Immunological tolerance to hapten prevents subsequent induction of hapten-immune pulmonary interstitial fibrosis (HIPIF).

Pulmonary interstitial fibrosis (PIF) is a morphological term which in part can be defined as accumulation of collagen in the extracellular matrix. Previously we showed that hamsters sensitized with 2,4,6-trinitro-1-chlorobenzene (TNCB) developed PIF 14 days after an intratracheal challenge with 2,4,6-trinitrobenzene sulfonic acid (TNBS). The participation of delayed-type hypersensitivity (DTH) in lung collagen deposition was clearly demonstrated. In this paper, we use an adaptation of this model to mice and show that the lung collagen deposition observed was related to the genetic ability of the strain to maintain a DTH response to the immunizing hapten (TNP). Specifically, the lung collagen deposition on Day 14 in hapten-sensitized, challenged animals in high responder to TNP (BALB/c, H-2d) was higher than that in low responder mouse (C57BL/6, H-2b). Furthermore, aged C57BL/6 strain (retired breeders) possessed a DTH response to TNP and produced significantly higher accumulation of hydroxyproline than that of TNBS-challenged-only animals. A DTH mechanism for the induction of the fibrosis is consistent with the observation that responder mice that were made tolerant to the antigen were unable to respond to the lung challenge with a specific increase in lung index or collagen deposition. These results suggest that effector T lymphocytes that are important in DTH play a key role in the regulation of lung collagen deposition in hapten-immune pulmonary interstitial fibrosis (HIPIF) in mice.


Mouse splenic macrophage cell lines with different antigen-presenting activities for CD4+ helper T cell subsets and allogeneic CD8+ T cells.

A panel of seven mouse splenic macrophage cell lines, derived from cloned progenitors, was compared for their ability to present antigen to Th1 or Th2 helper T cell lines and hybridomas, as well as to naive T cells, and to provide accessory cell function for the synthesis of antibody from primed B cells. One of the cell lines expressed MHC class II molecules and was the only line with constitutive antigen-presenting activity for Th1 cells. It may represent a subset of splenic macrophages responsible for the activation of naive Th1 helper cells in situ. The remaining six cell lines responded to INF-gamma by up-regulating their class II expression and acquiring Th1 antigen-presenting activity. They may represent cells which, in situ, lack constitutive antigen-presenting activity but are promoted to presenting status by Th1-derived INF-gamma. Five of the cell lines provided accessory cell function to Th2 cells, as indicated by antibody synthesis in suspensions of spleen cells from primed mice depleted of their antigen-presenting cells. One of the cell lines lacking accessory cell activity had constitutive antigen-presenting activity for Th1 cells. This reciprocal expression of antigen-presenting activity supports the idea that Th1 and Th2 helper cells are activated by different antigen-presenting cells. Finally, the cell lines differed in their ability to constitutively induce an allogeneic response; a response that was limited to CD8+ T cells occurred in a CD4+ helper cell-independent manner and was unaffected by the addition of INF-gamma. The alloantigen-presenting macrophage cell lines also possessed the most efficient accessory cell activity for antibody synthesis. These cell lines, which represent a spectrum of antigen-presenting activities in the spleen afford models for defining the roles of macrophages in the induction of immune responses and for resolving issues concerning their development.


Human recombinant migration inhibitory factor activates human macrophages to kill tumor cells.

A recombinant form of human migration inhibitory factor (rMIF) obtained from COS-1 cells transfected with MIF-specific cDNA is able to activate cultured human peripheral blood monocytes and monocyte-derived macrophages, in a dose-dependent manner to become cytotoxic for tumor cells in vitro. The cytotoxicity exhibited by macrophages treated with rMIF is > or = 30% above that of cells incubated with control supernatants or with media and peaks 72 hr after the addition of tumor targets. rMIF also induces macrophages to produce tumor necrosis factor (TNF-alpha) and interleukin-1 beta (IL-1 beta). These results demonstrate that rMIF is able to modulate macrophage functions and plays a role in cell-mediated immune response.


A high molecular weight centrosomal protein of mammalian cells is antigenically related to myosin II.

Available data on the molecular composition of the centrosome, the typical microtubule-organizing center of animal cells, are still fragmentary. To address this important issue we have taken advantage of centrosome isolation from a human lymphoblastic cell line (KE37) to generate a monoclonal antibody (mAb) library. Here we present the characterization of one of these mAbs (CTR56). On the basis of both its immunofluorescence staining pattern and its reactivity with a major 200 kD antigen on immunoblots, CTR56 has been tentatively classified as an anticellular myosin heavy chain. In light of cytological and biochemical data obtained in parallel with two other well-characterized myosin antibodies, it appears that myosin cannot be considered as a genuine centrosomal protein. We have resolved the paradoxical results with CTR56 by showing that in addition to the cellular myosin heavy chain, this antibody also recognizes a high molecular weight protein specifically enriched in centrosomal fractions. The possible biological significance of this finding is discussed in structural and functional terms.


Antikinetochore antibodies interfere with prometaphase but not anaphase chromosome movement in living PtK2 cells.

Injection of CREST antikinetochore antiserum (AKA) containing antibodies to the kinetochore into living prometaphase PtK2 cells decreased chromosome velocity to near zero. Injection of either phosphate-buffered saline or CREST antiserum without antikinetochore antibodies (antikinetochore negative: AKN) had no effect on prometaphase oscillations. AKA antiserum injected into anaphase cells at the beginning of chromatid separation had no effect on anaphase chromosome velocity, spindle elongation, or cytokinesis. Visible binding of antikinetochore antibodies in prometaphase cells at room temperature occurred between 5 and 15 minutes after injection. Anaphase cells injected at the beginning of chromatid separation had bound antibody at the end of anaphase. AKA antiserum recognizes in Western blots proteins associated with the primary constriction: CENP-B, -C, and -D, as reported by other workers. The control antiserum, AKN, does not recognize these proteins. These results imply that the antigens recognized by CREST antibodies are important for chromosome movement. Whether or not these antigens are themselves motor molecules cannot be addressed by the present data. In addition, the results suggest that these antigens are not involved in an important way in anaphase movement.


[An overview of the development of pharmacy education in Slovakia].

Before 1777, the pharmacist in Slovakia gained their professional qualification by practising in a pharmacy. From the establishment of the University of Trnava to 1777, they attended lectures and took examinations at its Faculty of Medicine, then from 1784 onwards in Budapest. After the establishment of Czechoslovakia, the candidates of pharmacy studied in Prague, and after the closing of Czech universities (1939) in Bratislava. Between 1940 and 1948 there existed a three-year course, and later a four-year course at the Faculty of Medicine, the contents of which were close to the level of the development of sciences and the requirements of pharmaceutical practice. A logical completion of the development of the course of studies was the establishment of independent Faculties of Pharmacy in Bratislava and Brno and the prolongation of the course to five years. Commencing with the academic year 1977/78, the course of studies was divided into three specializations, General Pharmacy, Clinical Pharmacy and Technological Pharmacy. Since the academic year 1990/91 the course is uniform again, with possible differentiations in the profile of the graduate during the course according to the interests and options of the student.


[Anti-inflammatory and antipyretic activity of aqua-dihydroxybenzoate copper complexes].

Using screening methods, the anti-inflammatory and antipyretic activities of mononuclear otahedral complexes [composition:Cu(2,YDHB)2.H2O;dihydroxybenzoate ion - DHB; Y(n)-4(8).5(4) and 6(8)] and the corresponding carboxylic acids were studied. On paw dextran edema (rats, an effective dose of 10 mg/kg), a higher efficacy of the complexes was found as compared with the acids. All compounds significantly reduced the endotoxin pyretic reaction (rabbits, in a single dose of 20 mg/kg; in the case of the first two complexes half-dose was administered). Marked toxic effects were determined for Cu(II) salts when they were administered i.p. The observed biological activities of complexes are discussed in relation to their proposed structures.


[Changes in the relative levels of fatty acids in blood and myocardium in the Prague breed of rats with hereditary hypercholesteremia after administration of slow calcium channel blockers].

The present paper describes the effect of six-week oral administration of verapamil and diltiazem (1 mg.kg-1 of weight two times daily in 12 hour intervals) on the content of fatty acids of the serum and myocardium of PHHC rats. A cholesterol diet changes the content of fatty acids of the serum and myocardium of PHHC rats in comparison with control rats without the cholesterol diet. A significant decrease in the content of palmitic acid, a decrease in the content of stearic acid, linoleic acid and arachidonic acid and a significant increase in the content of oleic acid were observed in the serum. Long-term administration of the slow calcium channel blockers produces another decrease in the content of the bound form of arachidonic acid. Changes in the representation of other fatty acids are not marked. Long-term administration of a cholesterol diet produces an increase in the content of palmitic acid and stearic acid and a decrease in the content of oleic acid, linoleic acid and arachidonic acid in the myocardium. Administration of verapamil results in a modification of the above-mentioned changes in all parameters excepting the content of arachidonic acid, the content of which was decreased in an even more marked manner. Administration of diltiazem produced an accumulation of both saturated and mono-unsaturated fatty acids (palmitic, stearic and oleic acids) and produced a significant decrease in the content of linoleic acid and mainly the bound form of arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)


[Substitutional relations in the expression of drug consumption].

The present paper analyzes the formal equivalence of expressing the consumption of medicines in financial and physical units. The study was carried out on a representative sample of population; for the sake of the need of analytical expression also the factor of the age in the consumption of drugs measured per 1 inhabitant was taken into consideration. A highly close relationship between the two specific variables is observed. On this basis the postulate of the validity of equivalence is formulated. The paper points to the stability of this formal equivalence also in the conditions of the action of the seasonal component and the pragmatic significance of the obtained results for pharmaco-epidemiological studies is stressed.


[Drug consumption of certain pharmacotherapeutic groups in relation to age and sex. Psychopharmacueticals].

The paper presents data on the consumption of psycho-active drugs in the urban population, which are expressed by the number of packages and costs. The consumption of the group of agents under study represents 6.2% of total costs of drugs within the framework of out-patient care. The results of a one-year survey have revealed that the curve of the consumption of psycho-active drugs for the whole population after calculation per one person possesses the shape of a 2nd degree parabola. Consumption of psycho-active drugs per one person is significantly higher in women than in man and it consistently grows with the age.


[Prescriptions for individually prepared dermatologic agents. I].

The present paper reports the results of a survey of contemporary medical prescriptions of solutions, suspensions and emulsions used in dermatological practice. The obtained results were compared with the district prescription lists from Slovakia. The analysis of contemporary prescription was carried out in 27 districts in the years 1987 and 1989. The results show that 112 drugs are prescribed in the preparation of solutions. Most solutions are composite and 90% of solutions are hydrophilic. An analysis of suspensions revealed that in hydrophilic suspensions the liquid media water-glycerol or spirit-water prevail, and in hydrophobic suspensions nearly always plant oils are used. Emulsions are represented in topical extemporaneous preparations in a smaller amount than solutions and suspensions; it is 0.7% in the set under study.


[Antibiotic consumption in relation to sex and age].

The present paper aims at an analysis of the consumption of antibiotics in relation to age, sex and diagnosis in the district of Bratislava-vidiek. The prescription of 17 primary out-patient care physicians was evaluated. The set under study included 17,771 inhabitants divided into 10 age categories. Drug consumption was expressed by the number of packages per 1000 inhabitants and a month. The processed data were statistically evaluated. The results of the paper showed a higher consumption in women. Within the framework of the age categories under study, the consumption of antibiotics does not increase with age. The highest consumption of antibiotics, 70.45%, was found in the diseases of the respiratory system, the consumption in acute diseases being 60.46%. Tetracycline and penicillin antibiotics are the most frequently used preparations in the population under study.


[The status of fluvoxamine among the antidepressive agents].

Fluvoxamine was administered in an open trial of 50 hospitalized patients with major depression of the melancholic type (DSM-III-R) for an average period of 24.56 days in mean minimal and maximal daily doses of 100-311 mg orally after a wash-out interval of 1-14 days. Treatment achieved complete improvement in 54% and partial improvement in 16% of the patients, significantly more frequently in women than in men. The antidepressant effect of fluvoxamine was confirmed also by a statistically significant reduction of the global HAMD and FKD score, starting on the 7th day of the trial. The therapeutic effect was clinically apparent during the second week of treatment. The best therapeutic effect was achieved in anxiety depressions (65%), to a lesser degree inhibitory depressions (50%) and atypical ones (46%), as apparent from the value of Náhunek's antidepressive index 0.88 which suggests a significant anxiolytic effectiveness of fluvoxamine. Fluvoxamine had a positive effect on the majority of HAMD and FKD items, incl. a depressive mood, anxiety, feelings of guilt, anhedonia, reduced interest and ability, obsession, depressive thoughts and suicidal tendencies. Reduced motor activity, loss of appetite, insight, somatic symptoms, paranoidity and hypochondria were less influenced. At the onset of treatment the preparation did not reduced insomnia and thus in 72% patients hypnotics were added. In the course of fluvoxamine therapy no suicidal attempts were observed although 34 (68%) of the patients initially admitted had suicidal thoughts. Fluvoxamine is well tolerated by patients; as to side-effects gastrointestinal complaints were most frequent (in 28% of the patients).


[Criteria for selection of first choice antidepressive agents].

Specific inhibitors of the re-uptake of serotonin provide more adequate criteria for the selection of antidepressants of first choice, as compared with classical tricyclic antidepressants. These criteria comprise a specific therapeutic effect (e.g. influence on suicidal thoughts and action), a wider area of indications, serotonergic side-effects and relative safety of overdosage.


[Fevarin--a selective serotonin uptake inhibitor. Clinical implications of serotonin selectivity].

The author explains the development of specific inhibitors of serotonin re-uptake. Fluvoxamine differs from classical tricyclic antidepressants by a pharmacological profile of side-effects and safety of overdosage, while the therapeutic effect is comparable. The serotonin selectivity opens perspectives of further indications.


[Adrenergic and serotonergic receptors during depression and its therapy].

It is supposed that adrenergic and serotonergic receptor systems can play a crucial role in pathophysiology of depressive disorder. The hypothesis are based on changes of levels of serotonin and noradrenaline and on changes of their binding sites during depression and its treatment. Study of adrenergic and serotonergic receptors by pharmacological and molecular biological methods give rise to their division to many types and subtypes. This division makes possible to study the depressive disorder and its treatment on well defined receptors systems. Decreased density of beta- and 5-HT1-receptors was found during depression. Antidepressants influence 5-HT2 and adrenergic receptors mainly. Consequently, interaction between adrenergic and serotonergic systems exerts both in the origin of depression and during the treatment. Mutual influence and cooperation of different receptors systems are the main topics of research in this field.


[A short questionnaire as a means of screening for psychiatric disorders in the aged].

The authors elaborated a brief questionnaire of mental health of old people. They discuss the the suitability of the self-evaluating part of the questionnaire for detection of mental disorders. Hundred and forty subjects above 65 years of age were examined: living in their homes or hospitalized at the psychiatric clinic. The mean score of the self-evaluating part of the questionnaire in the group of healthy and mentally ill differs significantly. The sensitivity of the self-evaluating part for the non-differentiated group of patients is 62.07% and the specificity is 73.08%. Self-evaluation with the best reliability differentiates from healthy subjects the group of depressive patients (sensitivity 82.76%). It was revealed that self-evaluation can help also with detection of dementia (sensitivity (61.11%). An enhanced discriminating sensitivity of the questionnaire is expected from a combination of self-evaluation with items expressing objective evaluation. The authors emphasize the possibility to entrust the questionnaire to paramedical workers, and its non-pretentious character which makes it suitable for old people.


[An international study of the course and outcome of schizophrenia coordinated by the World Health Organization].

Psychiatry Demography Unit of Psychiatric Center Prague is one of the participating sites in the transcultural study on Long-term Course and Outcome of Schizophrenia coordinated by World Health Organization (WHO). The aim of the project is to learn more about factors predicting the long-term course and outcome and to investigate socio-cultural differences in schizophrenic patients. The present research builds upon the earlier WHO coordinated studies: International Pilot Study of Schizophrenia (IPSS) carried out in 1968-1969 in 13 centers including Czechoslovakia (N = 1202) and Study on Determinants of Outcome of Severe Mental Disorder (DOSMed) taken place between 1978-1980. The finding of IPSS and DOSMed were notable: incidence of narrowly defined schizophrenia did not vary greatly across cultures in opposite of the variation of short term outcome of illness that was more favourable in developing than in industrialized nations. The present follow-up study of the DOSMed and the IPSS patients (after 14 and 24 years) allow the examination of a large enough sample in a relatively short time and facilitate the development of new instruments, which provide a unique opportunity of their further cultural valid application for our center.


[Present trends in the development of drugs within the cholinesterase inhibitor group as therapeutic agents for Alzheimer's disease].

With prolongation of human age rises also the incidence of senile dementia, inclusive dementia of Alzheimer's type (DAT). At the same time the authors present views in the aetiology of this illness, the role of cholinergic mechanisms of the development dementia and they mention DAT treatment strategy focusing attention on a group of drugs-cholinesterase inhibitors.


[The 140th anniversary of the birth of Dr. O. Binswanger].

Otto Binswanger be one of noted psychiatrist of this era. Authors get acquainted with his biography and extensive scientific, pedagogic and organize activity.


Neutrophils from patients undergoing hip surgery exhibit enhanced movement under spinal anaesthesia compared with general anaesthesia.

The purpose of this research was to investigate whether the effects of regional anaesthesia on neutrophil migration differ from those due to general anaesthesia during major orthopaedic surgery in human patients. Eighteen patients underwent spinal or general anaesthesia (halothane or isoflurane) for surgery (six patients in each group). Blood samples were taken prior to induction of anaesthesia and after surgery was in progress for one hour. The movement of isolated neutrophils was measured in both samples in the chemotactic chamber toward lipopolysaccharide activated pooled serum. In addition plasma concentrations of catecholamines were determined in the blood samples. Neutrophils extracted from peripheral blood during spinal anaesthesia and surgery moved further towards a complement-derived attractant than neutrophils obtained from patients undergoing surgery under general anaesthesia with halothane or isoflurane and surgery (156.4 +/- 7.6 microns vs 114.3 +/- 6.1 microns or 119 +/- 8.4 microns respectively, P < 0.05). Increased concentrations of adrenaline were present in both general anaesthetic groups whereas the spinal group had lower concentrations than those prior to anaesthesia and surgery. It is considered unlikely that these differences in neutrophil reactivity are due to the direct effects of anaesthetic agents employed. The effects are likely to be the result of differing effects of spinal anaesthesia on the stress response or immunological mediators.


Epidural morphine reduces halothane MAC in humans.

The effect of epidural morphine sulphate (4 mg in 10 ml saline) on the minimum alveolar concentration of halothane was investigated in a double-blind, randomized fashion in ten adult patients undergoing abdominal surgery, and compared with the minimum alveolar concentration of halothane after epidural administration of 10 ml saline in a similar group of patients. Morphine sulphate, administered through the epidural catheter 98 +/- 33 min before to skin incision reduced the minimum alveolar concentration of halothane by 28% (0.57% vs 0.78%, P < 0.05).


Spinal anaesthesia with lidocaine 2% for caesarean section.

Spinal anaesthesia with 2, 2.5 or 3 ml of glucose-free lidocaine 2% was studied in 50 patients undergoing Caesarean section. Onset time, cephalad spread of analgesia, quality of analgesia, muscle relaxation, the cardiovascular effects and duration of analgesia and motor block were assessed. Reliable anaesthesia was provided with 2.5 and 3 ml while 2 ml of 2% lidocaine was insufficient. Onset time varied between 5.5 to 6 min and maximum cephalad spread was achieved in 10-15 min. The mean maximum extent of sensory analgesia was higher after 2.5 ml (T4.1) and 3 ml (T3.6) than after 2 ml (T7) (P < 0.001). Complete motor block was achieved in all the patients. The mean duration of sensory block was 123 +/- 6.23 min (2 ml) to 126 +/- 7.53 min (2.5 and 3 ml). The mean duration of motor block in 2.5 and 3 ml groups was higher (P < 0.001) than in the 2 ml group and was correlated with the dose of lidocaine (P < 0.05). Hypotension (SBP < 100 mmHg) was noted in 10% (n = 5) of patients in whom the cephalad spread of analgesia was also higher. All the neonates had an apgar score of 7 or more at 1 min. These results suggest that 2.5 to 3 ml of 2% lidocaine provides satisfactory anaesthesia for Caesarean section.


Hyaluronidase improves regional ophthalmic anaesthesia with etidocaine.

The effect of adding hyaluronidase to regional ophthalmic anaesthesia with etidocaine 1.5% was examined. Two studies were performed in a double-blind fashion. In Study #1, 70 patients were given peribulbar anaesthesia with etidocaine either with or without hyaluronidase (7.5 IU.ml-1) using a standard intraorbital injection and separate lid injections. The block was supplemented as needed. Lower intraorbital volumes (6.4 +/- 2.2 ml vs 8.2 +/- 2.3 ml, P < 0.01) and improved scores for globe akinesia (P < 0.01), lid akinesia (P < 0.01) and analgesia (P < 0.05) were recorded in the hyaluronidase group than in the plain etidocaine group. In Study #2, 80 patients were randomized to receive etidocaine and hyaluronidase either at a concentration of 7.5 IU.ml-1 or 15 IU.ml-1 using a two-injection-site technique. No differences were noted in the volumes of local anaesthetics required or in the success rates between the two groups. It was concluded that the addition of hyaluronidase to etidocaine decreases the volume needed and improves the quality of block compared with plain etidocaine. Doubling the dose of hyaluronidase does not improve the effectiveness of block.


Treatment of intraoperative hypertension with enflurane, nicardipine, or human atrial natriuretic peptide: haemodynamic and renal effects.

The purpose of this study was to assess the effects of the calcium entry blocker nicardipine and alpha human atrial natriuretic peptide (hANP) on antihypertensive and diuretic activity in hypertensive surgical patients. The site of the diuretic actions of these drugs along the nephron were also investigated by measuring the excretion rate of inorganic phosphate (PO4). Hypertension during gastrectomy was treated by increasing the concentration of enflurane, by nicardipine infusion (0.5-2.0 micrograms.kg-1 x min-1), or by hANP infusion (0.05-0.2 microgram.kg-1 x min-1) under general anaesthesia. Enflurane, nicardipine and hANP all decreased arterial pressure to the same extent. Urine flow, Na and PO4 excretion increased following the administration of nicardipine or hANP. Fractional distal reabsorption of sodium was suppressed from 89.7 +/- 2.8% to 82.1 +/- 5.0% by the hANP, but not by the nicardipine infusion. Creatinine clearance was increased by hANP infusion, but did not change in the nicardipine group. It is concluded that nicardipine and hANP can be used safely for the treatment of hypertension during surgery. Both drugs induced phosphaturic diuresis, but the site of action of the two drugs on the nephron may be different. Phosphate reabsorption is considered to occur largely in the renal proximal tubule, so that its appearance in the urine in increased quantities without the change of renal circulation in the nicardipine group suggests a proximal tubular action of this drug. However, the site of action of hANP in the kidney was not determined because GFR increased and distal sodium reabsorption was suppressed due to the drug infusion.


Anaesthetic technique does not influence postoperative bowel function: a comparison of propofol, nitrous oxide and isoflurane.

The aim of this study was to evaluate the influence of propofol, nitrous oxide and isoflurane on recovery, postoperative bowel function and postoperative complications after major gastrointestinal surgery. Sixty patients undergoing elective colonic operations were included in the study. They were randomly allocated to anaesthesia with isoflurane-nitrous oxide, propofol-air, or propofol-nitrous oxide, with fentanyl and vecuronium being used in all three groups. The same anaesthetic and surgical teams performed all the operations. The postoperative course was judged once each day by the Acute Physiology Score (APS) based on the Apache II classification, passage of gas, tolerance of enteral feeding, hospital stay and complications up to 30 days after surgery. The demographic data, magnitude of operation, duration of operation, intraoperative blood loss, and post-operative analgesic needs were similar in the groups. In all groups the APS was normal by median day 1 (range 1-7). A similar impairment of bowel function after operation, with passage of gas median 3 (1-6) days after surgery and tolerance of enteral intake median day 5 (1-10), was found in all groups. The incidence of complications and the length of postoperative hospital stay, median 11 (6-45) days, did not differ among the groups. It is concluded that overall recovery, bowel function, postoperative hospital stay, and complications were not influenced by the anaesthetic technique.


Alfentanil sedation for cardiac catheterization of children with Fontan shunts.

After Fontan operation, prolonged invasive cardiac assessment is often needed. This study is a clinical evaluation of the effectiveness of flunitrazepam premedication, EMLA cream, and alfentanil continuous infusion for management of children undergoing such catheterization. Fourteen consecutive subjects aged 5-20 yr with Fontan shunts (right atrium to pulmonary artery) undergoing elective haemodynamic and electrophysiological catheterization were sedated with an individually titrated alfentanil infusion. After oral premedication with flunitrazepam 2 mg, the mean induction dose and mean maintenance requirement of alfentanil were 4.4 +/- 2.7 micrograms.kg-1 and 10.3 +/- 8.6 micrograms.kg-1 x hr-1, respectively. Mean oxygen consumption during haemodynamic catheterization was 4.1 +/- 0.4 ml.kg-1 x min-1 with an average individual variation of 10%. For every patient, tranquil and stable conditions during catheterization could be produced. It is concluded that alfentanil infusion is a method of sedation of children and adolescents with Fontan shunts during haemodynamic and electrophysiologic catheterization. However, continuous monitoring of ventilation and an understanding of the slow circulation time after Fontan operation are essential with such sedation in these patients.


Pulmonary arteriovenous fistula: mechanical ventilation and hypoxemia.

Pulmonary arteriovenous malformation (PAVM) is an uncommon congenital anomaly. As PAVM is a direct communication between branches of the pulmonary artery and vein, major disturbances in gas exchange can result. We present a patient with an unsuspected PAVM who came to our institution for drainage of a brain abscess. Arterial blood gas analysis during and after surgery demonstrated a large alveolar-arterial gradient for oxygen in the absence of any obvious pulmonary pathology while the patient was receiving positive pressure ventilation (PPV). Oxygenation improved considerably upon resumption of spontaneous ventilation. A diagnosis of PAVM was made subsequently. We conclude that positive pressure ventilation can worsen right to left shunting in patients with PAVM.


The use of muscle relaxants in the intensive care unit.

Neuromuscular blocking agents are frequently used in the Intensive Care Unit to facilitate tracheal intubation and the application of continuous paralysis. This review will focus on various conditions of the critically ill patient such as multi-organ dysfunction, acid-base and electrolyte imbalance, prolonged immobility, multiple drug interactions and specific disease/injury processes that may affect the pharmacokinetic and pharmacodynamic behaviour of muscle relaxants. As such, due to the complex nature of the critically ill patients, the effects of neuromuscular blocking agents are unpredictable. Therefore, guidelines regarding their administration and the methodology and requirement for continuous bedside monitoring of neuromuscular function will be presented.


Multicore myopathy in a patient with anhidrotic ectodermal dysplasia.

We report a patient with multicore myopathy, a rare myopathy not previously reported in the anaesthetic literature. It is characterised by a myopathy of proximal muscles which tends to follow a benign course but may be associated with a severe form of cardiomyopathy. The myopathy is related to central core disease so these patients should be considered to have a potential for developing malignant hyperthermia. Complicating this case was an associated anhidrotic type of ectodermal dysplasia resulting in the absence of sweating, febrile episodes, recurrent pulmonary infections, conical and missing teeth, scaly skin and fine, sparse hair. The patient had a scoliosis repair which was uneventful but died three weeks later following a major pulmonary aspiration while on the ward. The cause of the aspiration is thought to have been unsuspected laryngeal incompetence associated with ectodermal dysplasia, the myopathy involving his bulbar muscles and analgesic medication.


Kinetics of dissolution of gaseous halothane in Krebs-Ringer's solution.

The responses of biological tissues to volatile anaesthetics are commonly studied by incubating specimens in a bath containing dissolved anaesthetic. One accepted technique is to bubble an anaesthetic gas into several incubation chambers simultaneously. To assess the validity of this technique in producing dissolved anaesthetic (the biologically active form) at equal rates among the several chambers, we determined the kinetics of dissolution of halothane gas in three tissue incubation chambers containing Krebs-Ringer's solution. We found that (1) the dissolution kinetics were first-order in all three chambers; (2) the rate of halothane dissolution depended on the gas bubbling rate; (3) even with the same bubbling rates, chamber shapes and chamber volumes, the dissolution rates for the three chambers were not equal, suggesting that dissolution rate depended on small differences in chamber geometry; (4) the dissolution rates could be made equal by adjusting chamber bubbling rates according to calculations involving the first-order rate equation; and (5) the maximum coefficient of variation of dissolved halothane concentration was 9% at 63% approach to equilibrium and 3% at equilibrium.


Arterial baroreflex attenuation during and after continuous propofol infusion.

The reduction of arterial blood pressure produced by propofol may be, in part, attributable to impaired baroreflex integrity. The purpose of this study was to investigate arterial baroreflex sensitivity during and after continuous propofol infusion. In urethane anaesthetized rabbits, left renal sympathetic nerves were exposed and placed on a bipolar silver electrode to record renal sympathetic nerve activity (RSNA). Mean arterial pressure (MAP) via a femoral artery and heart rate (HR) by electrocardiogram were continuously recorded. The rabbits were divided into two groups of eight each: Group 1, propofol 5 mg.kg-1 bolus followed by infusion 0.5 mg.kg-1 x min-1; Group 2, propofol 2 mg.kg-1 bolus followed by 0.2 mg.kg-1 x min-1. Phenylephrine pressor and sodium nitroprusside (SNP) depressor tests were carried out before propofol was started (control), at 15 and 30 min during 30 min infusion, and at 15, 30 and 60 min after its discontinuation. The change of RSNA was plotted with respect to every 5 mmHg increment and decrement of MAP to construct sympathetic baroreflex sigmoid curves, and to evaluate baroreflex sensitivity. The baroreflex sensitivity was also evaluated by calculating the ratio of maximum increase of RSNA or HR to SNP-induced maximum decrease of MAP (delta RSNA/delta MAP, delta HR/delta MAP). Despite the same decreases or increases in MAP, RSNA was attenuated after 15 and 30 min of propofol infusion in both groups compared with control (P < 0.05). Decreased delta RSNA/delta MAP gradually returned to the control level 60 min after discontinuation of propofol in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)


Lupus anticoagulant, paramyotonia congenita and pregnancy.

A case report is presented of the anaesthetic management of a parturient with paramyotonia congenita and lupus anticoagulant antibodies. She had been treated with prophylactic, subcutaneous heparin and aspirin throughout her pregnancy. Epidural analgesia was provided for labour and delivery.


Inspiratory valve malfunction in a circle system: pitfalls in capnography.

Capnography is a useful technique in monitoring the integrity of anaesthetic equipment such as the malfunctioning of unidirectional valves in circle system. However, the lack of a precise mechanism in existing capnographs to identify the start of inspiration and the beginning of expiration in the capnograms, makes the analysis of the carbon dioxide waveforms during inspiration difficult and thus results in inaccurate assessment of rebreathing. We report a case where, during the malfunction of the inspiratory unidirectional valve in the circle system, the capnograph failed to detect the presence of substantial rebreathing. Critical analysis of the capnogram recorded during the malfunction revealed that there was substantial rebreathing which was underestimated by the capnograph as it reports only the lowest CO2 concentration rebreathed during inspiration in such abnormal situations.


Antitumor activity of treosulfan against human breast carcinomas.

Treosulfan (L-threitol-1,4-bismethanesulfonate, Ovastat) is a bifunctional alkylating agent that shows a formal structural similarity to busulfan and is applied clinically to patients suffering from ovarian cancer. The present study demonstrated the pronounced antitumor activity of this drug against three of five human breast carcinomas xenografted to athymic mice. It was shown that treosulfan is capable of inducing irreversible and complete remission of the heterotransplanted human breast carcinomas MDA-MB-436 and MX-1 within 14 days after drug application and of effecting growth inhibition by more than 90% in the MDA-MB-435S xenograft. In all three carcinomas, treosulfan caused more pronounced growth reduction than did equitoxic doses of the alkylator cyclophosphamide. Adriamycin, an intercalating cytostatic agent that is an important component of clinical nonhormonal chemotherapy of breast carcinomas, induced only partial remission of these three xenografts and inhibited the tumor growth by 80%-90% (MDA-MB-436, MX-1) and by 70%-80% (MDA-MB-435S), respectively. In the M 3 xenograft, treosulfan just led to a retardation and stagnation of tumor growth; it was again more effective than Adriamycin but was clearly less active than cyclophosphamide. The FM 2 breast carcinoma, finally, was the only xenograft whose growth was not influenced by treosulfan at doses up to that which was lethal to 50% of the treated mice (LD50 value). These results confirm that treosulfan is effective against human breast carcinomas. Because of this activity as well as the known low toxicity and good clinical compatibility of treosulfan, it should be considered for introduction into nonendocrine chemotherapeutic regimens against human breast carcinomas and investigation in clinical trials.


Hepatic intra-arterial infusion of fotemustine: pharmacokinetics.

Fotemustine is a new nitrosourea derivative that contains an alpha-aminophosphonic acid and has a short half-life and a high plasma clearance. As myelosuppression occurs as the dose-limiting toxicity, local drug delivery has been investigated in the treatment of liver metastases arising from colorectal cancer. A pharmacokinetic study was undertaken in patients who received either i.v. or hepatic intra-arterial (HIA) infusion of 100 mg/m2 fotemustine so as to estimate the advantage of local chemotherapy, considering the pharmacokinetic differences between the two routes together with the resultant toxicities (when available). Our findings substantiated the hypothesis that a 4-h HIA infusion of foetmustine would result in a lower exposure of healthy tissues to the drug, since the AUC measured in systemic plasma was reduced by approximately 50% following such treatment as compared with i.v. infusion. This reduction in AUC should indicate a manyfold increase in exposure of the liver tumour to the alkylating properties of the drug, since it represents the proportion of the dose that has degraded within the liver. The first-pass liver-extraction ratio of fotemustine given as a 4-h HIA infusion, which ranged from 0.4 to 0.9 as estimated in patients receiving i.v. and HIA infusions in a cross-over study, argues for further investigation of HIA foetemustine infusion for the treatment of liver metastases so as to increase the response rate and decrease the occurrence of major toxic side effects in such patients.


Intrathecal 5-fluorouracil in the rhesus monkey.

Because meningeal spread of both leukemia and solid tumors remains a difficult therapeutic problem, there is a compelling need to develop new agents for intrathecal administration. 5-Fluorouracil (5FU), an active anticancer agent, penetrates into the central nervous system to some degree following intravenous dosing. Significant systemic toxicity, however, is associated with this route of administration. Therefore, the pharmacokinetic behavior of 5FU following its intrathecal administration was studied in a rhesus monkey model. After a 10-mg intraventricular dose, the disappearance of the drug from ventricular cerebrospinal fluid was monoexponential, the half-life being 51 min; the area under the concentration-time curve (AUC) being greater than 18 mM h-1; and the peak ventricular 5FU concentrations ranging between 10 and 15 mM. After a 1-mg intralumbar dose, the AUC was 1235 microM h-1. No toxicity was observed following intraventricular administration of 5FU. After intralumbar administration of either a 10-mg or a 1-mg dose, however, local toxicity was observed in the lumbar spinal cord. These findings suggest that intrathecal administration of 5FU is not presently a feasible means of achieving cytotoxic cerebrospinal fluid concentrations.


Nitric oxide: its production in host-cell-infiltrated EMT6 spheroids and its role in tumour cell killing by flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid.

Flavone-8-acetic acid (FAA) and its more dose-potent analogue 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA), appear to exert their antitumor effects through vascular and other host-mediated mechanisms and are known to induce the synthesis of nitric oxide by murine macrophages. We investigated the role of nitric oxide in the cytotoxic effects of these drugs in host-cell-infiltrated spheroids. EMT6 murine mammary adenocarcinoma cells were grown in culture to produce multicellular spheroids in vitro spheroids), which were then inoculated i.p. into mice. After 6 days the spheroids were removed ex vivo spheroids). Exposure to FAA (890 microM) and 5,6-MeXAA (80 microM) in vitro for 20 h increased nitrite concentrations to 6.7 and 9.7 nmol/spheroid, respectively, as compared with 0.7 nmol/spheroid in the absence of drug. FAA and 5,6-MeXAA did not increase nitrite production in in vitro spheroids in cells obtained by peritoneal lavage. However, mixed cultures of in vitro spheroids and peritoneal cells treated with 5,6-MeXAA produced nitrite (2.4 nmol/spheroid), indicating that interactions between host cells and tumour cells were important for induction. The effects of these drugs on ex vivo spheroids were prevented by co-incubation with NG-monomethyl-L-arginine, indicating that nitrite originated from the oxidation of L-arginine to nitric oxide. Cell sorting of disaggregated spheroids into EMT6 cells and Mac-1-positive macrophage populations indicated that both of these cell populations could be induced to synthesise nitric oxide by subsequent incubation with 5,6-MeXAA. Incubation of ex vivo spheroids with FAA and 5,6-MeXAA decreased the clonogenicity of EMT6 cells, and this effect was wholly (FAA) or partially (5,6-MeXAA) reversed by the presence of NG-monomethylarginine (250 microM). FAA and 5,6-MeXAA may therefore exert some of their cytotoxic effects on tumour cells through the production of nitric oxide.


Analysis and pharmacokinetics of N-l-leucyldoxorubucin and metabolites in tissues of tumor-bearing BALB/c mice.

Leucyldoxorubicin (Leu-Dox) was developed as a prodrug of doxorubicin (Dox) with the aim of lowering the cardiotoxicity and improving the therapeutic index produced by Dox. To support the preclinical findings on its antitumor activity and cardiotoxicity, concentrations of Leu-Dox and its metabolites were determined in plasma, heart, and tumor after the administration of Leu-Dox to tumor-bearing mice. A liquid-liquid extraction procedure employing a chloroform/2-propanol/dimethylsulfoxide (DMSO) mixture was developed. By means of high-performance liquid chromatography (HPLC) with fluorescence detection, Leu-Dox and six of its metabolites could be assayed in the tissues with high sensitivity. Detection limits ranged from 0.01 nmol/g tissue for the aglycons to 0.06 nmol/g for Dox. Recoveries were in the range of 82%-110%, and calibration curves were linear over the concentration range tested (0.1-10 nmol/g tissue, r > or = 0.998). Concentration versus time curves were constructed for plasma, heart, and tumor over the first 72 h, and areas under the curves (AUCs) for the first 48 h were determined by the trapezoidal rule. Dox was rapidly formed from Leu-Dox, reaching peak levels in plasma within 5 min and in tissues within 1 h after i.v. administration of Leu-Dox (12 mg/kg). The elimination of Leu-Dox was also fast as illustrated by final half-lives of 1.1, 0.8, and 0.9 h in the plasma, heart, and tumor, respectively. For Dox, the final half-lives were 16.7 h in plasma, 15.3 h in heart tissues, and 27.4 h in tumor tissues. AUC values determined for Leu-Dox and Dox were 221 and 51 nmol ml-1 min, 443 and 4,262 nmol g-1 min, and 153 and 1,466 nmol g-1 min in the plasma, heart, and tumor, respectively. Comparison of these values with those obtained after an equimolar dose of Dox indicated 26%, 30%, and 16% of Leu-Dox appeared as Dox in the plasma, heart, and tumor, respectively. Thus, not only is the plasma compartment not representative for calculations of the conversion of Leu-Dox into Dox in tissue, but differences in its appearance also exist between the tissue compartments. The AUC values found for Dox in the heart may explain the reduced cardiotoxicity elicited by Leu-Dox as compared with Dox; however, the values obtained for Dox in the insensitive murine colon tumor cannot explain the enhanced antitumor activity exerted by Leu-Dox in the sensitive human tumor xenografts in nude mice.


Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck.

A total of 19 patients with advanced squamous-cell carcinoma of the head and neck who had not previously been exposed to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given intravenously at a median weekly dose of 1,200 mg/m2. The toxicity was moderate, with 7 patients (37%) experiencing grade 3 or 4 toxicity. In all, 16 patients who were evaluable for efficacy showed no objective response. We conclude that brequinar given at this dose and on this schedule has no significant activity in advanced squamous-cell carcinoma of the head and neck.


Is metabolism an important arbiter of anticancer activity of ether lipids? Metabolism of SRI 62-834 and hexadecylphosphocholine by [31P]-NMR spectroscopy and comparison of their cytotoxicities with those of their metabolites.

Antineoplastic ether lipids have entered phase I clinical trial and, although their mechanism of action remains unclear, it is widely believed that the plasma membrane is the primary cellular drug target. In the present study the hypothesis was tested that metabolism of ether lipids acts as a detoxification process. [31P]-nuclear magnetic resonance (NMR) spectroscopy was used to study the metabolism of the ether lipid SRI 62-834 (SRI) and the phosphate ester hexadecylphosphocholine (HPC) in the presence of both isolated phospholipases C and D and post-mitochondrial rat liver homogenate. Both SRI and HPC were slowly metabolised by phospholipase D to their alkyl phosphates and choline, and the alkyl phosphates were subsequently metabolised by phosphatase to yield the alcohols and inorganic phosphate. These studies failed to detect any metabolism of either SRI or HPC by phospholipase C, and the metabolism of platelet-activating factor (PAF) by this enzyme was not inhibited by the addition of either compound. The cytotoxicity of SRI, the related compound HPC and their metabolites was determined in vitro using three cell lines. Cytotoxicity was measured by analysis of cell growth kinetics, MTT assay and lactate dehydrogenase release. Closely similar results were obtained in the JB1 rat hepatoma cell line, in the non-transformed BL8 rat hepatocyte cell line, and in A549 human lung adenocarcinoma cells. SRI was the most toxic of the compounds analysed, the concentration required to produce 50% toxicity or growth inhibition (IC50) being 6-9 microM. The putative metabolite of SRI, 2,2'-bis(hydroxymethyl)tetrahydrofuran, and the known metabolites [2'-(octadecyloxymethyl)tetrahydrofuran-2'-yl]methyl phosphate and 2-hydroxymethyl-2-octadecyloxymethyltetrahydrofuran exhibited IC50 values of > 200, > 100 and 40-70 microM, respectively, consistent with metabolic detoxification. HPC was more cytotoxic (IC50, 37 microM) than its phosphate metabolite (IC50, 140 microM), but its toxicity was similar to that of its metabolite hexadecanol (IC50, 28 microM), suggesting that only the former metabolic route leads to detoxification.


Schedule-dependent synergistic action of tiazofurin and dipyridamole on hepatoma 3924A cells.

Tiazofurin is an oncolytic nucleoside analog that has shown therapeutic activity in end-stage acute non-lymphocytic leukemia and in chronic granulocytic leukemia in blast crisis. Tiazofurin is anabolized to the active metabolite, TAD, which inhibits IMP dehydrogenase activity, leading to a reduction in guanylate pools and to the cessation of neoplastic cell proliferation. The drug exhibits potent cytostatic and cytotoxic activity against hepatoma 3924A cells in culture. In growth-inhibition and clonogenic assays, the 50% inhibitory concentration of tiazofurin was 3.8 and 4.2 microM, respectively. Dipyridamole, an inhibitor of nucleoside transport, curtails the salvage of nucleosides and bases for nucleotide biosynthesis. Dipyridamole exhibited cytotoxicity against hepatoma 3924A cells, with an LC50 of 24 microM and an IC50 of 29 microM being recorded. A combination of tiazofurin and dipyridamole provided synergistic cytotoxicity in hepatoma 3924A cells in culture. This synergistic activity was dependent on the order of addition of the drugs. Simultaneous addition of the two drugs produced antagonism, whereas preincubation of cells with tiazofurin or dipyridamole followed by addition of the second drug resulted in synergy. TAD concentrations were significantly higher (129% and 135%) in cells that had been pretreated with tiazofurin or dipyridamole before the addition of the second agent as compared with cells that had been treated simultaneously (113%). These studies indicate the importance of the order of the addition of drugs to obtain a synergistic response in combination chemotherapy and suggest the need for a careful selection of drug modulation in clinical trials of tiazofurin and dipyridamole.


Interposed abdominal compression-cardiopulmonary resuscitation and resuscitation outcome during asystole and electromechanical dissociation.

Coronary perfusion pressure has been shown to be a significant determinant of return of spontaneous circulation from cardiac arrest during asystole and electromechanical dissociation. The addition of interposed abdominal compression to otherwise standard cardiopulmonary resuscitation (CPR) increases coronary perfusion pressure in animal and human models. Accordingly, we conducted a randomized prospective study of 143 consecutive patients experiencing cardiac arrest in a large university-affiliated teaching hospital in whom the initial arrest rhythm was asystole or electromechanical dissociation. Patients were randomized to receive either interposed abdominal compression-CPR or standard CPR. The two end points studied were return of spontaneous circulation and 24-hour survival. In addition, we studied the complications associated with interposed abdominal compression-CPR. Sixty-nine men and 74 women with a mean age of 64 years (range, 19-97 years) were studied. The overall rate of return of spontaneous circulation was 38%. Return of spontaneous circulation was significantly greater in the group receiving interposed abdominal compression-CPR compared with the group receiving standard CPR (49% versus 28%, p = 0.01). At 24 hours, there was a significantly greater number of patients alive in the experimental group than in the control group (33% versus 13%, p = 0.009). We found no complication directly related to the procedure of interposed abdominal compression in a small subset of patients who died and underwent necropsy. We conclude that the addition of interposed abdominal compression may be a useful adjunct to otherwise standard CPR that can improve resuscitation outcome of patients experiencing in-hospital cardiac arrest from asystole and electromechanical dissociation.


Evaluation of colestipol/niacin therapy with computer-derived coronary end point measures. A comparison of different measures of treatment effect.

The Cholesterol Lowering Atherosclerosis Study has demonstrated beneficial effect of colestipol/niacin on coronary atherosclerosis using a panel-determined global coronary change score. We now report treatment group comparisons using quantitative coronary angiographic (QCA) measures from all processable segments in 85 of 162 randomly selected baseline/2-year film pairs. Treatment benefit was established for percent stenosis for either continuous or categorical analyses with regression established regardless of the per-patient scoring procedure. In addition, treatment benefit favoring regression was established in some cases for roughness and for percent involvement, a longitudinal estimate of the percent of coronary surface involved by raised lesions. Benefit on minimum diameter was directly related to whether the segment was proximal to a graft insertion and hemodynamically related to the bypass graft. QCA correlates of panel-determined progression were increases in percent stenosis and numbers of occluded lesions in native arteries and the number of progressing lesions in bypass grafts. These results demonstrate that a variety of computer measures can be used as end points in coronary angiographic therapy trials, but change in percent stenosis correlates best with visual panel assessments and best reflects the treatment benefit; when treatment effect sizes are moderate to large, the required sample size of coronary angiographic trials can be reduced when QCA is used.


A prospective, placebo-controlled, randomized trial of intravenous streptokinase and angioplasty versus lone angioplasty therapy of acute myocardial infarction.

The value of routine administration of intravenous thrombolytic agents during percutaneous transluminal coronary angioplasty (PTCA) therapy of acute myocardial infarction (MI) has not been determined. Therefore, we prospectively randomized 122 patients with evolving MI to PTCA therapy with or without adjunctive intravenous streptokinase therapy. Patients with ECG ST segment elevation who presented within 4 hours of symptom onset, had no contraindication to thrombolytic therapy, and were not in cardiogenic shock were enrolled. They were treated immediately with intravenous heparin (10,000 units) and oral aspirin (325 mg) and randomized to treatment with placebo or streptokinase (1.5 M units) administered intravenously over 30 minutes. Patients then were taken immediately to the catheterization laboratory, and those with suitable coronary anatomy underwent immediate PTCA. Subsequent clinical course, serial radionuclide ventriculography, and 6-month repeat angiography were analyzed. A total of 106 patients were treated with PTCA. Use of PTCA was similar for placebo (92%) and streptokinase (83%) groups. Angioplasty was successful in 95% of patients, with no difference in placebo (93%) and streptokinase (98%) groups. Serial radionuclide ventriculography demonstrated no difference in 24-hour (52 +/- 12% versus 50 +/- 12%) or 6-week (51 +/- 12% versus 51 +/- 13%) ejection fraction values for placebo and streptokinase groups, respectively. Contrast ventriculography demonstrated improvement in immediate (54 +/- 12%) versus 6-month (60 +/- 15%, p < 0.05) values for the overall group. No differences in 6-month values were present (58 +/- 15% versus 62 +/- 15%, p = NS) for placebo and streptokinase groups, respectively. Coronary angiography was performed in 75% of the 90 patients eligible for restudy. Arterial patency was 87% at 6 months, and coronary restenosis was present in 38% of patients. No differences in chronic patency or restenosis were detected for the two treatment groups. Although adjunctive intravenous streptokinase therapy did not improve outcome, it did complicate the hospital course. Hospitalization was longer (9.3 +/- 5.0 versus 7.7 +/- 4.4 days, p = 0.046) and more costly ($25,191 +/- 15,368 versus $19,643 +/- 7,250, p < 0.02). Transfusion rate was higher (39% versus 8%, p = 0.0001) and need for emergency coronary bypass surgery was greater (10.3% versus 1.6%, p = 0.03) for the streptokinase-treated patients. Adjunctive intravenous streptokinase therapy does not enhance early preservation of ventricular function, improve arterial patency rates, or lower restenosis rates after PTCA therapy of acute MI. Hospital course is longer, more expensive, and more complicated. For these reasons, PTCA therapy of acute MI should not be routinely performed with adjunctive intravenous streptokinase therapy.


Mitral valve replacement with and without chordal preservation in patients with chronic mitral regurgitation. Mechanisms for differences in postoperative ejection performance.

Standard mitral valve replacement (MVR) in patients with chronic mitral regurgitation consistently results in a decrease in postoperative left ventricular (LV) ejection performance. This fall in ejection performance has been attributed, at least in part, to unfavorable loading conditions imposed by the elimination of the low-impedance pathway for LV emptying into the left atrium. In contrast to standard MVR in which the chordae tendineae are severed, however, MVR with chordal preservation (MVR-CP) does not usually decrease LV ejection performance despite similar removal of the low-impedance pathway. The purpose of the present study was to define the mechanisms responsible for this discordance in postoperative ejection performance between MVR with and without chordal preservation. Echocardiography and sphygmomanometer blood pressures were obtained in 15 patients with pure chronic mitral regurgitation before and 7-10 days after mitral valve surgery. These measurements were used to calculate ventricular volume, wall stress, and ejection fraction. Seven patients underwent MVR with chordal transection (MVR-CT), and eight patients underwent MVR-CP. MVR-CT resulted in no postoperative change in LV end-diastolic volume, a significant increase in LV end-systolic volume, a significant increase in end-systolic stress, from 89 +/- 9 to 111 +/- 12 g/cm2 (p < 0.05), and a significant decrease in ejection fraction, from 0.60 +/- 0.02 to 36 +/- 0.02 (p < 0.05). In contrast, patients who underwent MVR-CP had a significant decrease in LV end-diastolic and end-systolic volumes. End-systolic wall stress actually fell from 95 +/- 6 to 66 +/- 6 g/cm2 (p < 0.05), and ejection fraction was unchanged (0.63 +/- 0.01 before and 0.61 +/- 0.02 after mitral valve surgery) instead of reduced. MVR-CT resulted in a decrease in ejection performance caused in part by an increase in end-systolic stress, which in turn increased end-systolic volume. Conversely, MVR-CP resulted in a smaller LV size, allowing a reduced end-systolic stress and preservation of ejection performance despite closure of the low-impedance left atrial ejection pathway.


Increased expression and regional differences of atrial myosin light chain 1 in human ventricles with old myocardial infarction. Analyses using two monoclonal antibodies.

This study was designed to examine the expression of atrial/fetal-type myosin light chain 1 (ALC1) in human ventricles with old myocardial infarction and in control hearts. The expression of immunoreactive (ir) ALC1 was examined in the subendocardial and subepicardial myocardium of the infarcted and the noninfarcted regions in the left ventricles with old myocardial infarction (n = 12) and of the control left ventricles (n = 8). For the analysis, we prepared two monoclonal antibodies, KA1 and KB1, that were specific for only ALC1 and for both ALC1 and ventricular myosin light chain 1 (VLC1), respectively. The ir-ALC1 expression ratio [ALC1/(ALC1 + VLC1), %] of the subendocardial myocardium, determined densitometrically by Western blotting with KB1, was significantly higher in the infarcted region (11.4 +/- 7.3%) than in the noninfarcted region (4.7 +/- 2.3%, p < 0.001) and the control ventricle (1.0 +/- 1.5%, p < 0.0001). In the infarcted region, the subendocardial myocardium contained a significantly greater percentage of ir-ALC1 than the subepicardial myocardium (5.8 +/- 6.7%, p < 0.005). The ir-ALC1 expression ratio had a significant negative correlation with the value of tissue protein concentration (milligrams protein per gram wet weight). The immunohistochemical study with KA1 revealed that the surviving myocytes included in the infarcted region, especially in the ventricular aneurysm, expressed ir-ALC1 strongly in comparison with those in the noninfarcted or the control ventricles. These results demonstrate increased expression of ALC1 and the regional differences in the failing left ventricles with old myocardial infarction. We conclude that the reexpression of ALC1 in infarcted ventricles occurs as one of the regional responses to increased load and may be a useful biochemical marker for the appearance of fetal-type myocytes.


Preoperative prediction of the outcome of coronary revascularization using positron emission tomography.

Previous assessments of myocardial viability using positron emission tomography (PET) relied on demonstration of glucose metabolism in hypoperfused asynergic segments using the glucose analogue [18F]2-fluoro-2-deoxyglucose (FDG). Recently, it was shown that myocardial viability could be assessed by calculating the water-perfusable tissue index (PTI) for the asynergic region. PTI represents the proportion of the myocardium that is capable of rapid transsarcolemmal exchange of water and thus perfusable by water. The aim of the present study was to assess myocardial viability by PET using PTI in patients undergoing coronary revascularization. Twelve patients with chronic coronary artery disease and previous myocardial infarction were studied. Analysis of transmission (tissue density) and 15O-labeled carbon monoxide (blood pool), and 15O-labeled water (myocardial blood flow [MBF]) emission PET data enabled the simultaneous quantification of MBF (ml.min-1.g perfusable tissue-1) and PTI (gram of perfusable tissue per gram of total anatomic tissue). In addition, PET imaging with FDG after 75-g oral glucose load was performed in eight patients. Preoperative echocardiography identified 33 hypocontractile and 26 control segments. Follow-up echocardiography performed 3 to 5 months later demonstrated 26 of 33 segments with improved wall motion (recovery) and seven of 33 segments without improvement (nonrecovery). MBF in the control segments (0.97 +/- 0.22 ml.min-1.g perfusable tissue-1) was significantly higher (p < 0.001) than in both the recovery (0.73 +/- 0.18 ml.min-1.g perfusable tissue-1) and the nonrecovery (0.45 +/- 0.11 ml.min-1.g perfusable tissue-1) segments. PTI in the recovery regions (0.99 +/- 0.15) was > or = 0.7 in all cases and slightly less than in control regions (1.10 +/- 0.15, p < 0.02). FDG uptake in these regions was 92 +/- 17% (n = 13) of the uptake in control segments with normal wall motion. In the nonrecovery group, PTI was 0.62 +/- 0.06 (p < 0.02 versus control and recovery) and always < 0.7. In the one patient in whom a comparison with metabolic imaging was made, FDG uptake was 46% of the uptake in a reference region with normal wall motion. These data showed that contractile recovery occurred only in segments where PTI was > or = 0.7, suggesting that > or = 70% of myocardial tissue in a given asynergic segment should be perfusable by water to enable contractile recovery. There was good agreement between the PTI and FDG methods for predicting improvements in regional wall motion after revascularization. Although further studies should be performed in a larger patient group, the preliminary results are promising and suggest that PTI may be a good predictor of contractile recovery after coronary revascularization.


Preservation of atrioventricular nodal conduction during radiofrequency current catheter ablation of midseptal accessory pathways.

Septal accessory atrioventricular (AV) pathways may be located in close vicinity of the His bundle-AV nodal conduction system. Attempts at surgical or electrical interruption of these pathways may therefore result in impairment of normal AV conduction. This study focuses on a subset of septal pathways with an atrial insertion located inside the triangle of Koch. In this study, they were called "midseptal." Six patients with a midseptal accessory pathway (mean +/- SD age, 40 +/- 12 years; five with Wolff-Parkinson-White syndrome and one with a concealed accessory pathway) underwent attempts at ablation of their pathway using 500-kHz radiofrequency current applied to the atrial insertion of the accessory connection. Guided by the recording of accessory pathway activation potentials, the ablation catheter was positioned in all patients in an area bounded anteriorly by the tip electrode of the His bundle catheter and posteriorly by the coronary sinus ostium. All pathways were successfully ablated without the induction of complete heart block. First-degree AV conduction block occurred in one patient in whom a concealed accessory connection was located closer to the AV node than to the coronary sinus ostium. Radiofrequency current catheter ablation may be used effectively for midseptal accessory pathways and should be preferred in experienced centers as a safe alternative to surgical therapy.


Natural history and patterns of recovery of contractile function in single left ventricle after Fontan operation.

Before the era of the Fontan procedure, the typical course of patients with single left ventricle (LV) consisted of heart failure and death during the second or third decade of life. Despite the advent of effective palliative therapy, ventricular dysfunction remains a significant clinical problem for these patients. To investigate the causes of ventricular dysfunction in these patients and to determine whether Fontan-type repair reverses deterioration of LV function, the ventricular dimensions, volume, shape, wall stress, and systolic function were determined by echocardiography in 84 patients 0.2-35 years old with double-inlet single LV or tricuspid atresia. Measurements were obtained in 67 patients after palliation (arterial shunt or pulmonary artery band) and in 47 patients a median of 4.4 years after a Glenn (n = 9) or a Fontan operation (n = 38). Before a Fontan procedure, ventricular volumes were 2 to 3 times normal. Ventricular afterload, assessed as circumferential and meridional end-systolic wall stress, became abnormal after 2 years of age. With age, LV shape changed progressively from ellipsoidal to spherical, as indicated by the decrease in long axis:short axis ratio from normal (1.9) toward unity. Concomitantly, the ratio of circumferential to meridional end-systolic wall stress fell from 1.3 to unity, the ratio of a sphere at equilibrium. This age-related change in shape and load occurred in concert with progressive deterioration of LV systolic function and contractility. Aortic oxygen saturation, an indicator of pulmonary blood flow and therefore volume work in single-ventricle physiology, was inversely and independently correlated with contractility. In the group of patients in whom a Glenn or a Fontan operation was performed at < 10 years of age, ventricular dimensions, volumes, and wall stress diminished and LV function and contractility improved after surgery (p < 0.001). In patients undergoing surgery after 10 years of age, few had improvement of LV function after surgery. Postoperative ventricular function and contractility were inversely related to age at surgery and to aortic oxygen saturation measured before surgery. Although Fontan-type repair of single ventricle early in life is associated with reversal of the abnormal contractile mechanics associated with age and volume load, this capacity for recovery diminishes with age at surgery.


Effect of baffle fenestration on outcome of the modified Fontan operation.

The "fenestrated Fontan" (surgical baffle fenestration followed by transcatheter test occlusion and permanent closure after postoperative recovery) was adopted in an effort to reduce perioperative mortality and morbidity. This study assesses the effect of baffle fenestration on outcome. Patients having a modified Fontan operation with a cavocaval baffle and cavopulmonary anastomosis were retrospectively selected for study. Those with baffle fenestration (n = 91) were compared with those without baffle fenestration (n = 56) with respect to preoperative risk factors, age, anatomy, surgical date, and presence or absence of a previous bidirectional cavopulmonary anastomosis. Outcome variables were failure (death or take-down) and duration of postoperative pleural effusions and hospitalization. Survival and clinical status after hospital discharge were ascertained. The two groups did not appear to differ with respect to age or anatomic diagnosis. Patients having baffle fenestration were at significantly greater preoperative risk by univariate and multivariate analysis (p < 0.01). Operative failure was low in both groups (11% without and 7% with baffle fenestration, p = NS). Durations of pleural effusions and hospitalization were significantly shorter with baffle fenestration (p < 0.01). Neither date of surgery nor a previous bidirectional cavopulmonary anastomosis appeared to contribute to improved outcome. Patients with baffle fenestration had lower postoperative systemic venous pressure (p < 0.01). There were no late deaths. Functional status in both groups is good (82% in New York Heart Association class I). Baffle fenestration is associated with low mortality, significantly less pleural effusion, and significantly shorter hospitalization among high-risk patients having a modified Fontan operation.


Effects of pacing tachycardia and balloon valvuloplasty on pulmonary artery impedance and hydraulic power in mitral stenosis.

Mitral stenosis is characterized by progressive pulmonary hypertension and eventual right ventricular failure. However, the correlation between right ventricular failure and the level of pulmonary hypertension is poor, suggesting that factors other than those recognized from nonpulsatile hemodynamic parameters may contribute to impaired right ventricular performance in this condition. We studied 16 patients with severe mitral stenosis (mean valve area, 1.0 +/- 0.2 cm2) at supine rest and during pacing tachycardia using high-fidelity catheter recordings of pulmonary artery (PA) pressure and flow velocity. Pulmonary impedance spectra, wave reflection properties, and hydraulic power data were derived from Fourier analysis of signal-averaged data. Pacing tachycardia (baseline heart rate, 81 +/- 11 beats per minute; pacing, 132 +/- 11 beats per minute) significantly raised pulmonary wedge and mean PA pressures. There was no change in pulmonary vascular resistance (209 +/- 144 to 232 +/- 164 dyne-sec/cm5) or PA characteristic impedance (62 +/- 25 to 55 +/- 28 dyne-sec/cm5). However, first harmonic impedance (Z1) significantly decreased (134 +/- 71 to 100 +/- 68 dyne-sec/cm5; p < 0.001). Accordingly, oscillatory and total dissipated hydraulic power per unit forward flow (WT/CO) fell during tachycardia (2.6 +/- 1.6 to 2.3 +/- 1.4 mW/ml.sec-1; p = 0.06) despite acute pulmonary hypertension. Reflected pressure waves returned earlier to the proximal PA, suggesting increased vessel stiffness. Immediately after percutaneous balloon mitral valvuloplasty (PBV) in eight of the patients, baseline and pacing data were again recorded. Compared with the pre-PBV baseline state, post-PBV resting data demonstrated no change in resistance or characteristic impedance, but there was a significant fall in Z1 (166 +/- 75 to 103 +/- 45 dyne-sec/cm5; p < 0.05) and in the magnitude of pulmonary wave reflections. WT/CO tended to decrease after PBV, and pacing after PBV produced a further decrease in WT/CO, again in association with lower Z1. These data demonstrate that 1) increased pulmonary characteristic impedance, although a feature of mitral stenosis, is not exacerbated by the acute effects of increased distending pressure; 2) pacing tachycardia in mitral stenosis causes little change in the pulmonary impedance spectrum except at low frequencies, where decreased impedance lowers power requirements per unit flow; and 3) relief of mitral stenosis produces immediate improvement in low-frequency impedance and in hydraulic power requirements. These findings suggest that although characteristic impedance may be a measure of the long-term effects of pulmonary hypertension on the pulmonary circulation, acute increases and decreases in PA pressure produce effects on right ventricular load that are best described in terms of the low-frequency properties of the PA system. Improvement in low-frequency impedance diminishes hydraulic power requirements and thus reflects improved ventricular-vascular coupling, irrespective of distending PA pressure. Efforts to treat or prevent right heart failure in the presence of pulmonary hypertension should take account of the potential benefit of changes in low-frequency impedance characteristics of the pulmonary vascular bed.


Multivariate genetic analysis of blood pressure and body size. The Medical College of Virginia Twin Study.

In subjects of all ages, those who weigh the most often have the highest blood pressure. Thus, in epidemiological studies, weight is the most important correlate of blood pressure. Using the data from the Medical College of Virginia Twin Study, we asked these questions: 1) Do the same genetic paths that regulate body size also regulate systolic and diastolic blood pressure? 2) Are there distinct genetic pathways that regulate each of these variables? 3) Does environment play a major regulatory role? 4) Are the correlations among these variables mainly due to genetic or environmental effects? 5) Do genetic paths that regulate body size mediate the correlation between systolic blood pressure and diastolic blood pressure? We ascertained 253 Caucasian twin pairs living in the Commonwealth of Virginia. The average age was 11.2 +/- 0.2 years. We used multivariate path analyses to investigate the genetic relations among systolic blood pressure, diastolic blood pressure, and body size. We found that there was a highly significant genetic relation between systolic blood pressure and body size and between systolic and diastolic blood pressure. There are genetic paths that are shared within these two sets of variables, but in each case, the paths for each pair appear to be separate from one another. These analyses provide a method to partition correlation coefficients found in epidemiological studies into genetic and environmental components. The correlations found among these three variables are in large part due to these genetic relations. We found no genetic relation between diastolic blood pressure and body size.


Augmented forearm vasoconstriction during dynamic exercise in healthy older men.

We tested the hypothesis that the nonactive limb vasoconstriction evoked during large-muscle dynamic exercise becomes augmented with aging in humans. Sixteen young control subjects (age, 26 +/- 1 year) and twelve older (65 +/- 1 year) healthy men with similar chronic physical activity levels were studied during supine leg cycling exercise. Both peak work load (1,100 +/- 60 versus 1,400 +/- 40 kpm/min) and peak O2 uptake (1.85 +/- 0.10 versus 2.38 +/- 0.07 l/min) were lower in the older men (p < 0.05). There were no differences in the two groups under conditions of quiet supine (basal) rest. During cycling for 5 minutes each at mild, moderate, and heavy submaximal intensities (approximately 45%, 65%, and 85% of peak O2 uptake), the increases in arterial blood pressure generally were similar in the young and older subjects; however, heart rate rose less in the older men (p < 0.05). Whole forearm blood flow (venous occlusion plethysmography) was lower and vascular resistance was higher (approximately 55-90%) in the older men at all loads (p < 0.05), but the steady-state forearm skin blood flow responses (laser Doppler velocimetry) were not different in the two groups. The increases in antecubital venous norepinephrine concentrations were greater in the older men at each work load (p < 0.05), although the plasma epinephrine responses were similar in the two groups. In other studies, 1) peak whole forearm reactive hyperemia and vascular conductance after sustained circulatory arrest (ischemia) were slightly (approximately 20%) but not significantly lower in the older men and 2) the forearm vasoconstrictor and plasma norepinephrine responses to a nonexercise sympathoexcitatory stimulus (limb immersion in ice water) tended to be blunted in the older men. During brief, submaximal, large-muscle dynamic exercise, healthy older men demonstrate augmented forearm vasoconstriction that is probably caused by greater constriction of skeletal muscle resistance vessels; this appears to be mediated, at least in part, by increased sympathetic outflow. These altered sympathetic vasoconstrictor adjustments do not represent a nonspecific hyperresponsiveness to acute stress with human aging. Finally, the regulation of arterial blood pressure appears to be normal in these healthy older men.


Angiotensin converting enzyme inhibition restores cardiac and hormonal responses to volume overload in patients with dilated cardiomyopathy and mild heart failure.

Angiotensin converting enzyme (ACE) inhibition exerts a favorable effect on the response to exercise in heart failure. This study was planned to define the influence of ACE inhibition on the adaptation to volume overload. We studied the hemodynamic, hormonal, and renal responses to acute volume expansion (sodium chloride, 0.9%, 0.25 ml.kg-1.min-1 for 2 hours) in patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (New York Heart Association class I or II, ejection fraction < or = 50%). The patients were studied without any pretreatment (n = 14) or after 1 week of treatment with the oral ACE inhibitor quinapril at a dosage of 10 mg/day (n = 11). Seven patients were studied during constant intravenous infusion with nitroglycerin (0.1 micrograms.kg-1.min-1). The study groups had similar hemodynamic and clinical characteristics and hormonal profile at baseline evaluation. In the untreated patients, volume expansion did not increase left ventricular end-diastolic volume measured by echocardiography and was associated with a reduction in ejection fraction (p < 0.05) and with a paradoxical increase in forearm vascular resistance (p < 0.05) estimated by plethysmography. In addition, plasma atrial natriuretic factor did not change, and plasma norepinephrine was increased by saline loading. In contrast, in the patients treated with quinapril, volume expansion induced an increase of both left ventricular volumes (p < 0.001) without changing ejection fraction and reduced forearm vascular resistance (p < 0.05). In addition, in this group, plasma atrial natriuretic factor levels increased (p < 0.05) and plasma norepinephrine did not change during volume overload. During nitroglycerin infusion, volume expansion was associated with peripheral vasodilatation, increases of left ventricular volumes, and no change in ejection fraction. In this group, however, plasma atrial natriuretic factor levels did not change in response to volume overload. We conclude that pretreatment with the ACE inhibitor quinapril significantly improves compromised responses to acute isotonic volume overload in patients with dilated cardiomyopathy and mild heart failure. The favorable influence of ACE inhibition on cardiovascular and hormonal responses to volume expansion seems to be related to the cardiac unloading produced by this treatment.


31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure.

The purpose of this work was to further define the value of cardiac 31P magnetic resonance (MR) spectroscopy for patients with coronary artery disease and dilated cardiomyopathy. Blood-corrected and T1-corrected 31P MR spectra of anteroseptal myocardium were obtained at rest using image-selected in vivo spectroscopy localization, a selected volume of 85 +/- 12 cm3, and a field strength of 1.5 T. Nineteen volunteers had a creatine phosphate (CP)/ATP ratio of 1.95 +/- 0.45 (mean +/- SD) and a PDE/ATP ratio of 1.06 +/- 0.53; in four patients with left anterior descending coronary artery (LAD) stenosis, six patients with chronic anterior wall infarction, and four patients with chronic posterior wall infarction, CP/ATP and phosphodiester (PDE)/ATP ratios did not differ from those in volunteers. Twenty-five measurements of 19 patients with dilated cardiomyopathy yielded a CP/ATP of 1.78 +/- 0.51 and a PDE/ATP of 0.98 +/- 0.56 (p = NS versus volunteers). When these patients were grouped according to the severity of heart failure, however, CP/ATP was 1.94 +/- 0.43 in mild (p = NS versus volunteers) and 1.44 +/- 0.52 in severe DCM (p < 0.05), respectively. No correlation was found between CP/ATP and left ventricular ejection fraction or fractional shortening, but correlation of CP/ATP with the New York Heart Association (NYHA) class was significant (r = 0.60, p < 0.005). Six patients with dilated cardiomyopathy were studied repeatedly before and after 12 +/- 6 weeks of drug treatment leading to clinical recompensation with improvement of the NYHA status by 0.8 +/- 0.3 classes. Concomitantly, CP/ATP increased from 1.51 +/- 0.32 to 2.15 +/- 0.27 (p < 0.01), whereas PDE/ATP did not change significantly. Cardiac high-energy phosphate metabolism at rest is normal in LAD stenosis and chronic myocardial infarction in the absence of heart failure. The CP/ATP ratio has low specificity for the diagnosis of dilated cardiomyopathy. However, CP/ATP correlated with the clinical severity of heart failure and may improve during clinical recompensation.


Cross-bridge dynamics in human ventricular myocardium. Regulation of contractility in the failing heart.

To investigate whether altered cross-bridge kinetics contribute to the contractile abnormalities observed in heart failure, we determined the mechanical properties of cardiac muscles from control and myopathic hearts. Muscle fibers from normal (n = 5) and dilated cardiomyopathy (n = 6) hearts were obtained and chemically skinned with saponin. The muscles were then maximally activated at saturating calcium concentrations. Unloaded shortening velocities (V0) were determined in both groups. V0 in control was 0.72 +/- 0.09 Lmax/sec, whereas in myopathic muscles, V0 was 0.41 +/- 0.06 Lmax/sec at 22 degrees C. The muscles were also sinusoidally oscillated at frequencies ranging between 0.01 and 100 Hz. The dynamic stiffness of the muscles was calculated from the ratio of force response amplitude to length oscillation amplitude. At low frequencies (< 0.2 Hz) the stiffness was constant but was larger in myopathic muscles. In the range of 0.2-1 Hz, there was a drop in the magnitude of dynamic stiffness to approximately one quarter of the low-frequency baseline. This range reflects cross-bridge turnover kinetics. In control muscles, the frequency of minimum stiffness was 0.78 +/- 0.06 Hz, whereas it was 0.42 +/- 0.07 Hz in myopathic muscles. At higher frequencies, the dynamic stiffness increased and reached a plateau at 30 Hz. There were no differences in the plateau reached between control and myopathic muscles. Because myopathic hearts have a markedly diminished energy reserve, the slowing of the cross-bridge cycling rate plays an important adaptational role in the observed contractility changes in human heart failure. Although the potential to generate maximal Ca(2+)-activated force is similar in normal and myopathic hearts, alterations in contractile protein composition could explain the diminished cross-bridge cycling rate in failing hearts.


The importance of acute luminal diameter in determining restenosis after coronary atherectomy or stenting.

We evaluated native coronary arteries treated by directional coronary atherectomy or balloon-expandable stent placement in an effort to derive a quantitative geometric model relating the luminal diameter immediately after intervention to that present 6 months later. The minimal luminal diameter of each lesion was measured before and immediately after intervention in 102 single Palmaz-Schatz stents and 134 directional atherectomies, 192 (81%) of which had repeat angiographic measurement of minimal luminal diameter 6 months after the intervention. The immediate enlargement in luminal diameter produced by the intervention (acute gain) and the subsequent reduction in luminal diameter from the time of intervention to 6 months of follow-up (late loss) were calculated. Luminal diameter increased from 0.69 +/- 0.40 mm to 3.11 +/- 0.64 mm (acute gain, 2.41 +/- 0.64 mm) after intervention, providing an immediate postprocedure residual stenosis of 1 +/- 14% relative to a reference diameter of 3.13 +/- 0.65 mm. At 6-month follow-up, the late luminal diameter was 1.97 +/- 0.92 mm (late loss, 1.13 +/- 0.89 mm), yielding a late diameter stenosis of 36 +/- 26%. The restenosis rate (according to the traditional definition of diameter stenosis > or = 50%) was 30%. Multivariable analysis demonstrated that late luminal diameter (p = 0.02), late percent stenosis (p = 0.04), and restenosis (according to a > 50% definition, p = 0.04) were each strongly associated with the luminal diameter present immediately after the procedure. Whereas late luminal diameter was also influenced by reference artery size and the vessel treated (left anterior descending versus right coronary artery), reference vessel size was rejected by the multivariable models of late percent stenosis and binary restenosis after they were adjusted for the effect of postprocedure luminal diameter. Once adjusted for postprocedure luminal diameter, neither late luminal diameter nor late loss was found to be independently determined by which device was used (atherectomy versus stents). Rather, late loss was determined independently by the immediate postprocedure luminal diameter (p = 0.005) and the postprocedure percent stenosis (p = 0.02). Although late loss thus increased with acute gain, the net beneficial effect of increased acute gain was maintained: Late loss was only a fraction (0.47) of acute gain, so the ability of a larger postprocedure luminal diameter to reduce the probability of subsequent restenosis was preserved. This quantitative model demonstrates that the late coronary lumen diameter and the probability of restenosis after Palmaz-Schatz stenting or directional atherectomy are influenced strongly by the lumen diameter present immediately after the procedure rather than by the specific device used. Although the influence of a larger acute result on reduced restenosis appears to be well established in this treatment population, the interplay among the multiple other biological influences on restenosis limits the ability to predict the probability of restenosis for the individual patient based on a large acute result alone. Future studies of restenosis, however, can further refine this multivariable quantitative model by adjusting for the effects of other clinical variables, mechanical interventions, or drug therapies in addition to the clear effect of postprocedure luminal diameter.


Restenosis after placement of Palmaz-Schatz stents in native coronary arteries. Initial results of a multicenter experience.

Several metallic intracoronary stents are currently undergoing preliminary evaluation to ascertain potential benefit as means to reduce the 30-40% incidence of restenosis after balloon angioplasty. To determine the incidence and correlates of restenosis after placement of Palmaz-Schatz stents in native coronary arteries in the first group of patients selected for this procedure, clinical and quantitative angiographic data from 206 consecutive patients (221 stenoses) with successful stent placement (diameter stenosis < 50%) were analyzed. Six patients (2.9%) had thrombosis-mediated stent closure within 1 month after stent placement and were excluded from long-term angiographic follow-up. One hundred eighty-one (91%) of the remaining 200 patients had angiography at 5.8 +/- 2.1 months. Patients with and without follow-up did not differ in any baseline characteristic; in particular, history of restenosis at the site stented (73% versus 65%), placement of multiple overlapping stents (17% versus 20%), and mean poststent diameter stenosis (16 +/- 12% versus 14 +/- 12%). The overall incidence of restenosis (diameter stenosis > or = 50% at follow-up) in this group at high risk for restenosis was 36% (95% confidence interval, 29-43%) on a per-stenosis basis. The incidence of restenosis when a single stent was placed was 30% (95% confidence interval, 23-37%). Risk was dependent upon a history of restenosis (present versus absent 36% versus 16%, p = 0.02) and upon whether or not a poststent stenosis < or = 0% was achieved (6% versus 33%, p = 0.02). When multiple overlapping stents were placed, restenosis occurred at 64% of sites, and placement of multiple stents was discouraged during the later phases of this study as these results became apparent. Although multiple stents appear to yield a poor long-term result, placement of single stents may offer a benefit compared with standard coronary angioplasty, particularly if an excellent angiographic result can be obtained in patients without prior restenosis. Further randomized trials in such patients are needed.


How does angioplasty work? Serial analysis of human iliac arteries using intravascular ultrasound.

Previous studies regarding the mechanism by which balloon angioplasty increases luminal patency have generally used animal models or postmortem specimens from occasional fatal cases of angioplasty performed in human patients. In either case, conclusions regarding participatory mechanisms have relied exclusively on nonserial, postangioplasty histopathological examination. In the present study, intravascular ultrasound examination was performed before and after balloon angioplasty in 40 consecutive patients with iliac artery stenoses. The areas of the arterial wall, plaque, lumen, and areas resulting from angioplasty-induced plaque fractures were measured immediately after angioplasty in vivo and compared with findings recorded immediately before angioplasty. Angioplasty increased luminal cross-sectional area (CSA) from 11.5 +/- 0.6 mm2 before angioplasty to 25.4 +/- 1.2 mm2 after angioplasty (p = 0.0001). CSA of the portion of the postangioplasty neolumen contained within angioplasty-induced plaque fractures measured 10.0 +/- 0.8 mm2; the neolumen excluding the area contributed by these plaque fractures measured 15.4 +/- 0.8 mm2. Thus, the area contained within plaque fractures accounted for 10.0 mm2 (71.9%) of the 13.9-mm2 increase in luminal CSA after angioplasty. Analysis of CSA occupied by atherosclerotic plaque disclosed that plaque CSA decreased from 33.8 +/- 1.8 mm2 before angioplasty to 22.5 +/- 1.5 mm2 after angioplasty (p = 0.0001). Plaque CSA was thus reduced ("compressed") by 11.3 +/- 1.1 mm2. Total artery CSA increased ("stretched") slightly from 45.3 +/- 2.6 mm2 before angioplasty to 47.8 +/- 2.0 mm2 after angioplasty (p = 0.0025). In vivo analysis of iliac stenoses by intravascular ultrasound immediately before and after angioplasty demonstrates that plaque fractures and "compression" of atherosclerotic plaque are the principal factors responsible for increased luminal patency resulting from balloon angioplasty. "Stretching" of the arterial wall provides an additional, but minor, contribution.


Endothelial dysfunction in patients with chest pain and normal coronary arteries.

A subgroup of patients with chest pain and angiographically normal epicardial coronary arteries have reduced dilator response to metabolic or pharmacological stimuli, but the mechanisms responsible for this reduced dilator response are unknown. In this study, we have investigated whether microvascular endothelial dysfunction is a cause of the observed reduced vasodilator reserve. The functional response of the microvasculature was studied with rapid atrial pacing at 150 beats per minute. Fifty-one patients, 20 hypertensive and 31 normotensive, with chest pain and normal epicardial coronary arteries (< 10% stenosis) were studied. Endothelial function was tested with incremental infusions of acetylcholine to achieve estimated intracoronary concentrations ranging from 10(-7) M to 10(-5) M. Endothelium-independent smooth muscle vasomotion was measured using intracoronary sodium nitroprusside. Endothelial dysfunction of epicardial coronary arteries, demonstrated as severe (> 50%) constriction with < 10(-5) M acetylcholine concentration, was evident in five patients (10%). In the remaining 46 patients, coronary blood flow increased with acetylcholine (mean, 78 +/- 43%) and atrial pacing (mean, 51 +/- 37%), and coronary vascular resistance decreased by 35 +/- 16% and 29 +/- 14%, respectively, but the responses were heterogeneous. There was a correlation between the coronary resistance change with acetylcholine and the change with atrial pacing: r = 0.68, p < 0.001 in these 46 patients. Thus, patients with depressed dilation with atrial pacing had reduced endothelium-dependent dilation with acetylcholine, and vice versa. However, the microvascular dilation caused by sodium nitroprusside was not significantly different between patients with and those without reduced dilation with atrial pacing, indicating that the vasodilator defect was not caused by smooth muscle dysfunction. There were no differences in the vasodilator responses with atrial pacing, acetylcholine, or nitroprusside between normotensive and hypertensive patients. Multivariate regression analysis was performed to determine whether age, sex, serum cholesterol level, hypertension, presence of mild epicardial vessel atherosclerosis, resting left ventricular function, change in left ventricular ejection fraction with exercise, vasodilation with acetylcholine, and vasodilation with sodium nitroprusside were independently related to the vasodilator response to atrial pacing. Only the change in coronary vascular resistance with acetylcholine was independently correlated with the change in resistance with atrial pacing: R2 = 0.46, p < 0.0001. Patients with chest pain, normal epicardial coronary arteries, and reduced vasodilation in response to atrial pacing appear to have associated endothelial dysfunction of the coronary microvasculature. Thus, microvascular endothelial dysfunction may contribute to the reduced vasodilator reserve with atrial pacing and anginal chest pain in these patients.


Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart.

To determine the mechanisms of ventricular tachycardia (VT) in humans, three-dimensional intraoperative mapping of up to 156 intramural sites was performed in 13 patients with healed myocardial infarction and refractory VT. Mapping was of sufficient density to define the mechanism of 10 VTs in eight patients. In five of 10 cases, sustained VT was initiated in the subendocardium or epicardium by intramural reentry with marked conduction delay as well as functional and anatomic block most prominent in the subendocardium and midmyocardium. The initiating beats of reentrant VT induced by programmed electrical stimulation arose in the endocardium or midmyocardium by progressive slowing of conduction leading to unidirectional block. Multiple simultaneous reentrant circuits can be present. In contrast, five of the 10 sustained VTs were initiated by a focal mechanism as defined by the absence of electrical activity between the termination of one beat and the initiation of the next despite the presence of multiple intervening intramural electrode recording sites. Comparisons of the mapping data with results of histopathological analysis of tissue demonstrated that the location of infarction as well as that of adjacent fibrotic muscle determined sites of both fixed and functional conduction block during macroreentrant VT and that slowing of conduction occurred in a direction transverse rather than longitudinal to fiber orientation. Both intramural reentry and a focal mechanism underlie sustained VT in patients with healed myocardial infarction.