Suraj Kapa

Genetic Testing for Long-QT Syndrome Distinguishing Pathogenic Mutations From Benign Variants

Background— Genetic testing for long-QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically. Distinguishing pathogenic mutations from innocuous rare variants is critical to the interpretation of test results. We sought to quantify the value of mutation type and gene/protein region in determining the probability of pathogenicity for mutations. Methods and Results— Type, frequency, and location of mutations across KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) were compared between 388 unrelated “definite” (clinical diagnostic score ≥4 and/or QTc ≥480 ms) cases of LQTS and >1300 healthy controls for each gene. From these data, estimated predictive values (percent of mutations found in definite cases that would cause LQTS) were determined according to mutation type and location. Mutations were 10 times more common in cases than controls (0.58 per case versus 0.06 per control). Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1, KCNH2, and SCN5A in cases and >95% in controls. Nonmissense mutations have an estimated predictive value >99% regardless of location. In contrast, location appears to be critical for characterizing missense mutations. Relative frequency of missense mutations between cases and controls ranged from ≈1:1 in the SCN5A interdomain linker to infinity in the pore, transmembrane, and linker in KCNH2. These correspond to estimated predictive values ranging from 0% in the interdomain linker of SCN5A to 100% in the transmembrane/linker/pore regions of KCNH2. The estimated predictive value is also high in the linker, pore, transmembrane, and C terminus of KCNQ1 and the transmembrane/linker of SCN5A. Conclusions— Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic-specific background rates are critical factors in predicting the pathogenicity of novel mutations. Novel mutations in low–estimated predictive value regions such as the interdomain linker of SCN5A should be viewed as variants of uncertain significance and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the transmembrane, linker, and pore of KCNQ1 and KCNH2 may be defined confidently as high-probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.

ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy

Steven R. Bailey, MD, FACC, FSCAI, FAHA, Moderator Andrea M. Russo, MD, FACC, FHRS, Writing Group Liaison [⁎][1] Suraj Kapa, MD, Writing Group Liaison Michael B. Alexander, MD, FACC[§][2] Steven R. Bailey, MD, FACC, FSCAI, FAHA[∥][3] Ulrika Birgersdotter-Green, MD, FHRS[∥][3] Alan S.

Psychopathology in patients with ICDs over time: results of a prospective study.

Introduction: The effects of implantable cardioverter defibrillators (ICDs) and ICD shocks on psychological state have previously been studied. However, it is still unclear how health‐related quality‐of‐life changes over time using standardized assessments. We sought to characterize the effects of ICDs and ICD shocks on psychological outcomes.

The autonomic nervous system in cardiac electrophysiology: An elegant interaction and emerging concepts

The autonomic nervous system plays an integral role in the modulation of normal cardiac electrophysiology. This is achieved via a complex network of pre- and postganglionic sympathetic and parasympathetic fibers that synapse on extrinsic and intrinsic cardiac ganglia and ultimately directly innervate cardiac myocytes. Alterations in autonomic tone may induce changes in local cellular electrophysiology that may manifest clinically in a number of ways, ranging from changes in heart rate to changes in heart rhythm. These relationships between autonomic tone and the evolution of cardiac dysrhythmias are areas of evolving research, with increasing evidence for a key role for autonomic ganglia in the pathogenesis of atrial fibrillation and sympathetic nerves in the predilection toward ventricular tachycardia in areas of myocardial scar. In this review, we highlight what is known about the anatomy and physiology of the cardiac autonomic nervous system, the evidence supporting the relationship of autonomic tone to clinically significant arrhythmias, and a variety of mechanisms (eg, direct ion channel effects) and diagnostic tools that exist to help define this relationship. Further emphasized are potential future avenues of research needed to elucidate the relationship between changes in normal autonomic tone and the pathogenesis of cardiac arrhythmias.

ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance.

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Relevance of Endocavitary Structures in Ablation Procedures for Ventricular Tachycardia

Endocavitary Structures and Ventricular Tachycardia Ablation. Background: Radiofrequency (RF) ablation for ventricular tachycardia (VT) has high failure rates. Whether endocavitary structures (ECS) such as the papillary muscles (PMs), moderator bands (MBs), or false tendons (FTs) impact VT ablation is unknown.

Complication Risk with Pulse Generator Change: Implications When Reacting to a Device Advisory or Recall

Background: Recent advisories and recalls of pacemakers and implantable cardioverter‐defibrillators (ICDs) have highlighted the need for evidence‐based recommendations regarding management of patients with advisory devices. In order to better facilitate decision‐making when weighing the relative risks and benefits of performing generator changes in these patients, we conducted a review to assess operative complication rates.

Sleep Apnea and Hypertension: Interactions and Implications for Management

Obstructive sleep apnea (OSA) is highly prevalent in the United States, with an estimated 1 in 4 Americans at risk for OSA. In recent years, there has been a large body of work assessing the role of OSA as an independent risk factor for hypertension. Certain patient characteristics, such as age and the type of elevated blood pressure, may confer increased likelihood that the hypertension is secondary to underlying sleep apnea. Furthermore, early diagnosis and treatment of OSA may be beneficial in the management of hypertensive patients, particularly in those with poorly controlled hypertension. The focus of this brief review is on recent developments in the characteristics and treatment of sleep apnea-associated hypertension. Because of space limitations, only limited references are provided. The seventh report of the Joint National Committee identified OSA as an important identifiable cause of hypertension. As many as half of all patients with sleep apnea may have underlying hypertension, and many patients with hypertension, particularly resistant hypertension, may have OSA. In fact, there seems to be an interaction between OSA severity and resistance to antihypertensive medications.1 Elevated nocturnal blood pressure and reduced blood pressure “dipping” during sleep also suggest a higher likelihood of underlying sleep apnea, even in normotensive patients. Whether hypertension contributes to OSA remains unknown. OSA patients may not always exhibit elevated systolic pressures but may have a high prevalence of isolated diastolic hypertension.2–4 One study suggested that there was a significant association between the incidence of combined systolic and diastolic hypertension and the presence of sleep apnea in younger patients (<60 years of age) but not in older patients,5 and no significant association was seen between isolated systolic hypertension and sleep apnea in either age group. These studies suggest that the type of hypertension may need to be considered when …

Correlative anatomy for the electrophysiologist, part II: cardiac ganglia, phrenic nerve, coronary venous system.

Cardiac Ganglia, Phrenic Nerve, Coronary Venous System. There is an increasing need for invasive electrophysiologists to appreciate the exact anatomy of the epicardial space and the coronary veins. The location of the epicardial fat, the complementary relationship with the main cardiac veins, and the location of sensitive structures (arteries, phrenic nerve, esophagus) have become required knowledge for electrophysiologists, and accessing the epicardial space with this thorough knowledge of the pericardial sinuses and recesses is essential to allow radiographic correlation during catheter manipulation. In this review, we briefly describe the anatomy of the pericardial space and then discuss the specific correlation for the invasive electrophysiologist, highlighting epicardial access, catheter navigation, and avoidance of collateral injury, with specific attention to the important recesses of the pericardial space, their regional anatomy, and radiographic correlation when navigating catheters to these locations. We also discuss the anatomy of the main cardiac veins in the context of catheter mapping and ablation of the epicardial substrate through the venous system and without subxiphoid pericardial access. In part II of this series we discuss the detailed regional anatomy of the cardiac ganglia, phrenic nerve, and coronary venous system. (J Cardiovasc Electrophysiol, Vol. 22, pp. 104‐110, January 2011)

Sleep Apnea and Atrial Fibrillation. The Autonomic Link

The intuitive and postulated links ([1,2][1]) between the established association of obstructive sleep apnea with atrial fibrillation (AF) are hypertension, diastolic dysfunction, and the resultant long-term atrial remodeling ([3–6][2]). However, studies suggest that the relationship between sleep