Fibroblast growth factor receptor is a mechanistic link between visceral adiposity and cancer.

Epidemiological evidence implicates excess adipose tissue in increasing cancer risk. Despite a steeply rising global prevalence of obesity, how adiposity contributes to transformation (stage a non-tumorigenic cell undergoes to become malignant) is unknown. To determine the factors in adipose tissue that stimulate transformation, we used a novel ex vivo system of visceral adipose tissue (VAT)-condition medium-stimulated epithelial cell growth in soft agar. To extend this system in vivo, we used a murine lipectomy model of ultraviolet light B-induced, VAT-promoted skin tumor formation. We found that VAT from mice and obese human donors stimulated growth in soft agar of non-tumorigenic epithelial cells. The difference in VAT activity was associated with fibroblast growth factor-2 (FGF2) levels. Moreover, human and mouse VAT failed to stimulate growth in soft of agar in cells deficient in FGFR-1 (FGF2 receptor). We also demonstrated that circulating levels of FGF2 were associated with non-melanoma tumor formation in vivo. These data implicate FGF2 as a major factor VAT releases to transform epithelial cells-a novel, potential pathway of VAT-enhanced tumorigenesis. Strategies designed to deplete VAT stores of FGF2 or inhibit FGFR-1 in abdominally obese individuals may be important cancer prevention strategies as well as adjuvant therapies for improving outcomes.

A new approach for ICD rhythm classification based on support vector machines.

Inappropriate shocks due to misclassification of supraventricular and ventricular arrhythmias remain a major problem in the care of patients with Implantable Cardioverter Defibrillators (ICDs). The purpose of this study was to investigate the ability of a new covariance-based support vector machine classifier, to distinguish ventricular tachycardia from other rhythms such as supraventricular tachycardia. The proposed algorithm is applicable on both single and dual chamber ICDs and has a low computational demand. The results demonstrate that suggested algorithm has considerable promise and merits further investigation.

A covariance-based algorithm: a novel technique for rhythm discrimination in ICDs.

Inappropriate shocks due to misclassification of supraventricular and ventricular arrhythmias remain a major problem in the care of patients with Implantable Cardioverter defibrillators (ICDs). In this study we have investigated the ability of a new covariance-based algorithm, to distinguish Ventricular Tachycardia from other rhythms such as Supraventricular Tachycardia. The proposed algorithm has a low computational demand and with a small adjustment is applicable on both single-chamber and dual-chamber ICDs. The results are promising and suggest that the new covariance-based algorithm may be an effective method for ICD rhythm classification and may decrease inappropriate shocks.

Optimal cut-off values for obesity: using simple anthropometric indices to predict cardiovascular risk factors in Taiwan.

BACKGROUND: The increased health risks associated with obesity have been found to occur in Asians at lower body mass indices (BMIs). To determine the optimal cut-off values for overweight or obesity in Taiwan, we examined the relationships between four anthropometric indices and cardiovascular risk factors. METHODS: The data were collected from four health-screening centers from 1998 to 2000 in Taiwan. Included were 55 563 subjects (26 359 men and 29 204 women, mean age=37.3+/-10.9 and 37.0+/-11.1 y, respectively). None had known major systemic diseases or were taking medication. Individual body weight, height, waist circumference (WC), and a series of tests related to cardiovascular risk (blood pressure, fasting plasma glucose, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol) were assessed and their relationships were examined. Receiver operating characteristic (ROC) analysis was used to find out the optimal cut-off values of various anthropometric indices to predict hypertension, diabetes mellitus and dyslipidemia. RESULTS: Of the four anthropometric indices we studied, waist-to-height ratio (WHtR) in women was found to have the largest areas under the ROC curve (women=0.755, 95% CI 0.748-0.763) relative to at least one risk factor (ie hypertension or diabetes or dyslipidemia). The optimal cut-off values for overweight or obesity from our study in men and women showed that BMIs of 23.6 and 22.1 kg/m(2), WCs of 80.5 and 71.5 cm, waist-to-hip ratios (WHpR) of 0.85 and 0.76, and WHtR of 0.48 and 0.45, respectively, may be more appropriate in Taiwan. CONCLUSIONS: WHtR may be a better indicator for screening overweight- or obesity-related CVD risk factors than the other three indexes (BMI, WC and WHpR) in Taiwan. Our study also supported the hypothesis that the cut-off values using BMI and WC to define obesity should be much lower in Taiwan than in Western countries.

Four anthropometric indices and cardiovascular risk factors in Taiwan.

OBJECTIVE: To examine the relationships between four anthropometric measurements and cardiovascular risk factors in Taiwan. DESIGN: The data was collected from four nationwide health screen centers in Taiwan from 1998 to 1999. SUBJECTS: A total of 38 556 subjects: 18 280 men and 20 276 women, mean age=37.0+/-11.1 y. None had any known major systemic diseases or were currently on medication. MEASUREMENTS: Individual body weight, height, waist circumference (WC), and cardiovascular risk factors (blood pressure, fasting plasma glucose, triglycerides, total cholesterol level, low-density and high-density-lipoprotein cholesterol level) were assessed and their relationships were examined. RESULTS: In both sexes, with increasing body mass index (BMI), WC, WHpR (waist-to-hip ratio) and WHtR (waist-to-height ratio), there were significantly higher risks of hypertension, impaired fasting glucose, diabetes and dyslipidemia (P<0.001) in almost all age groups. In the age groups older than 65, however, the relationships were statistically inconsistent. CONCLUSIONS: In Taiwan, the four anthropometric indexes (BMI, WC, WHpR, WHtR) are closely related to cardiovascular risk factors.

Hybrid therapy for ventricular arrhythmia management.

Optimum arrhythmia management has evolved to couple ICD therapy with catheter ablative and drug therapy to attempt to eliminate or reduce arrhythmia risk. No longer should the clinician approach such therapy as a choice among single alternative strategies only. Optimum patient management includes not only recognition of the indications and benefits of such hybrid therapy but also a complete understanding of potential pitfalls of such therapy.

Radiofrequency catheter ablation of postinfarction ventricular tachycardia: long-term success and the significance of inducible nonclinical arrhythmias.

BACKGROUND: Radiofrequency (RF) catheter ablation is effective therapy for monomorphic ventricular tachycardia (VT) in patients without structural heart disease. In patients with postinfarction VT; however, this procedure has been used predominantly as adjunctive therapy, targeting only the patient's clinically documented arrhythmia. By targeting all inducible, sustained VT morphologies, we sought to determine the utility of RF catheter ablation as a primary cure in patients who present with hemodynamically tolerated VT. METHODS AND RESULTS: RF ablation was attempted in 35 patients with a previous myocardial infarction and recurrent, hemodynamically tolerated VT. A mean of 3.9+/-2.7 VTs were induced per patient (range, 1 to 10). The clinically documented arrhythmia was successfully ablated in 30 of 35 patients (86%), and on follow-up electrophysiological testing, 11 patients had no inducible VT and were discharged without other therapy. Nineteen patients had inducible "nonclinical" arrhythmias on follow-up testing, and the majority underwent cardiac defibrillator implantation. Freedom from recurrent arrhythmias, including sudden death, was 91% in patients without inducible VT and 53% in patients with persistently inducible "nonclinical" arrhythmias (P<.05; mean follow-up, 17+/-12 and 12+/-11 months, respectively). CONCLUSIONS: In patients with well-tolerated VT, RF catheter ablation may be useful as a primary cure if no other ventricular arrhythmias are inducible on follow-up testing. Ablation of all hemodynamically tolerated arrhythmias should be attempted in patients with multiple inducible VT morphologies because of the high rate of recurrence of unablated VTs in these patients.

Inappropriate pauses during bradycardia pacing in a third-generation implantable cardioverter defibrillator.

Many ICD devices have the capability for back up bradycardia pacing. Because of the use of a single sensing algorithm for both bradycardia and tachycardia functions, they may be prone to certain "sensing errors." Following implantation of an ICD in a patient with long QT syndrome, "inappropriate" pauses were noted during bradycardia pacing, which were exactly twice the programmed pacing cycle length. This was due to an automatic increase in the device's sensitivity during pacing, a characteristic of the automatic gain control of this particular ICD. Proper recognition of this ICD's special features, known as "lower threshold crossing," allowed noninvasive rectification of the problem and prevented these pauses.

The effects of isoproterenol on the cardiac conduction system: site-specific dose dependence.

INTRODUCTION: Isoproterenol is used to assess and facilitate AV nodal conduction, and thus potentiate the induction of supraventricular arrhythmias. It is commonly administered in increasing doses until a predetermined decrease in sinus cycle length, usually 20% to 30%, occurs. This regimen may result in undesirable side effects. We have observed that effects of isoproterenol on the AV node may occur prior to achieving the target sinus cycle length. The purpose of this study was to determine whether the sinus and AV nodes have equal sensitivity to isoproterenol. METHODS AND RESULTS: Thirty-eight consecutive patients, who underwent electrophysiologic evaluation for a variety of indications, were given incremental doses of isoproterenol at 0.007, 0.014, 0.021, and 0.028 microgram/kg per minute. Sinus cycle length and AV node function were assessed at baseline and after 5 minutes at each dose. The percent change from baseline in AV node function was compared with the change in sinus cycle length at each dose interval. Significantly greater decreases were observed in the anterograde and retrograde AV nodal Wenckebach cycle length (P < 0.0001) than in the sinus cycle length at the lowest isoproterenol dose (0.007 microgram/kg per min). These differences were not apparent at higher doses. A sustained supraventricular tachycardia was inducible in 15 of 38 patients in the presence of isoproterenol, of which 40% occurred at the lowest dose. CONCLUSIONS: The AV node is more sensitive than the sinus node to the effects of isoproterenol. Lower doses of isoproterenol than those commonly used may often facilitate the induction of a supraventricular tachyarrhythmia, thus reducing side effects.

Eliminating bradyarrhythmias after orthotopic heart transplantation.

BACKGROUND: Bradycardia and sinus node dysfunction are common causes of early postoperative morbidity in orthotopic heart transplant recipients and frequently require the use of chronotropic drugs or permanent pacemakers. Several causes have been postulated, including surgical trauma to the sinus node and its blood supply. We sought to eliminate sinus node dysfunction and postoperative bradyarrhythmias by altering the orthotopic heart transplantation technique. METHODS AND RESULTS: Seventy orthotopic heart transplant recipients underwent electrophysiological testing of sinus node function a mean of 9 +/- 3 days after surgery. Standard (atrial anastomosis) orthotopic heart transplantation was performed in 33 patients; total (bicaval anastomosis) heart transplantation was performed in 37 patients. Abnormalities of sinus node function were present in 14 of 33 patients (42%) undergoing standard orthotopic heart transplantation compared with 2 of 37 patients arrhythmia (5%) in whom total heart transplantation was performed (P < .005). The resting sinus heart rate of patients with a normal sinus rhythm was also significantly higher in the total heart transplantation group (90 +/- 12 versus 83 +/- 14 bpm, P < .05). Coronary angiography was performed before discharge in 63 patients. Eleven were found to have an abnormal sinoatrial nodal artery, and 7 of these patients also had evidence of sinus node dysfunction (P < .005). CONCLUSIONS: Surgical trauma to the donor sinus node and/or its blood supply is a significant cause of sinus node dysfunction in the orthotopic heart transplant recipient. By use of a bicaval anastomotic technique, the incidence of and need for treatment of postoperative bradyarrhythmias can be significantly reduced.

Primary ablation of atrial flutter and atrial fibrillation.

Direct treatment of atrial flutter and atrial fibrillation--that is, attempting to prevent arrhythmia recurrences by ablating atrial tissue--has been a challenge because of uncertainty about the location of optimal target tissues as well as the amount of atrial tissue requiring destruction to effect cure. Advances have yielded success rates for ablation of the common form of atrial flutter comparable to those for other types of supraventricular tachycardia and provide reason for optimism about the use of catheter techniques, to treat atrial fibrillation definitively. This article discusses some of these advances as well as the current status of catheter ablation for atrial flutter and atrial fibrillation and, finally, what the future may bring.

Transvaginal uterine cervical dilation with fluoroscopic guidance: preliminary results in patients with infertility.

PURPOSE: To assess efficacy of uterine cervical dilation performed with fluoroscopic guidance to treat patients with infertility who have cervical stenosis, false channels within the endocervical canal, or both. MATERIALS AND METHODS: Fifteen patients in whom infertility was diagnosed were referred because the uterine lumen could not be accessed. Three of the patients had endometriosis. With fluoroscopic guidance, the cervix was cannulated and the endocervical canal was dilated with an angioplasty balloon or with dilators. Five patients underwent simultaneous fallopian tube recanalization. Five of 15 patients who underwent dilation subsequently underwent in vitro fertilization for embryo transfer (IVF-ET) or intrauterine insemination. RESULTS: Four patients became pregnant. Of those four, one underwent IVF-ET and one underwent intrauterine insemination. Two patients became pregnant spontaneously. In the five patients who underwent IVF-ET or intrauterine insemination and in the remaining eight patients, the cervix could be easily cannulated up to 7 months after dilation. CONCLUSION: Dilation of the uterine cervix may provide options for treatment in selected patients with infertility. The effect of dilation on patients with other sequelae of cervical obstruction such as endometriosis remains uncertain.

Compatibility of a nonthoracotomy lead system with a biphasic implantable cardioverter-defibrillator. Cadence-Endotak 60-Series IDE investigators.

This prospective multicenter study was conducted under the Food and Drug Administration Investigational Device Exemption to evaluate the safety and efficacy of the combination of the Cadence implantable defibrillator (Ventritex, Inc.) and 60-series Endotak C leads (Cardiac Pacemakers, Inc.). Implantation was attempted in 148 patients with hemodynamically compromising ventricular tachycardia or fibrillation (VF), or with pace-terminable ventricular tachycardia. The system was successfully implanted in 97% of patients, with 96% of implants in a transvenous-lead-alone configuration. At implantation, the defibrillation threshold was 455 +/- 94 V (14 +/- 6 J) for lead-alone patients and 532 +/- 40 V (19 +/- 3 J) for those requiring a subcutaneous patch. VF conversion efficacy was reconfirmed in patients who underwent a 3-month chronic induction study. The system successfully detected all 763 induced arrhythmias and terminated 99.5% of them; after system modification, successful conversion was demonstrated in the 2 patients who initially had induced episodes requiring external defibrillation (1 lead revision; 1 reprogramming). All spontaneous episodes were terminated with an implantable-cardioverter defibrillator. Postshock VF redetection times were significantly shorter than initial detection times (4.5 +/- 1.8 seconds detection, 2.1 +/- 0.7 seconds redetection; p<0.0001). During an 8-month mean follow-up (range 1 to 31 months), 2 unwitnessed deaths were classified as sudden cardiac deaths, and 11 patients experienced a total of 12 complications, none of which was associated with the Cadence-Endotak combination.

The effects of chronic administration of indomethacin and misoprostol on renal function in cirrhotic patients with and without ascites.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) often cause renal dysfunction in cirrhotic patients with ascites through inhibition of prostaglandin synthesis. However, their renal effects in cirrhotic patients without ascites are controversial. In addition, the role of prostaglandins in cirrhotic patients with ascites and in non-ascitic cirrhotic patients receiving NSAIDs also remains elusive. Thus we evaluated the chronic renal effects of indomethacin and misoprostol in 9 cirrhotic patients with ascites (protocol 1) and 21 cirrhotic patients without ascites (protocol 2). METHODS: The patients of protocol 1 received 200 micrograms of misoprostol every 6 h for 7 consecutive days. In protocol 2, 11 patients received 25 mg indomethacin three times a day for 7 consecutive days. The other 10 patients received 25 mg indomethacin three times a day plus 200 micrograms misoprostol every 6 h for 7 consecutive days. Renal function tests, plasma renin activity, and plasma aldosterone concentration were measured before and after treatment. RESULTS: In protocol 1, misoprostol tended to reduce the urinary sodium excretion (p = 0.08). In protocol 2, indomethacin alone greatly impaired renal plasma flow (p < 0.05), creatinine clearance (p < 0.05), blood urea nitrogen (p < 0.05), and serum creatinine (p = 0.06) in 11 patients. Similar magnitudes of renal dysfunction were observed in the other 10 patients despite the concomitant misoprostol treatment. CONCLUSION: Chronic administration of misoprostol may have caused a negative natriuretic effect in cirrhotic patients with ascites. In cirrhotic patients without ascites chronic administration of indomethacin may induce a renal dysfunction that cannot be reversed by misoprostol.

Efficacy of antitachycardia pacing in patients presenting with cardiac arrest.

The efficacy of antitachycardia pacing (ATP) incorporated into implantable cardioverter defibrillators (ICDs) was assessed in 29 consecutive survivors of cardiac arrest, not attributable to acute myocardial infarction, ischemia, or drug and electrolyte effects. The cohort included 25 men and 4 women with a mean age of 65 years and a mean left ventricular ejection fraction of 29%. Seventeen patients had coronary artery disease, 11 had nonischemic dilated cardiomyopathy, and 1 had long QT syndrome. Programmed stimulation yielded monomorphic ventricular tachycardia (VT) in 17 patients, polymorphic VT in 6, and no inducible VT in 6. During a mean follow-up of 22 months, a total of 91 episodes of monomorphic VT occurred, 73 of which were successfully pace terminated (83%). Monomorphic VT amenable to pace termination recurred only in the group that had this arrhythmia inducible. The recurrent arrhythmias in the 12 patients having either no inducible VT or polymorphic VT were all rapid VTs, having a cycle length < 220 ms; and therefore, not amenable to pace termination. These results suggest that ATP incorporated into ICDs is useful in survivors of cardiac arrest and may significantly reduce the number of shocks that these patients would otherwise receive. Programmed stimulation may also help to define those patients who would receive the maximum benefit from ATP.

Radiofrequency ablation of a supraventricular tachycardia due to interatrial conduction from the recipient to donor atria in an orthotopic heart transplant recipient.

Interatrial conduction of recipient atrial tachycardia to the donor atria of an orthotopic heart transplant recipient resulted in a unique cause of supraventricular tachycardia. An electrophysiologic study was performed, and the recipient atria was found to be in an atrial tachycardia, cycle length of 210 msec, with periods of both 2:1 and 1:1 conduction to the donor atria resulting in a donor atrial cycle length of 420 msec and 210 msec, respectively. The site of interatrial conduction was mapped to the right atrial suture line, along the atrial free wall, and was successfully disrupted with radiofrequency energy. Arrhythmias of a similar mechanism may also be observed in other postsurgical patients.

Electrophysiologic effects of intravenous aminophylline in heart transplant recipients with sinus node dysfunction.

BACKGROUND: Sinus node dysfunction has been reported to occur in up to 50% of orthotopic heart transplant recipients, and oral theophylline has been used in an attempt to limit the morbidity associated with this abnormality. The purpose of this study was to evaluate the electrophysiologic effects of methylxanthines on sinus node function. METHODS: Sinus node testing performed in 26 patients before and after the infusion of 6 mg/kg of aminophylline. Thirteen of these patients had abnormal sinus node function at baseline, and thirteen had normal sinus node function. Sinus node dysfunction was diagnosed by a rhythm other than sinus in five patients, a prolonged corrected sinus node recovery time in two patients, and the presence of a secondary pause in six patients. RESULTS: In patients with abnormal sinus node function a significant decrease was observed in the sinus node recovery time (-14% +/- 5%) and corrected sinus node recovery time (-33% +/- 25%) in response to aminophylline; however, neither parameter was normalized. A decrease in the sinus cycle length (-6% +/- 8%) was not statistically significant. In patients with normal sinus node function, a significant decrease was seen in both the sinus node recovery time (-9% +/- 7%) and sinus cycle length (-9% +/- 4%). The corrected sinus node recovery time decreased by 4% +/- 28% in patients with normal conditions but was not significant. Overall, aminophylline resolved the underlying sinus node abnormality in only one of thirteen patients with abnormal sinus node function. CONCLUSIONS: This study suggests that the use of theophylline in patients with marked sinus node dysfunction may not decrease their risks for subsequent bradycardic events.

Pharmacological characterization of bradykinin receptors in canine cultured tracheal smooth muscle cells.

1. [3H]-bradykinin was used to characterize the bradykinin receptors associated with canine cultured tracheal smooth muscle cells (TSMCs). Receptor binding assay showed that TSMCs had specific, saturable, high-affinity binding sites for [3H]-bradykinin. 2. The specific [3H]-bradykinin binding increased linearly with increasing cell concentrations. The equilibrium for association of [3H]-bradykinin with the bradykinin receptors was attained within 2 h at 4 degrees C and 1 h at room temperature, respectively. 3. Analysis of binding isotherms yielded an apparent equilibrium dissociation constant (KD) of 2.5 +/- 0.3 nM and a maximum receptor density (Bmax) of 25.1 +/- 0.3 fmol mg-1 protein. The Hill coefficient for [3H]-bradykinin binding was 1.00 +/- 0.02. The association (K1) and dissociation (K-1) rate constants were (8.67 +/- 2.60) x 10(6) M-1 min-1 and 0.024 +/- 0.005 min-1, respectively. KD, calculated from the ratio of K-1 and K1 was 2.8 +/- 0.5 nM, a value close to that of KD calculated from Scatchard plots of binding isotherms. 4. The B1 receptor selective agonist, (des-Arg9-bradykinin, 0.1 nM-10 microM) and antagonist ([Leu8, des-Arg9]-bradykinin, 0.1 nM-10 microM) did not did not inhibit the [3H]-bradykinin binding to TSMCs, which excludes the presence of B1 receptors in canine TSMCs. 5. The specific binding of [3H]-bradykinin to canine TSMCs was inhibited by B2 receptor selective antagonists ([D-Arg0, Hyp3, Thi5, D-Tic7, Oicl-bradykinin, Hoe 140, 0.1 nM-10 micro M and [D-Arg0, Hyp3,Thi5,8, D-Phe7-bradykinin, 0.1 nM-10 micro M) and agonists (bradykinin and kallidin, 0.1 nM-10 micro M) with a best fit by a one-binding site model. The order of potency for the inhibition of [3H]-bradykinin binding was kallidin = bradykinin = Hoe 140> [D-Arg0, Hyp3, Thi5,8, D-Phel-bradykinin.6. Preincubation of TSMCs with forskolin for 24 h led to an up-regulation of B2 receptors, increasing in Bmax from 25.1 +/- 0.3 to 218 +/- 24 fmol mg-1 protein without changing the KD values. [3H]-bradykinin binding to TSMCs was inhibited by the B2 receptor selective antagonists and agonists, but not by the B1 receptor selective reagents. The up-regulation of the B2 receptor by forskolin was mediated through protein synthesis, since cycloheximide blocked this response.7 It is concluded that the pharmacological characteristics of the bradykinin receptors in canine cultured TSMCs are primarily of the B2 receptor subtype.