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<i>Circulation</i> : Clinical Summaries

Sex differences have the potential to impact diagnostic and therapeutic interventions in a wide variety of medical conditions, and cardiac arrhythmias are no exception.1 Studies evaluating pathophysiology, disease course, and therapeutic options for cardiac arrhythmias have been performed predominantly in male patients. However, catheter and device-based therapies coupled with landmark clinical trials have contributed to an improved understanding of this important aspect. The objective of this review is to present the current state of knowledge on sex differences in cardiac arrhythmias with a focus on clinical management, while highlighting gaps in knowledge that would benefit from future investigation. ### Atrial Fibrillation and Atrial Flutter #### Disease Burden Atrial fibrillation (AF) and atrial flutter (AFL) are the most commonly encountered tachyarrhythmias in clinical practice, with significant implications for public health and healthcare costs. Stroke, hospitalization, and loss of productivity are the major consequences of AF.2 The incidence of AF (per 1000 person-years) is reported to be between 1.6 and 2.7 in women and between 3.8 and 4.7 in men.2 The age-adjusted incidence and prevalence of AF is lower in women compared with that in men, and accordingly, the lifetime risk of AF from the Framingham Heart Study at 40 years of age was higher in men (26.0% for men versus 23.0% for women).3 Another analysis from the Framingham Heart Study demonstrated no significant sex differences in the risk of developing AFL.4 The prevalence of AF continues to rise among both men and women. In a study investigating the global burden of disease from 1980 to 2010, there was not only an increase in overall burden, incidence, and prevalence of AF, but most importantly an increase in AF-associated mortality in both men and women (Figure 1).5 The age-adjusted mortality for women was consistently higher compared with that for men from 1990 to 2010 (Figure …

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Disorders of the cardiac muscle or cardiomyopathies are a broad, yet collectively common, group of conditions. Despite the heterogeneous etiologies, mode of death from these conditions is remarkably similar - progressive decline in cardiac function leading to intractable heart failure (HF) and sustained ventricular arrhythmias resulting in sudden cardiac death (SCD). Nearly 50% of patients die within 5 years of a HF diagnosis.1 Indeed, in the United States, HF alone is thought to cause 55,000 deaths per year2 and further contribute to 1 in 9 deaths overall.1 However, while advanced HF and the risk of SCD were once thought to be untreatable, technological advances has seen the emergence of device therapies as viable treatment options. Specifically, implantable cardioverter-defibrillator (ICD) therapy for treatment of ventricular arrhythmias, cardiac resynchronization therapy (CRT) for restoring cardiac synchrony and mechanical efficiency, and ventricular assist device (VAD) therapy to temporarily or permanently replace the function of the failing heart, have all emerged as highly efficacious therapies. The expanding use of device therapies, however, poses many challenges. First, while the indications for these devices are well summarized in clinical guidelines,3,4 considerable hurdles remain in ensuring eligible patients receive these therapies.5 By the same token, establishing the safety and effectiveness of these therapies in populations that are found in clinical practice, yet commonly excluded from trials, such as the elderly6 and uncommon forms of cardiomyopathies,7 is a high priority. Second, rapid dissemination of technologies frequently results in disparities in care. Indeed, age, gender, and racial disparities, in both receipt of these devices and outcomes following implantation, have been well documented. Whether these disparities have persisted, and the potential causative mechanisms underlying these disparities, however, are uncertain.8,9 Third, these devices are not without significant untoward effects; understanding …

Noninvasive atrial fibrillation (AF) therapies are based on 2 separate strategies: rate or rhythm control aiming to slow ventricular rate to normal or to restore sinus rhythm, respectively.Hence, in rate control, AF itself is not resolved, whereas the curtailment of ventricular frequency reduces exercise tolerance.Rhythm control, on the other hand, is hampered by adverse effects such as ventricular proarrhythmia.Therefore, better insight into the contribution of ion channels, present in the atria but not the ventricles, to AF and the concordant exploration of possible atrium-specific therapies are essential if we are to diminish the burden of adverse effects in AF treatment.Previous studies showed that the acetylcholine-dependent potassium current (I K,ACh ), governed by the atrium-specific Kir3.x channels, can become constitutively active (I K,ACh-C ) in patients with AF.In the present study, we demonstrate the contribution of I K,ACh-C and Kir3.x to the initiation, maintenance, and termination of AF.We show for the first time that I K,ACh-C increases the chance of AF initiation through its steepening effects on the action potential duration and conduction velocity restitution curves, causing action potential duration and amplitude alternans.In addition, I K,ACh-C is shown to facilitate AF maintenance by stabilizing rotor dynamics, whereas AF termination can be elicited by blockade of I K,ACh-C , causing alternans-mediated rotor destabilization.Our findings provide evidence for a causal relationship between I K,ACh-C , alternans, and the initiation, maintenance, and termination of AF.Thus, not only I K,ACh-C or Kir3.x but also its consequent alternans might be an interesting atrium-specific target for future AF rhythm control or pharmacological cardioversion.Conclusions-Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with I K,ACh-c .This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies. 1 Incident Atrial Fibrillation Among Asians, Hispanics, Blacks, and WhitesSummary-Although atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice, the underlying mechanisms responsible for its induction and perpetuation remain incompletely understood.Blacks experience a substantially lower rate of AF compared with whites, and the relative strength of this association suggests the mechanism responsible for the race-AF association plays an important role in disease pathogenesis.Because AF rates have only been rigorously compared between black and white patients, it is unclear whether white race confers elevated AF risk or black race affords arrhythmia protection.The present investigation compared incident AF between whites, blacks, Hispanics, and Asians receiving hospital-based medical care in California.A significantly lower hazard of AF was observed among blacks, Hispanics, and Asians compared with whites both before and after controlling for established risk factors.These findings argue against a protective effect unique to black race and instead suggest an unidentified characteristic inherent to white race increases AF risk.In addition, the difference in AF risk between whites and nonwhites was most pronounced in the absence of established AF risk factors.This further suggests that an unknown, alternative disease mechanism is driving these racial differences.As nonwhite racial and ethnic populations within the United States continue to grow, clinicians should be aware of the importance of race in AF prediction and incorporate this knowledge into their care of patients at risk for this frequently encountered disease.Conclusions-In a large hospital-based cohort, whites have an increased risk of AF whether compared with blacks, Asians, or Hispanics.The heightened AF risk among whites is most pronounced in the absence of cardiovascular comorbidities. 2 Intramyocardial Adiposity After Myocardial Infarction: New Implications of a Substrate for Ventricular TachycardiaSummary-The prevalence of intramyocardial adipose tissue (IMAT) in patients after myocardial infarction is ≈15% to 89%, depending on disease progression and assessment modality.To date, the electrophysiological influence of IMAT in this setting has been undefined.In this large-animal study, we have provided histological and electrophysiological evidence that IMAT is associated with ventricular tachycardia in the chronic phase of myocardial infarction.If these findings are confirmed clinically, noninvasive identification of IMAT within infarct borders may be applied to predict the propensity for ventricular tachycardia and mortality.The "gray zone"

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Background— Intermittent rhythm monitoring (IRM) to detect atrial fibrillation (AF) recurrence is employed to evaluate the success of therapeutic interventions. In a large population of patients with continuous monitoring (CM), we investigated the sensitivity of various frequencies and durations of IRM strategies on the detection of AF recurrence, the dynamics behind AF recurrence detection, and we describe measures to evaluate temporal AF recurrence. Methods and Results— Rhythm histories of 647 patients (mean AF burden, 0.12±0.22; median, 0.014; 687 patient-years) with implantable CM devices were reconstructed and analyzed. With the use of computationally intensive simulation, the sensitivity of IRM of various frequencies and durations on the identification of AF recurrence was evaluated. Prolonged-duration IRM was superior to shorter IRM ( P &lt;0.0001). However, even with aggressive IRM strategies, AF recurrence was not detected in a great proportion of patients. The temporal AF burden aggregation (AF density) was directly related to IRM sensitivity ( P &lt;0.0001). Even at similar AF burdens, patients with high-density AF required higher-frequency or prolonged-duration IRM to achieve the same sensitivity as in low-density AF ( P &lt;0.0001). Patients with high-density, low-burden AF benefit the most from CM for detection of AF recurrence. Conclusions— IRM follow-up is significantly inferior to CM. IRM strategies will not identify AF recurrence in a great proportion of patients at risk. Temporal AF characteristics play a significant role in AF recurrence detection with the use of IRM. For the scientific, evidence-based evaluation of AF treatments, CM should be strongly recommended. Prospective studies are required to evaluate whether CM to guide clinical management can also improve patient outcomes. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00806689.

Despite advances in catheter ablation techniques and device-based therapies for cardiac arrhythmias, antiarrhythmic drugs remain essential components of any comprehensive therapeutic strategy. Antiarrhythmic drug therapy, however, has been limited by both incomplete efficacy and a substantial potential for cardiac and extracardiac toxicity. As a result, only a few new antiarrhythmic agents have successfully completed clinical development programs and reached routine clinical usage over the past 20 years. Antiarrhythmic drugs may be indicated for ventricular tachycardia, sudden death prevention, or specific types of supraventricular arrhythmia. Implantable cardioverter-defibrillator (ICD) therapy has evolved as the primary treatment for most life-threatening ventricular arrhythmias, and antiarrhythmic drugs for these rhythms are currently mostly used either as acute interventions or as adjuncts to chronic ICD therapy. Although numerous trials have evaluated the effect of antiarrhythmic drugs to decrease ICD shocks or therapies, such data have yet to provide the sole basis for approval for any new agent. At the same time, drug therapy for atrial arrhythmias is often limited by the drug’s simultaneous effects on the ventricles, which has led to efforts to identify ionic channel targets specific to or preferentially located in the atria. The sustained outward K+ current (IKur, encoded by the Kv 1.5 subunit), the acetylcholine-activated outward K+ current (IKAch), and both peak and late atrial Na+ currents have therefore become potential targets for antiarrhythmic drug developers.1–4 Another approach has been to seek agents that synergistically affect multiple channels simultaneously, resulting in a net beneficial effect while minimizing toxicity. Other nontraditional targets for drug therapy that do not directly involve ion channels have also emerged as our understanding of the mechanisms of arrhythmias has improved. As a result, several new compounds are now at or near completion of phase 3 clinical trials, and other promising …

See Article by Srivatsa et al It is well known that atrial fibrillation (AF) is an independent risk factor for all-cause mortality and is also associated with an increased risk of stroke and heart failure.1,2 If these risks are indeed causal, then it would be logical that maintenance of sinus rhythm should improve mortality. Randomized trials have sought to compare rate and rhythm control strategies with the hypothesis that patients with AF would derive a mortality benefit from maintaining sinus rhythm, but most have failed to prove this hypothesis. Previous studies comparing a rate versus rhythm control strategy using antiarrhythmic drugs, such as AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management), RACE (Rate Control Versus Electrical Cardioversion), and STAF (Strategies of Treatment of Atrial Fibrillation)3–5 failed to show a reduction in stroke and mortality with a rhythm control strategy and at most demonstrated an improvement in symptoms and quality of life.6–8 Explanations for these results have included that the benefit of sinus rhythm may be offset by the harmful effects of antiarrhythmic drugs (particularly amiodarone); the percentage of patients maintaining sinus rhythm with medical rhythm control is low; and the relationship of AF and mortality may be associative and not causative. It should be noted, however, that a substudy of AFFIRM did demonstrate reduce mortality in those patients who actually maintained sinus rhythm regardless of their randomized strategy.9 In recent years, several randomized trials have shown that catheter ablation is superior to antiarrhythmic drugs to maintain sinus rhythm.10,11 If part of the benefit of sinus rhythm is being undermined by the toxicities of antiarrhythmics, then it would be logical to retest the hypothesis that rhythm control could benefit mortality through the use of ablation. The major limitation …

DETECTION OF CONGENITAL LONG QT SYNDROME WITH ARTIFICIAL INTELLIGENCE

Managing atrial fibrillation in the CRT patient: Controversy or consensus?

A recent series of randomized prospective clinical trials that compared rate control with rhythm control in patients with atrial fibrillation (AF) found no significant difference in primary outcome between the two strategies. However, these trials lacked clear criteria for defining "successful" rate or rhythm control. Various measures have been used to gauge the success of antiarrhythmic drug therapy, including time to first recurrence of AF, any AF recurrence, AF burden, and a reduction in symptoms. Determining the success of antiarrhythmic therapy can be relatively straightforward by using how patients feel during therapy as a key endpoint. Most patients are satisfied with a major reduction in symptomatic AF episodes and can live comfortably with occasional episodes of AF. For those who are bothered by even infrequent, brief AF episodes, a treatment regimen that eliminates nearly all AF recurrences is required, although often hard to achieve. Catheter ablation may be necessary to achieve a successful outcome in these patients. Suppression of AF in a patient at high risk of stroke does not, however, remove the need for concomitant warfarin therapy. The endpoints of ventricular rate control are not clear, and the recently published rhythm versus rate control trials lacked standard criteria for judging acceptable rate control. One relatively simple method is to try and achieve a 24-hour heart rate that mimics expected normal sinus rhythm. It is important to achieve good rate control to minimize symptoms and the risk of tachycardia-mediated cardiomyopathy.

Sudden cardiac death (SCD) is a major public health problem in North America, responsible for approximately 400 000 deaths annually.1,2 Most episodes of SCD in ambulatory populations result from ventricular tachyarrhythmias,3 whereas bradyarrhythmias may be important in some populations, notably hospitalized patients with advanced heart failure4 (Figure 1). A prior article in this series by Zipes and Wellens2 provides a detailed review of the pathogenesis of SCD, its underlying causes, and treatment strategies. Figure 1. Mechanisms of SCD in ambulatory persons. Most SCDs result from ventricular fibrillation. VT, bradyarrhythmias, and other mechanisms account for the remainder. ### ICD Therapy The availability of a therapy that reliably terminates the vast majority of life-threatening tachyarrhythmic and bradyarrhythmic events has tremendous clinical appeal. The implantable cardioverter defibrillator (ICD) represents such a therapy. Despite its appeal, the ICD is imperfect. Currently, systems are costly, have a limited life expectancy, and are subject to complications in the long term.5,6 Furthermore, many patients at risk for SCD are at risk of dying from causes that the ICD would not alter. The impact of ICD shocks also merits consideration. Evidence links multiple shocks with myocardial injury7 and fibrosis,8 and sporadic shocks are associated with significant, independent reductions in quality of life. Compared with patients not having shocks, patients in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial who had ≥1 shocks in the initial year of follow-up had significant declines in self-perceived physical functioning and mental well-being, independent of ejection fraction (EF), social circumstances, and medication use. The reduction in quality of life associated with shocks was of a magnitude similar to clinically important adverse effects from amiodarone.9 Cost-efficacy is a vital issue in settings of limited or restricted health care resources6 and is particularly relevant as ICD use is expanded to …

The “modern” era of the treatment of ventricular tachyarrhythmias with device-based therapy may have begun in 1899, when Prevost and Battelli noted, almost as an afterthought, that direct current shock could terminate ventricular fibrillation (VF) in dogs.1 Three decades later, pioneering work in the field of defibrillation concluded that the passage of electrical current across the heart can both initiate and terminate VF.2,3 Still, little attention was paid to this phenomenon, as evidenced by Paul Dudley White’s Heart Disease , which devoted less than half a page to VF and characterized the arrhythmia as “a condition of little importance so far as we know now.”4 In 1947, the thoracic surgeon Claude Beck saved the first human life by the successful use of cardiac defibrillation in a 14-year-old boy who developed VF during a thoracic surgical procedure and went on to achieve a full recovery.5 These early accomplishments provided the foundation for the landmark work of Mirowski and Mower that ultimately led to the development of the implantable cardioverter-defibrillator (ICD) and its introduction in humans in 1980.6 Pacing may prevent sudden cardiac death due to bradyarrhythmias and in certain circumstances such as torsade de pointes associated with congenital long-QT syndrome (LQTS) and pause-dependent ventricular tachycardia (VT). Although no controlled studies exist, retrospective analyses suggest that recurrent torsade de pointes in patients with LQTS may be prevented by continuous pacing.7 Early clinical data on small numbers of patients suggested that the combination of β-adrenergic blockade plus continuous pacing reduced the number of syncopal events and the anticipated rate of sudden death in high-risk LQTS patients.8 The beneficial effects of pacing may be limited to patients with LQT2 and LQT3, in which the transmural dispersion of repolarization worsens steeply during bradycardia.9 Genotype-phenotype correlation confirms that …