Rate control in the medical management of atrial fibrillation.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
A J Camm
Publications and source records attributed to A J Camm.
Sudden cardiac death: opportunities for prevention.
The evidence base for implantable cardioverter-defibrillator (ICD) therapy requires expansion of guidance/indications to allow UK physicians to treat a broader range of patients. The ICD clinical consultees to the National Institute for Health and Clinical Excellence (NICE) review current guidance/guidelines, explain the evidence base, and suggest a UK ICD implantation strategy.
Cost-Benefit Analysis↗
The negative effect of red tape on research.
PURPOSES: To describe the kind of the difficulties encountered when seeking research governance approval for a nationwide public health and genetic study-the Drug-Induced Arrhythmia Risk Evaluation study-in England. METHODS: Description of the processes followed when seeking research governance approval for the Drug-Induced Arrhythmia Risk Evaluation study-a case control study with annual follow-up of cases and controls over 5 years, set in the English National Health Service (NHS). RESULTS: The authors describe wide variations in NHS research governance approval procedures in England. CONCLUSION: NHS research governance procedures in England are impeding the process of epidemiological studies; there is the need for a centralised NHS R&D approval of studies, which is analogous to MREC for ethical approval.
England↗
Effects of ventricular rate and regularity on the velocity and magnitude of left atrial appendage flow in atrial fibrillation.
OBJECTIVE: To prospectively determine whether ventricular rate and regularity are significant determinants of the velocity and magnitude of left atrial appendage (LAA) flow. DESIGN AND PATIENTS: 12 patients with atrial fibrillation (AF), high degree atrioventricular block, and indwelling permanent pacemakers were studied. SETTING: Cardiology department of a tertiary referral centre. INTERVENTIONS: Pacing was triggered by an external programmable transcutaneous device. Patients were paced at 60, 120, and 150 beats/min in both regular and irregular rhythm. LAA flow velocity and magnitude were assessed with transoesophageal Doppler echocardiography. MAIN OUTCOME MEASURES: Peak and mean LAA inflow and outflow velocity, and time-velocity interval (TVI) of LAA flow. RESULTS: Increasing ventricular rate was associated with significantly lower peak inflow (p < 0.01), peak outflow (p < 0.05), mean inflow (p < 0.01), and mean outflow (p < 0.05) velocities and with a lower TVI of LAA filling and emptying velocities (p < 0.01). This effect was noted at rates of 60 beats/min compared with both 120 and 150 beats/min. At a pacing rate of 120 beats/min there was a significantly higher total TVI when pacing at a regular than at an irregular rhythm (40.16 (14.6) cm v 30.74 (10.9) cm, p < 0.05). CONCLUSIONS: In this study, LAA filling velocities in patients in AF were significantly influenced by paced ventricular rate and to a much lesser extent ventricular rhythm. These results suggest that rapid ventricular rates may predispose to stasis in the LAA in AF.
Adult↗
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
OBJECTIVE: To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. METHODS: Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. RESULTS: Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. CONCLUSIONS: The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.
Animals↗
Rationale and design of a randomised controlled clinical trial on supplemental intake of n-3 fatty acids and incidence of cardiac arrhythmia: SOFA.
BACKGROUND: Evidence from earlier studies indicates that intake of very long-chain n-3 polyunsaturated fatty acids (n-3 PUFA, also named omega-3 fatty acids) as present in fish oil reduces the risk of sudden death. Sudden death forms a major part of mortality from cardiovascular disease and is in most cases a direct consequence of cardiac arrhythmia. n-3 PUFA may exert their protective effect through reducing the susceptibility for cardiac arrhythmia. OBJECTIVE: To investigate the effect of n-3 PUFA on the incidence of recurrent ventricular arrhythmia. This paper presents the rationale, design and methods of the Study on Omega-3 Fatty acids and ventricular Arrhythmia (SOFA) and discusses problems encountered in conducting a multicentre clinical trial on food. DESIGN: A randomised, parallel, placebo-controlled, double blind intervention study, which obeys the guidelines for Good Clinical Practice. SETTING: Multiple cardiology centres in Europe. SUBJECTS: A total of 500 patients with an implantable cardioverter defibrillator (ICD). An ICD detects, treats and stores cardiac arrhythmic events in its memory chip. INTERVENTIONS: Patients receive either 2 g/day of fish oil, containing approximately 450 mg eicosapentaenoic acid and 350 mg docosahexaenoic acid, or placebo for 12 months. PRIMARY OUTCOME: Spontaneous ventricular tachyarrhythmias as recorded by the ICD or all-cause mortality. CONCLUSION: SOFA is designed to answer the question whether intake of n-3 PUFA from fish-a regular food ingredient-can reduce the incidence of life-threatening cardiac arrhythmia. If this proves to be true, increasing the intake of n-3 PUFA could be an easy, effective and safe measure to prevent fatal arrhythmia in the general population.
Anti-Arrhythmia Agents↗
Comparison between biventricular pacing and single site pacing in patients with poor ventricular function: a hemodynamic study.
Biventricular pacing has been suggested as offering greater hemodynamic benefit than single site pacing in patients with advanced heart failure and left bundle branch block. This was tested using acute multisite pacing. Eighteen such patients were atrialsensed, ventricular multisite paced in random order for 5 minutes. The best achieved measure of cardiac output (CO), pulmonary capillary wedge pressure (PCWP) and left ventricular (LV) + dP/dtmax at RV, LV, and biventricular pacing sites compared. Baseline PCWP, CO, and LV + dP/dtmax were 20 +/- 10 mmHg 4.8 +/- 1.3 L/min and 680 +/- 173 mmHg/s respectively. In all 18 patients CO and in 17 of 18 patients LV + dP/dtmax and PCWP improved with pacing. In the group as a whole, no significant hemodynamic difference between pacing sites was observed in PCWP (pacing site RV 19 +/- 10 mmHg, LV 17 +/- 10, biventricular 18 +/- 11) or CO (RV 5.2 +/- 1.5 L/min, LV 5.1 +/- 1.5, biventricular 5.3 +/- 1.7). Increased stroke volume/PCWP with LV (5.6 +/- 3.7 mLs/mmHg) and biventricular pacing (5.4 +/- 4.0) were not significantly greater compared to RV pacing (4.7 +/- 3.0, ANOVA P = 0.20). Increase in LV + dP/dtmax with pacing at LV (814 +/- 190 mmHg/s) and biventricular (839 +/- 290) sites was not significantly greater than the increase with RV pacing (769 +/- 203 mmHg/s, ANOVA P = 0.30). Pacing in patients with heart failure and conduction delay can produce a hemodynamic benefit. There is individual variation in the pacing site that leads to the greatest improvement. In the group as a whole, biventricular and LV pacing produced only modest improvements compared to RV pacing.
Bundle-Branch Block↗
International consensus on nomenclature and classification of atrial fibrillation; a collaborative project of the Working Group on Arrhythmias and the Working Group on Cardiac Pacing of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.
Explore the source record for details and available documents.
Atrial Fibrillation↗
Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval.
OBJECTIVE: To compare the QT/RR relation in healthy subjects in order to investigate the differences in optimum heart rate correction of the QT interval. METHODS: 50 healthy volunteers (25 women, mean age 33.6 (9.5) years, range 19-59 years) took part. Each subject underwent serial 12 lead electrocardiographic monitoring over 24 hours with a 10 second ECG obtained every two minutes. QT intervals and heart rates were measured automatically. In each subject, the QT/RR relation was modelled using six generic regressions, including a linear model (QT = beta + alpha x RR), a hyperbolic model (QT = beta + alpha/RR), and a parabolic model (QT = beta x RR(alpha)). For each model, the parallelism and identity of the regression lines in separate subjects were statistically tested. RESULTS: The patterns of the QT/RR relation were very different among subjects. Regardless of the generic form of the regression model, highly significant differences were found not only between the regression lines but also between their slopes. For instance, with the linear model, the individual slope (parameter alpha) of any subject differed highly significantly (p < 0.000001) from the linear slope of no fewer than 21 (median 32) other subjects. The linear regression line of 20 subjects differed significantly (p < 0.000001) from the linear regression lines of each other subject. Conversion of the QT/RR regressions to QTc heart rate correction also showed substantial intersubject differences. Optimisation of the formula QTc = QT/RR(alpha) led to individual values of alpha ranging from 0.234 to 0.486. CONCLUSION: The QT/RR relation exhibits a very substantial intersubject variability in healthy volunteers. The hypothesis underlying each prospective heart rate correction formula that a "physiological" QT/RR relation exists that can be mathematically described and applied to all people is incorrect. Any general heart rate correction formula can be used only for very approximate clinical assessment of the QTc interval over a narrow window of resting heart rates. For detailed precise studies of the QTc interval (for example, drug induced QT interval prolongation), the individual QT/RR relation has to be taken into account.
Adult↗
Effect of multisite pacing on ventricular coordination.
OBJECTIVE: To determine the effect of multisite pacing on left ventricular function. DESIGN: Prospective observational study. PATIENTS: 18 patients with heart failure with a dilated poorly functioning left ventricle (LV) and left bundle branch block. INTERVENTIONS: Pacing for 5 minutes in random order at the right ventricle (RV) apex, RV outflow tract, mid posterolateral LV, RV apex and LV simultaneously, and RV outflow tract and LV simultaneously. The best achieved measurements with RV, LV, and biventricular pacing were compared. MAIN OUTCOME MEASURES: LV dimension, filling characteristics, and long axis indices were measured on echocardiography simultaneously with LV pressure. Cycle efficiency (%)--that is, the ratio of the area of the acquired pressure dimension loop to that of the ideal loop for that segment--quantified coordination. RESULTS: The pacing site that gave the best achieved cycle efficiency differed between patients (biventricular in five, LV in two, RV in seven, and no site in four). In patients with baseline incoordination (cycle efficiency < or = 72%, n = 12) cycle efficiency improved significantly with RV pacing (cycle efficiency 76%, p = 0.01) but not with LV (65%) or biventricular (67%) pacing. LV based pacing induced premature short axis contraction in a subset of patients (n = 4), which was associated with a prolonged time from the Q wave on the ECG to the onset of inward movement of the long axis (from apex to mitral ring): biventricular 145 ms, LV 105 ms, RV 85 ms (biventricular v RV, p < 0.05). Excluding patients with baseline incoordination in whom premature activation occurred, pacing at all sites led to a similar increase in cycle efficiency (RV 78%, LV 72%, biventricular 73%). CONCLUSIONS: Ventricular coordination can be improved with pacing in patients with baseline incoordination. Short and long axis fibres may be asynchronised in a subset of patients with LV or biventricular pacing, which may worsen coordination. The clinical significance of these findings remains to be defined.
Aged↗
Initial energy setting, outcome and efficiency in direct current cardioversion of atrial fibrillation and flutter.
OBJECTIVES: The purpose of this study was to design a more efficient protocol for the electrical cardioversion of atrial arrhythmias. BACKGROUND: Guidelines for electrical cardioversion of atrial arrhythmias recommend starting with low energy shocks, which are often ineffective. METHODS: We recorded the sequence of shocks in 1,838 attempts at cardioversion for atrial fibrillation (AF) and 678 attempts at cardioversion for atrial flutter. These data were used to calculate the probability of success for each shock of a standard series and the probability of success with a single shock at each intensity. In 150 cases, a rhythm strip with the time of each shock allowed us to calculate the time expended on unsuccessful shocks. RESULTS: We analyzed the effects of 5,152 shocks delivered to patients for AF and 1,238 shocks delivered to patients for atrial flutter. The probability of success on the first shock in AF of > 30 days duration was 5.5% at < 200 J, 35% at 200 J and 56% at 360 J. In atrial flutter, an initial 100 J shock worked in 68%. In AF of >30 days duration, shocks of < 200 J had a 6.1% probability of success; this fell to 2.2% with a duration >180 days. In those with AF for >180 days, the initial use of a 360 J shock was associated with the eventual use of less electrical energy than with an initial shock of < or =100 J (581 +/- 316 J vs. 758 +/- 433 J, p < 0.01, Mann-Whitney U test). CONCLUSIONS: An initial energy setting of > or =360 J can achieve cardioversion of AF more efficiently in patients than traditional protocols, particularly with AF of longer duration.
Analysis of Variance↗
Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials.
BACKGROUND: The need for accurate risk stratification is heightened by the expanding indications for the implantable cardioverter defibrillator. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) focused interest on patients with both depressed left ventricular ejection fraction (LVEF) and the presence of nonsustained ventricular tachycardia (NSVT). Meanwhile, the prospective study Autonomic Tone and Reflexes After Myocardial Infarctio (ATRAMI) demonstrated that markers of reduced vagal activity, such as depressed baroreflex sensitivity (BRS) an heart rate variability (HRV), are strong predictors of cardiac mortality after myocardial infarction. METHODS AND RESULTS: We analyzed 1071 ATRAMI patients after myocardial infarction who had data on LVEF, 24-hour ECG recording, and BRS. During follow-up (21 +/- 8 months), 43 patients experienced cardiac death, 5 patients had episodes of sustained VT, and 30 patients experienced sudden death and/or sustained VT. NSVT, depressed BRS, or HRV were all significantly and independently associated with increased mortality. The combination of all 3 risk factor increased the risk of death by 22x. Among patients with LVEF<35%, despite the absence of NSVT, depressed BRS predicted higher mortality (18% versus 4.6%, P = 0.01). This is a clinically important finding because this grou constitutes 25% of all patients with depressed LVEF. For both cardiac and arrhythmic mortality, the sensitivity of lo BRS was higher than that of NSVT and HRV CONCLUSIONS: BRS and HRV contribute importantly and additionally to risk stratification. Particularly when LVEF is depressed, the analysis of BRS identifies a large number of patients at high risk for cardiac and arrhythmic mortalit who might benefit from implantable cardioverter defibrillator therapy without disproportionately increasing the number of false-positives.
Arrhythmias, Cardiac↗
Pacing for heart failure.
Pacing for patients with severe heart failure without bradyarrhythmia has been proposed as an addition to medical therapy over the past decade. Alteration of the normal electrical activation sequence of the heart modifies its mechanical action, especially when ventricular function is poor. Both the site of ventricular-lead placement and timing with the atria have been manipulated in attempts to alleviate the symptoms of heart failure. Most recently, in addition to the conventional two leads used for pacing, a third lead to pace the left ventricle has been advocated in some patients with heart failure. We review the evidence for pacing in heart failure.
Algorithms↗
Pathophysiology and prevention of atrial fibrillation.
Explore the source record for details and available documents.
Atrial Fibrillation↗
Atrial fibrillation: is there a role for low-molecular-weight heparin?
Atrial fibrillation (AF) is the most common form of tachyarrhythmia and carries a significant risk of serious thromboembolic complications. Anticoagulation is used for long-term thromboprophylaxis and for short-term management in a number of clinical situations, among which is the medical or electrical cardioversion of AF to sinus rhythm. Current guidelines recommend prompt cardioversion with heparin cover for AF of <48 h duration, and several weeks of warfarin therapy prior to cardioversion when the duration of disease is longer. Recent animal and human studies, however, have shown that swifter cardioversion is likely to be more successful in achieving sinus rhythm and in reducing the risk of recurrence of AF. Other observations have demonstrated that thrombi can develop within a few hours of the development of AF. These considerations suggest that cardioversion should be carried out as early as possible in all cases, and that the most sensitive means of detecting atrial thrombi, currently transesophageal echocardiography (TEE), should be used to screen all patients prior to cardioversion. Within this context, there is growing interest in the use of low-molecular-weight heparin (LMWH) as an anticoagulant therapy in AF. Compared with unfractionated heparin, LMWH therapy does not involve prolonged intravenous administration, hospitalization, or laboratory monitoring; LMWH therefore has the potential to greatly simplify anticoagulation therapy for AF, especially pericardioversion. Recent studies have demonstrated that LMWH can be used safely and effectively in place of unfractionated heparin for acute treatment at the onset of AF and during early cardioversion. For example, in patients with AF, a strategy of immediate administration of dalteparin (100 IU/kg s.c. twice daily) continued for 11 days, combined with early TEE and immediate cardioversion in patients with no thrombus, resulted in sinus rhythm in 74% of patients after a median of 7 days. Low-molecular-weight heparin therapy may also find a role perioperatively and in selected patients, notably those with warfarin intolerance, as a replacement for warfarin following cardioversion. Controlled clinical studies are still required, however, to establish a firm, evidence-based foundation for the use of LMWHs in AF.
Anticoagulants↗
Evaluating the place of low-molecular-weight heparin in the management of acute coronary syndromes. A panel discussion with audience participation.
Explore the source record for details and available documents.
Angina, Unstable↗
Increased QT dispersion in patients with Prinzmetal's variant angina and cardiac arrest.
OBJECTIVES: We sought to compare QT dispersion in patients presenting with Prinzmetal's variant angina complicated by cardiac arrest or syncope and patients with uncomplicated variant angina. BACKGROUND: Despite the usually benign course of treated Prinzmetal's variant angina, a proportion of vasospastic angina patients develop ventricular arrhythmias and sudden death in association with coronary spasm. Increased QT dispersion has been suggested to increase susceptibility to ventricular arrhythmias in patients with coronary artery spasm. METHODS: We studied 25 consecutive patients (mean age 58 years; 14 men) with classical Prinzmetal's variant angina and documented coronary artery spasm. None of the patients had coronary artery stenoses < or =40%. Five patients had suffered a documented cardiac arrest, two had recurrent syncope and 18 had no arrhythmic events or syncopal episodes. In all patients QT dispersion (QT maximum-QT minimum in every ECG lead) was measured on the baseline 12-lead electrocardiogram at study entry using a digitising board. RESULTS: Mean (+/-S.D.) QT dispersion of study patients was 62.3+/-19.5 ms. QT dispersion in patients with cardiac arrest and syncope (79.4+/-17.3 ms) was significantly higher compared to patients with no such events (56.3+/-16.9 ms), (95% CI 7.5-38.8, P=0.005). No significant clinical, biochemical or angiographic differences were found between patients with and those without cardiac arrest or syncope. CONCLUSION: QT dispersion is increased in patients with Prinzmetal's variant angina complicated by cardiac arrest and syncope compared to patients without such events. Increased QT dispersion may be both a substrate for sudden cardiac death and a marker of risk in patients with Prinzmetal's variant angina.
Adult↗
Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey.
OBJECTIVE: To assess current practice in the pharmaceutical industry for assessing the potential for QT interval prolongation by non-cardiovascular medicinal products. METHODS: The survey was based on responses from the Toxicology and (Safety) Pharmacology laboratories (a total of 74 laboratories) of 54 companies based in Europe, Japan/Asia and the USA, received between January and March 1999. RESULTS: All 54 companies conducted preclinical in vivo electrocardiography (EGG) evaluation of new active substances (NASs). Thirty of these companies also conducted in vitro cardiac electrophysiology studies on their compounds. The majority of in vivo work was done in conscious beagle dogs. There was no consistency within the industry in defining the magnitude of change in QT interval that is considered biologically important. Most companies considered a change greater than 10% to be important, although the design of the studies suggested that group sizes used may not give sufficient statistical power to detect this size of change. Bazett's formula was used by 41% of laboratories to correct QT for changes in heart rate, despite the fact that this formula is generally deemed to be unsuitable for use in dogs. For studies in anaesthetised dogs, the majority of laboratories used barbiturate anaesthesia, but researchers should be aware of the effects of this and some other anaesthetic agents on QT interval. As for in vitro cardiac electrophysiology, there was wide diversity in the testing methodologies, particularly with regard to the test species and tissue type. As with QT prolongation, there was no consensus on the degree of action potential prolongation to cause concern. For both in vitro and in vivo testing, the majority of companies tested a minimum of three dose (or concentration) levels in order to ascertain any dose-response relationship. CONCLUSIONS: The survey provides a snapshot of the practice in the industry prior to any internationally-agreed consensus on the most effective and efficient approaches to minimising the risk of QT prolongation by new drugs in man. It must be stated that for any given methodology, the 'majority view' in the industry is not necessarily best practice.
Action Potentials↗