Paul Khairy

Catheter Ablation for Atrial Fibrillation Are Results Maintained at 5 Years of Follow-Up?

OBJECTIVES This study describes 5-year follow-up results of catheter ablation for atrial fibrillation (AF). BACKGROUND Long-term efficacy following catheter ablation of AF remains unknown. METHODS A total of 100 patients (86 men, 14 women), age 55.7 ± 9.6 years, referred to our center for a first AF ablation (63% paroxysmal; 3.5 ± 1.4 prior ineffective antiarrhythmic agents) were followed for 5 years. Complete success was defined as absence of any AF or atrial tachycardia recurrence (clinical or by 24-h Holter monitoring) lasting ≥ 30 s. RESULTS Arrhythmia-free survival rates after a single catheter ablation procedure were 40%, 37%, and 29% at 1, 2, and 5 years, respectively, with most recurrences over the first 6 months. Patients with long-standing persistent AF experienced a higher recurrence rate than those with paroxysmal or persistent forms (hazard ratio [HR]: 1.9, 95% confidence interval [CI]: 1.0 to 3.5; p = 0.0462). In all, 175 procedures were performed, with a median of 2 per patient. Arrhythmia-free survival following the last catheter ablation procedure was 87%, 81%, and 63% at 1, 2, and 5 years, respectively. Valvular heart disease (HR: 6.0, 95% CI: 2.0 to 17.6; p = 0.0012) and nonischemic dilated cardiomyopathy (HR: 34.0, 95% CI: 6.3 to 182.1; p < 0.0001) independently predicted recurrences. Major complications (cardiac tamponade requiring drainage) occurred in 3 patients (3%). CONCLUSIONS In selected patients with AF, a catheter ablation strategy with repeat intervention as necessary provides acceptable long-term relief. Although most recurrences transpire over the first 6 to 12 months, a slow but steady decline in arrhythmia-free survival is noted thereafter.

Catheter Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation The A4 Study

Background— The mainstay of treatment for atrial fibrillation (AF) remains pharmacological; however, catheter ablation has increasingly been used over the last decade. The relative merits of each strategy have not been extensively studied. Methods and Results— We conducted a randomized multicenter comparison of these 2 treatment strategies in patients with paroxysmal AF resistant to at least 1 antiarrhythmic drug. The primary end point was absence of recurrent AF between months 3 and 12, absence of recurrent AF after up to 3 ablation procedures, or changes in antiarrhythmic drugs during the first 3 months. Ablation consisted of pulmonary vein isolation in all cases, whereas additional extrapulmonary vein lesions were at the discretion of the physician. Crossover was permitted at 3 months in case of failure. Echocardiographic data, symptom score, exercise capacity, quality of life, and AF burden were evaluated at 3, 6, and 12 months by the supervising committee. Of 149 eligible patients, 112 (18 women [16%]; age, 51.1±11.1 years) were enrolled and randomized to ablation (n=53) or “new” antiarrhythmic drugs alone or in combination (n=59). Crossover from the antiarrhythmic drugs and ablation groups occurred in 37 (63%) and 5 patients (9%), respectively (P=0.0001). At the 1-year follow-up, 13 of 55 patients (23%) and 46 of 52 patients (89%) had no recurrence of AF in the antiarrhythmic drug and ablation groups, respectively (P<0.0001). Symptom score, exercise capacity, and quality of life were significantly higher in the ablation group. Conclusion— This randomized multicenter study demonstrates the superiority of catheter ablation over antiarrhythmic drugs in patients with AF with regard to maintenance of sinus rhythm and improvement in symptoms, exercise capacity, and quality of life.

Long-Term Survival, Modes of Death, and Predictors of Mortality in Patients With Fontan Surgery

Background— To better define determinants of mortality in patients with univentricular physiology, a database registry was created of patients born in 1985 or earlier with Fontan surgery who were followed up at Children’s Hospital Boston. Methods and Results— A total of 261 patients, 121 of whom (46.4%) were women, had a first Fontan surgery at a median age of 7.9 years: right atrium–to–pulmonary artery connection in 135 (51.7%); right atrium to right ventricle in 25 (9.6%); and total cavopulmonary connection in 101 (38.7%). Over a median of 12.2 years, 76 (29.1%) died, 5 (1.9%) had cardiac transplantation, 5 (1.9%) had Fontan revision, and 21 (8.0%) had Fontan conversion. Perioperative mortality decreased steadily over time and accounted for 68.4% of all deaths. In early survivors, actuarial freedom from death or transplantation was 93.7%, 89.9%, 87.3%, and 82.6% at 5, 10, 15, and 20 years, respectively, with no significant difference between right atrium to pulmonary artery versus total cavopulmonary connection. Late deaths were classified as sudden in 7 patients (9.2%), thromboembolic in 6 (7.9%), heart failure–related in 5 (6.7%), sepsis in 2 (2.6%), and other in 4 (5.2%). Most sudden deaths were of presumed arrhythmic origin with no identifiable predictor. Independent risk factors for thromboembolic death were lack of antiplatelet or anticoagulant therapy (hazard ratio [HR], 91.6; P=0.0041) and clinically diagnosed intracardiac thrombus (HR, 22.7; P=0.0002). Independent predictors of heart failure death were protein-losing enteropathy (HR, 7.1; P=0.0043), single morphologically right ventricle (HR, 10.5; P=0.0429), and higher right atrial pressure (HR, 1.3 per 1 mm Hg; P=0.0016). Conclusion— In perioperative survivors of Fontan surgery, gradual attrition occurs predominantly from thromboembolic, heart failure–related, and sudden deaths.

Changing Mortality in Congenital Heart Disease

OBJECTIVES This study sought to characterize temporal trends in all-cause mortality in patients with congenital heart disease (CHD). BACKGROUND Historically, most deaths in patients with CHD occurred in early childhood. Notable advances have since been achieved that may impact on mortality trends. METHODS We conducted a population-based cohort study of patients with CHD in Quebec, Canada, from July 1987 to June 2005. A total of 8,561 deaths occurred in 71,686 patients with CHD followed for 982,363 patient-years. RESULTS The proportion of infant and childhood deaths markedly declined from 1987 to 2005, with a reduction in mortality that exceeded that of the general population. Distribution of age at death transitioned from a bimodal to unimodal, albeit skewed, pattern, more closely approximating the general population. Overall, mortality decreased by 31% (mortality rate ratio: 0.69, 95% confidence interval [CI]: 0.61 to 0.79) in the last (2002 to 2005) relative to the first (1987 to 1990) period of observation. Mortality rates decreased in all age groups below 65 years, with the largest reduction in infants (mortality rate ratio: 0.23, 95% CI: 0.12 to 0.47). In adults 18 to 64 years, the mortality reduction (mortality rate ratio: 0.84, 95% CI: 0.73 to 0.97) paralleled the general population. Gains in survival were mostly driven by reduced mortality in severe forms of CHD, particularly in children (mortality rate ratio: 0.33, 95% CI: 0.19 to 0.60), and were consistent across most subtypes. CONCLUSIONS Deaths in CHD have shifted away from infants and towards adults, with a steady increase in age at death and decreasing mortality.

Lower Incidence of Thrombus Formation With Cryoenergy Versus Radiofrequency Catheter Ablation

Background—Radiofrequency (RF) catheter ablation is limited by thromboembolic complications. The objective of this study was to compare the incidence and characteristics of thrombi complicating RF and cryoenergy ablation, a novel technology for the catheter-based treatment of arrhythmias. Methods and Results—Ablation lesions (n=197) were performed in 22 mongrel dogs at right atrial, right ventricular, and left ventricular sites preselected by a randomized factorial design devised to compare RF ablation with cryocatheter configurations of varying sizes (7F and 9F), cooling rates (−1°C/s, −5°C/s, and −20°C/s) and target temperatures (−55°C and −75°C). Animals were pretreated with acetylsalicylic acid and received intraprocedural intravenous unfractionated heparin. Seven days after ablation, the incidence of thrombus formation was significantly higher with RF than with cryoablation (75.8% versus 30.1%, P =0.0005). In a multiple regression model, RF energy remained an independent predictor of thrombus formation compared with cryoenergy (OR, 5.6; 95% CI, 1.7, 18.1;P =0.0042). Thrombus volume was also significantly greater with RF than with cryoablation (median, 2.8 versus 0.0 mm3;P <0.0001). More voluminous thrombi were associated with larger RF lesions, but cryolesion dimensions were not predictive of thrombus size. Conclusions—RF energy is significantly more thrombogenic than cryoenergy, with a higher incidence of thrombus formation and larger thrombus volumes. The extent of hyperthermic tissue injury is positively correlated with thrombus bulk, whereas cryoenergy lesion size does not predict thrombus volume, most likely reflecting intact tissue ultrastructure with endothelial cell preservation.

Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review.

Despite extensive evaluation, the cause of ischemic stroke remains undefined in approximately 40% of patients (1-4). Passage of thromboemboli from the right to left atrium across a patent foramen ovale, a remnant of the fetal circulation, has been postulated as a mechanism responsible for some of these cryptogenic strokes. Thrombus straddling a patent foramen ovale has been imaged on rare occasions (5-8). The association between patent foramen ovale and cryptogenic embolic stroke has been strengthened by epidemiologic studies that found a prevalence of patent foramen ovale of 44% to 66% in patients with cryptogenic stroke compared with 27% in autopsy series of all-cause death (2, 9-13). The most appropriate therapy to prevent recurrent events in survivors of cryptogenic stroke or transient ischemic attack with documented patent foramen ovale is unknown and controversial. Traditionally, a conservative strategy of long-term medical therapy with antiplatelet agents or oral anticoagulants has been used. However, much debate exists over which agent provides the most favorable riskbenefit ratio. Surgical closure of patent foramen ovale has been proposed, but outcomes have varied (14-16). In the past decade, closure by implantation of a transcatheter device has emerged as a feasible low-risk alternative therapeutic option, but comparative studies are lacking. We therefore performed a systematic review to synthesize the current state of knowledge on transcatheter closure of patent foramen ovale compared with medical therapy. Methods Literature Search and Study Selection Relevant articles published between January 1985 through July 2003 were identified through an electronic search of the MEDLINE database by using the following query terms: patent foramen ovale or persistent foramen ovale combined with stroke, embolism, embolus, embolization, cerebral, cerebrovascular, and closure. This strategy was supplemented by a manual search of secondary sources, including selected references from primary articles. Both English-language and foreign-language journals were examined. Unpublished data were not sought. In the absence of controlled trials, identified articles were systematically screened for the following inclusion criteria: a study cohort that had secondary prevention of neurologic thromboembolic events by medical management of patent foramen ovale or transcatheter device implantation; minimum of 10 patients per cohort; assessment and report of neurologic thromboembolic events; mean duration of follow-up of at least 12 months (because the primary outcome of interest was the 1-year rate of recurrent events); and actuarial freedom from recurrent neurologic thromboembolic events at 1 year, as recorded or calculated from sufficient data. When more than 1 article originating from the same center met the above criteria, the study that reported on the most patients was included and those with fewer patients were excluded to avoid duplication. Data Synthesis Study Identification We identified 236 articles, of which 20 met the prespecified inclusion criteria (Figure 1). Four studies with potentially overlapping samples were excluded. Thus, 16 articles including 2250 patients were reviewed: 10 studies (1355 patients) on transcatheter closure and 6 studies (895 patients) on medical management. Table 1 shows the details of individual studies. Figure 1. Study identification. Table 1. Baseline Characteristics Definitions All patients were treated for presumed paradoxical emboli associated with patent foramen ovale. When defined, patent foramen ovale was described as spontaneous or provocable right-to-left interatrial shunting on contrast echocardiography. The maximum number of cardiac cycles allowed after right atrial opacification when assessing contrast in the left atrium was 3 (17-20) or 5 (21). The threshold for the number of left atrial microbubbles that were considered significant was 1 (17, 20, 22, 23), 3 (18, 19, 24, 25), or 4 (21). The most common definition of an aneurysmal or hypermobile atrial septum was septal movement into the right or left atrium exceeding 10 mm (20, 22, 23, 25-27). Other definitions included membrane mobility of 6.5 mm or greater (18), 11 mm (19), or 15 mm (21, 28) or diameter of the mobile portion of septum primum greater than 13 mm (27) or 15 mm (21). The outcomes and means of their assessment were not uniform among studies. When defined, transient ischemic attack was characterized as a transient reversible neurologic defect confirmed by a neurologist that resolved completely within 12 hours (25) or 24 hours (18, 22-24, 28, 29). Stroke was defined as a clinically and neuroradiologically confirmed focal deficit persisting for more than 24 hours (18-20, 22-25, 28, 29). Rigor of follow-up and surveillance for end points differed among the reports and was often liberally described as standard neurologic care. Patient Characteristics Among patients undergoing transcatheter closure of patent foramen ovale, the mean age per study ranged from 40 12 years to 50 12 years. In contrast, medically treated patients had a mean age older than 50 years in 3 of 6 studies. Overall, one third to two thirds of patients in studies of transcatheter device closure were male, whereas all studies of medically managed patients that reported sex included more men than women. A tendency toward a higher prevalence of risk factors for atherosclerosis was noted in medically managed patients. In studies of transcatheter device closure that reported such risk factors, hypertension was documented in 10% to 28% of patients, diabetes in 0% to 7%, and smoking in 14% to 36%. In contrast, medically managed patients had prevalences of hypertension, diabetes, and smoking of 9% to 53%, 3% to 84%, and 31% to 85%, respectively. No major differences were noted in the prevalence of hypercholesterolemia among patients having transcatheter closure (11% to 26%) and those receiving medical therapy (12% to 30%). Data were insufficient to analyze body mass index or the prevalence of previous recognized symptomatic atherosclerotic heart or peripheral vascular disease. Atrial septal aneurysms were present in a similar proportion of patients undergoing transcatheter closure (15% to 34%) or medical therapy (12% to 37%). The type of cerebrovascular accident, classified as stroke or transient ischemic attack, varied among patients who had transcatheter closure. However, all studies of medically treated patients that subclassified type of cerebrovascular accident reported a prevalence of previous stroke of at least 50% (100% of patients in the 2 largest studies). Multiple cerebrovascular events were, however, more common in patients undergoing transcatheter closure (10% to 75%, compared with 2% to 28% in 3 studies of medically treated patients that reported this information). Medical Therapy Medical treatment varied among the patients in this review. Antiplatelet therapy consisted of a daily prescribed aspirin dosage of 250 mg (21), 300 mg (19), or 325 mg (17, 20) or a mean (SD) dose of 233 83 mg (23). A minority of patients received clopidogrel or ticlopidine (17, 23). In anticoagulated patients, target international normalized ratios were 1.4 to 2.8 (20), 2.0 to 3.0 (23), 3.0 to 4.0 (21), or undefined (17, 18). Although therapy was randomly allocated in 1 study (20), in most patients, medical management decisions were individualized according to the discretion of the treating physician. Adherence to therapy was assessed monthly (20) or at 6-month intervals (19), or was not stated (17, 18, 21, 23). Transcatheter Device Closure Table 2 shows reported complications of closure of patent foramen ovale by using a transcatheter device. Technical procedural success, imaging techniques to assess complete closure, and device-related complications were not uniformly defined. Individual characteristics of patients who had complete closure after device implantation were not recorded, thereby limiting analysis. Table 2. Complications of Transcatheter Closure of Patent Foramen Ovale Major complications were death (26), hemorrhage requiring blood transfusion (27), cardiac tamponade (22, 24, 27, 28), need for surgical intervention (30), and massive fatal pulmonary emboli (24, 25, 27, 28, 31). Minor complications were defined differently in each study and included bleeding not requiring transfusion (27), periprocedural atrial arrhythmias (24-26, 30), transient atrioventricular node block (25), device arm fractures (25, 31), device embolization with successful catheter retrieval (22, 25-27), asymptomatic device thrombosis (25, 26), need for recatheterization (22, 26), symptomatic air embolism (22, 25, 28), transient ST-segment elevation (25, 27), arteriovenous fistula formation (22), and femoral hematoma (28). According to this classification scheme, the reported incidence of major and minor complications was 1.5% and 7.9%, respectively. Antiplatelet or anticoagulant regimens after transcatheter closure of patent foramen ovale differed in the clarity of definition, duration of therapy, and assessment of compliance. Regimens consisted of daily aspirin, 3 to 5 mg/kg of body weight (27), 5 to 10 mg/kg (29, 30), 81 mg (32), 100 mg (22, 25), or 325 mg (24), with or without clopidogrel, 75 mg/d (24-26), or ticlopidine, 250 mg twice daily (24). Aspirin therapy was continued for 6 to 12 weeks (30), 6 months (22, 26-29, 31), or 12 months (25). Most patients receiving warfarin did so for indications other than transcatheter closure of patent foramen ovale. Recurrence of Neurologic Thromboembolic Events Although the mean ( SD) duration of follow-up was similar in studies of transcatheter device closure (12 6 months to 47 14 months) and studies of medical management (13 11 to 43 27 months), pattern analysis suggests an overall longer duration of follow-up in medically managed patients (Table 3). The mean duration of follow-up was 1 or 2 years in 6 of 10 studies of transcatheter device

Pregnancy Outcomes in Women With Congenital Heart Disease

Background— Pregnant women with congenital heart disease are at increased risk for cardiac and neonatal complications, yet risk factors for adverse outcomes are not fully defined. Methods and Results— Between January 1998 and September 2004, 90 pregnancies at age 27.7±6.1 years were followed in 53 women with congenital heart disease. Spontaneous abortions occurred in 11 pregnancies at 10.8±3.7 weeks, and 7 underwent elective pregnancy termination. There were no maternal deaths. Primary maternal cardiac events complicated 19.4% of ongoing pregnancies, with pulmonary edema in 16.7% and sustained arrhythmias in 2.8%. Univariate risk factors included prior history of heart failure (odds ratio [OR], 15.5), NYHA functional class ≥2 (OR, 5.4), and decreased subpulmonary ventricular ejection fraction (OR, 7.7). Independent predictors were decreased subpulmonary ventricular ejection fraction and/or severe pulmonary regurgitation (OR, 9.0) and smoking history (OR, 27.2). Adverse neonatal outcomes occurred in 27.8% of ongoing pregnancies and included preterm delivery (20.8%), small for gestational age (8.3%), respiratory distress syndrome (8.3%), intraventricular hemorrhage (1.4%), intrauterine fetal demise (2.8%), and neonatal death (1.4%). A subaortic ventricular outflow tract gradient >30 mm Hg independently predicted an adverse neonatal outcome (OR, 7.5). Cardiac risk assessment was improved by including decreased subpulmonary ventricular systolic function and/or severe pulmonary regurgitation (OR, 10.3) in a previously proposed risk index developed in pregnant women with acquired and congenital heart disease. Conclusions— Maternal cardiac and neonatal complication rates are considerable in pregnant women with congenital heart disease. Patients with impaired subpulmonary ventricular systolic function and/or severe pulmonary regurgitation are at increased risk for adverse cardiac outcomes.

Implantable Cardioverter-Defibrillators in Tetralogy of Fallot

Background— Tetralogy of Fallot is the most common form of congenital heart disease in implantable cardioverter-defibrillator (ICD) recipients, yet little is known about the value of ICDs in this patient population. Methods and Results— We conducted a multicenter cohort study in high-risk patients with Tetralogy of Fallot to determine actuarial rates of ICD discharges, identify risk factors, and characterize ICD-related complications. A total of 121 patients (median age 33.3 years; 59.5% male) were enrolled from 11 sites and followed up for a median of 3.7 years. ICDs were implanted for primary prevention in 68 patients (56.2%) and for secondary prevention in 53 (43.8%), defined by clinical sustained ventricular tachyarrhythmia or resuscitated sudden death. Overall, 37 patients (30.6%) received at least 1 appropriate and effective ICD discharge, with a median ventricular tachyarrhythmia rate of 213 bpm. Annual actuarial rates of appropriate ICD shocks were 7.7% and 9.8% in primary and secondary prevention, respectively (P=0.11). A higher left ventricular end-diastolic pressure (hazard ratio 1.3 per mm Hg, P=0.004) and nonsustained ventricular tachycardia (hazard ratio 3.7, P=0.023) independently predicted appropriate ICD shocks in primary prevention. Inappropriate shocks occurred in 5.8% of patients yearly. Additionally, 36 patients (29.8%) experienced complications, of which 6 (5.0%) were acute, 25 (20.7%) were late lead-related, and 7 (5.8%) were late generator-related complications. Nine patients died during follow-up, which corresponds to an actuarial annual mortality rate of 2.2%, which did not differ between the primary and secondary prevention groups. Conclusions— Patients with tetralogy of Fallot and ICDs for primary and secondary prevention experience high rates of appropriate and effective shocks; however, inappropriate shocks and late lead-related complications are common.

Value of Programmed Ventricular Stimulation After Tetralogy of Fallot Repair A Multicenter Study

Background—Studies have consistently shown that ventricular tachycardia (VT) and sudden cardiac death (SCD) complicate the long-term outcome after tetralogy of Fallot repair, yet the diagnostic and predictive value of electrophysiological testing in this population is uncertain. Methods and Results—A multicenter cohort of 252 patients with repaired tetralogy of Fallot undergoing programmed ventricular stimulation was followed up for 18.5±9.6 and 6.5±4.5 years after corrective surgery and electrophysiological testing, respectively. Clinical VT and/or SCD occurred in 24.6%. Sustained monomorphic VT and polymorphic VT were induced in 30.2% and 4.4%. Including polymorphic VT in the definition of inducibility improved sensitivity (66.1±6.0% versus 77.4±5.3%, P = 0.0082) with a marginal reduction in specificity (81.6±2.8% versus 79.5±2.9%, P = 0.0455). Positive and negative predictive values were 55.2±5.3% and 91.5±2.2%. Independent risk factors for inducibility were age at study ≥18 years (OR, 3.3), palpitations (OR, 2.8), prior palliative surgery (OR, 3.1), modified Lown criteria ≥2 (OR, 5.6), and cardiothoracic ratio ≥0.6 (OR, 3.3). Event-free survival rates in noninducible and inducible patients at 1, 5, 10, and 15 years were 97.9%, 92.8%, 89.3%, and 89.3% versus 79.4%, 62.6%, 58.7%, and 50.3%, respectively (P < 0.0001). Both inducible monomorphic VT [relative risk (RR), 5.0; P = 0.0002] and polymorphic VT (RR, 12.9; P < 0.0001) predicted future clinical VT and SCD. In a multivariate analysis, inducible sustained VT was an independent risk factor for subsequent events (RR, 4.7; 95% CI, 1.2 to 18.5; P = 0.0268). Conclusions—Programmed ventricular stimulation is of diagnostic and prognostic value in risk stratifying patients with repaired tetralogy of Fallot. In this patient population, inducible sustained polymorphic VT should not be disregarded as nonspecific.

The Clinical Profile and Pathophysiology of Atrial Fibrillation Relationships Among Clinical Features, Epidemiology, and Mechanisms

Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%-26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca(2+)-handling abnormalities, (3) structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure, myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca(2+)-handling abnormalities that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease. Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to develop improved methods for AF prevention and management.