Regression analysis for comparing protein samples with 16O/18O stable-isotope labeled mass spectrometry.

MOTIVATION: Using stable isotopes in global proteome scans, labeled molecules from one sample are pooled with unlabeled molecules from another sample and subsequently subjected to mass-spectral analysis. Stable-isotope methodologies make use of the fact that identical molecules of different stable-isotope compositions are differentiated in a mass spectrometer and are represented in a mass spectrum as distinct isotopic clusters with a known mass shift. We describe two multivariable linear regression models for (16)O/(18)O stable-isotope labeled data that jointly model pairs of resolved isotopic clusters from the same peptide and quantify the abundance present in each of the two biological samples while concurrently accounting for peptide-specific incorporation rates of the heavy isotope. The abundance measure for each peptide from the two biological samples is then used in down-stream statistical analyses, e.g. differential expression analysis. Because the multivariable regression models are able to correct for the abundance of the labeled peptide that appear as an unlabeled peptide due to the inability to exchange the natural C-terminal oxygen for the heavy isotope, they are particularly advantageous for a two-step digestion/labeling procedure. We discuss how estimates from the regression model are used to quantify the variability of the estimated abundance measures for the paired samples. Although discussed in the context of (16)O/(18)O stable-isotope labeled data, the multivariable regression models are generalizable to other stable-isotope labeled technologies.

Constrictive pericarditis in the modern era: evolving clinical spectrum and impact on outcome after pericardiectomy.

BACKGROUND: The clinical spectrum of constrictive pericarditis (CP) has been affected by a change in incidence of etiological factors. We sought to determine the impact of these changes on the outcome of pericardiectomy. METHODS AND RESULTS: The contemporary spectrum of CP in 135 patients (76% male) evaluated at the Mayo Clinic from 1985 to 1995 was compared with that of a historic cohort. Notable trends were an increasing frequency of CP due to cardiac surgery and mediastinal radiation and presentation in older patients (median age, 61 versus 45 years). Perioperative mortality decreased (6% versus 14%, P = 0.011), but late survival was inferior to that of an age- and sex-matched US population (57+/-8% at 10 years). The long-term outcome was predicted independently by 3 variables in stepwise logistic regression analyses: (1) age, (2) NYHA class, and most powerfully, (3) a postradiation cause. Of 90 late survivors in whom functional class could be determined, functional status had improved markedly (2.6+/-0.7 at baseline versus 1.5+/-0.8 at latest follow-up [P<0.0001]), with 83% being free of clinical symptoms. CONCLUSIONS: The evolving profile of CP, with increasingly older patients and those with radiation-induced disease in the past decade, significantly affects postoperative prognosis. Long-term results of pericardiectomy are disappointing for some patient groups, especially those with radiation-induced CP. By contrast, surgery alleviates or improves symptoms in the majority of late survivors.

Prognostic stratification of diabetic patients by exercise echocardiography.

OBJECTIVES: The aim of this study was to assess the incremental value of exercise echocardiography for the risk stratification of diabetic patients. BACKGROUND: There are currently insufficient outcome data in diabetic patients to define the role of stress echocardiography as a prognostic tool. METHODS: We studied the prognostic value of exercise echocardiography in 563 patients with diabetes mellitus (mean age 64 +/- 11 years, 336 men) and known or suspected ischemic heart disease (IHD). RESULTS: Cardiac events occurred in 50 patients (cardiac death in 23 and nonfatal myocardial infarction [MI] in 27) during a median follow-up period of three years. Event rate was lower in patients with normal as compared to those with abnormal exercise echocardiography at one year (0% vs. 1.9%), three years (1.8% vs. 11.9%), and five years (7.6% vs. 23.3%), respectively (p = 0.0001). Patients with multivessel distribution of echocardiographic abnormalities had the highest event rate (2.9% at one year, 15.2% at three years, and 32.8% at five years). In an incremental multivariate analysis model, exercise echocardiography increased the chi-square of the clinical and exercise ECG model from 29 to 44.8 (p = 0.0001). CONCLUSIONS: Exercise echocardiography provides incremental data for risk stratification of diabetic patients with known or suspected IHD. Patients with a normal exercise echocardiogram have a low event rate. Patients with multivessel distribution of exercise echocardiographic abnormalities are at the highest risk of cardiac events, as one-third of these patients experience cardiac death or nonfatal MI during the five years following exercise echocardiography.

Nonexercise stress transthoracic echocardiography: transesophageal atrial pacing versus dobutamine stress.

OBJECTIVES: To compare transesophageal atrial pacing stress echocardiography with dobutamine stress echocardiography for feasibility, safety, duration, patient acceptance and concordance in inducing wall motion abnormalities. BACKGROUND: Transesophageal atrial pacing is an effective method of increasing heart rate and has been used in the assessment of coronary artery disease. METHODS: Both tests were performed in sequence on the same patients in random order. Transesophageal atrial pacing stress echocardiography began at a heart rate of 10 beats/min above the baseline value and was increased by 20 beats/min every two min until 85% of the age-predicted maximum heart rate or another end point was reached. Dobutamine echocardiography was performed using three-min stages and a maximum dose of 40 microg/kg per min. Atropine (total dose < or =2 mg) was administered at the start of the 40 microg/kg per min stage if needed to augment heart rate or during pacing if Wenckebach heart block occurred. RESULTS: Transesophageal atrial pacing stress echocardiography was feasible in 100 of 104 patients (96%); the duration (8.6+/-3.6 min) was significantly shorter than that of dobutamine stress echocardiography (15.1+/-3.9 min) (p = 0.0001). With transesophageal atrial pacing stress echocardiography, the recovery period was shorter, symptoms and dysrhythmias were fewer, hypertension and hypotension were less common and target heart rate was more frequently achieved. No complications occurred with either test. Patient acceptance was satisfactory. Agreement between results of both tests was good for segmental wall motion scoring with a 16-segment model, scores 1 to 5 (kappa: rest, 0.79; peak, 0.57) and test interpretation (normal, ischemia, infarction or resting wall motion abnormality with ischemia) (kappa: 0.77). CONCLUSIONS: Transesophageal atrial pacing stress echocardiography is a feasible, well-tolerated alternative to dobutamine stress echocardiography. It can be performed rapidly and shows good agreement with dobutamine stress echocardiography in the induction of myocardial ischemia.

Prognostic value of exercise echocardiography in 2,632 patients > or = 65 years of age.

OBJECTIVES: We sought to determine the prognostic value of exercise echocardiography in the elderly. BACKGROUND: Limited data exist regarding the prognostic value of exercise testing in the elderly, a population which may be less able to exercise and is at increased risk of cardiac death. METHODS: Follow-up (2.9 +/- 1.7 years) was obtained in 2,632 patients > or = 65 years who underwent exercise echocardiography. RESULTS: There were 1,488 (56%) men and 1,144 (44%) women (age 72 +/- 5 years). The rest ejection fraction was 56 +/- 9%. Rest wall motion abnormalities were present in 935 patients (36%). The mean work load was 7.7 +/- 2.3 metabolic equivalents (METs) for men and 6.5 +/- 1.9 METs for women. New or worsening wall motion abnormalities developed with stress in 1,082 patients (41%). Cardiac events included cardiac death in 68 patients and nonfatal myocardial infarction in 80 patients. The addition of the exercise electrocardiogram to the clinical and rest echocardiographic model provided incremental information in predicting both cardiac events (chi-square = 77 to chi-square = 86, p = 0.003) and cardiac death (chi-square = 71 to chi-square = 86, p < 0.0001). The addition of exercise echocardiographic variables, especially the change in left ventricular end-systolic volume with exercise and the exercise ejection fraction, further improved the model in terms of predicting cardiac events (chi-square = 86 to chi-square = 108, p < 0.0001) and cardiac death (chi-square = 86 to chi-square = 99, p = 0.004). CONCLUSIONS: Exercise echocardiography provides incremental prognostic information in patients > or = 65 years of age. The best model included clinical, exercise testing and exercise echocardiographic variables.

Exercise tolerance in patients with Ebstein's anomaly.

OBJECTIVES: The purpose of this study was to identify the determinants of exercise tolerance in patients with Ebstein's anomaly. BACKGROUND: Patients with Ebstein's anomaly of the tricuspid valve may have exercise limitation that improves after surgical repair. METHODS: One hundred seventeen patients performed cycle ergometry for a total of 124 tests (preoperative test in 76 patients, postoperative test in 23, test but no operation in 18, preoperative and postoperative test in 7). Multiple linear regression analysis was used to identify predictors of maximal oxygen uptake, oxygen saturation and heart rate at peak exercise. RESULTS: Age at the time of exercise ranged from 6 to 60 years (median 15). An atrial septal defect was present in 67 patients (88%) preoperatively. Compared with the preoperative group, the postoperative group had significantly higher maximal oxygen uptake (mean [+/- SD] 20.5 +/- 7.4 vs. 25.3 +/- 7.0 ml/kg body weight per min, p = 0.006). Postoperative rest and exercise blood oxygen saturation was higher than that measured preoperatively (p = 0.0001). Six of seven patients tested before and after the operation showed improved exercise tolerance. Preoperatively, major predictors of maximal oxygen uptake were oxygen saturation at rest (p = 0.01) and age (p = 0.0001). Preoperatively, the major predictor of oxygen saturation at peak exercise was rest oxygen saturation (p = 0.0001), and major predictors of peak exercise heart rate were rest heart rate (p = 0.01) and rest oxygen saturation (p = 0.01). In the postoperative group, predictors of maximal oxygen uptake included age at exercise testing, male gender and heart size. CONCLUSIONS: Definitive operation for Ebstein's anomaly results in improved exercise tolerance. Before the operation, rest oxygen saturation is the major predictor of exercise tolerance, oxygen saturation at peak exercise and peak heart rate. Postoperatively, age, gender and heart size influenced maximal oxygen uptake.

Cardiorespiratory response to exercise after modified Fontan operation: determinants of performance.

OBJECTIVES: This study sought to measure the cardiorespiratory responses to exercise and to identify the perioperative determinants of exercise performance in children, adolescents and young adults who underwent the modified Fontan operation. BACKGROUND: Several studies of the cardiorespiratory responses to exercise after the Fontan operation have demonstrated subnormal maximal oxygen uptake and exercise heart rate, but the perioperative variables that ultimately affect exercise responses have not been assessed systematically. METHODS: The study included 59 of the 548 patients who underwent a modified Fontan operation between January 1, 1984 and December 31, 1993 at the Mayo Clinic. Spirometry was performed at rest in all patients before exercise testing. The patients then exercised using a previously calibrated cycle ergometer and a 3-min incremental cycle exercise protocol. Multiple linear regression analysis was used to determine a subset of variables associated with oxygen uptake at peak exercise (VO2max), blood oxygen saturation (O2sat) and heart rate at peak exercise (HRmax). RESULTS: VO2max ranged from 29% to 95% of normal value; O2sat at peak exercise ranged from 77% to 96%; and HRmax ranged from 39.7% to 97.4% of normal value. Multivariate analysis showed that log VO2max/kg2/3 was associated with age at exercise, male gender, body surface area, preoperative confluent pulmonary arteries and rest VO2max/kg2/3. Preoperative left pulmonary artery stenosis, the presence of a classic Glenn anastomosis at exercise and rest O2sat were associated with O2sat at peak exercise. Age, body surface area at exercise, heart rate at rest and diastolic blood pressure were associated with HRmax at exercise. CONCLUSIONS: Subnormal VO2max and HRmax values were demonstrated at peak exercise. Several perioperative variables were associated with VO2max and O2sat at peak exercise. The presence of a classic Glenn anastomosis was associated with decreased O2sat at peak exercise, suggesting intrapulmonary shunting with the classic Glenn anastomosis.

Atropine augmentation in dobutamine stress echocardiography: role and incremental value in a clinical practice setting.

OBJECTIVES: This study sought to evaluate the role and incremental value of atropine in a large patient group undergoing dobutamine stress echocardiography. BACKGROUND: The use of atropine to potentiate dobutamine stress is not standard practice. Although the utility of atropine has been described, data on its incremental value remain limited and do not exist for a routine clinical practice setting. METHODS: Dobutamine stress echocardiography was performed in 1,171 patients with use of a standard protocol. Atropine (maximal dose 2.0 mg) was given to 299 patients (26%) who did not attain target heart rate. Coronary angiography was performed in 183 patients (46 received atropine), 148 of whom were found to have significant coronary artery disease (> or = 70% diameter stenosis in a major epicardial vessel, > or = 50% stenosis for left main coronary artery disease). All tests were reviewed independently by experienced observers. RESULTS: There were no major adverse events. Patients receiving atropine had a lower rest heart rate (65 vs. 74 beats/min, p < 0.0001) and more often received beta-adrenergic blocking agents (49% vs. 14%, p < 0.0001). Of 444 patients in whom stress-induced ischemia developed, 70 (16%) required atropine before ischemia became evident. Sensitivity for detection of significant coronary artery disease was 90% with dobutamine alone and 95% after the addition of atropine. In 66 patients with normal wall motion at rest, test sensitivity was 65% before and 84% after atropine was given. Atropine use did not compromise test specificity. New diagnostic information was obtained in 20 (50%) of 40 patients with angiographic coronary artery disease given atropine. Proportionately more patients with single-vessel disease required atropine before an ischemic response was observed; this effect appeared related to the higher ischemic threshold in these patients. CONCLUSIONS: Augmentation of heart rate had a modest influence on the overall diagnostic sensitivity of dobutamine stress echocardiography in our study cohort. However, it was particularly helpful in patients receiving beta-blockers and those with milder coronary disease. Despite the use of > or = 1 mg of atropine in some patients, this incremental value was not achieved at the expense of safety.

Assessment of cardiac risk before nonvascular surgery: dobutamine stress echocardiography in 530 patients.

OBJECTIVE: This study evaluated the incremental value of dobutamine stress echocardiography (DSE) for assessment of cardiac risk before nonvascular surgery. BACKGROUND: Limited information exists regarding the preoperative assessment of cardiac risk in patients with known or suspected coronary artery disease who are to undergo nonvascular surgery. METHODS: All patients (303 men, 227 women) who underwent DSE before nonvascular surgery and did not sustain an intervening event (coronary revascularization or cardiac event) were studied. Clinical, electrocardiographic and rest and stress echocardiographic variables were evaluated to identify predictors of postoperative cardiac events. RESULTS: Events occurred in 6% of patients: 1 cardiac death and 31 nonfatal myocardial infarctions. All of these patients had inducible ischemia on DSE (sensitivity 100%, specificity 63%). Multivariate predictors of postoperative events in patients with ischemia were history of congestive heart failure (p = 0.006; odds ratio = 4.66; confidence interval 1.55 to 14.02) and ischemic threshold less than 60% of age-predicted maximal heart rate (p = 0.0001; odds ratio 7.002; confidence interval 2.79 to 17.61). Clinical variables of Eagle's index identified 21% of patients as low, 68% as intermediate and 11% as high risk preoperatively; the postoperative event rates were 3%, 6%, and 14%, respectively. Dobutamine stress echocardiography identified 60% of patients as low (no ischemia), 32% as intermediate (ischemic threshold 60% or more) and 8% as high risk (ischemic threshold < 60%); postoperative event rates were 0%, 9% and 43%, respectively. CONCLUSIONS: In this population of patients with known or suspected coronary artery disease evaluated before nonvascular surgery, DSE had incremental value over clinical, electrocardiographic and rest echocardiographic variables for identifying patients at low, intermediate and high risk for postoperative cardiac events. Ischemia occurring at less than 60% of age-predicted maximal heart rate identified patients at highest risk.

Outcome after normal exercise echocardiography and predictors of subsequent cardiac events: follow-up of 1,325 patients.

OBJECTIVES: This study sought to examine the outcome of a large group of patients after normal exercise echocardiography and to identify potential predictors of subsequent cardiac events. BACKGROUND: Earlier studies suggested that prognosis after normal exercise echocardiography is favorable, with a low subsequent cardiac event rate. These studies involved a small number of patients and did not have sufficient statistical power to stratify risk. METHODS: The outcomes of 1,325 patients who had normal exercise echocardiograms were examined. End points were overall and cardiac event-free survival. Cardiac events were defined as cardiac death, nonfatal myocardial infarction and coronary revascularization. Patient characteristics were analyzed in relation to time to first cardiac event in a univariate and multivariate manner to determine which, if any, were associated with an increased hazard of subsequent cardiac events. RESULTS: Overall survival of the study group was significantly better than that of an age- and gender-matched group obtained from life tables (p < 0.0001). The cardiac event-free survival rates at 1, 2 and 3 years were 99.2%, 97.8% and 97.4%, respectively. The cardiac event rate per person-year of follow-up was 0.9%. Subgroups with an intermediate or high pretest probability of having coronary artery disease also had low cardiac event rates. Multivariate predictors of subsequent cardiac events were angina during treadmill exercise testing (risk ratio [RR] 4.1, 95% confidence interval [CI] 1.5 to 11.0), low work load (defined as < 7 metabolic equivalents [METs] for men and < 5 METs for women; RR 3.2, 95% CI 1.4 to 7.6), echocardiographic left ventricular hypertrophy (RR 2.6, 95% CI 1.1 to 6.3) and advancing age (RR 1.04/year, 95% CI 1.0 to 1.1). CONCLUSIONS: The outcome after normal exercise echocardiography is excellent. Subgroups with an intermediate or high pretest probability of having coronary artery disease also have a favorable prognosis after a normal exercise echocardiogram. Characteristics predictive of subsequent cardiac events (i.e., patient age, work load, angina during exercise testing and echocardiographic left ventricular hypertrophy) should be considered in the clinical interpretation of a normal exercise echocardiogram.

Exercise echocardiography for the prognostic stratification of patients with low pretest probability of coronary artery disease.

PURPOSE: The aim of this study was to determine whether exercise echocardiography provides incremental data for risk stratification of patients with a low pretest probability of coronary artery disease. PATIENTS AND METHODS: The study included patients referred for exercise echocardiography whose probability of coronary artery disease was 25% or less. We calculated an exercise wall motion score index (on a 1-5 scale), an indicator of the extent and severity of exercise-induced abnormalities. The primary outcomes of the study were subsequent cardiac events (cardiac death and nonfatal myocardial infarction). RESULTS: We studied 571 men and 1047 women; their mean (+/- SD) age was 55 +/- 13 years. During a median follow-up of 3 years, there were 19 cardiac events (6 cardiac deaths and 13 nonfatal myocardial infarctions); an additional 37 patients underwent coronary revascularization. In a multivariate analysis of clinical, exercise electrocardiographic, and echocardiographic parameters, exercise wall motion score index (hazard ratio [HR] = 2.1 per 0.5 units; 95% confidence interval [CI]: 1.3 to 3.4), and age (HR = 2.0 per decade; 95% CI: 1.2-2.8) were independently associated with the risk of cardiac events. Although exercise echocardiographic variables contributed significantly (P = 0.01) to a model of the risk of adverse events, only 9 (47%) of the 19 patients with cardiac events were identified by an abnormal exercise echocardiogram. CONCLUSION: Among patients with low pretest probability of coronary artery disease by clinical criteria, exercise echocardiography identifies some, but not all, patients at risk of future events. Because of the low event rate, routine application of exercise echocardiography in a patient with a low pretest probability does not appear to be cost-effective and therefore cannot be recommended.

Transthoracic Doppler echocardiographic comparison of left internal mammary grafts to left anterior descending coronary artery with ungrafted right internal mammary arteries in patients with and without myocardial ischemia by dobutamine stress echocardiography.

To characterize Doppler flow patterns of the grafted left internal mammary artery (LIMA) in patients with and without dobutamine stress induced wall motion abnormalities in the graft distribution, we studied 29 patients who underwent coronary artery bypass surgery using LIMA grafts to the left anterior descending coronary artery (LAD). The ungrafted right internal mammary artery (RIMA) was used as a control. RIMA Doppler flow pattern was predominantly systolic in all patients. In patients without ischemia in the LAD distribution, LIMA flow was predominantly diastolic. In patients with ischemia, LIMA flow was predominantly systolic. In the grafted LIMA, a ratio of diastolic to systolic time-velocity integral of > 1.5 best showed absence of ischemia in the graft distribution. In summary, characterization of the Doppler flow pattern in the internal mammary arteries is feasible. In the grafted LIMA, ratios of diastolic to systolic flow are less in patients with an ischemic response in the subtended vascular bed than in those without ischemia.

Prognostic value of exercise echocardiography in patients after coronary artery bypass surgery.

To assess the prognostic value of exercise echocardiography in patients with prior coronary artery bypass surgery, follow-up was obtained in 718 patients (591 men [82%] and 127 women [18%], aged 67 +/- 9 years) who underwent clinically indicated exercise echocardiography 5.7 +/- 4.7 years after coronary bypass surgery. Resting wall motion abnormalities were present in 479 patients (67%). New or worsening wall motion abnormalities developed with exercise in 366 patients (51%). During a median follow-up of 2.9 years, cardiac events included cardiac death in 36 patients and nonfatal myocardial infarction in 40 patients. The addition of the exercise echocardiographic variables, abnormal left ventricular end-systolic volume response and exercise ejection fraction to the clinical, resting echocardiographic and exercise electrocardiographic model provided incremental information in predicting cardiac events (chi-square 37 to chi-square 42, p = 0.02) and cardiac death (chi-square 38 to chi-square 43, p <0.02). Exercise echocardiography provides prognostic information in patients after coronary artery bypass surgery, incremental to clinical, rest echocardiographic, and exercise electrocardiographic variables.

Normal stroke volume and cardiac output response during dobutamine stress echocardiography in subjects without left ventricular wall motion abnormalities.

Dobutamine stress echocardiography has become widely utilized for evaluation of coronary artery disease, but the expected responses of stroke volume and cardiac output to the high doses of dobutamine administered in these studies are not known. To determine these responses, stroke volume and cardiac output were measured with 2-dimensional Doppler echocardiography at each stage of dobutamine stress echocardiography and after administration of atropine in 47 patients without resting or inducible wall motion abnormalities. Heart rate increased significantly at each stage of dobutamine infusion and after atropine. Mean blood pressure decreased at the 5 micrograms/kg/min dose, then showed little change. Stroke volume increased 27 +/- 18% from baseline, with significant increases occurring at both the 5 and 10 micrograms/kg/min doses (p < 0.00001). With higher doses of dobutamine, stroke volume tended to plateau or decrease. Mean changes in stroke volume were not significant between the doses of 10, 20, and 30 micrograms/kg/min. The mean change in stroke volume from the 30 to the 40 micrograms/kg/min dose was a significant decrease of 6.3% (p = 0.004); the decrease from the 40 micrograms/kg/min dose to atropine approached statistical significance (p = 0.06). Cardiac output increased throughout dobutamine infusion. Stroke volume during dobutamine stress echocardiography is commonly maximum at a dose of 20 micrograms/kg/min and tends to decline at higher infusion rates. At higher doses, increases in cardiac output are mediated primarily by increases in heart rate.

Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension.

Primary pulmonary hypertension is characterized by elevated pulmonary arterial pressure and vascular resistance, frequently producing right heart failure and death. Therefore, the Doppler right ventricular (RV) index, which is a measure of global RV function, could be a useful predictor of outcome in primary pulmonary hypertension. The Doppler RV index, defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by ejection time, was retrospectively measured in 53 patients (38 women, aged 45 +/- 14 years) with primary pulmonary hypertension. Ejection time was measured from the pulmonary outflow velocity signal. The sum of isovolumic contraction time and isovolumic relaxation time was obtained by subtracting ejection time from the duration of tricuspid regurgitation. The Doppler RV index tended to be elevated (median 0.83) compared with normal ranges. Normal Doppler RV index was 0.28 +/- 0.04. After a mean follow-up duration of 2.9 years, 4 patients underwent lung transplantation and 30 patients died; the cause was cardiac in 28, noncardiac in 1, and uncertain in 1. Univariately, the Doppler RV index (chi-square 20.7, p <0.0001), severity of tricuspid regurgitation (chi-square 8.2, p = 0.004), treatment with calcium blockers (chi-square 6.6, p = 0.01), heart rate (chi-square 5.1, p = 0.02), and symptom status (chi-square 4.9, p = 0.03) were associated with adverse outcome (cardiac deaths and lung transplantation). However, only the Doppler RV index and treatment with calcium blockers were independent predictors within the multivariate model. Our results indicate that the Doppler RV index is a useful predictor of adverse outcome in patients with primary pulmonary hypertension.

A dose-ranging pharmacokinetic study of nicotine tartrate following single-dose delayed-release oral and intravenous administration.

BACKGROUND: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine is therapeutic but often results in side-effects. Administration of nicotine tartrate as a liquid enema decreases systemic nicotine absorption and may be effective for treatment of active distal ulcerative colitis. Ileocolonic delivery of nicotine tartrate via a delayed release oral capsule would be the preferred route to deliver nicotine to the colon. AIM: To determine the bioavailability and pharmacokinetic parameters of delayed-release oral nicotine tartrate capsules (Eudragit S100 coated) at doses of 3 mg and 6 mg nicotine. METHODS: Twenty healthy human subjects received delayed-release oral nicotine tartrate at one of two doses (each group n = 10): 3 mg and 6 mg nicotine. All subjects also received intravenous nicotine tartrate (at a dose of 15 micrograms nicotine base/kg) during a separate study period. Serum nicotine concentrations were determined by gas chromatography-mass spectrometry. In addition, concentrations of serum cotinine (major nicotine metabolite) were determined by high-performance liquid chromatography in all samples for two subjects (both given 6 mg nicotine). Adverse reactions were determined by questionnaire. RESULTS: The mean bioavailabilities of nicotine after ileocolonic nicotine tartrate administration via delayed-release oral capsules at doses 3 mg and 6 mg nicotine were 41% and 42%, respectively. The ratios (after adjusting for nicotine dose) of cotinine area under the curve (AUC) for delayed-release oral nicotine to cotinine AUC for intravenous nicotine were 1.5 and 1.6 for the two subjects undergoing cotinine pharmacokinetics, demonstrating significant first-pass metabolism. Serum nicotine concentrations did not predict adverse reactions. CONCLUSIONS: Nicotine tartrate delivered to the ileocolon as a delayed-release oral capsule at doses of 3 mg and 6 mg nicotine considerably reduced systemic nicotine bioavailability. This reduction in bioavailability appears to be a result of first-pass hepatic metabolism rather than poor mucosal absorption of nicotine. The therapeutic potential of an ileocolonic delivery formulation of nicotine tartrate, which can potentially limit toxicity by local delivery of high doses of nicotine, should be investigated in patients with ulcerative colitis.

Operation for partial atrioventricular septal defect: a forty-year review.

BACKGROUND: We describe the long-term outcome of repair of partial atrioventricular septal defect by determining the rates of survival, reoperation, and occurrence of left atrioventricular valve regurgitation, left atrioventricular valve stenosis, left ventricular outflow tract obstruction, and arrhythmia. METHODS: We studied 334 patients who underwent repair of partial atrioventricular septal defect before 1995. RESULTS: The 30-day and 5-, 10-, 20-, and 40-year survival were 98%, 94%, 93%, 87%, and 76%, respectively. Closure of the left atrioventricular valve cleft (P =. 03) and age less than 20 years at operation (P <.001) were associated with better survival. Reoperation was performed for 38 patients (11%). Repair of residual/recurrent left atrioventricular valve regurgitation or stenosis was the most common reason for reoperation. Left ventricular outflow tract obstruction occurred in 36 patients, and 7 patients underwent reoperation to relieve this obstruction. Supraventricular arrhythmias were observed in 58 patients (16%) after the operation. Supraventricular arrhythmias increased with increasing age at primary operation (P =.001). Complete atrioventricular block occurred in 9 patients (3%). Permanent pacemakers were implanted in 11 patients. CONCLUSIONS: Long-term survival after repair of partial atrioventricular septal defect is good. It is important to close the cleft in the left atrioventricular valve. Reoperation for persistent or recurrent left atrioventricular valve malfunction and relief of left ventricular outflow tract obstruction is necessary in approximately 11% of patients.

A dose-ranging study of azathioprine pharmacokinetics after single-dose administration of a delayed-release oral formulation.

6-Mercaptopurine and its prodrug azathioprine are an effective treatment for inflammatory bowel disease, but widespread use has been limited by concern about toxicity. Ileocolonic delivery of azathioprine as a 50-mg delayed-release oral capsule has been shown to decrease bioavailability, thus potentially decreasing toxicity. This study aimed to determine the bioavailability and pharmacokinetic parameters of delayed-release oral azathioprine capsules at doses of 200 mg, 400 mg, and 600 mg relative to 100 mg of standard oral azathioprine tablets. Thirty healthy human volunteers each received delayed-release oral azathioprine at one of the three doses (n = 10 for each group). All participants also received a 100-mg tablet of standard oral azathioprine. Plasma concentrations of 6-mercaptopurine were determined by high-pressure liquid chromatography. The relative bioavailabilities of 6-mercaptopurine after ileocolonic azathioprine administration via delayed-release oral capsules at doses of 200 mg, 400 mg, and 600 mg (means of 15%, 15%, and 12%, respectively) were all significantly less than 100% compared with standard oral azathioprine at a 100-mg dose. Ileocolonic delivery of azathioprine by a delayed-release oral capsule formulation at doses up to 600 mg considerably reduces 6-mercaptopurine bioavailability, relative to standard oral azathioprine tablets. The therapeutic potential of this ileocolonic delivery formulation, which can limit toxicity by local delivery of azathioprine, should be investigated in patients with inflammatory bowel disease.

Pharmacokinetics of nicotine tartrate after single-dose liquid enema, oral, and intravenous administration.

Ulcerative colitis is predominantly a disease of nonsmokers, and transdermal nicotine is therapeutic but often results in adverse reactions. Colonic administration of nicotine tartrate as a liquid enema could decrease systemic nicotine absorption and adverse reactions. The purpose of the current study was to determine the bioavailability and pharmacokinetic parameters of nicotine after administration by hydrophilic liquid enema (acidic and basic), hydrophobic liquid enema (acidic and basic), and by oral and intravenous routes. Thirty healthy volunteers received 45 micrograms nicotine base/kg (as nicotine tartrate) in one of five formulations (each n = 6): hydrophilic acidic liquid enema, hydrophilic basic liquid enema, hydrophobic acidic liquid enema, hydrophobic basic liquid enema, and oral solution. All participants also received 15 micrograms nicotine base/kg (as nicotine tartrate) intravenously during a separate study period. Serum concentrations of nicotine were determined by gas chromatography with mass spectrometry. The mean (+/-SD) bioavailabilities of nicotine after administration in the liquid enema formulations (hydrophilic acidic 17 +/- 18%, hydrophilic basic 16 +/- 16%, hydrophobic acidic 25 +/- 17%, hydrophobic basic 15 +/- 12%) were similar to the bioavailability of nicotine after administration by oral solution (20 +/- 25%). The bioavailabilities of nicotine for all five nonintravenous formulations were significantly less than for intravenous nicotine (100%). Serum concentrations of nicotine did not predict adverse reactions. Nicotine tartrate administered as either a liquid enema or as an oral solution had low bioavailability and was well tolerated. The therapeutic potential of nicotine tartrate liquid enemas, which can potentially limit toxicity by local (colonic) delivery of high doses of nicotine should be investigated in patients with left-sided ulcerative colitis.

Short deceleration time of mitral inflow E velocity: prognostic implication with atrial fibrillation versus sinus rhythm.

The present study retrospectively identified 367 patients who had restrictive physiology as defined by deceleration time < or = 130 msec; 293 were in sinus rhythm (SR) (194 men and 99 women; mean age 64 +/- 14 years) and 74 were in atrial fibrillation (AF) (51 men and 23 women; mean age 72 +/- 11 years; p < 0.001). Both groups had similar underlying diagnoses and no significant difference in Doppler indices (E wave, 96 +/- 23 vs 99 +/- 22 cm/sec in SR and AF, respectively; deceleration time, 116 +/- 12 vs 116 +/- 13 msec; and left ventricular outflow tract time velocity integral, 14.8 +/- 4.8 vs 14.5 +/- 4.4 cm). Left ventricular ejection fraction was significantly lower in SR patients (29% +/- 16% vs 39% +/- 20%; p = 0.0003). There were 120 deaths (41%) in the SR group and 35 (47%) in the AF group (median follow-up for both groups, 2.2 years). Restrictive physiology as defined by Doppler echocardiography (deceleration time < or = 130 msec) appears to predict a similar poor prognosis with AF as with SR.