Vijay S. Chauhan

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.

Left atrial linear lesions are required for successful treatment of persistent atrial fibrillation

AIMS This study evaluates the clinical outcome and incidence of left atrial (LA) macro re-entrant atrial tachycardia (AT) in patients in whom persistent atrial fibrillation (AF) terminated during catheter ablation without the need of roof and mitral lines. METHODS AND RESULTS Persistent AF was terminated by ablation in 154 of 180 consecutive patients. AF history was 60 months including 11 months of continuous AF. Patients were divided into two groups: those who had not required both LA linear lesions to terminate AF (group A, 85 patients), and those who had (group B, 69 patients). There was no difference in clinical and echocardiographic characteristics between both groups except for a shorter duration of continuous AF in group A (9 vs.12 months, respectively) (P = 0.03). After 28 months of follow-up, the incidence of LA macro re-entrant AT necessitating linear ablation was higher in group A (76%) compared with group B (33%) (P = 0.002). When complete linear block could not be achieved during the index procedure, the incidence of subsequent roof (P = 0.008) or mitral isthmus (P = 0.010) dependent macro re-entrant AT was higher. CONCLUSION Although persistent AF can be terminated by catheter ablation without linear lesions, the majority will require linear lesions for macro re-entrant AT.

Prevalence and Characteristics of Early Repolarization in the CASPER Registry Cardiac Arrest Survivors With Preserved Ejection Fraction Registry

OBJECTIVES We evaluated the prevalence and characteristics of early repolarization in patients in CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry). BACKGROUND Early repolarization has been implicated in a syndrome of polymorphic ventricular tachycardia and fibrillation in patients without organic heart disease. METHODS One hundred patients with apparently unexplained cardiac arrest and preserved ejection fraction underwent extensive clinical and genetic testing to unmask subclinical electrical or structural disease. A blinded independent analysis of the 12-lead electrocardiogram (ECG) was performed. Early repolarization was defined as ≥0.1 mV QRS-ST junction (J-point) elevation with terminal QRS slurring or notching in at least 2 contiguous inferior and/or lateral leads. RESULTS One hundred cardiac arrest patients were enrolled (40 females, age 43 ± 14 years). Forty-four were diagnosed with an established cause for cardiac arrest. Significant early repolarization was found in 19 patients, including 6 with a primary diagnosis that explained their cardiac arrest (14%), compared with 23% of the 56 patients with idiopathic ventricular fibrillation (IVF) (p = 0.23). J-point elevation in IVF patients had higher amplitude (0.25 ± 0.11 mV vs. 0.13 ± 0.05 mV, p = 0.02) and wider distribution (4.3 ± 1.3 leads vs. 2.8 ± 0.8 leads; p = 0.01) than those with an established cause of cardiac arrest. J-wave amplitude was fluctuant on serial ECGs; at least 1 ECG failed to demonstrate early repolarization in 58% of patients. CONCLUSIONS Early repolarization is present in a significant proportion of causally diagnosed and idiopathic VF. It is often intermittent and more pronounced in IVF patients. (Registry of Unexplained Cardiac Arrest; NCT00292032).

Outcome of intra-atrial re-entrant tachycardia catheter ablation in adults with congenital heart disease: negative impact of age and complex atrial surgery.

OBJECTIVES The aim of this study was to determine the acute and long-term outcome of radiofrequency catheter ablation (RFCA) for intra-atrial re-entrant tachycardia (IART) in adults with congenital heart disease (CHD), and predictors of these outcomes. BACKGROUND Atrial myopathy can be progressive in CHD and contributes to the substrate for IART. Although the outcome of RFCA for IART has been well described in children and adolescents with CHD, it is unclear whether these results are similar in the adult population. METHODS Clinical records of adults with CHD undergoing attempted RFCA of IART were analyzed retrospectively. Multivariate analyses identified clinical and procedural factors that predicted acute and long-term outcomes. RESULTS A total of 193 procedures was performed in 130 patients (mean age 40 ± 13 years); 82 of 118 (69%) initially attempted RFCA were successful, defined as termination of all IART circuits. The use of electroanatomic mapping was associated with a successful RFCA, whereas Fontan palliation and Mustard repair were associated with an unsuccessful RFCA. Median clinical follow-up of 77 patients (≥2 months of follow-up) after a successful RFCA was 3.7 years (range 0.2 to 10.2 years). IART recurrence was noted in 48%, cardioversion/reablation in 42%, and death in 4%. Older age and Fontan palliation were independent predictors of IART recurrence. CONCLUSIONS In adults with CHD, acute and long-term outcomes of RFCA for IART are similar to those reported for younger cohorts. Complex atrial surgery limits the success of RFCA, and older age is associated with a higher risk of IART recurrence.

Localized rotational activation in the left atrium during human atrial fibrillation: Relationship to complex fractionated atrial electrograms and low-voltage zones

BACKGROUND In humans, the existence of rotors or reentrant sources maintaining atrial fibrillation (AF) and the underlying electroanatomic substrate has not been well defined. OBJECTIVE Our aim was to determine the prevalence of localized rotational activation (RotA) in the left atrium (LA) during human AF and whether complex fractionated atrial electrograms (CFAEs) or low-voltage areas colocalize with RotA sites. METHODS We prospectively studied 32 patients (mean age 57 ± 8 years; 88% with persistent AF) undergoing AF catheter ablation. Bipolar electrograms were recorded for 2.5 seconds during AF using a roving 20-pole circular catheter in the LA. RotA was defined as sequential temporal activation of bipoles around the circular catheter. Bipolar electrogram fractionation index and bipolar voltage were used to define CFAEs and low-voltage areas, respectively. RESULTS In 21 (66%) patients, 47 RotA sites were identified. Few (9%) lasted 2.5 seconds (cycle length 183 ± 6 ms), while the majority (91%) were nonsustained (duration 610 ± 288 ms; cycle length 149 ± 11 ms). RotA was most common in the pulmonary vein antrum (71%) and posterior LA (25%). CFAEs were recorded from 18% ± 12% of LA area, and most (92% ± 7%) were not associated with RotA sites. However, 85% of RotA sites contained CFAEs. Very low voltage (<0.1 mV) areas comprised 12% ± 10% of LA area and were present in 23% of RotA sites. CONCLUSIONS In patients with predominantly persistent AF, localized RotA is commonly present but tends to be transient (<1 second). Although most CFAEs do not colocalize with RotA sites, the high prevalence of CFAEs and very low voltages within RotA sites may indicate slow conduction in diseased myocardium necessary for their maintenance.

Role of KATP Channels in the Maintenance of Ventricular Fibrillation in Cardiomyopathic Human Hearts

Rationale: Ventricular fibrillation (VF) leads to global ischemia. The modulation of ischemia-dependent pathways may alter the electrophysiological evolution of VF. Objective: We addressed the hypotheses that there is regional disease-related expression of KATP channels in human cardiomyopathic hearts and that KATP channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness. Methods and Results: In a human Langendorff model, electric mapping of 6 control and 9 treatment (10 &mgr;mol/L glibenclamide) isolated cardiomyopathic hearts was performed. Spontaneous defibrillation was studied and mean VF cycle length was compared regionally at VF onset and after 180 seconds between control and treatment groups. KATP subunit gene expression was compared between LV endocardium versus epicardium in myopathic hearts. Spontaneous VF termination occurred in 1 of 6 control hearts and 7 of 8 glibenclamide-treated hearts (P=0.026). After 180 seconds of ischemia, a transmural dispersion in VF cycle length was observed between epicardium and endocardium (P=0.001), which was attenuated by glibenclamide. There was greater gene expression of all KATP subunit on the endocardium compared with the epicardium (P<0.02). In an ischemic rat heart model, transmural dispersion of refractoriness (&Dgr;ERPTransmural=ERPEpicardium−ERPEndocardium) was verified with pacing protocols. &Dgr;ERPTransmural in control was 5±2 ms and increased to 36±5 ms with ischemia. This effect was greatly attenuated by glibenclamide (&Dgr;ERPTransmural for glibenclamide+ischemia=4.9±4 ms, P=0.019 versus control ischemia). Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation in cardiomyopathic human hearts by attenuating the ischemia-dependent spatiotemporal heterogeneity of refractoriness during early VF.

Identifying High Risk in Adults With Congenital Heart Disease and Atrial Arrhythmias

Atrial arrhythmias are associated with an increased mortality risk in adults with congenital heart disease (CHD). However, little is known about risk stratification in the specific group of adult patients with CHD and atrial arrhythmias. We sought to identify predictors of mortality in adult with CHD and atrial arrhythmias and to establish a risk score. The study involved 378 adult patients with CHD (mean age 39 ± 13 years) and atrial arrhythmias who had serial follow-up in a tertiary referral center from 1999 through 2009. During a median follow-up of 5.2 years, there were 40 deaths (11%). Overall mortality rate was 2.0% per patient-year. Common modes of death included heart failure-related death (35%), sudden cardiac death (20%), and perioperative death (18%). Independent predictors of mortality were poor functional class (hazard ratio 3.69, 95% confidence interval [CI] 1.69 to 8.03, p = 0.001), single-ventricle physiology (hazard ratio 3.33, 95% CI 1.51 to 7.35, p = 0.003), pulmonary hypertension (hazard ratio 2.96, 95% CI 1.41 to 6.19, p = 0.004), and valvular heart disease (hazard ratio 2.73, 95% CI 1.33 to 5.59, p = 0.006). A risk score was constructed using these predictors in which patients were assigned 1 point for the presence of each risk factor. Mortality rates in the low-risk (no risk factor), moderate-risk (1 risk factor), and high-risk (>1 risk factor) groups were 0.5%, 1.9%, and 6.5% per patient-year, respectively (log-rank p <0.001). In conclusion, in adult with CHD and atrial arrhythmias specific clinical variables identify patients at high risk for death. Importantly, the absence of any of these risk factors is associated with an excellent survival despite the presence of atrial arrhythmias.

Evolving Electroanatomic Substrate and Intra-Atrial Reentrant Tachycardia Late After Fontan Surgery

Atrial Remodeling After the Fontan Operation.

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.

Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden death: from the cardiac arrest survivors with preserved Ejection Fraction Registry.

Background—Epinephrine infusion may unmask latent genetic conditions associated with cardiac arrest, including long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia (VT). Methods and Results—Patients with unexplained cardiac arrest (normal left ventricular function and QT interval) and selected family members from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) registry underwent epinephrine challenge at doses of 0.05, 0.10, and 0.20 &mgr;g/kg per minute. A test was considered positive for long-QT syndrome if the absolute QT interval prolonged by ≥30 ms at 0.10 &mgr;g/kg per minute and borderline if QT prolongation was 1 to 29 ms. Catecholaminergic polymorphic VT was diagnosed if epinephrine provoked ≥3 beats of polymorphic or bidirectional VT and borderline if polymorphic couplets, premature ventricular contractions, or nonsustained monomorphic VT was induced. Epinephrine infusion was performed in 170 patients (age, 42±16 years; 49% men), including 98 patients with unexplained cardiac arrest. Testing was positive for long-QT syndrome in 31 patients (18%) and borderline in 24 patients (14%). Exercise testing provoked an abnormal QT response in 42% of tested patients with a positive epinephrine response. Testing for catecholaminergic polymorphic VT was positive in 7% and borderline in 5%. Targeted genetic testing of abnormal patients was positive in 17% of long-QT syndrome patients and 13% of catecholaminergic polymorphic VT patients. Conclusions—Epinephrine challenge provoked abnormalities in a substantial proportion of patients, most commonly a prolonged QT interval. Exercise and genetic testing replicated the diagnosis suggested by the epinephrine response in a small proportion of patients. Epinephrine infusion combined with exercise testing and targeted genetic testing is recommended in the workup of suspected familial sudden death syndromes. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00292032.Background— Epinephrine infusion may unmask latent genetic conditions associated with cardiac arrest, including long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia (VT). Methods and Results— Patients with unexplained cardiac arrest (normal left ventricular function and QT interval) and selected family members from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) registry underwent epinephrine challenge at doses of 0.05, 0.10, and 0.20 μg/kg per minute. A test was considered positive for long-QT syndrome if the absolute QT interval prolonged by ≥30 ms at 0.10 μg/kg per minute and borderline if QT prolongation was 1 to 29 ms. Catecholaminergic polymorphic VT was diagnosed if epinephrine provoked ≥3 beats of polymorphic or bidirectional VT and borderline if polymorphic couplets, premature ventricular contractions, or nonsustained monomorphic VT was induced. Epinephrine infusion was performed in 170 patients (age, 42±16 years; 49% men), including 98 patients with unexplained cardiac arrest. Testing was positive for long-QT syndrome in 31 patients (18%) and borderline in 24 patients (14%). Exercise testing provoked an abnormal QT response in 42% of tested patients with a positive epinephrine response. Testing for catecholaminergic polymorphic VT was positive in 7% and borderline in 5%. Targeted genetic testing of abnormal patients was positive in 17% of long-QT syndrome patients and 13% of catecholaminergic polymorphic VT patients. Conclusions— Epinephrine challenge provoked abnormalities in a substantial proportion of patients, most commonly a prolonged QT interval. Exercise and genetic testing replicated the diagnosis suggested by the epinephrine response in a small proportion of patients. Epinephrine infusion combined with exercise testing and targeted genetic testing is recommended in the workup of suspected familial sudden death syndromes. Clinical Trial Registration— URL: . Unique identifier: [NCT00292032][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00292032&atom=%2Fcircae%2F5%2F5%2F933.atom