Michael H. Gollob

Systematic Assessment of Patients With Unexplained Cardiac Arrest Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)

Background— Cardiac arrest without evident cardiac disease may be caused by subclinical genetic conditions. Provocative testing to unmask a phenotype is often necessary to detect primary electrical disease, direct genetic testing, and perform family screening. Methods and Results— Patients with apparently unexplained cardiac arrest and no evident cardiac disease (normal cardiac function on echocardiogram, no evidence of coronary artery disease, and a normal ECG) underwent systematic evaluation that included cardiac magnetic resonance imaging, signal-averaged ECG, exercise testing, drug challenge, and selective electrophysiological testing. Diagnostic criteria were based on accepted criteria or provocation of the characteristic clinical features for long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, early repolarization, arrhythmogenic right ventricular cardiomyopathy, coronary spasm, and myocarditis. Sixty-three patients in 9 centers were enrolled (age 43.0±13.4 years, 29 women). A diagnosis was obtained in 35 patients (56%): Long-QT syndrome in 8, catecholaminergic polymorphic ventricular tachycardia in 8, arrhythmogenic right ventricular cardiomyopathy in 6, early repolarization in 5, coronary spasm in 4, Brugada syndrome in 3, and myocarditis in 1. Targeted genetic testing demonstrated evidence of causative mutations in 9 (47%) of 19 patients. Screening of 64 family members of these patients identified 15 affected individuals who were treated (24%). The remaining 28 patients (44%) were considered to have idiopathic ventricular fibrillation. Conclusions— Systematic clinical testing, including drug provocation and advanced imaging, results in unmasking of the cause of apparently unexplained cardiac arrest in >50% of patients. This approach assists in directing genetic testing to diagnose genetically mediated arrhythmia syndromes, which results in successful family screening.

Clinical ResearchHeart Rhythm DisorderThe Short QT Syndrome: Proposed Diagnostic Criteria

OBJECTIVES We aimed to develop diagnostic criteria for the short QT syndrome (SQTS) to facilitate clinical evaluation of suspected cases. BACKGROUND The SQTS is a cardiac channelopathy associated with atrial fibrillation and sudden cardiac death. Ten years after its original description, a consensus regarding an appropriate QT interval cutoff and specific diagnostic criteria have yet to be established. METHODS The MEDLINE database was searched for all reported cases of SQTS in the English language, and all relevant data were extracted. The distribution of QT intervals and electrocardiographic (ECG) features in affected cases were analyzed and compared to data derived from ECG analysis from general population studies. RESULTS A total of 61 reported cases of SQTS were identified. Index events, including sudden cardiac death, aborted cardiac arrest, syncope, and/or atrial fibrillation occurred in 35 of 61 (57.4%) cases. The cohort was predominantly male (75.4%) and had a mean QT(c) value of 306.7 ms with values ranging from 248 to 381 ms in symptomatic cases. In reference to the ECG characteristics of the general population, and in consideration of clinical presentation, family history, and genetic findings, a highly sensitive diagnostic scoring system was developed. CONCLUSIONS Based on a comprehensive review of 61 reported cases of the SQTS, formal diagnostic criteria have been proposed that will facilitate diagnostic evaluation in suspected cases of SQTS. Diagnostic criteria may lead to a greater recognition of this condition and provoke screening of at-risk family members.

Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands

Background— Genetic testing can diagnose long-QT syndrome (LQTS) in asymptomatic relatives of patients with an identified mutation; however, it is costly and subject to availability. The accuracy of a simple algorithm that incorporates resting and exercise ECG parameters for screening LQTS in asymptomatic relatives was evaluated, with genetic testing as the gold standard. Methods and Results— Asymptomatic first-degree relatives of genetically characterized probands were recruited from 5 centers. QT intervals were measured at rest, during exercise, and during recovery. Receiver operating characteristics were used to establish optimal cutoffs. An algorithm for identifying LQTS carriers was developed in a derivation cohort and validated in an independent cohort. The derivation cohort consisted of 69 relatives (28 with LQT1, 20 with LQT2, and 21 noncarriers). Mean age was 35±18 years, and resting corrected QT interval (QTc) was 466±39 ms. Abnormal resting QTc (females ≥480 ms; males ≥470 ms) was 100% specific for gene carrier status, but was observed in only 48% of patients; however, mutations were observed in 68% and 42% of patients with a borderline or normal resting QTc, respectively. Among these patients, 4-minute recovery QTc ≥445 ms correctly restratified 22 of 25 patients as having LQTS and 19 of 21 patients as being noncarriers. The combination of resting and 4-minute recovery QTc in a screening algorithm yielded a sensitivity of 0.94 and specificity of 0.90 for detecting LQTS carriers. When applied to the validation cohort (n=152; 58 with LQT1, 61 with LQT2, and 33 noncarriers; QTc=443±47 ms), sensitivity was 0.92 and specificity was 0.82. Conclusions— A simple algorithm that incorporates resting and exercise-recovery QTc is useful in identifying LQTS in asymptomatic relatives.

prkag2 cardiac syndrome: familial ventricular preexcitation, conduction system disease, and cardiac hypertrophy

Genetic studies of families with inherited cardiac rhythm disturbances have established a molecular basis for ventricular arrhythmogenic disorders. Genes responsible for the long QT syndrome, Brugada syndrome, and polymorphic ventricular tachycardia have been identified. The elucidation of genetic defects responsible for more commonly occurring supraventricular rhythm disturbances have not been as forthcoming, with the exception of SCN5A mutations known to cause conduction system disease. Recently, we identified the genetic cause of a familial arrhythmogenic syndrome characterized by ventricular preexcitation and tachyarrhythmias (Wolff–Parkinson–White syndrome), progressive conduction system disease, and cardiac hypertrophy. The causative gene was shown to be the &ggr;-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase. The role of AMP-activated protein kinase in the regulation of the glucose metabolic pathway in muscle suggests that genetic defects in PRKAG2 may induce a previously undescribed cardiac glycogenosis syndrome.

Use of implantable cardioverter defibrillators in Canadian and US survivors of out-of-hospital cardiac arrest

Background: Cardiac arrest due to ventricular arrhythmia in the absence of a reversible cause or contraindication has been a class I indication for insertion of an implantable cardioverter defibrillator since 1998. We compared and contrasted the use of implantable cardioverter defibrillator therapy in Canada and the United States among adults who survived a cardiac arrest. Method: Data on hospital separations from April 1, 1994 through March 31, 2003 were obtained from the Health Person-Oriented Information Database maintained by Statistics Canada and from the US National Hospital Discharge Survey on all patients with a primary diagnosis of cardiac arrest, ventricular fibrillation or ventricular flutter for the same 9-year period. We excluded all records of patients with a secondary diagnosis of acute myocardial infarction. Results: In Canada, 3793 patients survived to discharge after a cardiac arrest; 628 (16.6%) of these were implanted with a cardioverter defibrillator before discharge. The implant rate rose steadily from 5.4% in 1994/95 to 26.7% in 2002/03. In the United States, 23 688 (30.2%) of 78 538 such survivors received an implantable cardioverter defibrillator before discharge. Logistic regression analysis indicated that sex, age, fiscal year, the hospitals teaching status, hospital size and patient history of heart failure were positive predictors of implantable cardioverter defibrillator implantation. Age, renal failure, liver failure and cancer were negative predictors of receiving an implantable cardioverter defibrillator. Interpretation: The rate of use of implantable cardioverter defibrillator therapy for cardiac arrest survivors in Canada is increasing, but still is lower than the rate in the United States.

Evaluation of Genes Encoding for the Transient Outward Current (Ito) Identifies the KCND2 Gene as a Cause of J-Wave Syndrome Associated With Sudden Cardiac Death

Background—J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (Ito)-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the Ito in patients with J waves on ECG. Methods and Results—Comprehensive mutational analysis was performed on Ito-encoding KCNA4, KCND2, and KCND3 genes, as well as the previously described J-wave–associated KCNJ8 gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome. Only patients with a resuscitated cardiac arrest or type 1 Brugada ECG pattern were included for analysis. A rare genetic mutation of the KCND2 gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type KCND2 with KChIP2 in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak Ito density of 48% (P<0.05) in the heterozygous state. Using computer modeling, this increase in Ito resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural Ito gradient. The previously described KCNJ8-S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome. Conclusions—These findings are the first to implicate the KCND2 gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in Ito-encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.

Cardiac connexins as candidate genes for idiopathic atrial fibrillation.

Purpose of review Atrial fibrillation is the most common sustained cardiac arrhythmia and may cause significant morbidity. Current management strategies offer only modest success and may be associated with intolerable drug side effects or risk of procedural complications. As with other cardiac arrhythmias, the identification of genetic determinants predisposing to atrial fibrillation may provide novel molecular targets for drug development. This review discusses the role of cardiac connexins in the heart and suggests that genetic defects in cardiac connexins may predispose to arrhythmia vulnerability. Recent findings Animal models deficient in cardiac connexins demonstrate abnormalities in myocardial tissue conduction and vulnerability to re-entrant arrhythmias, including ventricular tachycardia and atrial fibrillation. Atrial tissue analyses from human patients with atrial fibrillation consistently demonstrate alterations in connexin distribution and protein levels, suggesting a role of connexins in the perpetuation of the arrhythmia. Most recently, genetic studies of Cx43 and Cx40 indicate that genetic variations in these genes may predispose to arrhythmia vulnerability in humans. Summary Current data support the critical role of cardiac connexins in mediating coordinated electrical activation and conduction through myocardial tissue. Alterations in the tissue distribution or function of cardiac connexins may predispose to cardiac arrhythmias, supporting a previously proposed hypothesis that cardiac connexins should be considered a major therapeutic target in the management of atrial fibrillation.

Outcome of Apparently Unexplained Cardiac Arrest: Results From Investigation and Follow-Up of the Prospective Cardiac Arrest Survivors With Preserved Ejection Fraction Registry

Background—The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) enrolls patients with apparently unexplained cardiac arrest and no evident cardiac disease to identify the pathogenesis of cardiac arrest through systematic clinical testing. Exercise testing, drug provocation, advanced cardiac imaging, and genetic testing may be useful when a cause is not apparent. Methods and Results—The first 200 survivors of unexplained cardiac arrest from 14 centers across Canada were evaluated to determine the results of investigation and follow-up (age, 48.6±14.7 years, 41% female). Patients were free of evidence of coronary artery disease, left ventricular dysfunction, or evident repolarization syndromes. Advanced testing determined a diagnosis in 34% of patients at baseline, with a diagnosis emerging during follow-up in 7% of patients. Of those who were diagnosed, 28 (35%) had an underlying structural condition and 53 (65%) had a primary electric disease. During a mean follow-up of 3.15±2.34 years, 23% of patients had either a shock or an appropriate antitachycardia pacing from their implantable cardioverter defibrillator, or both. The implantable cardioverter defibrillator appropriate intervention rate was 8.4% at 1 year and 18.1% at 3 years, with no clear difference between diagnosed and undiagnosed subjects, or between those diagnosed with a primary electric versus structural pathogenesis. Conclusions—Obtaining a diagnosis in previously unexplained cardiac arrest patients requires systematic clinical testing and regular follow-up to unmask the cause. Nearly half of apparently unexplained cardiac arrest patients ultimately received a diagnosis, allowing for improved treatment and family screening. A substantial proportion of patients received appropriate implantable cardioverter defibrillator therapy during medium-term follow-up. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00292032.

A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation

Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.

Clinical trials, the renin angiotensin system and atrial fibrillation

Purpose of review Atrial fibrillation is the most common clinical arrhythmia. Current treatment strategies are far from optimal. One new research direction is to target the atrial fibrillation substrate and to examine whether drugs can produce atrial structural and/or electrophysiological remodeling and whether this results in a reduction in atrial fibrillation burden. Recent findings Two prospective randomized studies have shown that the addition of an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker to amiodarone reduces the recurrence rate of atrial fibrillation after electrical cardioversion. There are ten completed prospective clinical trials with atrial fibrillation as a secondary endpoint or assessed in post-hoc analysis. Five of these studies have reported a positive impact of angiotensin converting enzyme inhibitors or angiotensin receptor blockers on atrial fibrillation burden. A meta-analysis showed that active drugs reduced the overall risk of development of atrial fibrillation by 28%. Patients in the heart failure trials obtained most benefit from these drugs (relative risk reduction 44%, P = 0.07). Summary The initial basic science and clinical trial data suggest that modulation of the renin angiotensin system may be an effective treatment for atrial fibrillation. The following, however, remain to be clarified: do these drugs have a clinically meaningful impact on atrial fibrillation burden; if there is an impact, is it similar in all atrial fibrillation patients or just in certain subsets; do angiotensin converting enzyme inhibitors and angiotensin receptor blockers have similar benefits; and is there a role for aldosterone antagonists?