psychometrically sound tool for the assessment of HRQoL in OA and RA patients.

Regional low-flow perfusion provides somatic circulatory support during neonatal aortic arch surgery.

BACKGROUND: Regional low-flow perfusion has been shown to provide cerebral circulatory support during neonatal aortic arch operations. However, its ability to provide somatic circulatory support remains unknown. METHODS: Fifteen neonates undergoing arch reconstruction with regional perfusion were studied. Three techniques were used to assess somatic perfusion: abdominal aortic blood pressure, quadriceps blood flow (near-infrared spectroscopy), and gastric tonometry. RESULTS: Twelve patients required operation for hypoplastic left heart syndrome, and 3 required arch reconstruction with a biventricular repair. There was one death (7%). Abdominal aortic blood pressure was higher (12+/-3 mm Hg versus 0+/-0 mm Hg), and quadriceps blood volumes (5+/-24 versus -17+/-26) and oxygen saturations (57+/-25 versus 33+/-12) were greater during regional perfusion than during deep hypothermic circulatory arrest (p < 0.05). During rewarming, the arterial-gastric mucosal carbon dioxide tension difference was lower after circulatory arrest than after regional perfusion (-3.3+/-0.3 mm Hg versus 7.8+/-7.6 mm Hg, p < 0.05). CONCLUSIONS: Regional low-flow perfusion provides somatic circulatory support during neonatal arch surgical procedures. Support of the subdiaphragmatic viscera should improve the ability of neonates to survive the postoperative period.

Economic impact of neutropenia and febrile neutropenia in breast cancer: estimates from two national databases.

STUDY OBJECTIVE: To estimate the economic burden of neutropenia and febrile neutropenia in female breast cancer hospital admissions in the United States. DESIGN: Retrospective database analysis. PATIENTS: Female admissions with a breast cancer diagnosis. MEASUREMENTS AND MAIN RESULTS: By reviewing two national databases (Healthcare Costs and Utilization Project, MarketScan), length of stay and charge or payment/admission were estimated from 1994-1996. Neutropenic and febrile neutropenic admissions were longer and incurred higher charges and payments than nonneutropenic and afebrile neutropenic admissions, respectively (p<0.05). The difference in mean charges between neutropenic and nonneutropenic admissions decreased from $13,143 in 1994 to $6913 in 1996, whereas the difference in payment was $4957 (adjusted to 1996 dollars). The difference in mean charges between febrile and afebrile neutropenic admissions decreased from $11,570 in 1994 to $2873 in 1996, whereas the difference in payment was $2390 (adjusted to 1996 dollars). CONCLUSION: There was a trend toward decreased charges for inpatient admissions with neutropenia in patients with breast cancer (1994-1996). Interventions that reduce the frequency of neutropenia and febrile neutropenia could reduce hospitalization costs of breast cancer admissions.

Cardiopulmonary transplantation for congenital heart disease in the adult.

BACKGROUND: Patients surviving into adulthood with congenital heart disease (CHD) often succumb to progressive cardiopulmonary dysfunction. For these patients transplantation is often considered. METHODS: We performed a retrospective review of 69 adults (age >18 years) with CHD transplanted between 1984 and 1999. RESULTS: We evaluated 31 heart-lung (HLTxp), 30 lung (LTxp), and 8 heart (HTxp) transplants performed in 22 men and 47 women with CHD. Mean age was 37 +/- 10 years with a mean follow-up of 3.1 +/- 3.5 years. A concomitant cardiovascular procedure was performed in 1 HLTxp, 23 LTxp, and 2 HTxp. Early mortality (>30 days) was 26% (8/31) for HLTxp, mostly due to bleeding. Early LTxp mortality was 23% (7/30), largely due to graft failure. One and 3-year survival was similar in adults transplanted for CHD and adults transplanted for other disease. Early mortality among HTxp recipients was 50% (4/8) from rejection or technical complications. Survival for patients undergoing HLTxp versus LTxp with cardiac repair was similar. When examined by era, the survival of patients transplanted for CHD between 1992 and 1999 was greater than that of patients transplanted between 1984 and 1991. CONCLUSIONS: Adults undergoing HLTxp and LTxp for CHD can expect survival comparable to that of non-CHD adults. In the presence of a reparable cardiac lesion, LTxp with cardiovascular repair for CHD is an attractive option, optimizing organ allocation. Specific technical concerns are discussed. Survival of adults undergoing cardiopulmonary transplantation for CHD has improved over time.

The pathogenesis of acute pulmonary edema associated with hypertension.

BACKGROUND: Patients with acute pulmonary edema often have marked hypertension but, after reduction of the blood pressure, have a normal left ventricular ejection fraction (> or =0.50). However, the pulmonary edema may not have resulted from isolated diastolic dysfunction but, instead, may be due to transient systolic dysfunction, acute mitral regurgitation, or both. METHODS: We studied 38 patients (14 men and 24 women; mean [+/-SD] age, 67+/-13 years) with acute pulmonary edema and systolic blood pressure greater than 160 mm Hg. We evaluated the ejection fraction and regional function by two-dimensional Doppler echocardiography, both during the acute episode and one to three days after treatment. RESULTS: The mean systolic blood pressure was 200+/-26 mm Hg during the initial echocardiographic examination and was reduced to 139+/-17 mm Hg (P< 0.01) at the time of the follow-up examination. Despite the marked difference in blood pressure, the ejection fraction was similar during the acute episode (0.50+/-0.15) and after treatment (0.50+/-0.13). The left ventricular regional wall-motion index (the mean value for 16 segments) was also the same during the acute episode (1.6+/-0.6) and after treatment (1.6+/-0.6). No patient had severe mitral regurgitation during the acute episode. Eighteen patients had a normal ejection fraction (at least 0.50) after treatment. In 16 of these 18 patients, the ejection fraction was at least 0.50 during the acute episode. CONCLUSIONS: In patients with hypertensive pulmonary edema, a normal ejection fraction after treatment suggests that the edema was due to the exacerbation of diastolic dysfunction by hypertension--not to transient systolic dysfunction or mitral regurgitation.

Complete surgical repair of aortic atresia with a normal left ventricle.

Aortic atresia with a normal left ventricle and normal mitral valve is an uncommon congenital lesion. We present two such cases and describe two different approaches of achieving biventricular surgical repair.

Similarity as a risk factor in drug-name confusion errors: the look-alike (orthographic) and sound-alike (phonetic) model.

BACKGROUND: One of every four medication errors reported in the United States is a name-confusion error. The rate of name-confusion errors might be reduced if new and confusing names were not allowed on the market and if safeguards could be put in place to avoid confusion between existing names. OBJECTIVES: To evaluate several prognostic tests of drug-name confusion, alone and in combination, with respect to their sensitivity, specificity, and overall accuracy. RESEARCH DESIGN: Case-control study. Twenty-two different computerized measures of orthographic similarity, orthographic distance, and phonetic similarity were used to compute similarity/distance scores for n = 1,127 cases (ie, pairs of names that appeared in published error reports or national error databases) and n = 1,127 controls. MAIN OUTCOME MEASURES: Mean similarity/distance scores were compared across cases and controls. The performance of each measure at distinguishing between cases and controls was evaluated by tenfold crossvalidation. Dose-response relationships were examined. Univariate and multivariate logistic regression models were formed and evaluated by 10 fold crossvalidation. RESULTS: Cases had significantly higher similarity scores than controls. Every measure of similarity proved to be a significant risk factor for error. There was a significant increasing trend in the odds-ratio as a function of similarity. A three-predictor logistic regression model had crossvalidated sensitivity of 93.7%, specificity of 95.9% and accuracy of 94.8%. CONCLUSIONS: A sensitive and specific test of drug-name confusion potential can be formed using objective measures of orthographic similarity, orthographic distance, and phonetic distance.

ACE insertion/deletion genotype affects bradykinin metabolism.

A deletion allele of the angiotensin-converting enzyme (ACE) gene has been associated with increased serum ACE activity, enhanced conversion of angiotensin (Ang) I to Ang II, and cardiovascular morbidity. This study tested the hypothesis that the ACE deletion allele is also associated with enhanced degradation of bradykinin, a vasoprotective peptide. Metabolism of synthetic bradykinin was measured in sera obtained from subjects who were homozygous for either the ACE deletion (n=12) or insertion (n=8) allele and who had participated in an Ang I-infusion protocol. ACE levels tended to be increased in subjects who were DD compared with those who were II [41.2 (95% CI, 27.9, 54.3) vs. 28.0 IU/L (20.0, 35.9); t=-1.6; p=0.1 18]. During Ang I infusion, plasma Ang II concentrations were increased in DD compared with II subjects (F =4.4; p=0.052). In contrast, the half-life of bradykinin was significantly decreased in sera obtained from ACE DD compared with II subjects [26.3 s (17.8, 34.6 s) vs. 42.1 s (24.4, 59.9 s); t=-2.4; p=0.029]. Moreover, there were significant inverse relations between the half-life of bradykinin and serum ACE activity (p < 0.001) and between the half-life of bradykinin and the conversion of Ang I to Ang II (p=0.026). This study confirms that ACE genotype determines bradykinin degradation and suggests another mechanism whereby the ACE D allele could be associated with deleterious cardiovascular effects.

A canine model of atrial flutter following the intra-atrial lateral tunnel Fontan operation.

Atrial flutter (AFL) is a common problem in children who have undergone a Fontan operation for single ventricle physiology. Although this has been attributed to the atrial stretch inherent in the earlier forms of this operation, AFL has persisted in spite of a modification that minimizes atrial distension. Therefore, it was hypothesized that AFL following the modified Fontan procedure may result from anatomic barriers related to suture lines rather than from atrial stretch or hypertension. In a series of experiments performed in dogs under general anesthesia, the modified Fontan repair was simulated by placing only the suture line of the intra-atrial repair. No baffle was placed, thus avoiding any hemodynamic alterations. After closure of the atriotomy, 253 point unipolar atrial endocardial form-fitting electrodes were inserted through the mitral and tricuspid valves via bilateral ventriculotomies. Induction of AFL was attempted with atrial burst pacing and programmed extrastimulation, and activation sequence maps of subsequent reentry were generated from the endocardial electrodes. Atrial flutter was induced in all of 17 dogs, with a median cycle length of 177 +/- 31 ms. Activation sequence maps demonstrated conduction block along the crista terminalis corresponding to the free wall portion of the suture line. This created an isthmus between the suture line and tricuspid annulus, which appeared critical for sustaining AFL, although the circuit used both the septal and free wall surfaces of the right atrium. In seven dogs, a cryolesion was placed from the tricuspid annulus to the free wall segment of the suture line, terminating the AFL, in all seven. When the free wall segment of the suture line was moved 5 mm medial to the crista terminalis, AFL was induced in four of five dogs, but only in the presence of isoproterenol and at a shorter cycle length (136 +/- 8 ms, P < .001). Atrial flutter was not inducible, even with the addition of isoproterenol, in any of five dogs in which the suture line was placed 10 mm anterior to the crista terminalis and incorporated into closure of the atriotomy. This acute canine model of the modified Fontan operation demonstrates that conduction block from the free wall portion of the suture line creates an isthmus of tissue between the suture line and the tricuspid annulus. This is a sufficient substrate to produce AFL; no hemodynamic alteration is required. Injury to the crista terminalis is a significant risk factor in this model, which suggests that a modification of the suture line might reduce the incidence of AFL in patients following this operation.