Current Gaps in the Provision of Safe and Effective Anticoagulation in Atrial Fibrillation and the Potential for Factor XI-Directed Therapeutics.

The global prevalence of atrial fibrillation is rapidly increasing, in large part due to the aging of the population. Atrial fibrillation is known to increase the risk of thromboembolic stroke by five times, but it has been evident for decades that well-managed anticoagulation therapy can greatly attenuate this risk. Despite advances in pharmacology (such as the shift from vitamin K antagonists to direct oral anticoagulants) that have increased the safety and convenience of chronic oral anticoagulation in atrial fibrillation, a preponderance of recent observational data indicates that protection from stroke is poorly achieved on a population basis. This outcomes deficit is multifactorial in origin, stemming from a combination of underprescribing of anticoagulants (often as a result of bleeding concerns by prescribers), limitations of the drugs themselves (drug-drug interactions, bioaccumulation in renal insufficiency, short half-lives that result in lapses in therapeutic effect, etc.), and suboptimal patient adherence that results from lack of understanding/education, polypharmacy, fear of bleeding, forgetfulness, and socioeconomic barriers, among other obstacles. Often this adherence is not reported to treating clinicians, further subverting efforts to optimize care. A multidisciplinary, interprofessional panel of clinicians met during the 2023 International Society of Thrombosis and Haemostasis Congress to discuss these gaps in therapy, how they can be more readily recognized, and the potential for Factor XI-directed anticoagulants to improve the safety and efficacy of stroke prevention. A full appreciation of this potential requires a re-evaluation of traditional teaching about the "coagulation cascade" and decoupling the processes that result in (physiologic) hemostasis and (pathologic) thrombosis. The panel discussion is summarized and presented here.

Racial and ethnic differences in implantable cardioverter-defibrillator patient selection, management, and outcomes.

Racial and ethnic differences in treatment-cardiovascular and otherwise-have been documented in many aspects of the American health care system and can be seen in implantable cardioverter-defibrillator (ICD) patient selection, counseling, and management. ICDs have been demonstrated to be a powerful tool in the prevention of sudden cardiac death, yet uptake across all eligible patients has been modest. Although patients who do not identify as White are disproportionately eligible for ICDs in the United States, they are less likely to see specialists, be counseled on ICDs, and ultimately have an ICD implanted. This review explores racial and ethnic differences demonstrated in ICD patient selection, outcomes including shock effectiveness, and postimplantation monitoring for both primary and secondary prevention devices. It also highlights barriers for uptake at the health system, physician, and patient levels and suggests areas of further research needed to clarify the differences, illuminate the driving forces of these differences, and investigate strategies to address them.

Effect of ranolazine on ventricular vulnerability and defibrillation threshold in the intact porcine heart.

INTRODUCTION: Extensive in vitro studies and clinical evidence (MERLIN trial) indicate an antiarrhythmic potential of ranolazine, a novel antianginal agent. Programmed electrophysiologic testing was performed to quantify ranolazine's effects on ventricular vulnerability and defibrillation thresholds and to gain insights into mechanisms. METHODS AND RESULTS: Effects of ranolazine (9.2 +/- 2.1 microM, plasma level) on surface ECG, right ventricular effective refractory period (ERP), and repetitive extrasystole (RE), ventricular fibrillation (VF), and defibrillation (DFT) thresholds were determined in 29 normal closed-chest anesthetized pigs. The single extrastimulus method was employed for ERP and for RE and VF thresholds. DFT(50) was determined using an up-down testing protocol with an implantable cardioverter-defibrillator. Ranolazine increased rate-corrected QT interval from 490 +/- 30 to 527 +/- 24 ms (P < 0.05) but did not alter T(peak)-T(end) interval (59 +/- 8 to 62 +/- 11, P = 0.65). ERP increased by 40 +/- 6 ms (P < 0.001). Compared with baseline, ranolazine raised RE threshold from 20 +/- 6 to 34 +/- 9 mA (P < 0.001) and VF threshold from 38 +/- 4 to 48 +/- 10 mA (P < 0.05). DFT(50) was unchanged (baseline: 14 +/- 2 J; ranolazine: 14 +/- 2 J; P = 0.6), whereas diastolic pacing threshold increased from baseline pulse width of 0.07 +/- 0.03 to 0.17 +/- 0.07 ms (P < 0.01) with 1V pulse amplitude. CONCLUSIONS: Ranolazine, at therapeutic concentrations, produces a mild increase in QT interval and a marked increase in both RE and VF thresholds. Thus, ranolazine does not augment and may improve dispersion of ventricular repolarization, suggesting a potential antiarrhythmic action. Ranolazine is unlikely to affect the margin of safety of defibrillation, given no significant effect on DFT, but could result in a mild increase in pacing threshold.

Treatment options for patients with coronary artery disease identified as high risk by T-wave alternans testing.

Risk stratification for primary prevention of sudden cardiac death (SCD) remains a major challenge in cardiology. The utility of T-wave alternans (TWA) as a marker of risk of life-threatening ventricular tachycardia and fibrillation is supported by two decades of basic and clinical research. Both frequency- and time-domain methods have been developed, validated, and made available in clinical practice. A principal application of TWA testing has been to improve assessment of patients with depressed left ventricular ejection fraction (EF;

Reduction and redistribution of gap and adherens junction proteins after ischemia and reperfusion.

BACKGROUND: Previous studies have demonstrated that alterations in myocardial structure, consistent with tissue and sarcomere disruption as well as myofibril dissociation, occur after myocardial ischemia and reperfusion. In this study we determine the onset of these structural changes and their contribution to electrical conduction. METHODS: Langendorff perfused rabbit hearts (n = 47) were subjected to 0, 5, 10, 15, 20, 25, and 30 minutes global ischemia, followed by 120 minutes reperfusion. Hemodynamics were recorded and tissue samples were collected for histochemical and immunohistochemical studies. Orthogonal epicardial conduction velocities were measured, with temperature controlled, in a separate group of 10 hearts subjected to 0 or 30 minutes of global ischemia, followed by 120 minutes of reperfusion. RESULTS: Histochemical and quantitative light microscopy spatial analysis showed significantly increased longitudinal and transverse interfibrillar separation after 15 minutes or more of ischemia (p < 0.05 versus control). Confocal immunohistochemistry and Western blot analysis demonstrated significant reductions (p < .05 versus control) of the intercellular adherens junction protein, N-cadherin, and the active phosphorylated isoform of the principal gap junction protein, connexin 43 at more than 15 minutes of ischemia. Cellular redistribution of connexin 43 was also evidenced on immunohistochemistry. No change in integrin-beta1, an extracellular matrix attachment protein, or in epicardial conduction velocity anisotropy was observed. CONCLUSIONS: These data indicate that there are significant alterations in the structural integrity of the myocardium as well as gap and adherens junction protein expression with increasing global ischemia time. The changes occur coincident with previously observed significant decreases in postischemic functional recovery, but are not associated with altered expression of matrix binding proteins or electrical anisotropic conduction.

Suppression of calcium-induced repolarization heterogeneity as a mechanism of nitroglycerin's antiarrhythmic action.

This study examined whether the antifibrillatory action of nitroglycerin (NTG) is attributable to reduction in calcium-induced heterogeneity of repolarization independent of autonomic and coronary vasodilatory influences. The effects of intrapericardial (IPC) NTG on coronary blood flow, contractility, repolarization, and arrhythmia susceptibility were measured in anesthetized pigs (N = 43). Autonomic influences were minimized by vagotomy and beta-adrenergic blockade (metoprolol, 1.25 mg/kg, intravenous). Electrophysiological parameters were tested at 30 min, a time when coronary hemodynamics had returned to baseline. Intracoronary calcium chloride (CaCl2, 50-mg bolus) injection augmented contractility (dP/dt(max), 1760 +/- 144 to 2769 +/- 274 mmHg/s, and following NTG, 1531 +/- 384 to 2138 +/- 242 mmHg/s, P < 0.0002), reflecting increased myocardial intracellular calcium. Calcium increased repolarization heterogeneity (interlead precordial T-wave heterogeneity, 95 +/- 15 to 264 +/- 33 microV, P < 0.006; T(peak)-T(end), an index of transmural dispersion of repolarization, 37 +/- 3 to 76 +/- 6 ms, P < 0.05) and lowered repetitive extrasystole threshold (RET; 24 +/- 2 to 13 +/- 1 mA, and following NTG, 32 +/- 4 to 18 +/- 1 mA, P < 0.0001). IPC NTG raised the RET from baseline by 33% and blunted calcium-induced contractility (dP/dt(max) by 23%, P < 0.05), repolarization changes (T-wave heterogeneity by 24%, P < 0.006; T(peak)-T(end) by 18%, P = 0.04), and arrhythmia vulnerability (RET by 39%, P < 0.003). Thus, the capacity of NTG to suppress calcium-induced repolarization heterogeneity is an important mechanism of its antiarrhythmic action, which is independent of autonomic and vasodilatory actions.

Atrioventricular nodal reentrant tachycardia in two siblings with Wolfram syndrome.

This is a case of two siblings with the autosomal recessive Wolfram syndrome who both have documented atrioventricular nodal reentrant tachycardia (AVNRT). This is the first report to our knowledge that links AVNRT to a syndrome in which the putative gene has been identified.

Cardiac conduction through engineered tissue.

In children, interruption of cardiac atrioventricular (AV) electrical conduction can result from congenital defects, surgical interventions, and maternal autoimmune diseases during pregnancy. Complete AV conduction block is typically treated by implanting an electronic pacemaker device, although long-term pacing therapy in pediatric patients has significant complications. As a first step toward developing a substitute treatment, we implanted engineered tissue constructs in rat hearts to create an alternative AV conduction pathway. We found that skeletal muscle-derived cells in the constructs exhibited sustained electrical coupling through persistent expression and function of gap junction proteins. Using fluorescence in situ hybridization and polymerase chain reaction analyses, myogenic cells in the constructs were shown to survive in the AV groove of implanted hearts for the duration of the animal's natural life. Perfusion of hearts with fluorescently labeled lec-tin demonstrated that implanted tissues became vascularized and immunostaining verified the presence of proteins important in electromechanical integration of myogenic cells with surrounding re-cipient rat cardiomyocytes. Finally, using optical mapping and electrophysiological analyses, we provide evidence of permanent AV conduction through the implant in one-third of recipient animals. Our experiments provide a proof-of-principle that engineered tissue constructs can function as an electrical conduit and, ultimately, may offer a substitute treatment to conventional pacing therapy.

Non-inducibility post-pulmonary vein isolation achieving exit block predicts freedom from atrial fibrillation.

AIMS: This study evaluates whether non-inducibility of atrial fibrillation (AF) after achieving bi-directional electrical pulmonary vein (PV) isolation is a useful predictor of freedom from AF recurrence. METHODS AND RESULTS: This study included 102 consecutive patients who underwent PV isolation for symptomatic paroxysmal (59%), persistent (32%), or permanent (9%) AF. Patients were followed for 16+/-10 months. Complete isolation of all four PVs was confirmed by demonstration of bi-directional block, defined by both loss of PV potentials and failure to capture the LA by pacing (at 10 mA) 10-14 bipolar pairs of electrodes on a circumferential catheter positioned at the entrance of the PV. Induction of AF by burst pacing on/off isoproterenol was attempted after PV isolation. Freedom from recurrent symptomatic or asymptomatic AF was present in 70% of patients at 6 months and 62% of patients at 12 months. In multi-variable analysis, non-inducibility post-PV isolation (OR=3.84, P=0.047) and paroxysmal AF (OR=4.80, P=0.012) predicted freedom from AF at 12 months. CONCLUSION: Non-inducibility of AF after bi-directional PV isolation predicts maintenance of sinus rhythm. This finding suggests that routine extensive left atrial ablation may be unnecessary.

Noninvasive sudden death risk stratification by ambulatory ECG-based T-wave alternans analysis: evidence and methodological guidelines.

Extensive experimental and clinical evidence supports the utility of T-wave alternans (TWA) as a marker of risk for ventricular fibrillation. This entity appears to reflect the fundamental arrhythmogenic property of enhanced dispersion of repolarization. This relationship probably accounts for its relative ubiquity in patients with diverse types of cardiac disease, as has been recognized with the development of analytical tools. A basic premise of this review is that ambulatory ECG monitoring of TWA as patients experience the provocative stimuli of daily activities can expose latent electrical instability in individuals at heightened risk for arrhythmias. We will discuss the literature that supports this concept and summarize the current state of knowledge regarding the use of routine ambulatory ECGs to evaluate TWA for arrhythmia risk stratification. The dynamic, nonspectral modified moving average analysis method for assessing TWA, which is compatible with ambulatory ECG monitoring, is described along with methodological guidelines for its implementation. Finally, the rationale for combined monitoring of autonomic markers along with TWA will be presented.

Typical AVNRT--an update on mechanisms and therapy.

Typical atrioventricular reentrant tachycardia (AVNRT) is the most common paroxysmal supraventricular tachycardia among adults, and accounts for considerable morbidity. The concept of dual pathway physiology remains useful, although this physiology likely results from the functional properties of anisotropic tissue within the triangle of Koch, rather than anatomically distinct tracts of conduction. Also, there remains debate regarding whether the critical reentrant circuit path requires participation of the atrium. In our opinion, current evidence favors functional anisotropic reentry limited to the subatrial tissues as the arrhythmia mechanism. Reasons for this are reviewed. Fortunately, typical AVNRT is readily amenable to definitive therapy by catheter-based radiofrequency energy delivery at the so-called slow pathway region located at the posterior Triangle of Koch. Anterior or left-sided approaches are very rarely indicated. Results from multiple series have shown this strategy to be both safe and effective, therefore ablation therapy should now be considered as the definitive therapy of choice for the majority of patients.