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ABSTRACTObesity-associated type 2 diabetes (DM) leads to adipose tissue dysfunction. Lumican is a proteoglycan implicated in obesity, insulin resistance (IR), and adipocyte dysfunction. Using human visceral adipose tissue (VAT) from subjects with and without DM, we studied lumican effects on adipocyte function. Lumican was increased in VAT and adipocytes in DM. Lumican knockdown in adipocytes decreased lipolysis and improved adipogenesis and insulin sensitivity in VAT adipocytes in DM, while treatment with human recombinant lumican increased lipolysis and impaired insulin-sensitivity in an ERK-dependent manner. We demonstrate that lumican impairs adipocyte metabolism, partially via ERK signalling, and is a potential target for developing adipose tissue-targeted therapeutics in DM.

ABSTRACTSubcutaneous (SAT) and visceral (VAT) adipose tissues have distinct metabolic phenotypes. We hypothesized that the extracellular matrix (ECM) regulates depot-specific differences in adipocyte metabolic function in murine obesity. VAT and SAT preadipocytes from lean or obese mice were subject to adipogenic differentiation in standard 2D culture on plastic tissue culture plates or in 3D culture in ECM, followed by metabolic profiling. Adipocytes from VAT relative to SAT manifested impaired insulin-stimulated glucose uptake and decreased adipogenic capacity. In 3D-ECM-adipocyte culture, ECM regulated adipocyte metabolism in a depot-specific manner, with SAT ECM rescuing defects in glucose uptake and adipogenic gene expression in VAT adipocytes, while VAT ECM impaired adipogenic gene expression in SAT adipocytes. These findings demonstrate that ECM-adipocyte crosstalk regulates depot-specific differences in adipocyte metabolic dysfunction in murine obesity.

ABSTRACTAlterations of the extracellular matrix contribute to adipose tissue dysfunction in metabolic disease. We studied the role of matrix density in regulating human adipocyte phenotype in a tunable hydrogel culture system. Lipid accumulation was maximal in intermediate hydrogel density of 5 weight %, relative to 3% and 10%. Adipogenesis and lipid and oxidative metabolic gene pathways were enriched in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways were enriched in 3% hydrogels. These data demonstrate that the intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. These observations contribute to a growing literature describing the role of matrix density in regulating adipose tissue function.

Recently, it has been demonstrated in multiple clinical research studies that non-Q-wave myocardial infarction shares many of the features of unstable angina pectoris and that both diseases initially are managed similarly. Important new antiplatelet drugs (glycoprotein IIb-IIIa inhibitors) and antithrombin agents (low-molecular-weight heparin) are currently recommended for patients with unstable angina pectoris/non-ST-segment elevation MI who are at high or intermediate risk on the basis of symptoms, electrocardiographic findings, and the presence or absence of serum markers (eg, troponin I, troponin T, and creatine kinase-MB). This review provides important information concerning the results of clinical studies of glycoprotein IIb-IIIa inhibitors (tirofiban hydrochloride and eptifibatide) when used with unfractionated heparin in patients with this syndrome or with low-molecular weight heparin (enoxaparin sodium) in similar patients. The Thrombolysis in Myocardial Infarction IIIB, Veterans Affairs Non-Q-Wave Infarction Studies in Hospital, and Fast Revascularization During Instability in Coronary Artery Disease II studies evaluating a conservative, ischemia-guided approach vs an early aggressive approach to such patients are presented, with a practical algorithm for treating such patients.

Revising this gray iron castings standard will help prevent disputes between foundries and their designer customers, where strength is an important issue. The appendix of ASTM A48, section X1.1 addresses [...]

ABSTRACTPredictors of weight loss responses are not well-defined. We hypothesized that adipose tissue phenotypic features related to remodeling would be associated with bariatric surgery weight loss responses. Visceral and subcutaneous adipose tissues collected from patients during bariatric surgery were studied with flow cytometry, immunohistochemistry, and QRTPCR, and results correlated with weight loss outcomes. Age, male sex, and a diagnosis of type 2 diabetes were associated with less weight loss. Adipocyte size was increased and preadipocyte frequency was decreased in visceral adipose tissue from diabetic subjects. Decreased adipose tissue preadipocyte frequency was associated with less weight loss in women but not men. These data suggest that phenotypic features of adipose tissue remodeling may predict responses to weight loss interventions.

The role of the extracellular matrix (ECM) in regulating adipocyte metabolism in the context of metabolic disease is poorly defined.

Adipocytes promote progression of multiple cancers, but their role in pancreatic intraepithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC) is poorly defined. Nutrient transfer is a mechanism underlying stromal cell-cancer crosstalk. We studied the role of adipocytes in regulating in vitroPanIN and PDAC cell proliferation with a focus on glutamine metabolism. Murine 3T3L1 adipocytes were used to model adipocytes. Cell lines derived from PKCY mice were used to model PanIN and PDAC. Co-culture was used to study the effect of adipocytes on PanIN and PDAC cell proliferation in response to manipulation of glutamine metabolism. Glutamine secretion was measured with a bioanalyzer. Western blotting was used to study the effect of PanIN and PDAC cells on expression of glutamine-related enzymes in adipocytes. Adipocytes promote proliferation of PanIN and PDAC cells, an effect that was amplified in nutrient-poor conditions. Adipocytes secrete glutamine and rescue PanIN and PDAC cell proliferation in the absence of glutamine, an effect that was glutamine synthetase-dependent and involved PDAC cell-induced down-regulation of glutaminase expression in adipocytes. These findings suggest glutamine transfer as a potential mechanism underlying adipocyte-induced PanIN and PDAC cell proliferation.

CD40‐deficient mice fail to induce conventional CD4+cells in adipose tissue associated with decreased markers of antigen presentation in ATMs. Obesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen‐presenting cells and CD4+T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity‐induced inflammation in mice. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen‐presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40‐deficient mice had reduced accumulation of conventional CD4+T cells (Tconv: CD3+CD4+Foxp3−) in visceral fat compared with wild‐type mice. By contrast, the number of regulatory CD4+T cells (Treg: CD3+CD4+Foxp3+) in lean and obese fat was similar between wild‐type and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild‐type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40‐deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity‐induced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4+T cells; however, this is largely dispensable for the development of obesity‐induced inflammation and insulin resistance in mice.

The extent to which recurrent events in patients with stable coronary artery disease is attributable to progression of an index lesion originally ≥50 diameter stenosis (DS) but not revascularized or originally <50 DS is unknown during optimal medical therapy (OMT).

HYPOTHESIS Screening for esophageal adenocarcinoma has focused on identifying Barrett esophagus (BE) in patients with severe, long-standing symptoms of gastroesophageal reflux disease (GERD). Unfortunately, 95% of patients who develop esophageal adenocarcinoma are unaware of the presence of BE before their cancer diagnosis, which means they never had been selected for screening. One possible explanation is that no correlation exists between the severity of GERD symptoms and cancer risk. We hypothesize that severe GERD symptoms are not associated with an increase in the prevalence of BE, dysplasia, or cancer in patients undergoing primary endoscopic screening. DESIGN Cross-sectional study. SETTING University hospital. PATIENTS A total of 769 patients with GERD. INTERVENTIONS Primary screening endoscopy performed from November 1, 2004, through June 7, 2007. MAIN OUTCOMES MEASURES Symptom severity, proton pump inhibitor therapy, and esophageal adenocarcinogenesis (ie, BE, dysplasia, or cancer). RESULTS Endoscopy revealed adenocarcinogenesis in 122 patients. An increasing number of severe GERD symptoms correlated positively with endoscopic findings of esophagitis (odds ratio, 1.05; 95% confidence interval, 1.01-1.09). Conversely, an increasing number of severe GERD symptoms were associated with decreased odds of adenocarcinogenesis (odds ratio, 0.94; 95% confidence interval, 0.89-0.98). Patients taking proton pump inhibitors were 61.3% and 81.5% more likely to have adenocarcinogenesis if they reported no severe typical or atypical GERD symptoms, respectively, compared with patients taking proton pump inhibitors, who reported that all symptoms were severe. CONCLUSIONS Medically treated patients with mild or absent GERD symptoms have significantly higher odds of adenocarcinogenesis compared with medically treated patients with severe GERD symptoms. This finding may explain the failure of the current screening paradigm in which the threshold for primary endoscopic examination is based on symptom severity.

The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial compared percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) to OMT alone in reducing the risk of cardiovascular events in 2287 patients with stable coronary disease. We examined the cost-effectiveness of PCI as a function of angina severity at the time of randomization.

The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial enrolled patients from 3 distinct healthcare systems (HCSs) in North America. The primary aim of this study was to determine whether there is a treatment difference in cardiovascular outcomes by HCS.

HYPOTHESIS Volume criteria are poor predictors of inpatient mortality after esophagectomy. Because many factors influence mortality for complex procedures, this study was designed to quantify such factors and analyze the volume-outcome relationship for esophagectomy. DESIGN Retrospective review of the Nationwide Inpatient Sample database for esophagectomies. We performed multivariate analysis to identify patient and institution risk factors for death and, by using all reported volume thresholds, calculated the probability of choosing a provider with a low mortality. PATIENTS AND SETTING Patients undergoing esophagectomy between January 1, 1988, and December 31, 2000, included in the Nationwide Inpatient Sample database. MAIN OUTCOME MEASURE Inpatient mortality. RESULTS We identified 8075 cases of esophagectomy; 3243 had complete data sets. The national average mortality rate was 11.4%. Independent risk factors for mortality included comorbidity, age (> 65 years), female sex, race, and surgeon volume. Choosing a surgeon or hospital on the basis of a particular volume threshold had a modest influence on the probability of that provider having a low mortality. A low-volume hospital (defined by the Leapfrog Group criterion as &lt; 13 cases per year) had a probability of 61% of having a mortality of less than 10%, whereas a high-volume hospital had a probability of 68%. CONCLUSIONS Patient factors have a greater influence on inpatient mortality than case volume does. Although there is generally an inverse relationship between case volume and mortality, there is wide scatter between individual surgeons and hospitals, with a complex volume-outcome relationship. Using volume criteria alone to choose a provider may in some instances increase the risk of mortality.arch surg. 2007;142(9):829-839--

HYPOTHESIS Laparoscopy has become the standard approach for surgical treatment of uncomplicated gastroesophageal reflux disease. Laparoscopic reintervention following failure of primary antireflux surgery (ARS) remains controversial. The purposes of this study were to assess outcomes in patients operated on for failed ARS, to describe reasons for failure of the primary surgery, and to identify factors predictive of failure of the revision. DESIGN Retrospective analysis of prospectively collected data. SETTING Tertiary-care teaching hospital. PATIENTS A total of 176 patients (20 with multiple ARS) undergoing laparoscopic reintervention between September 12, 1993, and August 1, 2006, for failed ARS. INTERVENTIONS Patients had preoperative subjective and/or objective documentation of failure after primary ARS: 131 patients had reoperative Nissen fundoplication, 28 patients had a partial wrap, and 17 patients had other procedures. MAIN OUTCOME MEASURES Preoperative and postoperative symptom scores and results of objective studies were prospectively collected. Postoperative patients with symptom scores of 2 or greater and/or abnormal 24-hour pH study results (DeMeester score > 14.7) were considered to have treatment failures. Logistic regression was performed to identify variables significant for poor outcomes. RESULTS Median follow-up was 9.2 months in 145 patients (82.4%). One hundred eight patients (74.5%) demonstrated excellent symptomatic outcomes (P = .001). Twenty of 37 patients with failures had reflux symptoms and 23 experienced dysphagia. Sixty-seven patients had 24-hour pH and manometry studies; 18 (11 asymptomatic) patients had a DeMeester score greater than 14.7. Odds of failure were higher among patients presenting with dysphagia (odds ratio, 3.38; 95% confidence interval, 1.35-8.40; P = .009) or requiring an esophageal-lengthening procedure (odds ratio, 5.77; 95% confidence interval, 1.38-24.11; P = .02). CONCLUSIONS Laparoscopic reintervention following failed primary ARS provides excellent subjective and objective outcomes in most patients. Patients having laparoscopic reintervention for dysphagia relief or those requiring an esophageal-lengthening procedure have a significantly greater chance of a poor outcome.Arch Surg. 2007;142(8):785-792--

Background: Few in vivomodels of esophageal reflux and fundoplication suitable for the study of the pathogenesis of Barrett’s esophagus and esophageal cancer exist. We describe a modification of a rat model of duodenoesophageal reflux that incorporates Nissen fundoplication and uses it to study the role of fundoplication in ameliorating esophageal reflux. Methods: A previously described rat model of duodenoesophageal reflux was modified to include Nissen fundoplication. Reflux threshold (RT), defined as the gastric pressure required to cause gastroesophageal reflux during transgastric instillation of saline, was measured in 12 Sprague-Dawley rats at baseline, after cardiomyotomy with esophagogastroduodenal anastomosis (EGDA), after subsequent Nissen fundoplication, and, finally, after takedown of Nissen fundoplication (NF). Results: Cardiomyotomy with EGDA induced no significant change in RT compared with baseline (mean RT ± SD: 4.0 ± 1.9 mmHg and 6.0 ± 2.5 mmHg, respectively, p =0.741). Nissen fundoplication led to a 14-fold increase in RT (56.4 ± 18.2 mmHg) compared with cardiomyotomy. RT pressure reverted to baseline levels after NF takedown (4.7 ± 2.9 mmHg, p &lt;0.001). Antegrade esophageal flow was demonstrated without an increase in distal esophageal pressure after NF. Conclusions: Nissen fundoplication creates a one-way antireflux mechanism that eliminates gastroesophageal reflux in this rat model. This modification of an in vivomodel of duodenoesophageal reflux represents a unique opportunity to investigate the effect of NF on cardiomyotomy-induced reflux and distal esophageal exposure to duodenogastric refluxate, and could be useful in the study of the role of NF in preventing progression to BE and ECA.

HYPOTHESIS The laparoscopic transhiatal esophagectomy can be simplified and performed safely and effectively by using a novel esophageal inversion technique. DESIGN Case series describing technique, initial experience, and learning curve with laparoscopic inversion esophagectomy. SETTING Tertiary care university hospital and veteran's hospital. PATIENTS Twenty consecutive patients with high-grade dysplasia (n = 16) and esophageal adenocarcinoma (n = 4). INTERVENTION Laparoscopic inversion esophagectomy, a totally laparoscopic approach to transhiatal esophagectomy that incorporates distal to proximal inversion to improve mediastinal exposure and ease of dissection. MAIN OUTCOME MEASURES Perioperative end points and complications, compared between the first and second groups of 10 patients. RESULTS There were 19 men and 1 woman. Median operative time was 448 minutes. Median blood loss was 175 cm3. Median intensive care unit stay was 4 days, and median total hospital stay was 9 days. Overall anastomotic leak rate was 20%. Five patients developed an anastomotic stricture, all successfully managed with endoscopic dilation. There were 2 recurrent laryngeal nerve injuries, which resolved. There was no intraoperative or 30-day mortality. Between the first 10 consecutive cases and last 10 procedures, the incidence of anastomotic leak and stricture formation decreased from 30% to 10% and 40% to 10%, respectively. During this period, the number of lymph nodes harvested increased 9-fold, and duration of intensive care unit stay decreased from 8.00 to 2.50 days. CONCLUSIONS Laparoscopic inversion esophagectomy is a safe procedure. The learning curve for the inversion approach is approximately 10 operations in the hands of esophageal surgeons with advanced laparoscopic expertise.Arch Surg. 2006;141:857-866--

Roux-en-Y gastric bypass (RYGBP) is a mainstay of bariatric surgical therapy. Gastro-gastric fistula (GGF) is an infrequent but potentially serious complication of gastric bypass, and diagnosis may be difficult. We report two patients who underwent RYGBP complicated by development of GGF who nevertheless achieved excellent, durable weight loss. The pathogenesis, diagnosis, prevention and management of GGF after RYGBP is reviewed. GGF may not result in poor weight loss after RYGBP and is not an absolute indication for surgical revision.

HYPOTHESIS As the demand for bariatric surgery increases, it becomes increasingly important to define predictors of morbidity and mortality. We hypothesize that specific clinical variables predict postoperative morbidity after bariatric surgery. DESIGN, SETTING, AND PATIENTS This is a retrospective review of 452 patients undergoing inpatient bariatric surgery at an academic tertiary care institution. INTERVENTIONS Patients underwent open or laparoscopic gastric bypass or biliopancreatic diversion with duodenal switch at Oregon Health & Science University, Portland, from 2000 to 2003. Patient data were prospectively entered into a database. MAIN OUTCOME MEASURES Postoperative morbidity and mortality were analyzed among all patients, and logistic regression was used to identify clinical predictors of morbidity. RESULTS Major and minor morbidity rates were 10% and 13%, respectively; mortality was 0.9%. Age was associated with postoperative complications (odds ratio = 1.056 for each additional year). Duodenal switch was also associated with higher morbidity than gastric bypass (odds ratio = 2.149). Body mass index, sex, diabetes, surgical approach, and surgeon experience did not predict complications. CONCLUSIONS Increased age is a predictor of complications after bariatric surgery. Duodenal switch is also associated with a higher morbidity rate than gastric bypass. Surgeons should caution older patients (≥60 years) of a higher risk of postoperative complications, and a higher risk associated with duodenal switch. Large multicenter studies will be necessary to accurately define other clinical predictors of morbidity and mortality after bariatric surgery.Arch Surg. 2006;141:262-268--

Background: Obesity affects the regulation of immune and inflammatory responses. This study characterizes differences in peripheral blood lymphocyte phenotype in obese humans. Methods: Frequencies of lymphocyte subsets among peripheral blood mononuclear cells were compared between 10 obese (BMI ≥35) and 10 lean subjects, as determined by antibodies directed against cluster differentiation (CD) markers. Results: Obese patients demonstrated an increased frequency of CD3+CD4+ T-cells (mean difference 12%, P=0.004), a decreased frequency of CD3+CD8+ T-cells (mean difference 9.4%, P=0.016) and an increased frequency of CD3+CD8+CD95+ T-cells (mean difference 13.3%, P=0.032). No other differences among T-cell or monocyte subsets were noted. Conclusions: Obesity is associated with alterations in frequencies of peripheral CD4+ and CD8+ T-cells and aberrations in the expression of CD95 among CD8+ T-cells. These data suggest both CD4+ and CD8+ T-cell compartments, as well as the regulation of CD95 expression on CD8+ T-cells, as targets for further study into obesity's effects on the immune system.

Fas ligand (FasL) mediates apoptosis of susceptible Fas-expressing lymphocytes, and may contribute to the maintenance of peripheral tolerance. In transplantation models, however, artificial expression of FasL on cellular as well as islet transplants results in accelerated rejection by neutrophils. The mechanism of the neutrophilic response to FasL expression is unknown. FasL, like other members of the tumor necrosis factor family, is cleaved to a soluble form by metalloproteases. We tested the hypothesis that soluble FasL (sFasL) was responsible for neutrophil migration by creating a non-cleavable mutant of FasL.

Dendritic cells are potent antigen-presenting cells that bind allogeneic T cells. They are thus candidates for targeting immunoregulatory molecules to the alloreactive T cell compartment and suppressing the alloimmune response.

The accuracy and sensitivity of myocardial imaging using intravenous Rb-81 in delineating the extent and subsequent changes in regional myocardial perfusion abnormalities were examined serially in 12 patients one to 510 days after an acute myocardial infarction. Definite regions of decreased Rb-81 uptake were noted in 10 patients with transmural infarction. There was excellent correlation between the site of perfusion abnormalities, the electrocardiographic infarct location and the region of segmental wall motion disorders. Follow-up studies revealed in 8 of 11 patients a decrease in the extent of the perfusion defect, which was associated with an improvement in the extent and/or severity of regional wall motion disorders. Conversely, wall motion abnormalities did not change in the remaining three patients in whom perfusion abnormalities persisted unchanged. We conclude that intravenous myocardial imaging permits visualization of myocardial perfusion abnormalities early after acute myocardial infarction. Serial imaging allows detection of changes in the extent of perfusion abnormalities, and, thus, might provide useful information with respect to the patient's prognosis and the effects of therapeutic interventions.

Individuals with mitral valve prolapse (MVP) frequently show symptoms of a hyperadrenergic state.βadrenergic receptor characteristics were compared in the lymphocytes of subjects with symptomatic MVP and control subjects during rest and exercise. At rest, the proportion of receptors binding agonist with high affinity, as determined from isoproterenol competition for (—)[125I]-iodopindolol binding sites, was greater in MVP subjects than in controls. With exercise, the proportion of high-affinity receptors in MVP subjects decreased to control levels. Isoproterenol stimulation of lymphocyte 3’, 5’-cyclic adenosine monophosphate (cyclic AMP) also was greater in MVP subjects than in controls at rest, but not during exercise. Plasma catecholamine concentrations in MVP subjects were normal during both rest and exercise. Unlike exercise, isoproterenol infusion elicited clinical manifestations of increased adrenergic responsiveness in MVP subjects. Theβreceptor in exercised MVP subjects exhibited unusually high affinity agonist binding (i.e. a lower dissociation constant KHthan in either the same subjects at rest or exercised controls) and also abnormal coupling to the stimulatory guanine nucleotide-binding regulatory protein (GS) of adenylate cyclase, as reflected by the inability of guanine nucleotide to convert the receptor to a low-affinity state. These findings suggest that functional alteration of theβadrenergic receptor, in the absence of abnormal plasma catecholamine levels, might contribute to the hyperadrenergic state of MVP subjects at rest. However, desensitization of high affinityβreceptors or altered receptor-Gs coupling might preserve normal adrenergic responsiveness during exercise.

To determine the relative value of electrocardiographic (ECG) ST-segment depression alone compared to angina alone for predicting multivessel coronary artery disease during early and repeat postinfarction exercise tests, we evaluated 93 postmyocardial infarction patients with modified treadmill exercise tests prior to hospital discharge (mean 14 ± 2 days), and 36 of these 93 patients with repeat exercise tests at six weeks following infarction. It was concluded that angina alone or angina irrespective of the presence of ST-segment depression are better predictors of multivessel coronary artery disease than ECG ST-segment depression alone, and the persistence of ischemic abnormalities during repeat treadmill exercise tests following infarction is useful for confirming the presence of multivessel coronary artery disease.

In 38 patients undergoing elective coronary arterial bypass graft surgery, the radiographic dimension of the left side of the heart was determined and echocardiographic studies were performed before and after surgery. On the plain chest x-ray film one week after surgery, all patients showed an increase in the size of the left side of the heart, which usually was not accompanied by an increase in the echocardiographic left ventricular end-diastolic dimension; however, in 25 patients, pericardial fluid was detected soon after surgery, which would explain the enlarged cardiac silhouettes. Several months after surgery, the radiographic size of the heart returned to the preoperative value in most patients, and pericardial fluid was no longer demonstrated on the echocardiogram. Thus, pericardial fluid frequently is found in the first week following coronary arterial bypass graft surgery and may give the impression of increased cardiac size on plain chest x-ray films; however, echocardiographic studies provide a more accurate estimate of left ventricular size and reveal the presence of pericardial effusion.

DECISIONS concerning the optimal time for cardiac surgery in patients with valvular heart disease are often extremely difficult. Factors to be considered when recommending valve replacement include the patient's symptoms and physical findings; the severity of valvular obstruction or regurgitation, or both; the natural history of the disease process; the presence of normal or abnormal ventricular performance; the presence or absence of coexistent coronary artery disease; and the morbidity and mortality associated with valve replacement.1-5During the past two decades, cardiac catheterization with cineangiography, and often with selective coronary arteriography, has been the "gold standard" for determining the extent of valvular obstruction or regurgitation, or both, the number of cardiac valves affected, the effects of valvular disease on resting and exercise cardiac hemodynamics, the presence of normal or reduced left ventricular (LV) performance, and the existence or absence of important coincident coronary artery disease. Noninvasive techniques, particularly echocardiography and

The hemodynamic differences between bolus administration and constant intravenous infusion over a 48-h period with enoximone, a new positive inotropic/vasodilator agent, were evaluated. Twenty-four patients were studied, 15 patients in the bolus group (Group A) and nine patients in the constant infusion group (Group B). The overall hemodynamic results were similar in both groups. Cardiac output increased in Group A from 3.1 ± 0.71 to 5.5 ± 1.3 L/min and in Group B from 3.6 ± 1.0 to 5.9 ± 1.2 L/min. Significant decreases occurred in pulmonary capillary wedge pressure (30 ± 7 to 20 ± 8 mm Hg and 37 ± 5 to 21 ± 11 mm Hg) and systemic vascular resistance (2184 ± 456 to 1300 ± 305 dyn · s · cm−5and 1752 ± 415 to 1035 ± 130 dyn · s · cm−5). Group A required repeat drug boluses every 3–5 h to maintain these hemodynamic effects. The terminal blood half-life of enoximone derived following the continuous infusion in Group B was 10.6 ± 7.0 h. In conclusion, intravenous enoximone produces acute salutary hemodynamic effects in patients with severe congestive heart failure that can be sustained for at least 48 h by intermittent boluses or a continuous infusion.

Objectives. This study was conducted to determine the diagostic yield and risks of a symptom limited treadmill exercise test before hospital discharge.

The beta-adrenergic and calcium channel blocking drugs, which individually and combined have proven efficacious in the treatment of angina pectoris, appear to have opposing effects on coronary artery vasomotion. Previous studies have shown that beta-adrenergic blockade may potentiate and calcium channel blockade reverse coronary vasoconstriction during adrenergic cold stimulation in patients with coronary artery disease. To assess the coronary hemodynamic effects of combined drug therapy, thermodilution coronary sinus and great cardiac vein flow and mean arterial pressure were measured during serial cold pressor testing, both before and after 0.1 mg/kg of intravenous propranolol and again after the addition of 10 mg of sublingual nifedipine in 21 patients (9 without [group Al] and 12 with [group A2] >50% narrowing of the left anterior descending coronary artery). In an additional 15 patients (6 patients without [group Bl] and 9 with [group B2] left anterior descending artery stenosis), serial cold pressor testing was performed reversing the drug order.

The slope of the left ventricular end-systolic pressure-volume relation has been proposed as a sensitive index of left ventricular function since it increases in response to positive inotropic agents and decreases with global depression of contractility. The effect of a segmental depression of left ventricular contractile function produced by circumflex coronary artery occlusion on the left ventricular end-systolic pressure-volume relation was evaluated in seven chronically instrumented dogs. Left ventricular volume was calculated from three ultrasonically measured, orthogonal left ventricular endocardial dimensions. Left ventricular pressure was measured with a micromanometer. The left ventricular end-systolic pressure-volume relation was generated by occlusion of the inferior vena cava, before and after inducing regional ischemia, in the presence of autonomic blockade with propranolol and atropine.

In six normal subjects and 6 patients with primary cardiomyopathy, left ventricular performance was evaluated at rest and during isometric handgrip exercise after 4 days of oral N-acetylprocainamide (NAPA) at each of three dosage levels (3, 4.5, and 6 gm/day). Changes in heart rate, blood pressure, and echocardiographic performance indices were noted during isometric exercise, but no effect of NAPA could be demonstrated. In five additional patients with ventricular dysrhythmias due to cardiac diseases, NAPA was given by vein until dysrhythmias were controlled and then a maintenance infusion was continued for 48 hr. Continuous ECG recordings showed excellent dysrhythmia control in four of the five patients, but no effect of NAPA on heart rate, blood pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, or cardiac output was demonstrated, either at the peak of initial infusion (serum NAPA 27 ±6.7 μgm/ml) or at steady state during the maintenance infusion (16 ±4.5 μgm/ml). We conclude that NAPA by vein and mouth in clinically appropriate doses should be safe in patients with reduced left ventricular performance due to cardiac disease.

Objectives. The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non–Q wave myocardial infarction (NQMI) who were randomized prospectively to an early “invasive” strategy versus an early “conservative” strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up.