The changing circumstance of atrial fibrillation - progress towards precision medicine.

The prevalence of atrial fibrillation (AF) in the general population is between 1% and 2% in the developed world and is higher in men than in women. The arrhythmia occurs much more commonly in the elderly, and the estimated lifetime risk of developing AF is one in four for men and women aged 40 years and above. Projected data from multiple population-based studies in the USA and Europe predict a two- to threefold increase in the number of AF patients by 2060. The high lifetime risk of AF and increased longevity underscore the important public health burden posed by this arrhythmia worldwide. AF has multiple aetiologies and a broad variety of presentations. The primary pathologies underlying or promoting the occurrence of AF vary more than for any other cardiac arrhythmia, ranging from autonomic imbalance to organic heart disease and metabolic disorders, such as diabetes mellitus, metabolic syndrome, hyperthyroidism and kidney disease, and lifestyle factors such as smoking, alcohol consumption and participation in endurance sports. Biomarkers are increasingly being investigated and, together with clinical and genetic factors, will eventually lead to a clinically valuable detailed classification of AF which will also incorporate pathophysiological determinants and mechanisms of the arrhythmia. In turn, this will allow the development and application of precision medicine to this troublesome arrhythmia.

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.

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.

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.

Impact of electrocardiogram recording format on QT interval measurement and QT dispersion assessment.

The aim of this study was to determine the effect of recording conditions on the operator dependent measures of QT dispersion in patients with known and/or suspected repolarization abnormalities. Among several methods for risk stratification, QT dispersion has been suggested as a simple estimate of repolarization abnormalities. In a cohort of high and low risk patients, different components of the repolarization process were assessed in the 12-lead ECG using three different paper speeds and amplifier gains. To assess measurement error and reproducibility, a straight line was repeatedly measured. The operator error was 0.675 +/- 0.02 mm and the repeatability of the measurement error was 31 +/- 6%. The QT interval was most frequently measurable in V2-V5. Depending on the lead selected for analysis, the incidence of visible U waves was greatest in the precordial leads with high amplifier gain and low paper speed, strongly affecting QT interval measurement. The timing of the onset of the QRS complex (QRS onset dispersion) or offset of the T wave was strongly dependent on the paper speed. Paper speed, but not amplifier gain, had a significant shortening effect on the measurement of the maximum QT interval. As QT interval measurement in each ECG lead incorporates QRS onset and T wave offset (depending on the number of visible U waves), the dispersion of each of these parameters significantly affected QT dispersion. Thus, QT dispersion appears to reflect merely the presence of more complex repolarization patterns in patients at risk of arrhythmias.

Clinical relevance of silent atrial fibrillation: prevalence, prognosis, quality of life, and management.

Although first described about 100yr ago, atrial fibrillation (AF) is now recognized as the most common of all arrhythmias. It has a substantial morbidity and presents a considerable health care burden. Improved diagnosis and an ageing population with an increased likelihood of underlying cardiac disease results in AF in more than 1% of population. AF is associated with an approximately two-fold increase in mortality, largely due to stroke which occurs at an annual rate of 5-7%. Another risk to survival is heart failure, which is aggravated by poor control of the ventricular rate during AF. Usually AF is associated with a variety of symptoms: palpitations, dyspnea, chest discomfort, fatigue, dizziness, and syncope. Paroxysmal AF is likely to be symptomatic and frequently presents with specific symptoms, while permanent AF is usually associated with less specific symptoms. However, in at least one third of patients, no obvious symptoms or noticeable degradation of quality of life are observed. This asymptomatic, or silent, AF is diagnosed incidentally during routine physical examinations, pre-operative assessments or population surveys. Recently, a very large incidence of generally short paroxysms of AF has been seen in patients with implantable pacemakers or defibrillators and these arrhythmias are often silent. Pharmacological suppression of arrhythmia may be associated with a conversion from a symptomatic to an asymptomatic form of AF. Holter monitoring and transtelephonic monitoring studies have demonstrated that asymptomatic episodes of AF exceed symptomatic paroxysms by twelve-fold or more. Although symptoms may not stem directly from AF, the risk of complications is probably the same for symptomatic and asymptomatic patients. AF is found incidentally in about 25% of admissions for a stroke. Studies in patients with little or no awareness of their arrhythmia condition indicate that unrecognized and untreated AF may cause congestive heart failure. In patients with coronary bypass, AF may not only represent risk for immediate postoperative morbidity and increase hospital resource utilization, but being unrecognized, may produce a significant impact on long-term survival and quality of life. Although silent AF merits consideration for anticoagulation and rate control therapy according to standard criteria, whether antiarrhythmic therapy is relevant in this condition remains unclear.

Stepwise strategy on the cost of risk stratification after acute myocardial infarction: a retrospective simulation study.

Stratification of postinfarction patients at high risk of mortality and/or other adverse events can be improved by combining several prognostic markers. As the clinical impact of risk stratification has only recently emerged in prospective trials, there are a lack of data regarding the cost-effectiveness of multimarker strategies. This study performed a comprehensive search of a postinfarction database and simulated different risk stratification strategies involving left ventricular ejection fraction, signal-averaged electrocardiography, Holter monitoring, and heart rate variability, The parameters were assessed before discharge in 417 survivors of acute myocardial infarction followed-up for 1 year. Cardiac mortality was used as the clinical endpoint. A statistical computer model of a stepwise strategy using every feasible sequence of the four tests was used and, based on prices derived from European and American centers, the cost estimates of all possible combinations were compared. During the 1 year after myocardial infarction there were 24 cardiac deaths (5.8%). In all the population, 6% had all four tests positive (cardiac mortality 20%); 25% had at least three tests positive (cardiac mortality 12.5%); 58% had at least two tests positive (cardiac mortality 8.3%); and 92% presented with at least one test positive (cardiac mortality 6.3%). The cost of performing all the tests ranged between $398 and $1,887 for each patient. However, by selecting patients according to a step wise strategy, the costs ranged from $96 (> or = 1 test positive) to $510 (for the least expensive sequences of four tests positive). For each of the centers considered, the costs resulting from the risk stratification protocol were determined by the number of variables combined and sequences of tests adopted. Thus, a step wise strategy using the combination of all four parameters, starting with analysis of Holter variables and finishing with signal-averaged electrocardiography, appears to be the most appropriate and the least expensive approach for selecting patients at high risk of cardiac death.

Short- and long-term assessment of heart rate variability for risk stratification after acute myocardial infarction.

Depressed heart rate variability (HRV) has been shown to be a powerful and independent risk factor in patients following acute myocardial infarction (AMI). A detailed comparison of the predictive values between short- and long-term HRV has not been made. The predictive value of short-term HRV for 1-year total cardiac mortality was studied in 700 consecutive patients after AMI. All patients underwent 24-hour Holter monitoring before discharge from the hospital (5 to 8 days after AMI) and were followed up for 1 year. Short-term HRV was computed as the standard deviation of all normal RR intervals (SDNN) from a 5-minute stationary period selected from 24-hour Holter electrocardiographic recordings. Long-term HRV was computed as an HRV index over the entire 24 hours. There was a significant but relatively poor correlation between SDNN and HRV index (r = 0.51, p <0.001). The positive predictive accuracy of SDNN for 1-year mortality (13% to 18%) was lower than the HRV index (17% to 43%) over a range of sensitivity of 25% to 75%. Assessment of HRV index in > or = 35% of the patients preselected by the lowest SDNN was able to achieve predictive power similar to that of HRV index assessed in all the patients. These data suggest that lower predischarge short-term HRV is associated with increased 1-year total cardiac mortality in patients after AMI. Analysis of long-term HRV for postinfarction risk stratification can safely be limited to patients preselected by depressed short-term HRV measures.

Assessment of arrhythmias after myocardial infarction in the post-CAST era.

Prevention of sudden cardiac death after myocardial infarction (MI) has become a continuing challenge for clinical cardiology. Of the many treatment modalities available, some have been shown to save lives while others may even have deleterious effects. Further survival studies exploring the efficacy of prophylactic treatment will be necessary before conclusions for routine clinical practice can be drawn. For this purpose, improvements in the process of risk stratification must be made before these studies are able to demonstrate potential survival benefit. This article will review both the established and the new methods of risk stratification for the post MI patient, with particular attention to antiarrhythmic therapy.

Risk assessment and prevention of sudden cardiac death in hypertrophic cardiomyopathy.

One of the principle aims in the assessment of the patient with hypertrophic cardiomyopathy is assessment of risk for sudden cardiac death. Conventional risk stratification is reviewed together with other non-invasive techniques such as exercise physiology; the signal averaged electrocardiogram and heart rate variability. The role of arrhythmias in the pathogenesis of sudden cardiac death in hypertrophic cardiomyopathy is reviewed together with the role of programmed ventricular stimulation. A novel electrophysiological technique is described in detail which aims to measure the electrophysiological effects of myocardial disarray and seems safer and more sensitive and specific than conventional electrophysiological techniques. Current therapeutic strategies are discussed including the role of drugs, the implantable cardioverter defibrillator, surgery and dual chamber pacing.

Ambulatory assessment of the QT interval in patients with hypertrophic cardiomyopathy: risk stratification and effect of low dose amiodarone.

This study aims to assess the dynamics of the QT interval in patients with hypertrophic cardiomyopathy (HCM). Three consecutive QT intervals and the preceding RR intervals were measured on 24 hour ambulatory electrocardiograms at 30-minute intervals in ten high risk patients with HCM (sudden cardiac death [SCD] and/or documented ventricular fibrillation), aged 29 +/- 17 years, compared with ten age and sex matched low risk patients with HCM (no syncope, no adverse family history, and no ventricular tachycardia on Holter monitoring), and ten normal subjects. Another ten patients who were on amiodarone therapy (200-mg daily) were also studied. Patients with intraventricular conduction defects were excluded. There were 4,424 pairs of QT intervals and their preceding RR intervals were measured in this study. A nonsignificant prolongation in the QT interval and a significant prolongation in QTc values (Bazett's and Fridericia's formulas) were demonstrated in patients with HCM compared with normals. There were no significant differences in the QT and QTc between high and low risk patients. The slope of regression line for the QT against RR interval was significantly different between normals and HCM (0.1583 +/- 0.040 vs. 0.2017 +/- 0.043, P < 0.05), but not between high and low risk patients. Amiodarone significantly prolonged the QT and QTc without significantly altering the slope of the regression line (0.2017 +/- 0.043 vs 0.2099 +/- 0.037, NS). Our findings support the observations that there is a prolonged QT interval in patients with HCM and that there is no significant use dependent effect of amiodarone on ventricular repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of autonomic function in patients with neurally mediated syncope: augmented cardiopulmonary baroreceptor responses to graded orthostatic stress.

OBJECTIVES: The purpose of this study was to assess vagal tone and cardiopulmonary baroreceptor activity in patients with tilt-induced neurally mediated syncope. BACKGROUND: The causes of individual susceptibility to orthostatic stress leading to recurrent neurally mediated syncope remain obscure. The trigger for sympathetic withdrawal and increased vagal activity is believed to be stimulation of ventricular mechanoreceptors. METHODS: Seventeen patients (mean age 50.6 years) with recurrent syncope and a positive response on a 45-min 60 degrees head-up tilt test were compared with a control group of 17 patients (mean age 47.5 years) with unexplained syncope and negative tilt test findings. Vagal activity was assessed by high pressure baroreceptor testing and by temporal and spectral analysis of heart rate variability during Holter ambulatory electrocardiographic monitoring. Cardiopulmonary baroreceptor sensitivity was assessed by measurement of forearm vascular responses to lower body negative pressure. RESULTS: Mean high pressure baroreceptor sensitivity was 16.4 +/- 12.2 ms/mm Hg in the group with a positive tilt test response compared with 15.1 +/- 13.0 ms/mm Hg in the control group (p = NS). There were no significant differences between the groups in any of the temporal or spectral measures of heart rate variability. The increase in forearm vascular resistance in response to lower body negative pressure was 11.5 +/- 14.2 U in patients with tilt-induced syncope and 3.5 +/- 3.2 U in the control group at -5 mm Hg, 16.8 +/- 18.6 U and 4.8 +/- 5.3 U, respectively, at -10 mm Hg and 26.4 +/- 24.3 U and 10.2 +/- 7.8 U, respectively, at -20 mm Hg (p < 0.001). CONCLUSIONS: Patients with tilt-induced neurally mediated syncope have augmented cardiopulmonary baroreceptor responses to orthostatic stress. This finding sheds new light on the etiology of neurally mediated syncope.

Implications for present and future applications of the implantable cardioverter-defibrillator resulting from the use of a simple model of cost efficacy.

OBJECTIVE: To develop a model to assess the cost-efficacy of the implantable cardioverter defibrillator to prevent sudden death. The model must be sufficiently flexible to allow the use of cost and survival figures derived from different sources. SETTING: The study was conducted in a teaching hospital department of cardiology with experience of 40 implantable cardioverter defibrillator implants and a large database of over 500 survivors of myocardial infarction. PROCEDURE: The basic costs of screening tests, stay in hospital, and purchase of implantable cardioverter defibrillators were derived from St George's Hospital during 1991. To assess the cost-efficacy of various strategies for the use of implantable cardioverter defibrillators, survival data taken from published studies or from our own database. Implications of the national cost of the various strategies were calculated by estimating the number of patients a year requiring implantation of a defibrillator if the strategy was adopted. RESULTS: Use of implantable cardioverter defibrillators in survivors of cardiac arrest costs between 22,400 pounds and 57,000 pounds for each year of life saved. Most of the strategies proposed by the current generation of implantable cardioverter defibrillator trials have cost efficacies in the same range, and adoption of any one of these strategies in the United Kingdom could cost between 2 million pounds and 100 million pounds a year. Future technical and medical developments mean that cost-efficacy may be improved by up to 80%. Due to the limitations of screening tests currently available restriction on the use of implantable cardioverter defibrillators to those groups where it seems highly cost-effective will result in a small impact on overall mortality from sudden cardiac death. CONCLUSION: Present and possible future applications of the implantable cardioverter defibrillator seem expensive when compared with currently accepted treatments. Technical and medical developments are, however, likely to result in a dramatic improvement in cost efficacy over the next few years.

Cost implications of the British Pacing and Electrophysiology Group's recommendations for pacing.

OBJECTIVE: To compare present pacing practice with the recommendations recently published by the British Pacing and Electrophysiology Group and to assess the increase in annual budget required to implement these recommendations in a regional cardiothoracic unit. DESIGN: Retrospective analysis of pacemaker implantation for 1991 with calculation of the costs required to implement the group's recommendations based on average 1991 costs of the types of pacing generators and electrode leads used. SETTING: Regional cardiothoracic unit for South West Thames Health Authority. PATIENTS: 433 consecutive patients receiving permanent pacemaker generators: 76 (18%) with sinus node disease; 270 (62%) with atrioventricular block; 25 (6%) with both sinus node disease and atrioventricular block; 59 (14%) with chronic atrial fibrillation and atrioventricular block; and 3 (1%) with carotid sinus or malignant vasovagal syndromes. RESULTS: Only 102 (24%) patients received pacemaker generators recommended by the British Pacing and Electrophysiology Group; however, 355 (82%) patients were older than 65 years, and 264 (61%) were aged 75 or over. The cost of hardware for pacing was 462,885 pounds. Using generators as recommended would have cost 810,525 pounds for "optimal" systems (an increase of 75%) and 710,750 pounds for "alternative" systems (an increase of 54%). These increases would have been considerably reduced by limiting the use of sophisticated pacing to younger patients (aged under 75). Further savings could be made by using the least expensive pacing models available. CONCLUSIONS: Implementing these recommendations should reduce morbidity related to bradyarrhythmia but will lead to major increases in pacing costs. Age and patients' expected activity may be used to select simple pacing systems and thus to contain cost. More research is needed to determine which patient groups will benefit most from complex pacing systems.

Implantable defibrillators for prevention of sudden death. Technology at a medical and economic crossroad.

Implantable cardioverter-defibrillator therapy is now widely used for the treatment of symptomatic patients with documented or suspected life-threatening VTs. Although sudden death recurrence in ICD recipients is virtually eliminated, the extent of benefit both with respect to cardiac mortality and total survival in this patient population remains to be accurately quantitated, particularly vis-à-vis alternative antiarrhythmic therapies. Advanced device and lead systems can be expected to further improve both patient survival and quality of life after implant. The economic impact of unrestrained proliferation in ICD therapy can be enormous; however, available cost-benefit analyses support judicious use of this therapy with comparable economic impact to other accepted cardiovascular therapies. Such prospective risk stratification becomes economically essential when considering expanding its application to asymptomatic or minimally symptomatic populations at potential risk for future cardiac arrest.

Assessment of QT dispersion in symptomatic patients with congenital long QT syndromes.

It has been suggested that QT dispersion recorded on the surface electrocardiogram may be a predictor of arrhythmic events in patients with congenital QT prolongation. To evaluate this, 9 patients (6 female, mean age 17.6 years) with congenital long QT syndromes, all of whom had syncope and documented torsades de pointes, were studied. Patients were studied off treatment and during therapy with beta-blocking agents. Three patients were also studied after left stellate ganglionectomy. An age-matched control group was also studied. Good quality 12-lead electrocardiograms were recorded from all patients. For each lead, QT and RR intervals were measured, and QTc value was calculated. QT and QTc dispersions were calculated for each patient. Patients had a significantly longer mean QT interval compared with that of the control group (450 +/- 100 vs 359 +/- 63 ms; p = 0.015) at similar mean RR intervals (736 +/- 231 vs 783 +/- 289 ms), with a longer mean QTc value (0.53 +/- 0.08 vs 0.41 +/- 0.02 s1/2; p = 0.004). Patients also had longer QT and QTc dispersions compared with those of the control group (110 +/- 45 vs 43 +/- 12 ms [p = 0.004], and 0.108 +/- 0.03 vs 0.05 +/- 0.02 s1/2 [p = 0.002], respectively). QT and QTc dispersions on and off beta-blocking agents were not significantly different. Comparing patients with frequent and those with infrequent symptoms, there was no difference in QT or QTc dispersion either off treatment or during therapy with beta-blocking agents.(ABSTRACT TRUNCATED AT 250 WORDS)