Right ventricular pressure during ventricular arrhythmias in humans: potential implications for implantable antitachycardia devices

Implantable defibrillators use algorithms based on ventricular electrographic data to detect the onset and termination of arrhythmias, but these algorithms do not always differentiate hemodynamically stable from unstable arrhythmias. Although, ideally, left ventricular function should be used to assess the hemodynamic state, right ventricular pulse pressure can be assessed in humans on a long-term basis with a transvenous lead. The potential utility of right ventricular pulse pressure to assess hemodynamic stability was studied in 22 patients with induced ventricular arrhythmias. Right ventricular pressure was measured with use of a transvenous right ventricular endocardial pacing lead with a piezoelectric bender pressure sensor 3 cm from its tip. Single ventricular premature paced beats administered in up to a bigeminal frequency did not alter the mean right ventricular pulse pressure (control 33.7 +/- 26, bigeminy 35.7 +/- 26 mm Hg). Twenty-one episodes of induced ventricular tachycardia were studied in the electrophysiology laboratory. Five seconds after tachycardia induction, hemodynamically stable ventricular tachycardia had a longer cycle length (294 +/- 41 ms) and the right ventricular pulse pressure ratio was higher (0.55 +/- 0.26) than that in unstable ventricular tachycardia (cycle length 256 +/- 55 ms, p = 0.06; pulse pressure ratio 0.26 +/- 0.09, p less than 0.05). Twenty episodes of ventricular fibrillation were induced in eight patients. One second after induction, right ventricular pulse pressure decreased from 25 +/- 5 to 6 +/- 3 mm Hg (p less than 0.05). On the first beat after defibrillation, right ventricular pulse pressure increased to 24 +/- 14 mm Hg, a level not significantly different from that before the induction of ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular basis of fever in humans

This review presents several areas of research on the pathogenesis of fever in humans and updates new information concerning the role of fever in host defense mechanisms. Fever is mediated by a polypeptide of phagocytic cell origin called leukocytic pyrogen. Several agents and disease processes are associated with the synthesis and release of leukocytic pyrogen. Although the original studies on leukocytic pyrogen suggested that the neutrophil was the primary source, recent experiments indicate the mononuclear phagocyte to be the major producer of leukocytic pyrogen. The mechanism by which human monocytes are stimulated to produce leukocytic pyrogen is discussed, including the effects of corticosteroids, estrogens and antipyretics on the synthesis of leukocytic pyrogen in vitro. The ability of leukocytic pyrogen to alter the hypothalamic thermoregulatory center by increasing arachidonic acid metabolite levels is the most likely mechanism by which leukocytic pyrogen initiates fever. Antipyretics prevent the synthesis of certain cyclooxygenase metabolites, which accounts for their ability to reduce fever. Studies on the chemical and physical properties of human leukocytic pyrogen are reviewed and form the basis for current experiments on the similarities between leukocytic pyrogen and lymphocyte activating factor. These studies suggest that leukocytic pyrogen, in addition to producing fever, also stimulates non-hypothalamic cells involved in aspects of the acute-phase response. In this regard, leukocytic pyrogen may be an important mechanism for host defenses. Hyperthermia may also be beneficial to the host but is distinct from fever; the role of leukocytic pyrogen as well as hyperthermia as a defense mechanism is discussed.     

Usefulness of an implantable antitachycardia pacemaker system for supraventricular or ventricular tachycardia

The Cordis Omni-Orthocor model 234A, an implantable antitachycardia system, was evaluated in 13 patients. Two patients had recurrent sustained supraventricular tachycardia (SVT) and 11 had ventricular tachycardia (VT). The system was used for SVT or VT termination (group 1: SVT, 2 patients; VT, 4 patients) or for demand pacing and noninvasive electrophysiologic studies for tachycardia induction and serial electrophysiologic testing alone (group 2: VT, 7 patients). The overdriver was used successfully in 4 of 6 patients in group 1 for repeated tachycardia termination (SVT and VT) during a mean follow-up period of 18 months. One patient had 1 sustained VT episode unresponsive to pacing and 1 patient had no recurrence of tachycardia. Tachycardia termination zones varied when using the system in 2 patients receiving long-term amiodarone therapy. Eighteen noninvasive electrophysiologic studies for serial drug testing were performed, 4 in group 1 and 14 in group 2. Clinical tachycardia was induced and successfully terminated by use of the overdriver in 12 studies. It is concluded that implantable antitachycardia systems can be used successfully for noninvasive tachycardia induction and termination and for reliable serial electrophysiologic studies. Such systems provide improved patient safety and acceptability and are reasonable in cost.     

A new dual-chamber pacemaker with an automatic antitachycardia system in the treatment of the bradycardia-tachycardia syndrome

A new dual-chamber pacemaker with automatic tachycardia terminating system was used in three patients with bradycardia-tachycardia syndrome. This pacemaker (Medtronic Symbios 7008) is a multiprogrammable, bipolar device with bidirectional telemetry and six permanent pacing modes (DDD-DVI-VVI-DOO-VOO-AOO). The antitachycardia system can be programmed in two different modes: underdrive dual demand and overdrive atrial burts (1 to 16 stimuli with selectable coupling interval from 135 to 360 msec). The pacing modes are automatically activated when five consecutive R-R cycles shorter than the tachycardia detection interval are sensed. The pacemaker may sense the ventricle (when set on VVI or DVI mode) or sense both the atrium and the ventricle (in DDD mode). The pacemaker was programmed on DVI mode in all three patients, and the overdrive atrial burst program was used for tachycardia termination, with promptly and costantly effective results. The underdrive dual demand program was tested after the implantation, but it did not show constant results because inefficacy or late termination of tachycardias.     

Comparison of immediate and delayed automatic antitachycardia pacing for the termination of atrial tachyarrhythmias.

AIMS: Automatic atrial antitachycardia pacing (ATP) can terminate atrial tachyarrhythmias (ATs) in patients with an implanted device. We investigated if the programmable delay between AT onset and ATP influences therapy efficacy. METHODS: Patients with intermittent ATs and an implanted DDDRP pacemaker were randomized to receive ATP either immediately or 30min after AT detection. After four months stored data were interrogated, AT-related symptoms were assessed, and patients crossed over to the alternative treatment arm for another four months. Stored atrial electrograms were analyzed for degree of AT organization and ATP success. RESULTS: In 22 patients (64% male; 72+/-7 years), ATP success rates were higher during immediate than during delayed ATP (device classification: 59+/-7% vs. 22+/-5%, P<0.01; manual analysis: 36+/-6% vs. 12+/-5%, P<0.01). Higher efficacy of immediate ATP was associated with a larger proportion of organized (Type I) AT prior to therapy (71% vs. 44% during delayed ATP). No difference was found in total AT numbers and duration, AT burden or related symptoms. CONCLUSIONS: The programmable delay between arrhythmia onset and therapy delivery significantly influences the success-rate of ATP. However, a higher efficacy of immediate compared with delayed ATP does not translate into a reduction of AT burden or related symptoms.     

Long-term efficacy of antitachycardia pacing for supraventricular and ventricular tachycardias

Over a 14-year period, 53 patients received implanted pacemakers to assist in the control of recurrent tachycardias. Indications were: prevention of tachycardia in 2 patients with supraventricular tachycardia (SVT), and 4 with ventricular tachycardia (VT); termination of tachycardia (15 SVT, 20 VT); and long-term periodic programmed electrical stimulation with potential for tachycardia termination (12 VT). Pacemakers for prevention of VT were implanted in 3 patients with prolonged QT interval syndromes and 1 in whom Holter monitoring showed a significant reduction in ectopic activity during pacing. Pacers were implanted for tachycardia termination only after patients underwent a rigorous protocol aimed at achieving 100 trials of the proposed modality. Patients with tachycardia also requiring antibradycardia pacemakers received pacemakers capable of noninvasive programmed stimulation for use during follow-up. There were no tachycardia recurrences among those patients in whom pacemakers were implanted for prevention. Pacers capable of outpatient programmed stimulation were useful, and it may be desirable to expand their use. The 15 patients with pacers designed for termination of SVT were followed for a mean of 68 months. Among these, actuarial continuation of pacing efficacy was 93% at 1 year, and 78% at 5 years. The 20 patients with pacers for termination of VT were followed for a mean of 37 months. Actuarial efficacy was 78% at 1 year, and 55% at 5 years. Sudden death occurred in 4 of these patients, none clearly pacer related. Pacemakers can play a major therapeutic role in some patients with recurrent tachycardias. The role of such pacemakers in patients with VT may be expanded with the advent of combined pacer-defibrillators.(ABSTRACT TRUNCATED AT 250 WORDS)     

Financial audit of antitachycardia pacing for the control of recurrent supraventricular tachycardia.

OBJECTIVE--To assess the financial implications of antitachycardia pacing in patients with frequent supraventricular tachycardia. PATIENTS--Intertach pacemakers were implanted in 25 patients (mean age 47 years, five men): 22 had atrioventricular nodal reentry tachycardia. The patients had failed a mean of 4.9 (range zero to eight) drugs and had been admitted to hospital 3.7 (zero to 31) times over a symptomatic period of 13.9 years (two months to 54 years). RESULTS--The mean admission time for implantation was 2.8 (two to seven) days. One patient with Wolff-Parkinson-White syndrome subsequently underwent surgery. Infection occurred in two patients, and pain over the pacemaker required its resiting in two. Two patients have had one admission each for tachycardia. Six patients remain on anti-arrhythmic drugs. Costs were calculated including value added tax, capital charges, and allocated overheads. The cost a year before pacing was 1174 pounds including drug costs, clinic visits, and hospital admissions. The mean cost of pacemaker implantation was 3364.22 pounds, including the pacemaker and lead, admission and procedure, readmissions and first pacing check. Subsequent annual follow up cost was 73.72 pounds including annual clinic visits and drug costs. The cost of pacing is 4241 pounds whereas medical management costs 7044 pounds assuming pacemaker life of six years: with a 10 year life the cost is 4537 pounds compared with 11,740 pounds: with a 12 year life the cost is 4685 pounds compared with 14,088 pounds. CONCLUSION--The excess cost of implantation of an antitachycardia pacemaker is minimal in patients with frequent supraventricular tachycardia despite drug treatment and is justified by excellent control of symptoms and reduction of drug use and hospital admissions.     

The neural basis of intermittent motor control in humans

The basic question of whether the human brain controls continuous movements intermittently is still under debate. Here we show that 6- to 9-Hz pulsatile velocity changes of slow finger movements are directly correlated to oscillatory activity in the motor cortex, which is sustained by cerebellar drive through thalamus and premotor cortex. Our findings suggest that coupling of 6- to 9-Hz oscillatory activity in the cerebello-thalamo-cortical loop represents the neural mechanism for the intermittent control of continuous movements.     

Functional reconstitution of a proton-translocating system responsive to fusicoccin.

Crude fusicoccin binding proteins and a partially purified plasma membrane H+-transporting ATPase (EC 3.6.1.34), both solubilized from maize tissues, were simultaneously inserted into liposomes by the freeze-thaw method. ATP-driven intravesicular acidification in the proteoliposomes, measured by the fluorescence quenching of the dye 9-amino-6-chloro-2-methoxyacridine, markedly increased upon addition of fusicoccin to the reconstituted system. This effect could not be observed when binding sites and ATPase preparations were separately reconstituted into the proteoliposomes, thus demonstrating that fusicoccin binding to its receptor is a prerequisite for ATPase stimulation.     

Microcirculatory basis for the design of artificial blood

Artificial blood or blood substitutes are being developed using molecular solutions of modified free hemoglobin. When these products are used and the red blood cell mass is reduced below the transfusion trigger, there is a condition of extreme hemodilution which is characterized by a significant reduction of blood viscosity and NO production, reflex vasoconstriction, decreased functional capillary density, and impaired microvascular function. This combination of events may be lethal because decreased NO availability may also increase the intrinsic oxygen consumption of the tissue. Current developments in the understanding of the physiology of the microcirculation in extreme hemodilution, and the physical events associated with the substitution of red blood cells with molecular hemoglobin solutions show that a viable "artificial blood" can be obtained from a new formulation of the product, where viscosity is such that when introduced in the circulation the resulting viscosity of blood is close to normal, the dissociation curve is left shifted and the concentration of hemoglobin is in the range of 3-5 g Hb/dl. This formulation redistributes viscous losses in the circulation causing higher capillary pressure which maintains functional capillary density, a key parameter in tissue survival. Furthermore the increased plasma viscosity increases shear stress in the microcirculation, enhancing the production shear dependent vasodilators, thus counteracting the vasoconstrictor effects due to NO scavenging by free hemoglobin solutions. A principal feature of this formulation is that it maintains microvascular function when the transfusion trigger is passed and the circulation is subjected to extreme hemodilution.     

The glutathione biotransformation system and colorectal cancer risk in humans.

Evidence for a protective role of the glutathione biotransformation system in carcinogenesis is growing. However, most data on this system in relation to colorectal cancer originate from animal studies. Here we review the human data. In humans, a significant association was found between glutathione S-transferase (GST) activity in the mucosa along the gastrointestinal tract and the corresponding tumour incidence. Low activity was correlated with high tumour incidence and vice versa. Also, in normal colonic mucosa, GST activity is lower in patients at risk of colon cancer than in healthy controls and therefore interventions which increase the glutathione detoxification capacity may reduce cancer incidence. Consumption of vegetables and fruit is associated with a lower risk of colorectal cancer. Human intervention studies showed that (components from) vegetables induced colonic glutathione detoxification capacity. Such an effect could contribute to a lower colon cancer risk, but further data are needed. The human GSTs consist of four main classes--alpha (A), mu (M), pi (P) and theta (T)--each of which is divided into one or more isoforms. Functional polymorphisms are known for the GST genes M1, P1 and T1 and they all lead to less active enzymes compared to the wild-type gene products. However, studies that compared these GST polymorphisms in relation to colon cancer risk were not conclusive with respect to an increased or decreased risk of a particular genotype. Diet or medication can also influence the expression levels of specific isoenzymes and the effect of such interventions on cancer risk deserves more attention.     

A vascular basis for repetitive strain injury.

OBJECTIVE: The blanket term 'repetitive strain injury' (RSI) covers a wide variety of work-related clinical syndromes, most of which are localized lesions. However, some patients complain of diffuse forearm pain, a clinically distinct form of RSI, the aetiology of which is unknown. METHODS: Using Doppler ultrasound, we measured the vascular responses to muscular work in the radial artery in 13 patients with bilateral diffuse forearm pain, seven with unilateral diffuse pain and 19 controls with localized arm pain. RESULTS: We found that in diffuse forearm pain the radial artery is relatively constricted compared to the controls and fails to vasodilate with exercise, which suggests that diffuse forearm pain may be due to physiological claudication of the working forearm muscle. CONCLUSION: A possible explanation is inhibition of local endothelial nitric oxide function, and this may be an unusual secondary, but self-perpetuating, pain condition which can follow other more specific, but chronic, arm pain syndromes in susceptible individuals.     

Comparison of burst versus ramp antitachycardia pacing therapy for ventricular tachycardia: A meta-analysis

Current guidelines recommend at least one attempt of defibrillator antitachycardia pacing (ATP) therapy, showing preference for burst therapy. The objective of this study is to compare ramp versus burst ATP therapy proportion of success and acceleration in treating spontaneous or induced ventricular tachycardia (VT). The review protocol was previously published in PROSPERO. Data synthesis and measures of heterogeneity (I²) was performed by CMA® software v.3 comparing proportions in both groups. Sensitivity analysis was performed as subgroup or meta-regression according to quality, clinical characteristics, and differences in design. Thirteen studies including 30,117 VT episodes in 1672 patients were analyzed. There was no significant difference in the proportion of success between burst and ramp therapy in spontaneous VT (odds ratio = 1.116; 95% confidence interval [CI] = 0.788–1.579; I² = 89%). There was no significant difference in the proportion of success between burst and ramp therapy in induced VT (odds ratio = 0.820; 95% CI = 0.468–1.437; I² = 93%). No significant difference was found in the proportion of acceleration between burst and ramp in spontaneous VT (odds ratio = 0.792; 95% CI = 0.476–1.317; I² = 83%). No significant difference was found in the proportion of acceleration between burst and ramp in induced VT (odds ratio = 1.234; 95% CI = 0.802–1.898; I² = 55%). Sensitivity analysis did not change main results. There is no difference in success or in acceleration proportion between burst or ramp ATP therapy irrespective if the VT was spontaneous or induced. Future implantable cardioverter defibrillator programming guidelines should offer both ATP therapies without preference in one of them.     

Genetic basis of atherosclerosis: insights from mice and humans

Atherosclerosis is a complex and heritable disease involving multiple cell types and the interactions of many different molecular pathways. The genetic and molecular mechanisms of atherosclerosis have, in part, been elucidated by mouse models; at least 100 different genes have been shown to influence atherosclerosis in mice. Importantly, unbiased genome-wide association studies have recently identified a number of novel loci robustly associated with atherosclerotic coronary artery disease. Here, we review the genetic data elucidated from mouse models of atherosclerosis, as well as significant associations for human coronary artery disease. Furthermore, we discuss in greater detail some of these novel human coronary artery disease loci. The combination of mouse and human genetics has the potential to identify and validate novel genes that influence atherosclerosis, some of which may be candidates for new therapeutic approaches.