Irina Savelieva

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.

Agreement and Reproducibility of Automatic Versus Manual Measurement of QT Interval and QT Dispersion

To determine whether the automatic measurement of the QT interval is consistent with the manual measurement, this study evaluated the reproducibility and agreement of both methods in 70 normal subjects and 54 patients with hypertrophic cardiomyopathy. The mean, minimum, and maximum QT interval and QT dispersion were computed in a set of 6 consecutive electrocardiograms (3 in the supine and 3 in the standing position) obtained from each subject. The automatic method determined the T-wave end as the intersect of the least-squares-fit line around the tangent to the T-wave downslope with the isoelectric baseline. Manual measurements were obtained using a high-resolution digitizing board. QT dispersion was defined as the difference between the maximum and minimum QT interval and as standard deviations of the QT interval duration in all and precordial leads. In patients with hypertrophic cardiomyopathy, the absolute values of the QT interval and QT dispersion were significantly higher than those in normal subjects (p < 0.0001). In both groups, the intrasubject variability of the QT interval was significantly lower with automatic than with manual measurement (p < 0.05). The agreement between automatic and manual QT interval measurements was surprisingly poor, but it was better in patients with hypertrophic cardiomyopathy (r2 = 0.46 to 0.67) than in normal subjects (r2 = 0.10 to 0.25). In both groups, the reproducibility and agreement of both methods for QT dispersion were significantly poorer than for QT interval. Hence, the automatic QT interval measurements are more stable and reproducible than manual measurement, but the lack of agreement between manual and automatic measurement suggests that clinical experience gained with manual assessment cannot be applied blindly to data obtained from the automatic systems.

Current concepts in the pathogenesis of atrial fibrillation

Current evidence suggests that the pathogenesis of atrial fibrillation (AF) is multifactorial. The observation that AF, once present, alters the electrophysiologic properties of the atrial myocardium causing self-perpetuation of the arrhythmia raised the importance of electrical remodeling in its pathogenesis. Although these changes are potentially reversible, maintenance of AF continues even after electrical remodeling has occurred. Clinical and experimental studies have highlighted the role of a susceptible atrial anatomical substrate with features of myocyte degeneration and interstitial fibrosis in the initiation and maintenance of AF. Finally, the association of increased inflammatory burden with the presence and future development of AF has implicated inflammation in the pathogenesis of the arrhythmia. The purpose of this review is to provide current evidence on the dominant theories on AF pathogenesis, namely, electrical remodeling, structural remodeling, and inflammation; describe the various experimental models and methods used; and identify a cause-effect association, when present. In addition, the interrelation between different mechanisms responsible for AF will be demonstrated, providing further insight into the complex pathophysiology.

Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches

By 2050, atrial fibrillation (AF) will be present in 2% of the general population and in a far higher proportion of elderly patients. Currently, we are content with rate control and anticoagulation in elderly asymptomatic patients, whereas in younger patients with symptomatic recurrent AF, pulmonary vein isolation is the treatment of choice. However, in a large number of patients, there remains a genuine choice between anti-arrhythmic therapy to suppress the arrhythmia and rate control to control the ventricular rate. This review provides a contemporary evidence-based insight into the buoyant development of new anti-arrhythmic agents, exploring new mechanisms of action or novel combinations of established anti-arrhythmic activity. An attractive prospect for AF therapy is the introduction of agents with selective affinity to ion channels specifically involved in atrial repolarization, so-called atrial repolarization-delaying agents. Presently, there are several potential anti-arrhythmic drugs with this mode of action, which are currently in pre-clinical and clinical development. Vernakalant is in the most advanced phase of investigation and its intravenous formulation has recently been recommended for approval for pharmacological cardioversion of AF. However, although this agent has some electrophysiological effects which are specific to the atria, it has others which affect both the atria and the ventricles. Other drugs, such as XEND0101, block a single atrial-specific membrane current. The success of such agents depends critically on their atrial electrophysiological selectivity, freedom from cardiac adverse effects, and general safety. Other possibilities include modified analogues of traditional anti-arrhythmic drugs with additional novel mechanisms of action and less complex metabolic profiles. Dronedarone is an investigational agent with multiple electrophysiological effects, which is devoid of iodine substituents and is believed to have a better side effect profile than its predecessor amiodarone. The development portfolio of dronedarone is practically complete and approval for several indications in AF may soon be assessed. Innovative anti-arrhythmic agents with unconventional anti-arrhythmic mechanisms, such as stretch receptor antagonism, sodium-calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation, have not yet reached clinical studies in AF. Gene- and cell-based therapies, which can selectively target individual currents, could provide ideal one-time only curative therapy for arrhythmias, and the first proof-of-concept studies have been reported. There is accumulating evidence in support of the anti-arrhythmic effects of non-anti-arrhythmic drugs. Treatments with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, statins, and omega-3 fatty acids all seem promising, over and above any effect related to the treatment of underlying heart disease. However, despite exciting results from animal experiments and promising outcomes from retrospective analyses, there is no robust evidence of specific effects of these drugs to transform current clinical practice.

If Inhibition with Ivabradine

Ivabradine belongs to a new class of specific heart rate reducing agents that inhibit spontaneous pacemaker activity of the sinus node by selectively and specifically inhibiting the If current; thus, allowing heart rate reduction without affecting myocardial contractility, relaxation and peripheral vascular resistance.In clinical studies involving >3500 patients and 800 healthy volunteers, ivabradine demonstrated a good safety profile during its clinical development. The most common adverse events were visual symptoms in 16.4% (n = 270) and sinus bradycardia ≤55 beats per minute in 3.2% (n = 53) of all patients treated with recommended doses of 5 mg and 7.5 mg twice daily. However, because the heart rate reducing effect of ivabradine is proportional to the resting heart rate and is associated with a clear trend to a plateau-dose effect, severe sinus bradycardia is uncommon. Less than 1% of patients withdrew from therapy because of untoward sinus bradycardia. The QT interval is prolonged in accordance with the reduction in heart rate; however, after appropriate correction for heart rate and in direct comparisons of the QT interval when the influence of the heart rate was controlled by atrial pacing, no significant effect of ivabradine on ventricular repolarization duration was demonstrated. Consequently, ivabradine has no direct torsadogenic potential. Because ivabradine also inhibits h-channels, which carry the Ihh current in the eye, it may cause luminous phenomena (phosphenes). Visual symptoms are transient, do not interfere with quality of life and have led to few withdrawals (<1%; 24 of 2545 patients); symptoms resolved during treatment in 77.5% (383 of 491) of patients. Since constitutionally active If and Ih currents are confined to the sinus node, retina and CNS neurons (ivabradine does not cross blood-brain barrier), ivabradine does not affect other tissues. The safety of ivabradine will be further assessed by postmarketing surveillance and during on-going clinical trials.

Update on Atrial Fibrillation: Part I

Atrial fibrillation (AF) is an epidemic, affecting 1% to 1.5% of the population in the developed world. Projected data from the population‐based studies suggest that the prevalence of AF will grow at least 3‐fold by 2050. The health and economic burden imposed by AF and AF‐related morbidity is enormous.

Comparative Reproducibility of QT, QT Peak, and T Peak-T End Intervals and Dispersion in Normal Subjects, Patients with Myocardial Infarction, and Patients with Hypertrophic Cardiomyopathy

Abnormal repolarizaiion is associated with arrhythmogenesis. Because of controversies in existing methodology, new computerized methods may provide more reliable tools for the noninvasive assessment of myocardial repolarization from the surface electrocardiogram (ECC). Measurement of the interval between the peak and the end of the T wave (TpTe interval) has been suggested for the detection of repolarization abnormalities, but its clinical value has not been fully studied. The intrasubject reproducibility and reliability of automatic measurements of QT, QT peak, and TpTe interval and dispersion were assessed in 70 normal subjects, 49 patients with acute myocardial infarction (5th day; MI), and 37 patients with hypertrophic cardiomyopathy (HC). Measurements were performed automatically in a set of 10 ECCs obtained from each subject using a commercial software package (Marquette Medical Systems, Milwaukee, WI, U.S.A.). Compared to normal subjects, all intervals were significantly longer in HC patients (P < 0.001 for QT and QTp; p < 0.05 for TpTe); in MI patients, this difference was only significant for the maximum QT and QTp intervals (P < 0.05). In both patient groups, the QT and QTp dispersion was significantly greater compared to normal subjects (P < 0.05) but no consistent difference was observed in the TpTe dispersion among all three groups. In all subjects, the reproducibility of automatic measurement of QT and QTp intervals was high (coefficient of variation, CV, 1%‐2%) and slightly lower for that of TpTe interval (2%–5%; p < 0.05). The reproducibility of QT, QTp, and TpTe dispersion was lower (12%–24%, 18%–28%, 16%–23% in normal subjects, MI and HC patients, respectively). The reliability of automatic measurement of QT, QTp, and TpTe intervals is high but the reproducibility of the repeated measurements of QT, QTp and TpTe dispersion is comparatively low.

Stroke in atrial fibrillation: update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices.

Atrial fibrillation (AF) is said to be an epidemic, affecting 1%–1.5% of the population in the developed world. The clinical significance of AF lies predominantly in a 5‐fold increased risk of stroke. Strokes associated with AF are usually more severe and confer increased risk of morbidity, mortality, and poor functional outcome. Despite the advent of promising experimental therapies for selected patients with acute stroke, pharmacological primary prevention remains the best approach to reducing the burden of stroke. New antithrombotic drugs include both parenteral agents (e.g. a long‐acting factor Xa inhibitor idraparinux) and oral anticoagulants, such as oral factor Xa inhibitors and direct oral thrombin inhibitors (ximelagatran, dabigatran). Ximelagatran had shown significant potential as a possible replacement to warfarin therapy, but has been withdrawn because of potential liver toxicity. Its congener dabigatran appears to have a better safety profile and has recently entered a phase III randomized clinical trial in AF. Oral factor Xa inhibitors (rivaroxaban, apixaban, YM150) inhibit factor Xa directly, without antithrombin III mediation, and may prove to be more potent and safe. Selective inhibitors of specific coagulation factors involved in the initiation and propagation of the coagulation cascade (factor IXa, factor VIIa, circulating tissue factor) are at an early stage of development. Additional new agents with hypothetical, although not yet proven, anticoagulation benefits include nematode anticoagulant peptide (NAPc2), protein C derivatives, and soluble thrombomodulin. A battery of novel mechanical approaches for the prevention of cardioembolic stroke has recently been evaluated, including various models of percutaneous left atrial appendage occluders which block the connection between the left atrium and the left atrial appendage, minimally invasive surgical isolation of the left atrial appendage, and implantation of the carotid filtering devices which divert large emboli from the internal to the external carotid artery, preventing the embolic material from reaching intracranial circulation. Despite recent advances and promising new approaches, prevention of recurrent AF may be one of the best protections against AF‐related stroke and may reduce the prevalence of stroke by almost 25%. Improved pharmacological and nonpharmacological rhythm control strategies for AF as well as primary prevention of AF with ‘upstream’ therapy and risk factor modification are likely to produce a larger effect on the reduction of stroke rates in the general population than will specific interventions.

Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies

To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1×10−6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4×10−83) and the phospholamban (PLN) gene (P = 1.9×10−29). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.

Novel If Current Inhibitor Ivabradine: Safety Considerations

Ivabradine is a novel heart-rate-lowering agent that acts specifically on the sinoatrial node by selectively inhibiting the I(f) current, which is the current predominantly responsible for the slow diastolic depolarization of pacemaker cells. Unlike many rate-lowering agents, ivabradine reduces heart rate in a dose-dependent manner both at rest and during exercise without producing any negative inotropic or vasoconstrictor effect. The bradycardic effect of ivabradine is proportional to the resting heart rate, such that the effect tends to plateau. Thus, extreme sinus bradycardia is uncommon. Less than 1% of patients withdrew from therapy because of untoward sinus bradycardia. The QT interval is expectedly prolonged with the reduction in heart rate, but after appropriate correction for heart rate and in direct comparisons of the QT interval when the influence of the heart rate was controlled by atrial pacing, no significant effect of ivabradine on ventricular repolarization duration was demonstrated. Consequently, ivabradine has no direct torsadogenic potential, although, for obvious reasons, the specific bradycardic drug should not be administered with agents which have known rate-lowering and/or QTprolonging effects. Ivabradine has little effect on the atrioventricular node and ventricular refractoriness, but because of its effect on the sinus node, it should be avoided in patients with sick sinus syndrome. The physiological significance of upregulation of the I(f) current in the His-Purkinje system and ventricular myocardium due to ionic remodeling in pathophysiological conditions, such as end-stage heart failure, and the effects of ivabradine have yet to be explored. Because ivabradine also binds to hyperpolarization voltage-gated channels which carry the I(h) current in the eye, transient, dose-dependent changes of the electroretinogram resulting in mild to moderate visual side effects (phenomes) may occur in approximately 15% of patients exposed to ivabradine. Ivabradine does not cross the blood-brain barrier and therefore, has no effect on the I(h) current in central nervous system neurons. The safety of ivabradine has been assessed in a development program that enrolled over 3,500 patients and 800 healthy volunteers in 36 countries from Europe, North and South America, Africa, Asia and Australia, 1,200 of whom were exposed to ivabradine for over 1 year. Ivabradine has been associated with a good safety profile during its clinical development and its safety will be further assessed by postmarketing surveillance and during on-going clinical trials.