Destabilizing effects of mental stress on ventricular arrhythmias in patients with implantable cardioverter-defibrillators.

BACKGROUND: The incidence of sudden cardiac death increases in populations who experience disasters such as earthquakes. The physiological link between psychological stress and sudden death is unknown; one mechanism may be the direct effects of sympathetic arousal on arrhythmias. To determine whether mental stress alters the induction, rate, or termination of ventricular arrhythmias, we performed noninvasive programmed stimulation (NIPS) in patients with defibrillators and ventricular tachycardia (VT), which is known to be inducible and terminated by antitachycardia pacing, at rest and during varying states of mental arousal. METHODS AND RESULTS: Eighteen patients underwent NIPS in the resting-awake state (nonsedated). Ten underwent repeat testing during mental stress (mental arithmetic and anger recall). Induced VT was faster in 5 patients (P=0.03). VT became more difficult to terminate in 5 patients during mental stress; 4 required a shock (P=0.03). There was no change in ease of induction with mental stress. There was no evidence of ischemia on ECG or continuous ejection fraction monitoring. Eight patients received a shock in the resting-awake state and did not perform mental stress. Four underwent repeat NIPS after sedation; 3 then had induced VT terminated with antitachycardia pacing. All patients with an increase in norepinephrine of >50% had alterations in VT that required shock for termination (P<0.01). CONCLUSIONS: Mental stress alters VT cycle length and termination without evidence of ischemia. This suggests that mental stress may lead to sudden death through the facilitation of lethal ventricular arrhythmias.

Inappropriate sensing of atrial stimuli in patients with third-generation defibrillators and DDD pacemakers.

Although the problem of ICD sensing of paced ventricular stimuli has been resolved by incorporation of VVI pacing into current ICDs, many patients required separate DDD pacemakers. We report a problematic PM-ICD interaction: the inability to prevent sensing of paced atrial stimuli ("atrial sensing") leading to double-counting in DDD-PM-requiring patients with transvenous (TV) ICDs with aggressive autogain sensing (CPI Ventak PRxII or III). Four of eight patients receiving both transvenous DDD PMs and ICDs (CPI Endotak lead, at the RV apex), had atrial sensing, leading to double counting, despite intraoperative testing of multiple atrial locations with an active fixation lead. Five patients had a PRxII/III ICD, four with atrial sensing (80%), and three a PRx without atrial sensing. Patients with atrial sensing were not distinguished by any clinical or device related variable. In patients with atrial sensing (all with heart block), the PM was programmed to VDD mode. No patient has received inappropriate therapy or failed to sense VF in follow-up. In many patients with TV ICDs who required DDD pacing, no atrial position can be found without ICD sensing of atrial stimuli. While in patients with heart block this problem can be circumvented by programming to the VDD mode, in patients with sinus incompetence it may only be resolved by the combination ICD-DDD PM, currently in development.

Long QTc and torsades de pointes in human immunodeficiency virus disease.

Three patients with human immunodeficiency virus (HIV) infection presented with QT, prolongation (> 440 ms) and torsades de pointes. We sought to evaluate the etiology of the long QT syndrome in these patients without previously identified causes for QT, prolongation, and determine the prevalence among patients with HIV infection. The three index patients underwent: (1) left stellate ganglion block; (2) beta-blocker challenge; and (3) electrocardiographic stress testing. QTc interval was measured before and after intervention. We undertook a retrospective analysis of prevalence of QTC prolongation among all patients with computerized ECGs over a 6-month period at one institution and compared it to the prevalence in hospitalized patients with HIV disease. Thirty-four thousand one hundred eighty-one patients with computerized ECGs were screened for QTc prolongation. Forty-two hospitalized patients with HI disease had computerized ECG during the same 6-month period. In the three index patients, the QTc failed to shorten with left stellate ganglion blockade, beta-blocker challenge, or stress testing, suggesting an acquired form of the long QT syndrome in these patients with HIV disease. None had previously recognized acquired causes of QT, prolongation. Mexiletine hydrochloride was useful in preventing recurrences of torsades de pointes. We observed a 7.0% prevalence of QT, prolongation among all patients screened. Hospitalized patients with HIV disease (n = 42) during this same period, demonstrated an increased prevalence of QT, prolongation (28.6%, P = 0.002). Patients with HIV disease have a significantly higher prevalence of QTc prolongation than a general hospital-based population, may have an unrecognized acquired form of the long QT syndrome, and are at risk for torsades de pointes.

Relationship of scar and ischemia to the results of programmed electrophysiological stimulation in patients with coronary artery disease.

BACKGROUND: Although myocardial perfusion imaging (MPI) is widely used in patients with coronary artery disease, few data are available concerning the relationship between myocardial scar and ischemia and arrhythmic potential. PATIENTS AND METHODS: One hundred forty-four patients with chronic coronary artery disease who underwent electrophysiological studies (EPS) and MPI within 3 months constituted the study population. By history, 26% of the patients had sustained ventricular tachycardia (VT), 21% had cardiac arrest with ventricular fibrillation, and 53% had nonsustained VT. Eighty-five percent had previous myocardial infarction. Standard EPS protocol with up to three extra stimuli was used. Patients with a response of sustained monomorphic VT were defined as inducible. Quantitative MPI was used to define stress perfusion defect size and reversibility. The relations of ischemia (reversible defect) and scar (fixed defect) to inducibility on EPS were assessed by univariate analysis. Multivariate analysis was used to compare MPI results with known clinical predictors of inducibility. RESULTS: Fifty-two percent of the patients had inducible monomorphic sustained VT. MPI showed scar alone in 33%, scar with additional ischemia in 53%, ischemia alone in 8%, and no abnormality in 6%. No relation was found between the scintigraphic presence or size of ischemia and the likelihood of inducibility or to the type of arrhythmia history. In contrast, scar size was related to the result of EPS; inducible patients had significantly larger resting defect integrals (27 +/- 23 vs 14 +/- 15) than noninducible patients (p < 0.0001). Of 37 patients with very large defects (defect integral > 30), 78% were inducible, whereas only 30% of 33 patients with defect integrals < 5 were inducible. On multivariate analysis resting defect integral was an independent predictor of inducibility. In comparison with left ventricular ejection fraction (available in 122 patients), perfusion defect size was a better independent predictor of sustained VT on EPS. CONCLUSION: The presence or size of potentially ischemic myocardium does not appear to be related to the inducibility during EPS. Size of scar as quantified by myocardial perfusion imaging correlates well and better than the global left ventricular function with inducibility of sustained VT on EPS.

Reduction ventriculoplasty for the cardiomyopathic heart: a case report.

A 44-year-old morbidly obese and hypertensive woman had been diagnosed with idiopathic cardiomyopathy seven years previously. She was referred for consideration for heart transplantation because of progression of symptoms to class IV. Massive obesity and pulmonary hypertension were strong relative contraindications to transplantation. During outpatient evaluation, the patient developed pulmonary edema, was hospitalized, and became intensive care unit-bound and immobile. Exercise radionuclide angiocardiography revealed left ventricular ejection fraction of 17%, and left ventricular end-diastolic volume of 408 mL. A reduction ventriculoplasty procedure was performed by resection of the lateral wall of the left ventricle. The patient did very well, and was discharged on postoperative day nine. Two weeks after the procedure, exercise radionuclide angiocardiography demonstrated left ventricular ejection fraction of 30% (76% increase) and left ventricular end-diastolic volume of 293 mL (28% decrease). The patient remains in stable New York Heart Association class II, now three months postprocedure. This initial positive experience in New England encourages-continued investigation of the reduction ventriculoplasty procedure, either as a bridge or as an alternative to heart transplantation in patients with dilated cardiomyopathy.

Quality-of-life in patients receiving implantable cardioverter defibrillators at or before age 40.

As the use of ICDs increases, more young patients will be eligible to receive these devices. Such patients may have different concerns than older patients who more commonly receive ICDs. We investigated quality-of-life issues in patients followed by the Yale electrophysiology service who were < or = 40 years old (mean = 28) at the time of ICD implant. Mean time since ICD placement was 3.3 years. Each patient received a modified SF-36 health questionnaire; 16 (88%) of 18 responded. Nine were women; ten were married. The highest education level attained was high school for 6 (37%), and college or beyond for 10 (63%). Ten patients were employed; eight held the same job before and after ICD placement. Four women conceived after ICD implantation; one experienced ICD discharge during pregnancy. All delivered healthy infants. All patients felt their health was good to excellent, with 6 (38%) reporting an improvement in health since ICD placement. All felt capable of performing the activities of daily living, while 68% engaged freely in moderate physical activities. All patients felt they were average to very attractive. However, 63% worried about how their clothes fit with the ICD. Three quarters of the patients felt the ICD interfered with social interactions, while 50% were concerned about sexual encounters. Thus, even though these young patients have body image concerns and may limit their activities to some degree, they are productive, active members of society who have benefitted from ICD placement.

Ventricular arrhythmias in heart failure.

The management of ventricular arrhythmias in patients with heart failure continues to pose many challenges. Three principles of therapy can be identified: (1) Empiric therapy is not warranted for asymptomatic ventricular arrhythmias. (2) Therapy for asymptomatic ventricular arrhythmias must be individualized. Appropriate management of the underlying cardiac disease is critical, and careful identification of therapeutic goals is necessary. (3) Patients at high risk should be included in prospective, controlled clinical trials whenever possible.

Double sequential external shocks for refractory ventricular fibrillation.

OBJECTIVES: A technique for terminating refractory ventricular fibrillation is described. BACKGROUND: Refractory ventricular fibrillation can occur in up to 0.1% of electrophysiologic studies. Animal studies have shown that rapid sequential shocks may reduce ventricular fibrillation threshold. METHODS: Five patients of 2,990 consecutive patients in a 3-year period experienced refractory ventricular fibrillation during 5,450 routine electrophysiologic studies. Multiple shocks were delivered by means of a single defibrillator. Double sequential shocks were delivered externally 0.5 to 4.5 s apart by means of two defibrillators with separate pairs of electrodes. RESULTS: In all patients, standard defibrillation was unsuccessful, but all were successfully resuscitated using the double sequential shocks. CONCLUSIONS: This report stresses the importance of an additional defibrillator being readily available during electrophysiologic testing. This technique of rapid, double sequential external shocks may have general applicability, providing a simple and potentially lifesaving approach to refractory ventricular fibrillation.

Intraatrial conduction delay associated with an epicardial implantable cardioverter-defibrillator.

The implantable cardioverter-defibrillator (ICD) has become an important mode of therapy for patients at risk for sustained ventricular arrhythmias. While the survival benefit of these devices is clear, adverse consequences are coming to light. The authors report a case of dramatic intraatrial conduction delay associated with repeated ICD shocks, resulting in pacemaker syndrome in a patient who had received both an ICD and a dual-chamber pacemaker. This and other conduction disturbances may become more common as experience with ICDs grows, and may demand adjunctive or alternative therapies to prevent frequent shocks.

Linear left ventricular aneurysmectomy: modern imaging studies reveal improved morphology and function.

It remains uncertain whether left ventricular aneurysmectomy (LVA) improves ventricular function and whether LVA improves or distorts left ventricular contour. We applied the powerful imaging techniques of multiple-gated acquisition scanning, intraoperative transesophageal echocardiography, and magnetic resonance imaging to assess functional and morphologic changes after LVA in 75 consecutive patients undergoing LVA by conventional resection and linear closure. Fifty-two patients (69%) underwent concomitant coronary artery bypass grafting, 25 (33%) had directed endocardial resection, and 4 (5%) had valve replacement. The hospital mortality rate was 6.7% (5/75). Actuarial survival rates were 86%, 80%, and 64% at 1 year, 2 years, and 5 years, respectively. Mean anginal class improved from 3.49 to 1.24 (p < 0.0001). Mean congestive heart failure class improved from 3.04 to 1.70 (p < 0.0001). By multiple-gated acquisition scan (48 patients), mean ejection fraction improved from 0.25 preoperatively to 0.33 postoperatively (p < 0.0001). Intraoperative transesophageal echocardiography (28 patients) revealed no cases of distortion and demonstrated normalization of left ventricular contour in 69% of patients. Mean wall motion score improved from 16.4 to 18.8 (p < 0.001). Mean cross-sectional area of the left ventricle decreased from 18.7 cm2 to 12.8 cm2 (p < 0.006). Magnetic resonance imaging confirmed normalization of left ventricular contour without distortion. We conclude that linear LVA is clinically effective and objectively improves left ventricular morphology and function. On this basis, we have extended application of LVA to include patients with at least moderate-sized aneurysms undergoing coronary artery bypass grafting, despite the absence of traditional indications of arrhythmia, embolism, and frank congestive heart failure.

Determinants of the hemodynamic consequence to sustained ventricular arrhythmias after a single myocardial infarction.

Patients who have sustained ventricular arrhythmias after myocardial infarction present with either a cardiac arrest or with hemodynamically stable sustained ventricular tachycardia. Recent reports have suggested a different electrophysiologic milieu in these two patient groups and a higher incidence of cardiac arrest in patients with a history of more than one myocardial infarction. No studies have examined patients with only a single previous myocardial infarction. To assess the determinants of the hemodynamic consequence of sustained ventricular arrhythmias more than 3 days after a single myocardial infarction, 82 patients who were resuscitated from arrhythmic cardiac arrest (CA group, 40 patients) or who had hemodynamically stable sustained ventricular tachycardia (No CA group, 42 patients) were examined. Patients in both groups had similar global left ventricular ejection fractions (mean +/- SD; 30% +/- 12% vs 27% +/- 12%; p = NS), proportion of patients with anterior wall infarctions as compared with the proportion of patients with inferior wall infarctions (55% vs 50%; p = NS), time from infarction to arrhythmia development, severity of coronary artery disease, and the proportion of patients with congestive heart failure or bundle branch block. Patients who presented without cardiac arrest, however, more frequently had left ventricular aneurysms (58% vs 28%; p = 0.005). Sixty-seven patients underwent baseline drug-free electrophysiologic studies. Sustained ventricular tachycardia was induced in 79% of patients in the CA group and 85% of patients in the No CA group (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Strategies in the surgical treatment of malignant ventricular arrhythmias. An 8-year experience.

Introduction of the automatic implantable cardioverter defibrillator (AICD) has dramatically affected the surgical treatment of malignant ventricular tachyarrhythmias. The authors continue to perform electrophysiologically directed subendocardial resection (SER) of left ventricular (LV) scars in selected patients, and we revascularize (CABG) those patients undergoing AICD implantation who have significant myocardial ischemia. In an attempt to define the optimal role of each procedure, this report analyzes our 8-year experience with 348 consecutive patients treated surgically for these arrhythmias (SER since 1983 and AICD since 1986). All patients undergoing SER had organized ventricular tachycardia (VT) as a result of myocardial infarction, and most had LV aneurysms; of those undergoing AICD or AICD/CABG, 60% had VT, 15% had ventricular fibrillation, and 25% had both or were noninducible. The thirty-day mortality rate was 1.5% (3/197) for AICD, 5.4% (5/93) for AICD/CABG, and 8.6% (5/58) for SER; these mortality figures are not significant different. Late deaths in all groups were predominantly due to congestive heart failure, and actuarial survival as well as freedom from sudden death was similar between the groups at 4 years. Recurrent VT occurred in 167 of 282 (59%) of long-term survivors of AICD or AICD/CABG during follow-up and in nine of 53 (17%) of those with SER. Forty-eight per cent of survivors of AICD or AICD/CABG required antiarrhythmic medications, whereas only 11% of those with SER required antiarrhythmics. Long-term survival in each group is much higher than that reported for comparable patients with severe LV dysfunction treated medically. In those patients with organized VT and LV aneurysm who are judged able to survive the procedure, SER offers a high likelihood of cure rather than simple prevention of sudden death.

Antiarrhythmic drug exacerbation of ventricular tachycardia inducibility during electrophysiologic study.

Most studies examining antiarrhythmic drug exacerbation of ventricular arrhythmias have been performed in patients in whom clinical proarrhythmia developed. The clinical significance and predictors of antiarrhythmic drug exacerbation of inducible ventricular arrhythmias during electrophysiologic study have received less attention. Accordingly, a consecutive number of patients undergoing electrophysiologic study for evaluation of ventricular arrhythmias (but who had no history of clinical proarrhythmia) were prospectively examined. Drug-induced exacerbation was defined as no inducible ventricular tachycardia in the baseline drug-free state that increased to inducible nonsustained or sustained ventricular tachycardia, or inducible nonsustained ventricular tachycardia at baseline that increased to inducible sustained ventricular tachycardia. After administration of primarily type IA antiarrhythmic agents (procainamide and quinidine in 97% of the patients), patients were considered drug test negative (n = 80) when they had no increase in inducible ventricular tachycardia, and patients were considered drug test positive (n = 16) when they had exacerbation of inducible arrhythmias. The drug test-positive group's clinical characteristics differed markedly from those of the drug test-negative group. Compared with the drug test-negative group, the drug test-positive group had reduced (less than 40%) left ventricular ejection fractions (80% vs 39%, p = 0.005) and higher prevalences of myocardial infarctions (81% vs 35%, p = 0.027), left ventricular aneurysms (27% vs 5%, p = 0.026), and bundle branch blocks (53% vs 16%, p = 0.005). Thus exacerbation of ventricular tachycardia induction after antiarrhythmic agent administration was most common in patients with significant organic heart disease. The drug test-positive group was more frequently treated with antiarrhythmic therapy than was the drug test-negative group.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of clinical and electrophysiologic features of preexcitation syndromes in patients presenting initially after age 50 years with those presenting at younger ages.

Although patients may develop arrhythmias due to preexcitation syndromes at any time from the prenatal period to late adulthood, presentation in late adulthood is considered uncommon and has not been well studied. From June 1981 to June 1989, 73 patients were documented to have preexcitation syndromes on the basis of electrophysiologic studies. Those whose initial arrhythmias appeared at an age greater than 50 years (group 1, n = 13) were compared with the remaining 60 patients (group 2). All group 1 patients presented in the setting of acute medical or surgical diseases (n = 7), or chronic cardiac disease (n = 6) commonly associated with middle age and often with atrial arrhythmias; only 13 group 2 patients had underlying illnesses (p = 0.0001). Almost two-thirds of group 2 patients were evaluated because of narrow complex orthodromic tachycardia or palpitations and electrocardiographic evidence of preexcitation. Wide complex tachycardia was more often a reason for referral of older patients (7 of 13 vs 11 of 60, p less than 0.05), among whom atrial fibrillation/flutter also tended to be more frequent (4 of 13 vs 11 of 60, difference not significant). The PR and QRS intervals of group 1 patients were within the normal range and differed significantly from those of group 2 patients (PR, 0.15 +/- 0.04 vs 0.11 +/- 0.03 second, p less than 0.001; QRS, 0.09 +/- 0.01 vs 0.12 +/- 0.03 second, p less than 0.001), making electrocardiographic identification of preexcitation more difficult in group 1. Several factors likely contributed.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary embolism presenting as exercise-induced hypotension.

A 68-year-old man with remote history of previous myocardial infarction presented with a four-week history of intermittent dyspnea. After developing hypotension during an exercise tolerance test, he underwent cardiac catheterization, revealing significant pulmonary hypertension and two-vessel coronary artery disease. Pulmonary angiography confirmed the presence of pulmonary emboli which partially resolved after thrombolytic therapy. Subsequent treadmill testing confirmed the absence of exercise-induced hypotension two months following treatment. This case underscores the importance of considering pulmonary embolism as a potential cause of exercise-induced hypotension, since it can be successfully treated with thrombolytic agents weeks after the initial onset of symptoms.

Treatment of encainide proarrhythmia with hypertonic saline.

We report a case of successful treatment of encainide-induced ventricular tachycardia with 3% hypertonic saline. To our knowledge, no other report exists in the literature of this treatment for proarrhythmic ventricular tachycardia from a type 1C agent. Metabolic consequences of the treatment included severe hypernatremia, hyperosmolarity, hypocalcemia, and hypophosphatemia, which were reversible over 24 hours. In spite of the risks, treatment of incessant ventricular tachycardia induced by type 1C agents with hypertonic saline may be life saving.

Two accessory pathways, dual AV nodal conduction, and 1:2 ventriculoatrial conduction in a patient with multiple supraventricular tachycardias.

Multiple supraventricular tachycardias were induced in a patient with two left posterior accessory pathways and dual atrioventricular nodal conduction. One of the accessory pathways conducts slowly and exhibits decremental conduction. A "double retrograde response" (2:1 ventriculoatrial conduction) due to simultaneous retrograde propagation of a single ventricular depolarization over two longitudinally dissociated pathways plays a role not only in tachycardia initiation, but in the maintenance of a unique, irregular tachycardia.

Evolving patterns in the surgical treatment of malignant ventricular tachyarrhythmias.

The advent of the automatic implantable cardioverter defibrillator (AICD), generally viewed as a safe and effective intervention, has in some measure discouraged the use of electrophysiologically directed endocardial resection for intractable ventricular arrhythmias. We reviewed the records of 127 patients undergoing either AICD procedures or resection over a 6-year period. Thirty-day mortality was 5.6% (5/89 patients) for all AICD procedures, 10.7% (3/28) for AICD placement plus coronary artery bypass grafting, and 11.8% (4/34) for resection. These mortality figures are not significantly different. Patients undergoing resection were less likely to require antiarrhythmic agents than patients given an AICD (33% versus 61%). Survival at 2 years was 78% in the resection group and 72% in the AICD group. Survival at 4 years was still 78% in the resection group. Only 1 late sudden death occurred in the AICD group and none in the resection group. We conclude that resection continues to be a valuable alternative, offering a greater overall benefit at only slightly increased risk.

Rapid self-terminating ventricular tachycardia induced during electrophysiologic study: a prospective evaluation.

The clinical significance of rapid self-terminating ventricular tachycardia induced during electrophysiologic study was prospectively evaluated in three patient groups with clinical ventricular arrhythmias. Group A (11 patients) had inducible rapid self-terminating ventricular tachycardia only (mean cycle length less than or equal to 250 ms and greater than or equal to 10 beats in duration). In Group B (22 patients) induction of this arrhythmia was followed by the induction of sustained ventricular tachycardia. In Group C (82 patients) sustained ventricular tachycardia was induced without preceding rapid self-terminating ventricular tachycardia. All clinical characteristics of Group B patients were similar to those of Group C patients but differed markedly from those of Group A patients. Compared with Group A patients, Group B patients had a lower left ventricular ejection fraction (32 +/- 13% versus 52 +/- 17%, p = 0.004) and a greater prevalence of coronary artery disease (82% versus 0%, p less than 0.0001), structural heart disease and a history of clinical sustained ventrical arrhythmias. Similarly, the induced self-terminating ventricular tachycardia differed in Group A and Group B patients. The arrhythmias in Group B patients were more often monomorphic, were more often induced with one or two extrastimuli and had a longer cycle length than those in Group A patients. In Group B patients, the electrophysiologic characteristics of the self-terminating and the sustained induced ventricular tachycardias were similar. Cardioversion was required in 50% of Group B patients compared with 27% of Group C patients (p = 0.038).(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic effects of thrombolytic therapy in patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation.

To assess the effects of early thrombolytic therapy on the incidence of clinical and induced ventricular arrhythmias in high risk postmyocardial infarction patients, 32 patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation were prospectively evaluated. Sixteen patients (Group A) received routine care because of contraindication to thrombolytic therapy or other factors and 16 (Group B) received either tissue plasminogen activator or streptokinase within 6 h of the onset of chest pain. The two groups were similar in left ventricular ejection fraction (mean +/- SD, 28 +/- 9% [Group A] versus 30 +/- 8% [Group B]) and occurrence of spontaneous nonsustained ventricular tachycardia, new bundle branch block and congestive heart failure. Group B patients had higher peak creatine kinase MB levels (446 +/- 336 versus 205 +/- 120 IU; p = 0.017) and earlier time to peak creatine kinase values (13.4 +/- 6.6 versus 19.1 +/- 6.1 h; p = 0.006). Twenty patients who had no clinical sustained ventricular arrhythmias underwent electrophysiologic study 13 +/- 6 days after infarction. Ventricular tachycardia was induced during the study in 7 (88%) of 8 Group A patients, but in only 1 (8%) of 12 Group B patients given thrombolytic therapy (p = 0.0008). During a mean follow-up period of 11 +/- 8 months, eight Group A patients (50%) died suddenly or were resuscitated from sustained ventricular tachycardia; all Group B patients are alive and have had no clinical arrhythmic events (p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)