Instantaneous effects of resynchronisation therapy on exercise performance in heart failure patients: the mechanistic role and predictive power of total isovolumic time.

BACKGROUND: Cardiac resynchronisation therapy improves peak oxygen uptake (peak VO(2)) 3-9 months after device implantation. In chronic heart failure, total isovolumic time (t-IVT) is a major determinant of peak VO(2) and of cardiac output at peak dobutamine stress. In selected patients, resynchronisation can instantaneously shorten t-IVT. We sought to determine the acute effect of resynchronisation on exercise performance and determine, with pharmacological stress echocardiography, the mechanism underlying this effect. METHODS AND RESULTS: Twenty-two patients with resynchronisation were studied within 3 months after device implantation. On a single study day, sequential cardiopulmonary exercise tests were performed during native activation (left bundle branch block) and resynchronisation (atrio-biventricular pacing) in random order. Total-IVT and cardiac output (at rest and peak dobutamine stress) were then measured in each activation mode. Resynchronisation acutely increased peak VO(2) by 1.6 (SD 1.5) ml/kg/min (p<0.001) and shortened peak stress t-IVT by 10 (SD 7) s/min (p<0.001), with the effects in individual patients showing a correlation (r = -0.46, p<0.05). Amongst all measurements during native activation, the best predictor of gain in peak VO(2) from resynchronisation was peak stress t-IVT (r = 0.71, p<0.001) with every increment of 5 s/min of peak stress t-IVT during native activation predicting an 8% gain in peak VO(2). No conventional measures during native activation at rest or on stress (including QRS duration, Tei index, tissue Doppler intraventricular delay, and resting t-IVT) added significant additional information. CONCLUSIONS: In eligible patients, resynchronisation can acutely augment peak VO(2), possibly through a mechanism of t-IVT shortening. Under native activation, long t-IVT during peak stress is the single best predictor of acute resynchronisation-mediated increment in peak VO(2).

Automated quantitation of peripheral blood neutrophil activation in patients with myocardial ischaemia.

BACKGROUND: Coronary ischaemic syndromes are associated with neutrophil activation. The Bayer automated haematology analysers can detect increased light scatter of neutrophil populations, which correlates with neutrophil activation. We aimed to assess the role of an automated analyser in detecting systemic neutrophil activation in peripheral blood samples of patients with coronary ischaemia. METHODS: A prospective cross-sectional study was undertaken in 18 patients with chronic stable angina, 9 with unstable angina and 26 normal control subjects. Whole blood samples were taken to assess neutrophil count and light scatter, and serum samples were taken from some patients for assessment of Troponin T, C-reactive protein (CRP) and myeloperoxidase (MPO). In addition, whole blood was stimulated in vitro with interleukin (IL)-8 and N-formyl-methionyl-leucyl-phenylalanine (fMLP) to assess changes in neutrophil light scatter detected by the analyser. RESULTS: Neutrophil light scatter was increased in patients with chronic stable and unstable angina compared to normal control subjects (normal subjects 74.1 (73.3, 75.0) (mean arbitrary units (95% confidence intervals, (CI)) vs. 78.6 (76.9, 80.3) in the chronic stable angina group P<0.001 and 77.1 (75.3, 79.0) in the unstable angina group P<0.007). In vitro stimulation of whole blood produced comparable increases in neutrophil light scatter when morphological changes in neutrophils were demonstrable under electron microscopy. CONCLUSIONS: Automated measurement of neutrophil activation by light scatter is possible using the Advia 120 analyser and is superior to a neutrophil count in discriminating groups with angina. This technique may be useful in monitoring disease activity and progression in coronary artery disease and in guiding the use of anti-inflammatory therapies.

Clinical outcome of coronary angioplasty in patients with ischaemic cardiomyopathy.

OBJECTIVE: To assess the clinical outcome of successful percutaneous transluminal coronary angioplasty (PTCA) in patients with poor ventricular function. METHODS: Analysis of angiographic, echocardiographic and clinical records of patients with severe LV dysfunction who underwent PTCA from January 1, 1995 to December 31, 1997 was undertaken. Forty-one patients aged 63+/-10 years, 36 men, all with significant coronary artery disease and impaired LV function (fractional shortening, FS

Low clinical utility of routine angiographic surveillance in the detection and management of cardiac allograft vasculopathy in transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV), a form of accelerated atherosclerosis, is the major cause of late death in heart transplant recipients. Routine annual coronary angiography has been used as the standard surveillance technique for CAV in most transplant centers. HYPOTHESIS: The aim of this study was to investigate the clinical utility of routine angiographic surveillance in the detection and management of CAV in transplant recipients. METHODS: We reviewed the case notes and angiograms of 230 patients who underwent cardiac transplantation in our unit between January 1986 and January 1996 and survived beyond the first year post transplantation. RESULTS: Significant complications secondary to angiography arose in 19 patients (8.2%). Cardiac allograft vasculopathy was present on none of angiograms performed 3 weeks post transplantation, but was identified in 9 patients (4%) at the first annual angiogram and an additional 25 patients by the fifth annual angiogram. A target lesion suitable for angioplasty was only identified in two patients, and only limited procedural success was achieved in both cases. Twenty-five patients (11%) died during the study period, and the most common cause of late death was graft failure which occurred in 10 patients. All patients who died from graft failure had significant CAV at autopsy, but the most recent coronary angiogram had been normal in eight of these patients. CONCLUSIONS: These data clearly illustrate the limited clinical utility of routine angiographic surveillance for CAV in heart transplant recipients and prompted us to abandon this method of surveillance in our unit.

Impact of radiofrequency catheter ablation of accessory pathways on the frequency of atrial fibrillation during long-term follow-up; high recurrence rate of atrial fibrillation in patients older than 50 years of age.

AIMS: Atrial fibrillation represents a frequent and potentially life-threatening arrhythmia in patients with accessory atrioventricular pathways. Radiofrequency ablation has become the curative treatment of first choice for these patients. Investigations after successful surgical pathway dissection reported an almost complete elimination of paroxysmal atrial fibrillation. However, there are only a few reports which include a small number of patients undergoing radiofrequency ablation. The purpose of this study was to examine whether successful radiofrequency ablation of accessory pathways prevents the occurrence of paroxysmal atrial fibrillation, and to identify possible predictors of atrial fibrillation recurrence. METHODS AND RESULTS: A total of 116 consecutive patients (mean age 42+/-15 years) with manifest or concealed accessory pathways and documented paroxysmal atrial fibrillation underwent radiofrequency catheter ablation. The patients were reexamined at 6 and 12 months. Long-term follow-up information was obtained by questionnaire and/or by consulting the referring physician. Pathway conduction was abolished in 101 cases (87%). Late follow-up information was obtained from 91 of these 101 patients (90%) with successful ablation with a mean follow-up duration of 23.9+/-12.3 months. During follow-up, 25 of 91 patients (27%) experienced arrhythmias. Recurrent episodes of atrial fibrillation were observed in 18 of these 25 cases (i.e. 20% of the 91 patients). Differences between patients with and without recurrences of atrial fibrillation were examined for age, sex, associated cardiac disease, presence of multiple pathways, pathway location, atrial fibrillation inducibility during the procedure and cycle length of the atrioventricular reentrant tachycardia. Only older age was a significant independent predictor of atrial fibrillation recurrence (P=0.02). Eleven of 31 patients (35%) older than 50 years of age had atrial fibrillation recurrences during follow-up compared to seven of 60 patients (12%) under age 50. The recurrence rate of atrial fibrillation was even higher in patients older than 60 years (6 of 11 patients, i.e. 55%). In comparison, the occurrence rate of atrial fibrillation during follow-up in a control group of 100 consecutive patients with successful accessory pathway ablation, who did not have evidence of paroxysmal atrial fibrillation prior to ablation, was 4% and, thus, significantly lower than in the study group of the 91 patients (P=0.001). CONCLUSIONS: The recurrence rate of paroxysmal atrial fibrillation after successful radiofrequency ablation of accessory pathways shows an age-related increase, being low in patients younger than 50 years of age (12%) and high in the older patients: 35% in patients older than 50 years and 55% in patients older than 60. These results have significant therapeutic implications concerning the decisions on pharmacological therapy after successful ablation in patients older than 50 years. Furthermore, these data will help physicians advise older patients properly about their risk of recurrence of atrial fibrillation after ablation.

Targeting the slow pathway for atrioventricular nodal reentrant tachycardia: initial results and long-term follow-up in 379 consecutive patients.

OBJECTIVES: This study is designed to examine the immediate and short-term outcomes of patients who have undergone slow pathway ablation/modification for atrioventricular nodal reentrant tachycardia. BACKGROUND: Targeting the slow pathway has emerged as the superior form of treatment for atrioventricular nodal reentrant tachycardia. This technique has been found effective and is associated with a low complication rate. However, little is known of the long-term outcome of patients undergoing this procedure. METHODS: Over a 40-month period the slow pathway was targeted in 379 consecutive patients with proven atrioventricular nodal reentrant tachycardia. The case records of all patients were examined. Accurate follow-up data is available in 96% of patients a mean of 20.6 months after the procedure. RESULTS: The initial success rate was 97%. The incidence of complete heart block was 0.8% and the mean fluoroscopy duration was 27.3 min. The recurrence rate was 6.9%. Age, number of pulses and fluoroscopy time were positively associated with either initial failure or recurrence. A total of 11.3% of patients were still taking antiarrhythmic medication at follow-up. CONCLUSIONS: Targeting the slow pathway is an effective form of treatment for atrioventricular nodal reentrant tachycardia. The technique has a high initial success rate, a low complication rate and a low recurrence rate at long-term follow-up. Slow pathway modification is associated with similar success rates and recurrence rates as slow pathway ablation and may confer theoretical long-term benefits.

Endothelial dysfunction, subangiographic atheroma, and unstable symptoms in patients with chest pain and normal coronary arteriograms.

BACKGROUND: Patients with chest pain and normal coronary arteriograms (CPNA) may present with unstable symptoms and other evidence of ischemia during clinical follow-up. Although repeat angiography usually proves negative, functional assessment of coronary vasomotor abnormalities may provide additional pathophysiologic information. HYPOTHESIS: The study was undertaken to evaluate the relationship between endothelial dysfunction and subangiographic atheroma in patients with CPNA undergoing repeat angiography because of unstable symptoms. METHODS: We investigated nine patients with CPNA (8 women, mean age 57 +/- 9 years) undergoing repeat angiography because of unstable anginal symptoms. After normal angiography, simultaneous coronary epicardial and microvascular vasomotor responses to intracoronary vasodilators [acetylcholine (10(-6) M), adenosine (18 micrograms) and nitroglycerin (300 micrograms)] were investigated in the left anterior descending artery using quantitative angiography and Doppler flow measurements. The presence of subangiographic atheroma was assessed by intravascular ultrasound. RESULTS: Three patients demonstrated proximal and distal epicardial vasoconstriction and a reduction in coronary flow in response to acetylcholine, indicating concordant epicardial and microvascular endothelial dysfunction. These changes were associated with chest pain and ischemic electrocardiographic changes in two patients. None of the remaining patients suffered chest pain in response to intracoronary acetylcholine. Six patients had significant subangiographic disease (intimal thickness > 0.3 mm) on intravascular ultrasound imaging, and multivariate analysis indicated a significant relationship (R2 = 0.89, overall p = 0.001) between the extent of subangiographic disease and both plasma cholesterol concentration and hypertensive history. No significant relationship was demonstrated between endothelial dysfunction and the extent of subangiographic disease. CONCLUSION: Concordant epicardial and microvascular endothelial dysfunction may be pathophysiologically and clinically significant in unstable patients with CPNA but does not appear to be directly related to the extent of subangiographic atheroma.

Antidromic atrioventricular reentrant tachycardia mimicking ventricular tachycardia in the setting of previous myocardial infarction.

The differentiation between ventricular tachycardia and broad-complex supraventricular tachycardia can be extremely difficult, particularly in emergency situations. We report a case of hemodynamically compromising broad-complex tachycardia in a 63-year-old man. The patient had previously sustained an anteroseptal myocardial infarction and had subsequently undergone coronary artery bypass surgery because of triple-vessel coronary artery disease. Intravenous treatment with ajmalin terminated the tachycardia and revealed preexcited QRS complexes compatible with the presence of a left-sided atrioventricular accessory pathway. An antidromic atrioventricular reentrant tachycardia (identical to the clinical tachycardia) was induced during an electrophysiologic study. In conclusion, there are several causes of broad-complex tachycardia, even in patients with previous myocardial infarction, and, where doubt exists, electrophysiologic studies should be performed.

Radiofrequency catheter ablation of accessory pathways. Outcome and use of antiarrhythmic drugs during follow-up.

AIMS: The purpose of this study was to assess the acute and long-term success of accessory pathway ablation in a single large-volume centre, concentrating on long-term recurrences and the clinical use of antiarrhythmic drugs. METHODS AND RESULTS: A total of 519 consecutive patients (mean age 40+/-14 years) underwent radiofrequency ablation of manifest or concealed accessory pathways. The patients were seen in the hospital or by the referring physician at 6 and 12 months. Long-term follow-up information was obtained by questionnaire. Pathway conduction was abolished in 476 cases (91.7%). 'Redo' procedures, due to recurrence, were performed in 38 patients (7.3%) and were successful in 30 (78.9%). Follow-up data were obtained from 454 patients (87.5%) with a follow-up duration of 22. 6+/-12.4 months. Among the 398 patients with successful ablations who responded to the questionnaire, 340 (85.4%) were asymptomatic with only 10.6% taking antiarrhythmic drugs. An additional 20 patients (5.0%) had symptoms suspicious of recurrence. In total, 66 out of 398 successfully treated patients (16.6%) were taking antiarrhythmic drugs. Twenty-three out of 56 (41.1%) patients with failed ablations were asymptomatic, 12 of whom (21.4% of patients with failed ablations) had not been administered antiarrhythmic drugs. In the total group of 454 patients with ablation attempts and available follow-up data, 99 (21.8%) were still taking antiarrhythmic drugs during follow-up. CONCLUSIONS: Patients with successful ablation of accessory pathways show excellent long-term results. However, 17% of successfully treated patients were still taking antiarrhythmic drugs during the period of long-term follow-up. On the other hand, 21% of patients with failed ablations were symptom-free without antiarrhythmic drugs. On an intention-to-treat basis, 22% of the patients with ablation attempts were still taking antiarrhythmic drugs during follow-up.

Drug-related torsades de pointes in the isolated rabbit heart: comparison of clofilium, d,l-sotalol, and erythromycin.

Torsades de pointes is a potentially life-threatening form of polymorphic ventricular tachyarrhythmia typically seen in the presence of repolarization-prolonging agents. We investigated this particular form of tachyarrhythmia in the isolated, perfused rabbit heart. The experimental model was designed to reproduce conditions that are clinically known to be associated with an increased propensity to the development of torsades de pointes. The class III agent clofilium (1 microM) and d,l-sotalol (10 microM), as well as the antibiotic erythromycin (30-150 microM) were infused in the presence of either normal (5.88 mM) or low (1.5 mM) potassium concentration in sinus-driven or atrioventricular (AV)-blocked hearts. Ventricular tachyarrhythmias spontaneously emerged in the clofilium-, d,l-sotalol-, and erythromycin-treated AV-blocked hearts. The episodes showed typical features of torsades de pointes found in humans. They developed within 4-12 min after the onset of infusion, were normally nonsustained, and only rarely degenerated into ventricular fibrillation. Electrical stimulation at cycle lengths <600 ms and perfusion with MgSO4 suppressed arrhythmic activity. In the d,l-sotalol- and erythromycin-treated hearts, torsades de pointes occurred only in the presence of hypokalemia and bradycardia, whereas, in the presence of clofilium, bradycardia alone caused torsades de pointes. Monophasic action-potential recordings demonstrated early afterdepolarizations in endocardial and epicardial recordings. Thus the isolated AV-blocked rabbit heart represents a model for studying drug-related torsades de pointes and its mechanism.

First clinical experience with a new flexible low profile metallic stent and delivery system.

We report the first clinical use of a new, flexible, low profile, balloon-expandable metallic stent and delivery system (ACS Multi-Link). The stent, designed in an effort to overcome the shortcoming of existing stents, has a low metal mass, superior scaffolding properties and favourable rheological characteristics. It also allows side branch access and is delivered via an innovative stent catheter. Ten stents were used to treat 10 patients with threatened abrupt closure after balloon angioplasty. All were successfully deployed, with a satisfactory angiographic result in nine. The patient with an unsatisfactory angiographic result proceeded to uneventful coronary bypass surgery. There were no other procedural or in-hospital complications. One patient developed restenosis and one had an intra-cerebral bleed following a fall. This new stent thus appears safe and effective when used to treat threatened abrupt closure. Due to its favourable characteristics, it may be well suited for reduction of restenosis. A multi-centre European registry (WEST) for primary implantation in 100 consecutive patients has now been completed.

Increase in calcium leak channel activity by metabolic inhibition or hydrogen peroxide in rat ventricular myocytes and its inhibition by polycation.

Ca influx in cultured neonatal myocardium can be augmented by metabolic inhibition or free radical exposure. This increase cannot be prevented by blockade of L-type Ca channels or inhibition of Na-Ca exchange. It is speculated that a specific Ca leak may be involved in this process. In the present study patch clamp techniques were used to examine this hypothesis. Currents were measured in a recording configuration of cell attached or excised inside-out membrane patches in adult rat ventricular myocytes as affected by metabolic inhibition or free radical exposure. The metabolic inhibition was achieved by use of 1 mM iodoacetic acid and 10 mM 2-deoxyglucose with omission of glucose in the perfusate. Free radicals were generated by application of 100 microM hydrogen peroxide in the perfusate. Specific Ca leak channels were identified. The channels were not significantly permeable to monovalent cations. The activity of these channels was increased markedly over a period of minutes by metabolic inhibition or free radical exposure. In the presence of 100 microM hydrogen peroxide the open probability (NPo) of the channels increased from 0.0083 +/- 0.003 (mean +/- S.D.) in control to 0.09 +/- 0.024 (P < 0.01). During metabolic inhibition it was augmented from 0.0075 +/- 0.0035 to 0.062 +/- 0.018 (P < 0.01). The increase of the Ca leak channel activity under both conditions could be completely blocked by addition of polycationic protamine to the patch pipette solution. The results support the hypothesis that Ca leak channels are involved in the Ca overload induced by metabolic inhibition or free radical exposure. The inhibitory effect of polycation may have important therapeutic implications for the treatment of ischemic cardiac heart disease.

The pathogenesis of free radical-induced calcium leak in cultured rat cardiomyocytes.

Elevated levels of intracellular calcium are generally accepted to be of critical importance in determining the outcome of cardiac myocytes exposed to ischemia and reperfusion. The mechanisms involved are obscure, but a favorite candidate is the Na-Ca exchanger operating in reversed mode, permitting calcium influx. Using exogenous free radicals and a unique, on-line, isotopic technique to measure calcium fluxes in cultured neonatal rat cardiomyocytes, we show that Na-Ca exchange is not the primary mechanism of calcium overload in this cell type during free radical exposure. We also demonstrate that neither L-type calcium channels nor general sarcolemmal defects are responsible. A specific calcium leak is present at a time when the sarcolemma remains intact with respect to its potassium permeability. The leak shares many properties with specific calcium leak channels demonstrated electrophysiologically in other tissues. It can be modulated by alterations in surface charge such that cationic amphiphiles inhibit the leak and anionic amphiphiles augment it. It is concluded that the calcium leak, in this cell type, is specific to calcium and that leak channels may be responsible.

Protamine and other polycationic drugs inhibit calcium leak in cardiac cells during metabolic inhibition and free radical exposure.

We studied the effect of the polycationic compounds protamine, polybrene and gentamicin on the calcium leak induced by metabolic inhibition and free radical exposure in cultured neonatal rat cardiac cells. All of the drugs tested inhibited the calcium leak. The potency of the compound in this respect was related to the magnitude of the positive charge borne by the molecule. Protamine was the most potent drug tested. None of the drugs tested had more than a small effect on lactate dehydrogenase release. The physicochemical properties of these compounds lead us to predict that they are acting at negatively charged sites on the outer surface of the sarcolemma. We conclude that polycationic compounds, exemplified by protamine, are able to inhibit calcium overload. It is anticipated that this group of compounds may be effective as cardioprotective agents.

Sarcolemmal phospholipid asymmetry and Ca fluxes on metabolic inhibition of neonatal rat heart cells.

The present study examines the hypothesis that during depletion of high-energy phosphates a change will occur in the phospholipid topology and in Ca fluxes in cultured neonatal cells and that these two events may be causally related. A combination of 2-deoxyglucose and iodoacetic acid was used to produce graded changes in the adenine nucleotides in the cells. An on-line technique for 45Ca measurement was used to follow Ca uptake and compartmentation by the cells, and chemical and enzymatic probes were used to study sarcolemmal phospholipid topology. After 15 min of metabolic inhibition (ATP = 10% of control) an increase in cellular Ca occurs, which progresses with time. Over 70% of this Ca accumulates in the mitochondria. After 30 min of metabolic inhibition (ATP < 10% of control) a change in the phospholipid topology is observed, and an increased amount (two times control) of sarcolemmal phosphatidylethanolamine is present in the outer monolayer of the sarcolemma. This change in phospholipid topology was independent of the extracellular Ca concentration. The sequence of altered Ca fluxes and distribution followed by the altered phospholipid topology is discussed in terms of its possible role in the pathogenesis of sarcolemmal disruption.

Cationic amphiphiles prevent calcium leak induced by ATP depletion in myocardial cells.

Excessive calcium influx is important in the irreversible injury of cardiac myocytes and other cell types. The mechanism is unknown, but possibilities include L-type channels, Na(+)-Ca2+ exchange, sarcolemmal (SL) defects, and calcium leak channels. In this study, metabolic inhibition was used to induce ATP depletion and augmented calcium influx in cultured cardiac myocytes. Inhibition of the L-type calcium channel and Na(+)-Ca2+ exchanger had no significant effect on the calcium leak. There was no significant lactate dehydrogenase release, indicating that the leak did not occur through major SL defects. No alterations in the asymmetric distribution of SL phospholipids were demonstrated. Phospholipid rearrangements were therefore not responsible. The leak was unaffected by 0.5 mM cadmium and 1 microM nifedipine but was augmented by 50 microM nifedipine, characteristics in common with calcium leak channels. Insertion of the cationic amphiphiles dodecyltrimethylammonium bromide or polymyxin B sulfate into the SL had a profound inhibitory effect on the calcium leak. The anionic amphiphile sodium dodecyl sulfate had the opposite effect, and the neutral amphiphile lauryl acetate had no effect. These results suggest that an alteration in the SL surface charge affects calcium leak. It is proposed that the augmented calcium influx occurs via calcium leak channels and that these can be modulated by charged amphiphiles.